Niacin receptor agonists, compositions containing such compounds and methods of treatment

1 . A compound represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof is disclosed wherein:

X represents CH 2 , O, S, S(O), SO 2 or NH, such that when X represents NH, the nitrogen atom may be optionally substituted with R 6 , C(O)R 6 , or SO 2 R 6 , wherein:

R 6 represents C 1-3 alkyl optionally substituted with 1-3 groups, 0-3 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-3 alkyl, OH, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CN, Hetcy, Aryl and HAR,

said Aryl and HAR being further optionally substituted with 1-3 groups, 1-3 of which are halo, and 0-1 of which are selected from the group consisting of: OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy groups;

a and b are each integers 1, 2 or 3, such that the sum of a and b is 2, 3 or 4;

ring A represents a 6-10 membered aryl, a 5-13 membered heteroaryl or a partially aromatic heterocyclic group, said heteroaryl and partially aromatic heterocyclic group containing at least one heteroatom selected from O, S, S(O), S(O) 2 and N, and optionally containing 1 other heteroatom selected from O and S, and optionally containing 1-3 additional N atoms, with up to 5 heteroatoms being present;

each R 2 and R 3 is independently H, C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkoxy, OH or F;

n represents an integer of from 1 to 5;

each R 4 is H or is independently selected from halo and R 6 ;

R 5 represents —CO 2 H,

 or —C(O)NHSO 2 R e wherein R e represents C 1-4 alkyl or phenyl, said C 1-4 alkyl and phenyl each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo and C 1-3 alkyl, and 1-2 of which are selected from the group consisting of: OC 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, OH, NH 2 and NHC 1-3 alkyl;

and each R 1 is H or is independently selected from the group consisting of:

a) halo, OH, CO 2 H, CN, NH 2 , S(O) 0-2 R e , C(O)RC, OC(O)R e and CO 2 R e , wherein R e is as previously defined;

b) C 1-6 alkyl and OC 1-4 alkyl, said C 1 -alkyl and alkyl portion of OC 1-4 alkyl being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, OCO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , Hetcy and CN;

c) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above;

d) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)Hetcy, C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in (b) above;

e) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,

R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl or haloC 1-4 alkoxy groups; or

(b) Hetcy, Aryl or HAR, each being optionally substituted with 1-3 members selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;

and R′″ representing H or R″;

f) phenyl or a 5-6 membered heteroaryl or a Hetcy group attached at any available ring atom and each being optionally substituted with 1-3 groups, 1-3 of which are selected from halo, C 1-3 alkyl and haloC 1-3 alkyl groups, and 1-2 of which are selected from OC 1-3 alkyl and haloOC 1-3 alkyl groups, and 0-1 of which is selected from the group consisting of:

i) OH; CO 2 H; CN; NH 2 and S(O) 0-2 R e wherein R e is as described above;

ii) NHC 1-4 alkyl and N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;

iii) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NHOC 1-4 alkyl and C(O)N(C 1-4 alkyl)(OC 1-4 alkyl), the alkyl portions of which are optionally substituted as set forth in b) above; and

iv) NR′C(O)R″, NR′SO 2 R″, NR′CO 2 R″ and NR′C(O)NR″R′″ wherein R′, R″ and R′″ are as described above.

2 . A compound in accordance with claim 1 wherein up to 4 R 2 and R 3 moieties are selected from the group consisting of: C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkoxy, OH and F, and any remaining R 2 and R 3 moieties represent H.

3 . A compound in accordance with claim 1 wherein ring A is a phenyl or naphthyl group, a 5-6 membered monocyclic heteroaryl group or a 9-13 membered bicyclic or tricyclic heteroaryl group.

