IP Library › Granted Patent US 9,120,770

Granted Patent B2

US 9,120,770 · App. 14/204,934 · Granted Sep 1, 2015

Substituted pyridine and pyrazine compounds as PDE4 inhibitors

Inventors: Venkataiah Bollu (San Diego, CA); James Breitenbucher (Escondido, CA); Alan Kaplan (San Diego, CA); Robert Lemus (Escondido, CA); Andrew Lindstrom (San Diego, CA); Troy Vickers (San Diego, CA); Mark E. Wilson (Ramona, CA); James Zapf (San Diego, CA)

Assignee: Dart NeuroScience (Cayman) Ltd.

C07D409/06 C07D213/64 C07D241/18 C07D401/06 C07D401/14 C07D403/06 C07D405/12 C07D405/14 C07D413/06 C07D417/06

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Quick Facts

Patent No.: US 9,120,770
App. No.: 14/204,934
Granted: Sep 1, 2015
Kind: B2

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Abstract

The invention provides a chemical entity of Formula (I) wherein R 1 , R 2 , R 3 , R 4 , Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.

Claims (292)

1. A chemical entity of Formula (I):

wherein:

Z is CH;

R 1 is a member selected from the group consisting of: —H, —C 1-3 alkyl and —C 1-3 haloalkyl;

Y is —C(R a ) 2 —, where each R a is independently selected from the group consisting of: —H, —F, —CH 3 , —OH and —N(R b ) 2 ;

R 2 is a member selected from the group consisting of:

A) phenyl unsubstituted or substituted with one or two R c members, where each R c is independently selected from the group consisting of: halo, —CN, —CO 2 R b , —CONH 2 , —SO 2 CH 3 , —C(R b ) 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CH 2 CO 2 CH 3 , —NHCONH 2 , —NHCONH-oxetane, —CONH-oxetane,

B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, —C 1-3 alkyl, —C 1-3 haloalkyl, —CN, —C(R b ) 2 OH, —CH 2 NH 2 , —OC 1-3 alkyl, —O—CH 2 -cyclopropyl, —CO 2 H, —CON(R b ) 2 , —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 N(CH 3 ) 2 , —NHcyclopropyl, and —NHCOCH 3 ;

C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, —C 1-3 alkyl, —C 1-3 haloalkyl, —C(R b ) 2 OH, —N(R b ) 2 , —NO 2 , —CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 NH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and

D) five or six-membered heteroaromatic ring selected from: 1,2-dihydro-pyridin-2-one, tetrazole, thiazole or oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of —CH 3 , and —NH 2 ;

R 3 is a member selected from the group consisting of: phenyl, pyridyl, thiophene, and pyrazole, each substituted with a member selected from the group consisting of: halo, —C 1-3 alkyl, —C 1-3 haloalkyl, —OC 1-3 alkyl, —Ocyclopropyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH and —SO 2 CH 3 ;

R 4 is a member selected from the group consisting of —C 1-3 alkyl and —C 1-3 haloalkyl; and

each R b is independently selected from —H or —CH 3 ;

wherein the chemical entity is selected from the group consisting of compounds of Formula (I), and pharmaceutically acceptable salts of compounds of Formula (I).

2. A chemical entity as in claim 1 , wherein R 1 is selected from the group consisting of —H, —CH 3 , and —CF 3 .

3. A chemical entity as in claim 1 , wherein Y is selected from the group consisting of —CH 2 —, —CH(F)—, —CH(OH)—, —C(OH)(CH 3 )—, and —CH(CH 3 )—.

4. A chemical entity as in claim 1 , wherein R 2 is

and R c is a member selected from the group consisting of: —F, —CN, —CO 2 H, —CONH 2 , —SO 2 CH 3 , —C(CH 3 ) 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CH 2 CO 2 CH 3 , —NHCONH 2 , —NHCONH-oxetane, —CONH-oxetane,

5. A chemical entity as in claim 1 , wherein R 2 is

and R c is selected from —F, —CONH 2 , —CH 2 CONH 2 , —CH 2 NH 2 , —C(CH 3 ) 2 OH, —SO 2 CH 3 , and —NHCONH 2 .

6. A chemical entity as in claim 1 , wherein R 2 is pyridine, unsubstituted or substituted with one or two members each independently selected from the group consisting of —F, —C 1-3 alkyl, —C 1-3 haloalkyl, —OC 1-3 alkyl, —OCH 2 cyclopropyl, —CN, —N(R b ) 2 , —CH 2 NH 2 , —CO 2 H, —CON(R b ) 2 , and —C(CH 3 ) 2 OH.

