Pyrazolopyrimidine PDE 10 inhibitors

1. A compound of the formula I:

wherein:

X is —NR 4 R 5 or —O—R 5 ;

Y is —O—, —(CR 3 R 4 )—, —(C═O)NR 4 —, or a bond between the carbon of the pyrazolopyrimidine ring and R 1 ;

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

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

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

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

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

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

(6) —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) hydrogen,

(2) fluoro,

(3) C 1-6 alkyl, and

(4) C 3-6 cycloalkyl;

R 3 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

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) C 3-6 cycloalkyl,

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

(7) —(C═O)—NR 10 R 11 ,

(8) —S(O) 2 —NR 10 R 11 ,

(9) —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

(10) —CN;

R 13 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

R 14 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 of the formula Ib:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 of the formula Id:

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 3 — 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 4 is hydrogen.

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

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

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

N-[(1-methyl-1, H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)—N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)—N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)—N-(1H-pyrazol-3-ylmethyl)-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}-pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[2-(6-methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[(1R,2R)-2-(6-Methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[(1S,2S)-2-(6-Methoxypyridin-2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(1-methyl-1H-pyrazol-3-yl)methyl]-5-{2-[2-(quinolin-2-yl)cyclopropyl]ethyl}-pyrazolo[1,5-a]pyrimidin-7-amine;

N-(2-(1,5-naphthyridin-2-yl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

5-{[2-(5-fluoropyridin-2-yl)cyclopropyl]methoxy}-N-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazolo pyrimidin-7-amine;

N-{2-[(5-[2-(quinolin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]-pyrimidin-7-yl)amino]-ethyl acetamide;

N-[(2,4-dimethyl-1,3-oxazol-5-yl)methyl]-5-{[2-(5-methoxy-pyridin-2-yl)cyclopropyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridine -2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)—N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)—N-[(2-methyl-1,3-thiazol-5-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[2-(quinolin-2-yl)cyclopropyl]methoxy}-N-(1,3-thiazol-5-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}-N-(pyridin-3-ylmethyl)pyrazolo[1,5-N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)—N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)—N-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-5-{[2-(5-methylpyridin-2-yl)cyclo-propyl]-methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(S,S)—N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

(R,R)—N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

5-cyclopropyl-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]pyrazolo[1,5-a]pyrim-idin-7-amine;

N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(5-methoxy-pyridin-2-yl)butyl]pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-{2-[2-(5-methoxy-pyridin-2-yl)cyclo-propyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;

2-methyl-1-[(5-{2-[2-(5-methylpyridin-2-yl)cyclopropyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]propan-2-ol;

N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-{1-[2-(pyridin-2-yl)cyclopropyl]propan-2-yl}pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{2-[2-(quinolin-2-yl)cyclopropyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(quinolin -2-yl)but-3-yn-1-yl]pyrazolo[1,5-a]pyrimidin-7-amine;

5-[4-(5-methoxypyridin-2-yl)butyl]-N,N-dimethylpyrazolo[1,5-a]pyrimidin-7-amine;

N-[2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-[4-(5-methoxy-pyridin-2-yl)but-3-yn-1-yl]pyrazolo[1,5-a]pyrimidin-7-amine;

6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[(R1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

6-fluoro-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

6-methyl-N-[(1-methyl-1-[1H-pyrazol-4-yl)methyl]-5-{[(1S,2S)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

6-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-5-{[(1R,2R)-2-(pyridin-2-yl)cyclopropyl]methoxy}pyrazolo[1,5-a]pyrimidin-7-amine;

N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine;

5-{[2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine;

5-{[(1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine;

5-{[(1R,2R)-2-(5-methylpyridin-2-yl)cyclopropyl]methoxy}-7-[(6-methylpyridin-3-yl)oxy]pyrazolo[1,5-a]pyrimidine;

7-((2,4-dimethylthiazol-5-yl)methylamino)-N-((2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(((1R,2R)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-((2-(quinolin -2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-((1S,2S)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((1,3-dimethyl-1H-pyrazol-5-yl)methylamino)-N-(((1R,2R)-2-(quinolin-2-yl)cyclopropyl)methyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

7-((2,4-dimethylthiazol-5-yl)methylamino)-N-(2-(pyridin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

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

13. A method for treating a neurological or psychiatric disorder by inhibiting PDE10 in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein treating does not embrace preventing.

14. A method for treating schizophrenia by inhibiting PDE10 in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein treating does not embrace preventing.