1,2-DIAMIDO-ETHYLENE DERIVATIVES AS OREXIN ANTAGONISTS

Title:

1,2-DIAMIDO-ETHYLENE DERIVATIVES AS OREXIN ANTAGONISTS

Document Type and Number:

WIPO Patent Application WO/2009/022311

Kind Code:

Abstract:

The invention relates to 1,2-diamido-ethylene derivatives of the formula (I) wherein R1, R 2, R 3, and A are as described in the description and their use as medicaments, especially as orexin receptor antagonists.

Inventors:

AISSAOUI HAMED (FR)
BOSS CHRISTOPH (CH)
GUDE MARKUS (CH)
KOBERSTEIN RALF (DE)
SIFFERLEN THIERRY (FR)

Application Number:

PCT/IB2008/053264

Publication Date:

February 19, 2009

Filing Date:

August 14, 2008

Export Citation:

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Assignee:

ACTELION PHARMACEUTICALS LTD (CH)
AISSAOUI HAMED (FR)
BOSS CHRISTOPH (CH)
GUDE MARKUS (CH)
KOBERSTEIN RALF (DE)
SIFFERLEN THIERRY (FR)

International Classes:

A61K31/343; C07D417/12; A61K31/353; A61K31/416; A61K31/4188; A61K31/427; A61P25/00; C07D231/56; C07D307/79; C07D319/18; C07D513/04

Domestic Patent References:

WO2003051872A1	2003-06-26
WO2001096302A1	2001-12-20
WO2001096302A1	2001-12-20
WO1995029922A1	1995-11-09

Other References:

SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 451
CAI ET AL., EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 16, no. 5, 2006, pages 631 - 646
"Salt selection for basic drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
T. EICHER; S. HAUPTMANN: "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2003, WILEY

Attorney, Agent or Firm:

SCHAGER, Frank (Legal DepartmentGewerbestrasse 16, Allschwil, CH)

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Claims:

Claims

1. A compound of formula (I)

(I) wherein

R ¹ represents hydrogen, (Ci _-6 )alkyl, (C _3-6 )cycloalkyl, (C _3-6 )cycloalkyl-(Ci. ₄ )alkyl, or aryl-(Ci- ₄ )alkyl, wherein the aryl is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (Ci _-4 )alkoxy, trifluoromethyl, and halogen;

R ² represents hydrogen, (Ci _-4 )alkyl, (C _3-6 )cycloalkyl, or aryl-(Ci_ ₄ )alkyl, wherein the aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci _-4 )alkyl, (Ci _-4 )alkoxy, trifluoromethyl, and halogen; wherein R ¹ and R ² do not represent hydrogen at the same time;

R ³ represents heterocyclyl, which is unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci _-4 )alkyl, (Ci _-4 )alkoxy, halogen, and trifluoromethyl;

A represents

R ⁴ represents bromo, cyclopropyl, Or -NR ⁵ R ⁶ ; R ⁵ represents hydrogen, or R ⁶ represents hydrogen, or and

D represents aryl, which is unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C _1-4 )alkyl, (C _1-4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, and halogen; or a salt of such a compound.

2. A compound of formula (I) according to claim 1 , wherein A represents or a salt of such a compound.

3. A compound of formula (I) according to claim 1 or 2, wherein R ⁴ represents methyl, -NH ₂ , bromo, or cyclopropyl; or a salt of such a compound.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein D represents phenyl, which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C _1-4 )alkyl, (Ci _-4 )alkoxy, trifluoromethyl, cyano, and halogen; or a salt of such a compound.

5. A compound according to any one of claims 1 to 4, wherein R ¹ represents hydrogen, methyl, cyclopropyl, cyclopropyl-methyl, or aryl-(Ci _-4 )alkyl, wherein the aryl is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of trifluoromethyl, and halogen; or a salt of such a compound.

6. A compound according to any one of claims 1 to 5, wherein R ² represents hydrogen, methyl, cyclopropyl, or aryl-(Ci _-2 )alkyl, wherein the aryl is unsubstituted; or a salt of such a compound.

