INDOLE CARBOXAMIDE DERIVATIVES AS P2X7 RECEPTOR ANTAGONISTS

Title:

INDOLE CARBOXAMIDE DERIVATIVES AS P2X7 RECEPTOR ANTAGONISTS

Document Type and Number:

WIPO Patent Application WO/2014/091415

Kind Code:

Abstract:

The invention relates to indole carboxamide derivatives of formula (I), (I) wherein R1, R 2, R 3, R 4, R5 and R6 are as defined in the description, their preparation and their use as pharmaceutically active compounds.

Inventors:

HILPERT KURT (CH)
HUBLER FRANCIS (CH)
KIMMERLIN THIERRY (CH)
RENNEBERG DORTE (CH)
STAMM SIMON (CH)

Application Number:

PCT/IB2013/060794

Publication Date:

June 19, 2014

Filing Date:

December 11, 2013

Export Citation:

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Assignee:

ACTELION PHARMACEUTICALS LTD (CH)

International Classes:

C07D401/14; A61K31/405; A61K31/506; A61P11/00; A61P19/00; A61P25/28; C07D209/08; C07D401/12; C07D403/12; C07D403/14; C07D405/14; C07D413/12; C07D413/14; C07D417/12; C07D498/08

Domestic Patent References:

WO2005014529A1	2005-02-17
WO2005111003A1	2005-11-24
WO2009023623A1	2009-02-19
WO2009108551A2	2009-09-03
WO2009118175A1	2009-10-01
WO2009132000A1	2009-10-29

Other References:

NORTH, R. A., PHYSIOL. REV., vol. 82, no. 4, 2002, pages 1013 - 67
SURPRENANT, A.; RASSENDREN, F. ET AL., SCIENCE, vol. 272, no. 5262, 1996, pages 735 - 8
VIRGINIO, C.; MACKENZIE, A. ET AL., J. PHYSIOL., vol. 519, 1999, pages 335 - 46
SOLLE, M.; LABASI, J. ET AL., J. BIOL. CHEM., vol. 276, no. 1, 2001, pages 125 - 32
FERRARI, D.; CHIOZZI, P. ET AL., NEUROPHARMACOLOGY, vol. 36, no. 9, 1997, pages 1295 - 301
WILEY, J. S.; CHEN, J. R. ET AL., CIBA FOUND SYMP., vol. 198, 1996, pages 149 - 60,160-5
DEUCHARS, S. A.; ATKINSON, L. ET AL., J. NEUROSCI., vol. 21, no. 18, 2001, pages 7143 - 52
SPERLAGH, B.; KOFALVI, A. ET AL., J. NEUROCHEM., vol. 81, no. 6, 2002, pages 1196 - 211
YU, Y.; UGAWA, S. ET AL., BRAIN. RES., vol. 1194, 2008, pages 45 - 55
CHESSELL, I. P.; HATCHER, J. P. ET AL., PAIN, vol. 114, no. 3, 2005, pages 386 - 96
"Salt selection for basic drugs", INT. J. PHANN., vol. 33, 1986, pages 201 - 217
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & VVILKINS, article "Pharmaceutical Manufacturing"
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY- INTERSCIENCE
J. ORG. CHEM., vol. 73, no. 4, 2008, pages 1643 - 1645
J. AM. CHEM. SOC., vol. 133, 2011, pages 6948 - 6951
JACS, vol. 133, 2011, pages 6948 - 6951

Attorney, Agent or Firm:

KOBERSTEIN, Ralf (Gewerbestrasse 16, Allschwil, CH)

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Claims:

Claims

1. A compound of the formula

(I)

wherein

R¹ represents a heteroaryl or an aryl group which groups are independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-C₄)alkyl, (C₃-C₆)cycloalkyl, (C^-C^alkoxy, (C₁-C₃)fluoroalkyl, (C₁-C₃)fluoroalkoxy, hydroxy, halogen and phenoxy;

R² represents

• heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from (C^-C^alkyl, (C_!-C^alkylcarbonyl, (C_!-C^alkoxycarbonyl, (C_!-C^alkylsulfonyl, and halogen;

heterocyclyloxy;

· (C₃-C₆)cycloalkyl which is unsubstituted or mono- or di-substituted with halogen;

(C₃-C₆)cycloalkyloxy;

/V-(C₃-C₆)cycloalkyl-amino;

/V-(C₃-C₆)cycloalkylmethyl-amino;

(C₃-C₆)alkyl;

· (C₂-C₆)alkoxy;

/V-^-C alkylamino;

^/V-di-tCd-C^alkylj-amino; or

/V-arylmethyl-ZV-CC^C^alkyl-amino;

R³ represents hydrogen or halogen;

R⁴ represents hydrogen, fluoro, chloro, (C^-C^alkyl, (d-C^alkoxy, (d-C^alkyl-carbonyl, hydroxy-^-C^alkyl, hydroxy-(C₂-C₄)alkoxy, (C₁-C₂)alkoxy-(C₁-C₄)alkyl or (Ci- C₄) a I koxy- (C₂-C₄) a I koxy ;

R⁵ represents hydrogen or (C^-C^alkyl; and

R⁶ represents fluoro, chloro, methyl, ethyl or (Ci-C₂)fluoroalkyl;

or a salt of such a compound.

2. A compound of formula (I) according to claim 1 , wherein

R¹ represents a 5- or 6-membered monocyclic heteroaryl group which is unsubstituted, mono- or di-substituted , wherein the substituents are independently selected from the group consisting of (C!-C^alkyl, (C₃-C₆)cycloalkyl, (C!-C^alkoxy, (C₁-C₃)fluoroalkyl and halogen ;

R² represents

• heterocyclyl which is unsubstituted, mono- or di-substituted , wherein the substituents are independently selected from methyl and fluoro; or

· (C₃-C₆)cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro; R³ represents hydrogen ;

R⁴ represents hydrogen or (C!-C^alkyl;

R⁵ represents hydrogen ; and

R⁶ represents chloro or methyl;

or a salt of such a compound.

3. A compound of formula (I) according to claim 1 , wherein

R¹ represents a 5- or 6-membered monocyclic heteroaryl or a phenyl group which groups are independently unsubstituted , mono- or di-substituted , wherein the substituents are independently selected from the group consisting of (C!-C^alkyl, (C₃-C₆)cycloalkyl, (C^- C₃)fluoroalkyl and halogen;

or a salt of such a compound.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein

R² represents heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro; or a salt of such a compound. 5. A compound of formula (I) according to any one of claims 1 or 3, wherein

R² represents (C₃-C₆)alkyl; or (C₃-C₆)cycloalkyl which is unsubstituted or mono- or di- substituted with fluoro;

or a salt of such a compound.

