US2016009691A1PendingUtilityA1
Substituted pyridine and pyrazine compounds as pde4 inhibitors
Assignee: DART NEUROSCIENCE CAYMAN LTDPriority: Mar 14, 2013Filed: Mar 6, 2014Published: Jan 14, 2016
Est. expiryMar 14, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Venkataiah BolluJames BreitenbucherAlan P. KaplanRobert Huerta LemusAndrew LindstromTroy VickersMichael WeinhouseMark E. WilsonJames Zapf
A61P 7/00A61P 37/08A61P 9/10A61P 43/00A61P 35/00A61P 9/00A61P 9/12A61P 25/04A61P 25/20A61P 25/36A61P 25/28A61P 25/34A61P 25/16A61P 25/24A61P 25/18A61P 29/00A61P 25/32A61P 25/22A61P 25/14A61P 17/00A61P 13/12A61P 1/04A61P 11/02A61P 17/06A61P 21/00A61P 25/00A61P 11/00A61P 11/06A61P 1/00A61P 19/02C07D 241/18C07D 405/12C07D 413/06C07D 417/06C07D 213/73C07D 213/64C07D 213/81A61K 51/0459C07D 213/74C07D 403/06C07D 401/06C07D 405/14C07D 401/14C07D 409/06C07D 239/34C07D 409/14A61K 31/506A61K 31/501A61K 31/497A61K 31/4965A61K 31/455A61K 31/444A61K 31/4418A61K 31/427A61K 31/422A61K 31/4196A61K 31/4178A61K 31/337
64
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The invention provides a chemical entity of Formula (I), 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
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A chemical entity of Formula (I):
wherein:
Z is CH or N;
i) wherein when Z is CH, then;
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 C 1-3 alkyl, —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, —OH, —C(R b ) 2 OH, —CH 2 NH 2 , —C(R b ) 2 CN, —C(R b ) 2 CONH 2 , —OCH 2 CONH 2 , —OC 1-3 alkyl, —OCH 2 C(R b ) 2 OH, —OCH 2 cyclopropyl, —OC 1-3 haloalkyl, —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 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;
C) five-membered monocyclic heteroaromatic ring containing two, three, or four 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, —CH 2 CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and
D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-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 phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, —C 1-3 alkyl, —OC 1-3 alkyl, —Ocyclopropyl, —O-oxetane, —C 1-3 haloalkyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH, —SO 2 CH 3 , or —N(CH 3 ) 2 ;
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 ;
ii) wherein when Z is N, then;
R 1 is —H;
Y is —CH 2 —;
R 2 is a member selected from the group consisting of:
A) phenyl substituted with one or two R d members, where each R d is independently selected from the group consisting of: —CN, —CONH 2 , and —CO 2 C 1-3 alkyl;
B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl;
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 —C 1-3 alkyl, —C 1-3 haloalkyl, —CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , or cyclopropyl; and
D) 1,2-oxazole optionally substituted with one or two R b members;
R 3 phenyl substituted with one or two members each independently selected from the group consisting of: —Cl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl;
R 4 is —C 1-3 alkyl; 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), pharmaceutically acceptable salts of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); and pharmaceutically active metabolites of compounds of Formula (I).
2 . A chemical entity as in claim 1 , wherein Z is CH.
3 . A chemical entity as in claim 1 , wherein Z is N.
4 . A chemical entity as in claim 2 , wherein R 1 is selected from the group consisting of —H, —CH 3 , and —CF 3 .
5 . A chemical entity as in claim 3 , wherein R 1 is —H.
6 . A chemical entity as in claim 2 , wherein Y is selected from the group consisting of —CH 2 —, —CH(F)—, —CH(OH)—, —C(OH)(CH 3 )—, and —CH(CH 3 )—.
7 . A chemical entity as in claim 3 , wherein Y is —CH 2 —.
8 . A chemical entity as in claim 1 , wherein Z is CH and R 2 is
where 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 , —CH 2 CO 2 CH 2 CH 3 , —NHCONH 2 , —NHCONH-oxetane, —CONH-oxetane,
9 . A chemical entity as in claim 2 , 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 .
10 . A chemical entity as in claim 3 , wherein R 2 is 4-cyanophenyl, 4-phenylamide or 4-phenylcarboxylic acid methyl ester.