7. A compound according to any one of claims 1 to 6, wherein R ³ represents a group selected from quinoline-8-yl, isoquinoline-1-yl, indol-3-yl, indol-4-yl, indol-7-yl, indazol-3-yl, indazol-4-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-7-yl, benzoxazol-4-yl, benzoxazol-7-yl, benzoxadiazol-4-yl, benzoxadiazol-7-yl, benzothiophene-3-yl, benzothiophene-4-yl, benzothiophene-7-yl, benzthiazol-4-yl, benzthiazol-7-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-7-yl, benzothiadiazol-4-yl, benzothiadiazol-7-yl, benzimidazol-4-yl, benzimidazol-7-yl, imidazo[2,1-b]thiazol-3-yl, imidazo[2,1-b]thiazol-5-yl, pyrazolo[1 ,5-a]pyridine-3-yl, imidazo[1 ,2-a]pyridine-3-yl, 2,3-dihydro-thieno[3,4-b][1 ,4]dioxine-5-yl, benzo[1 ,3]dioxol-4-yl, 2,3-dihydro- benzofuran-4-yl, 2,3-dihydro-benzofuran-7-yl, 4H-benzo[1 ,3]dioxin-8-yl, 4H- benzo[1 ,3]dioxin-5-yl, and 2,3-dihydro-benzo[1 ,4]dioxin-5-yl; wherein said group is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of methyl, methoxy, halogen, and trifluoromethyl;

or a salt of such a compound.

8. A compound according to any one of claims 1 to 6, wherein R ³ represents

or a salt of such a compound.

9. A compound according to any one of claims 1 to 8 selected from the group consisting of:

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - cyclopropyl-ethyl}-methyl-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-benzyl-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-methyl-amide;

1-Methyl-1 H-indazole-3-carboxylic acid (2-{[5-(4-fluoro-phenyl)-2-methyl-thiazole-4- carbonyl]-methyl-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzofuran-

7-carbonyl)-amino]-ethyl}-methyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[5-(4-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-methyl-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid benzyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{benzyl-[5-(4-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid benzyl-{2-[(2,3-dihydro- benzofuran-7-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{benzyl-[5-(4-fluoro-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(3,3-dimethyl-butyl)-amide; θ-Methyl-imidazoP.I-blthiazole-δ-carboxylic acid {2-[(3,3-dimethyl-butyl)-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(3,3-dimethyl-butyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(3-phenyl-propyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-(3-phenyl-propyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(3-phenyl-propyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(4-fluoro-benzyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(4-fluoro-benzyl)-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(4-fluoro-benzyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-phenethyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-phenethyl-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-phenethyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(4-trifluoromethyl-benzyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-(4-trifluoromethyl-benzyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(4-trifluoromethyl-benzyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclohexylmethyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclohexylmethyl-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid cyclohexylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-isobutyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[isobutyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-isobutyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropylmethyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-benzyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid benzyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-methyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[methyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropyl-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - cyclopropyl-ethylj-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - cyclopropyl-ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-2-cyclopropyl-ethyl}- amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-cyclopropyl-2-[methyl-(2-methyl-

5-phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole^-carbonyl^aminol^-cyclopropyl-ethylj-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-cyclopropyl-2-[(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-2- cyclopropyl-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-phenyl-propyl)-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-phenyl-propyl)-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-phenyl-propyl)-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[methyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-4- phenyl-butyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - methyl-ethyl}-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - methyl-ethyl}-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - methyl-ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-amino]-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]- propyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - benzyl-ethyl}-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - benzyl-ethyl}-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - benzyl-ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-3-phenyl-propyl}- amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[methyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-3-phenyl-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-3-phenyl-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-amino]-3-phenyl-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-3- phenyl-propyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-2-methyl-propyl)-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-2-methyl-propyl)-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-2-methyl-propyl)-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-3-methyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-3-methyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {3-methyl-2-[(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-3- methyl-butyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-methyl-butyl)-methyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-methyl-butyl)-benzyl-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid (1 -{[(benzofuran-4-carbonyl)-amino]- methyl}-3-methyl-butyl)-amide;

Benzofuran-4-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-4-methyl-pentyl}- amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {4-methyl-2-[methyl-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-4-methyl-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {4-methyl-2-[(2-methyl-5-phenyl- thiazole-4-carbonyl)-amino]-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-amino]-4- methyl-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-2-cyclopropyl-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-3-phenyl-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-3-methyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(biphenyl-2-carbonyl)-methyl- amino]-4-methyl-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-2-cyclopropyl-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-4-phenyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-3-phenyl-propyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-3-methyl-butyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[benzyl-(biphenyl-2-carbonyl)- amino]-4-methyl-pentyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(2-cyclopropyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(2-cyclopropyl-5-m- tolyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid ^-{cyclopropyl-p-cyclopiOpyl-S-^- methoxy-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-amino-5-m-tolyl-thiazole-4- carbonyl)-cyclopropyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-fluoro-phenyl)- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-methoxy-phenyl)- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(4-fluoro-phenyl)- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-chloro-phenyl)- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-amino-5-phenyl-thiazole-4- carbonyl)-cyclopropyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-bromo-5-(3-methoxy-phenyl)- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-bromo-5-p-tolyl-thiazole-4- carbonyl)-cyclopropyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[5-(2-fluoro-phenyl)-