6. A compound of formula (I) according to claim 1 , which is also a compound of formula (l_Ar)

wherein

A represents N or CH;

B represents N or CH;

R² represents heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro, wherein the heterocyclyl is selected from pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, azepanyl, 1 ,4-oxazepanyl and 6-oxa-3-azabicyclo[3.1 .1 ]heptanyl; or

R² represents cyclohexyl which is unsubstituted or mono- or di-substituted with fluoro; R⁴ represents hydrogen, fluoro, chloro, (C!-C^alkyl, (C!-C^alkoxy, hydroxy-(C₂- C₄)alkoxy or (C₁-C₂)alkoxy-(C₁-C₄)alkyl;

R⁶ represents fluoro, chloro, methyl, ethyl or (C₁-C₂)fluoroalkyl; and

R⁷ represents hydrogen , halogen, (C!-C^alkyl, (C₃-C₆)cycloalkyl, (C!-C^alkoxy or (C^- C₃)fluoroalkyl;

or a salt of such a compound.

7. A compound of formula (l_Ar) according to claim 6, wherein

A and B represent N and R⁷ represents hydrogen, methyl, cyclopropyl or trifluoromethyl; or

A represents N, B represents CH and R⁷ represents chloro, methyl, methoxy or trifluoromethyl; or

A and B represent CH and R⁷ represents fluoro or chloro;

R² represents 3,3-difluoro-pyrrolidin-1 -yl, piperidin-1 -yl, 4-fluoro-piperidin-1 -yl, 3,3-difluoro- piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, tetrahydropyran-4-yl, morpholin-4-yl, azepan-1 -yl, 1 ,4-oxazepan-4-yl, or 6-oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl;

R⁴ represents hydrogen, chloro, methyl, ethyl, n-propyl, /^'so-butyl, methoxy, ethoxy, 2- hydroxy-ethoxy or 3-methoxy-prop-1 -yl;

R⁶ represents fluoro, chloro, methyl, ethyl or trifluoromethyl;

or a salt of such a compound.

8. A compound of formula (l_Ar) according to any one of claims 6 or 7, wherein

A and B represent N ; or a salt of such a compound.

9. A compound of formula (I) according to any one of claims 1 to 8, wherein

R⁶ represents chloro;

or a salt of such a compound. 10. A compound of formula (I) according to any one of claims 1 to 8, wherein

R⁶ represents methyl;

or a salt of such a compound.

11. A compound of formula (I) according to claim 1 , selected from the group consisting of:

4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(2-trifluoromethyl-pyrimidin-5-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-(4,4-difluoro-piperidin-1 - yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [(R)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [(S)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [(R)-2-(4,4-difluoro-piperidin-1 -yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [(S)-2-(4,4-difluoro-piperidin-1 -yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-methyl-pyridin-3-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4,4-difluoro-piperidin-1 -yl)-2-(2-trifluoromethyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-cyclopropyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-methoxy-pyridin-3-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-dimethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-azetidin-1 -yl-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-pyrrolidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-diethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(3,5-difluoro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-{2-[(4-Chloro-1 H-indole-5-carbonyl)-amino]-1 -pyridin-3-yl-ethyl}-piperidine-1 -carboxylic acid fe/ -butyl ester;

4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-4-yl-2-pyridin-3-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -methyl-piperidin-4-yl)-2-pyridin-3-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -acetyl-piperidin-4-yl)-2-pyridin-3-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -methanesulfonyl-piperidin-4-yl)-2-pyridin-3-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-morpholin-4-yl-2-pyrimidin-5-yl-ethyl)-amide; 4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-1 -yl-2-pyrimidin-5-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -methyl-1 H-pyrazol-4-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -methyl-1 H-pyrazol-4-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-piperidin-1 -yl-2-(2,4,6-trifluoro-phenyl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2,4-difluoro-phenyl)-2-piperidin-1 -yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(5-fluoro-pyridin-2-yl)-2-piperidin-1 -yl-ethyl]- amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(2,4,6-trifluoro-phenyl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2,4-difluoro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(5-fluoro-pyridin-2-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(2,4-dichloro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4-chloro-2-fluoro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(c/^'s-2,6-dimethyl-morpholin-4-yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(frar)s-2,6-dimethyl-morpholin-4-yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3-fluoro-phenyl)-2-piperidin-1 -yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-piperidin-1 -yl-2-(4-trifluoromethyl-phenyl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3,4-difluoro-phenyl)-2-piperidin-1 -yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-1 -yl-2-pyridin-3-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-morpholin-4-yl-2-p-tolyl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(4-trifluoromethoxy-phenyl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(4-trifluoromethyl-phenyl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3,4-difluoro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-(tetrahydro-pyran-4- yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-cyclopentyloxy-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3,5-dimethyl-isoxazol-4-yl)-2-morpholin-4-yl- ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(3,5-dimethyl-isoxazol-4-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-1 -yl-2-p-tolyl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4-phenoxy-phenyl)-2-piperidin-1 -yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(4-phenoxy-phenyl)-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(5-methyl-pyrazin-2-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-isothiazol-5-yl-2-piperidin-1 -yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-1 -yl-2-thiazol-5-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(5-methyl-pyrazin-2-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-morpholin-4-yl-2-thiazol-5-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-cyclohexyl-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-4-methyl-pentyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-ethoxy-2-(2-methyl-pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-(2-oxa-5-aza- bicyclo[2.2.1 ]hept-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-cyclohexyloxy-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-(tetrahydro-pyran-4- yloxy)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -ethyl-propoxy)-2-(2-methyl-pyrimidin-5-yl)- ethyl]-amide;

4-Chloro-2-methyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-1 -yl-2-pyridazin-3-yl-ethyl)-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-hydroxypyridin-4-yl)-2-piperidin-1 -yl-ethyl]- amide;

1 -[2-[(4-Chloro-1 H-indole-5-carbonyl)-amino]-1 -(2-methyl-pyrimidin-5-yl)-ethyl]-piperidine- 4-carboxylic acid fe/ -butyl ester;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4-methyl-piperidin-1 -yl)-2-(2-methyl-pyrimidin-5- yl)-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [(R)-2-(2-methyl-piperidin-1 -yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4- Chloro-1 H-indole-5-carboxylic acid [2-(4-fluoro-piperidin-1 -yl)-2-(2-methyl-pyrimidin-5- yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(3,3-difluoro-piperidin-1 -yl)-2-(2-methyl-pyrimidin-

5- yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-azepan-1 -yl-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-[1 ,4]oxazepan-4-yl- ethyl]-amide;

4- Chloro-1 H-indole-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1 -yl)-2-(2-methyl-pyrimidin-

5- yl)-ethyl]-amide;

4- Chloro-1 H-indole-5-carboxylic acid [2-cyclopentylamino-2-(2-methyl-pyrimidin-5-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(cyclopentylmethyl-amino)-2-(2-methyl-pyrimidin-

5- yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-isobutylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(isobutyl-methyl-amino)-2-(2-methyl-pyrimidin-5- yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(benzyl-methyl-amino)-2-(2-methyl-pyrimidin-5-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid (3-ethyl-2-pyrimidin-5-yl-pentyl)-amide;

4-[2-[(4-Chloro-1 H-indole-5-carbonyl)-amino]-1 -(2-methyl-pyrimidin-5-yl)-ethyl]-piperazi 1 -carboxylic acid fe/ -butyl ester;

4-Chloro-1 H-indole-5-carboxylic acid (2-morpholin-4-yl-2-pyridazin-3-yl-ethyl)-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(2-hydroxypyridin-4-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(1 ,1 -dioxo-thiomorpholin-4-yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(4,4-difluoro-cyclohexyl)-2-(2-methyl-pyrimidin-5- yl)-ethyl]-amide;

4,6-Dichloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-(6-oxa-3-aza- bicyclo[3.1 .1 ]hept-3-yl)-ethyl]-amide;

4-Chloro-7-methyl-1 H-indole-5-carboxylic acid [(R)-2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Chloro-7-methyl-1 H-indole-5-carboxylic acid [(S)-2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Chloro-7-isobutyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide;

4-Chloro-7-(3-methoxy-propyl)-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Methyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Ethyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]- amide;

7-Acetyl-4-chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide;

7-Methyl-4-trifluoromethyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4,7-Dimethyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Methyl-1 H-indole-5-carboxylic acid [(S)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Methyl-1 H-indole-5-carboxylic acid [(R)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-7-ethyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

7-Chloro-4-methyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide;

7-Methoxy-4-methyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin- 4-yl-ethyl]-amide;

4-Chloro-7-ethoxy-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide;

4-Chloro-7-propyl-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4- yl-ethyl]-amide; 7-(2-tert-Butoxy-ethoxy)-4-chloro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)- 2-morpholin-4-yl-ethyl]-amide;

4-Chloro-7-(2-hydroxy-ethoxy)-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Chloro-7-methoxy-1 H-indole-5-carboxylic acid [(S)-2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Chloro-7-methoxy-1 H-indole-5-carboxylic acid [(R)-2-(2-methyl-pyrimidin-5-yl)-2- morpholin-4-yl-ethyl]-amide;

4-Chloro-7-(1 -hydroxy-1 -methyl-ethyl)-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin- 5-yl)-2-morpholin-4-yl-ethyl]-amide;

4,7-Difluoro-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide; and

4-Fluoro-7-methoxy-1 H-indole-5-carboxylic acid [2-(2-methyl-pyrimidin-5-yl)-2-morpholin- 4-yl-ethyl]-amide;

or a salt of such a compound.

12. A compound of formula (I) according to any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, for use as a medicament.

13. A pharmaceutical composition containing, as active principle, a compound of formula (I) according to any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

14. Use of a compound of formula (I) according to any one of claims 1 to 1 1 , or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease selected from pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; other auto-immune and allergic disorders; and other disorders with an inflammatory or immunological component.

15. A compound of formula (I) according to any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease selected from pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; other auto-immune and allergic disorders; and other disorders with an inflammatory or immunological component.

Description:

Indole carboxamide derivatives as P2X _Z receptor antagonists

The present invention relates to indole carboxamide derivatives of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as P2X ₇ receptor antagonists.

The P2X ₇ receptors (P2RX7) belong to the family of P2X ionotropic receptors that are activated by extracellular nucleotides, in particular adenosine triphosphate (ATP). P2RX7 is distinguished from other P2X family members by the high concentrations (mM range) of ATP required to activate it and its ability to form a large pore upon prolonged or repeated stimulation (North, R. A., Physiol. Rev. 2002, 82(4), 1013-67; Surprenant, A., Rassendren, F. et al., Science 1996, 272(5262), 735-8; Virginio, C, MacKenzie, A. et al., J. Physiol., 1999, 519, 335-46). P2RX7 is present on many cell types, especially ones known to be involved in inflammatory and immune processes. This is reflected within both the periphery and the CNS as Lipopolysaccharide S (LPS) priming of monocytes and microglia followed by ATP stimulation has been shown to lead to the local release and processing of I L1 β and other family members including IL18 through a P2RX7 mediated mechanism. Indeed mice lacking the P2X7 receptor are unable to release I L1 β following LPS priming and ATP stimulation providing further evidence of its role in this pathway (Solle, M., Labasi, J. et al., J. Biol. Chem., 2001 , 276(1), 125-32). In addition L-selectin shedding from monocytes, macrophages and lymphocytes, degranulation in mast cells and apoptosis in lymphocytes are all associated with P2RX7 stimulation. P2RX7 is also expressed on epithelial and endothelial cells (Ferrari, D., Chiozzi, P. et al., Neuropharmacology 1997, 36(9), 1295-301 ; Wiley, J. S., Chen, J. R. et al., Ciba Found Symp. 1996, 198, 149-60 and 160-5; North, R. A., Physiol. Rev. 2002, 82(4), 1013-67). In addition to its role in the periphery it may have an important function in neurotransmission within the CNS through its activation on postsynaptic and / or presynaptic central and peripheral neurons and glia (Deuchars, S. A., Atkinson, L. et al., J. Neurosci. 2001 , 21 (18), 7143-52; Sperlagh, B., Kofalvi, A. et al., J. Neurochem. 2002, 81 (6), 1 196-21 1). Recent data that has emerged using in situ hybridization demonstrated that P2X7 receptor mRNA was widely distributed throughout the rat brain. Specifically, among the areas of high P2X7mRNA expression noted were the piriform cortex, hippocampus, pontine nuclei and the anterior horn of the spinal cord (Yu, Y., Ugawa, S. et al., Brain. Res. 2008, 1 194, 45-55). Hence there is therapeutic rationale for the use of P2X7 ion channel blockers in the treatment of a variety of disease states. These include but are not limited to diseases associated with the central nervous system such as stroke or injury and diseases associated with neuro-degeneration and neuroinflammation such as Alzheimer's disease, Huntington's disease, epilepsy, Amyotrophic lateral sclerosis, acute spinal cord injury additionally to meningitis, sleep disorders, mood and anxiety disorders as well as chronic and neuropathic and inflammatory pain. Furthermore, peripheral inflammatory disorders and autoimmune diseases including but not limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel disease, skin injury, lung emphysema, Limb girdle dystrophy type 2B, fibrosis, Syndrome of synovitis Acne Pustulosis, atherosclerosis, burn injury, spinal cord injury, Hyperostosis Osteitis, Crohn's disease, ulcerative colitis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, trauma, meningitis, osteoporosis, burn injury, ischemic heart disease, and varicose veins and trauma, are all examples where the involvement of P2X7 channels has been implicated. In addition a recent report suggests a link between P2RX7 and chronic, inflammatory and neuropathic pain (Chessell, I. P., Hatcher, J. P. et al., Pain, 2005, 1 14(3), 386-96). Overall, these findings indicate a role for the P2X7 receptor in the process of neuronal synaptic transmission and therefore a potential role for P2X7 antagonists as novel therapeutic tools to treat neuropathic pain.