11 . A chemical entity as in claim 1 , wherein Z is CH and R 2 is selected from the group consisting of 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 , —CH 2 OH, —CO 2 H, —CON(R b ) 2 , and —C(CH 3 ) 2 OH.
12 . A chemical entity as in claim 1 , wherein Z is CH and 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 , —CH 2 OH, —C(CH 3 ) 2 OH, —OCH 2 cyclopropyl, and —OCH(CH 3 ) 2 .
13 . A chemical entity as in claim 1 , wherein Z is CH and 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, —CH 2 OH, —C(CH 3 ) 2 OH, or —OCH 2 cyclopropyl.
14 . A chemical entity as in claim 3 , wherein R 2 is
R d1 is —CN or —CONH 2 .
15 . A chemical entity as in claim 2 , wherein R 2 is selected from the group consisting of pyrazine, pyridazine and pyrimidine; where pyrazine is optionally unsubstituted or substituted with —C 1-3 alkyl, —OC 1-3 alkyl, —N(R b ) 2 , or —NHCH 2 CH 2 OH; pyridazine is optionally unsubstituted or substituted with —C 1-3 alkyl; and pyrimidine is optionally substituted with a group consisting of: —H, —Cl, —C 1-3 alkyl, —CN, —OH, —OC 1-3 alkyl, —OC 1-3 haloalkyl, —CO 2 H, —CON(R b ) 2 , —C(R b ) 2 CONH 2 , —C(R b ) 2 OH, —C(R b ) 2 CN, —CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 C(R b ) 2 OH, —OCH 2 CONH 2 , —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.
16 . A chemical entity as in claim 2 , wherein R 2 is
unsubstituted or substituted with one or two R e members, where each R e is independently —H, —Cl, —C 1-3 alkyl, —CN, —OCH 3 , —OC 1-3 haloalkyl, —CO 2 H, —CONH 2 , —C(R b ) 2 CONH 2 , —C(R b ) 2 OH, —C(R b ) 2 CN, —CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 C(R b ) 2 OH, —OCH 2 CONH 2 , —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol.
17 . A chemical entity as in claim 3 , wherein R 2 is
unsubstituted or substituted with R e1 , where R e1 is —OCH 3 , —CN, —CONH 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 2 OH, —NHcyclopropyl.
18 . A chemical entity as in claim 2 , wherein R 2 is
unsubstituted or substituted with R e , where R e is selected from: —H, —Cl, —CH 3 , —CN, —OH, —OCH 3 , —OCHF 2 , —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 .
19 . A chemical entity as in claim 2 , wherein R 2 is selected from the group consisting of imidazole, pyrazole, triazole, and tetrazole, where each is unsubstituted or substituted with one or two members each independently selected from the group consisting of: —Cl, —CH 3 , —CHF 2 , —CF 3 , —CH 2 OH, —CH 2 CN, —CH 2 CONH 2 , —CH 2 CH 2 OH, —NH 2 , —NO 2 , —CN, —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , and —NHCOCH 3 .
20 . A chemical entity as in claim 2 , wherein R 2 is
and R f is a member selected from the group consisting of: —H, —Cl, —CH 3 , —NO 2 , —NH 2 , —NHCOCH 3 , —CH 2 OH, —CN, —CONH 2 , —CO 2 H, and —CO 2 CH 2 CH 3 .
21 . 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.
22 . 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, —CONH 2 , and —NH 2 .
23 . A chemical entity as in claim 2 , 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 , —CH 2 OH, —CH 2 CH 2 OH, and —NH 2 .
24 . A chemical entity as in claim 2 , 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 independently selected from the group consisting of: —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , —CN, —CH 2 CN, —CH 2 CONH 2 , —C(R b )OH, —CH 2 OCH 3 , N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CONH 2 , cyclopropyl and —CH 2 NH 2 .
25 . 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, —CH 2 CN, —CH 2 CONH 2 , —CONH 2 , —CO 2 CH 3 , and -cyclopropyl.
26 . A chemical entity as in claim 2 , 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 .
27 . A chemical entity as in claim 2 , 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.
