Organic compounds

Abstract

Optionally substituted (5- or 7-amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or 4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-ones, Compounds of Formula (I), processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

1 . A optionally substituted (5- or 7-amino)-3,4-dihydro-(optionally 4-oxo, 4-thioxo or 4-imino)-1H-pyrrolo[3,4-d]pyrimidin-2(6H)-one, in free or salt form. 
     
     
         2 . The compound according to  claim 1 , wherein said compound is a Compound of formula II-A or II-B: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is —C(═S)—, —C(═O)—, —C(═N(R 7 ))- or —C(R 14 )(R 15 )—; 
 (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
 (iii) R 2  is
 H, 
 C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for example, R 2  may be a trifluoromethyl or 2,2,2-trifluoroethyl, 
 N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl or 2-aminopropyl), arylC 0-6 alkyl (e.g., phenyl or benzyl), 
 heteroarylC 0-6 alkyl (e.g., pyridinylmethyl), 
 C 1-6 alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl); 
 -G-J wherein:
 G is a single bond or, alkylene (e.g., methylene); 
 J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with one or more C 1-6 alkyl (e.g., (1-methylpyrolidin-2-yl)), amino (e.g., —NH 2 ), 
 for example, -G-J may be —C 0-4 alkyl-C 3-8  cycloalkyl (e.g., cyclopentyl, cyclohexyl or cyclopropylmethyl) optionally substituted with one or more C 1-6 alkyl, amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl, wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or pyrrolidin-2-yl, 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl); 
 
 
 (iv) R 3  is
 1) -D-E-F wherein:
 D is a single bond, C 1-6 alkylene (e.g., methylene), or arylalkylene (e.g., p-benzylene or —CH 2 C 6 H 4 —); 
 E is
 a single bond, 
 C 1-4 alkylene (e.g., methylene) 
 C 2-6 alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),ethynylene, prop-2-yn-1-ylene), 
 —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), 
 heteroarylene (e.g., pyridinylene or pyrimidinylene), 
 aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), 
 amino (e.g., —N(H)—); 
 C 3-8  cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene), 
 
 F is
 H, 
 halo (e.g., F, Br, Cl), 
 C 1-6 alkyl (e.g., isopropyl or isobutyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 C 3-8  cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, 
 heteroaryl optionally substituted with C 1-6 alkyl, (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said heteroaryl is optionally substituted with halo (e.g., fluoro) or haloC 1-6 alkyl, for example, 6-fluoropyrid-2-yl; 
 amino (e.g., —NH 2 ), 
 C 1-6 alkoxy, 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), 
 —C(O)—R 13 , 
 —N(R 14 )(R 15 ); or 
 
 
 2) a substituted heteroarylaklyl, e.g., substituted with haloalkyl; or 
 3) attached to the nitrogen on the pyrrolo portion of Formula I and is a moiety of Formula A 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and R 10  is
 halogen, 
 C 1-6 alkyl, 
 C 1-6 alkoxy (e.g., methoxy), 
 C 3-8  cycloalkyl, 
 heteroC 3-8  cycloalkyl (e.g., pyrrolidinyl or piperidinyl) 
 haloC 1-6 alkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), 
 C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), 
 arylcarbonyl (e.g., benzoyl), 
 heteroarylcarbonyl, 
 alkoxycarbonyl, (e.g., methoxycarbonyl), 
 aminocarbonyl; 
 wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloC 1-6 alkyl (e.g., trifluoromethyl), hydroxy, carboxy, —SH, or an additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl) 
 preferably R 10  is phenyl or pyridyl, e.g., 2-pyridyl optionally substituted with the substituents previously defined; 
 provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
           
         
         (v) R 4  and R 5  are independently
 H, 
 C 1-6 alkyl (e.g., methyl, isopropyl), 
 C 3-8  cycloalkyl (e.g., cyclopentyl), 
 C 3-8  heterocycloalkyl (e.g., pyrrolidin-3-yl), 
 aryl (e.g., phenyl) or 
 heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) 
 wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); 
 
