Substituted quinoxalines, their preparation and their therapeutical use as 11βHSD1 modulators

1. A compound of formula (I):

wherein:

X is NR 2a , NR 2b , NR 2c or NR 2d ;

R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are, independently, hydrogen, halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, hydroxy(C 1 -C 5 )alkyl, cyano, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 )alkyl, R 6 R 7 N—(C 1 -C 5 )alkyl, —CONR 6 R 7 , R 6 R 7 NCO—(C 1 -C 5 )alkyl, —SO 2 NR 6 R 7 , —COR 5 , aryl, heteroaryl, aryl(C 1 -C 5 )alkyl, heteroaryl(C 1 -C 5 )alkyl or heterocycloalkyl(C 1 -C 5 )alkyl, wherein the aryl or heteroaryl moiety is optionally substituted by 1 to 3 times by cyano, COOR 5 , CONR 6 R 7 , SO 2 R 5 , (C 1 -C 5 )alkoxy, OCH 2 CONR 6 R 7 , halogen, or (C 1 -C 5 )haloalkyl, and when one or more of R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are aryl(C 1 -C 5 )alkyl, then one of the aryl(C 1 -C 5 )alkyl is additionally optionally substituted by heteroaryl;

R 3a and R 3b are, independently, hydrogen, fluorine, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, alkoxy(C 1 -C 5 )alkyl, hydroxyl, hydroxy(C 1 -C 5 )alkyl, (C 1 -C 5 )haloalkyl, cyano, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 )alkyl, R 6 R 7 N—(C 1 -C 5 )alkyl, —CONR 6 R 7 or R 6 R 7 NCO—(C 1 -C 5 )alkyl;

R 4 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, mono- or bicyclic aryl having from 5 to 10 carbon atoms, or mono- or bicyclic heteroaryl having from 2 to 9 carbon atoms, wherein when R 4 is aryl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1 to 4 times by halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, hydroxy(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy(C 1 -C 5 )alkyl, cyano, optionally substituted phenyl, optionally substituted benzyl, —COOR 5 , —NR 6 R 7 , R 5 OOC—(C 1 -C 5 )alkyl, R 6 R 7 N—(C 1 -C 5 )alkyl, —CONR 6 R 7 or —SO 2 NR 6 R 7 , or

when two of R 3a , R 3b and R 4 are carried by the same carbon atom, they can form together with the carbon atom to which they are attached a spiro ring of formula a), b), c) or d):

wherein:

is a single bond or a double bond;

s is 0, 1, 2 or 3,

t is 0, 1, 2 or 3, provided that s and t are not 0 at the same time;

R 8 is hydrogen, halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, trifluoromethyl, hydroxyl, hydroxymethyl, cyano, —COOR 5 , or —NR 6 R 7 ;

R 9 is hydrogen, (C 1 -C 5 )alkyl or hydroxyl;

Y is a bond, carbon or nitrogen;

n is 0 or 1;

o, p, q and r are, independently, 0, 1 or 2;

i and j are 0, 1, 2, 3 or 4;

R 5 is hydrogen, (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, or halo(C 1 -C 5 )alkyl; and

R 6 and R 7 are, independently, hydrogen, (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 5 )alkylcarbonyl, hydroxymethyl(C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxymethyl(C 1 -C 5 )alkyl, aryl, optionally substituted heterocycloalkyl, or —SO 2 R 5 , or

R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl;

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1 , wherein:

R 3a , R 3b and R 4 are carried by different carbon atoms;

or a pharmaceutically acceptable acid addition salt thereof.

3. The compound according to claim 1 , wherein:

two of R 3a , R 3b and R 4 are carried by the same carbon atom but do not form a spiro group;

or a pharmaceutically acceptable acid addition salt thereof.

4. The compound according to claim 1 , wherein:

R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are, independently, hydrogen, halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl or hydroxy(C 1 -C 5 )alkyl, —COOR 5 , —CONR 6 R 7 , —SO 2 NR 6 R 7 , —COR 5 , aryl, heteroaryl, aryl(C 1 -C 5 )alkyl, heteroaryl(C 1 -C 5 )alkyl or heterocycloalkyl(C 1 -C 5 )alkyl, wherein the aryl or heteroaryl moiety is optionally substituted by 1 to 3 times by cyano, COOR 5 , CONR 6 R 7 , SO 2 R 5 , (C 1 -C 5 )alkoxy, OCH 2 CONR 6 R 7 , halogen, or (C 1 -C 5 )haloalkyl, and when one or more of R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are aryl(C 1 -C 5 )alkyl, then one of the aryl(C 1 -C 5 )alkyl is additionally optionally substituted by heteroaryl;

R 3a and R 3b are hydrogen;

R 4 is (C 1 -C 5 )alkyl,

(C 3 -C 6 )cycloalkyl,

heterocycloalkyl,

a monocyclic aryl group having from 5 to 6 carbon atoms, or a monocyclic heteroaryl group having from 2 to 5 carbon atoms,

wherein when R 4 is aryl, heteroaryl, or heterocycloalkyl, it is optionally substituted by 1 to 2 times by halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, cyano, optionally substituted phenyl, optionally substituted benzyl, or —CONR 6 R 7 ;

o, p, q and r are , independently, 0 or 1;

i and j are 0 or 1;

R 5 is hydrogen or (C 1 -C 5 )alkyl; and

R 6 and R 7 are, independently, hydrogen, (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl or heterocycloalkyl, or

R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl;

or a pharmaceutically acceptable acid addition salt thereof.