2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[2-methyl-5-(3- trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[5-(3-fluoro-phenyl)-

2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[2-methyl-5-(4- trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[5-(4-chloro-phenyl)-2-methyl- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[5-(3-methoxy- phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[5-(3-cyano-phenyl)-2-methyl- thiazole-4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropyl-[5-(3,4-dimethyl- phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(2-methyl-5-p-tolyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(3'-methyl-biphenyl-

2-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(4'-methyl-biphenyl-

2-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropyl-(4'-fluoro-biphenyl-

2-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(2-cyclopropyl-5-phenyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(2-cyclopropyl-5-m-tolyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[2-cyclopropyl-5-(3-methoxy- phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[(2-amino-5-m-tolyl-thiazole-4-carbonyl)- cyclopropyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-fluoro-phenyl)-thiazole-4- carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-methoxy-phenyl)-thiazole-

4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(4-fluoro-phenyl)-thiazole-4- carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-chloro-phenyl)-thiazole-4- carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[(2-amino-5-phenyl-thiazole-4-carbonyl)- cyclopropyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-bromo-5-(3-methoxy-phenyl)-thiazole-

4-carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[(2-bromo-5-p-tolyl-thiazole-4-carbonyl)- cyclopropyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[5-(2-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[2-methyl-5-(3-trifluoromethyl- phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[5-(3-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[2-methyl-5-(4-trifluoromethyl- phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[5-(4-chloro-phenyl)-2-methyl-thiazole-4- carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[5-(3-methoxy-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[5-(3-cyano-phenyl)-2-methyl-thiazole-4- carbonyl]-cyclopropyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropyl-[5-(3,4-dimethyl-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(2-methyl-5-p-tolyl-thiazole-4- carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(3'-methyl-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(4'-methyl-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropyl-(4'-fluoro-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Cyclopropyl-5-m-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Cyclopropyl-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

2-Amino-5-m-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropyl-amide;

2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Amino-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

2-Amino-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Amino-5-(3-chloro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Amino-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropyl-amide;

2-Bromo-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

2-Bromo-5-p-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropyl-amide;

5-(2-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

2-Methyl-5-(4-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

5-(4-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

5-(3-Methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

5-(3-Cyano-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropyl-amide;

5-(3,4-Dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropyl-amide;

2-Methyl-5-p-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropyl-amide;

Benzofuran-4-carboxylic acid {2-[cyclopropyl-(3'-methyl-biphenyl-2-carbonyl)-amino]- ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[cyclopropyl-(4'-methyl-biphenyl-2-carbonyl)-amino]- ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[cyclopropyl-(4'-fluoro-biphenyl-2-carbonyl)-amino]- ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(2- cyclopropyl-δ-phenyl-thiazole^-carbonyO-aminol-ethylJ-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(2- cyclopropyl-δ-m-tolyl-thiazole^-carbonyO-aminol-ethylJ-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-cyclopropyl-5-(3-methoxy- phenyO-thiazole^-carbonyO-cyclopropylmethyl-aminoJ-ethyO-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-amino-5-m-tolyl-thiazole-4- carbonyl)-cyclopropylmethyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-fluoro-phenyl)- thiazole^-carbonyll-cyclopropylmethyl-aminoJ-ethyO-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-methoxy-phenyl)- thiazole^-carbonyll-cyclopropylmethyl-aminoJ-ethyO-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(4-fluoro-phenyl)- thiazole^-carbonylJ-cyclopropylmethyl-aminoJ-ethyO-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-amino-5-(3-chloro-phenyl)- thiazole^-carbonyll-cyclopropylmethyl-aminoJ-ethyO-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-amino-5-phenyl-thiazole-4- carbonyl)-cyclopropylmethyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[2-bromo-5-(3-methoxy-phenyl)- thiazole-4-carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(2-bromo-5-p-tolyl-thiazole-4- carbonyl)-cyclopropylmethyl-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[5-(2-fluoro- phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[2-methyl-5-