28 . A chemical entity as in claim 2 , wherein R 3 is a member selected from the group consisting of:
where R m is —Cl, —F, —CH 3 , —CHF 2 , —CF 3 , —CN, —OCH 3 , —CH 2 OH, —OCH 2 CH 3 , —OCF 3 , —OCHF 2 , —N(CH 3 ) 2 , —SO 2 CH 3 , —OCH(CH 3 ) 2 ,
29 . A chemical entity as in claim 2 , wherein R 3 is a member selected from the group consisting of: 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl, 3-(difluoromethyl)phenyl, 3-(dimethylamino)phenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chloropyridin-3-yl, 3,4-difluorophenyl, 3,5-difluorophenyl, (3-fluoro-5-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methoxyphenyl or 3-ethoxy-4-fluorophenyl.
30 . A chemical entity as in claim 2 , 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 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCHF 2 , —OCF 3 and —CN.
31 . A chemical entity as in claim 2 , 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 .
32 . A chemical entity, selected from the group consisting of:
5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile; 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-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide; [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-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile; 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; 3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine; 3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine; (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; Methyl 4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate; 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}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-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide; 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)pyrazine; 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)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine; 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; 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile; 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine; 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine; 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine; 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile; 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile; 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; 4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide; 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; 5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide; 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide; 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide; 5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide; Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate; 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-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine; 3-(3-Chlorophenyl)-2-(difluoromethoxy)-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]pyrazine; 3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine; 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-(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; 3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine; 3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine; 3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine; 3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine; 5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate; Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate; 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine; 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine; Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate; Methyl 1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate; Methyl 1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate; 1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide; (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (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; [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol; (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol; [1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-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-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine; 1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-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; 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-(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-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine; 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; [1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol; (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol; [1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol; (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-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; 4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoic acid; (1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol; 5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine; 5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine; 2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide; 2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 2-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-01; 2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile; 2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile; 3-(3-Chlorophenyl)-5-[(5-ethoxypyridin-2-yl)methyl]-2-methoxypyridine; 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine; 5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine; 2-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5-ethoxypyrazine; 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino) ethanol; 3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1H-tetrazol-1-yl)methylpyridine; 4-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine; 5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine; 2-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol; 2-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol; 2-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine; 2′-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4′-bipyridine; 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide; (5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol; (1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol; 5-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine; 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol; 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol; 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine; 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine; 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine; 1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide; 1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide; 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide; 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide; 1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-imidazole-4-carboxamide; 1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide; 1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide; 1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide; [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol; [1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol; 1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine; 1-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol; (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol; (1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; [1-({6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; [1-({6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; (1-{[6-Ethoxy-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; [1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; [1-({6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; (1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[6-Ethoxy-5-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; (1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 4-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile; 2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile; 5-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile; 5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile; 5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 2-(4-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 2-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide; 2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 2-(5-{[5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide; 5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol; (5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol; 2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine; 6-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-3-carbonitrile; 5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine; 3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; (2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; (1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; (2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; (1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; (2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; (1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; (1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; (2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; 1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol; 1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-ol; 2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol; 2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 2-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 2-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 2-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine; (5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol; [5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol; (1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; Ethyl 2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate; Ethyl 2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate; and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, or pharmaceutically active metabolites thereof.
33 . A pharmaceutical composition comprising an effective amount of at least one chemical entity selected from the compounds of Formula (I):
wherein:
Z is CH or N;
i) wherein when Z is CH, then;
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 C 1-3 alkyl, —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, —OH, —C(R b ) 2 OH, —CH 2 NH 2 , —C(R b ) 2 CN, —C(R b ) 2 CONH 2 , —OCH 2 CONH 2 , —OC 1-3 alkyl, —OCH 2 C(R b ) 2 OH, —OCH 2 cyclopropyl, —OC 1-3 haloalkyl, —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 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;
C) five-membered monocyclic heteroaromatic ring containing two, three, or four 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, —CH 2 CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and
D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-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 phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, —C 1-3 alkyl, —OC 1-3 alkyl, —Ocyclopropyl, —C 1-3 haloalkyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH, —SO 2 CH 3 , or —N(CH 3 ) 2 ; 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 ;
ii) wherein when Z is N, then;
R 1 is —H;
Y is —CH 2 —;
R 2 is a member selected from the group consisting of:
A) phenyl substituted with one or two R d members, where each R d is independently selected from the group consisting of: —CN, —CONH 2 , and —CO 2 C 1-3 alkyl;
B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl;
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 —C 1-3 alkyl, —C 1-3 haloalkyl, —CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , or cyclopropyl; and
D) 1,2-oxazole optionally substituted with one or two R b members;
R 3 phenyl substituted with one or two members each independently selected from the group consisting of: —Cl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl;
R 4 is —C 1-3 alkyl; and
each R b is independently selected from —H or —CH 3 ;
and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).
