Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment

1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof wherein:

ring B is selected from the group consisting of: phenyl, pyridyl, pyrazolyl, thiadiazolyl, benzisoxazolyl, benzthiazolyl; benzopyrazinyl; pyrimidinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl and tetrahydronaphthyl;

each R a is defined as follows:

a) each R a is H or halo, or

b) 1-2 R a groups represent H or halo,

0-1 R a represents Aryl, HAR or Hetcy, each of which being optionally substituted with 1-3 halo, C 1-3 alkyl or haloC 1-3 alkyl groups, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl;

and any remaining R a groups are selected from the group consisting of: C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl, OhaloC 1-3 alkyl, S(O) x C 1-3 alkyl, S(O) x -haloC 1-3 alkyl, S(O) x Aryl wherein x is 0, 1 or 2, CO 2 R b and C 1-3 alkyl-CO 2 R b , wherein R b is H, C 1-4 alkyl, haloC 1-4 alkyl, Aryl, HAR or Hetcy;

R 1 is selected from the group consisting of:

a) CO 2 R d in which R d represents H, C 1-3 alkyl-R e , Aryl, HAR or Hetcy, wherein R e is selected from the group consisting of: H, OC 1-3 alkyl, halo, OhaloC 1-3 alkyl, S(O) x C 1-3 alkyl, S(O) x haloC 1-3 alkyl, Aryl, HAR, Hetcy, S(O) X -Aryl and CO 2 R b ;

b) halo or CN;

c) C 1-6 alkyl or OC 1-6 alkyl, each optionally substituted with up to 3 halo groups, and a member selected from the group consisting of:

i) CN, C(O)NH 2 , C(O)NHCH 3 or C(O)N(CH 3 ) 2 ;

ii) CO 2 R d with R d as previously defined in a) above;

iii) OH, OC 1-3 alkyl, haloOC 1-3 alkyl, NH 2 , NHCH 3 or N(CH 3 ) 2 ; and

iv) Aryl or HAR, each being optionally substituted with 1-3 halo, C 1-3 alkyl or haloC 1-3 alkyl groups, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl; and

d) Aryl or HAR, each optionally substituted with 1-2 halo, C 1-3 alkyl, haloC 1-3 alkyl, OC 1-3 alkyl, OhaloC 1-3 alkyl or Aryl(R a ) 3 groups and 0-1 members selected from the group consisting of: CN, HAR(R a ) 3 , CO 2 C 1-6 alkyl, CO 2 H, C(O)N(R f ) 2 , NHC(O)N(R f ) 2 and NHC(O)OR g wherein each R f is H or C 1-6 alkyl and each R g represents C 1-3 alkyl, haloC 1-3 alkyl, Aryl, HAR or Hetcy;

R 2 is selected from the group consisting of: —(CR h 2 ) 0-2 —Y—(CR h 2 ) 0-2 -Aryl(R a ) 3 , and —(CR h 2 ) 0-2 —Y—(CR h 2 ) 0-2 —HAR(R a ) 3 ,

wherein Y represents a bond, CH 2 , O, S(O) x , C(O)NR f , NR f C(O), C(O) or NR f C(O)O; x, and R f are as previously defined and R h represents a member selected from the group consisting of: H, C 1-3 alkyl, OC 1-3 alkyl and halo;

and each R 3 is selected from the group consisting of: H, halo, C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl and OhaloC 1-3 alkyl, or one R 3 group is selected from d) above, and the other two R 3 groups represent H, halo, C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl, OhaloC 1-3 alkyl, CO 2 R b or C(O)NHR b .

