Alkoxy pyrimidine PDE10 inhibitors

1. A compound of the formula I:

wherein:

R 1 is C 1-6 alkyl or C 1-6 alkyl-C 3-6 cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(1) phenyl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 ,

(2) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 ,

(3) —O-phenyl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 , and

(4) —O-heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 ;

R 2 is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) C 1-6 alkyl,

(4) —O—C 1-6 alkyl,

(5) hydrogen,

(6) —CN,

(7) —S—C 1-6 alkyl,

(8) —NR 10 R 11 , wherein R 10 and R 11 are independently selected from the group consisting of hydrogen and C 1-6 alkyl, and

(9) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 ,

R 3 is

C 1-6 alkyl, which is unsubstituted or substituted with halogen;

R 4 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

R 5 is C 1-6 alkyl, C 1-6 alkyl-C 3-6 cycloalkyl or C 2-6 alkenyl which is unsubstituted or substituted with a substituent selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl,

(4) phenyl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 , and

(5) heteroaryl, which is unsubstituted or substituted with one to five substituents selected from R 6 , R 7 and R 8 ;

R 6 , R 7 and R 8 are independently selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) C 1-6 alkyl, which is unsubstituted or substituted with fluoro,

(4) —O—C 1-6 alkyl, which is unsubstituted or substituted with fluoro,

(5) —NR 10 R 11 ,

(6) —(C═O)—NR 10 R 11 ,

(7) —S(O) 2 —NR 10 R 11 ,

(8) —S(O) q —R 12 , where q is 0, 1 or 2 and where R 12 is selected from the group consisting of hydrogen and C 1-6 alkyl, and

(9) —CN;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the formula Ic:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 of the formula Id:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 of the formula Ig:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 of the formula Ih:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 CH 2 CH 2 — substituted with (2), (3), (4), (5), or (6), or —CH 2 -cyclopropyl, which is substituted with a substituent selected from the group consisting of:

(1) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl,

(2) —O—C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl,

(3) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH 2 , —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), —O—C 1-6 alkyl or C 1-6 alkyl, which is unsubstituted or substituted with fluoro,

(4) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH 2 , —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), —O—C 1-6 alkyl or C 1-6 alkyl, which is unsubstituted or substituted with fluoro,

(5) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, —NH 2 , —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), —O—C 1-6 alkyl or C 1-6 alkyl, which is unsubstituted or substituted with fluoro, and

(6) —O-heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, —NH 2 , —NH—C 1-6 alkyl, or —N(C 1-6 alkyl)(C 1-6 alkyl), —O—C 1-6 alkyl or C 1-6 alkyl, which is unsubstituted or substituted with fluoro.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is chloro or methoxy.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: hydrogen and methyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of:

12. A compound which is selected from the group consisting of:

2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;

{6-Chloro-5-methyl-2-[2-([1,8]naphthyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-(2,4-dimethylthiazol-5-ylmethyl)-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[3-(quinolin-2-yl)propoxy]pyrimidin-4-amine;

trans 6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-{[2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-5-methylpyrimidin-4-amine;

6-methoxy-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[(1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxy-5-methylpyrimidin-4-amine;

2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-ethyl-5-methylpyrimidin-4-amine;

2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-5-methyl-N-prop-2-en-1-ylpyrimidin-4-amine;

6-chloro-2-(3-imidazo[1,2-a]pyridin-2-ylpropoxy)-5-methyl-N-(1-methylethyl)pyrimidin-4-amine;

6-chloro-5-methyl-N-propyl-2-(3-[1,2,4]triazolo[1,5-a]pyridin-2-ylpropoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-amine;

6-chloro-5-methyl-N-propyl-2-(3-quinolin-2-ylpropoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(pyridin-4-ylmethoxy)pyrimidin-4-amine;

2-[3-(1,3-benzoxazol-2-yl)propoxy]-6-chloro-N-(2-fluoroprop-2-en-1-yl)-5-methylpyrimidin-4-amine;

6-chloro-N-(2-fluoroprop-2-en-1-yl)-5-methyl-2-[3-(1,8-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;