5. The compound according to claim 1 , wherein:

R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are, independently, hydrogen, halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, hydroxy(C 1 -C 5 )alkyl, —COOR 5 , —CONR 6 R 7 , —SO 2 NR 6 R 7 , —COR 5 , aryl, heteroaryl, aryl(C 1 -C 5 )alkyl, heteroaryl(C 1 -C 5 )alkyl or heterocycloalkyl(C 1 -C 5 )alkyl, wherein the aryl or heteroaryl moiety is optionally substituted by 1 to 3 times by cyano, COOR 5 , CONR 6 R 7 , SO 2 R 5 , (C 1 -C 5 )alkoxy, OCH 2 CONR 6 R 7 , halogen, or (C 1 -C 5 )haloalkyl, and when one or more of R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are aryl(C 1 -C 5 )alkyl, then one of the aryl(C 1 -C 5 )alkyl is additionally optionally substituted by heteroaryl;

R 3a and R 3b are hydrogen or hydroxyl;

R 4 is (C 1 -C 5 )alkyl,

(C 3 -C 6 )cycloalkyl,

heterocycloalkyl,

a monocyclic aryl group having from 5 to 6 carbon atoms, or a monocyclic heteroaryl group having from 2 to 5 carbon atoms,

wherein when R 4 is aryl, heteroaryl or heterocycloalkyl, it is optionally substituted by 1 to 2 times by halogen, (C 1 -C 5 )alkyl, (C 1 -C 5 )alkoxy, (C 1 -C 5 )haloalkyl, hydroxyl, cyano, optionally substituted phenyl, optionally substituted benzyl, or —CONR 6 R 7 ;

o, p, q and r are, independently, 0 or 1;

i and j are 0 or 1;

R 5 is hydrogen, or (C 1 -C 5 )alkyl; and

R 6 and R 7 are, independently, hydrogen, (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl or heterocycloalkyl, or

R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl;

or a pharmaceutically acceptable acid addition salt thereof.

6. The compound according to claim 1 of formula

wherein:

p and r are 1;

o and q are 0;

i and j are 1 or 2;

n is 0 or 1;

R 1a , R 1b , R 1c , and R 1d are hydrogen, or one of R 1a , R 1b , R 1c , and R 1d is halogen and the others are hydrogen;

R 2a and R 2b are hydrogen, or one of R 2a and R 2b is (C 1 -C 5 )alkyl, and the other is hydrogen;

R 3a and R 3b are hydrogen; and

R 4 is pyridine, pyrazine, pyrazole, oxadiazole, thiazole, or imidazole;

or a pharmaceutically acceptable acid addition salt thereof.

7. The compound according to claim 1 of formula

wherein:

n is 0; and

R 4 is pyrazole or pyridine;

or a pharmaceutically acceptable acid addition salt thereof.

8. The compound according to claim 1 of formula

wherein:

n is 0 or 1;

i is 1; and

R 3a is cyano or (C 1 -C 5 )alkoxy;

or a pharmaceutically acceptable acid addition salt thereof.

9. The compound according to claim 1 of formula

wherein:

R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c and R 2d are hydrogen;

i is 1; and

R 3a and R 4 together with the carbon atom to which they are attached, form one of the following optionally substituted groups at the spiro position:

or a pharmaceutically acceptable acid addition salt thereof.

10. The compound according to claim 1 of formula

wherein:

n is 0;

p is 1;

r, q and o are 0;

R 2a is carried by X, and is aryl optionally substituted by CONR 6 R 7 or OCH 2 CONR 6 R 7 ; and

R 4 is pyrazole or pyridine;

or a pharmaceutically acceptable acid addition salt thereof.

11. A process for preparing the compound according to claim 1 , comprising reacting a compound of formula (IV):

wherein R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , o, p, q and r are as defined in claim 1 , and Lg is a leaving group,

with a compound of formula (V)

wherein i, j, n, R 3a , R 3b and R 4 are as defined in claim 1 , optionally in the presence of a base at a temperature varying from ambient temperature to 100° C.

12. A process for preparing the compound according to claim 1 , comprising hydrogenating a compound of formula (XV):

wherein i, j, n, o, p, q, r, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d , R 3a , R 3b and R 4 are as defined in claim 1 .

13. A process for preparing the compound according to claim 1 , wherein R 3a and R 4 are at the 4-position, and R 3a is cyano, comprising reacting a compound of formula (XX):

wherein j, n, o, p, q, r, R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , R 2c , R 2d and R 3b are as defined in claim 1 ,

with a compound of formula (XXI) Lg-R 4 wherein R 4 is as defined in claim 1 , and Lg is a leaving group.