Piperazine derivatives as liver X receptor modulators

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Q is:

1) R 10 OC(═O)—;

2) a heteroaryl ring optionally substituted with 1 to 3 groups independently selected from R 21 ;

3) a group of formula R 30 -L, wherein R 30 is optionally substituted with 1 to 3 groups independently selected from R 31 ; or

4) a group of formula R 40 -L, wherein R 40 is optionally substituted with 1 to 3 groups independently selected from R 41 ;

R 1 is selected from (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkylalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, aryl(C 1 -C 3 )alkylamino and {aryl(C 1 -C 3 )alkyl}{(C 1 -C 6 ) alkyl}amino, wherein the aryl groups are optionally substituted with 1 to 3 groups independently selected from halogen, cyano, CONH 2 , (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy;

R 2 is selected from hydrogen, halogen, cyano, CONH 2 , hydroxy(C 1 -C 3 )alkyl, amino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylcarbonyl(C 1 -C 3 )alkyl and (C 1 -C 3 )alkylcarbonylamino(C 1 -C 3 )alkyl; or R 2 is a 5-membered heteroaryl, optionally substituted with 1 or 2 groups independently selected from halogen, cyano, methyl, CF 3 , methoxy, methoxycarbonyl, ethoxycarbonyl and CONH 2 ;

R 3 is (1) (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl or (C 1 -C 6 )alkoxycarbonyl(C 1 -C 3 )alkyl, or cyano(C 1 -C 6 )alkyl; or (2) aryl, heteroaryl, aryl(C 1 -C 3 )alkyl or heteroaryl(C 1 -C 3 )alkyl, each optionally substituted with 1 to 3 substituents selected from halogen, cyano, (C 1 -C 3 )alkyl, CF 3 , methoxy and CONH 2 ;

R 4 is hydrogen or (C 1 -C 6 )alkyl;

R 10 is selected from (C 1 -C 8 )alkyl, aryl(C 1 -C 3 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl, halo(C 3 -C 7 )cycloalkyl and halo(C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl;

R 30 is an aryl or a monocyclic 5- or 6-membered heteroaromatic radical containing 1-4 heteroatoms independently selected from N, O, and S;

R 40 is (C 4 -C 7 )cycloalkyl or heterocyclyl;

R 21 , R 31 , and R 41 are each independently selected from halogen, hydroxy, amino, nitro, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )haloalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )haloalkyl, (C 1 -C 6 )alkylthio, halo(C 1 -C 6 )alkylthio, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, cyano(C 1 -C 6 )alkyl, CO 2 H, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )haloalkylsulfonyl, (C 1 -C 3 )alkylsulfonyl(C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkylsulfonyl(C 1 -C 3 )alkyl, heterocyclyl, R 22 R 23 NCO, R 22 R 23 NCO(C 1 -C 3 )alkyl, R 22 CONH, R 22 CONH(C 1 -C 3 )alkyl, R 22 SO 2 NH, R 22 SO 2 NH(C 1 -C 3 )alkyl, R 22 R 23 N, R 22 R 23 N(C 1 -C 3 )alkyl and aryl(C 1 -C 3 )alkyl, wherein aryl(C 1 -C 3 )alkyl is optionally substituted by R 25 ;

R 22 is selected from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonylamino(C 1 -C 6 )alkyl and heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 groups independently selected from R 24 ;

R 23 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkyl; or R 22 and R 23 , together with the nitrogen to which they are attached, form an azetidine, pyrrolidine, piperidine, piperazine or morpholine ring, each optionally substituted by 1 or 2 groups independently selected from R 24 ;

R 24 is selected from halogen, hydroxy, amino (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy and (C 1 -C 6 )alkoxycarbonyl;

R 25 is hydroxy(C 1 -C 6 )alkyl or CO 2 H;

L is CH 2 , CHCH 3 or C(CH 3 ) 2 ; and

Y is hydrogen, halogen, cyano, (C 1 -C 3 )alkyl, methyl, haloalkyl, or methoxy.