(3-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[5-(3-fluoro- phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[2-methyl-5-

(4-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[5-(4-chloro-phenyl)-2-methyl- thiazole-4-carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[5-(3- methoxy-phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{[5-(3-cyano-phenyl)-2-methyl- thiazole-4-carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{cyclopropylmethyl-[5-(3,4- dimethyl-phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(2-methyl-5- p-tolyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(3'-methyl- biphenyl-2-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[cyclopropylmethyl-(4'-methyl- biphenyl-2-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 /-/-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(2-cyclopropyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 /-/-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(2-cyclopropyl-5-m- tolyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 /-/-indazole-3-carboxylic acid (2-{[2-cyclopropyl-5-(3-methoxy-phenyl)- thiazole^-carbonyll-cyclopropylmethyl-aminoJ-ethyO-amide;

1 -Methyl-1 /-/-indazole-3-carboxylic acid {2-[(2-amino-5-m-tolyl-thiazole-4-carbonyl)- cyclopropylmethyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-fluoro-phenyl)-thiazole-4- carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-methoxy-phenyl)-thiazole-

4-carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(4-fluoro-phenyl)-thiazole-4- carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-amino-5-(3-chloro-phenyl)-thiazole-4- carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[(2-amino-5-phenyl-thiazole-4-carbonyl)- cyclopropylmethyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[2-bromo-5-(3-methoxy-phenyl)-thiazole-

4-carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[(2-bromo-5-p-tolyl-thiazole-4-carbonyl)- cyclopropylmethyl-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[5-(2-fluoro-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[2-methyl-5-(3- trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[5-(3-fluoro-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[2-methyl-5-(4- trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[5-(4-chloro-phenyl)-2-methyl-thiazole-4- carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[5-(3-methoxy-phenyl)-

2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{[5-(3-cyano-phenyl)-2-methyl-thiazole-4- carbonyl]-cyclopropylmethyl-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{cyclopropylmethyl-[5-(3,4-dimethyl- phenyl)-2-methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(2-methyl-5-p-tolyl- thiazole-4-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(3'-methyl-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(4'-methyl-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

i-Methyl-I H-indazole-3-carboxylic acid {2-[cyclopropylmethyl-(4'-fluoro-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-phenyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-m-tolyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide; 2-Amino-5-m-tolyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide; 2-Amino-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-(3-chloro-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide; 2-Amino-5-phenyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Bromo-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide; 2-Bromo-5-p-tolyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(2-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(4-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3-Methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide; 5-(3,4-Dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-p-tolyl-thiazole-4-carboxylic acid cyclopropyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropyl-(3'-methyl-biphenyl-

2-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropyl-(4'-methyl-biphenyl-

2-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropyl-(4'-fluoro-biphenyl-2- carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-phenyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-m-tolyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropylmethyl-{2-

[(2,3-dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-m-tolyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Amino-5-phenyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Bromo-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Bromo-5-p-tolyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(2-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid cyclopropylmethyl-{2-

[(2,3-dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3-Methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3-Cyano-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3- dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

5-(3,4-Dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-

[(2,3-dihydro-benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-p-tolyl-thiazole-4-carboxylic acid cyclopropylmethyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropylmethyl-(3'-methyl- biphenyl-2-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropylmethyl-(4'-methyl- biphenyl-2-carbonyl)-amino]-ethyl}-amide;

2,3-Dihydro-benzo[1 ,4]dioxine-5-carboxylic acid {2-[cyclopropylmethyl-(4'-fluoro- biphenyl-2-carbonyl)-amino]-ethyl}-amide;

2-Cyclopropyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Cyclopropyl-5-m-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Cyclopropyl-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

2-Amino-5-m-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropylmethyl-amide;

2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Amino-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

2-Amino-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Amino-5-(3-chloro-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Amino-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropylmethyl-amide;

2-Bromo-5-(3-methoxy-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

2-Bromo-5-p-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropylmethyl-amide;

5-(2-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

2-Methyl-5-(4-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

5-(4-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

5-(3-Methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

5-(3-Cyano-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-cyclopropylmethyl-amide;

5-(3,4-Dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4- carbonyl)-amino]-ethyl}-cyclopropylmethyl-amide;

2-Methyl-5-p-tolyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-cyclopropylmethyl-amide;

Benzofuran-4-carboxylic acid {2-[cyclopropylmethyl-(3'-methyl-biphenyl-2-carbonyl)- amino]-ethyl}-amide;

Benzofuran-4-carboxylic acid {2-[cyclopropylmethyl-(4'-methyl-biphenyl-2-carbonyl)- amino]-ethyl}-amide; and

Benzofuran-4-carboxylic acid {2-[cyclopropylmethyl-(4'-fluoro-biphenyl-2-carbonyl)- amino]-ethyl}-amide; or a salt of such a compound.

