MX2007015356A - Organic compounds - Google Patents

Abstract

The invention provides novel 7,8-dihydro-imidazo[l,2-α]pyrazolo[4,3-e]pyrimidin-4- one compounds and 7,8,9-trihydro-[lHor 2/f]-pyrimido [l,2-a]pyrazolo[4,3- e]pyrimidin-4(5H)-one compounds, substituted at the 1 or 2 position with C2-g allcyl, C3-9 cycloalkyl, heteroarylalkyl, or substituted arylalkyl, in free, salt or prodrug form, processes for their production, their use as pharmaceuticals, particularly as PDEl inhibitors, and pharmaceutical compositions comprising them.

Description

ORGANIC COMPOUNDS This application claims the priority of United States Provisional Application No. 60 / 687,715, filed on June 6, 2005, the contents of which are incorporated herein by reference. Field of the Invention The present invention relates to compounds of 7,8-dihydro-imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4-one and compounds of 7,8,9-trihydro- [1 H or 2 H] -pyrimido [1,2-a] pyrazolo [4,3-e) pyrimidin-4 (5H) -one novel, processes for their production, their use as pharmaceuticals or pharmaceutical compositions containing them. Of particular interest are novel compounds useful as inhibitors of phosphodiesterase 1 (PDE1), for example, in the treatment of diseases involving disorders of the intracellular pathway of the dopamine D1 receptor, such as Parkinson's disease, depression and damage to the cognitive function, for example, in schizophrenia. Background of the Invention Eleven families of phosphodiesterases (PDEs) have been identified but only the PDEs in Family I, the Ca2 + -dependent phosphodiesterases -calmodulin (CaM-PDEs), have been shown to mediate the calcium and cyclic nucleotide signaling pathways. (for example cAMP and cGMP). The three known CaM-PDE genes, PDE1A, PDE1B and PDE1C, are all expressed in the tissue of the central nervous system. PDE1A is expressed throughout the brain with higher levels of expression in CA1 to CA3 layers of the hippocampus and cerebellum and at a low level in the striatum (striatum). PDE1A is also expressed in the lung and heart. PDE1B is predominantly expressed in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression correlates with regions of the brain that have high levels of dopaminergic innervation. Although PDE1B is expressed mainly in the central nervous system, it can be detected in the heart. PDE1C is expressed mainly in the olfactory epithelium, cerebellar granule cells, and striatum. PDE1C is also expressed in the heart and vascular smooth muscle. Cyclic nucleotide phosphodiesterases decrease the intracellular signaling of cAMP and cGMP by hydrolyzing those cyclic nucleotides to their respective inactive 5'-monophosphates (5 'AMP and 5'GMP). CaM-PDEs play a critical role in mediating signal transduction in brain cells, particularly within an area of the brain known as the basal ganglia or striatum. For example, activation of the glutamate-like NMDA receptor and / or activation of the dopamine D2 receptor results in increased intracellular calcium concentrations, leading to the activation of effectors such as calmodulin-dependent kinase II (CaMKII) and calcineurin and CaM activation -PDEs, resulting in reduced cAMP and cGMP. Activation of the dopamine D1 receptor, on the other hand, leads to the activation of calcium-dependent nucleotide cyclases, resulting in increased cAMP and cGMP. These cyclic nucleotides in turn activate protein kinase A (PKA, cAMP-dependent protein kinase) and / or protein kinase G (PKG, cGMP-dependent protein kinase) that phosphorylate elements of the descending signal transduction pathway such as DARPP-32. (Phosphoprotein regulated with dopamine and cAMP) and cAMP responsive element binding protein (CREB). The CaM-PDEs can therefore affect the signaling pathways regulated by dopamine and other intracellular signaling pathways in the basal ganglia (striatum), including but not limited to intracellular signaling pathways of nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) and endorphin. Phosphodiesterase (PDE) activity, in particular, phosphodiesterase 1 (PDE1) activity, functions in brain tissue as a regulator of locomotor activity and learning and memory. PDE1 is a therapeutic target for the regulation of intracellular signaling pathways, preferably in the nervous system, including but not limited to intracellular signaling pathway of dopamine D1 receptor, dopamine D2 receptor, nitric oxide, noradrenergic, neurotensin, CCK, VIP, serotonin, glutamate (eg, NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoid receptor, natriuretic peptide (e.g., ANP, BNP, CNP) or endorphin. For example, inhibition of PDE1B must act to potentiate the effect of a dopamine D1 agonist by protecting cGMP and cAMP from degradation, and must similarly inhibit the signaling pathways of the dopamine D2 receptor, by inhibiting PDE1 activity. Chronic elevation in intracellular calcium is linked to cell death in various disorders, particularly in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, and in disorders of the circulatory system that leads to stroke (attack) and myocardial infarction. Therefore, PDE1 inhibitors are potentially useful in diseases characterized by reduced dopamine D1 receptor signaling activity, such as Parkinson's disease, restless leg syndrome, depression, and cognitive impairment. Thus there is a need for compounds that selectively inhibit the activity of PDE1, especially the activity of PDE1B. Brief Description of the Invention The invention provides 7,8-dihydro- [1 H or 2 H] -midazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -ones or 7.8 , 9-tri hyd ro- [1 H or 2 H] -pyrimido [1,2-a] pyrazolo [4,3-e) pyrimidin-4 (5H) -no-novel, substituted in the 1 or 2 position with alkyl of C2.9 or C3-9 cycloalkyl >; or optionally substituted heteroarylalkyl or substituted arylalkyl, in free form, of salt or prodrug (hereinafter "Compounds of the Invention"). The substituent of the 1 or 2 position is preferably substituted benzyl or pyridylmethyl, for example para-substituted with respect to the point of attachment, for example, with aryl, for example, phenyl, or heteroaryl, for example, pyridyl or thiadiazolyl. These compounds are surprisingly found to selectively inhibit the activity of phosphodiesterase 1 (PDE1), especially the activity of PDE1B. Preferably, the Compounds of the Invention are 7,8-dihydro- [1 H or 2 H] -imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -ones or 7, 8, 9-tri h id ro- [1 H or 2 H] -pyridido [1,2-a] pyrazolo [4,3-e) pyrimidin-4 (5H) -ones, of the formula I Formula I nde (i) Ri is H or C? - alkyl (eg, methyl); (ii) R 4 is H or C 4 alkyl, and R 2 and R 3 are, independently, H or C 4 alkyl, (eg, R2 and R3 are both methyl, or R2 is H and R3 is isopropyl), aryl, heteroaryl, (optionally hetero) -lapplycoxy, or (optionally hetero) arylalkyl; or R2 is H and R3 and R4 together form a bridge of di-, tri- or tetramethylene (preferably, wherein R3 and R4 together have the cis configuration, for example the carbons bearing R3 and R4 have the R and R configurations. S, respectively); (iii) R5 is a substituted heteroarylalkyl, for example with haloalkyl and is a portion of Formula A: Formula A wherein X, Y and Z are, independently, N or C, and R8, Rg, R11 and R? 2 are independently H or halogen (e.g., Cl or F), and Rio is halogen, alkyl, cycloalkyl, haloalkyl (for example, trifluoromethyl), aryl (for example, phenyl), heteroaryl (for example, pyridyl (for example pyrid-2-yl), or thiadiazolyl (for example, 1,3-thiadiazol-4-yl) ), diazolyl, triazolyl, tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g., methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; with the proviso that when X, Y or Z is nitrogen, R8, Rg or R10, respectively, is not present; and (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), arylamino (e.g., phenylamino), heteroarylamino, N, N-dialkylamino, N, N-diarylamino, or N-aryl-N - (arylalkyl) amino (for example, N-phenyl-N- (1,1'-biphenyl-4-ylmethyl) amino); and (v) n = 0 or, 1; (vi) when n = 1, A is -C (R? 3R1) - wherein R13 and R14 are, independently, H or C? - alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero) arylalkyl; in free form, of salt or prodrug, including its enantiomers, diastereoisomers and racemates. The invention further provides compounds of Formula I as follows: 1.1 Formula I wherein Ri is methyl and n = 0; 1.2 Formula I or 1.1 wherein R 4 is H or C 4 alkyl and at least one of R 2 and R 3 is lower alkyl, such that when the carbon bearing R 3 is chiral, it has the R configuration, for example, wherein both R2 and R3 are methyl, or wherein one is hydrogen and the other isopropyl; 1.3 Formula I or 1.1 wherein R 4 is H and at least one of R 2 and R 3 is arylalkoxy; 1.4 Formula I wherein R-is methyl, R2, R3 and R4 are H, n = 1 > and R13 and? are, independently, H or C? - alkyl (eg, methyl or isopropyl); 1.5 Formula I or 1.1 wherein R2 is H and R3 and R4 together form a tri- or tetramethylene bridge, having the cis configuration, preferably wherein the carbon bearing R3 and R4 have the R and S configurations, respectively; 1.6 Formula I, 1.1 or 1.5 wherein R5 is a substituted heteroarylmethyl, for example, para substituted with haloalkyl; .7 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R5 is a portion of Formula A wherein R8, Rg, R-n and R-? 2 are H and R10 is phenyl; 1.8 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R5 is a portion of Formula A wherein R8, Rg, R-n and R12 are H and R10 is pyridyl or thiazolyl ilo; 1.9 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R5 is a portion of Formula A wherein R8, Rg, R-n and R12 are independently, H or halogen, and R10 is haloalkyl; 1.10 Formula I, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R5 is a portion of Formula A wherein R8, Rg, Rn and R12 are independently, H and R10 is alkylsulfonyl; 1.11 any of the preceding formulas wherein R5 is attached to the nitrogen of the 2-position in the pyrazolo ring; 1.12 any of the preceding formulas wherein R6 is benzyl; 1.13 any of the preceding formulas wherein R6 is phenylamino or phenylalkylamino (e.g., benzylamino); 1.14 any of the preceding formulas wherein R6 is phenylamino; 1.15 any of the preceding formulas in which X, Y and Z are all C; 1.16 any of the preceding formulas wherein X, Y and Z are all C and Rio is phenyl or 2-pyridyl; and / or 1.17 any of the preceding formulas wherein the compounds inhibit phosphodiesterase-mediated hydrolysis (eg, mediated with PDE1, especially mediated with PDE1B) of cGMP, for example, with an IC50 of less than 1 μM, preferably of less than 25 nM in a metal-immobilized particle affinity reactive PDE assay, for example, as described in Example 24; in free form or salt. For example, Compounds of the Invention include 7,8-dihydro- [1 H or 2 H] -imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -ones of Formula Formula wherein (i) Ri is H or C 1-4 alkyl [eg, methyl]; (ii) R4 is H and R2 and R3 are, independently, H or C1- alkyl [eg, R2 and R3 are both methyl, or R2 is H and R3 is isopropyl], aryl, or arylalkyl; or R2 is H and R3 and R4 together form a bridge of di-, tri- or tetramethylene [pref. wherein the R3 and R have the cis configuration, for example, where the R3 and R4 carrying carbons have the R and S configurations, respectively]; (iii) R5 is attached to one of the nitrogens in the pyrazolo portion of formula I and is a substituted benzyl of formula B Formula B wherein R8, R9, Rn and R12 are independently H or halogen (e.g., Cl or F); and R10 is halogen, alkyl, cycloalkyl, haloalkyl (for example, trifluoromethyl) aryl (for example, phenyl), heteroaryl (for example, pyridyl (for example pyrid-2-yl), or thiadiazolyl (for example, 1, 2, 3-thiadiazol-4-yl)), arylcarbonyl (eg, benzoyl), alkylsulfonyl or heteroarylcarbonyl; and (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl [e.g., benzyl], arylamino [e.g., phenylamino), heteroarylamino, arylalkylamino, N, N-dialkylamino, N, N-diarylamino, or N-aryl -N- (arylalkyl) amino [for example N-phenyl-N- (1, 1 '-bifen-4-ylmethyl) amino]; in free, salt or prodrug form. The invention further provides compounds of Formula as follows: 1.1 Formula wherein Ri is methyl; 1.2 Formula 1.1 wherein R4 is H and at least one of R2 and R3 is lower alkyl, such that when the carbon bearing R3 is chiral, it has the R configuration, for example, wherein both R2 and R3 are methyl, or wherein one is hydrogen and the other isopropyl; 1.3 Formula o 1.1 wherein R2 is H and R3 and R together form a tri- or tetramethylene bridge, having the cis configuration, preferably wherein the carbon bearing R3 and R have the R and S configurations respectively; 1.4 Formula la, 1.1 or 1.3 wherein R5 is a portion of Formula A wherein R8, R9, Rn and R12 are H and R10 is phenyl; 1.5 Formula la, 1.1, 1.2 or 1.3 wherein R5 is a portion of Formula A wherein R8, Rg, Rn and R? 2 are H and Rio is pyridyl or thiadiazolyl; 1.6 Formula la, 1.1, 1.2, 1.3, 1.4 or 1.5 wherein R5 is attached to the nitrogen of the 2-position in the pyrazolo ring; 1.7 Formula la, 1.1, 1.2, 1.3, 1.4, 1.5 or 1.6 where R6 is benzyl; 1.8 Formula la, 1.1, 1.2, 1.3, 1.4, 1.5 or 1.6 wherein R6 is phenylamino or phenylalkylamino (e.g., benzylamino); and / or 1.9, Formula 1.1, 1.2, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 or 1.8 wherein the compounds inhibit phosphodiesterase-mediated hydrolysis (e.g., PDE1-mediated, especially PDE1B-mediated) of cGMP, e.g. , with an IC or less than 1 μM, preferably less than 25 nM in a metal-immobilized affinity reactive PDE assay, for example, as described in Example fifteen; in free form or salt. In another embodiment, the Compounds of the Invention are compounds of Formula I, wherein (i) Ri is methyl; (ii) R2, R3 and R4 are H; (iii) n = 1 and Ra and Rb are, independently, H or methyl; (iv) R5 is a portion of Formula A wherein R8, R9, R and R12 are H and R10 is phenyl, pyridyl (e.g., pyrid-2-yl), or thiadiazolyl (e.g., 1,2,3-thiadiazole -4-ilo); (v) R6 is benzyl, phenylamino or benzylamino; in free form or salt. In another embodiment, the Compounds of the Invention are compounds of Formula I wherein (i) Ri is methyl; (ii) n = 0; (iii) R2 is H and R3 and R4 together form a tri- or tetra-methylene bridge [pref. with R3 and R carrying carbons having the R and S configuration respectively]; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R is H; or R2 and R3 are H and R4 is a C1- alkyl; (iv) R5 is heteroarylmethyl substituted, for example, para substituted with haloalkyl; or Rs is a portion of Formula A wherein R8, R9, Rn and R? 2 are H or halogen and R10 is haloalkyl, phenyl, pyridyl (e.g. pyrid-2-yl), or thiadiazolyl (e.g. , 3-thiadiazol-4-yl); and (v) R6 is benzyl, phenylamino or benzylamino; in free form or salt. In another embodiment, the Compounds of the Invention are compounds of Formula wherein (i) R- \ is methyl; (ii) R2 is H and R3 and R together form a tri- or tetra-methylene bridge [pref. with R3 and R4 carrying carbons having the R and S configuration respectively]; or R2 and R3 are each methyl and R is H; or R2 and R4 are H and R3 is isopropyl [pref. the R3 that carries carbon that has the R configuration; (iii) R5 is a portion of Formula A wherein R8, Rg, Rn and R12 are H and R-? 0 is haloalkyl, phenyl, pyridyl (e.g. pyrid-2-yl), or thiadiazolyl (e.g., 1, 2,3-thiadiazol-4-yl); and (iv) R6 is benzyl, phenylamino or benzylamino; in free form or salt. For example, Compounds of the Invention include compounds according to Formulas II, III and IV.