34 . A pharmaceutical composition comprising an effective amount of at least one chemical entity of claim 1 or 32 .
35 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by PDE4 enzymatic activity, comprising administering to a subject in need of such treatment an effective amount of a chemical entity selected from compounds of Formula (I)
wherein:
Z is CH or N;
i) wherein when Z is CH, then;
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 C 1-3 alkyl, —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, —OH, —C(R b ) 2 OH, —CH 2 NH 2 , —C(R b ) 2 CN, —C(R b ) 2 CONH 2 , —OCH 2 CONH 2 , —OC 1-3 alkyl, —OCH 2 C(R b ) 2 OH, —OCH 2 cyclopropyl, —OC 1-3 haloalkyl, —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 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;
C) five-membered monocyclic heteroaromatic ring containing two, three, or four 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, —CH 2 CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and
D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-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 phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, —C 1-3 alkyl, —OC 1-3 alkyl, —Ocyclopropyl, —O-oxetane, —C 1-3 haloalkyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH, —SO 2 CH 3 , or —N(CH 3 ) 2 ; R 4 is a member selected from the group consisting of —C 1 -3alkyl and —C 1-3 haloalkyl; and
each R b is independently selected from —H or —CH 3 ;
ii) wherein when Z is N, then;
R 1 is —H;
Y is —CH 2 —;
R 2 is a member selected from the group consisting of:
A) phenyl substituted with one or two R d members, where each R d is independently selected from the group consisting of: —CN, —CONH 2 , and —CO 2 C 1-3 alkyl;
B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl;
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 —C 1-3 alkyl, —C 1-3 haloalkyl, —CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , or cyclopropyl; and
D) 1,2-oxazole optionally substituted with one or two R b members;
R 3 phenyl substituted with one or two members each independently selected from the group consisting of: —Cl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl;
R 4 is —C 1-3 alkyl; and
each R b is independently selected from —H or —CH 3 ;
and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).
36 . The method of claim 35 , wherein Y is —CH 2 — and Z is CH.
37 . A method of treating a disease, disorder, or medical condition mediated by a PDE4 enzyme, comprising administering to an animal in need of such treatment an effective amount of a chemical entity of claim 1 or claim 32 .
38 . The method of claim 35 , 36 , or 37 , wherein the disorder is selected from one or more of the group selected from Alzheimer's Disease, Age Associated Memory Impairment (AAMI), Age Associated Cognitive Decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, an affective disorder, psychotic disorders, neurotic disorders, attention deficit disorder, subdural hematoma, normal-pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis.
39 . A method for modulating PDE4 enzyme activity, comprising exposing a PDE4 enzyme to an effective amount of at least one chemical entity selected from compounds of Formula (I)
wherein:
Z is CH or N;
i) wherein when Z is CH, then;
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 C 1-3 alkyl, —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, —OH, —C(R b ) 2 OH, —CH 2 NH 2 , —C(R b ) 2 CN, —C(R b ) 2 CONH 2 , —OCH 2 CONH 2 , —OC 1-3 alkyl, —OCH 2 C(R b ) 2 OH, —OCH 2 cyclopropyl, —OC 1-3 haloalkyl, —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 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;
C) five-membered monocyclic heteroaromatic ring containing two, three, or four 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, —CH 2 CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and
D) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-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 phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, —C 1-3 alkyl, —OC 1-3 alkyl, —Ocyclopropyl, —C 1-3 haloalkyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH, —SO 2 CH 3 , or —N(CH 3 ) 2 ; R 4 is a member selected from the group consisting of —C 1-3 alkyl and —C 1 -3haloalkyl; and
each R b is independently selected from —H or —CH 3 ;
ii) wherein when Z is N, then;
R 1 is —H;
Y is —CH 2 —;
R 2 is a member selected from the group consisting of:
A) phenyl substituted with one or two R d members, where each R d is independently selected from the group consisting of: —CN, —CONH 2 , and —CO 2 C 1-3 alkyl;
B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl;
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 —C 1-3 alkyl, —C 1-3 haloalkyl, —CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , or cyclopropyl; and
D) 1,2-oxazole optionally substituted with one or two R b members;
R 3 phenyl substituted with one or two members each independently selected from the group consisting of: —Cl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl;
R 4 is —C 1-3 alkyl; and
each R b is independently selected from —H or —CH 3 ;
and pharmaceutically acceptable salt of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I); or pharmaceutically active metabolites of compounds of Formula (I).