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

1 1. A compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as medicament.

12. A compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the the prevention or treatment of diseases selected from the group consisting of all types of sleep disorders, of stress-related syndromes, of psychoactive substance use and abuse, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.

13. Use of a compound according to any of claims 1 to 9, or of a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of all types of sleep

disorders, of stress-related syndromes, of psychoactive substance use and abuse, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.

Description:

1 ,2-Diamido-ethylene derivatives

The present invention relates to novel 1 ,2-diamido-ethylene 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 orexin receptor antagonists.

Orexins (orexin A or OX-A and orexin B or OX-B) are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein- coupled receptors (OXi and OX ₂ receptors). The orexin-1 receptor (OXi) is selective for OX-A, and the orexin-2 receptor (OX ₂ ) is capable to bind OX-A as well as OX-B. Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585). On the other hand, it was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to narcolepsy as well as insomnia and other sleep disorders (Chemelli R.M. et ai, Cell, 1999, 98, 437-451 ).

Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies as known from the literature.

The present invention provides 1 ,2-diamido-ethylene derivatives, which are non- peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.

Up to now, several low molecular weight compounds are known having a potential to antagonise either specifically OXi or OX ₂ , or both receptors at the same time. Ethylene diamine derivatives useful as orexin receptor antagonists are disclosed in WO03/051872.

The present invention describes for the first time 1 ,2-diamido-ethylene derivatives as orexin receptor antagonists.

i) A first aspect of the invention consists of 1 ,2-diamido-ethylene derivatives of the formula (I)

(I) wherein

R ¹ represents hydrogen, (d _-6 )alkyl, (C _3-6 )cycloalkyl, (C ₃ - ₆ )cycloalkyl-(Ci- ₄ )alkyl, or aryl-(Ci _-4 )alkyl, wherein the aryl is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (Ci _-4 )alkoxy, trifluoromethyl, and halogen;

R ² represents hydrogen, (Ci _-4 )alkyl, (C _3-6 )cycloalkyl, or aryl-(Ci _-4 )alkyl, wherein the aryl is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci _-4 )alkyl, (Ci _-4 )alkoxy, trifluoromethyl, and halogen; wherein R ¹ and R ² do not represent hydrogen at the same time;

A represents

R ⁴ represents bromo, cyclopropyl, Or -NR ⁵ R ⁶ ; R ⁵ represents hydrogen, or R ⁶ represents hydrogen, or and

The compounds of formula (I) 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 Z- or E-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.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to a compound of formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

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 "halogen" means fluorine, chlorine, or bromine, preferably fluorine or chlorine.

The term "alkyl", alone or in any combination, means a straight-chain or branched- chain alkyl group with the indicated number of carbon atoms. For example, the term "(C _1-6 )alkyl" means an alkyl group with 1 to 6 carbon atoms. Examples of (C _1-6 )alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n- pentyl, isopentyl, n-hexyl, and 3,3-dimethyl-butyl. The term "(d^alkyl" means an alkyl group with 1 to 4 carbon atoms. Examples of groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert.-butyl. Preferred are methyl, ethyl, and n-propyl. Most preferred is methyl. Examples of "R ¹ " representing (Ci_ ₆ )alkyl are methyl, isobutyl, and 3,3-dimethyl-butyl, preferred is methyl. Examples of "R ² " representing (Ci _-4 )alkyl are methyl, isopropyl, and isobutyl.

The term "(C _3-6 )cycloalkyl" means a saturated cyclic hydrocarbon moiety containing 3-6 carbon atoms. Examples are cyclopropyl, cyclopentyl and cyclohexyl, preferred is cyclopropyl.

The term "(C _3-6 )cycloalkyl-(Ci. ₄ )alkyl" means a (C _3-6 )cycloalkyl group as previously defined that is attached to the parent molecular moiety through a group as previously defined. Examples are cyclopropyl-methyl, cyclopentyl-methyl and

cyclohexyl-methyl, preferred are cyclopropyl-methyl, and cyclohexyl-methyl; most preferred is cyclopropyl-methyl.