Formula II wherein Ra and Rb are, independently, H or C? -4 alkyl; R6 is phenylamino or benzylamino; R-io is phenyl, pyridyl (for example pyrid-2-yl), thiadiazolyl (for example, 1,3-thiadiazol-4-yl); in free form or salt.

Formula III wherein R2 is H and R3 and R together form a tri- or tetramethylene bridge [pref. with R3 and R carrying carbons having the R and S configuration respectively]; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R is H; or R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C? - alkyl; Re is phenylamino or benzylamino; R-io is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl); in free form or salt.

Formula IV wherein R 2 is H and R 3 and R together form a tri- or tetramethylene bridge [pref. with R3 and R4 carrying carbons having the R and S configuration respectively]; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl; R6 is phenylamino or benzylamino; R-io is phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (for example, 1,3-thiadiazol-4-yl); in free form or salt. Compounds of the Invention include, for example, the title compounds of Examples 1-23 below. If not otherwise specified or clear from the context, the following terms as used herein have the following meanings: a. "Alkyl" as used herein is a saturated or unsaturated hydrocarbon portion, preferably saturated, preferably one to four carbon atoms in length, which may be linear or branched, and may be optionally substituted, eg, mono -, di-, or tri-substituted, for example, with halogen (for example, chloro or fluoro), hydroxy, or carboxy. b. "Cycloalkyl" as used herein is a non-aromatic, saturated or unsaturated hydrocarbon portion, preferably saturated, preferably comprising three to nine carbon atoms, at least some of which forms a monocyclic non-aromatic cyclic structure. or bicyclic, or bridged, and which may be optionally substituted, for example, with halogen (eg, chloro or fluoro), hydroxy, or carboxy. c. "Aryl" as used herein is a mono- or bicyclic aromatic hydrocarbon, preferably phenyl, optionally substituted, for example, with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro), haloalkyl (e.g. example, trifluoromethyl), hydroxy, carboxy, or an additional aryl or heteroaryl (for example, biphenyl or pyridylphenyl). d. "Heteroaryl" as used herein is an aromatic portion wherein one or more of the atoms that make the aromatic ring is sulfur or nitrogen rather than carbon, for example, pyridyl or thiadiazolyl, which may be optionally substituted, by example, with alkyl, halogen, haloalkyl, hydroxy or carboxy. The Compounds of the Invention may exist in free or salt form, for example, as acid addition salts. In this specification unless language is otherwise indicated such as Compounds of Invention it is to be understood that it encompasses compounds in any form, for example free form or acid addition salt, or where the compounds contain acid substituents, in the form of base addition salt. The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts that are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of the free Compounds of the Invention or their pharmaceutically acceptable salts, they are therefore also included. The Compounds of the Invention may in some cases also exist in the form of a prodrug. For example, when the compounds contain hydroxy or carboxy substituents, these substituents can form physiologically hydrolysable and acceptable esters. As used herein, "physiologically hydrolysable and acceptable esters" means esters of Compounds of the Invention that are hydrolysable under physiological conditions to produce acids (in the case of the Compounds of the Invention having hydroxy substituents) or alcohols (in the case of Compounds of the Invention that have carboxy substituents) that are themselves physiologically tolerable at doses that are administered. As will be appreciated, the term thus embraces conventional forms of pharmaceutical prodrug. The invention also provides methods for making the Compounds of the Invention, novel intermediates useful for making the Compounds of the Invention, and methods for using the Compounds of the Invention for the treatment of diseases and disorders as set forth below (especially treatment of diseases characterized by reduced dopamine D1 receptor signaling activity, such as Parkinson's disease, restless legs syndrome, depression, and cognitive impairment of schizophrenia). Detailed Description of the Invention Methods of Making the Compounds of the Invention The compounds of Formula I and their pharmaceutically acceptable salts can be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the art. the chemical technique Such methods include, but are not limited to, those described below. If they are not commercially available, starting materials for those processes can be made by methods, which are selected from the chemical technique using techniques that are similar or analogous to the synthesis of known compounds. All references cited herein are incorporated herein by reference in their entirety. Some individual compounds within the scope of this invention may contain double bonds. The double bond representations in this invention are to mean that they include both the E and Z isomers of the double bond. In addition, some compounds within the scope of this invention may contain one or more asymmetric centers. This invention includes the use of any of the optically pure stereoisomers as well as any combination of the stereoisomers. The melting points are incorrect and (dec) indicates decomposition. Temperatures are given in degrees Celsius (° C); unless stated otherwise, the operations are carried out at room temperature, that is, at a temperature in the range of 18-25CC. Chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) is carried out on silica gel plates. The NMR data is in the delta values of the main diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Conventional abbreviations are used to form the signal. The coupling constants (J) are given in Hz. For mass spectra (MS), the minimum mass major ion is reported for molecules where the division of isotopes results in multiple mass spectral peaks. The solvent mixture compositions are given as percentages by volume or proportions by volume. In cases where the NMR spectra are complex, only diagnostic signals are reported. Terms and abbreviations: Bu'OH tert-butyl alcohol, CAN ammonium nitrate and cerium (IV), DIPEA diisopropylethylamine, DMF N, N-dimethyl formamide, DMSO dimethyl sulfoxide, Et2O diethyl ether, EtOAc ethyl acetate, equiv. equivalent (s), h hour (s), HPLC high performance liquid chromatography, K2CO3 potassium carbonate, MeOH = sodium bicarbonate, NH4OH = ammonium hydroxide, PMB = p-methoxybenzyl, POCI3 = phosphorus oxychloride, SOCI2 = thionyl chloride, TFA = trifluoroacetic acid, THF = tetrahydrofuran. The synthetic methods in this invention are illustrated below. The meanings for the R groups are as stated above for the formula I unless otherwise indicated. In one aspect of the invention, intermediary compounds of the formula 11b can be synthesized by reacting a compound of the formula lia with a dicarboxylic acid, acetic anhydride and acetic acid by mixing with heat for about 3 hours and then cooling: í, la) «n». wherein R1 is H or C? -4 alkyl [eg, methyl]. The intermediary lie can be prepared for example by reacting a compound of llb with for example a chlorination compound such as POCI3 sometimes with small amounts of water and heating for about 4 hours and then cooling: (llb) (lie) Intermediary lid can be formed by reacting a compound of Me with for example a P1-X in a solvent such as DMF and a base such as K2CO3 at room temperature or with heating: (\\ c) (lid) wherein P1 is a protecting group [e.g., p-methoxybenzyl group (PMB)]; X is a leaving group such as a halogen, mesylate, or tosylate. The Intermediate can be prepared by reacting a lid compound with hydrazine or hydrazine hydrate in a solvent such as methanol and refluxing for about 4 hours and then cooling: (lid) file) The Mf Intermediate can be synthesized by reacting a compound of Me with hydrazine or hydrazine hydrate in a solvent such as methoxymethanol and brought to reflux for about 30 minutes and then cooled: (lie) (lff) Intermediate llg (wherein R13 is alkyl, aryl [eg, phenyl], heteroaryl, arylalkyl, or heteroarylalkyl), can be synthesized by reacting a compound of Me with for example an isocyanate or aryl isothiocyanate in a solvent such as DMF and heated at 110 ° C for about 2 days and then cooled: file) The Intermediary Mh can be synthesized from a compound of llg by removing the protecting group P1 with an appropriate method. For example, if P1 is a p-methoxybenzyl group, then it can be removed with AICI3 at room temperature or with TFA under hot conditions. The Intermediary Mh can also be prepared directly from an Mf compound using similar methods, but the yields are relatively low. illa) (llh) The intermediate 11-I can be prepared for example by reacting an Mh compound with for example a chlorination compound such as POCI3. The reaction may be carried out at atmospheric pressure and brought to reflux for about 2 days, or heated at 150 ~ 200 ° C for about 10 minutes in a sealed jar with a microwave instrument.

(Hh) (H-l) Intermediary MJ can be prepared by reacting a compound of ll-1 with an aminoalcohol under basic conditions in a solvent such as DMF. The reaction can be heated overnight and then cooled: OW) din Unless otherwise specified or defined, R2, R3 and R4 are the same as those previously defined, for example, with respect to Formula 1. Intermediary 11K can be formed by reacting a compound of IIJ with for example a dehydration agent such as SOCI2 in a solvent such as CH2Cl2 at room temperature overnight or heating at 35 ° C for about 4 hours, and then cooling: (HJ) r ???) The compound la and Ib can be formed by reacting a lik compound with for example an R5-X in a solvent such as DMF and a base such as K2CO3 at room temperature or with heating: flIK) (la) (Ib) wherein R5 is as previously defined [e.g., an optionally substituted benzyl group]; X is a leaving group such as a halogen, mesylate or tosylate. R5 can also be introduced before, for example by reacting llg with R5X and then performing a similar procedure as described above to form compound la and Ib, whereas R5 would not dissociate in the deprotection step of P1. The second synthetic route is designated for the preparation of the compound la and Ib wherein R6 is an alkyl, aryl or heteroaryl group. Intermediate Illa (wherein R7 is aryl, preferably phenyl substituted with Rβ-? 2 corresponding to the substituted benzyl of Formula A supra) can be formed by reacting a compound of Me with an aldehyde R7CHO in a solvent such as EtOAc at 0 °. C or room temperature: The intermediate lllb can be prepared for example by reacting an Illa compound with for example an aldehyde in a solvent such as DMF and heating overnight and then cooling: (Illa) (lllb) The lile Intermediate can be synthesized from a lllb compound by removing the protecting group P1 with an appropriate method. For example, if P1 is a p-methoxybenzyl group, then it can be removed with CAN at room temperature. The lile Intermediary can also be prepared directly from a llf compound using similar methods, but the yields are relatively low. (lllb) (Ule) (llf) ("Id) (lile) The lile Intermediate can be prepared by reacting a lile compound with for example a chlorination compound such as POCI3. The reaction may be carried out at atmospheric pressure and brought to reflux for about 2 days, or heated at 150 ~ 200 ° C for about 10 minutes in a sealed jar with a microwave instrument. (lile) (lile) Intermediate Mlf can be formed by reacting a lile compound with an aminoalcohol under basic conditions in a solvent such as DMF and heating overnight and then cooling: (lile) piifi The compound can be formed by reacting a lllf compound with for example a dehydration agent such as SOCI2 in a solvent such as CH2Cl2 at room temperature overnight or heating at 35 ° C for about 4 hours, and then cooling: (lllf) (the) There is an alternative approach for the synthesis of compound la and Ib wherein R6 is an alkyl or aryl group. If a more severe condition is used for the deprotection of lllb, then the group R7CH2 can also be dissociated. For example, if P1 is a p-methoxybenzyl group and R7 is a substituted phenyl group, then both of P1 and R7CH2 can be dissociated with AlCl3 at room temperature. In this way, Intermediary lllg can be formed with this approach: (lllb) (HlR) Intermediate Mlh can be prepared by reacting a lllg compound with for example a chlorination compound such as POCI3. The reaction may be carried out at atmospheric pressure and brought to reflux for about 2 days, or heated at 150 ~ 200 ° C for about 10 minutes in a sealed jar with a microwave instrument. (uig) (lllh) Intermediary MI-I can be formed by reacting a lllh compound with an aminoalcohol under a basic condition in a solvent such as DMF and heating overnight and then cooling: The MU Intermediate can be formed by reacting an MI-I compound with for example a dehydration agent such as SOCI2 in a solvent such as CH2Cl2 or methanol at room temperature overnight or heating at 35 ° C for about 4 hours, and then it cools: ("'•') (IIIJ) The MU Intermediate can also be formed by reacting a compound of with for example a strong acid or Lewis acid such as AICI3: (la) (IIIJ) The compound la and Ib can be formed by reacting a MU compound with for example an R5-X in a solvent such as DMF and a base such as K2CO3 at room temperature or with heating: C'J) ila) (b) The third synthetic route is designated for the preparation of the compound la and Ib wherein R6 is hydrogen. Intermediary IVa can be formed for example by reacting a compound of Me with POCI3 and DMF: (He) (IVa) Intermediate IVb can be formed by reacting an IVa compound with for example an R5-X in a solvent such as DMF and a base such as K2CO3 at room temperature or with heating: (IVa) (IVb) Intermediate IVc can be synthesized from an IVb compound by removing the protecting group P1 with an appropriate method. For example, if P1 is a PMB group, then it can be removed with CAN at room temperature: (IVb) (IVc) Intermediate IVd can be prepared by reacting an IVc compound with for example a chlorination compound such as POCI3 and brought to reflux for about 2 days, or heated at 150-200 ° C for about 10 minutes in a sealed jar with a microwave instrument and then cooled: (IVc) (IVd) Intermediate IVe can be formed by reacting an IVd compound with an aminoalcohol under a basic condition in a solvent such as DMF and heating overnight then cooling: The compound can be formed by reacting an IVe compound with for example a dehydration agent such as SOCI2 in a solvent such as CH2Cl2 at room temperature overnight or heating at 35 ° C for about 4 hours, and then cooling. Similar to the methods described above, the R5 group in a compound can be dissociated using an appropriate method, and then the obtained intermediate can react with another R5X to give the compound la and Ib.

