PYRIDAZINONE GLUCOKINASE ACTIVATORS

• US 20090264434A1
• Filed: 03/09/2009
• Published: 10/22/2009
• Est. Priority Date: 04/16/2008
• Status: Active Grant

• Current Assignee: Jefferson Wright Tilley, Lee Apostle Mcdermott, Nancy-Ellen Haynes, Nathan Robert Scott, Ramakanth Sarabu, Robert Francis Kester, Steven Joseph Berthel, Yimin Qian
• Original Assignee: Jefferson Wright Tilley, Lee Apostle Mcdermott, Nancy-Ellen Haynes, Nathan Robert Scott, Ramakanth Sarabu, Robert Francis Kester, Steven Joseph Berthel, Yimin Qian
• Inventors: Berthel, Steven Joseph, Kester, Robert Francis, McDermott, Lee Apostle, Scott, Nathan Robert, Haynes, Nancy-Ellen, Tilley, Jefferson Wright, Sarabu, Ramakanth, Qian, Yimin
• Granted Patent: US 8,258,134 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings

Abstract

Provided herein are compounds of the formula (I):

as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.

Claims

1. A compound of formula (I):

wherein;

X is oxygen, nitrogen, sulfur, carbon or absent;

R₁ is hydrogen,

lower alkyl,

cycloalkyl,

CH₂-cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono-, bi- or tri-substituted independently with halogen, alkyl, alkoxy, —

S(O₂)-lower alkyl, —

CH₂-aryl, heteroaryl, cyano, alkoyl, —

O-aryl, cycloalkyl, heterocycloalkyl or —

C(O)-heterocycloalkyl,

heteroaryl, unsubstituted or substituted with halogen or lower alkyl,

2,3-dihydro-benzo[1,4]dioxin-5-yl,

2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl

5,6,7,8-tetrahydro-naphthalen-1-yl,

naphthalen-1-yl or

isoquinolin;

R₂ is lower alkyl,

cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono- or bi-substituted independently with halogen, or

heteroaryl having at least one ring heteroatom being either O or S; and

R₃ is lower alkyl-carbamoyl or

an unsubstituted or substituted heteroaryl connected by a ring carbon atom to the amine group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, said substituted heteroaryl being substituted at a position other than adjacent to said connecting carbon atom independently with halogen, lower alkyl, ester, acid, cycloalkyl, aryl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein X is oxygen.

3. The compound according to claim 1, wherein X is nitrogen, sulfur or carbon.

4. The compound according to claim 1, wherein R₁ is phenyl, unsubstituted or mono-, bi- or tri-substituted independently with halogen, cyano, alkoxy, lower alkyl or alkoyl.

5. The compound according to claim 1, wherein R₂ is cycloalkyl, lower alkyl or heterocycloalkyl.

6. The compound according to claim 1, wherein R₃ is:

pyridine, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

pyrazole, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

pyrazine, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

thiadiazole, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

thiazole, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl or

benzothiazole, unsubstituted or mono- or bi-substituted independently with halogen, lower alkyl, ester, acid, cycloalkyl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl.

7. The compound according to claim 1, wherein said heteroaryl at R₃ is substituted with halogen, lower alkyl, lower alkyl hydroxy or lower alkyl dihydroxy.

8. The compound according to claim 1, wherein said heteroaryl at R₃ is substituted with 1-(S)-2,3-dihydroxy-propyl, 1-(R)-2,3-dihydroxy-propyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-ethyl, 2-Methoxy-ethyl, methyl, chloro, fluoro, trifluoromethyl, methoxycarbonyl or carboxy.

9. The compound according to claim 1, wherein R₁ is 2,3-Difluoro-phenyl, 2,4-Difluoro-phenyl, 2,5-Difluoro-phenyl, 2,6-Difluoro-phenyl, 5,6,7,8-Tetrahydro-naphthalen-1-yl, 3-Phenoxy-phenyl, 2-(Pyrrolidine-1-carbonyl)-phenyl, 2-Cyclopentyl-phenyl, 2-Cyclohexyl-phenyl, 2-Pyrrolidin-1-yl-phenyl, 2-Piperidin-1-yl-phenyl, 2-Morpholin-4-yl-phenyl, 2-Acetyl-phenyl, 2-Cyano-phenyl, 2-Fluoro-phenyl, 2-Methanesulfonyl-phenyl, 2-Methoxy-phenyl, 2-Methyl-pyridin-3-yl, 2-Trifluoromethyl-phenyl, 3-Fluoro-phenyl, 3-Methoxy-phenyl, 3-Trifluoromethyl-phenyl, 4-Methoxy-phenyl, 4-Trifluoromethyl-phenyl, Cyclopentyl, Cyclopentyl methyl, Isoquinolin-5-yl, Methyl, Naphthalen-1-yl, o-Tolyl, Phenyl, Pyridin-3-yl, Quinolin-5-yl, Quinolin-8-yl, 2-Biphenyl, 2,3,6-Trimethyl-phenyl, 2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl, 2-tert-Butyl-phenyl, 2,6-Dimethyl-cyclohexane, 2,3-Dichloro-phenyl, 7-Methyl-indan-4-yl, Cyclobutane, 1H-Indol-4-yl, 2-Methyl-4-oxo-4H-pyran-3-yl, 2-Trifluoromethoxy-phenyl, 6-Methyl-pyridin-2-yl, 2-Fluoro-5-methyl-phenyl, 2-(2-Hydroxy-ethyl)-phenyl, 4,6-Dimethyl-pyrimidin-2-yl, 2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl, 3-Chloro-2-fluoro-phenyl, 2,6-Difluoro-3-methyl-phenyl, 4-Trifluoromethyl-pyrimidin-2-yl, 2-Fluoro-4-methoxy-phenyl, 2,4-Dimethyl-phenyl, 2-Chloro-4-methoxy-phenyl, 2-Chloro-4-trifluoromethoxy-phenyl, 3-Ethoxy-2,6-difluoro-phenyl, 2-Chloro-phenyl, 2,3-Dihydro-benzo[1,4]dioxin-5-yl, 2-(2-Chloro-phenyl)-ethyl and 2-Chloro-3-trifluoromethyl-phenyl, 2-Chloro-3-methoxy-phenyl and 4-(3-Fluoro-pyridin-2-yl