In view of the above observations, there is significant requirement for P2X7 antagonists that can be efficiently used in treating neuropathic pain, chronic inflammatory pain, inflammation, and neurodegenerative conditions.

Different indole carboxamide derivatives, which are also P2X ₇ receptor antagonists, have been disclosed in WO 2009/023623, WO 2009/108551 and WO 2009/1 18175. Quinoline and isoquinoline derivatives which are also P2X ₇ receptor antagonists, have been disclosed in WO2009/132000.

Various embodiments of the invention are presented hereafter:

1 ) The present invention relates to indole carboxamide derivatives of formula (I),

(I)

wherein R ¹ represents a heteroaryl or an aryl group which groups are independently unsubstituted, mono-, di-, or tri-substituted , wherein the substituents are independently selected from the group consisting of (Ci-C ₄)alkyl, (C ₃-C ₆)cycloalkyl, (Ci-C ₄)alkoxy, (C ₁-C ₃)fluoroalkyl, (C ₁-C ₃)fluoroalkoxy, hydroxy, halogen and phenoxy;

R ² represents

• heterocyclyl which is unsubstituted , mono- or di-substituted, wherein the substituents are independently selected from (C^-C^alkyl, (C!-C^alkylcarbonyl, (C!-C^alkoxycarbonyl, (C!-C^alkylsulfonyl, and halogen;

• heterocyclyloxy;

· (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di-substituted with halogen;

• (C ₃-C ₆)cycloalkyloxy;

• /V-(C ₃-C ₆)cycloalkyl-amino;

• /V-(C ₃-C ₆)cycloalkylmethyl-amino;

• (C ₃-C ₆)alkyl;

· (C ₂-C ₆)alkoxy;

• /V-^-C alkylamino;

• N,N-d\-[(C^-C ₄)a\ky\]-am o; or

• /V-arylmethyl-ZV-CC^C^alkyl-amino;

R ³ represents hydrogen or halogen;

R ⁴ represents hydrogen, fluoro, chloro, (C^-C^alkyl, (C!-C^alkoxy, (C!-C^alkyl-carbonyl, hydroxy-(Ci-C ₄)alkyl, hydroxy-(C ₂-C ₄)alkoxy, (C ₁-C ₂)alkoxy-(C ₁-C ₄)alkyl or (Ci-

C ₄) a I koxy- (C ₂-C ₄) a I koxy ;

R ⁵ represents hydrogen or (C^-C^alkyl; and

R ⁶ represents fluoro, chloro, methyl, ethyl or (Ci-C ₂)fluoroalkyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

The compounds of formula (I) according to embodiment 1 ) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (2 or (£)-configuration unless indicated otherwise. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. Definitions:

The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.

The term "alkyl", used alone or in combination, refers to a straight or branched chain alkyl group containing one to six carbon atoms. The term "(Cx-C _y)alkyl" (x and y each being an integer), refers to an alkyl group as defined before containing x to y carbon atoms. For example a (C^C^alkyl group contains from one to four carbon atoms. Representative examples of (C C ₄)alkyl groups include methyl, ethyl, n-propyl, / ^'so-propyl, n-butyl, iso- butyl, sec-butyl and fe/ -butyl. A (C ₃-C ₆)alkyl group contains from three to six carbon atoms. Representative examples of (C ₃-C ₆)alkyl groups include n-propyl, / ^'so-propyl, n- butyl, / ^'so-butyl, sec-butyl, fe/ -butyl, pent-1 -yl, pent-2-yl, pent-3-yl, 2-methyl-but-1 -yl, 3- methyl-but-1 -yl, 2-methyl-but-2-yl, 3-methyl-but-2-yl, hex-1 -yl, hex-2-yl, hex-3-yl, 2-methyl- pent-2-yl, 3-methyl-pent-2-yl, 4-methyl-pent-2-yl, 2-methyl-pent-3-yl, 3-methyl-pent-3-yl, 2,3-dimethyl-but-2-yl and 3,3-dimethyl-but-2-yl.

The term "alkoxy", used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined above. The term "(C _x-C _y) alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (CrC^alkoxy group contains from one to four carbon atoms. Representative examples of (C C^alkoxy groups include methoxy, ethoxy, n-propoxy, / ^'so-propoxy, n-butoxy, iso- butoxy, sec-butoxy and fe/ -butoxy. A (C ₂-C ₆)alkoxy group contains from two to six carbon atoms. Representative examples of (C ₂-C ₆)alkoxy groups include ethoxy, n-propoxy, / ^'so- propoxy, n-butoxy, / ^'so-butoxy, sec-butoxy, fe/ -butoxy, pent-1 -yloxy, pent-2-yloxy, pent-3- yloxy, 2-methyl-but-1 -yloxy, 3-methyl-but-1 -yloxy, 2-methyl-but-2-yloxy, 3-methyl-but-2- yloxy, hex-1 -yloxy, hex-2-yloxy, hex-3-yloxy, 2-methyl-pent-2-yloxy, 3-methyl-pent-2-yloxy, 4-methyl-pent-2-yloxy, 2-methyl-pent-3-yloxy, 3-methyl-pent-3-yloxy, 2,3-dimethyl-but-2- yloxy and 3,3-dimethyl-but-2-yloxy.