         (vi) R 6  is H, C 1-6 alkyl (e.g., methyl), hydroxy, C 1-6 alkoxy, aryloxy, —N(R 16 )(R 17 ), oxo (e.g., ═O), or C 3-8  cycloalkyl; 
         (vii) R 7  is H, C 1-6 alkyl (e.g., methyl) or C 3-8  cycloalkyl wherein said cycloalkyl is optionally substituted with one or more oxo (e.g., 2,5-dioxopyrrolidin-1-yl); 
         (viii) R 13  is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and 
         (ix) R 14  and R 15  are independently H or C 1-6 alkyl; 
         (x) R 16  and R 17  are independently H, C 1-6 alkyl, aryl (e.g., phenyl), heteroaryl, wherein said aryl or heteroaryl is optionally substituted with halo (e.g., fluoro), C 1-6 alkoxy (e.g., methoxy); 
       
       in free or salt form. 
     
     
         3 . The Compound according to  claim 1 , wherein said compound is a Compound of formula I-A or I-B: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) Q is —C(═S)—, —C(═O)—, —C(═N(R 6 ))- or —C(R 14 )(R 15 )—; 
 (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
 (iii) R 2  is
 H, 
 C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is optionally substituted with halo (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), 
 —C 0-4 alkyl-C 3-8  cycloalkyl (e.g., cyclopentyl, cyclohexyl) optionally substituted with one or more amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), wherein said cycloalkyl optionally contains one or more heteroatom selected from N and O and is optionally substituted with C 1-6 alkyl (e.g., 1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or 1-methyl-pyrrolindin-3-yl-methyl), 
 C 3-8  heterocycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or pyrrolidin-2-yl) optionally substituted with C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-3-yl or 1-methylpyrrolidin-2-yl, 
 C 3-8 cycloalkyl-C 1-6 alkyl (e.g., cyclopropylmethyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), 
 —N(R 14 )(R 15 )—C 1-6 alkyl (e.g., 2-(dimethylamino)ethyl,2-aminopropyl), 
 hydroxyC 1-6 alkyl (e.g., (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl), 
 arylC 0-6 alkyl (e.g., benzyl), 
 heteroarylC 1-6 alkyl (e.g., pyridinylmethyl), 
 C 1-6 alkoxyarylC 1-6 alkyl (e.g., 4-methoxybenzyl); 
 -G-J wherein:
 G is a single bond or, alkylene (e.g., methylene); 
 J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl, pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with C 1-6 alkyl (e.g., (1-methylpyrolidin-2-yl)); 
 
 
 (iv) R 3  is
 1) -D-E-F wherein:
 D is a single bond, C 1-6 alkylene (e.g., methylene), or arylalkylene (e.g., p-benzylene or —CH 2 C 6 H 4 —); 
 E is
 a single bond, 
 C 1-4 alkylene (e.g., methylene) 
 C 2-6 alkynylene (e.g., ethynylene, prop-2-yn-1-ylene),ethynylene, prop-2-yn-1-ylene), 
 —C 0-4 alkylarylene (e.g., phenylene or —C 6 H 4 —, -benzylene- or —CH 2 C 6 H 4 —), wherein the arylene group is optionally substituted with halo (e.g., Cl or F), 
 heteroarylene (e.g., pyridinylene or pyrimidinylene), 
 aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), 
 amino (e.g., —N(H)—); 
 C 3-8  cycloalkylene optionally containing one or more heteroatom selected from N or O (e.g., piperidinylene), 
 
 F is
 H, 
 halo (e.g., F, Br, Cl), 
 C 1-6 alkyl (e.g., isopropyl or isobutyl), 
 haloC 1-6 alkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl), 
 C 3-8  cycloalkyl optionally containing at least one atom selected from a group consisting of N or O (e.g., cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl is optionally substituted with C 1-6 alkyl (e.g., methyl or isopropyl), for example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, 
 heteroaryl optionally substituted with C 1-6 alkyl, (e.g., pyridyl, (for example, pyrid-2-yl), pyrimidinyl (for example, pyrimidin-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for example, pyrazol-1-yl) or imidazolyl (for example, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl,), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), wherein said heteroaryl is optionally substituted with halo (e.g., fluoro) or haloC 1-6 alkyl, for example, 6-fluoropyrid-2-yl; 
 amino (e.g., —NH 2 ), 
 C 1-6 alkoxy, 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 C 1-6 alkylsulfonyl (for example, methylsulfonyl or —S(O) 2 CH 3 ), 
 —C(O)—R 13 , 
 —N(R 14 )(R 15 ); or 
 