The term "(C _1-4 )alkoxy" means a group of the formula (C _1-4 )alkyl-O- in which the term "(Ci _-4 )alkyl" has the previously given significance. Examples of (Ci _-4 )BIkOXy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are methoxy and ethoxy. Most preferred is methoxy.

The term "heterocyclyl" means a 8- to 10-membered bicyclic ring containing 1 , 2 or 3 heteroatoms, each independently selected from oxygen, nitrogen and sulfur, wherein at least one ring of said bicyclic ring system is aromatic and the bond with which the heterocyclyl is attached to the rest of the molecule is positioned on an aromatic carbon atom of said bicyclic ring system in alpha position to a bridgehead atom as further illustrated in the following examples:

O ₌ b brriidgehead atom of the bicyclic ring system . bond with which in these examples the heterocyclyl group may be attached to the rest of the molecule

Examples of such heterocyclyl groups are quinoline-8-yl, isoquinoline-1-yl, indol-3-yl, indol-4-yl, indol-7-yl, indazol-3-yl, indazol-4-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-7-yl, benzoxazol- 4-yl, benzoxazol-7-yl, benzoxadiazol-4-yl, benzoxadiazol-7-yl, benzothiophene-3-yl, benzothiophene-4-yl, benzothiophene-7-yl, benzthiazol-4-yl, benzthiazol-7-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-7-yl, benzothiadiazol-4-yl, benzothiadiazol-7-yl, benzimidazol-4-yl, benzimidazol-7-yl, imidazo[2,1-b]thiazol-3-yl, imidazo[2,1-b]thiazol-5-yl, pyrazolo[1 ,5-a]pyridine-3-yl, imidazo[1 ,2-a]pyridine-3-yl, 2,3-dihydro-thieno[3,4-b][1 ,4]dioxine-5-yl, benzo[1 ,3]dioxol-4-yl, 2,3-dihydro- benzofuran-4-yl, 2,3-dihydro-benzofuran-7-yl, 4H-benzo[1 ,3]dioxin-8-yl, 4H- benzo[1 ,3]dioxin-5-yl, and 2,3-dihydro-benzo[1 ,4]dioxin-5-yl. The above-mentioned heterocyclyl groups are unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C _1-4 )alkyl, (C _1-4 )alkoxy, halogen, and trifluoromethyl.

In "R ³ " representing "heterocyclyl" said heterocyclyl group is preferably unsubstituted, mono-, or di-substituted, wherein the substituents preferably are independently selected from the group consisting of (C _1-4 )alkyl. If substituted, indolyl, indazolyl, and imidazo[2,1-b]thiazolyl groups are preferably mono- or di-substituted (preferred mono-substituted) with methyl. 2,3-Dihydro-benzofuranyl, benzo[1 ,3]dioxol-4-yl, 4H- benzo[1 ,3]dioxinyl, and 2,3-dihydro-benzo[1 ,4]dioxin-5-yl groups are preferably unsubstituted. Particular examples of R ³ representing "heterocyclyl" are quinoline-8- yl, isoquinoline-1-yl, 1 ,2-dimethyl-indol-3-yl, 1-methyl-indol-3-yl, indazol-3-yl, 1-methyl-indazol-3-yl, 2-methyl-benzofuran-4-yl, benzofuran-4-yl, benzisoxazole- 3-yl, 2-methyl-benzoxazole-4-yl, benzoisothiazole-3-yl, imidazo[2,1-b]-thiazole-5-yl, 2-methyl-imidazo[2,1-b]thiazol-5-yl, 3-methyl-imidazo[2,1-b]thiazol-5-yl, 6-methyl- imidazo[2,1-b]-thiazole-5-yl, pyrazolo[1 ,5-a]pyridine-3-yl, imidazo[1 ,2-a]pyridine-3-yl, 2,3-dihydro-thieno[3,4-b][1 ,4]dioxine-5-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro- benzofuran-7-yl, and 2,3-dihydro-benzo[1 ,4]dioxine-5-yl. Preferred examples are 1-methyl-indazol-3-yl, benzofuran-4-yl, imidazo[2,1-b]-thiazole-5-yl, 6-methyl- imidazo[2,1-b]-thiazole-5-yl, 3-methyl-imidazo[2,1-b]thiazol-5-yl, and 2,3-dihydro- benzo[1 ,4]dioxine-5-yl; more preferred examples are 1-methyl-indazol-3-yl, benzofuran-4-yl, and 6-methyl-imidazo[2,1-b]-thiazole-5-yl.