(IVe) (la) The invention thus provides methods of making Compounds of the Invention as described above, for example, comprising (i) reacting a 7,8-dihydro-imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one or a 7,8,9-trihydro- [1 H or 2 H] -pyrimido [1,2-a] pyrazolo [4,3-e) pyrimidine -4 (5H) -one with a compound of formula X-R5 wherein X is a leaving group, eg, halogen, mesylate, or tosylate, and R5 is C2-9 alkyl, C3-9 cycloalkyl, heteroarylalkyl, or substituted arylalkyl, for example wherein R 5 is a substituted benzyl of formula A as defined above, for example, under basic conditions, for example wherein 7,8-dihydro-imidazo [1,2-a] pyrazolo [4] , 3-e] pyrimidin-4 (5H) -one is a compound of the Formula MU: O R6 R3 R4 (IIIJ) wherein R1-6 are as defined above, for example, with reference to Formula I; and / or (ii) dehydrating a compound of Formula V V wherein R1-6 and [A] n are as defined above, for example, with reference to Formula I, for example, using a dehydrating agent, for example thionyl chloride; and isolating the Compound of the Invention obtained in this way. Methods for Using the Compounds of the Invention The Compounds of the Invention are useful in the treatment of diseases characterized by disruption of or damage to pathways mediated by cAMP and cGMP, for example, as a result of increased expression of PDE1 or decrease in the expression of cAMP and cGMP due to inhibition or reduced levels of inducers of cyclic nucleotide synthesis, such as dopamine and nitric oxide (NO). By preventing the degradation of cAMP and cGMP by PDE1B, thus increasing intracellular levels of cAMP and cGMP, the Compounds of the invention enhance the activity of the inducers of cyclic nucleotide synthesis. The invention provides methods of treating any one or more of the following conditions: (i) Neurodegenerative diseases, including Parkinson's disease, restless legs, tremors, dyskinesias, Huntington's disease, Alzheimer's disease, and drug-induced movement disorders; (ii) Mental disorders, including depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar illness, anxiety, sleep disorders, cognitive impairment, dementia, abstention from psychostimulants, and drug addiction; (iii) Circulatory and cardiovascular disorders, including cerebrovascular disease, stroke (attack), congestive heart disease, hypertension, pulmonary hypertension, and sexual dysfunction; (iv) Respiratory and inflammatory disorders, including asthma, chronic obstructive pulmonary disease, and allergic rhinitis, as well as autoimmune and inflammatory diseases; and / or (v) 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. which comprise administering an effective amount of a Composite of the Invention to a human or animal patient that needs it. The invention also provides a method for improving or enhancing the intracellular dopamine D1 signaling activity in a cell or tissue comprising contacting the cell or tissue with an amount of a Compound of the invention sufficient to inhibit the activity of PDE1B. The invention also provides a method for treating a disorder related to PDE1, especially PDE1B, or a disorder of the intracellular signaling pathway of the dopamine D1 receptor, in a patient in need thereof comprising administering to the patient an effective amount of a Compound. of the Invention that inhibits PDE1B, wherein the activity of PDE1B modulates the phosphorylation of DARPP-32 and / or of the GluR1 AMPA receptor. The present invention also provides (i) a Compound of the Invention for use as a pharmacist, for example for use in any method or in the treatment of any disease or condition as set forth in the foregoing, (i) the use of a Compound of the Invention in the manufacture of a medicament for treating any disease or condition as set forth in the foregoing, and (iii) a pharmaceutical composition comprising a Compound of the invention in combination or association with a pharmaceutically acceptable diluent or carrier. The words "treatment" and "treat" are to be understood accordingly as they encompass the prophylaxis and treatment or improvement of the symptoms of the disease as well as the treatment of the cause of the disease. The Compounds of the Invention are particularly useful for the treatment of Parkinson's disease. The Compounds of the Invention may be used as a single therapeutic agent, but may also be used in combination or for co-administration with other active agents. For example, as Compounds of the Invention enhance the activity of D1 agonists, such as dopamine, they can be administered simultaneously, sequentially or contemporaneously with conventional dopaminergic drugs, such as levodopa and levodopa auxiliaries. (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, for example, in the treatment of a patient who has Parkinson's disease. Doses employed in the practice of the present invention will vary in course depending, for example, on the particular disease or condition to be treated, the particular Invention Compound used, the mode of administration, and the desired therapy. The Compounds of the Invention can be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally. In general, satisfactory results, for example, for the treatment of diseases as set forth in the foregoing, are indicated to be obtained in oral administration in doses of the order of approximately 0.01 to 2.0 mg / kg. In larger mammals, for example humans, a daily dose indicated for oral administration would therefore be in the range of from about 0.75 to 150 mg, conveniently administered once, or in divided doses of 2 to 4 times, per day or in the form of prolonged release. Unit dosage forms for oral administration for example in this manner may comprise from about 0.2 to 75 or 150 mg, for example from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of the Invention, together with a pharmaceutically acceptable diluent or carrier therefor. Pharmaceutical compositions comprising Compounds of the Invention can be prepared using conventional diluents or excipients and techniques known in the galenic art. Oral dosage forms may well include tablets, capsules, solutions, suspensions and the like. EXAMPLES Example 1: 2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] -imidazo- [1,2-a] pyrazolo [4,3-e] pyrimidine -4 (5H) -one (a) 1-Methylpyrimidin-2,4,6 (1H, 3H, 5H) -trione To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid a 70 ° C, acetic anhydride (130 ml, 1.37 mol) was slowly added. After the completion of the addition, the reaction mixture was stirred at 90 ° C for 3 hours, and then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was treated with 350 mL of ethanol to precipitate a yellowish solid. The solid was recrystallized from ethanol to give 63.1 g of product as crystalline solids (Yield: 65.8%). P.f. = 131.2-133.1 ° C [Lit.1: p.f. = 130- 131.5 ° C]. (b) 6-Chloro-3-methylpyrimidin-2,4 (1H, 3H) -dione Water (2.7 mL) was added dropwise to a suspension of 1-methylpyrimidine-2,4,6 (1H, 3H, 5H) -trione (14.2 g, 100 mol) in POCI3 (95 mL) at 0 ° C. The reaction mixture was then heated at 80 ° C for 5 hours. The resulting brownish-brown solution was cooled, and POCI3 was evaporated under reduced pressure. The residue was treated with MeOH, and the obtained solid was recrystallized from ethanol to give 11.5 g of product (Yield: 71.6%). P.f. = 279-282 ° C (dec) [Lit.2: 280-282 ° C]. H-NMR (400 MHz, DMSO-d6) d 3.10 (S, 3H), 5.90 (S, 1H), 12.4 (br, 1H). (c) 6-Chloro-1- (4-methoxybenzyl) -3-methylpyrimidine-2,4 (1H, 3H) -dione A mixture of 6-chloro-3-methylpyrimidin-2,4 (1 H, 3H) - dione (16.2 g, 101 mmol), p-methoxybenzyl chloride (16.5 mL, 122 mmol) and potassium carbonate (7.0 g, 50.7 mmol) in anhydrous DMF (200 mL) was heated at 60 ° C for 3 hours. Additional potassium carbonate (3.0 g, 21.7 mmol) was added, and the reaction mixture was heated at 60 ° C for another 3 hours. After the hot filtration, the filtrate was evaporated to dryness under reduced pressure. The oil obtained is used directly for the synthesis in the next stage. A small amount of product was further purified by flash chromatography on silica gel to give the pure product as crystals. 1 H NMR (400 MHz, MeOH-d 4) d 3.37 (s, 3 H), 3.83 (s, 3 H), 5.24 (s, 2 H), 5.96 (s, 1 H), 6.91 and 7.32 (AB, 4 H, J = 6.8 Hz). MS (FAB) m / z 281.23 [M + H] \ (d) 6-Hydrazinyl-1- (4-methoxybenzyl) -3-methylpyrimidine-2,4 (1H, 3H) -dione To a solution of 6-chloro -1- (4-methoxybenzyl) -3-methylpyrimidine-2,4 (1H, 3H) -dione (2.4 g, 8.6 mmol) in EtOH (25 mL) and MeOH (50 mL), anhydrous hydrazine (1.2. mL). The reaction mixture was refluxed for three hours, and then cooled. A large amount of ether was added in the reaction mixture, and then filtered to give 2.0 g of product as crystalline solids (Yield: 84%). 1 H NMR (DMSO-de) d 3.13 (s, 3N), 3.73 (s, 3H), 4.42 (br, 1H), 5.03 (s, 2H), 5.15 (s, 1H), 6.88 and 7.15 (AB, 4H) , J = 6.4 Hz), 8.08 (br, 1H). MS (FAB) m / z 277.28 [M + H] \ (e) 7- (4-Methoxybenzyl) -5-methyl-1H-pyrazolo [3,4-d] pyrimidine-4,6 (5H, 7H) - dione To a solution of 6-hydrazinyl-1- (4-methoxybenzyl) -3-methylpyrimidin-2,4 (1 H, 3H) -dione (0.45 g, 1.6 mmol) in DMF (2 mL), was added dropwise POCI3 (0.3 mL, 3.3 mmol) at 0 ° C. After the reaction mixture was stirred at 0 ° C for 1 hour, the mixture was treated with methanol carefully to give a white solid. The solid was further purified by chromatography to give 0.4 g of product (Yield: 85%). 1H-NMR (DMSO-d6) d 3.23 (s, 3H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85 and 7.31 (AB, 4H, J = 11.6 Hz), 8.47 (s, 1H), 13.5 (br, 1H). MS (FAB) m / z 287.21 [M + H] +. (f) 2- (B ifen i l-4-i I methyl) -7- (4-methoxy-benzyl) -5-methyl-2 H -pyrazolo [3,4-d] pyrimidine-4,6 (5H, 7H) -dione A mixture of 7- (4-methoxybenzyl) -5-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (0.312 g, 1.09 mmol), p-Biphenylmethyl bromide (0.296 g, 1.20 mmol) and potassium carbonate (0.151 g, 1.09 mmol) in acetone (20 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was purified directly by chromatography to give 0.382 g of product as white solids (Yield: 77.5). 1 H NMR (400 MHz, CDCI3) d 3.37 (s, 3H), 3.75 (s, 3H), 5.15 (s, 2H), 5.34 (s, 2H), 6.81 (m, 2H), 7.27 (m, 3H), 7.47 (m, 4H), 7.60 (m, 4H), 7.87 (s, 1H). MS (FAB) m / z 453.3 [M + H] +. (g) 2- (Biphenyl-4-ylmethyl) -5-methyl-2H-pyrazolo [3,4-d] pyrimidine-4,6 (5H, 7H) -dione To a solution of 2- (biphenyl-4-) ilmethyl) -7- (4-methoxybenzyl) -5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (300 mg, 0.663 mmol) in THF (9 mL) , a solution of ammonium nitrate and cerium (IV) (1.82 g, 3.32 mmol) in water (3 mL) was added. The resulting orange solution was stirred at room temperature overnight. Another batch of CAN (1.82 g, 3.32 mmol) was added and the mixture was stirred for 6 hours, and then the third batch of CAN (1.82 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was treated with brine, and extracted with methylene chloride five times. The organic phase was combined and concentrated. The residue was purified by chromatography to give the product as white solids in high yield. 1 H NMR (400 MHz, DMDO-d 6) d 3.16 (s, 3 H), 5.37 (s, 2 H), 7.38 (m, 3 H), 7.46 (m, 2 H), 7.65 (m, 4 H), 8.59 (s, 1H), 11.6 (s, 1H). MS (FAB) m / z 333.3 [M + H] +. (h) 2- (Biphenyl-4-ylmethyl) -6-chloro-5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one 2- (biphenyl-4-ylmethyl) - 5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (25 mg, 0.075 mmol) was refluxed in POCI3 (10 mL) for 60 hours, and the mixture it evaporated to dryness. The residue was purified by flash chromatography on silica gel to give 26 mg of product as white solids (Yield: 98.5%). 1 H NMR (400 MHz, CDCl 3) d 3.68 (s, 3 H), 5.45 (s, 2 H), 7.39 (m, 3 H), 7.43 (m, 2 H), 7.59 (m, 4 H), 8.01 (s, 1 H) . MS (FAB) m / z 351.2 [M + H] +. (i) 2- (Biphenyl-4-ylmethyl) -6- (1-hydroxy-2-methylpropan-2-ylamino) -5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) - ona A solution of 2- (biphenyl-4-ylmethyl) -6-chloro-5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one (26 mg, 0.074 mmol) and 2- amino-2-methyl-1-propanol (71 μL, 0.74 mmol) in DMF (1 mL) was heated at 110 ° C overnight. The reaction mixture was then purified by chromatography to give 21.1 mg of product (Yield: 71%). MS (FAB) m / z 404.2 [M + H] +. (j) 2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] -imidazo- [1,2-a] pyrazolo [4,3-e] pyrimidine- 4 (5H) -one To a solution of 2- (biphenyl-4-ylmethyl) -6- (1-hydroxy-2-methylpropan-2-ylamino) -5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one (17 mg, 0.042 mmol) in methylene chloride (1 mL), was added a 2.0 M CH 2 Cl 2 solution of thionyl chloride (63 μL, 0.126 mmol) under argon. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with 5% NaHCO3, and the resulting mixture was purified by chromatography to give 11 mg of the final product as white solids (Yield: 68%). 1 H NMR (400 MHz, DMSO-d 6 + CDCl 3) d 1.36 (s, 6H), 3.30 (s, 3H), 3.69 (s, 2H), 5.30 (s, 2H), 7.36 (m, 3H), 7.43 ( m, 2H), 7.58 (m, 4H), 8.10 (s, 1H). MS (FAB) m / z 386.1 [M + H] +. Example 2 Cis- (6aR *, 10aS *) - 1- (4-Benzoylbenzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) cyclohex [4 , 5] imidazo [1,2-a] pyrazolo [4,3- e] pyrimidin-4 (1H) -one (a) 7- (4-Methoxybenzyl) -5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione Phenyl isothiocyanate was added (3.9 mL, 32.7 mmol) was added to a suspension of 6-hydrazinyl-1- (4-methoxybenzyl) -3-methylpyrimidine-2,4 (1 H, 3 H) -dione (0.45 g, 1.6 mmol) in DMF (12 mL). ). The reaction mixture was heated at 120 ° C for 40 hours, and then evaporated to remove the solvent under reduced pressure. The residue was washed with hexanes, and then treated with MeOH (125 mL), and stored at -15 ° C for 2 days to give a crystalline solid. The solid was recrystallized from CH3OH-EtOA to yield 2.5 g of product (Yield: 61%). 1 H NMR (400 MHz, DMSO-d 6) d 3.21 (s, 3 H), 3.73 (s, 3 H), 5.01 (s, 2 H), 6.88-7.36 (m, 9 H). MS (FAB) m / z 378.3 [M + H] +. (b) 5-Methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidine-4,6 (5H, 7H) -dione AICI3 (0.733 g, 5.50 mmol) was added to a solution 7- (4-methoxybenzyl) -5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (0.692 g, 1.83 mmol) and anisole (40 μL, 0.367 mmol) in 1,2-dichloroethane (10 mL) under argon. The reaction mixture was stirred at room temperature for 30 minutes, and then quenched with water and with cooling. The resulting suspension was filtered through a celite layer and this was washed with MeOH (20 mL). The product was eluted from celite with a large amount of THF. The eluent of THF was evaporated to yield 0.47 g of product (Yield: 99%). MS (FAB) m / z 258.2 [M + H] +. (c) 6-Chloro-5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one The 5-methyl-3- (phenylamino) -H-pyrazolo [ 3,4-d! Pyrimidin-4,6 (5H, 7H) -dione (450 mg, 1.75 mmol) was refluxed in POCI3 (20 mL) for 60 hours, and the mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel to give 122 mg of product as white solids and 207 mg of starting material was recovered (Yield: 47%). MS (FAB) m / z 276.1 [M + H] +. (d) 6 - ((1R *, 2R *) - 2-Hydroxycyclohexylamino) -5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one A solution of 6-Chloro-5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one (75.8 mg, 0.275 mmol), trans-2-amino-cyclohexanol hydrochloride (83.4 mg, 0.55 mmol) and DIPEA (144 μL, 0.825 mmol) in DMF (3 mL) was heated at 110 ° C overnight. The reaction mixture was evaporated to remove DMF under reduced pressure. The residue was then purified by chromatography to give 63.1 mg of product (Yield: 64.7%). MS (ESI) m / z 355.0 [M + H] \ (e) Cis- (6aR *, 10aS *) - 5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- ( phenylamino) cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1 H) -one A 2.0 M solution of thionyl chloride in CH 2 Cl 2 (267 μL, 0.534 mmol) was added to a solution of 6 - ((1 R *, 2R *) - 2-hydroxycyclohexylamino) -5-methyl-3- (phenylamino) -1H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one (63.1 mg, 0.178 mmol) in CH2Cl2 (6 mL) and THF (4 mL). The reaction mixture was stirred at room temperature overnight, and then warmed with 100 μL of 28% NH4OH. The resulting mixture was concentrated and purified by chromatography to give 25 mg of product as white solids (Yield: 42%). MS (ESI) m / z 337.1 [M + H] +. (f) Cis- (6a R *, 10aS *) - 1 - (4-Benzoyl I benzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1H) -one A mixture of Cis- (6aR *, 10aS *) - 5, 6a, 7.8, 9, 10, 10a-heptahydro-5-methyl-3- (phenylamino) cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1 H) -one (7.1 mg, 0.021 mmol), 4-benzoylbenzyl bromide (5.8 mg, 0.021 mmol), and K2CO3 (2.92 mg, 0.021 mmol) in DMF (1 mL) was stirred at room temperature overnight under argon. The reaction mixture was purified by a semi-preparative HPLC to give 3.5 mg of the final product (Yield: 31%). MS (ESI) m / z 531.1 [M + H] +. Example 3 3-Benzyl-2- (biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] -imidazo- [1,2-a] pyrazolo [4,3-e] ] pyrimidin-4 (5H) -one (a) 6- (2- (Biphenyl-4-methylmethyl) hydrazinyl) -1- (4-methoxybenzyl) -3-methylpyrimidin-2, 4 (1H, 3H) -dione A solution of 4-phenylbenzaldehyde (395 mg, 2.17 mmol) in EtOAc was added slowly to a dry ice cooled suspension of 6-hydrazinyl-1- (4-methoxybenzyl) -3-methylpyrimidine. -2.4 (1H, 3H) -dione (200 mg, 0.724 mmol) in EtOAc. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with MeOH, followed by filtration to give 256 mg of product as pale yellow solids (Yield: 80.3%). 1 H NMR (400 MHz, DMSO-d 6) d 3.17 (s, 3 H), 3.71 (s, 3 H), 5.22 (s, 2 H), 5.59 (s, 1 H), 6.91 and 7.21 (AB, J = 7.2 Hz, 4H), 7.37-7.81 (m, 9H), 8.36 (s, 1H), 10.67 (s, 1H). MS (FAB) m / z 441.4 [M + H] +. (b) 3-Benzyl-2- (biphenyl-4-ylmethyl) -7- (4-methoxybenzyl) -5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) - dione Acetic acid (4.4 mL) was added in a solution of 6- (2- (Biphenyl-4-ylmethylene) hydrazinyl) -1- (4-methoxybenzyl) -3-methylpyrimidin-2,4 (1 H, 3H) - dione (3.2 g, 7.26 mmol) in DMF (50 ML) and Bu'OH (25 mL) at 50 ° C. Piperidine (8.7 mL) was mixed with a solution of 2-phenylacetaldehyde (8.5 mL, 72.6 mmol) in DMF (20 mL), and the resulting greenish solution was added to the above solution. The reaction mixture was stirred at 40-45 ° C for 36 hours under argon, and the solvent was evaporated under high vacuum. The residue was treated with MeOH (200 mL) until 1.23 g of product were precipitated as sand-colored solids (Yield: 31.4%). MS (FAB) m / z 543.4 [M + H] +. (c) 3-Benzyl-2- (biphenyl-4-ylmethyl) -5-methyl-2H-pyrazolo [3,4-d] pyrimidine-4,6 (5H, 7H) -dione A nitrate solution of Ammonium and cerium (IV) (204 mg, 0.371 mmol) in water (0.6 mL) was added to a solution of 3-benzyl-2- (biphenyl-4-ylmethyl) -7- (4-methoxybenzyl) -5-methyl -2H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (40.3 mg, 0.0743 mmol) in THF (2 mL). The resulting orange solution was stirred at room temperature overnight. Another batch of CAN (204 mg, 0.371 mmol) was added and the mixture was stirred for 3 hours, and then the third batch of CAN (204 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was treated with brine, and extracted with methylene chloride five times. The organic phase was combined and concentrated. The residue was purified by chromatography to give 11.6 mg of product as white solids (Yield: 36.9%). 1 H NMR (400 MHz, acetone-d 6) d 3.27 (s, 3 H), 4.51 (s, 2 H), 5.33 (s, 2 H), 7.13-7.62 (m, 14 H), 10.26 (s, 1 H). MS (FAB) m / z 423.2 [M + H] +. (d) 3-Benzyl-2- (biphenyl-4-ylmethyl) -6-chloro-5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one 3-Benzyl-2- (biphenyl-4-ylmethyl) -5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4,6 (5H, 7H) -dione (10 mg, 0.024 mmol) was refluxed in POCI3 ( 10 mL) for 4 days, and then the mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel to give 10.4 mg of product as white solids (Yield: 100%). MS (FAB) m / z 441.2 [M + H] +. (e) 3-Benzyl-2- (biphenyl-4-ylmethyl) -6- (1-hydroxy-2-methylpropan-3-ylimino) -5-methyl-6,7-dihydro-2H-pyrazolo [3,4 -d] pyrimidin-4 (5H) -one A solution of 3-Benzyl-2- (biphenyl-4-ylmethyl) -6-chloro-5-methyl-2H-pyrazolo [3,4-d] pyrimidin-4 ( 5H) -one (9.5 mg, 0.022 mmol) and 2-amino-2-methyl-1-propanol (21 μL, 0.22 mmol) in DMF (2 mL) was heated at 110 ° C overnight. The reaction mixture was then purified by chromatography to give 5.5 mg of product (Yield: 52%). MS (FAB) m / z 494.4 [M + H] +. (f) 3-Benzyl-2- (biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] -imidazo- [1,2-a] pyrazolo [4,3- e] pyrimidin-4 (5H) -one A 2.0 M solution of thionyl chloride (25 μL, 0.050 mmol) in CH2Cl2 was added to a solution of 3-benzyl-2- (biphenyl-4-ylmethyl) -6- ( 1-hydroxy-2-methylpropan-3-ylimino) -5-methyl-6,7-dihydro-2H-pyrazolo [3,4-d] pyrimidin-4 (5H) -one (5.0 mg, 0.010 mmol) in chloride of methylene (1 mL). The reaction mixture was stirred at room temperature overnight, and then quenched with 5% NaHCO3. The resulting mixture was purified by chromatography to give 3.2 mg of the final product (Yield: 67%). MS (FAB) m / z 476.4 [M + H] +. Example 4 1- (Biphenyl-4-ylmethyl) -7, 8-dihydro-5,7,7-trimethyl-3- (phenylamino) - [1 H] -imidazo- [1,2-a] pyrazolo [4,3- e] pyrimidin-4 (5H) -one The synthesis method is analogous to example 2 wherein 2-amino-2-methyl-1-propanol is added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and p-biphenylmethyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 5 1- (4- (1,2,3-thiadiazol-4-yl) benzyl) -7,8-dihydro-5,7,7-trimethyl-3- (phenylamino) - [1 H] -imidazo- [ 1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one The method of synthesis is analogous to example 2 wherein 2-amino-2-methyl-1-propanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (1, 2,3-thiadiazol-4-yl) benzyl bromide was added in step (f) in place of benzoylbenzyl bromide. EXAMPLE 6 1 - (Bifenyl-4-i-methyl) -3 - ((bifenyl-4-i-methyl) (f-enyl) -amino) -7,8-dihydro-5,7,7-tr MethyI- [1 H] -imidazo- [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one The method of synthesis is analogous to example 2 wherein 2-amino-2-methyl-1-propanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and p-biphenylmethyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 7 Cis- (6aR *, 10aS *) - 5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) -1- (4- (pyridin-2-yl) benzyl) - cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1H) -one The method of synthesis is analogous to example 2 wherein 2- (4- (bromomethyl) phenyl) pyridine was added in step (f) in place of benzoylbenzyl bromide. Example 8 Cis- (6aR *, 10aS *) - 2- (4- (pyridin-2-yl) benzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- ( phenylamino) cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3- e] pyrimidin-4 (2H) -one The method of synthesis is analogous to example 2 wherein 4-pyrid-2-ylbenzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 9 Cis- (6aR *, 10aS *) - 3- (Benzyl) -5,6a, 7,8,9,10I10a- heptahydro-5-methyl-2- (4- (1,2,3-thiadiazole- 4-yl) benzyl) -cyclohex [4, 5] imidazo [1,2-a] pi, but only [4,3-e] pyrimidin-4 (2H) -one The method of synthesis is analogous to Example 3 wherein 4- (1, 2,3-thiadiazol-4-yl) benzaldehyde and DMF were added in step (a) in place of 4-phenylbenzaldehyde and heated overnight; and trans-2-amino-cyclohexanol hydrochloride was added in step (e) in place of 2-amino-2-methyl-1-propanol. Example 10 Cis- (6aR *, 10aS *) - 3- (Benzyl) -2- (4-B-phenyl-4-ylmethyl) -5,6a, 7,8,9,10,10a-heptahydro-5- methyl-cyclohex [4.5] midazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one The synthesis method is analogous to example 3 wherein trans-2-amino-cyclohexanol hydrochloride was added in step (e) in place of 2-amino-2-methyl-1-propanol. Example 11 (R) -3- (Benzyl) -2- (biphenyl-4-ylmethyl) -7,8-dihydro-7-isopropyl-5-methyl- [2 H] -imidazo- [1,2-a] pyrazole [4.3- e] pyrimidin-4 (5H) -one The synthesis method is analogous to Example 3 wherein (R) -2-amino-3-methylbutan-1 -ol was added in step (e) in place of 2-amino-2-methyl-1-propanol.

Example 12 (6aR, 9aS) -5, 6a, 7,8,9, 9a-hexahydro-5-m and il-3- (phenylamino) -2 - (4-pyridin-2-yl) -benzyl) -cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine 4 (2H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 2- (4-bromomethyl) phenyl) pyridine was added in step (f) in place of benzoylbenzyl bromide. Example 13 (6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-5-methyl-3- (phenylamino) -1- (4-pyridin-2-M) -benzyl) -cyclopent [4 , 5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4-pyrid-2-ylbenzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 14 (6aR, 9aS) -3- (benzylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (4-pyridin-2-yl) -benzyl) -cyclopent [4 , 5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one The synthesis method is analogous to example 2 wherein benzyl isothiocyanate was added in step (a) in place of phenyl isothiocyanate; (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4-pyrid-2-ylbenzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 15 (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (biphenyl-4-ylmethyl) -cyclopent [4,5] imidazo [ 1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (bromomethyl) biphenyl was added in step (f) in place of benzoylbenzyl bromide. Example 16 2- (Bifenyl-4-ylmethyl) -7,8,9-trihydro-5,8,8-trimetM-3- (phenylamino) - [2 H] -pyrimido- [1,2-a] pi razólo [4, 3- e] pyrimidin-4 (5H) -one The method of synthesis is analogous to example 2 wherein 3-amino-2,2-dimethyl-1-propanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (bromomethyl) biphenyl was added in step (f) in place of benzoylbenzyl bromide. Example 17 (7R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7-dimethyl-3- (phenylamino) - [2 H] -imidazo- [1,2-a] pyrazole [4.3- e] pyrimidin-4 (5H) -one The synthesis method is analogous to example 2 wherein (R) -2-aminoprop-1 -ol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (bromomethyl) biphenyl was added in step (f) in place of benzoylbenzyl bromide. Example 18 (8R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,8-dimethyl-3- (nylamino) - [2 H] -imidazo- [1,2-a] pi just [4.3- e] pyrimidin-4 (5H) -one The synthesis method is analogous to example 2 wherein (R) -1 -aminopropan-1 -ol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (bromomethyl) biphenyl was added in step (f) in place of benzoylbenzyl bromide. Example 19 (7R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-3-dihydro-3- (phenylamino) -5-methyl-7- (1-methylethyl) - [2H] -imidazo- [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one The method of synthesis is analogous to example 2 wherein (R) -2-amino-3-methylbutan-1 -ol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 4- (bromomethyl) biphenyl was added in step (f) in place of benzoylbenzyl bromide. Example 20 (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (4- (trifluoromethyl) -benzyl) -cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidine- The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and p-trifluoromethylbenzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 21 (6aR, 9aS) -3- (phenylamino) -5, 6a, 7,8,9, 9a-hexahydro-5-m ethyl -2 - ((6-trifluoromethyl) -pyrid i n-3-i I) meti I) - cyclopent [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 5- (bromomethyl) -2- (trifluoromethyl) pyridine was added in step (f) in place of benzoylbenzyl bromide. Example 22 (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-ethyl-2- (3-f I uoro-4- (trifluoromethyl) -benz I) - cyclopent [4,5] imidazo [1, 2-a] pi, ra, [4,3-e] pyrimidin-4 (2H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and 3-fluoro-4-trifluoromethyl-benzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 23 (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (4-methylsulfonyl-benzyl) -cyclopent [4,5] imidazo [ 1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one The method of synthesis is analogous to example 2 wherein (1R, 2R) -2-amino-cyclopentanol was added in step (d) in place of trans-2-amino-cyclohexanol hydrochloride; and p-methylsulfonylbenzyl bromide was added in step (f) in place of benzoylbenzyl bromide. Example 24 Measurement of PDE1B inhibition in vitro using an IMAP Phosphodiesterase Assay Kit Phosphodiesterase 1B (PDE1B) is a calcium / calmodulin-dependent phosphodiesterase enzyme that converts cyclic guanosine monophosphate (cGMP) to 5'- monophosphate guanosine (5'-GMP). PDE1B can also convert a modified cGMP substrate, such as the fluorescent molecule of cGMP-fluorescein, to the corresponding GMP-fluorescein. The generation of GMP-fluorescein from cGMP-fluorescein can be quantified, using, for example, affinity particle reagents immobilized with metal IMAP (Molecular Devices, Sunnyvale, CA). Briefly, the IMAP reagent binds with high affinity to the free 5'-phosphate found in the GMP-fluorescein and not in the cGMP-fluorescein. The resulting GMP-fluorescein-IMAP complex is large relative to cGMP-fluorescein. Small fluorophores that are attached even in a gradual, large tamboreación, the complex can be distinguished from fluoroforas limited, because the emitted photons that give off fluorescent light rays retain the same polarity as the photons used to excite the fluorescence. In the phosphodiesterase assay, cGMP-fluorescein, which can not be limited to IMAP, and therefore retains low fluorescence polarization, is converted to GMP-fluorescein, which, when limited to IMAP, produces a large increase in polarization of fluorescence (? mp). Inhibition of phosphodiesterase, therefore, is detected as a decrease in? Mp. Enzyme Assay Materials: All chemicals are available from Sigma-Aldrich (St. Louis, MO) except for IMAP reagents (reaction buffer, binding buffer, FL-GMP and IMAP beads), which are available from Molecular Devices (Sunnyvale, CA). Assay: 3 ', 5'-cyclic nucleotide-specific bovine brain phosphodiesterase (Sigma, St. Louis, MO) is reconstituted with 50% glycerol at 2.5 U / ml. One unit of the enzyme would hydrolyse 1.0 μmol of 3 ', 5'-cAMP to 5'-AMP per minute at pH 7.5 at 30 ° C. A portion of enzyme is added to 1999 parts of reaction buffer (30 μM CaCl2, 10 U / ml calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10 mM MgCl2, 0.1% BSA, 0.05 % NaN3) to produce a final concentration of 1.25 mU / ml. 99 μl of diluted enzyme solution was added to each well in a 96-well flat bottom polystyrene plate to which 1 μl of the test compound dissolved in 100% DMSO is added. The compounds are mixed and pre-incubated with the enzyme for 10 minutes at room temperature. The FL-GMP conversion reaction is initiated by combining 4 parts of the enzyme and inhibitor mixture with 1 part of the substrate solution (0.225 μM) in a 384 well microtiter plate. The reaction is incubated in the dark at room temperature for 15 minutes. The reaction is interrupted by the addition of 60 μl of binding reagent (1: 400 dilution of IMAP beads in linkage buffer supplemented with 1: 1800 antifoam dilution) to each well of the 384-well plate. The plate was incubated at room temperature for 1 hour to allow the IMAP link to proceed to completion, and then placed in an Envision multimode microplate reader (PerkinElmer, Shelton, CT) to measure fluorescence polarization (? Mp ). A decrease in the concentration of GMP, is measured as decreased mp, is indicative of the inhibition of PDE activity. The IC50 values were determined by measuring the activity of the enzyme in the presence of 8 to 16 concentrations of the compound ranging from 0.0037 nM to 80,000 nM and then plotting the concentration of the drug versus? MP, which allows IC 0 values to be estimated using the non-linear regression software (XLFit; IDBS, Cambridge, MA).

The compounds of Examples 1-14 have IC 50 values of less than 1 μM in this assay, generally less than 10 nM.

Claims (16)

1. A 7,8-dihydro- [1 H or 2 H] -imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one or 7, 8,9-trih idro- [1 H or 2H] -pyrimido [1,2-a] pyrazolo [4,3-e) pyrimidin-4 (5H) -one, characterized in that it is substituted in the 1 or 2 position with C2-9 alkyl, C3 cycloalkyl -9, heteroarylalkyl, or substituted arylalkyl, in free form, of salt or prodrug. 2. The compound according to claim 1, of the formula I characterized in that (i) Ri is H or C? - alkyl [eg, methyl]; (ii) R 4 is H or C 1-4 alkyl and R 2 and R 3 are, independently, H or C 1 -alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylalkyl, or arylalkyl; or R2 is H and R3 and R4 together form a bridge of di-, tri- or tetramethylene; (iii) R5 is a substituted heteroarylalkyl, for example substituted with haloalkyl or R5 is attached to one of the nitrogens in the pyrazolo portion of Formula A and is a portion of Formula A

Formula A wherein X, Y and Z are, independently, N or C, and R8, R9, R11 and R? 2 are independently H or halogen; and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl; with the proviso that when X, Y or Z is nitrogen, R8, R9 or R10, respectively, is not present; (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, N, N-dialkylamino, N, N-diarylamino, or N-aryl-N- (arylalkyl) amino; and (v) n = 0 or 1; (vi) when n = 1, A is -C (R 13 R 4) - wherein R 13 and R 1 are, independently, H or C 1 - alkyl, aryl, heteroaryl, heteroarylalkoxy, arylalkoxy, heteroarylalkyl or arylalkyl; in free, salt or prodrug form. 3. The compound according to claim 2, characterized in that it is a compound of Formula II

Formula II wherein Ra and Rb are, independently, H or C1- alkyl; R6 is phenylamino or benzylamino; R10 is phenyl, pyridyl, or thiadiazolyl; in free form or salt. 4. The compound according to claim 2, characterized in that it is a compound of the Formula III

Formula III wherein R2 is H and R3 and R together form a tri- or tetramethylene bridge [pref. with R3 and R carrying carbons having the R and S configuration respectively]; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C? -4 alkyl; R6 is phenylamino or benzylamino; R-io is haloalkyl, phenyl, pyridyl (for example pyrid-2-yl), or thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl); in free form or salt. 5. The compound according to claim 2, characterized in that it is a compound of Formula IV

Formula IV wherein R 2 is H and R 3 and R together form a tri- or tetramethylene bridge [pref. with R3 and R carrying carbons having the R and S configuration respectively]; or at least one of R2 and R3 is methyl, isopropyl or arylalkoxy and R4 is H; or R2 and R3 are H and R4 is a C1-4 alkyl; R6 is phenylamino or benzylamino; R-io is phenyl, pyridyl, or thiadiazolyl; in free form or salt.

6. The compound according to claim 1 of the formula Formula characterized in that (i) Ri is H or C? - alkyl; (ii) R 4 is H and R 2 and R 3 are, independently, H or C 4 alkyl, aryl, or arylalkyl; or R2 is H and R3 and R4 together form a bridge of di-, tri- or tetramethylene; (iii) R5 is attached to one of the nitrogens in the pyrazolo portion of formula I and is a substituted benzyl of formula B Formula B wherein R 8, R 9, R n and R 2 are independently H or halogen; and R-io is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl, and (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, arylalkylamino, N, N-dialkylamino, N, N-diarylamino, or N-aryl-N- (arylalkyl) amino; in free, salt or prodrug form.

7. The compound according to claim 6, characterized in that it is a compound of Formula V Formula V wherein R2 is H and R3 and R4 together form a tri- or tetramethylene bridge [pref. with R3 and R carrying carbons having the R and S configuration respectively]; or R2 and 3 are each methyl and R is H; or R2 and R3 are H and R3 is isopropyl [pref. the R3 carrying carbon having the R configuration]; R6 is phenylamino or benzylamino; River is phenyl, pyridyl, or thiadiazolyl; in free form or salt.

8. A compound, characterized in that it is selected from the following: 2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] -imidazo- [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one; Cis- (6aR *, 10aS *) - 1- (4-Benzoylbenzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) cyclohex [4,5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (1 H) -one; 3-Benzyl-2- (biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl- [2 H] - imidazo- [1,2-a] pyrazolo [4,3-e] pyrimidine -4 (5H) -one; 1- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7,7-trimethyl-3- (phenylamino) - [1 H] -imidazo- [1,2-a] pyrazolo [4,3-e] ] pyrimidin-4 (5H) -one; 1- (4- (1,2,3-thiadiazol-4-yl) benzyl) -7,8-dihydro-5,7,7-trimethyl-3- (phenylamino) - [1 H] -imidazo- [ 1,2-a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one; 1- (Biphenyl-4-ylmethyl) -3 - ((biphenyl-4-ylmethyl) (phenyl) amino) -7,8-dihydro-5,7,7-trimethyl- [1 H] -imidazo- [1,2 -a] pyrazolo [4,3-e] pyrimidin-4 (5H) -one; Cis- (6aR *, 10aS *) - 5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) -1- (4- (pyridin-2-yl) benzyl) - cyclohex [4.5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (1 H) -one; Cis- (6aR *, 10aS *) - 2- (4- (Pyridin-2-yl) benzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-3- (phenylamino) cyclohex [4.5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; Cis- (6aR *, 10aS *) - 3- (Benzyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-2- (4- (1,2,3-thiadiazole- 4-yl) benzyl) -cyclohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; Cis- (6aR *, 10aS *) - 3- (Benzyl) -2- (4-Biphenyl-4-ylmethyl) -5,6a, 7,8,9,10,10a-heptahydro-5-methyl-ci clohex [4,5] imidazo [1,2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; (R) -3- (Benzyl) -2- (biphenyl-4-ylmethyl) -7,8-dihydro-7-isopropyl-5-methyl- [2H] -imidazo- [1,2-a] pyrazole [4,3-e] pyrimidin-4 (5H) -one; (6aR, 9aS) -5,6a, 7,8,9,9a-hexahydro-5-methyl-3- (phenylamino) -2- (4-pyridin-2-yl) -benzyl) -cyclopent [4,5 ] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; (6aR, 9aS) -5,6a, 7,8,9,9a-hexa-idro-5-methyl-3- (phenylamino) -1- (4-pyridin-2-yl) -benzyl) -cyclopent [4, 5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (1H) -one; (6aR, 9aS) -3- (benzylamino) -5,6a, 7,8,9,9a-hexahydro-5-m ethyl -2- (4-pyridin-2-yl) -benzyl) -cyclopent [4 , 5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-m ethyl -2 - (biphenyl-4-ylmethyl) -cyclopent [4,5] imidazo [1 , 2-a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; 2- (Biphenyl-4-ylmethyl) -7,8,9-trihydro-5,8,8-trimethyl-3- (phenylamino) - [2 H] -pyrimido- [1,2-a] pyrazolo [4, 3-e] pyrimidin-4 (5H) -one; (7R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,7-dimethyl-3- (phenylamino) - [2 H] -imidazo- [1,2-a] pyrazolo [4,3 -e] pyrimidin-4 (5H) -one; (8R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-5,8-dimethyl-3- (phenylamino) - [2 H] -imidazo- [1,2-a] pyrazolo [4,3] -e] pyrimidin-4 (5H) -one; (7R) -2- (Biphenyl-4-ylmethyl) -7,8-dihydro-3-dihydro-3- (phenylamino) -5-methyl-7- (1-methylethyl) - [2H] -imidazo- [1 , 2-a] pyrazole or [4,3-e] pyrimidin-4 (5H) -one; (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (4- (trifluoromethyl) -benzyl) -cyclopent [4,5] imidazo [ 1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; (6aR, 9aS) -3- (phenylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2 - ((6-trifluoromethyl) -pyridin-3-yl) methyl) -cyclopent [ 4,5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; (6aR, 9aS) -3- (nylamino) -5, 6a, 7,8,9, 9a-hexahydro-5-methyl-2- (3-fluoro-4- (trifluoromethyl) -benzyl) -cyclopent [ 4,5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; and (6aR, 9aS) -3- (f -ynylamino) -5,6a, 7,8,9,9a-hexahydro-5-methyl-2- (4-methylsulfonyl-benzyl) -cyclopent [4,5] imidazo [1,2- a] pyrazolo [4,3-e] pyrimidin-4 (2H) -one; in free or salt form, or in pure enantiomeric form.

9. A pharmaceutical composition, characterized in that it comprises a compound according to any of the preceding claims in admixture with a pharmaceutically acceptable diluent or carrier.

10. A method to treat any of the following conditions: Parkinson's disease, restless legs, 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 disorders, cognitive impairment, dementia, abstention from psychostimulants, and / or drug addiction; cerebrovascular disease, stroke (attack), 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 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; characterized in that it comprises administering an effective amount of a compound according to any of claims 1, 2, 3, 4, 5, 6, 7 or 8 or a pharmaceutical composition according to claim 9, to a patient in need of such a treatment.

11. The method according to claim 10, characterized in that the condition is Parkinson's disease.

12. The method according to claim 10, characterized in that the condition is cognitive impairment.

13. A method for making a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that it comprises reacting a 7,8-dihydro-imidazo [1,2-a] pyrazole [4,3-e] pyrimidin-4 (5H) -one or a 7,8,9-trihydro- [1 H or 2 H] -pyrimido [1,2-a] pyrazolo [4,3-e] pyrimidine- 4 (5H) -one with a compound of formula X-R5 wherein X is a leaving group and R5 is C2- alkyl, C3-9 cycloalkyl, heteroarylalkyl, or substituted arylalkyl, and isolate the thus obtained compound in accordance with claim 1, 2, 3, 4, 5, 6, 7 or 8. The method according to claim 13, characterized in that 7,8-dihydro-imidazo [1,2-a] pyrazolo [4]. , 3-e] pyrimidin-4 (5H) -one is a compound of the Formula MU:

(IIIJ) wherein R1- and R6 are as defined according to any claim 2, 3, 4 or 5 of Formula I or according to claim 6 and 7 for Formula la.

15. A method for making a compound according to any of claims 1, 2, 3, 4, 5, 6 or 8, characterized in that it comprises dehydrating a compound of the formula VI wherein R? -6 and [A] n are as defined in any claim 2, 3, 4 or 5 for Formula I or claim 6 and 7 for Formula la., And recovering the compound according to claims 1, 2, 3, 4, 5, 6, 7 or 8.

16. A method for making a compound according to claim 6 or 7, characterized in that it comprises dehydrating a compound of the Formula V according to claim 15, wherein n is 0 and wherein R1-6 are as defined for the Formula according to claim 6 or 7, and recovering the compound according to claim 6 or 7.