10. The compound according to claim 1, wherein R₂ is dichloro-phenyl, difluoro-phenyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, butyl, ethyl, propyl, 3-pentyl, isopropyl, phenyl, tert-butoxy, tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl or tetrahydro-pyran-4-yl.

11. The compound according to claim 1, wherein R₃ is 3-Methyl-[1,2,4]thiadiazol-5-yl, 5-Methyl-[1,3,4]thiadiazol-2-yl, 5-Methoxycarbonyl-1-methyl-1H-pyrazol-3-yl, 1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl, 1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl, 1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl, 1-(2-Hydroxy-ethyl)-1H-pyrazol-3-yl, 1-Methyl-1H-pyrazol-3-yl, 5-Carboxy-pyridin-2-yl, 5-Chloro-1-methyl-1H-pyrazol-3-yl, 5-Methoxycarbonyl-pyridin-2-yl, Pyrazin-2-yl, Thiazol-2-yl, 1-(2-Methoxy-ethyl)-1H-pyrazol-3-yl, 1-(2-Methoxy-2-methyl-propyl)-1H-pyrazol-3-yl, 1-(2-Isopropoxy-ethyl)-1H-pyrazol-3-yl, 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl, 1-(3-Cyano-benzyl)-1H-pyrazol-3-yl, 1-(2-tert-Butoxycarbonylamino-ethyl)-1H-pyrazol-3 yl, 5-Fluoro-thiazol-2-yl, 5-Chloro-thiazol-2-yl, Benzothiazol-2-yl or Methylcarbamoyl.

12. The compound according to claim 1, having formula (Ia):

wherein;

Z₁, Z₂, Z₃, independently of each other, are hydrogen, halogen, lower alkyl, aryl, alkoxy, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, alkoyl or —

C(O)-heterocycloalkyl;

R₂ is lower alkyl,

cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono- or bi-substituted independently with halogen, or

heteroaryl having at least one ring heteroatom being either O or S; and

R₃ is—

an unsubstituted or substituted heteroaryl connected by a ring carbon atom to the amine group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, said substituted heteroaryl being substituted at a position other than adjacent to said connecting carbon atom independently with halogen, lower alkyl, ester, acid, cycloalkyl, aryl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl.

13. The compound according to claim 12, wherein:

Z₁, Z₂, Z₃, independently of each other, are hydrogen, chloro, ethoxy, fluoro, trifluoromethyl or methoxy;

R₂ is 2,6-difluoro-phenyl, cyclohexyl, cyclopentyl, isopropyl, phenyl, tert-butoxy, tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl, tetrahydro-pyran-4-yl or cyclobutyl; and

R₃ is 3-Methyl-[1,2,4]thiadiazol-5-yl, 5-Methyl-[1,3,4]thiadiazol-2-yl, 1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl, 1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl, 1-(2-Hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl, 1-(2-Hydroxy-ethyl)-1H-pyrazol-3-yl, 1-Methyl-1H-pyrazol-3-yl, 5-Carboxy-pyridin-2-yl, 5-Methoxycarbonyl-pyridin-2-yl, Pyrazin-2-yl, Thiazol-2-yl.

14. The compound according to claim 1, having formula (Ib):

wherein;

Z₁, Z₂, Z₃, independently of each other, are hydrogen, halogen, lower alkyl, aryl, alkoxy, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, alkoyl, trifluoromethyl or —

C(O)-heterocycloalkyl;

R₂ is lower alkyl, cycloalkyl or heterocycloalkyl; and

R₄ is hydrogen, methyl, 1-(S)-2,3-dihydroxy-propyl, 1-(R)-2,3-dihydroxy-propyl, 2-Hydroxy-2-methyl-propyl, 2-hydroxy-ethyl or 2-methoxy-ethyl.