40 . The method of claim 39 , wherein Y is —CH 2 — and Z is CH.
41 . A method for modulating PDE4 enzyme activity, comprising exposing a PDE4 enzyme to an effective amount of a chemical entity of claim 1 or claim 32 .
42 . The method of claim 41 , wherein said one or more PDE4 enzymes are in a human subject.
43 . The method of claim 42 , wherein said human subject is suffering from or is diagnosed with a disease, disorder, or medical condition mediated by PDE4 enzymatic activity.
44 . The method of claim 43 , wherein said disease, disorder, or medical condition is of the central nervous system selected from the group consisting of age-associated memory impairment, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, and Pick's disease.
45 . A method of treating a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a chemical entity of claim 1 or claim 32 .
46 . The method of claim 45 , wherein the disorder is selected from the group consisting of a central nervous system (CNS) disorder, psychiatric disorder, personality disorder, substance-related disorder, dissociative disorder, eating disorder, sleep disorder, developmental disorder, neurodegenerative disorder, trauma-related disorder, pain disorder, and a cognitive disorder.
47 . The method of claim 46 , wherein the psychiatric disorder is selected from the group consisting of a mood disorder, psychotic disorder, and anxiety disorder.
48 . The method of claim 47 , wherein the mood disorder is selected from the group consisting of a depressive disorder, including a dysthymic disorder, major depressive disorder, mania, bipolar disorders (I and II), and cyclothymic disorder.
49 . The method of claim 47 , wherein the psychotic disorder is one or more selected from the group consisting of schizophrenia; schizophreniform disorder; schizoaffective disorder; a delusional disorder; a brief psychotic disorder; shared psychotic disorder; and a substance-induced psychotic disorder.
50 . The method of claim 47 , wherein the anxiety disorder is selected from the group consisting of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder; and acute stress disorder.
51 . The method of claim 46 , wherein the personality disorder is selected from the group consisting of a disorder of Cluster A (odd or eccentric), such as paranoid or schizoid personality disorder; a disorder of Cluster B (dramatic, emotional, or erratic), such as antisocial, borderline, or narcissistic personality disorder; and a disorder of Cluster C (anxious or fearful), such as avoidant, dependent, or obsessive-compulsive personality disorder.
52 . The method of claim 46 , wherein the substance-related disorder is selected from the group consisting of an alcohol-related disorder, a cocaine-related disorder, a hallucinogen-related disorder, an inhalant-related disorder, a nicotine-related disorder, an opioid-related disorder, a phencyclidine (or phencyclidine-like) related disorder, and a sedative-, hypnotic-, or anxiolytic-related disorder.
53 . A method of smoking cessation, comprising administering to an animal in need thereof of a chemical entity of claim 1 or claim 32 .
54 . The method of claim 53 , wherein the dissociative disorder is selected from the group consisting of depersonalization disorder, dissociative amnesia, and dissociative identity disorder.
55 . The method of claim 46 , wherein the eating disorder is selected from the group consisting of anorexia nervosa and bulimia nervosa.
56 . The method of claim 46 , wherein the sleep disorder is selected from the group consisting of a primary sleep disorder, parasomnia, and restless legs syndrome.
57 . The method of claim 46 , wherein the developmental disorder is selected from the group consisting of mental retardation, a learning disorder, a motor skill disorder, a communication disorder, a pervasive developmental disorder, an attention-deficit or disruptive disorder, and a tic disorder.
58 . The method of claim 57 , wherein the pervasive developmental disorder is an autistic disorder.
59 . The method of claim 57 , wherein the attention-deficit or disruptive disorder is an attention-deficit hyperactivity disorder.
60 . The method of claim 46 , wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis (ALS).
61 . The method of claim 60 , wherein the neurodegenerative disorder is Parkinson's disease.
