Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and cns disorders

Abstract

The present invention relates to a genus of biaryl compounds containing at least one further ring. The compounds are PDE4 inhibitors useful for the treatment and prevention of stroke, myocardial infarct and cardiovascular inflammatory diseases and disorders. The compounds have general formula I: A particular embodiment is

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         or salt thereof wherein 
         R 1  is an optionally substituted carbocycle or optionally substituted heterocycle of three or fewer rings; 
         R 2  is an optionally substituted carbocycle or optionally substituted heterocycle of two or fewer rings; 
         R 3  is chosen from H, —C(═O)NH 2 , —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-R 30 , —(C 2 -C 6 )alkyl-R 31 , and saturated 4- or 5-membered heterocycle optionally substituted with methyl; 
         R 30  is chosen from —C(═O)NH 2  and 4- or 5-membered heterocycle optionally substituted with methyl; 
         R 31  is chosen from (C 1 -C 4 )alkoxy, amino, hydroxy, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino; 
         R 4  is chosen from H and F; 
         R 6  is chosen from H, (C 1 -C 6 )alkyl and halogen; 
         X is N, N→O, or C—R 5 ; 
         R 5  is chosen from H, halogen, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, CF 3 , CN, NH 2 , CH 2 OH, CH 2 NH 2  and C≡CH; and 
         M is chosen from direct bond, —C(R 20 )(R 21 )—, —O—, —NR 22 —, —S(O) n —, —C(═O)—, —C(R 20 )(R 21 )C(R 20 )(R 21 )—, —C(R 20 )═C(R 21 )—, —C(R 20 )(R 21 )—, —C(R 20 )(R 21 )—NR 22 —, —C(R 20 )(R 21 )—S(O) n —, —C(R 20 )(R 21 )—C(═O)—, —O—C(R 20 )(R 21 )—, —NR 22 —C(R 20 )(R 21 )—, —S(O) n —C(R 20 )(R 21 )—, —C(═O)—C(R 20 )(R 21 )— and 
       
       
         
           
           
               
               
           
         
       
       is a five or six-membered ring optionally substituted with methyl; and
 n is zero, one or two; and 
 R 20 , R 21  and R 22  are selected independently in each occurrence from H and (C 1 -C 4 )alkyl; 
 with the provisos that:
 (a) when R 3  is methyl, M is CH 2  and R 2  is a five-membered ring heterocycle, then R 1  cannot be pentamethyltetralin; 
 (b) when R 3  is methyl, M is CH 2  and R 1  is a five-membered ring heterocycle, then R 2  cannot be pentamethyltetralin. 
 
 
     
     
         2 . A compound or salt according to  claim 1  wherein X is N or N→O: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound or salt according to  claim 1  wherein X is CR 5  of formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is chosen from pyrazolyl and substituted phenyl. 
     
     
         4 . A compound or salt according to  claim 1  wherein M is chosen from direct bond, —CH 2 —, —CH(OH)—, —C[(CH 3 )(OH)]—, —C[(CH 3 )(NH 2 )]—, —C(═O)—, —O—, —NH—, —N(CH 3 )—, —S(O) n —, —CH 2 NH—, —CH 2 CH 2 —, —CH═CH—, —CH 2 S(O) n —, —CH 2 O— and 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound or salt according to  claim 1  wherein R 1  is a substituted phenyl. 
     
     
         6 . A compound or salt according to  claim 1  wherein R 1  is an optionally substituted heterocycle chosen from pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thiene, furan, oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, purine, imidazolopyridine, pyrazine, thiazolidine, isothiazole, 1,2-thiazine-1,1-dioxide, 2,6,7-trioxabicyclo[2.2.2]octane, quinuclidine, isothiazolidine, benzimidazole, thiadiazole, benzopyran, benzothiazole, benzotriazole, benzoxazole, benzoxadiazole, tetrahydrofuran, tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, oxadiazole, triazole, tetrazole, isoindole, pyrrolopyridine, triazolopyridine and the dihydro and tetrahydro congeners thereof. 
     
     
         7 . A compound or salt according to  claim 6  wherein R 1  is an optionally substituted heterocycle chosen from pyrazole, benzodioxole, morpholine, thiazole, pyridine, pyridine N-oxide, pyrimidine, thiene, oxazolidine, isoxazole, azetidine, piperazine, pyrrolidine, imidazole, imidazolidine, imidazolopyridine, pyrazine, 1,2-thiazine-1,1-dioxide, benzimidazole, thiadiazole, benzotriazole, benzoxazole, oxadiazole, triazole, tetrazole, isoindole, pyrrolopyridine, triazolopyridine and the dihydro and tetrahydro congeners thereof. 
     
