Isoxazolo-pyridazine derivatives

1. A compound of formula I

wherein

X is O or NH;

R 1 is phenyl, pyridinyl, or pyrimidinyl each optionally substituted with one, two or three halo,

R 2 is C 1-4 alkyl, H or C 1-4 haloalkyl;

R 3 , R 4 , and R 5 each are independently

H,

C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy,

C 1-7 alkoxy, optionally substituted with one or more halo,

CN,

halo,

NO 2 ,

—C(O)—R a , wherein R a is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl,

—NR b R c , wherein R b and R c are each independently

hydrogen,

C 1-7 alkyl,

—C(O)C 1-7 alkyl, optionally substituted with one or more halo,

—C(O)(CH 2 ) m —O—C 1-7 alkyl, wherein m is 0, 1, 2, 3, 4, 5 or 6,

—C(O)C(O)OC 1-7 -alkyl,

—C(O)CH 2 C(O)OC 1-7 -alkyl,

—C(O)R i , wherein R i is phenyl or 5- to 6-membered heteroaryl, each optionally substituted with one or more E,

—C(O)—C 3-7 cycloalkyl, optionally substituted with one or more B,

—C(O)—R ii , wherein R ii is 3- to 7-membered heterocyclyl, optionally substituted by one or more A,

3- to 7-membered heterocyclyl, optionally substituted with one or more A,

5- or 6-membered heteroaryl, optionally substituted with one or more E,

—C(O)—NR d R e , wherein R d and R e are each independently

H,

C 1-7 alkyl, optionally substituted with one or more halo, hydroxy, or cyano,

—(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3 or 4,

—(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6,

—(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is optionally substituted by one or more A

R d and R e together with the nitrogen to which they are bound form a heterocyclyl moiety, optionally substituted with one or more A, or

R 3 together with the neighboring pyridazine-nitrogen form a 5-membered annelated aromatic ring with two additional ring nitrogen atoms, the annelated ring is optionally substituted by R f , wherein R f is C 1-7 -alkyl,

—C(O)OC 1-7 alkyl, —C(O)C 1-7 alkyl, 5- or 6-membered heteroaryl or phenyl, each optionally substituted by one or more E,

A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN,

B is halo, hydroxy, CN, C 1-4 alkyl, or C 1-4 haloalkyl,

E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 4 and R 5 are each independently H or C 1-7 alkyl.

3. The compound of claim 2 , wherein R 4 and R 5 are each independently H or Me.

4. The compound of claim 1 , wherein R 3 is

H,

C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy,

C 1-7 alkoxy, optionally substituted with one or more halo,

halo,

—C(O)—R a , wherein R a is hydroxy, C 1-7 alkoxy, or C 1-7 alkyl,

—NR b R c , wherein R b and R c are each independently

hydrogen,

C 1-7 alkyl,

—C(O)C 1-7 alkyl, optionally substituted with one or more halo,

—C(O)(CH 2 ) m —O—C 1-7 alkyl, wherein m is 0 or 1,

—C(O)C(O)OC 1-7 -alkyl,

—C(O)CH 2 C(O)OC 1-7 -alkyl,

—C(O)R i , wherein R i is phenyl, furanyl, or isoxazolyl, each optionally substituted with one or more E,

—C(O)—C 3-7 cycloalkyl, optionally substituted with one or more B,

—C(O)—R ii , wherein R ii is tetrahydropyranyl, optionally substituted with one or more A,

pyrrolidinyl or morpholinyl, each optionally substituted with one or more A,

pyrazolyl, optionally substituted with one or more E,

—C(O)—NR d R e , wherein R d and R e are each independently

H,

C 1-7 alkyl, optionally substituted with one or more halo, or hydroxy,

—(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0 or 1;

—(CH 2 ) 2 —O—C 1-7 alkyl,

tetrahydropyranyl, optionally substituted by one or more A

R d and R e together with the nitrogen to which they are bound form morpholinyl, or thiomorpholinyl, each optionally substituted with one or more A, or

R 3 together with the neighboring pyridazine-nitrogen form a 5-membered annelated aromatic ring with two additional ring nitrogen atoms, the annelated ring is optionally substituted by R f , wherein R f is C 1-7 -alkyl, —C(O)OC 1-7 alkyl, or furanyl,

A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN,

B is halo, hydroxy, CN, C 1-4 alkyl, or C 1-4 haloalkyl,

E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl.