15. The compound according to claim 14, wherein Z₁, Z₂ and Z₃, independently of each other are, hydrogen, trifluoromethyl, —

OCH₃, fluorine, pyrrolidine, piperidine, morpholine, —

C(O)CH₃, cyclopentyl, ethoxy, methoxy or methyl.

16. The compound according to claim 14, wherein R₂ is lower alkyl, cyclopentyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrofuranyl.

17. The compound according to claim 14, wherein R₄ is 1-(S)-2,3-dihydroxy-propyl, 1-(R)-2,3-dihydroxy-propyl, 2-hydroxy-2-methyl-propyl or 2-hydroxy-ethyl, 2-methoxy-ethyl.

18. The compound according to claim 1, wherein said compound is:

6-{3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester

6-{3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid

6-[3-Cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionylamino]-nicotinic acid methyl ester

6-{3-Cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester

3-Cyclopentyl-2-[4-(2,6-difluoro-3-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

6-{3-Cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid

3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

6-[3-Cyclopentyl-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionylamino]-nicotinic acid

3-Cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

N-[1-((R)-2,3-Dihydroxy-propyl)-1H-pyrazol-3-yl]-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

2-[4-(2-Chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

6-{3-Cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid

3-Cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

3-Cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

6-{3-Cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester

3-Cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-2-[4-(2,3-dichloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(3-Chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide

N-(5-Chloro-1-methyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-o-tolyloxy-6H-pyridazin-1-yl)-propionamide

2-[4-(3-Ethoxy-2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-pyrrolidin-1-yl-phenoxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-2-[4-(2,3-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2-Cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2-Acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

2-[4-(2-Chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

2-[4-(2-Chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide

4-Methyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

4-Methyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

3-Cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

6-{3-Cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid

2-[4-(2-Chloro-3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

3-Cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

3-Cyclohexyl-2-[4-(2,4-dimethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

3-Cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-N-pyrazin-2-yl-propionamide

4-Methyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide

2-[4-(2,6-Difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionamide

2-[4-(2-tert-Butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

3-Cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

22. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A compound of formula I(c):

wherein;

Q is —

O-aryl;

R₂ is lower alkyl,

cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono- or bi-substituted independently with halogen, or

heteroaryl having at least one ring heteroatom being either O or S; and

R₃ is lower alkyl-carbamoyl or

an unsubstituted or substituted heteroaryl connected by a ring carbon atom to the amine group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, said substituted heteroaryl being substituted at a position other than adjacent to said connecting carbon atom independently with halogen, lower alkyl, ester, acid, cycloalkyl, aryl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

or pharmaceutically acceptable salts thereof.

20. A compound of formula I(d):

wherein;

X is oxygen;

Y is—

halogen, lower alkyl or aryl;

R₁ is hydrogen,

lower alkyl,

cycloalkyl,

CH₂-cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono-, bi- or tri-substituted independently with halogen, alkyl, alkoxy, —

CF₃, —

S(O₂)CH₃, —

CH₂-aryl, heteroaryl, cyano, alkoyl, —

O-aryl, cycloalkyl, heterocycloalkyl or —

C(O)-heterocycloalkyl,

heteroaryl, unsubstituted or substituted with halogen or lower alkyl,

2,3-dihydro-benzo[1,4]dioxin-5-yl,

2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl

5,6,7,8-tetrahydro-naphthalen-1-yloxy,

naphthalen-1-yloxy or

isoquinolin;

R₂ is lower alkyl,

cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono- or bi-substituted independently with halogen, or

heteroaryl having at least one ring heteroatom being either O or S; and

R₃ is lower alkyl-carbamoyl or

an unsubstituted or substituted heteroaryl connected by a ring carbon atom to the amine group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, said substituted heteroaryl being substituted at a position other than adjacent to said connecting carbon atom independently with halogen, lower alkyl, ester, acid, cycloalkyl, aryl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

or pharmaceutically acceptable salts thereof.

21. A compound of formula I(e):

wherein;

R₂ is lower alkyl,

cycloalkyl,

heterocycloalkyl,

aryl, unsubstituted or mono- or bi-substituted independently with halogen, or

heteroaryl having at least one ring heteroatom being either O or S; and

R₃ is lower alkyl-carbamoyl or

an unsubstituted or substituted heteroaryl connected by a ring carbon atom to the amine group shown, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, said substituted heteroaryl being substituted at a position other than adjacent to said connecting carbon atom independently with halogen, lower alkyl, ester, acid, cycloalkyl, aryl, —

CH₂-aryl, heterocycloalkyl or —

CH₂-heterocycloalkyl,

wherein the phenyl moiety in the 2H-phthalazin-1-one shown in formula I(e) may be unsubstituted or mono-, bi- or tri-substituted with halogen, lower alkyl or alkoxy, or pharmaceutically acceptable salts thereof.