     
         8 . A compound or salt according to  claim 5  wherein said substituted phenyl is substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, —NHC(═O)NHalkyl, —NHC(═O)NH-heterocyclyl, -alkyl-NHC(═O)N(alkyl) 2 , heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides. 
     
     
         9 . A compound or salt according to  claim 5  wherein said substituted phenyl is substituted with a substituent chosen from —CH 3 , —CH 2 CF 3 , —CF 3 , —CHO, —COOH, —CN, halogen, —OH, —OEt, —C(═O)NH 2 , —C(═O)NHEt, —C(═O)NMe 2 -COOCH 3 , —COOEt, —CH 2 NHC(═O)NH 2 , —CH(CH 3 )NHC(═O)NH 2 , —CH 2 NHC(═O)H, —CH 2 NHC(═O)CH 3 , —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CH 2 NHC(═O)OEt, —CH 2 NHC(═O)O—C 6 H 5 , —CH 2 NHC(═O)C(═O)NH 2 , —CH 2 NHC(═O)NHEt, —C(CH 3 ) 2 OH, —CH 2 NHC(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)NHCH 3 , —CH 2 NH 2 , —CH(CH 3 )NH 2 , —C(CH 3 ) 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —CH 2 C(═O)NHEt, —OCH 3 , —OC(═O)NH 2 , —OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , —NHC(═O)NH 2 , —NHC(═O)NHEt, —NHCH 3 , —NHEt, —NH(tBoc), —NHCH 2 COOH, —N(CH 3 )CH 2 COOH, —NHC(═O)NHCH 2 CH 2 Cl, —NHSO 2 NH 2 , —NHEt, —N(CH 3 ) 2 , —NH 2 , —NH(CH 3 )C(═O)NH 2 , —NHSO 2 CH 3 , —N(SO 2 CH 3 ) 2 , —NHC(═O)OCH 3 , —NHC(═O)OtBu, —NHC(═O)CH 3 , —SO 2 NH 2 , —NHC(═O)CH 2 CH 2 COOH, —NHC(═O)NHCH 2 COOH, —CH 2 NHCHO, —NHC(═O)NHCH 2 COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —N(CH 3 )CH 2 CH 2 OH, —NHC(═O)OEt, —N(Et)C(═O)OEt, —NHC(═O)NH(CH 2 ) 2 COOH, —NHC(═O)CH 2 N(CH 3 ) 2 , —NHC(═O)NH(CH 2 ) 3 COOH, —NHC(═O)CH 2 NH 2 , —NHC(═O)CH 2 CH 2 NH 2 , —NHC(═O)CH 2 NH(tBoc), 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound or salt according to  claim 6  wherein said substituted heterocycle is substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, —NHC(═O)NHalkyl, —NHC(═O)NH-heterocyclyl, -alkyl-NHC(═O)N(alkyl) 2 , heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides. 
     
     
         11 . A compound or salt according to  claim 6  wherein said substituted heterocycle is substituted with a substituent chosen from —CH 3 , —CH 2 CF 3 , —CF 3 , —CHO, —COOH, —CN, halogen, —OH, —OEt, —C(═O)NH 2 , —C(═O)NHEt, —C(═O)NMe 2 -COOCH 3 , —COOEt, —CH 2 NHC(═O)NH 2 , —CH(CH 3 )NHC(═O)NH 2 , —CH 2 NHC(═O)H, —CH 2 NHC(═O)CH 3 , —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CH 2 NHC(═O)OEt, —CH 2 NHC(═O)O—C 6 H 5 , —CH 2 NHC(═O)C(═O)NH 2 , —CH 2 NHC(═O)NHEt, —C(CH 3 ) 2 OH, —CH 2 NHC(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)NHCH 3 , —CH 2 NH 2 , —CH(CH 3 )NH 2 , —C(CH 3 ) 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —CH 2 C(═O)NHEt, —OCH 3 , —OC(═O)NH 2 , —OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , —NHC(═O)NH 2 , —NHC(═O)NHEt, —NHCH 3 , —NHEt, —NH(tBoc), —NHCH 2 COOH, —N(CH 3 )CH 2 COOH, —NHC(═O)NHCH 2 CH 2 Cl, —NHSO 2 NH 2 , —NHEt, —N(CH 3 ) 2 , —NH 2 , —NH(CH 3 )C(═O)NH 2 , —NHSO 2 CH 3 , —N(SO 2 CH 3 ) 2 , —NHC(═O)OCH 3 , —NHC(═O)OtBu, —NHC(═O)CH 3 , —SO 2 NH 2 , —NHC(═O)CH 2 CH 2 COOH, —NHC(═O)NHCH 2 COOH, —CH 2 NHCHO, —NHC(═O)NHCH 2 COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —N(CH 3 )CH 2 CH 2 OH, —NHC(═O)OEt, —N(Et)C(═O)OEt, —NHC(═O)NH(CH 2 ) 2 COOH, —NHC(═O)CH 2 N(CH 3 ) 2 , —NHC(═O)NH(CH 2 ) 3 COOH, —NHC(═O)CH 2 NH 2 , —NHC(═O)CH 2 CH 2 NH 2 , —NHC(═O)CH 2 NH(tBoc), 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound or salt according to  claim 1  wherein R 2  is chosen from optionally substituted phenyl, optionally substituted monocyclic unsaturated heterocycle, unsubstituted bicyclic unsaturated heterocycle and fluoro-substituted bicyclic unsaturated heterocycle. 
     