4 . A compound in accordance with claim 3 wherein ring A is selected from the group consisting of: phenyl; naphthyl; HAR which represents a member selected from the group consisting of: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benzotriazolyl, furo(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, quinolyl, isoquinolyl, indolyl, dihydroindolyl, quinoxalinyl, quinazolinyl, naphthyridinyl, pteridinyl, 2,3-dihydrofuro(2,3-b)pyridyl indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, or a member selected from the group consisting of:

5 . A compound in accordance with claim 4 wherein ring A is selected from the group consisting of: phenyl; naphthyl; and

HAR which is a member selected from the group consisting of: isoxazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, thienyl, benzothiazolyl, and a member selected from the group consisting of:

6 . A compound in accordance with claim 1 wherein each R 1 is H or is selected from the group consisting of:

a) halo, OH, CN, NH 2 and S(O) 0-2 R e wherein R 1 is methyl or phenyl optionally substituted with 1-3 halo groups;

b) C 1-3 alkyl and OC 1-3 alkyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, NH 2 , NHC 1-4 alkyl and CN;

c) NR′SO 2 R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,

R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, OCO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1-3 groups selected from: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being optionally substituted with 1-3 groups selected from: halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy;

and R′″ representing H or R″; and

d) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attached at any available point and being optionally substituted with 1-3 groups, 1-3 of which are halo, C 1-3 alkyl or haloC 1-3 alkyl groups, 1-2 of which are OC 1-3 alkyl or haloOC 1-3 alkyl groups, and 1 of which is selected from the group consisting of:

i) OH; CO 2 H; CN; NH 2 and S(O) 0-2 R e wherein R e is as described above;

ii) NHC 1-4 alkyl, the alkyl portion of which is optionally substituted with 1-3 groups, 1-3 of which are halo and 1 of which is selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;

iii) C(O)NH 2 , C(O)NHC 1-4 alkyl and C(O)N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above; and

iv) NR′C(O)R″ and NR′SO 2 R″ wherein R′ and R″ are as described above.

7 . A compound in accordance with claim 6 wherein each R 1 is H or is selected from the group consisting of:

a) halo, OH, CN and NH 2

b) C 1-3 alkyl and OC 1-3 alkyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, NH 2 , NHC 1-4 alkyl and CN;

c) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attached at any available point and being optionally substituted with 1-3 groups, 1-3 of which are halo, C 1-3 alkyl or haloC 1-3 alkyl groups, 1-2 of which are OC 1-3 alkyl or haloOC 1-3 alkyl groups, and 1 of which is selected from the group consisting of:

i) OH, CN and NH 2 .

8 . A compound in accordance with claim 1 wherein a and b are 1 or 2 such that the sum of a and b is 2 or 3.

9 . A compound in accordance with claim 1 wherein X represents O, S, N or CH 2 .

10 . A compound in accordance with claim 9 wherein X represents O or CH 2 .

11 . A compound in accordance with claim 1 wherein R 2 and R 3 are independently H, C 1-3 alkyl, OH or haloC 1-3 alkyl.

12 . A compound in accordance with claim 11 wherein R 2 and R 3 are independently H, C 1-3 alkyl or haloC 1-3 alkyl.

13 . A compound in accordance with claim 12 wherein R 2 and R 3 are independently H or methyl.

14 . A compound in accordance with claim 1 wherein n represents an integer of from 2 to 4.

15 . A compound in accordance with claim 14 wherein n is 2.

16 . A compound in accordance with claim 1 wherein each R 4 is H or is independently selected from the group consisting of: halo, C 1-3 alkyl optionally substituted with 1-3 halo groups or 0-1 OC 1-3 alkyl groups.

17 . A compound in accordance with claim 16 wherein each R 4 is H or is independently selected from halo or C 1-3 alkyl optionally substituted with 1-3 halo groups.

18 . A compound in accordance with claim 1 wherein R 5 represents —CO 2 H.

