Diacylglycerol acyltransferase inhibitors

• US 20070123504A1
• Filed: 11/17/2006
• Published: 05/31/2007
• Est. Priority Date: 11/28/2005
• Status: Active Grant

• Current Assignee: Madrigal Pharmaceuticals, Inc.
• Original Assignee: VIA Pharmaceuticals, Inc.
• Inventors: Yun, Weiya, Hamilton, Matthew, Qian, Yimin, Firooznia, Fariborz, Li, Shiming, Bolin, David, Cheung, Adrian, McDermott, Lee
• Granted Patent: US 7,714,126 B2
• Time in Patent Office: Days
• US Class Current: 514/210.20
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 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 diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

Claims

1. A compound of the formula (I):

2. The compound according to claim 1, wherein:

R₁ is unsubstituted aryl or aryl substituted with a group selected from the group consisting of alkyl and halogen;

R₂ is C;

R₃ is N;

R₄ is O;

R₅ is C;

R₆ is alkyl;

R₇ is

at least one of R₈ or R₉ is N; and

R₁₀ is —

NR₁₁R₁₂, O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —

N(CH₃)C(O)CH₃, cyclopropanecarbonyl-methyl, —

OCH₃, —

OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH, —

CH₂OH, —

CH₂OCH₃ and —

OH;

R₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —

CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —

OCH₃, —

CH₂OH, —

CH₂OCH₃, —

OCH₂C(O)OC(CH₃)₃, —

OCH₂C(O)OH and —

OH;

R₁₂ is H or lower alkyl;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein:

R₁ is unsubstituted aryl or aryl substituted with a group selected from the group consisting of alkyl and halogen;

R₂ is C;

R₃ is O;

R₄ is N;

R₅ is C;

R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R₇ is

at least one of R₈ or R₉ is N; and

R₁₀ is —

NR₁₁R₁₂, O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —

N(CH₃)C(O)CH₃, cyclopropanecarbonyl-methyl, —

OCH₃, —

OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH, —

CH₂OH, —

CH₂OCH₃ and —

OH;

R₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —

CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —

OCH₃, —

CH₂OH, —

CH₂OCH₃, —

OCH₂C(O)OC(CH₃)₃, —

OCH₂C(O)OH and —

OH;

R₁₂ is H or lower alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein:

R₁ is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —

O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;

R₂ is C or N;

R₃ is C, N, S or O;

R₄ is C, O, S or N;

R₅ is C, N or S;

R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R₇ is

at least one of R₈ or R₉ is N; and

R₁₀ is —

NR₁₁R₁₂;

R₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —

OCH₃, —

CH₂OH, —

CH₂OCH₃ and —

OH;

R₁₂ is H or lower alkyl;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein:

R₁ is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —

O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;

R₂ is C or N;

R₃ is C, N, S or O;

R₄ is C, O, S or N;

R₅ is C, N or S;

R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R₇ is

at least one of R₈ or R₉ is N; and

R₁₀ is —

NR₁₁R₁₂, O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —

N(CH₃)C(O)CH₃, cyclopropanecarbonyl-methyl, —

OCH₃, —

OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH, —

CH₂OH, —

CH₂OCH₃ and —

OH;

R₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —

CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —

OCH₃, —

CH₂OH, —

CH₂OCH₃, —

OCH₂C(O)OC(CH₃)₃, —

OCH₂C(O)OH and —

OH;

R₁₂ is H or lower alkyl;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein:

R₁ is unsubstituted aryl, aryl substituted with a group selected from the group consisting of alkyl, —

O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl;

R₂ is C or N;

R₃ is C, N, S or O;

R₄ is C, O, S or N;

R₅ is C, N or S;

R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R₇ is

at least one of R₈ or R₉ is N; and

R₁₀ is —

NR₁₁R₁₂, O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of amino, amide, —

N(CH₃)C(O)CH₃, cyclopropanecarbonyl-methyl, —

OCH₃, —

OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH, —

CH₂OH, —

CH₂OCH₃ and —

OH;

R₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —

CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from 1 to 3 hetero ring atoms selected from the group consisting of S, N and O, unsubstituted or substituted with a group selected from the group consisting of —

OCH₃, —

CH₂OH, —

CH₂OCH₃, —

OCH₂C(O)OC(CH₃)₃, —

OCH₂C(O)OH and —

OH;

R₁₂ is H or lower alkyl;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R₆ is —

CF₃.

8. The compound according to claim 1, wherein R₁₀ is —

N(CH₃)(CH₂)_nOCH₃, —

N(CH₃)CH₂C(O)OCH₃, —

N(CH₃)CH₂C(O)NHCH₃, —

N(CH₃)C(O)CH₃, —

N(CH₃)(CH₂)_nCH₃, —

NH(CH₂)_nCH₃, —

N(CH₂CH₃)(CH₂)_nOCH₃, diethylamino, —

N(CH₃)C(O)CH₂OCH₃, —

N(CH₃)CH(CH₃)CH₂OCH₃, —

N(CH₃)(CH₂)_nO, —

N(CH₂)_nO, —

NCH₂(CH₃)CH₂O or —

N-tetrahydropyran;

wherein n is 1, 2 or 3.

9. The compound according to claim 1, wherein said compound is 5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide,

10. The compound according to claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide.

11. The compound according to claim 1, wherein said compound is 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide.

12. The compound according to claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide.

13. The compound according to claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide.

14. The compound according to claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide.

15. The compound according to claim 1, wherein said compound is 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide.

16. The compound according to claim 1, wherein said compound is 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide.

17. 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.

18. A method of treating obesity, type II diabetes, dyslipidemia or metabolic syndrome, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.

19. The method according to claim 18, wherein said therapeutically effective amount is in an amount of from about 1 mg to about 1000 mg per day.

20. The method according to claim 19, wherein said therapeutically effective amount is in an amount of from about 1 mg to about 500 mg per day.