     
         13 . A compound or salt according to  claim 8  wherein R 2  is chosen from optionally substituted phenyl, indole, benzodioxole, benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and pyridine N-oxide. 
     
     
         14 . A compound or salt according to  claim 13  wherein R 2  is chosen from meta-substituted phenyl, indole, benzodioxole, 2,2-difluorobenzodioxole, benzooxadiazole, benzimidazole, 5-(pyridin-4-yl)[1,2,4]oxadiazole, 5-(pyridin-4-yl)[1,3,4]oxadiazole, benzodioxan, 4-chloropyrazole, 4-(pyridin-4-yl)pyrazole, 6-chloropyridine, 3-(trifluoromethyl)pyrazole, and pyridine N-oxide. 
     
     
         15 . A compound or salt according to  claim 13  wherein R 2  is substituted phenyl: 
       
         
           
           
               
               
           
         
       
       wherein R 7  is chosen from hydrogen, halogen, nitro, cyano, halo(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )oxaalkyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl (—CONH 2 ), (C 1 -C 6 )alkylaminocarbonyl, acyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, di[(C 1 -C 6 )alkyl]amino, mercapto, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonamido, acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy, benzyloxy, and heteroaryloxy; and 
       R 8  and R 13  are chosen independently from H and F. 
     
     
         16 . A compound or salt according to  claim 15 , wherein R 8  and R 13  are H and R 7  is chosen from hydrogen, fluoro, chloro, bromo, nitro, cyano, acetyl, trifluoromethyl, methoxy, trifluoromethoxy, oxadiazolyl, tetrazolyl, methylthio, methanesulfinyl, methanesulfonyl, methanesulfonamido, amino, methoxymethyl, hydroxyethyl, and morpholinyl. 
     
     
         17 . A compound or salt according to  claim 1  wherein R 1  is chosen from optionally substituted phenyl, optionally substituted five membered heteroaryl, optionally substituted six-membered heteroaryl, optionally substituted 4-7 membered non-aryl heterocycle, and optionally substituted fused bicycle. 
     