 
 2) a substituted heteroarylaklyl, e.g., substituted with haloalkyl; or 
 3) attached to the nitrogen on the pyrrolo portion of Formula I and is a moiety of Formula A
 Formula A 
 wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and R 10  is halogen, alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) or e.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl), alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl or pyridyl, e.g., 2-pyridyl; provided that when X, Y or X is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
 
 (v) R 4  and R 5  are independently
 H, 
 C 1-6 alkyl (e.g., methyl, isopropyl), 
 C 3-8  cycloalkyl (e.g., cyclopentyl), 
 C 3-8  heterocycloalkyl (e.g., pyrrolidin-3-yl), 
 aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl is optionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C 1-6 alkyl, C 1-6 alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl); 
 
 (vi) R 6  is H, C 1-6 alkyl (e.g., methyl) or C 3-8  cycloalkyl; 
 (vii) R 13  is —N(R 14 )(R 15 ), C 1-6 alkyl (e.g., methyl), —OC 1-6 alkyl (e.g., —OCH 3 ), haloC 1-6 alkyl (trifluoromethyl), aryl (e.g., phenyl), or heteroaryl; and 
 (viii) R 14  and R 15  are independently H or C 1-6 alkyl, 
 
       in free or salt form. 
     
     
         4 . The Compound according to  claim 1 , wherein said compound is a Compound of formula P-A or P-B: 
       
         
           
           
               
               
           
         
       
       wherein
 (i) X═O or S 
 (ii) R 1  is H or C 1-6 alkyl (e.g., methyl or ethyl); 
 (iii) R 2  is
 H, 
 C 1-6 alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl, 2,2-dimethyl propyl), 
 —C 0-66 alkyl-C 3-9  cycloalkyl (e.g., cyclopentyl, cyclohexyl or cyclopropylmethyl) wherein said cycloalkyl is optionally substituted with one or more groups selected from C 1-4 alkyl and amino (e.g., —NH 2 ), for example, 2-aminocyclopentyl or 2-aminocyclohexyl), 
 —C 0-6 alkyl-heteroC 3-9  cycloalkyl (e.g., pyrrolidinyl, for example, pyrrolidin-3-yl or pyrrolyin-2-yl; oxetan-2-yl; tetrahydrofuran-2-yl or tetrahydrofuran-2-ylmethyl) wherein said heterocycloalkyl is optionally substituted with one ore more C 1-6 alkyl (e.g., methyl), for example, 1-methylpyrrolidin-2-yl or 1-methylpyrrolidin-3-yl, 
 haloC 1-6 alkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), 
 C 0-6 alkylaminoC 0-6 alkyl (e.g., 2-(dimethylamino)ethyl, 2-aminopropyl), hydroxyC 1-6 alkyl (e.g., 3-hydroxy-2-methylpropyl or 2-hydroxy-1-methylethyl), 
 arylC 0-6 alkyl (e.g., phenyl or benzyl) wherein said aryl group is optionally substituted with one or more C 1-6 alkoxy, for example, 4-methoxybenzyl, 
 heteroarylC 1-6 alkyl (e.g., pyridylmethyl), 
 
 (iv) R 3  is
 a) hydrogen, 
 b) -D-E-F wherein
 D is single bond, C 1-6 alkylene (e.g., methylene, ethynylene, prop-2-yn-1-ylene), or arylC 1-6 alkylene (e.g., benzylene or —CH 2 C 6 H 4 —); 
 E is
 arylene (e.g., phenylene or —C 6 H 4 —), wherein the arylene is optionally substituted with one or more halo, 
 arylC 1-6 alkylene (e.g., -benzylene- or —CH 2 C 6 H 4 —), 
 aminoC 1-6 alkylene (e.g., —CH 2 N(H)—), 
 amino (e.g., —N(H)—), 
 heteroarylene (e.g., pyrid-3-ylene) or heteroC 3-9  cycloakylene (e.g., piperidin-4-ylene) wherein the heteroarylene and the heterocycloalkylene are independently and optionally substituted with one or more halo; and 
 