2. The compound of claim 1 , wherein

Q is

1) R 10 OC(═O)—;

2) 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 2-thiazolyl, 1,3,4-thiadiazol-2-yl, 2-pyridon-4-yl, 2-benzoxazolyl, 2-benzothiazolyl, thiazolo[4,5-b]pyridin-2-yl, thiazolo[4,5-c]pyridin-2-yl, thiazolo[5,4-c]pyridin-2-yl or thiazolo[5,4-b]pyridin-2-yl, each optionally substituted by one to three groups independently selected from R 21 ;

3) phenylCH 2 , phenylCHMe, pyridylCH 2 , furanylCH 2 , each optionally substituted with one to three substituents independently selected from R 31 ; or

4) cyclohexylCH 2 , bicyclo[3.1.0]hexylCH 2 , spiro[2.5]octylCH 2 , piperidinylCH 2 , pyrrolidinylCH 2 and tetrahydropyranylCH 2 , each optionally substituted with one to three substituents independently selected from R 41 ;

R 1 is selected from Me, —NH 2 , —NHMe, and —NMe-4-methoxybenzyl;

R 2 is selected from (1) H, F, Cl, CN, CF 3 , CH 2 OH, CH 2 NH 2 , CONH 2 , CH 2 OAc, CH 2 OMe, and CH 2 NHAc or (2) 2-oxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl and 1,3,4-thiadiazol-2-yl each of which is optionally substituted with a group selected from methyl, cyano, ethoxycarbonyl and CONH 2 ;

Y is H, F or Cl;

R 3 is selected from i-Pr, i-Bu, t-Bu, CF 3 , CF 2 Me, CH 2 CMe 2 F, CH 2 CF 3 , CH(OMe)Me, c-Pr, c-hexyl, phenyl, 2-Cl-phenyl, 2-Br-phenyl, 2-Me-phenyl, 3-Cl-phenyl, 3-Me-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-Br-phenyl, benzyl, 4-methyl-2-thiazolyl, CO 2 Me, CMe 2 OH and CH 2 CMe 2 OH;

R 4 is H or methyl;

R 10 is selected from i-Pr, t-Bu, i-Bu, t-BuCH 2 , benzyl, CF 3 CH 2 , CF 3 CHMe, CF 3 CMe 2 , and 2,2,3,3-tetrafluorocyclobutyl;

R 21 is selected from F, Cl, Br, CN, NO 2 , NH 2 , OH, Me, i-Pr, c-Pr, C(═CH 2 )Me, CHF 2 , CF 3 , CF 2 Me, OMe, Oi-Pr, OCHF 2 , OCH 2 CF 3 , CH 2 OH, CH(OH)Me, CH(OH)Et, CH(OH)CF 3 , CMe 2 OH, CMe(OH)CF 3 , CH(OMe)CF 3 , CMe 2 CN, C(═O)H, C(═O)Me, SO 2 Me, CO 2 H, CO 2 Me, CO 2 Et, CONR 22 R 23 , CH 2 NR 22 R 23 , CH 2 NHAc, CH 2 SMe, CH 2 NHSO 2 Me, CH 2 C 6 H 4 R 25 and 4,4-dimethyl-2-oxazolidinyl;

R 22 is selected from H, Me, Et, n-Bu, t-Bu, CH 2 CH 2 OH, CH 2 CH 2 OMe, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CMe 2 OH, CH 2 CH 2 CH 2 OMe, CH 2 CO 2 Et, CH 2 CH 2 CO 2 Et; CH 2 CH 2 CH 2 NHCO 2 Me, CH 2 CH 2 CH 2 NHCO 2 t-Bu, and N-t-BuOC(═O)-3-azetidinyl;

R 23 is hydrogen, methyl, ethyl or methoxy; or R 22 and R 23 , together with the nitrogen to which they are attached, form an azetidine or morpholine ring, each optionally substituted by one or two groups independently selected from R 24 ;

R 24 is F, OH, OMe, or NH 2 ;

R 25 is CO 2 H or CMe 2 OH;

R 31 is selected from F, Cl, Br, Me, i-Pr, CF 3 , OCHF 2 , OCF 3 , CMe(OH)CF 3 , CO 2 Me and CMe 2 OH; and

R 41 is selected from F, OH, OMe, Me, i-Pr, CHF 2 , CF 3 , CH 2 CF 3 , CF 2 CH 3 , and CMe 2 OH.

