Substituted pyridine and pyrazine compounds as pde4 inhibitors

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 treating peripheral disorders, including inflammatory and renal disorders.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof,
 wherein: 
 Z is N; 
 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 , and cyclopropyl; and 
 
 R 3  is phenyl substituted with one or two members each independently selected from the group consisting of —Cl, —OCl 3 alkyl, and —OC 1-3 haloalkyl; 
 R 4  is —C 1-3 alkyl; and 
 each R b  is independently —H or —CH 3 . 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OCl 3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is a 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 -Cl 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 , and cyclopropyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is 4-phenylamide or 4-phenylcarboxylic acid methyl ester. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       where R d1  is —CONH 2 . 
     
     
         6 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       where R e1  is —OCH 3 , —CONH 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 2 OH, or -NHcyclopropyl. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       where R f  is —NH 2 , or —CH 2 OH. 
     
     
         8 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       R g , where R is —H, —CH 3 , —CH 2 OH, or —NH 2 . 
     
     
         9 . The chemical entity as in  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       where 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 , —CH 2 CONH 2 , —CONH 2 , —CO 2 CH 3 , and -cyclopropyl. 
     
     
         10 . The compound of  claim 1 , selected from the group consisting of:
 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;   5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;   5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile;   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;   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;   5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide;   3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine;   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;   4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide;   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)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine;   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-[(4-nitro-H-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-{[6-(3-Chlorophenyl)-5-methoxypyrazin-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-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;   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;   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;   [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-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;   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-{[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;   3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine; and   pharmaceutically acceptable salts thereof.   
     
     
         11 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof,
 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) 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; 
 B) 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 
 C) 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 ; 
 
     
     
         12 . The compound of  claim 11 , wherein R 2  is 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. 
     
     
         13 . The compound of  claim 11 , wherein R 2  is a 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 , and cyclopropyl. 
     
     
         14 . The compound of  claim 11 , selected from the group consisting of:
 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;   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;   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}-1,3-thiazol-2-amine;   5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;   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;   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; and   pharmaceutically acceptable salts thereof.   
     
     
         15 . A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, of  claim 1 ; and a pharmaceutically acceptable excipient. 
     
     
         16 . A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, of  claim 11 ; and a pharmaceutically acceptable excipient. 
     
     
         17 . 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 compound of  claim 1 , 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 disabilitie; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis. 
     
     
         18 . 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 compound of  claim 11 , 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 disabilitie; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis. 
     
     
         19 . A method of treating a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         20 . A method of treating a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of  claim 11 .