Heteroarylphenoxy benzamide kappa opioid ligands

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof;

wherein

R 1 is hydrogen, fluoro or hydroxy;

R 2 and R 3 are each independently hydrogen or fluoro;

X is CR 5 R 6 or O;

m is 1 or 2;

n is 0, 1 or 2;

R 4 is selected from the group consisting of

R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;

R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy are optionally substituted with one to three fluoro; and

R 9 at each occurrence is independently selected from fluoro, C 1 -C 3 alkyl and C r C 6 alkoxy, wherein the C 1 -C 3 alkyl and C 1 -C 6 alkoxy are optionally substituted with one to three fluoro.

2. The compound of claim 1 wherein

m is 1;

X is CR 5 R 6 ;

R 5 and R 6 are each independently selected from the group consisting of hydrogen, fluoro and methyl;

R 7 is selected from the group consisting of hydrogen, methyl and methoxy; and

R 8 is methyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 of the Formula Ia

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 wherein

R 4 is

R 5 and R 6 are each hydrogen and

R 7 is methyl or methoxy;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein

m is 2;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein

X is O;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 of the Formula Ib

wherein

R 4 is

R 7 is methyl or methoxy; and

R 8 is methyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5 wherein

X is CR 5 R 6 ;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 of the Formula Ic

wherein

R 4 is

R 5 and R 6 are each hydrogen;

R 7 is methyl or methoxy; and

R 8 is methyl or hydrogen;

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 selected from the group consisting of

(+/−)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}-2-fluorophenoxy)benzamide;

(+)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}-2-fluorophenoxy) benzamide;

(−)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}-2-fluorophenoxy) benzamide;

(+/−)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide;

4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide, ENT-1;

4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide, ENT-2;

(+/−)-3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide;

(−)-3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide;

(+)-3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide;

4-(4-{[(2S)-2-(5-methyl-1,2,4-thiadiazol-3-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

4-(4-{[(2S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

(+/−)-4-(4-{[2-(3-methoxy-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

(+4-(4-{[2-(3-methoxy-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

(+)-4-(4-{[2-(3-methoxy-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

(+/−)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-2-hydroxybenzamide;

(+)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-2-hydroxybenzamide;

(−)-4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)-2-hydroxybenzamide;

3-fluoro-4-(4-{[(2S)-2-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

3-fluoro-4-(4-{[3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]methyl} phenoxy)benzamide, ENT-1;

4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]methyl}phenoxy) benzamide, ENT-1;

4-(2-fluoro-4-{[3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]methyl} phenoxy)benzamide, ENT-1;

4-(4-{[3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]methyl}phenoxy) benzamide, ENT-1;

4-(4-{[4-fluoro-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl} phenoxy)benzamide, Isomer 2, assumed racemic, either cis or trans;

4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoropyrrolidin-1-yl]methyl}phenoxy) benzamide, Isomer 1;

4-(4-{[2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-fluoropyrrolidin-1-yl]methyl}phenoxy) benzamide, Isomer 2;

4-(4-{[(2S)-2-(1,3-dimethyl-1H-pyrazol-5-yl)pyrrolidin-1-yl]methyl}phenoxy)-2-hydroxybenzamide;

3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-methylpyrrolidin-1-yl] methyl}phenoxy)benzamide, Isomer 1;

3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-methylpyrrolidin-1-yl] methyl}phenoxy)benzamide, Isomer 2;

3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-methylpyrrolidin-1-yl] methyl}phenoxy)benzamide, Isomer 3;

3-fluoro-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-methylpyrrolidin-1-yl] methyl}phenoxy)benzamide, Isomer 4;

4-(2-fluoro-4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl} phenoxy)benzamide, ENT-2;

2-hydroxy-4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl} phenoxy)benzamide, ENT-2;

2-hydroxy-4-(4-{[(2S)-2-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide;

4-(4-{[2-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy) benzamide, ENT-2;

4-(4-{[2-(2,5-dimethyl-2H-1,2,3-triazol-4-yl)pyrrolidin-1-yl]methyl}-2-fluorophenoxy)benzamide, ENT-2;

4-(4-{[(2S)-2-(1,3-dimethyl-1H-pyrazol-5-yl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide; and

a pharmaceutically acceptable salt thereof.

11. The compound 4-(4-{[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide; or a pharmaceutically acceptable salt thereof.

12. The compound 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide; or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable vehicle, diluent or carrier.

14. A crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2), wherein said crystalline form has an analytical parameter selected from the group consisting of:

a solid state NMR spectrum comprising 13C chemical shifts (ppm) at 124.2±0.2, 126.4±0.2, and 152.6±0.2;

a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 17.8±0.2, 10.1±0.2, and 15.1±0.2; and

a Raman spectrum comprising Raman peak shifts (cm-1) at 1660±2, 1597±2, and 815±2.

15. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has a solid state NMR spectrum further comprising a 13C chemical shift (ppm) at 37.9±0.2.

16. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has a solid state NMR spectrum further comprising a 13C chemical shift (ppm) at 119.6±0.2.

17. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising a peak at a diffraction angle (20) of 13.3±0.2.

18. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has powder X-ray diffraction pattern further comprising a peak at a diffraction angle (20) of 24.7±0.2.

19. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has a Raman spectrum further comprising a Raman peak shift (cm-1) at 639±2.

20. The crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]methyl}phenoxy)benzamide (Form 2) of claim 14 , wherein said crystalline form has a Raman spectrum further comprising a Raman peak shift (cm-1) at 1174±2.

21. A pharmaceutical composition comprising the crystalline form of 4-(4-{[(2S)-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl] methyl}phenoxy)benzamide (Form 2) of claim 14 in a therapeutically effective amount in admixture with at least one pharmaceutically acceptable excipient.

22. A method of antagonizing kappa opioid receptors, the method comprising administering to a patient a therapeutically effective amount of the crystalline form of claim 14 .

23. A method of treating a neurological disorder or a psychiatric disorder in which the kappa opioid receptor is involved in a patient having said disorder, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of claim 14 .

24. A crystalline form according to claim 14 , or a pharmaceutically acceptable salt thereof for use in antagonizing kappa opioid receptors.

25. A crystalline form according to claim 14 , or a pharmaceutically acceptable salt thereof for use in treatment of a neurological disorder or a psychiatric disorder in which the kappa opioid receptor is involved in a patient having said disorder.