3. The compound of claim 1 , wherein

Q is pyridyl or pyrimidinyl, each being substituted with one or two groups independently selected from R 21 ;

R 1 is selected from methyl, NH 2 and NHMe;

R 2 is H, F or CH 2 OH; Y is H;

R 3 is i-Pr; and

R 4 is H.

4. The compound of claim 1 , wherein

Q is 2-pyridyl or 2-pyrimidinyl, each being substituted with one CF 3 group and optionally substituted with a second group selected from R 21 ; and

R 1 is methyl.

5. The compound of claim 1 , wherein at least one R 21 is a hydroxy(C 1 -C 4 )alkyl group.

6. The compound of claim 1 , wherein

Q is phenylCH 2 or pyridylCH 2 , each being optionally substituted with one to three substituents independently selected from R 31 ;

R 1 is methyl, NH 2 or NHMe;

R 2 is H, F or CH 2 OH;

Y is H;

R 3 is selected from i-Pr, phenyl and halophenyl; and

R 4 is H.

7. The compound of claim 1 , wherein

Q is phenylCH 2 or 3-pyridylCH 2 , each being substituted with one CF 3 group and optionally substituted with one other group selected from R 31 ;

R 1 is methyl; and

R 3 is isopropyl.

8. The compound of claim 1 , wherein

Q is cyclohexylCH 2 , piperidinylCH 2 or tetrahydropyranylCH 2 , each being optionally substituted with one to three substituents independently selected from R 41 ;

R 1 is methyl, NH 2 or NHMe;

R 2 is H, F or CH 2 OH;

Y is H;

R 3 is isopropyl, phenyl or halophenyl; and

R 4 is H.

9. The compound of claim 1 , wherein

Q is cyclohexylCH 2 , 3-piperidinylCH 2 , or 3-tetrahydropyranylCH 2 , each being substituted with one CF 3 group and optionally substituted with one other group selected from R 41 ;

R 1 is methyl; and

R 3 is isopropyl.

10. The compound of claim 1 , wherein the compound is of the Formula Ia or Ib:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is represented by structural Formula Ic or Id:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

12. The compound of claim 1 , wherein the compound is represented by structural Formula IIc:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; and A is CH 2 , NH, NMe or 0.

13. A pharmaceutical composition comprising a pharmaceutical carrier or diluent and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is represented by structural Formula Ie or If:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is represented by structural Formula Ig:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

16. The compound of claim 1 , wherein the compound is represented by structural Formula III:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

17. The compound of claim 1 , wherein the compound is represented by structural Formula Ii:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3.

18. The compound of claim 1 , wherein the compound is represented by structural Formula Ij:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound is represented by structural Formula Il:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2; and A is CH 2 , NH, NMe or O.

20. The compound of claim 1 , wherein the compound is represented by structural Formula Im:

or a pharmaceutically acceptable salt thereof, wherein A is CH 2 , NH, NMe or O.

21. The compound of claim 1 , wherein the compound is represented by structural Formula In:

or a pharmaceutically acceptable salt thereof, wherein A is CH 2 , NH, NMe or O.

22. The compound of claim 1 , wherein the compound is represented by structural Formula Io:

or a pharmaceutically acceptable salt thereof, wherein A is CH 2 , NH, NMe or O.

23. The compound of claim 1 , wherein the compound is represented by structural Formula Ip:

or a pharmaceutically acceptable salt thereof.