Compounds as diacylglycerol acyltransferase inhibitors

Patent metadata

Field	Value
Publication number	US-9624174-B2
Application number	US-201514943091-A
Country	US
Kind code	B2
Filing date	Nov 17, 2015
Priority date	Nov 9, 2012
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

Compounds of Formula (I) are inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), useful in the treatment of obesity, obesity related disorders, genetic (Type 1, Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia-related disorders, caused by but not limited to lipodystrophy, hypothyroidism, medications (beta blockers, thiazides, estrogen, glucocorticoids, transplant) and other factors (pregnancy, alcohol intake), hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess hair growth (including syndromes associated with hirsutism), nephrotic syndrome, fibrosis such as mycocardial, renal and liver fibrosis, hepatitis C virus infection and acne or other skin disorders.

First claim

The invention claimed is:

1. A compound of Formula (I):

wherein:
A represents

each X is independently CH, CR 2 , or N, provided that at least one X is CH and at most two X's are N;
Y is O, S, or NR 6 ;
each Z is independently CH, CR 2 , or N;
R 1 is phenyl or 5- or 6-membered heteroaryl, which is optionally substituted by —O(C 1 -C 2 )alkylO— or optionally substituted with one to three substituents independently selected from halogen, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, —C(O)OR 6 , —C(O)R 6 , and —OR 6 ;
each R 2 is independently selected from the group consisting of halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, and —OR 6 ;
R 3 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxyl, or (C 1 -C 4 )alkoxy;
R 4 is —C(O)OR 6 ;
each R 5 is hydrogen; and
each R 6 is independently hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, phenyl, or 5- or 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt according to claim 1 , which is represented by Formula (II):

wherein:
A represents

each X is independently CH, CR 2 , or N, provided that at least one X is CH and at most two X's are N;
Y is O, S, or NR 6 ;
each Z is independently CH, CR 2 , or N;
R 1 is phenyl or 5- or 6-membered heteroaryl, which is optionally substituted by —O(C 1 -C 2 )alkylO— or optionally substituted with one to three substituents independently selected from halogen, cyano, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, —C(O)OR 6 , —C(O)R 6 , and —OR 6 ;
each R 2 is independently selected from the group consisting of halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, and —OR 6 ;
R 3 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxyl, or (C 1 -C 4 )alkoxy; and
each R 6 is independently hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, phenyl, or 5- or 6-membered heteroaryl.

3. The compound or pharmaceutically acceptable salt according to claim 2 , which is represented by Formula (III):

4. The compound or pharmaceutically acceptable salt according to claim 2 , which is represented by Formula (IV):

5. The compound or pharmaceutically acceptable salt according to claim 2 wherein A represents

6. The compound or pharmaceutically acceptable salt according to claim 5 wherein each X is independently CH or N, provided that at most two X's are N.

7. The compound or pharmaceutically acceptable salt according to claim 2 wherein A represents

8. The compound or pharmaceutically acceptable salt according to claim 7 wherein Y is O, S, or NH; and each Z is independently CH or N.

9. The compound or pharmaceutically acceptable salt according to claim 2 wherein R 3 is (C 1 -C 4 )alkyl or halo(C 1 -C 4 )alkyl.

10. The compound or pharmaceutically acceptable salt according to claim 2 wherein R 3 is halo(C 1 -C 4 )alkyl.

11. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 1 is phenyl which is optionally substituted by —O(C 1 -C 2 )alkylO— or with one or two substituents independently selected from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxyl, and (C 1 -C 4 )alkoxy.

12. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 1 is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, each of which is optionally substituted with one or two substituents independently selected from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxyl, and (C 1 -C 4 )alkoxy.

13. The compound or pharmaceutically acceptable salt according to claim 6 , wherein:
R 1 is phenyl or 5- or 6-membered heteroaryl, which is optionally substituted by —O(C 1 -C 2 )alkylO— or optionally substituted with one or two substituents independently selected from halogen, (C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkyl; and
R 3 is (C 1 -C 4 )alkyl or halo(C 1 -C 4 )alkyl.

14. The compound or pharmaceutically acceptable salt according to claim 13 , wherein R 1 is phenyl which is optionally substituted by —O(C 1 -C 2 )alkylO— or optionally substituted with one or two substituents independently selected from halogen, (C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkyl.

15. The compound or pharmaceutically acceptable salt according to claim 13 , wherein R 1 is pyridinyl which is optionally substituted with one or two substituents independently selected from halogen, (C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkyl.

16. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 3 is —CH 2 CF 3 .

17. The compound according to claim 1 which is:
2-(1-oxo-2-(2,2,2-trifluoroethyl)-6-(5-(6-(trifluoromethyl)pyridin-3-ylamino)pyridin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(4-chlorophenylamino)pyridin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(2-methyl-1-oxo-6-(5-(6-(trifluoromethyl)pyridin-3-ylamino)pyridin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(2-ethyl-1-oxo-6-(5-(6-(trifluoromethyl)pyridin-3-ylamino)pyridin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(5-chloropyridin-2-ylamino)pyridin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(1-oxo-6-(5-(p-tolylamino)pyridin-2-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(3,4-difluorophenylamino)pyridin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(3-chlorophenylamino)pyridin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(5-methylpyridin-2-ylamino)pyridin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(1-oxo-2-(2,2,2-trifluoroethyl)-6-(5-(6-(trifluoromethyl)pyridin-3-ylamino)pyrazin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(5-methylpyridin-2-ylamino)pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(5-chloropyridin-2-ylamino)pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(5-(benzo[d][1,3]dioxol-5-ylamino)pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(6-(3-chlorophenylamino)pyridazin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;
2-(6-(6-(6-methylpyridin-3-ylamino)pyridazin-3-yl)-1-oxo-2-(2,2,2-trifluoroet

Assignees

• Glaxosmithkline Llc

Inventors

• Cheung Mui
• Tangirala Raghuram S

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title