5. A compound of claim 1

wherein

X is O or NH;

R 1 is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with one halo;

R 2 is H or C 1-4 alkyl;

R 4 is H or C 1-7 alkyl;

R 5 is H or C 1-7 alkyl;

R 3 is H,

C 1-7 alkyl,

C 1-7 alkoxy;

halo,

—C(O)—R a , wherein R a is hydroxy, C 1-7 alkoxy;

—NR b R c , wherein R b and R c are each independently

hydrogen,

C 1-7 alkyl,

—C(O)C 1-7 alkyl, optionally substituted with one or more halo,

—C(O)(CH 2 ) m —O—C 1-7 alkyl, wherein m is 0 or 1;

—C(O)C(O)OC 1-7 -alkyl,

—C(O)CH 2 C(O)OC 1-7 -alkyl,

—C(O)R i , wherein R i is phenyl or 5- to 6-membered heteroaryl, each optionally substituted with one E,

—C(O)—C 3-7 cycloalkyl;

—C(O)—R ii , wherein R ii is 3- to 7-membered heterocyclyl,

3- to 7-membered heterocyclyl, optionally substituted with one A;

5- or 6-membered heteroaryl;

—C(O)—NR d R e , wherein R d and R e are each independently

H,

C 1-7 alkyl, optionally substituted with one or more halo or hydroxy;

—(CH 2 ) t —C 3-7 cycloalkyl, and t is 0, 1;

—(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2;

-heterocyclyl;

R d and R e together with the nitrogen to which they are bound form a heterocyclyl moiety, or

R 3 together with the neighboring pyridazine-nitrogen form a 5-membered annelated aromatic ring with two additional ring nitrogen atoms, the annelated ring is optionally substituted by R f , wherein R f is C 1-7 -alkyl, —C(O)OC 1-7 alkyl or 5- or 6-membered heteroaryl;

A is oxo;

E is C 1-7 alkyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , where in R 3 , R 4 , and R 5 all are not hydrogen.

7. The compound of claim 1 , selected from the group consisting of

3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine,

3-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine,

3-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-methoxy-ethyl)-amide,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid isopropylamide,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylamide,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-ethyl)-amide,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide, and

3-methoxy-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine.

8. The compound of claim 1 , selected from the group consisting of

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine,

N-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-acetamide,

N-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-isobutyramide,

cyclopropanecarboxylic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amide,

cyclobutanecarboxylic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amide,

tetrahydro-pyran-4-carboxylic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amide,

1-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-pyrrolidin-2-one,

N-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-oxalamic acid methyl ester,

N-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-benzamide,

furan-2-carboxylic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amide, and

isoxazole-5-carboxylic acid [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amide.

9. The compound of claim 1 , selected from the group consisting of

[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-carbamic acid ethyl ester,

4-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-morpholine,

methyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amine,

dimethyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-amine,

3-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine,

5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester,

3-chloro-4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine,

4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester,

4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide,

4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylamide, and

4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid isopropylamide.

10. The compound of claim 1 , selected from the group consisting of

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester,

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid methylamide,

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethylamide,

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (2-hydroxy-ethyl)-amide,

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid isopropylamide,

6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid cyclopropylamide,

3-chloro-6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine,

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester,

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid cyclopropylmethyl-amide,

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (2,2,2-trifluoro -ethyl)-amide, and

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid isopropylamide.

11. The compound of claim 1 , selected from the group consisting of

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid cyclopropylamide,

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide,

(1,1-dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazin-3-yl}-methanone,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine,

6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic acid ethyl ester,

6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-[1,2,4]triazolo[4,3-b]pyridazine,

3-chloro-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid isopropylamide, and

[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-morpholin-4-yl-methanone.