 F is
 Hydrogen, 
 C 1-6 alkyl (e.g., isobutyl, isopropyl), 
 aryl (e.g., phenyl) wherein said aryl is optionally substituted with one or more halo and/or haloC 1-6 alkyl, 
 heteroaryl (e.g., triazolyl, diazolyl, oxadiazolyl, pyridyl, pyrimidinyl) wherein said heteroaryl is optionally substituted with one or more groups selected from halo (e.g., fluoro), C 1-6 alkyl and haloC 1-6 alkyl (e.g., trifluoromethyl), for example, pyrid-2-yl, 4,6-dimethyl-pyrid-2-yl, 5-fluoropyrimidin-2-yl, imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, 5-methyl-1,2,4-oxadiazol-3-yl or pyrimidin-2-yl, 
 heteroC 3-9  cycloalkyl (e.g., piperidinyl, pyrrolidinyl) wherein said heterocycloalkyl is optionally substituted with one or more Cl —  6alkyl (e.g., methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl, 
 —N(R a )(R b ) wherein R a  and R b  are independently H or C 1-6 alkyl (e.g., —NH 2 , dimethylamino or isopropylamino), 
 aminocarbonyl (e.g., —C(O)NH 2 ), 
 C 1-6 alkoxy, 
 arylcarbonyl (e.g., benzoyl), 
 heteroarylcarbonyl, 
 C 1-6 alkoxycarbonyl (e.g., methoxycarbonyl), 
 C 1-6 alkyl sulfonyl(e.g., —S(O) 2 —CH 3 ), 
 halo (e.g., chloro or fluoro), 
 haloC 1-6 alkyl (e.g., —CF 3 ), or 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 
 
 c) R 3  is heteroarylC 0-6 alkyl, wherein the heteroaryl group is optionally substituted with one or more C 1-6  haloalkyl; or 
 d) R 3  is a moiety of Formula A
 Formula A 
 wherein X, Y and Z are, independently, N or C, and R 8 , R 9 , R 11  and R 12  are independently H or halogen (e.g., Cl or F); and 
 R 10  is
 hydrogen, 
 halogen (e.g., fluoro or chloro), 
 C 1-6 alkyl, 
 C 3-9  cycloalkyl, 
 C 1-6  haloalkyl (e.g., trifluoromethyl), 
 aryl (e.g., phenyl) wherein said aryl is optionally substituted with one or more halo and/or haloC 1-6 alkyl, 
 heteroaryl wherein said heteroaryl group is optionally substituted with one or more groups selected from halo (e.g., fluoro), C 1-6 alkyl and haloC 1-6 alkyl, e.g., pyridyl, (for example, pyrid-2-yl, 6-fluoro-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl-pyrid-3-yl, 4,6-dimethylpyrid-2-yl), thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl), diazolyl (for example, pyrazolyl, e.g., pyrazol-1-yl), triazolyl (for example, 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl), oxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol-3-yl), 
 C 1-6 alkyl sulfonyl (e.g., methyl sulfonyl), 
 arylcarbonyl (e.g., benzoyl), 
 heteroarylcarbonyl, 
 C 1-6 alkoxycarbonyl, (e.g., methoxycarbonyl), 
 aminocarbonyl (i.e., —C(O)NH 2 ), 
 —N(R a )(R b ) wherein R a  and R b  are independently H or C 1-6 alkyl (e.g., —NH 2 , dimethylamino or isopropylamino), 
 haloC 1-6 alkyl, 
 —O-haloC 1-6 alkyl (e.g., —O—CF 3 ), 
 heteroC 3-9  cycloalkyl-C 0-6 alkyl (e.g., piperidinyl, pyrrolidinyl, pyrrolidinylmethyl) wherein said heterocycloalkyl is optionally substituted with one or more C 1-6 alkyl (e.g., methyl), for example, pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, piperidin-2-yl, 1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl; 
 provided that when X, Y or Z is nitrogen, R 8 , R 9  or R 10 , respectively, is not present; 
 