19 . A compound in accordance with claim 1 wherein:

ring A is a phenyl or naphthyl group, a 5-6 membered monocyclic heteroaryl group or a 9-13 membered bicyclic or tricyclic heteroaryl group;

each R 1 is H or is selected from the group consisting of:

a) halo, OH, CN, NH 2 and S(O) 0-2 R e wherein R e is methyl or phenyl optionally substituted with 1-3 halo groups;

b) C 1-3 alkyl and OC 1-3 alkyl, each being optionally substituted with 1-3 groups, 1-3 of which are halo and 1-2 of which are selected from: OH, NH 2 , NHC 1-4 alkyl and CN;

c) NR′SO 2 R″ and NR′C(O)NR″R′″ wherein:

R′ represents H, C 1-3 alkyl or haloC 1-3 alkyl,

R″ represents (a) C 1-8 alkyl optionally substituted with 1-4 groups, 0-4 of which are halo, and 0-1 of which are selected from the group consisting of: OC 1-6 alkyl, OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, OCO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, Hetcy, Aryl and HAR,

said Hetcy, Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;

(b) Hetcy, Aryl or HAR, said Aryl and HAR being further optionally substituted with 1-3 halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl and haloC 1-4 alkoxy groups;

and R′″ representing H or R″; and

d) phenyl or a 5-6 membered heteroaryl or a heterocyclic group attached at any available point and being optionally substituted with 1-3 groups, 1-3 of which are halo, C 1-3 alkyl or haloC 1-3 alkyl groups, 1-2 of which are OC 1-3 alkyl or haloOC 1-3 alkyl groups, and 1 of which is selected from the group consisting of:

i) OH; CO 2 H; CN; NH 2 ; S(O) 0-2 R e wherein R e is as described above;

ii) NHC 1-4 alkyl the alkyl portion of which is optionally substituted with 1-3 groups, 1-3 of which are halo and 1 of which is selected from: OH, CO 2 H, CO 2 C 1-4 alkyl, CO 2 C 1-4 haloalkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 and CN;

iii) C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , the alkyl portions of which are optionally substituted as set forth in (b) above; and

iv) NR′C(O)R″ and NR′SO 2 R″ wherein R′ and R″ are as described above;

a and b are 1 or 2 such that the sum of a and b is 2 or 3;

X represents O or CH 2 ;

R 2 and R 3 are independently H, OH, C 1-3 alkyl or haloC 1-3 alkyl;

n represents 2;

R 4 is H or is independently selected from the group consisting of: halo, C 1-3 alkyl optionally substituted with 1-3 halo groups or 0-1 OC 1-3 alkyl groups; and

R 5 represents —CO 2 H.

20 . A compound in accordance with claim 1 wherein:

ring A is selected from the group consisting of:

each R 1 is independently H, CH 3 , phenyl, 4-hydroxy-phenyl, OH, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 3-amino-phenyl, 2,3-dihydro-benzofuran-6-yl, 2-chloro-4-hydroxy-phenyl, 1H-pyrazol-4-yl, 5-hydroxy-pyridin-2-yl, 4-hydroxy-pyrazol-1-yl, 1H-[1,2,3]triazol-4-yl, or 5-fluoro-pyridin-2-yl;

a and b are 1 or 2 such that the sum of a and b is 2 or 3;

X represents CH 2 ;

each R 2 and R 3 is independently H, OH or CH 3 ;

n represents 2;

R 4 is H, CH 3 , CH 2 CH 3 , CF 3 or CH 2 OCH 3 ; and

R 5 represents —CO 2 H.

21 . A compound in accordance with claim 1 selected from the following table:

TABLE 1

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

or a pharmaceutically acceptable salt or solvate thereof.

22 . A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

23 . A method of treating atherosclerosis in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating atherosclerosis.

24 . A method of treating dyslipidemia in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating dyslipidemias.

25 . A method of treating diabetes in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating diabetes.

26 . A method of treating metabolic syndrome in a human patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating metabolic syndrome.

27 . A method of treating atherosclerosis, dyslipidemias, diabetes, metabolic syndrome or a related condition in a human patient in need of such treatment, comprising administering to the patient a compound of claim 1 and a DP receptor antagonist, said compounds being administered in an amount that is effective to treat atherosclerosis, dyslipidemia, diabetes or a related condition in the absence of substantial flushing.

28 . A method in accordance with claim 27 wherein the DP receptor antagonist selected from the group consisting of compounds A through AJ: