[1,2,4]triazolo[3,4-C][1,4]oxazines as P2X7 modulators

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is:

phenyl substituted one, two three or four times, with a substituent or substituents each independently selected from: halo; C 1-6 alkyl; C 1-6 alkoxy; halo-C 1-6 alkyl; halo-C 1-6 alkoxy; C 1-6 alkylsulfonyl; C 1-6 alkylsulfanyl; C 1-6 alkylsulfinyl;

phenylsulfonyl wherein the phenyl portion may be substituted with: C 1-6 alkyl;

nitrile; hydroxy; C 1-6 alkylcarbonyl; aminocarbonyl; C 1-6 alkoxycarbonyl; C 1-6 alkoxycarbonyl-C 1-6 alkoxy; hydroxycarbonyl; hydroxycarbonyl-C 1-6 alkoxy; C 1-6 alkylaminocarbonyl-C 1-6 alkoxy; C 1-6 alkoxy-C 1-6 alkoxy; hydroxy-C 1-6 alkoxy; C 1-6 alkylamino-C 1-6 alkoxy; C 1-6 alkylsulfony-C 1-6 alkoxy; hydroxy-C 1-6 alkyl; C 3-6 cycloalkyl-C 1-6 alkoxy; amino; amino-C 1-6 alkyl; C 1-6 alkenyl; C 1-6 alkynyl; morpholinyl; morpholinyl-C 1-6 alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C 1-6 alkoxy; hydroxy C 1-6 alkoxy-C 1-6 alkyl; C 1-6 alkoxyamino-C 1-6 alkyl; hydroxy-C 1-6 alkylamino-C 1-6 alkyl; C 1-6 alkoxycarbonylamino-C 1-6 alkyl; C 1-6 alkylcarbonylamino-C 1-6 alkyl; C 1-6 alkylaminocarbonyl; C 1-6 alkoxycarbonyl-C 1-6 alkyl; C 1-6 alkylaminocarbonyl-C 1-6 alkyl; C 1-6 alkylamino-C 1-6 alkyl; hydroxycarbonyl-C 1-6 alkyl; or nitro; or

a five or six membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each of which may be substituted once or twice with a group or groups independently selected from: C 1-6 alkyl; halo; C 1-6 alkoxy; hydroxy-C 1-6 alkyl; halo; and oxo; or two adjacent substituents may form a C 1-2 alkylenedioxy or halo-C 1-2 alkylenedioxy;

R 2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile;

R 3 is:

hydrogen; or

C 1-6 alkyl;

X is: —O; and

Y is: —O—; —NR d —; —S(O) n — or —CR e R f — wherein n is 0, 1 or 2, wherein R d , R e and R f each independently is hydrogen or C 1-6 alkyl.

2. The compound of claim 1 , wherein Y is —NR d —.

3. The compound of claim 2 , wherein R d is hydrogen.

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

5. The compound of claim 1 , wherein R 2 is phenyl substituted once or twice with fluoro.

6. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a compound of claim 1 .

7. A compound of formula II:

and wherein:

p is 0, 1, 2or 3;

each R 5 independently is: halo; C 1-6 alkyl; C 1-6 alkoxy; halo-C 1-6 alkyl; halo-C 1-6 alkoxy; C 1-6 alkylsulfonyl; or nitrile;

R 6 , R 7 , R 8 , R 9 and R 10 each independently is: hydrogen; halo; C 1-6 alkyl; C 1-6 alkoxy; halo-C 1-6 alkyl; halo-C 1-6 alkoxy; C 1-6 alkylsulfonyl; C 1-6 alkylsulfanyl; C 1-6 alkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with C 1-6 alkyl; nitrile; hydroxy; C 1-6 alkylcarbonyl; aminocarbonyl; C 1-6 alkoxycarbonyl; C 1-6 alkoxycarbonyl-C 1-6 alkoxy; hydroxycarbonyl; hydroxycarbonyl-C 1-6 alkoxy; C 1-6 alkylaminocarbonyl-C 1-6 alkoxy; C 1-6 alkoxy-C 1-6 alkoxy; hydroxy-C 1-6 alkoxy; C 1-6 alkylamino-C 1-6 alkoxy; C 1-6 alkylsulfony-C 1-6 alkoxy; hydroxy-C 1-6 alkyl; C 3-6 cycloalkyl-C 1-6 alkoxy; amino; amino-C 1-6 alkyl; C 1-6 alkenyl; C 1-6 alkynyl; morpholinyl; morpholinyl-C 1-6 alkyl; piperazinyl; piperidinyloxy; aminocarbonyl-C 1-6 alkoxy; C 1-6 alkoxyamino-C 1-6 alkyl; hydroxy-C 1-6 alkylamino-C 1-6 alkyl; C 1-6 alkoxycarbonylamino-C 1-6 alkyl; C 1-6 alkyl carbonylamino-C 1-6 alkyl; C 1-6 alkylaminocarbonyl; C 1-6 alkoxycarbonyl-C 1-6 alkyl; C 1-6 alkylaminocarbonyl-C 1-6 alkyl; C 1-6 alkylamino-C 1-6 alkyl; hydroxycarbonyl-C 1-6 alkyl; or nitro; or two adjacent substituents may form a C 1-2 alkylenedioxy; halo-C 1-2 alkylenedioxy; or a five- or six-membered heteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each of which may be substituted once or twice with a group or groups independently selected from: C 1-6 alkyl; halo; C 1-6 alkoxy; hydroxy-C 1-6 alkyl; halo; and oxo;