2. A compound in accordance with claim 1 wherein: C 0-5 alkyl is selected from: a direct bond; —CH 2 —; —(CH 2 ) 2 —; —(CH 2 ) 3 —; —(CH 2 ) 4 —;

3. A compound in accordance with claim 1 wherein: each R a is defined as follows:

a) each R a is H or halo which is F or Cl, or

b) 1-2 R a groups represent H or halo which is F or Cl,

0-1 R a represents phenyl, or a 5-10 membered heteroaryl group having 1-2 N atoms, each of which being optionally substituted with 1-3 halo, C 1-3 alkyl or haloC 1-3 alkyl groups, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl;

and any remaining R a groups are selected from the group consisting of: C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl and OhaloC 1-3 alkyl.

4. A compound in accordance with claim 1 wherein:

R 1 is selected from the group consisting of:

a) CO 2 R d in which R d represents H or C 1-3 alkyl-R e , wherein R e represents H or Aryl;

b) CN or halo, which is F or Cl;

c) C 1-6 alkyl or OC 1-6 alkyl, each optionally substituted with up to 3 halo groups selected from Cl and F, and a member selected from the group consisting of:

i) CN, C(O)NH 2 , or C(O)NHCH 3 ;

ii) CO 2 R d with R d as previously defined in a) above;

iii) OC 1-3 alkyl or OhaloC 1-3 alkyl, in which the halo atoms are selected from Cl and F; and

iv) phenyl, or a 5-10 membered mono or bicyclic ring system with 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 0-4 of which are N,

said phenyl and 5-10 membered mono or bicyclic ring system each being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl or haloC 1-2 alkyl groups, in which the halo atoms are selected from F and Cl, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl; and

d) Aryl or HAR, each optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl, haloC 1-2 alkyl, OC 1-2 alkyl, OhaloC 1-2 alkyl, the halo atoms contained in haloalkyl and Ohaloalkyl being selected from F and Cl, and Aryl(R a ) 3 in which the Aryl portion is phenyl,

and 0-1 members selected from the group consisting of: CN, HAR(R a ) 3 , CO 2 C 1-4 alkyl, CO 2 H and C(O)N(R f ) 2 , wherein each R f is H or C 1-6 alkyl.

5. A compound in accordance with claim 1

wherein R 2 is selected from the group consisting of: —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -Aryl(R a ) 3 , and —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -HAR(R a ) 3 , in which Aryl represents phenyl or naphthyl, and HAR represents a 5-10 membered mono or bicyclic aromatic ring system containing 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 1-4 of which are N;

Y represents a bond, CH 2 , O, C(O)NR f , NR f C(O) or NR f C(O)O; and R h represents a member selected from the group consisting of: H, CH 3 and F.

6. A compound in accordance with claim 1 wherein each R 3 is selected from the group consisting of: H, F, CH 3 , OCH 3 , CF 3 and OCF 3 .

7. A compound in accordance with claim 1 wherein ring B is selected from the group consisting of: phenyl, pyridyl, pyrazolyl, thiadiazolyl, benzthiazolyl, pyrimidinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl and tetrahydronaphthyl.

8. A compound in accordance with claim 7 wherein ring B is selected from the group consisting of: phenyl, pyridyl, pyrazolyl, and thiadiazolyl.

9. A compound in accordance with claim 8 wherein ring B represents phenyl.

10. A compound in accordance with claim 2 wherein C 0-5 alkyl represents a member selected from the group consisting of: a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —,

11. A compound in accordance with claim 10 wherein C 0-5 alkyl represents a member selected from the group consisting of: a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — and

12. A compound in accordance with claim 3 wherein: one R a represents H;

another R a is selected from the group consisting of: H and Cl, and the third R a is selected from the group consisting of H, Cl, phenyl, pyridyl, indolyl, isoquinolinyl, and benzopyrazolyl, CH 3 , OCH 3 , CF 3 , SCF 3 and OCF 3 .

13. A compound in accordance with claim 12 wherein: two R a groups represents H;

and the third R a is selected from the group consisting of H, Cl, phenyl, pyridyl, CH 3 , OCH 3 , CF 3 , SCF 3 and OCF 3 .

14. A compound in accordance with claim 4 wherein:

R 1 is selected from the group consisting of:

a) CO 2 R d in which R d represents H or CH 2 —R e , wherein R e represents H, CH 3 , or phenyl;

b) F, Cl or CN;

c) C 1-3 alkyl or OC 1-3 alkyl, each optionally substituted with up to 3 fluorine atoms, and a member selected from the group consisting of:

i) CN or C(O)NH 2 ;

ii) CO 2 R d with R d as previously defined in a) above; and

iii) Phenyl or HAR, which is a 5-10 membered mono or bicyclic ring system with 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 0-4 of which are N,

said Aryl and HAR each being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl or haloC 1-2 alkyl groups, in which the halo atoms are selected from F and Cl, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl; and

d) Phenyl or HAR containing 5-10 atoms, 1-4 of which are heteroatoms, 0-1 being selected from O and S, and 1-4 of which are N atoms, said Phenyl and HAR being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl, haloC 1-2 alkyl, OC 1-2 alkyl, OhaloC 1-2 alkyl, the halo atoms contained in haloalkyl and Ohaloalkyl being selected from F and Cl, and Phenyl(R a ) 3 ,

and 0-1 members selected from the group consisting of: CN, HAR(R a ) 3 , CO 2 C 1-4 alkyl, CO 2 H and C(O)N(R f ) 2 , wherein each R f is H or C 1-6 alkyl.

15. A compound in accordance with claim 5 wherein:

R 2 is selected from the group consisting of:

—(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -Aryl(R a ) 3 , and —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -HAR(R a ) 3 , in which Aryl represents phenyl or naphthyl, and HAR represents a 5-9 membered mono or bicyclic aromatic ring system containing 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 1-4 of which are N;

Y represents a bond, CH 2 , O, C(O)NR f , NR f C(O), or NR f C(O)O; and each R h represents a hydrogen atom.

16. A compound in accordance with claim 6 wherein:

each R 3 is selected from the group consisting of: H, F and CH 3 .

17. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein:

ring B represents: a) phenyl; b) HAR which is selected from the group consisting of: pyridyl, pyrazolyl, thiadiazolyl, benzisoxazolyl, benzthiazolyl, pyrimidinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl and benzopyrazinyl; c) C 10 -bicycloalkyl or d) C 6-7 cycloalkyl fused to phenyl;

—C 0-5 alkyl is selected from: a direct bond; —CH 2 —; —(CH 2 ) 2 —;

—(CH 2 ) 3 —; —(CH 2 ) 4 —;

each R a is defined as follows:

a) each R a is H or halo which is F or Cl, or

b) 1-2 R a groups represent H or halo which is F or Cl,

0-1 R a represents phenyl, or a 5-10 membered heteroaryl group having 1-2 N atoms, each of which being optionally substituted with 1-3 halo, C 1-3 alkyl or haloC 1-3 alkyl groups, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl;

and any remaining R a groups are selected from the group consisting of: C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl and OhaloC 1-3 alkyl;

R 1 is selected from the group consisting of:

a) CO 2 R d in which R d represents H or C 1-3 alkyl-R e , wherein R e represents H or Aryl;

b) halo, which is F or Cl, or CN;

c) C 1-6 alkyl or OC 1-6 alkyl, each optionally substituted with up to 3 halo groups selected from Cl and F, and a member selected from the group consisting of:

i) CN, C(O)NH 2 , or C(O)NHCH 3 ;

ii) CO 2 R d with R d as previously defined in a) above;

iii) OC 1-3 alkyl or OhaloC 1-3 alkyl, in which the halo atoms are selected from Cl and F; and

iv) phenyl, or a 5-10 membered mono or bicyclic ring system with 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 0-4 of which are N,

said phenyl or 5-10 membered mono or bicyclic ring system each being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl or haloC 1-2 alkyl groups, in which the halo atoms are selected from F and Cl, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl; and

d) Aryl or HAR, each optionally substituted with 1-2 halo atoms selected from F and C, C 1-2 alkyl, haloC 1-2 alkyl, OC 1-2 alkyl, OhaloC 1-2 alkyl, the halo atoms contained in haloalkyl and Ohaloalkyl being selected from F and Cl, and Aryl(R a ) 3 in which the Aryl portion is phenyl,

and 0-1 members selected from the group consisting of: CN, HAR(R a ) 3 , CO 2 C 1-4 alkyl, CO 2 H and C(O)N(R f ) 2 , wherein each R f is H or C 1-6 alkyl;