     
         18 . A compound or salt according to  claim 17 , wherein R 1  is chosen from optionally substituted phenyls; optionally substituted five membered heteroaryls selected from thiazoles, thiadiazoles, pyrazoles, oxadiazole, isoxazoles, triazoles, imidazoles, thiophenes, tetrazoles and oxazoles; optionally substituted six membered heteroaryls selected from pyridines, pyrimidines, pyridazinones, pyrimidinone, pyridinone, pyrazines and diazines; optionally substituted 5- and 6-membered non-aryl heterocyclics selected from tetrahydrothiophenes, piperazine, oxazolidinones, imidazolidinones, morpholines, piperidines, pyrrolidinones, pyrrolidinediones, pyrrolidines, piperidinones, piperidinediones and trioxabicyclo[2.2.2]octanes; and optionally substituted fused bicycles selected from benzoxazolones, indoles, isoindolinediones, 2H-pyrrolopyridinediones, purines, indolinediones, triazolopyridinones, benzimidazoles, benzoxadiazoles, quinolines and quinolones; wherein the substituents are chosen independently from hydrogen, halogen, halo(C 1 -C 6 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy, carboxy, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl (—CONH 2 ), (C 1 -C 6 )alkylaminocarbonyl, cyano, carbonyl (oxo), acyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, nitro, amino, (C 1 -C 6 )alkylamino, di[(C 1 -C 6 )alkyl]amino, mercapto, (C 1 -C 6 )alkylthio, sulfoxide, sulfone, sulfonate, sulfonimide, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, aminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, formylamino(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkylamino, —(CH 2 ) p —NR 12 CO—(CH 2 ) q —NR 9 R 10 , —NHSO 2 R 11 , —OCH 2 CH 2 NR 9 R 10 —NHSO 2 NR 9 R 10 , —SO 2 NR 9 R 10 , —(CH 2 ) p —NHCOR 9 , OCONR 9 R 10  and NR 12 COOR 11 ;
 R 3  is chosen from —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2  and —CH 2 F;   R 5  is chosen from H, —F, —OH, —CH 3 , —OCH 3 , —CF 3 , —CN, —NH 2  and —C≡CH;   R 2  is
 (a) phenyl and R 7  is chosen from H, halogen, nitro, acetyl, hydroxyethyl, —NH 2 , —SCH 3 , methoxycarbonyl, —SOCH 3 , —SO 2 CH 3 , —OCH 3 , —OCF 3 , —CN, —CF 3 , —CH 2 OCH 3 ; or 
 (b) benzoxadiazole, benzodioxole, 2,2-difluorobenzodioxole, benzoxadiazole, benzodioxan, benzimidazole, oxadiazole, pyrazole, pyridine and pyridine N-oxide; 
   R 9  is chosen from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarboxy(C 1 -C 6 )alkyl;   R 10  is H, (C 1 -C 6 )alkyl, or taken together, or   R 9  and R 10  together form a heterocycle optionally substituted with (C 1 -C 6 )alkyl;   p is 0 or 1,   q is 0, 1 or 2,   R 11  is linear (C 1 -C 6 )alkyl,   R 12  is H or (C 1 -C 6 )alkyl; or   two adjacent substituents together form an optionally substituted fused heterocyclic ring;   with the provisos that
 (i) when R 5  is H, R 3  is —CH 3  and R 1  is substituted or unsubstituted pyrazole, then R 2  is m-nitrophenyl or optionally substituted heterocycle; 
 (ii) when R 5  is H, R 3  is —CH 3 , and R 2  is meta-(trifluoromethyl)phenyl, then R 1  is not 
   
       
         
           
           
               
               
           
         
         
           (iii) when R 5  is H, R 3  is —CH 3 , and R 2  is m-nitrophenyl then R 1  is not and 
         
       
       
         
           
           
               
               
           
         
         
           (iv) when R 5  is H, R 3  is —CH 3 , and R 2  is m-methoxyphenyl or m-acetylphenyl, then R 1  is not 
         
       
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound or salt according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is phenyl, five-membered heteroaryl, six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle; 
         R 14  is chosen from H, —CH 2 NHC(═O)NH 2 , —NHC(═O)NH 2 , —NHC(═O)NHEt, —CH 3 , —CH 2 CF 3 , —CH 2 NHC(═O)CH 3 , —NHCH 3 , —NHEt, —NH(tBoc), —CHO, —NHC(═O)NHCH 2 CH 2 Cl, —NHSO 2 NH 2 , —NHEt, —N(CH 3 ) 2 , —NH 2 , —COOH, —C(═O)NH 2 , —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CN, —OCH 3 , —OC(═O)NH 2 , —NH(CH 3 )C(═O)NH 2 , halogen, —CH 2 NHC(═O)OEt, —NHSO 2 CH 3 , —N(SO 2 CH 3 ) 2 , —NHC(═O)OCH 3 , —OH, —CH 2 NHC(═O)N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —SO 2 NH 2 , —NHC(═O)NHCH 2 COOH, —CH 2 NHCHO, —NHC(═O)NHCH 2 COOEt, —COOCH 3 , —COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —NH(Et)C(═O)OEt, —NHC(═O)NH(CH 2 ) 2 COOH, —CH 2 NHSO 2 CH 3 , —OEt, —NHC(═O)CH 2 N(CH 3 ) 2 , —NHC(═O)NH(CH 2 ) 3 COOH, —NHC(═O)CH 2 NH 2 , —NHC(═O)CH 2 CH 2 NH 2 , —NHC(═O)CH 2 NH(tBoc), —OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , 3′-nitro-6-methoxybiphenyl-3-ylmethyl, tetrahydroimidazol-2-on-1-yl, 3-methyltetrahydroimidazol-2-one-1-yl, pyrazol -1-yl, 
       
       
         
           
           
               
               
           
         
         R 15  is chosen from H, NO 2 , OH, NH 2 , and —NHSO 2 NH 2 ; or 
         R 15  together with R 14  forms methylene dioxy; 
         R 27  is chosen from hydrogen, halogen, nitro, cyano, halo(C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )oxaalkyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, aminocarbonyl (—CONH 2 ), (C 1 -C 6 )alkylaminocarbonyl, acyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, amino(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, di[(C 1 -C 6 )alkyl]amino, mercapto, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonamido, acylamino, amidino, phenyl, benzyl, heterocyclyl, phenoxy, benzyloxy, and heteroaryloxy; 
         R 28  is chosen from H and F, or 
         R 27  together with R 28  forms a five-membered ring. 
       