 
 
 (v) R 4  and R 5  are independently selected from
 H, 
 C 1-6 alkyl (e.g., methyl or isopropyl), 
 C 3-9  cycloalkyl (e.g., cyclopentyl), 
 C 3-9  heterocycloalkyl (e.g., pyrrolidin-3-yl), 
 heteroaryl (e.g., pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, pyrazol-3-yl), aryl (e.g., phenyl) or arylC 1-6 alkyl (e.g., benzyl), wherein the aryl group is optionally substituted with one or more halo (e.g., F or Cl), hydroxy and/or another aryl, (e.g., p-benzylaryl, e.g., biphenyl-4-ylmethyl); 
 
 (vi) R 6  is H or C 1-6 alkyl (e.g., ethyl); 
 
       in free or salt form. 
     
     
         6 . The compound according to  claim 1 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         7 . The compound according to  claim 1 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         8 . The compound according to  claim 1 , selected from any of the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in free or salt form. 
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1 , in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         10 . A method of treating any of the following conditions: Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling; comprising administering a therapeutically effective amount of a compound according to  claim 1 , in free or pharmaceutically acceptable salt form, or a pharmaceutical composition, to a patient in need of such treatment. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 13  further comprising administering a compound or compounds selected from central nervous system stimulants, modafinil, antidepressants, and gamma hydroxybutyrate, to a patient in need thereof. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 15 , further comprising administering a compound or compounds selected from a group consisting of estradiol, estriol, estradiol esters, progesterone and progestins to a patient in need thereof. 
     
     
         17 . A method for the treatment of treatment for glaucoma or elevated intraocular pressure comprising topical administration of a therapeutically effective amount of a compound according to  claim 1 , in free or pharmaceutically acceptable salt form, in an opthalmically compatible carrier to the eye of a patient in need thereof. 
     
     
         18 . A method for the treatment of psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder, comprising administering a therapeutically effective amount of a compound according to  claim 1 , in free or pharmaceutically acceptable salt form, to a patient in need thereof. 
     
     
         19 . A method for the treatment of traumatic brain injury comprising administering to a patient in need thereof, a compound according to  claim 1 , in free or pharmaceutically acceptable salt form. 
     
     
         20 . A method for lengthening or enhancing growth of the eyelashes by administering an effective amount of a prostaglandin analogue, e.g., bimatoprost, concomitantly, simultaneously or sequentially with an effective amount of a compound according to  claim 1 , in free or salt form. 
     
     
         21 . Use of the Compound according to  claim 1 , in free or pharmaceutically acceptable salt form, or a pharmaceutical composition for the manufacture of a medicament for the treatment or prophylactic treatment of the following diseases: Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling. 
     
     
         22 . (canceled) 
     
     
         23 . A pharmaceutical comprising a Compound according to  claim 1 , in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment of any disease or condition selected from:
 Parkinson's disease, restless leg, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorder, narcolepsy, cognitive impairment, dementia, Tourette's syndrome, autism, fragile X syndrome, psychostimulant withdrawal, and/or drug addiction; cerebrovascular disease, stroke, congestive heart disease, hypertension, pulmonary hypertension, and/or sexual dysfunction; asthma, chronic obstructive pulmonary disease, and/or allergic rhinitis, as well as autoimmune and inflammatory diseases; and/or female sexual dysfunction, exercise amenorrhoea, anovulation, menopause, menopausal symptoms, hypothyroidism, pre-menstrual syndrome, premature labor, infertility, irregular menstrual cycles, abnormal uterine bleeding, osteoporosis, multiple sclerosis, prostate enlargement, prostate cancer, hypothyroidism, estrogen-induced endometrial hyperplasia or carcinoma; and/or any disease or condition characterized by low levels of cAMP and/or cGMP (or inhibition of cAMP and/or cGMP signaling pathways) in cells expressing PDE1, and/or by reduced dopamine D1 receptor signaling activity; and/or any disease or condition that may be ameliorated by the enhancement of progesterone signaling;   glaucoma or elevated intraocular pressure;   psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, and mania, such as in acute manic episodes and bipolar disorder; and   traumatic brain injury.