IP Library › Granted Patent US 8,258,160

Granted Patent B2

US 8,258,160 · App. 12/520,332 · Granted Sep 4, 2012

SCD1 inhibitors triazole and tetrazole compounds

Assignee: Novartis AG

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Quick Facts

Patent No.: US 8,258,160
App. No.: 12/520,332
Granted: Sep 4, 2012
Kind: B2

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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 (217)

1. A compound represented by the Formula (I):

wherein when Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7 )—;

V is —N(R 7 )C(O)—, —N(R 7 )C(O)O—, —N(R 7 )C(O)N(R 7 )—, —N(R 7 )—, —N(R 7 )S(O) 2 —, —O—, —S—, —S(O) t —, —N(R 7 )S(O) t —, —S(O) 2 N(R 7 )—, —C(O), —OC(O)—, —C(O)O—, —C(O)N(R 7 )—, —OC(O)N(R 7 )—, —C(R 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, —C(═N(R 7a ))N(R 7 )—, an alkenylene group, an alkynylene group, or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

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

R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

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

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, halo, trifluoromethyl, trifluoromethoxyl, cyano, nitro and —N(R 7 ) 2 ;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

each R 7 is the same or different and independents selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, aryl, alkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

R 7a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, and cyano; and

R 8 is hydrogen or alkyl;

wherein when Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7 )—;

V is —S(O) t —, —S(O) 2 N(R 7 )—, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —C(R 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n N(R 7 —, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, or —C(═N(R 7a ))N(R 7 )—, an alkenylene group, an alkynylene group or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

each R 7 is the same or different and independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, -aryl, alkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl; and

R 7a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano;

a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt.

2. The compound according to claim 1 , wherein

Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7 )—;

V is —N(R 7 )C(O)—, —N(R 7 )C(O)O—, —N(R 7 )C(O)N(R 7 )—, —N(R 7 )—, —N(R 7 )S(O) 2 —, —S(O) t —, —S(O) 2 N(R 7 )—, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, —C(═N(R 7a ))N(R 7 )—, an alkenylene group, an alkynylene group or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

each R 7 is the same or different and independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, aryl, alkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl; and

R 7a is selected from the group consisting of hydrogen, alkyl and cycloalkylalkyl and cyano;

a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein:

Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7 )—;

V is selected from —C(O)N(R 7 )—, —S(O) t , —S(O) 2 N(R 7 )—, —C(O)—, —C(O)O—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 )—, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—,—(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxyl, cyano, nitro and —N(R 7 ) 2 ;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl; and

each R 7 is the same or different and independently selected from the group consisting of hydrogen, halo, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl.

4. The compound according to claim 3 , wherein:

W is —N(R 7 )C(O)—;

V is selected from —C(O)—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —C(O)O—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;

R 3 is hydrogen or alkyl;

R 5 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen, halo or hydroxy.

5. The compound according to claim 2 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ia-1) below:

Formula (Ia-1) wherein, W is —N(R 7 )C(O)— or —OC(O)—;

V is —C(O)N(R 7 )—, —C(O)—, —C(O)O—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; R 6 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen, halo or hydroxy.

6. The compound according to claim 2 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ia-3) below:

wherein, W is —N(R 7 )C(O)—;

V is —C(O)N(R 7 )—, C(O)—, —C(O)O—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl;

R 6 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen, halo or hydroxy.

7. The compound according to claim 2 , wherein:

X is CH; Y is S; Q is

which compounds can be represented by Formula (Ib-1) below:

wherein, W is —N(R 7 )C(O)—;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

R 3 is hydrogen or alkyl;

R 6 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen, halo or hydroxy.

8. The compound according to claim 2 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ia-2) below:

wherein, W is —N(R 7 )C(O)—;

V is —C(O)N(R 7 )—, —C(O)—, —C(O)O—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl;

R 6 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen, halo or hydroxy.

9. The compound according to claim 2 , wherein:

Q is

W is —N(R 7 )C(O)—, —C(O)N(R 7 )—;

V is —C(O)N(R 7 )—, —S(O) t —, —S(O) 2 N(R 7 )—, —C(O)—, —C(O)O—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen or alkyl.