The term "hydroxy-CC C^alkyl", used alone or in combination, refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with hydroxy. Examples of said groups are hydroxy- methyl, 1 -hydroxy- ethyl, 2-hydroxy-ethyl, 1 -hydroxy-prop-1 -yl, 2-hydroxy-prop-1 -yl, 3-hydroxy-prop-1 -yl, 1 - hydroxy-prop-2-yl, 2-hydroxy-prop-2-yl, 1 -hydroxy-but-1 -yl, 2-hydroxy-but-1 -yl, 3-hydroxy- but-1 -yl, 4-hydroxy-but-1 -yl, 1 -hydroxy-but-2-yl, 2-hydroxy-but-2-yl, 3-hydroxy-but-2-yl, 4- hydroxy-but-2-yl, 1 -hydroxy-2-methyl-prop-1 -yl, 2-hydroxy-2-methyl-prop-1 -yl, 3-hydroxy- 2-methyl-prop-1 -yl, and 2-hydroxy-1 ,1 -dimethyl-eth-1 -yl.

The term "hydroxy-(C ₂-C ₄)alkoxy", used alone or in combination, refers to an alkoxy group as defined before containing from two to four carbon atoms in which one hydrogen atom has been replaced with hydroxy. Examples of said groups are 2-hydroxy-ethoxy, 2- hydroxy-prop-1 -yloxy, 3-hydroxy-prop-1 -yloxy, 1 -hydroxy-prop-2-yloxy, 2-hydroxy-but-1 - yloxy, 3-hydroxy-but-1 -yloxy, 4-hydroxy-but-1 -yloxy, 1 -hydroxy-but-2-yloxy, 3-hydroxy-but- 2-yloxy, 4-hydroxy-but-2-yloxy, 2-hydroxy-2-methyl-prop-1 -yloxy, 3-hydroxy-2-methyl- prop-1 -yloxy, and 2-hydroxy-1 ,1 -dimethyl-eth-1 -yloxy.

The term "(C ₁-C ₂)alkoxy-(C ₁-C ₄)alky ', used alone or in combination, refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with (C ₁-C ₂)alkoxy as defined before. Examples of said groups are methoxy-methyl, methoxy-ethyl, methoxy-propyl, methoxy-butyl, ethoxy-methyl, ethoxy-ethyl, ethoxy-propyl and ethoxy-butyl.

The term "(C C^alkoxy-^-C^alkoxy", used alone or in combination, refers to an alkoxy group as defined before containing from two to four carbon atoms in which one hydrogen atom has been replaced with (CrC ₄)alkoxy as defined before. A preferred example of said groups is 2-fe/ -butoxy-ethoxy.

The term "(C C ₄)alkylcarbonyr, used alone or in combination, refers to a (C ₁-C ₄)alkyl- C(O)- group wherein the (CrC ₄)alkyl group is as defined before, which is attached to the rest of the molecule via the carbonyl-C-atom. Representative examples of (C C^alkyl- carbonyl groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso- propylcarbonyl, n-butylcarbonyl, / ^'so-butylcarbonyl, sec-butylcarbonyl and tert- butylcarbonyl.

The term "(C C^alkoxycarbonyl", used alone or in combination, refers to a (C C^alkyl- O-C(O)- group wherein the (C^C^alkyl group is as defined before, which is attached to the rest of the molecule via the carboxyl-C-atom. Representative examples of (C C ₄)alkoxy-carbonyl groups include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, / ^'so-propoxycarbonyl, n-butoxycarbonyl, / ^'so-butoxycarbonyl, sec-butoxycarbonyl and tert- butoxycarbonyl.

The term "(CrC^alkylsulfonyl", used alone or in combination, refers to a (CrC ₄)alkyl- S(0) ₂- group wherein the (C^C^alkyl group is as defined before, which is attached to the rest of the molecule via the sulfonyl-S-atom. Representative examples of (C C^alkyl- sulfonyl groups include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, / ^'so-propylsulfonyl, n-butylsulfonyl, / ^'so-butylsulfonyl, sec-butylsulfonyl and fe/ -butylsulfonyl.

The term "/V-CCrC^alkylamino", used alone or in combination, refers to an amino group (-NH ₂) wherein one hydrogen atom has been replaced with (C C^alkyl as defined before. Representative examples of /V-CC C^alkylamino groups include methylamino, ethylamino, n-propylamino, / ^'so-propylamino, n-butylamino, / ^'so-butylamino, sec-butylamino and fe/ -butylamino.

The term '^/V-di- C C^alkylj-amino", used alone or in combination, refers to an amino group (-NH ₂) wherein both hydrogen atoms have been replaced with (C C^alkyl groups as defined before, wherein the two alkyl groups are the same or different. Representative examples of A^/V-di- C C^alkylJ-amino groups include dimethylamino, methyl- ethylamino, methyl-n-propylamino, methyl-/ ^'so-propylamino, methyl-n-butylamino, methyl- / ^'so-butylamino, methyl-sec-butylamino, methyl-fe/ -butylamino, diethylamino, ethyl-n- propylamino, ethyl-/ ^'so-propylamino, ethyl-n-butylamino, ethyl-/ ^'so-butylamino, ethyl-sec- butylamino and ethyl-fe/ -butylamino.

The term "/V-arylmethyl-ZV-CC^C^alkyl-amino", used alone or in combination, refers to an amino group (-NH ₂) wherein one hydrogen atom has been replaced with (C C ₄)alkyl as defined before and the other hydrogen atom has been replaced with arylmethyl, wherein the term aryl refers to phenyl or naphthyl. Representative examples of /V-arylmethyl-/V- (C^-C^alkyl-amino groups include benzyl-methylamino, benzyl-ethylamino, benzyl-n- propylamino, benzyl-/ ^'so-propylamino, benzyl-n-butylamino, benzyl-/ ^'so-butylamino, benzyl- sec-butylamino, benzyl-fe/ -butylamino, naphthylmethyl-methylamino, naphthylmethyl- ethylamino, naphthylmethyl-n-propylamino, naphthylmethyl-/ ^'so-propylamino, naphthylmethyl-n-butylamino, naphthylmethyl-/ ^'so-butylamino, naphthylmethyl-sec- butylamino and naphthylmethyl-fe/ -butylamino.