R 2 is selected from the group consisting of: —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -Aryl(R a ) 3 , and —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -HAR(R a ) 3 , in which Aryl represents phenyl or naphthyl, and HAR represents a 5-10 membered mono or bicyclic aromatic ring system containing 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 1-4 of which are N;

Y represents a bond, CH 2 , O, C(O)NR f , NR f C(O) or NR f C(O)O; and R h represents a member selected from the group consisting of: H, CH 3 and F;

and

each R 3 is selected form the group consisting of: H, F, CH 3 , OCH 3 , CF 3 and OCF 3 .

18. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof wherein:

ring B is selected from the group consisting of: phenyl; pyridyl, pyrazolyl, thiadiazolyl, benzisoxazolyl, benzthiazolyl, benzopyrazinyl, pyrimidinyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl and tetrahydronaphthyl;

C 0-5 alkyl represents a member selected from the group consisting of: a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, and

one R a represents H;

another R a is selected from the group consisting of: H and Cl, and the third R a is selected from the group consisting of H, Cl, phenyl, pyridyl, indolyl, isoquinolinyl, and benzopyrazolyl, CH 3 , OCH 3 , CF 3 and OCF 3 ;

R 1 is selected from the group consisting of:

a) CO 2 R d in which R d represents H or CH 2 —R e , wherein R e represents H or methyl;

b) For CN;

c) C 1-3 alkyl or OC 1-3 alkyl, each optionally substituted with up to 3 fluorine atoms, and a member selected from the group consisting of:

i) CN or C(O)NH 2 ;

ii) CO 2 R d with R d as previously defined in a) above; and

iii) Phenyl or HAR, which is a 5-10 membered mono or bicyclic ring system with 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 0-4 of which are N,

said Phenyl and HAR each being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl or haloC 1-2 alkyl groups, in which the halo atoms are F atoms, and 0-1 members selected from —C 1-3 alkyl-Aryl and —CO 2 —C 1-6 alkyl; and

d) Phenyl or HAR containing 5-10 atoms, 1-4 of which are heteroatoms, 0-1 being selected from O and S, and 1-4 of which are N atoms, said Phenyl and HAR being optionally substituted with 1-2 halo atoms selected from F and Cl, C 1-2 alkyl, haloC 1-2 alkyl, OC 1-2 alkyl, OhaloC 1-2 alkyl, the halo atoms contained in haloalkyl and Ohaloalkyl being selected from F and Cl, and Phenyl(R a ) 3 ,

and 0-1 members selected from the group consisting of: CN, HAR(R a ) 3 , CO 2 C 1-4 alkyl, CO 2 H and C(O)N(R f ) 2 , wherein each R f is H or C 1-6 alkyl;

R 2 is selected from the group consisting of:

—(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -Aryl(R a ) 3 , and —(CR h 2 ) 0-1 —Y—(CR h 2 ) 0-2 -HAR(R a ) 3 , in which Aryl represents phenyl or naphthyl, and HAR represents a 5-10 membered mono or bicyclic aromatic ring system containing 1-4 heteroatoms selected from 0, S and N, 0-1 of which are O or S, and 1-4 of which are N;

Y represents a bond, CH 2 , O, C(O)NR f , NR f C(O) or NR f C(O)O; and each R h represents a hydrogen atom, and

each R 3 is selected from the group consisting of: H, F and CH 3 .

19. A compound selected from Table I:

TABLE 1

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

21. A method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective for treating type 2 diabetes.