The term "aryl", alone or in any combination, means phenyl, wherein the aryl group is unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C _1-4 )alkyl, (C _1-4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, and halogen.

Examples of "D" representing "aryl" are phenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3-cyanophenyl, 3-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl and 4-trifluoromethylphenyl.

The term "aryl-(Ci _-4 )alkyl" means an aryl group as previously defined that is attached to the parent molecular moiety through a group as previously defined.

In "R ¹ " representing "aryl-(Ci _-4 )alkyl" the term aryl preferably means phenyl, which is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of (Ci _-4 )alkyl, (Ci _-4 )BIkOXy, trifluoromethyl, and halogen (preferred trifluoromethyl, and halogen). Examples of "R ¹ " representing aryl-(Ci _-4 )alkyl are benzyl, 4-fluoro-benzyl, 4-trifluoromethyl-benzyl, phenyl-ethyl, and phenyl-propyl.

In "R ² " representing "aryl-(Ci _-4 )alkyl" the term aryl preferably means phenyl, which is unsubstituted. In another embodiment the phenyl group may be mono-, di-, or tri-

substituted (preferably mono-substituted), wherein the substituents preferably are independently selected from the group consisting of (C _1-4 )alkyl, (C _1-4 )alkoxy, trifluoromethyl, and halogen. Preferred examples of "R ² " representing aryl-(C _1-4 )alkyl are aryl-(Ci _-2 )alkyl groups such as benzyl, and phenyl-ethyl.

Examples of "-NR ⁵ R ⁶ " groups are -NH ₂ (preferred) and -N(CH ₃ ) ₂ .

The term "acyl" as used in the specification means an aryl-CO-, an alkyl-CO-, or a heteroaryl-CO- group, such as for example A-CO-, or R ³ -CO-, wherein A and R ³ have the meaning given for formula (I). ii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to embodiment i), wherein

A represents

iii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to embodiments i) and ii), wherein

R ⁴ represents methyl, -NH ₂ , bromo, or cyclopropyl (especially methyl, or -NH ₂ ). iv) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to embodiments i) and ii), wherein

R ⁴ represents cyclopropyl. v) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to embodiment i), wherein

A represents

vi) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to v), wherein D represents phenyl, which is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from the group consisting of (C _1-4 )alkyl, (C _1-4 )alkoxy, trifluoromethyl, cyano, and halogen.

vii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to vi), wherein R ¹ represents hydrogen, methyl, cyclopropyl, cyclopropyl-methyl, or aryl-(C _1-4 )alkyl, wherein the aryl is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of trifluoromethyl, and halogen. viii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to vi), wherein R ¹ represents methyl, cyclopropyl, cyclopropyl-methyl, or aryl-(Ci_ ₄ )alkyl, wherein the aryl is unsubstituted, or mono-substituted, wherein the substituent is selected from the group consisting of trifluoromethyl, and halogen. ix) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to vi), wherein R ¹ represents hydrogen. x) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to ix), wherein R ² represents hydrogen, methyl, cyclopropyl, or aryl-(Ci _-2 )alkyl, wherein the aryl is unsubstituted. xi) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to ix), wherein R ² represents methyl, cyclopropyl, or aryl-(C _1-2 )alkyl, wherein the aryl is unsubstituted. xii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xi), wherein, in case R ² represents other than hydrogen, the carbon center to which R ² is attached is in (R)-configuration. xiii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xi), wherein, in case R ² represents other than hydrogen, the carbon center to which R ² is attached is in (S)-configuration. xiv) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to viii), wherein R ² represents hydrogen. xv) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents a group selected from quinoline-8-yl, isoquinoline-1-yl, indol-3-yl, indol-4-yl, indol-7-yl, indazol-3-yl, indazol-4-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-7-yl, benzoxazol-4-yl, benzoxazol-7-yl, benzoxadiazol-4-yl, benzoxadiazol-7-yl, benzothiophene-3-yl, benzothiophene-4-yl, benzothiophene-7-yl, benzthiazol-4-yl, benzthiazol-7-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-7-yl, benzothiadiazol-4-yl,

benzothiadiazol-7-yl, benzimidazol-4-yl, benzimidazol-7-yl, imidazo[2,1-b]thiazol-3-yl, imidazo[2,1-b]thiazol-5-yl, pyrazolo[1 ,5-a]pyridine-3-yl, imidazo[1 ,2-a]pyridine-3-yl, 2,3-dihydro-thieno[3,4-b][1 ,4]dioxine-5-yl, benzo[1 ,3]dioxol-4-yl, 2,3-dihydro- benzofuran-4-yl, 2,3-dihydro-benzofuran-7-yl, 4H-benzo[1 ,3]dioxin-8-yl,