7. A chemical entity as in claim 1 , wherein R 2 is

R d is selected from the group consisting of: —CH 3 , —CF 3 , —CN, —N(R b ) 2 , —CO 2 H, —CON(R b ) 2 , —OC 1-3 alkyl, —CH 2 NH 2 , —C(CH 3 ) 2 OH, —OCH 2 cyclopropyl, and —OCH(CH 3 ) 2 .

8. A chemical entity as in claim 1 , wherein R 2 is

unsubstituted or substituted with R d ; where R d is —CH 3 , —CF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —OC 1-3 alkyl, —C(CH 3 ) 2 OH, or —OCH 2 cyclopropyl.

9. A chemical entity as in claim 1 , wherein R 2 is selected from the group consisting of pyrazine, 6-methylpyridazin-3-amine and pyrimidine, where pyrimidine is optionally substituted with —Cl, —CH 3 , —CN, —OC 1-3 alkyl, —CO 2 H, —CON(R b ) 2 , —C(CH 3 ) 2 OH, —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —NHcyclopropyl, or —NHCOCH 3 .

10. A chemical entity as in claim 1 , wherein R 2 is

unsubstituted or substituted with one or two R e members, where each R e is independently —CH 3 , —CN, —OCH 3 , —CO 2 H, —CONH 2 , —C(CH 3 ) 2 OH, —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —NHcyclopropyl, or —NHCOCH 3 .

11. A chemical entity as in claim 1 , wherein R 2 is

unsubstituted or substituted with R e , where R e is selected from the group consisting of: —CH 3 , —CN, —OCH 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CF 3 , —NHcyclopropyl, —C(CH 3 ) 2 OH, —CONH 2 , —CONHCH 3 , and —CON(CH 3 ) 2 .

12. A chemical entity as in claim 1 , wherein R 2 is selected from the group consisting of imidazole, pyrazole, and triazole, unsubstituted or substituted with one or two members each independently selected from the group consisting of: —Cl, —CH 3 , —CF 3 , —CH 2 OH, —NH 2 , —NO 2 , —CN, —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , and —NHCOCH 3 .

13. A chemical entity as in claim 1 , wherein R 2 is

and R f is a member selected from the group consisting of: —H, —CH 3 , —NO 2 , —NH 2 , —NHCOCH 3 , —CH 2 OH, —CN, —CONH 2 , —CO 2 H, and —CO 2 CH 2 CH 3 .

14. A chemical entity as in claim 1 , wherein R 2 is

and R f is a member selected from the group consisting of: —H, —NH 2 , and —CH 2 OH.

15. A chemical entity as in claim 1 , wherein R 2 is

where R g is a member selected from the group consisting of: —H, —CH 3 , —CH 2 OH, and —NH 2 .

16. A chemical entity as in claim 1 , wherein R 2 is 1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, optionally unsubstituted or substituted with a member independently selected from the group consisting of: —CH 3 , and —NH 2 .

17. A chemical entity as in claim 1 , wherein R 2 is selected from the group consisting of 1,2,3-triazole and 1,2,4-triazole, each unsubstituted or substituted with a member selected from the group consisting of: —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , —CN, —C(R 1 )OH, —CH 2 OCH 3 , N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CONH 2 , cyclopropyl and —CH 2 NH 2 .

18. A chemical entity as in claim 1 , wherein R 2 is

and R h is a member selected from the group consisting of: —H, —CH 3 , —CF 3 , —CH 2 F, —CHF 2 , —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CN, —CONH 2 , —CO 2 CH 3 , and -cyclopropyl.

19. A chemical entity as in claim 1 , wherein R 2 is

and R j is a member selected from the group consisting of: —H, —CH 3 , —CF 3 , —OCH 3 , —CH 2 (OH), —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CO 2 CH 3 , and —NO 2 .

20. A chemical entity as in claim 1 , wherein R 2 is

and R k is a member selected from the group consisting of: —H, —CH 3 , —CF 3 , —CH 2 F, —CHF 2 , —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CN, —CONH 2 , —CO 2 CH 3 , and -cyclopropyl.