     
     
         20 . A compound or salt according to  claim 19  wherein R 27  and R 28  represent a fused heterocycle at 3- and 4-positions so that the residue formed from R 27  and R 28  together with the phenyl to which they are attached is chosen from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound or salt according to  claim 19  wherein R 27  is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken together R 7  and R 8  are methylenedioxy or difluoromethylenedioxy. 
     
     
         22 . A compound or salt according to  claim 21  wherein R 1a  is chosen from a benzene ring, a triazole, a pyridine or pyridine-N-oxide, a pyrazole, a tetrahydrothiophene, an imidazole, a pyrimidine, a thiadiazole, and an imidazopyridine. 
     
     
         23 . A compound or salt according to  claim 1  wherein R 5  is fluoro, H, CN or OH. 
     
     
         24 . A compound or salt according to  claim 1  wherein R 3  is methyl or fluoromethyl. 
     
     
         25 . A compound or salt according to  claim 1  of formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 3  is methyl or fluorinated methyl; 
         Y is CH or N; 
         R 27a  is chosen from halogen, cyano, acetyl, methylthio, nitro and trifluoromethyl; and 
         R 16  is chosen from —NR 17 C(═O)NR 18 R 19  and 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
       
       is a 4-7 membered ring heterocycle attached through its nitrogen;
 R 17 , and R 18  are independently chosen from H, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl; 
 R 19  is chosen from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —[(C 1 -C 6 )alkyl]COOH, and —[(C 1 -C 6 )alkyl]COO(C 1 -C 6 )alkyl; and 
 R 20  is chosen from a carboxylic acid, a carboxamide, a carboxylic ester, a primary, secondary or tertiary alcohol and a primary, secondary or tertiary amine. 
 
     
     
         26 . A compound or salt according to  claim 25  wherein
 X is CH, CF or N—O;   M is —CH 2 — or —S—;   R 27a  is chosen from chloro, cyano, acetyl and methylthio; and   R 16  is chosen from —NR 17 C(═O)NR 18 R 19 ,   
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound or salt according to  claim 26  wherein Y is CH; M is —CH 2 —; R 27a  is chloro; and R 16  is —NR 17 C(═O)NR 18 R 19 . 
     
     
         28 . A compound or salt according to  claim 27  wherein R 16  is —NR 17 C(═O)NR 18 R 19  and R 17 , R 18  and R 19  are all hydrogen. 
     
     
         29 . A salt of a compound of  claim 1  wherein the salt is a pharmaceutically acceptable salt. 
     
     
         30 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt according to  claim 1 . 
     
     
         31 . A pharmaceutical composition comprising
 (a) a pharmaceutically acceptable carrier;   (b) a compound or pharmaceutically acceptable salt according to  claim 1 ; and   (c) a second agent chosen from cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and antioxidants.   
     
     
         32 . A pharmaceutical composition according to  claim 31  wherein said second agent is chosen from tacrine, huperzine, donepezil, lanicemine, remacemide, neramexane, memantine, vitamin E and coenzyme Q10. 
     
     
         33 . A method for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4 comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         34 . A method according to  claim 33  wherein said disease or condition is chosen from stroke, myocardial infarct, and cardiovascular inflammatory conditions. 
     
     
         35 . A method according to  claim 33  wherein said disease or condition is cancer. 
     
     
         36 . A method according to  claim 33  wherein said disease or condition is chosen from asthma and COPD. 
     
     
         37 . A method for improving cognitive function comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         38 . A method according to  claim 37  wherein said cognitive function is memory or cognition. 
     
     
         39 . A method according to  claim 37  for treating learning disorders. 
     
     
         40 . A method for treating schizophrenia or Huntington's disease comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         41 . A method for treating or preventing bone loss comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         42 . A method for treating depression or anxiety comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         43 . A method for treating bladder inflammation, bladder overactivity and pain arising from bladder inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 .