1-[({2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-5-methylpyrimidin-4-yl}amino)methyl]cyclopropanol;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-phenylethoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-pyridin-3-ylethoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine;

1-{[6-chloro-5-methyl-2-(3-[1,2,4]triazolo[1,5-a]pyridin-2-ylpropoxy)pyrimidin-4-yl]amino}-2-methylpropan-2-ol;

1-{[6-chloro-5-methyl-2-(3-quinoxalin-2-ylpropoxy)pyrimidin-4-yl]amino}-2-methylpropan-2-ol;

6-chloro-2-[3-(6-methoxy-1,5-naphthyridin-2-yl)propoxy]-5-methyl-N-(1-methylethyl)pyrimidin-4-amine;

6-chloro-5-methyl-2-[3-(1,5-naphthyridin-2-yl)propoxy]-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine;

2-[3-(1,3-benzoxazol-2-yl)propoxy]-6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-{[2-pyridin-2-ylcyclopropyl]methoxy}pyrimidin-4-amine;

6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-[3-(1,5-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;

6-chloro-5-methyl-N-[(3-methylisoxazol-5-yl)methyl]-2-[3-(1,8-naphthyridin-2-yl)propoxy]pyrimidin-4-amine;

6-chloro-5-methyl-N-[(3-methylisoxazol-5-yl)methyl]-2-(3-quinoxalin-2-ylpropoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-[2-(1H-indol-3-yl)ethoxy]-5-methylpyrimidin-4-amine;

2-[3-(2-bromoimidazo[2,1-b][1,3]thiazol-6-yl)propoxy]-6-chloro-N-ethyl-5-methylpyrimidin-4-amine;

6-chloro-2-{2-[4-(dimethylamino)phenyl]ethoxy}-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;

2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-(3-imidazo[2,1-b][1,3]thiazol-6-ylpropoxy)-5-methylpyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-quinolin-2-ylpropoxy)pyrimidin-4-amine;

6-chloro-2-[3-(6-methoxy-1,5-naphthyridin-2-yl)propoxy]-5-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(3-pyridin-2-yl-1H-pyrazol-1-yl)ethoxy]pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(1,8-naphthyridin-2-yloxy)ethoxy]pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-thieno[3,2-b]pyridin-5-ylpropoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-thieno[2,3-b]pyridin-6-ylpropoxy)pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-{2-[(6-methoxy-1,8-naphthyridin-2-yl)oxy]ethoxy}-5-methylpyrimidin-4-amine;

2-[3-(2-bromoimidazo[2,1-b][1,3]thiazol-6-yl)propoxy]-6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrimidin-4-amine;

6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;

6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-{[2-(quinolin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;

6-chloro-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;

6-methoxy-5-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-{[(1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy}pyrimidin-4-amine;

6-((1-methyl-1H-pyrazol-4-yl)methylamino)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidine-4-carbonitrile;

6-((2,4-dimethylthiazol-5-yl)methylamino)-5-methyl-2-(2-(pyridin-2-yl)ethoxy)pyrimidine-4-carbonitrile;

5-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-6-(methylthio)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine;

N4,N4,5-trimethyl-N-6-((1-methyl-1H-pyrazol-4-yl)methyl)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidine-4,6-diamine;

2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-N-((2,4-dimethylthiazol-5-yl)methyl)-5-methylpyrimidin-4-amine;

N-((2,4-dimethylthiazol-5-yl)methyl)-5-methyl-6-(oxazol-2-yl)-2-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-amine;

2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)methyl)-5-methylpyrimidin-4-amine;

2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((2,4-dimethyloxazol-5-yl)methyl)-5-methylpyrimidin-4-amine;

2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,3-dimethyl-1H-1,2,4-triazol-5-yl)methyl)-5-methylpyrimidin-4-amine;

6-chloro-2-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-5-methyl-N-((2-methyl-2H-1,2,3-triazol-4-yl)methyl)pyrimidin-4-amine; and

2-(((1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl)methoxy)-6-chloro-N-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-5-methylpyrimidin-4-amine;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.