X is: —O; and

R d is hydrogen or C 1-6 alkyl.

8. The compound of claim 7 , wherein p is 1 or 2 and R 5 is halo.

9. The compound of claim 8 , wherein R 7 and R 10 are hydrogen.

10. The compound of claim 9 , wherein R 6 is: halo; or methyl.

11. The compound of claim 10 , wherein R 8 is: hydrogen; methoxy; or halo.

12. The compound of claim 11 , wherein R 9 is: methoxy; 2-hydroxy-ethoxy; or a five- or six-membered heteroaryl selected from pyrazolyl and pyridazinyl, the pyrazolyl and pyridazinyl, each of which may be substituted one, two or three times with a group or groups independently selected from: oxo; C 1-6 alkyl; halo; or hydroxy-C 1-6 alkyl.

13. The compound of claim 7 , wherein said compound is of formula III:

14. A compound selected from:

(2-Bromo-4,5-dimethoxy-phenyl)-[5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine;

(6-Methyl-quinolin-5-yl)-((R)-5-phenyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-amine;

(2-Bromo-4,5-dimethoxy-phenyl)-[(S)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine;

(2-Bromo-4,5-dimethoxy-phenyl)-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine;

[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-[2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-amine;

[5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-quinolin-5-yl-amine;

2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol;

[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-[2-methyl-5-(4-methyl-pyrazol-1-yl)-phenyl]-amine;

(4,5-Dimethoxy-2-methyl-phenyl)-[5-(4-fluoro-phenyl)-5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine;

[5-(3-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(6-methyl-quinolin-5-yl)-amine;

[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(2-methyl-quinolin-5-yl)-amine;

7-Chloro-4-[5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2-((R)-2-hydroxy-1-methyl-ethyl)-2,3-dihydro-isoindol-1-one;

2-{2-Chloro-5-[5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol;

2-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-ethanol;

(R)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propan-2-ol;

(R)-3-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propane-1,2-diol;

(R)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-3-methoxy-propan-2-ol;

(S)-1-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propan-2-ol;

(S)-3-(3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-5-methyl-pyrazol-1-yl)-propane-1,2-diol;

[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-(6-methyl-quinolin-5-yl)-amine;

4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2-methyl-2H-pyridazin-3-one;

5-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-6-methyl-1H-quinolin-2-one;

2-{6-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-5-methyl-indazol-1-yl}-ethanol;

2-(3-{4-Chloro-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-5-methyl-pyrazol-1-yl)-ethanol;

6-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one;

5-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2H-phthalazin-1-one;

4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one;

2-{2-Chloro-5-[(R)-5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol;

2-{2-Chloro-5-[(S)-5-(3-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol;

6-Bromo-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-2H-phthalazin-1-one;

4-{4-Bromo-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-2H-pyridazin-3-one;

2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one;

4-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2-(2-hydroxy-ethyl)-2H-pyridazin-3-one;

1-{4-Bromo-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-tetrahydro-pyrimidin-2-one;

4-{4-Fluoro-3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-phenyl}-2-methyl-2H-pyridazin-3-one;

2-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione;

3-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-1-methyl-1H-pyridin-2-one;

2-{3-Fluoro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one;

2-{2-Fluoro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one;

4-Ethyl-2-{3-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione;

1-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-1H-pyridin-2-one; and

2-{3-[(R)-5-(4-Fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenyl}-4-((R)-2-hydroxy-3-methoxy-propyl)-2H-[1,2,4]triazine-3,5-dione.