10. The compound according to claim 9 , wherein:

W is —N(R 7 )C(O)—;

V is —C(O)—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )— or a direct bond;

R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen or alkyl.

11. The compound according to claim 9 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ia-4) below:

wherein, W is —N(R 7 )C(O)—;

V is —(CR 7 2 ) n O— or a direct bond;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; and

each R 7 is the same or different and independently hydrogen or alkyl.

12. The compound according to claim 9 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ib-3) below:

wherein, W is —N(R 7 )C(O)—;

V is a direct bond;

R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; and

R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen or alkyl.

13. The compound according to claim 9 , wherein:

X is N; Y is S; Q is

which compounds can be represented by Formula (Ia-5) below:

wherein, W is —N(R 7 )C(O)—;

V is a direct bond;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; and

R 2 is selected from the group consisting of hydrogen, alkyl cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 3 is hydrogen or alkyl; and

each R 7 is the same or different and independents hydrogen or alkyl.

14. The compound of claim 2 , wherein:

Q is

W is —N(R 7 )C(O)— or —OC(O)N(R 7 )—;

V is —N(R 7 )C(O)—, —N(R 7 )C(O)—, —N(R 7 )C(O)N(R 7 )—, —N(R 7 )—, —N(R 7 )S(O) 2 —, —S(O) t —, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —(CR 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, or —C(═N(R 7 ))N(R 7 )—, an alkenylene group, an alkynylene group or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxyl, cyano, nitro and —N(R 7 ) 2 ;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

R 7a is selected from the group consisting of hydrogen, alkyl and cycloalkylalkyl, and cyano; and

R 8 is hydrogen or alkyl.

15. A pharmaceutical composition, comprising:

the compound of Formula (I) according to claim 2 and

a pharmaceutically acceptable excipient or carrier.

16. A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of Formula (I):

wherein when Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7 )—;

V is —N(R 7 )C(O)—, —N(R 7 )C(O)O—, —N(R 7 )C(O)N(R 7 )—, —N(R 7 )—, —N(R 7 )S(O) 2 —, —O—, —S—, —S(O) t —, —N(R 7 )S(O) t —, —S(O) 2 N(R 7 )—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R 7 )—, —OC(O)N(R 7 )—, C(R 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O), —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —(CR 7 2 ) n N(R 7 ) n —, —(CR 7 2 ) n N(R 7 )C(O), —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, —C(═N(R 7a ))N(R 7 )—, an alkenylene group, an alkynylene group, or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloakyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

R 7a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl and cyano; and

R 8 is hydrogen or alkyl;

wherein when Q is

W is —N(R 7 )C(O)— or —C(O)N(R 7y —;

V is selected from —S(O—, —S(O) 2 N(R 7 )—, —C(O)—, —C(O)O—, —C(O)N(R 7 )—, —C(R 7 2 ) n C(O)N(R 7 )—, —(CR 7 2 ) n C(O)—, —(CR 7 2 ) n O—, —(CR 7 2 ) n —, —(C R 7 2 ) n N(R 7 )—, —(CR 7 2 ) n N(R 7 )C(O)—, —(CR 7 2 ) n N(R 7 )C(O)N(R 7 )—, —C(═N(R 7a ))N(R 7 )—, an alkenylene group, an alkynylene group or a direct bond;

X is N;

Y is S;

t is 1 or 2;

n is 1-6;

R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl and aralkyl;

each R 7 is the same or different and independents selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -aryl, alkoxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl and aralkyl; and

R 7a is selected from the group consisting of hydrogen, alkyl, cycloalkylalkyl, and cyano;

a stereoisomer, enantiomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. A method of treating Type II diabetes or obesity mediated by stearoyl-CoA desaturase (SCD) in a mammal, comprising:

administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) according to claim 1 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 6, 2011

From: DALES, NATALIE; ZHANG, ZAIHUI; FONAREV, JULIA; FU, JIANMIN; KAMBOJ, RAJENDER; KODUMURU, VISHNUMURTHY; POKROVSKAIA, NATALIA; SUN, SHAOYI

To: NOVARTIS AG; XENON PHARMACEUTICALS INC.

Reel/Frame 026549/0159 →

Continuity (2)

Provisional Application 60870919 · Dec 20, 2006

Related Publication 20100029722A1 · Feb 4, 2010