The term "(Cx-C _y)fluoroalkyl" (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C ₁-C ₃)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluoro. In analogy, a (C ₁-C ₂)fluoroalkyl group contains one or two carbon atoms in which one to five hydrogen atoms have been replaced with fluoro. Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoro- ethyl and 2,2,2-trifluoroethyl. The term "(C _x-C _y)fluoroalkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro. For example a (C ₁-C ₃)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluoro. Representative examples of said groups are difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.

The term "(C ₃-C ₆)cycloalkyl", used alone or in combination, refers to a cycloalkyl group with 3 to 6 carbon atoms. Examples of (C ₃-C ₆)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "(C ₃-C ₆)cycloalkyloxy", used alone or in combination, refers to a (C ₃- C ₆)cycloalkyl-0- group wherein the (C ₃-C ₆)cycloalkyl group is as defined above. Examples of (C ₃-C ₆)cycloalkyloxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

The term "/V-(C ₃-C ₆)cycloalkyl-amino", used alone or in combination, refers to an amino group (-NH ₂) wherein one hydrogen atom has been replaced with (C ₃-C ₆)cycloalkyl as defined before. Representative examples of /V-(C ₃-C ₆)cycloalkyl-amino groups include cyclopropyl-amino, cyclobutyl-amino, cyclopentyl-amino and cyclohexyl-amino.

The term "/V-(C ₃-C ₆)cycloalkylmethyl-amino", used alone or in combination, refers to an amino group (-NH ₂) wherein one hydrogen atom has been replaced with a (C ₃- C ₆)cycloalkylmethyl group wherein the (C ₃-C ₆)cycloalkyl group is as defined before. Representative examples of /V-(C ₃-C ₆)cycloalkylmethyl-amino groups include cyclopropylmethyl-amino, cyclobutylmethyl-amino, cyclopentylmethyl-amino and cyclohexylmethyl-amino.

The term halogen means fluoro, chloro, bromo or iodo.

The term "aryl", used alone or in combination, means a phenyl or a naphthyl group. The aryl group is unsubstituted or substituted as explicitly defined. Examples of unsubstituted or substituted aryl groups are 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,4- difluoro-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl, 2,4,6-trifluoro-phenyl, 4-chloro- phenyl, 4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl and 4-phenoxy-phenyl.

The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 , 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1 ,3]oxadiazolyl, benzo[2,1 ,3]thiadiazolyl, benzo[1 ,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl. The heteroaryl groups are unsubstituted or substituted as explicitly defined. Examples of such unsubstituted or substituted heteroaryl groups are 3,5-dimethyl-isoxazolyl (notably 3,5-dimethyl-isoxazol-4- yl), thiazolyl (notably thiazol-5-yl), isothiazolyl (notably isothiazol-5-yl), 1 -methyl-pyrazolyl (notably 1 -methyl-pyrazol-4-yl), pyridyl (notably pyridin-3-yl), 5-fluoro-pyridyl (notably 5- fluoro-pyridin-2-yl), 6-chloro-pyridyl (notably 6-chloro-pyridin-3-yl), 6-methyl-pyridyl (notably 6-methyl-pyridin-3-yl), 6-methoxy-pyridyl (notably 6-methoxy-pyridin-3-yl), 6- trifluoromethyl-pyridyl (notably 6-trifluoromethyl-pyridin-3-yl), 2-hydroxy-pyridyl (notably 2- hydroxy-pyridin-4-yl), pyrimidyl (notably pyrimidin-5-yl), 2-methyl-pyrimidyl (notably 2- methyl-pyrimidin-5-yl), 2-cyclopropyl-pyrimidyl (notably 2-cyclopropyl-pyrimidin-5-yl), 2- trifluoromethyl-pyrimidyl (notably 2-trifluoromethyl-pyrimidin-5-yl), pyridazinyl (notably pyridazin-3-yl) and 5-methyl-pyrazinyl (notably 5-methyl-pyrazin-2-yl).

The term "5- or 6-membered monocyclic heteroaryl", used alone or in combination, means a 5- or 6-membered monocyclic aromatic ring containing one nitrogen atom and optionally one additional heteroatom selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. The heteroaryl groups are unsubstituted or substituted as explicitly defined. Examples of such unsubstituted or substituted heteroaryl groups are 3,5-dimethyl-isoxazolyl (notably 3,5-dimethyl-isoxazol-4- yl), thiazolyl (notably thiazol-5-yl), isothiazolyl (notably isothiazol-5-yl), 1 -methyl-pyrazolyl (notably 1 -methyl-pyrazol-4-yl), pyridyl (notably pyridin-3-yl), 5-fluoro-pyridyl (notably 5- fluoro-pyridin-2-yl), 6-chloro-pyridyl (notably 6-chloro-pyridin-3-yl), 6-methyl-pyridyl (notably 6-methyl-pyridin-3-yl), 6-methoxy-pyridyl (notably 6-methoxy-pyridin-3-yl), 6- trifluoromethyl-pyridyl (notably 6-trifluoromethyl-pyridin-3-yl), 2-hydroxy-pyridyl (notably 2- hydroxy-pyridin-4-yl), pyrimidyl (notably pyrimidin-5-yl), 2-methyl-pyrimidyl (notably 2- methyl-pyrimidin-5-yl), 2-cyclopropyl-pyrimidyl (notably 2-cyclopropyl-pyrimidin-5-yl), 2- trifluoromethyl-pyrimidyl (notably 2-trifluoromethyl-pyrimidin-5-yl), pyridazinyl (notably pyridazin-3-yl) and 5-methyl-pyrazinyl (notably 5-methyl-pyrazin-2-yl).