12. The compound of claim 1 , selected from the group consisting of

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylamide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2,2,2-trifluoro-ethyl)-amide,

(1,1-dioxo-1λ6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-methanone,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylmethyl-amide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-ethyl)-amide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methylamide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethylamide,

[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazin-3-yl]-thiomorpholin-4-yl-methanone,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide,

6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-methoxy-ethyl)-amide, and

6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-ethyl)-amide.

13. The compound of claim 1 , selected from the group consisting of

6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methylamide,

6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethylamide,

3-chloro-6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine,

6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester,

6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide,

6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid,

6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-ethyl)-amide,

6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide,

6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid cyclopropylamide,

6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid cyclopropylmethyl-amide, and

6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid (2,2,2-trifluoro-ethyl)-amide.

14. The compound of claim 1 , selected from the group consisting of

6-{[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide,

6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester,

6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid isopropylamide,

6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide,

6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid isopropylamide,

6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylamide,

6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid cyclopropylmethyl-amide,

6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (2,2,2-trifluoro-ethyl)-amide, and

6-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I

wherein

X is O or NH;

R 1 is phenyl, pyridinyl, or pyrimidinyl each optionally substituted with one, two or three halo,

R 2 is C 1-4 alkyl, H or C 1-4 haloalkyl;

R 3 , R 4 , and R 5 each are independently

H,

C 1-7 alkyl, optionally substituted with one or more halo, cyano, or hydroxy,

C 1-7 alkoxy, optionally substituted with one or more halo,

CN,

halo,

NO 2 ,

—C(O)—R a , wherein R a is hydroxy, C 1-7 alkoxy, C 1-7 alkyl, phenoxy or phenyl,

—NR b R c , wherein R b and R c are each independently

hydrogen,

C 1-7 alkyl,

—C(O)C 1-7 alkyl, optionally substituted with one or more halo,

—C(O)(CH 2 ) m —O—C 1-7 alkyl, wherein m is 0, 1, 2, 3, 4, 5 or 6,

—C(O)C(O)OC 1-7 -alkyl,

—C(O)CH 2 C(O)OC 1-7 -alkyl,

—C(O)R i , wherein R i is phenyl or 5- to 6-membered heteroaryl, each optionally substituted with one or more E,

—C(O)—C 3-7 cycloalkyl, optionally substituted with one or more B,

—C(O)—R i , wherein R i is 3- to 7-membered heterocyclyl, optionally substituted by one or more A,

3- to 7-membered heterocyclyl, optionally substituted with one or more A,

5- or 6-membered heteroaryl, optionally substituted with one or more E,

—C(O)—NR d R e , wherein R d and R e are each independently

H,

C 1-7 alkyl, optionally substituted with one or more halo, hydroxy, or cyano,

—(CH 2 ) t —C 3-7 cycloalkyl, optionally substituted by one or more B, and t is 0, 1, 2, 3 or 4,

—(CH 2 ) u —O—C 1-7 alkyl, wherein u is 2, 3, 4, 5 or 6,

—(CH 2 ) x -heterocyclyl, wherein x is 0, 1, 2, 3 or 4, and wherein heterocyclyl is optionally substituted by one or more A

R d and R e together with the nitrogen to which they are bound form a heterocyclyl moiety, optionally substituted with one or more A, or

R 3 together with the neighboring pyridazine-nitrogen form a 5-membered annelated aromatic ring with two additional ring nitrogen atoms, the annelated ring is optionally substituted by R f , wherein R f is C 1-7 -alkyl,

—C(O)OC 1-7 alkyl, —C(O)C 1-7 alkyl, 5- or 6-membered heteroaryl or phenyl, each optionally substituted by one or more E,

A is hydroxy, oxo, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, halo, or CN,

B is halo, hydroxy, CN, C 1-4 alkyl, or C 1-4 haloalkyl,

E is halo, CN, NO 2 , hydroxy, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 cyanoalkyl, C 1-7 haloalkoxy, or C 3-7 cycloalkyl,

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.