IP Library Granted Patent US 8,063,084
Granted Patent B2
US 8,063,084 · App. 12/377,499 · Granted Nov 22, 2011

Heterocyclic compounds suitable for the treatment of diseases related to elevated lipid levels

Assignees: Novartis AG; Xenon Pharmaceuticals Inc.
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Quick Facts
Patent No.
US 8,063,084
App. No.
12/377,499
Granted
Nov 22, 2011
Kind
B2
Abstract

The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.

Claims (151)

1. A compound of Formula (I):

wherein:

X is N;

Y is S;

Q is

W is —N(R 6 )C(O)— or —R 8 —C(O)N(R 6 )—;

V is a direct bond;

n is 1, 2, or 3;

p is 0, 1, 2, to 2n;

R 1 is halo, hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

or R 1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;

R 2 is hydrogen, aryl, aralkyl, or heteroaryl;

R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, haloalkyl, haloalkoxyl, cyano, or —N(R 6 ) 2 ;

R 4 and R 4a are independently hydrogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, cycloalkylalkyl or aralkyl;

or R 4 and R 4a are together to form an oxo (═O) group or a cycloaklyl;

each R 5 is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, alkoxy, cycloalkylalkyl, aralkyl, —N(R 6 )C(O)R 2 , —C(O)N(R 6 )R 2 , —OC(O)N(R 6 )R 2 , —N(R 6 )C(O)OR 2 , —N(R 6 )C(O)N(R 6 )R 2 , —OR 2 , —SR 2 —, —N(R 6 )R 2 , —S(O) t R 2 , —N(R 6 )S(O) 2 R 2 , —S(O) 2 N(R 6 )R 2 , —OS(O) 2 N(R 6 )R 2 , —C(O)R 2 , —OC(O)R 2 , —C(O)OR 2 , —N(R 6 )C(═N(R 6a ))N(R 6 )R 2 , —N(R 6 )C(═S)N(R 6 )R 2 , —N(R 6 )((R 6a )N═)CR 2 , or —C(═N(R 6a ))N(R 6 )R 2 ;

each R 6 is independently hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl or aralkyl;

each R 6a is independently hydrogen, alkyl, cycloalkylalkyl, or cyano;

each R 7 is independently hydrogen, alkyl, trifluoromethyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, cycloalkylalkyl or aralkyl; and

R 8 is a direct bond; or

a pharmaceutically acceptable salt thereof.

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

wherein:

V is a direct bond;

W is —N(R 6 )C(O)— or —R 8 —C(O)N(R 6 );

X is N;

Y is S;

R 1 is halo, hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 2 is aryl, aralkyl, or heteroaryl;

R 6 is hydrogen; and

R 8 is a direct bond.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (II):

wherein:

V is a direct bond;

W is —N(R 6 )C(O)—;

X is N;

Y is S;

R 1 is aralkyl, or heteroarylalkyl;

R 2 is aryl or aralkyl; and

R 6 is hydrogen.

4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein:

V is a direct bond;

W is —N(R 6 )C(O)—;

X is N;

Y is S;

R 1 is select aralkyl or heteroarylalkyl;

R 2 is aryl or aralkyl; and

R 6 is hydrogen.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

N-benzyl-2-(3-(4-fluorophenyl)-5-methoxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorophenyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorophenyl)-2,5-dioxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3-fluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(2-fluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(2,5-difluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3,5-difluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(2,4-difluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3-chlorobenzyl)-4-methylthiazole-5-carboxamide;

(R)—N-benzyl-2-(4-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-2-ylmethyl)thiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-4-ylmethyl)thiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-phenethylimidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methyl-N-((5-methylfuran-2-yl)methyl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-(4-(difluoromethoxy)benzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide;

N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylthiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(3-phenylpropyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-((5-(difluoromethyl)furan-2-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-benzyl-2-(3-(4-cyanobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-(cyclopropylmethyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

(R)—N-(2-hydroxy-2-phenylethyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

N-ethyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

N-(2-cyclopropylethyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-phenylthiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-(2-(pyridin-3-yl)ethyl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)-N-phenethylthiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-(2-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-butyl-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

2-(5-hydroxy-2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-imidazol-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

5-(3-(2-hydroxy-2-phenylethyl)-2-oxoimidazolidin-1-yl)-3-methyl-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide;

Ethyl 4-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate;

N-benzyl-2-(3-(3-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

2-(3-(4-fluorophenethyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorophenethyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-N-(pyridin-3-ylmethypthiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)-4-(trifluoromethyl)thiazole-5-carboxamide;

Methyl 2-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate;

4-methyl-N-((5-methylpyrazin-2-yl)methyl)-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-((5-methylpyrazin-2-yl)methyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(oxazol-2-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-((2-methylthiazol-5-yl)methyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-((1-methyl-1H-pyrazol-4

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyrimidin-2-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyrazin-2-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridazin-3-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N,4-dimethylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorobenzoyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-2-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-4-ylmethyl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide; or a pharmaceutically acceptable salt.

6. A pharmaceutical composition, comprising:

the compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and

a pharmaceutically acceptable excipient or carrier.

7. A pharmaceutical composition, comprising:

a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more agents selected from the group consisting of insulin, Glipizide, glyburide, Amaryl, nateqlinide, repaglinide, MCC-555, MK767, L-165041, GW7282, rosiqlitazone, pioqlitazone, troqlitazone, PTP-112, metformin, acarbose, qlucaqon like peptide-1, Exendin-4 Vildagliptin, lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, fluindostatin, rivastatin, cholestyramine, nicotinic acid; and aspirin.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorophenyl)-5-methoxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-2-(3-(4-fluorophenyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3-fluorobenzyl)-4-methylthiazole-5-carboxamide;

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(2,5-difluorobenzyl)-4-methylthiazole-5-carboxamide; or

2-(3-benzyl-2-oxoimidazolidin-1-yl)-N-(3-chlorobenzyl)-4-methylthiazole-5-carboxamide.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

N-benzyl-4-methyl-2-(2-oxo-3-phenethylimidazolidin-1-yl)thiazole-5-carboxamide;

4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide;

N-benzyl-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide;

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide; or

N-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

Methyl 2-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

N-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxamide;

2-(1-(2-(4-Chlorophenylamino)-2-oxoethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide; or

2-(3-(isoquinolin-1-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide.

12. 2-(3-(4-Fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, comprising:

2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide or a pharmaceutically acceptable salt thereof, and

a pharmaceutically acceptable excipient or carrier.

14. A method of treating Type II diabetes, or obesity, in a mammal in need thereof, comprising:

administering to the mammal a therapeutically effective amount of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 28, 2016
From: NOVARTIS AG
To: XENON PHARMACEUTICALS INC.
Reel/Frame 039876/0645 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2011
From: DALES, NATALIE
To: NOVARTIS AG
Reel/Frame 026414/0413 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 9, 2011
From: FONAREV, JULIA; FU, JIANMIN; KAMBOJ, RAJENDER; KODUMURU, VISHNUMURTHY; LIU, SHIFENG; POKROVSKAIA, NATALIA; RAINA, VANDNA; SUN, SHAOYI; ZHANG, ZAIHUI
To: XENON PHARMACEUTICALS INC.
Reel/Frame 026414/0496 →
Continuity (2)
Provisional Application 60822459 · Aug 15, 2006
Related Publication 20100233116A1 · Sep 16, 2010