The term "heterocyclyl", used alone or in combination, refers to a saturated mono- or bi- cyclic moiety of 4 to 8 ring members containing one heteroatom selected from nitrogen, oxygen and sulfur and optionally one additional nitrogen atom. The sulfur atom of a heterocyclyl group may be in an oxidised form, i.e. as a sulfoxide or sulfonyl. Examples of such heterocyclyl groups are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1 -oxo-thiomorpholinyl, 1 ,1 -dioxo- thiomorpholinyl, azepanyl, 1 ,4-oxazepanyl, 6-oxa-3-azabicyclo[3.1 .1 ]heptanyl and 2-oxa- 5-azabicyclo[2.2.1 ]heptanyl. The heterocyclyl groups are unsubstituted or substituted as explicitly defined. Examples of such unsubstituted or substituted heterocyclyl groups are azetidin-1 -yl, pyrrolidin-1 -yl, 3,3-difluoro-pyrrolidin-1 -yl, piperidin-1 -yl, 4-fluoro-piperidin-1 - yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro-piperidin-1 -yl, 2-methyl-piperidin-1 -yl, 4-methyl- piperidin-1 -yl, 4-(fe/?-butoxy-carbonyl)-piperidin-1 -yl, piperidin-4-yl, 1 -methyl-piperidin-4-yl, 1 -acetyl-piperidin-4-yl, 1 -(fe/?-butoxy-carbonyl)-piperidin-4-yl, 1 -methylsulfonyl-piperidin-4- yl, 4-(fe/?-butoxy-carbonyl)-piperazin-1 -yl, tetrahydropyran-4-yl, morpholin-4-yl, 2,6- dimethyl-morpholin-4-yl, 1 ,1 -dioxo-thiomorpholin-4-yl, azepan-1 -yl, 1 ,4-oxazepan-4-yl, 6- oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl and 2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl.

The term "heterocyclyloxy", used alone or in combination, refers to a heterocyclyl-O- group, wherein the heterocyclyl group is as defined above. An example of such a heterocyclyl group is tetrahydropyranoxy (notably tetrahydropyran-4-oxy).

Further embodiments of the invention are presented hereinafter:

1 P) A further embodiment of the invention relates to compounds according to embodiment 1 ), wherein

R ¹ represents a heteroaryl or an aryl group which groups are independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C _!-C^alkyl, (C ₃-C ₆)cycloalkyl, (C _!-C^alkoxy, (C ₁-C ₃)fluoroalkyl, (C ₁-C ₃)fluoroalkoxy, hydroxy, halogen and phenoxy;

R ² represents

• heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from (C^-C^alkyl, (C^-C^alkylcarbonyl, (C _!-C^alkoxycarbonyl, (C _!-C^alkylsulfonyl, and halogen;

• heterocyclyloxy;

· (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di-substituted with halogen;

• (C ₃-C ₆)cycloalkyloxy;

• /V-(C ₃-C ₆)cycloalkyl-amino;

• /V-(C ₃-C ₆)cycloalkylmethyl-amino;

• (C ₃-C ₆)alkyl; • (C ₂-C ₆)alkoxy;

• /V-^-C^alkylamino;

• N,N-d\-[(C^-C ₄)a\ky\]-am o; or

• /V-arylmethyl-ZV-CC^C^alkyl-amino;

R ³ represents hydrogen or halogen;

R ⁴ represents hydrogen, (C!-C^alkyl or (C ₁-C ₂)alkoxy-(C ₁-C ₄)alkyl;

R ⁵ represents hydrogen or (C^-C^alkyl; and

R ⁶ represents chloro or methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

2) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ) or 1 P), wherein

R ¹ represents a 5- or 6-membered monocyclic heteroaryl or a phenyl group which groups are independently unsubstituted , mono- or di-substituted , wherein the substituents are independently selected from the group consisting of methyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, fluoro, chloro and phenoxy;

R ² represents

• heterocyclyl which is unsubstituted , mono- or di-substituted, wherein the substituents are independently selected from methyl, methylcarbonyl, fe/ -butoxy- carbonyl, methylsulfonyl, and fluoro;

tetrahydropyran-4-oxy;

cyclohexyl which is unsubstituted or mono- or di-substituted with fluoro;

cyclopentyloxy; cyclohexyloxy;

cylopentyl-amino;

cylopentylmethyl-amino;

/ ^'so-butyl; pent-3-yl;

ethoxy; pent-3-yloxy;

/ ^'so-butylamino;

dimethylamino; diethylamino; methyl-/ ^'so-butylamino; or

/V-benzyl-/V-methyl-amino;

R ³ represents hydrogen or chloro;

R ⁴ represents hydrogen, methyl, / ^'so-butyl or 3-methoxy-prop-1 -yl;

R ⁵ represents hydrogen or methyl; and

R ⁶ represents chloro or methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 3) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 1 P), wherein

R ¹ represents a heteroaryl or an aryl group which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (d-C^alkyl, (C ₃-C ₆)cycloalkyl, (d-C^alkoxy, (C ₁-C ₃)fluoroalkyl and halogen;

R ² represents

• heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from (d-C ₄)alkyl and halogen;

· (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro;

• cyclopentyloxy;

• (C ₃-C ₆)alkyl; or

• pent-3-yloxy;

R ³ represents hydrogen;

R ⁴ represents hydrogen, (d-C^alkyl or (C ₁-C ₂)alkoxy-(C ₁-C ₄)alkyl;

R ⁵ represents hydrogen; and

R ⁶ represents chloro or methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

4) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 1 P), wherein

R ¹ represents a 5- or 6-membered monocyclic heteroaryl group which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C ₁-C ₄)alkyl, (C ₃-C ₆)cycloalkyl, (d-C^alkoxy, (d-C^fluoroalkyl and halogen;

R ² represents

• heterocyclyl which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from methyl and fluoro; or

• (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro; R ³ represents hydrogen;

R ⁴ represents hydrogen or (Ci-C ₄)alkyl;

R ⁵ represents hydrogen; and

R ⁶ represents chloro or methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 5) A further embodiment of the invention relates to compounds according to any one of embodiments 1) or 1 P), wherein

R ¹ represents a pyrimidyl or pyridyl group which is unsubstituted or mono-substituted with methyl, cyclopropyl, methoxy, trifluoromethyl or chloro;

R ² represents heterocyclyl, wherein the heterocyclyl is selected from 3,3-difluoro- pyrrolidin-1 -yl, piperidin-1 -yl, 4-fluoro-piperidin-1 -yl, 3,3-difluoro-piperidin-1 -yl, 4,4-difluoro- piperidin-1 -yl, morpholin-4-yl, azepan-1 -yl, 1 ,4-oxazepan-4-yl and 6-oxa-3- azabicyclo[3.1 .1 ]heptan-3-yl;

R ³ represents hydrogen;

R ⁴ represents hydrogen or methyl;

R ⁵ represents hydrogen; and

R ⁶ represents chloro or methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

6) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3) or 4), wherein the term "(C C ₄)alkyr means methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

7) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3) or 6), wherein the term "(C ₃-C ₆)alkyl" means / ^'so-butyl or pent-3- yi;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

8) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4), 6) or 7), wherein the term "(C C ₄)alkoxy" means methoxy; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

9) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4) or 6) to 8), wherein the term "(C ₃-C ₆)cycloalkyr, if representing a substituent to a heteroaryl or an aryl group, means cyclopropyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

10) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4) or 6) to 9), wherein the term "(C ₃-C ₆)cycloalkyr, if representing R ², means cyclohexyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 1 1) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ), 1 P), 3), 4) or 6) to 10), wherein the terms "(C ₁-C ₃)fluoroalkyl" and, if present, "(C ₁-C ₂)fluoroalkyl" mean trifluoromethyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 12) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3) or 6) to 1 1), wherein the term "(C ₁-C ₂)alkoxy-(C ₁-C ₄)alky ' means 3-methoxy-prop-1 -yl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

13) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4) or 6) to 12), wherein the term "halogen" means fluoro or chloro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

14) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4) or 6) to 12), wherein the term "halogen" means fluoro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

15) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ), 1 P), 3) or 6) to 14), wherein the term "heteroaryl" means "5- or 6- membered monocyclic heteroaryl";

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 16) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4) or 6) to 14), wherein the term "heteroaryl" or the term "5- or 6- membered monocyclic heteroaryl" means thiazolyl, isothiazolyl, pyridyl or pyrimidyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

17) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4) or 6) to 14), wherein the term "heteroaryl" or the term "5- or 6- membered monocyclic heteroaryl" means pyridyl or pyrimidyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

18) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3) or 6) to 17), wherein the term "aryl" means phenyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 19) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4) or 6) to 18), wherein the term "heterocyclyl" means pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, azepanyl, 1 ,4-oxazepanyl or 6-oxa-3- azabicyclo[3.1 .1 ]heptanyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

20) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4) or 6) to 18), wherein the term "heterocyclyl" means piperidin-1 -yl, morpholin-4-yl, azepan-1 -yl, 1 ,4-oxazepan-4-yl or 6-oxa-3-azabicyclo[3.1 .1 ]heptan-3-yl; and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 21) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 6) to 14), 16), 17), 19) or 20), wherein

R ¹ represents a 5- or 6-membered monocyclic heteroaryl or a phenyl group which groups are independently unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-C ₄)alkyl, (C ₃-C ₆)cycloalkyl, (Ci- C ₃)fluoroalkyl and halogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

22) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 4), 6) to 14), 16), 17), 19) or 20), wherein

R ¹ represents a 5- or 6-membered monocyclic heteroaryl group which is unsubstituted or mono-substituted with (C^-C^alkyl, (C ₃-C ₆)cycloalkyl, (C ₁-C ₃)fluoroalkyl and halogen; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

23) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 6) to 14), 19) or 20), wherein

R ¹ represents a phenyl group which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-C ₄)alkyl, (Ci- C ₄)alkoxy, (C^-C^fluoroalkyl and halogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

24) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 6) or 8) to 23), wherein

R ² represents

• heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro; or

• (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di-substituted with fluoro; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

25) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 4), 6), 8), 9) or 1 1 ) to 23), wherein

R ² represents heterocyclyl which is unsubstituted or mono- or di-substituted with fluoro; and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

26) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 6) to 18) or 21) to 23), wherein

R ² represents (C ₃-C ₆)alkyl; or (C ₃-C ₆)cycloalkyl which is unsubstituted or mono- or di- substituted with fluoro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

27) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 6), 8) to 18) or 21) to 23), wherein

R ² represents (C ₃-C ₆)cycloalkyloxy or (C ₂-C ₆)alkoxy;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 28) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 2) or 6) to 27), wherein

R ³ represents hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

29) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3), 6) to 1 1) or 13) to 28), wherein

R ⁴ represents hydrogen or (C^-C^alkyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

30) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 3) or 6) to 28), wherein

R ⁴ represents (C ₁-C ₂)alkoxy-(C ₁-C ₄)alkyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

31) A further embodiment of the invention relates to compounds according to any one of embodiments 1), 1 P), 2) or 6) to 30), wherein

R ⁵ represents hydrogen;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds. 32) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 31 ), wherein

R ⁶ represents chloro;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

33) A further embodiment of the invention relates to compounds according to any one of embodiments 1) to 31 ), wherein

R ⁶ represents methyl;

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

34) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 33), wherein the absolute configuration of the stereogenic center is as depicted in formula (l _sti)

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

35) A further embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 33), wherein the absolute configuration of the stereogenic center is as depicted in formula (l _st2)

and to the salts (in particular pharmaceutically acceptable salts) of such compounds.

36) Preferred compounds of formula (I) as defined in embodiment 1 ) are selected from the group consisting of:

4-Chloro-1 H-indole-5-carboxylic acid [2-morpholin-4-yl-2-(2-trifluoromethyl-pyrimidin-5-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid [2-(6-chloro-pyridin-3-yl)-2-(4,4-difluoro-piperidin-1 - yl)-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid (R)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid (S)-2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid (R)-2-(4,4-difluoro-piperidin-1 -yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid (S)-2-(4,4-difluoro-piperidin-1 -yl)-2-(2-methyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(6-methyl-pyridin-3-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(4,4-difluoro-piperidin-1 -yl)-2-(2-trifluoromethyl- pyrimidin-5-yl)-ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(2-cyclopropyl-pyrimidin-5-yl)-2-morpholin-4-yl- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)- ethyl]-amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(6-methoxy-pyridin-3-yl)-2-morpholin-4-yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-dimethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-azetidin-1 -yl-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(2-methyl-pyrimidin-5-yl)-2-pyrrolidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-diethylamino-2-(2-methyl-pyrimidin-5-yl)-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(2-methyl-pyrimidin-5-yl)-2-piperidin-1 -yl-ethyl]- amide;

4-Chloro-1 H-indole-5-carboxylic acid 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-amide; 4-Chloro-1 H-indole-5-carboxylic acid 2-(3,5-difluoro-phenyl)-2-morpholin-4-yl-ethyl]- amide;

4-{2-[(4-Chloro-1 H-indole-5-carbonyl)-amino]-1 -pyridin-3-yl-ethyl}-piperidine-1 -carboxylic acid fe/ -butyl ester;

4-Chloro-1 H-indole-5-carboxylic acid (2-piperidin-4-yl-2-pyridin-3-yl-ethyl)-amide; 4-Chloro-1 H-indole-5-carboxylic acid [2-(1 -methyl-piperidin-4-yl)-2-pyridin-3-yl-ethyl]- amide;