21. A chemical entity as in claim 1 , wherein R 3 is

where R m is a member selected from the group consisting of: —Cl, —F, —CH 3 , —CHF 2 , —CN, —OCH 3 , —CH 2 OH, —OCH 2 CH 3 , —OCF 3 , —OCHF 2 , —SO 2 CH 3 , —OCH(CH 3 ) 2 ,

22. A chemical entity as in claim 1 , wherein R 3 is a member selected from the group consisting of: 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl and 3-(difluoromethyl)phenyl.

23. A chemical entity as in claim 1 , wherein R 3 is

substituted or unsubstituted with R n , where R n is a member selected from the group consisting of: —Cl, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCHF 2 , and —OCF 3 .

24. A chemical entity as in claim 1 , wherein R 3 is a member selected from the group consisting of: 4-chlorothiophen-2-yl, 4-chloro-1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl, and 1H-pyrazol-4-yl.

25. A chemical entity as in claim 1 , wherein R 4 is a member selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and —CHF 2 .

26. A chemical entity, selected from the group consisting of:

2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;

{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine;

2-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol;

3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol;

1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol;

[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol;

{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine;

[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine;

{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine;

3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine;

4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;

(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea;

4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine;

5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;

1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea;

3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine;

(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol;

5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile;

5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;

N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine;

5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine;

2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol;

3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one;

3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid;

(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine;

4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;

3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine;

4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile;

4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;

3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine;

3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine;

3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;

(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine;

3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;

3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine;

3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine;

Methyl 2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate;

Ethyl 1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate;

3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine;

2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine;

6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine;

3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide;

5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide;

5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;

5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;

5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;

5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;

5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide;

3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine;

3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile;

2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine;

3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;

Methyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;

3-(4-Chlorothiophen-2-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine;

3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine;

1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine;

1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide;

Ethyl 1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile;

2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide;

3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine;

2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one;

5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine;

3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine;

1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide;

(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;

[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol;

(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;

[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;

3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine;

1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile;

1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;

1-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;

1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine;

1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine;

1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine;

1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine;

4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine;

4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine;

1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine;

1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine;

(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide;

2-Methoxy-3-(1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide;

1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide;

2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide;

2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol;

2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol;

2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol;

2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;

2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol;

3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine;

2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;

3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine;

3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine;

3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine;

[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;

(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol;

3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid;

1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide;

[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol;

(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol;

(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol;

[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol;

(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol;

(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol;

(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol;

3-(4-Chloro-1H-pyrazol-1-yl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;

4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid;

and pharmaceutically acceptable salts thereof.

27. A pharmaceutical composition comprising an effective amount of at least one chemical entity selected from the compounds of Formula (I):

wherein:

Z is CH;

R 1 is a member selected from the group consisting of: —H, —C 1-3 alkyl and —C 1-3 haloalkyl;

Y is —C(R a ) 2 —, where each R a is independently selected from the group consisting of: —H, —F, —CH 3 , —OH and —N(R b ) 2 ;

R 2 is a member selected from the group consisting of:

R 3 is a member selected from the group consisting of: phenyl, pyridyl, thiophene, and pyrazole, each unsubstituted or substituted with a member selected from the group consisting of: halo, —C 1-3 alkyl, —C 1-3 halo alkyl, —Ocyclopropyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH and —SO 2 CH 3 ;

R 4 is a member selected from the group consisting of —C 1-3 alkyl and —C 1-3 haloalkyl;

where each R b is independently selected from —H or —CH 3 ;

and pharmaceutically acceptable salt of compounds of Formula (I).

28. A pharmaceutical composition comprising an effective amount of at least one chemical entity of claim 1 .

29. A chemical entity as in claim 1 , wherein the chemical entity is a compound of Formula (I).

30. A composition of claim 1 , wherein the chemical entity is selected from compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I).

Assignments (10)

MERGER Recorded Dec 2, 2021

From: DART NEUROSCIENCE (CAYMAN) LTD.

To: DART NEUROSCIENCE LLC

Reel/Frame 058275/0272 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2015

From: DART NEUROSCIENCE, LLC

To: DART NEUROSCIENCE (CAYMAN) LTD.

Reel/Frame 035268/0601 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2014

From: LEMUS, ROBERT

To: DART NEUROSCIENCE, LLC