62 . The method of claim 46 , wherein the neurodegenerative disorder is selected from the group consisting of a dyskinesia, a basal ganglia disease, a hypokinetic disease, a movement disorder, and neuronal damage.
63 . The method of claim 62 , wherein the neuronal damage is selected from the group consisting of brain edema and ocular damage.
64 . The method of claim 46 , wherein the pain disorder is selected from the group consisting of acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
65 . The method of claim 46 , wherein the cognitive disorder is selected from the group consisting of age-associated memory impairment (AAMI), mild cognitive impairment (MCI), delirium, and dementia.
66 . A method of treating Alzheimer's disease or Parkinson's disease, comprising administering to an animal in need thereof an effective amount of a chemical entity of claim 1 or claim 32 .
67 . A method of treating a cognitive disorder, comprising administering to an animal in need thereof an effective amount of a compound, or derivative of claim 1 or claim 32 .
68 . The method of claim 67 , wherein the cognitive disorder is an age-associated cognitive disorder.
69 . The method of claim 68 , wherein the age-associated cognitive disorder is age-associated memory impairment (AAMI or AMI).
70 . The method of claim 68 , wherein the age-associated cognitive disorder is mild cognitive impairment (MCI).
71 . A method of treating a cognitive deficit associated with Parkinson's disease, comprising administering to an animal in need thereof an effective amount of a chemical entity of claim 1 or claim 32 .
72 . A method of treating a cognitive disorder, comprising:
(a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a chemical entity of claim 1 or claim 32 to the animal in conjunction with said cognitive training; and (c) repeating steps (a) and (b) one or more times; whereby the number of training sessions sufficient to produce the improvement in performance are reduced relative to the same improvement in performance produced by cognitive training alone.
73 . A method of treating a motor deficit, comprising:
(a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said motor deficit; (b) administering a chemical entity of claim 1 or claim 32 to the animal in conjunction with said motor training; and (c) repeating steps (a) and (b) one or more times; whereby the number of training sessions sufficient to produce the improvement in performance are reduced relative to the same improvement in performance produced by motor training alone.
74 . The method of claim 35 - 38 , 42 - 73 , wherein said subject is a human.
75 . A method comprising:
a) administering a CREB augmenting agent to a non-human animal; b) providing to said animal a training protocol under conditions to improve performance by said animal of one or more tasks, wherein said training protocol comprises multiple training sessions; whereby the number of training sessions necessary to improve said performance relative to the number of said training sessions required to improve said performance in the absence of said CREB augmenting agent are reduced, wherein said CREB augmenting agent is a chemical entity of claim 1 or claim 32 .
76 . The method of claim 75 , wherein providing step b) is under conditions to improve performance of a single task.
77 . The method of claim 75 , wherein said providing step b) is under conditions to improve performance of a complex set of tasks.
78 . The method of claim 75 , wherein said providing step b) is under conditions that improve performance by said animal of related tasks that are not part of the training protocol.
79 . The method of claim 75 , wherein said non-human animal is a horse.
80 . The method of claim 75 , wherein said non-human animal is a dog.
81 . The method of claim 75 , wherein said one or more tasks relate to a skill useful in law enforcement.
82 . The method of claim 81 , wherein said skill includes one or more of the following: public order maintenance, search and rescue, and contraband detection.
83 . The method of claim 75 , wherein said one or more tasks relate to a skill useful in private security.
84 . The method of claim 75 , wherein said one or more tasks relate to a skill useful in service to the handicapped.
85 . The method of claim 75 , wherein said one or more tasks relate to a skill useful in health care.
86 . The method of claim 75 , wherein said one or more tasks relate to a skill useful in psychiatric assistance.
87 . The method of claim 75 , wherein said one or more tasks relate to pest control.
88 . The method of claim 75 , wherein said training protocol is provided under conditions to improve performance by said non-human animal of a wide scope of tasks, thereby resulting in a generalized improved function of one or more cognitive domains in said non-human animal.
89 . A method of augmenting neurorehabilitation or neurorecovery from a cognitive impairment, comprising (a) providing cognitive training to a subject in need of treatment of a cognitive deficit under conditions sufficient to produce an improvement in performance by said animal of a cognitive function whose impairment is associated with said cognitive deficit; (b) administering a chemical entity of claim 1 or claim 32 to the subject in conjunction with said cognitive training; repeating steps (a) and (b) one or more times; and (d) producing a long-lasting improvement in performance of said function relative to the improvement in performance of said function produced by cognitive training alone.