4H-benzo[1 ,3]dioxin-5-yl, and 2,3-dihydro-benzo[1 ,4]dioxin-5-yl; wherein said group is unsubstituted, mono-, or di-substituted (especially unsubstituted or mono- substituted), wherein the substituents are independently selected from the group consisting of methyl, methoxy, halogen, and trifluoromethyl (especially methyl). xvi) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents quinoline-8-yl, isoquinoline-1-yl, 1 ,2-dimethyl-indol-3-yl, 1-methyl-indol-3-yl, indazol-3-yl, 1-methyl- indazol-3-yl, 2-methyl-benzofuran-4-yl, benzofuran-4-yl, benzisoxazole-3-yl, 2-methyl-benzoxazole-4-yl, benzoisothiazole-3-yl, imidazo[2,1-b]-thiazole-5-yl, 2-methyl-imidazo[2,1-b]thiazol-5-yl, 3-methyl-imidazo[2,1-b]thiazol-5-yl, 6-methyl- imidazo[2,1-b]-thiazole-5-yl, pyrazolo[1 ,5-a]pyridine-3-yl, imidazo[1 ,2-a]pyridine-3-yl, 2,3-dihydro-thieno[3,4-b][1 ,4]dioxine-5-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro- benzofuran-7-yl, and 2,3-dihydro-benzo[1 ,4]dioxine-5-yl (especially 1-methyl-indazol- 3-yl, benzofuran-4-yl, 6-methyl-imidazo[2,1-b]-thiazole-5-yl, or 2,3-dihydro- benzo[1 ,4]dioxine-5-yl). xvii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents

xviii) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents

xix) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents

xx) A further embodiment of the invention relates to 1 ,2-diamido-ethylene derivatives according to any one of embodiments i) to xiv), wherein R ³ represents

xxi) Preferred examples of 1 ,2-diamido-ethylene derivatives of formula (I) according to embodiment i) are selected from the group consisting of:

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]-1 - cyclopropyl-ethylj-methyl-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-benzyl-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)- amino]-ethyl}-methyl-amide;

1-Methyl-1 /-/-indazole-3-carboxylic acid (2-{[5-(4-fluoro-phenyl)-2-methyl-thiazole-4- carbonyl]-methyl-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzofuran-

7-carbonyl)-amino]-ethyl}-methyl-amide; θ-Methyl-imidazo^i-blthiazole-δ-carboxylic acid (2-{[5-(4-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-methyl-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid benzyl-{2-[(2,3-dihydro- benzo[1 ,4]dioxine-5-carbonyl)-amino]-ethyl}-amide;

1 -Methyl-1 H-indazole-3-carboxylic acid (2-{benzyl-[5-(4-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-amino}-ethyl)-amide;

5-(4-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid benzyl-{2-[(2,3-dihydro- benzofuran-7-carbonyl)-amino]-ethyl}-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid (2-{benzyl-[5-(4-fluoro-phenyl)-2- methyl-thiazole-4-carbonyl]-amino}-ethyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(3,3-dimethyl-butyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(3,3-dimethyl-butyl)-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(3,3-dimethyl-butyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(3-phenyl-propyl)-amide; θ-Methyl-imidazo^i-blthiazole-δ-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-(3-phenyl-propyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(3-phenyl-propyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-(4-fluoro-benzyl)-amide;

6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid {2-[(4-fluoro-benzyl)-(2-methyl-5- phenyl-thiazole-4-carbonyl)-amino]-ethyl}-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(2,3-dihydro-benzo[1 ,4]dioxine-5- carbonyl)-amino]-ethyl}-(4-fluoro-benzyl)-amide;

2-Methyl-5-phenyl-thiazole-4-carboxylic acid {2-[(benzofuran-4-carbonyl)-amino]- ethyl}-phenethyl-amide; θ-Methyl-imidazo^i-blthiazole-δ-carboxylic acid {2-[(2-methyl-5-phenyl-thiazole-4- carbonyl)-phenethyl-amino]-ethyl}-amide;