90 . A method of augmenting neurorehabilitation or neurorecovery from a motor impairment, comprising: (a) providing motor training to a subject in need of treatment of a motor deficit under conditions sufficient to produce an improvement in performance by said animal of a motor function whose impairment is associated with said cognitive deficit; and (b) administering a chemical entity of claim 1 or claim 32 to the subject in conjunction with said motor training; repeating steps (a) and (b) one or more times; thereby reducing the number of training sessions sufficient to produce the improvement in performance, relative to the same improvement in performance produced by motor training alone.
91 . A method of providing neuroprotection, comprising administering to an animal in need thereof an effective amount of a chemical entity as in claim 1 or claim 32 .
92 . The method of any one of claims 75 - 91 wherein the animal or subject is a human.
93 . A method of using a chemical entity as in claim 1 or claim 32 in metabolic studies, detection or imaging techniques, or radioactive treatment.
94 . A chemical entity as in claim 1 or claim 32 , further comprising an isotopic label.
95 . The a chemical entity as in claim 94 , wherein the isotopic label includes at least one atom selected from Hydrogen-2, Hydrogen-3, Carbon-11, Nitrogen-13, Fluorine-18, and Iodine-123.
96 . A method of treating a disorder selected from the group consisting of inflammatory bowel disease; rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases, and psoriasis, comprising administering to a subject in need thereof an effective amount of a chemical entity as in claim 1 or claim 32 .
97 . The method of claim 96 , wherein the disorder is inflammatory bowel disease.
98 . The method of claim 96 , wherein the disorder is rheumatoid arthritis.
99 . The method of claim 96 , wherein the disorder is COPD.
100 . The method of claim 96 , wherein the disorder is asthma.
101 . The method of claim 96 , wherein the disorder is allergic rhinitis.
102 . The method of claim 96 , wherein the disorder is pulmonary artery hypertension.
103 . The method of claim 96 , wherein the disorder is a renal disease.
104 . The method of claim 96 , wherein the disorder is an allergic skin disease.
105 . The method of claim 96 , wherein the disorder is psoriasis.
106 . The method of any one of claims 97 - 105 , wherein the animal or subject is a human.
108 . A chemical entity as in claim 33 or claim 34 , wherein the chemical entity of claim 1 or 32 is a compound of Formula (I).
109 . A composition of claim 33 or claim 34 , wherein the chemical entity of claim 1 or 32 is selected from compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I).
110 . The method of any one of claims 36 - 107 , wherein the chemical entity of claim 1 or 32 is a compound of Formula (I).
111 . The method of any one of claims 36 - 107 , wherein the chemical entity of claim 1 or 32 is selected from compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I).
112 . The use of a chemical entity of claim 1 or 32 in a method of treating stroke.
113 . The use of claim 1 , wherein the method of treating stroke is post-stroke rehabilitation.
114 . A method of post-stroke rehabilitation, comprising:
a. administering to a subject in need thereof a PDE4 inhibitor during recovery of the subject from stroke; b. providing training to the subject under conditions sufficient to improve performance of a neurological function whose impairment is due to said stroke; c. repeating steps (a) and (b) one or more times, whereby the amount of training sufficient to improve said performance is reduced relative to that produced by training alone.
115 . The method of claim 114 , wherein said PDE4 inhibitor is a chemical entity of claim 1 or 32 .
116 . The method of claim 114 , wherein the impairment of the neurological function is a motor deficit.
117 . The method of claim 114 , wherein the impairment of the neurological function is a cognitive deficit.
118 . The method of claim 117 , wherein the cognitive deficit is a deficit in memory formation.
119 . The method of claim 118 , wherein the deficit in memory formation is a deficit in long-term memory formation.
120 . The method of claim 114 , wherein the training comprises a battery of tasks directed to the neurological function.
121 . The method of claim 114 , wherein said administering step (a) occurs in conjunction with said training step (b).
122 . The method of claim 114 , wherein the one or more training steps are separated by a discrete interval.
123 . The method of claim 122 , wherein each training step is provided daily.
124 . The method of claim 123 , wherein the reduction in the amount of training is a reduction in the number of training sessions.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.