TW201247672A - 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders - Google Patents

Abstract

The invention relates to novel pyrazolopyrimidinones according to formula (I). wherein X is CRe or unsubstituted N, D is optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3- or 4-pyridyl, Ra, Rb, Rc, Rd, Re are either H or optional substituents, m= 1 or 2 and n is 0, 1 or 2. The new compounds are for use as the active entity of medicaments or for the manufacture of medicaments respectively, in particular medicaments for the treatment of conditions concerning deficits in perception, concentration, learning or memory. Such conditions may for example be associated with Alzheirmer's disease, schizophrenia and other diseases. The new compounds are also for example for the manufacture of medicaments and/or for use in the treatment of these diseases, in particular for cognitive impairment associated with such disease. The compounds of the invention show PDE9 inhibiting properties.

Description

201247672 VI. Description of the invention: [Technical field to which the invention pertains]

The present invention relates to a new sitting according to formula (1). Mouth _ r^Q

Wherein X-based CRe or unsubstituted N, D is optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-pyridyl, 3 pyridyl or 44 bite' Ra, Rb, Re, Rd, Ru or an optional substituent 'm=l or 2 and n is 0, 1 or 2. These novel compounds are useful as active entities of the medicament or for the manufacture of medicaments, in particular for the treatment of conditions involving sensation, attention, learning or memory deficits. Such conditions may be associated with, for example, Alzheimer's disease, schizophrenia, and other diseases, and specifically, cognitive impairment associated with such diseases. The compounds of the invention exhibit PDE9 inhibitory properties. [Prior Art] Inhibition of phosphodiesterase 9A (PDE9A) is one of the current concepts of finding new accessible pathways for the treatment of cognitive impairments, such as Alzheimer's disease, schizophrenia and CNS disorders such as other diseases or caused by any other neurodegenerative process in the brain. In the present invention, a novel compound that follows this concept is provided. 161368.doc 201247672 A member of the large family of phosphodiesterase 9A phosphodiesterase. These enzymes modulate the content of the cyclic nucleotide 5'-3' cyclic adenosine monophosphate (cAMP) and 5'-3' cyclic guanosine monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP) are important second messengers and therefore play an important role in the cellular signaling cascade. Each of them reactivates protein kinases in particular, but not exclusively. The protein kinase activated by cAMP is called protein kinase A (PKA), and the protein kinase activated by cGMP is called protein kinase G (PKG). Activated PKA and PKG, in turn, phosphorylate many cellular effector proteins (eg, ion channels, G protein-coupled receptors, structural proteins, transcription factors). The second messenger cAMP and cGMP can control multiple physiological processes in a variety of organs in this manner. However, these cyclic nucleotides can also act directly on the effector molecule. Thus, for example, it is known that cGMP can act directly on ion channels and thus can affect cellular ion concentration (summarized in: Wei et al, /^ 1998, 56, 37-64). Phosphodiesterase (PDE) is the controlling mechanism for cAMP and cGMP activity, and is therefore the controlling body for the corresponding physiological processes. PDE hydrolyzes cyclic monophosphate to inactive monophosphate AMP and GMP. Currently, 11 PDE families have been defined based on sequence homology of the corresponding genes. Individual PDE genes within the family are distinguished by letters (eg, PDE1A and PDE1B). If different splice variants are also present in the gene, they are indicated by an additional number following the letter (eg PDE1A1). Human PDE9A has been cloned and sequenced in 1998. The identity with other PDE amino acids is no more than 34% (PDE8A) and never less than 28% (PDE5A). The M-Man's two constant (Km) is 1 70 nanomolar (nM), so PDE9A has a high affinity for cGMP. In addition, PDE9A has a selectivity to cGMP of 161368.doc 201247672 (Km = 230 micromoles (μΜ) for cAMP). PDE9A has no cGMP binding domain, indicating that the enzyme activity is not regulated by cGMP. Western blot analysis has shown that PDE9A is particularly expressed in human testicles, brain, small intestine, skeletal muscle, heart, lung, thymus and spleen. The highest performance was found in the brain, small intestine, kidney, prostate, colon, and spleen (Fisher et al., //. 〇/. C/iew., 1998, 273 (25), 15559-15564; Wang et al., 2003, 15-27). The gene for human PDE9A is located on chromosome 21q22.3 and contains 21 exons. Four alternative splice variants of PDE9A have been identified (Guipponi# A » Hum. Genet·, 1998, 103, 386-392)°, and classical PDE inhibitors do not inhibit human PDE9A. Thus, IBMX, dipyridamole, SKF94120, rolipram, and vinpocetine did not show inhibition of the isolated enzyme at concentrations up to 100 micromoles (μΜ). The IC50 of zaprinast has been confirmed to be 35 micromoles (pM) (Fisher et al, J. B/o/. C/zew., 1998, 273 (25), 15559-15564).

Soderling et al. (J. 5b/. C/zem., 1998, 273 (19), 1 5553-15558) have selected and sequenced murine PDE9A in 1998. As with the human form, this has a high affinity for cGMP, where Km is 70 nanomolar (nM). Particularly high performance was found in the kidney, brain, lung and liver of mice. At concentrations below 200 micromoles, murine PDE9A is also not inhibited by sputum; for zapstat, IC50 is 29 micromoles (Soderling et al., 乂C/zewi., 1998, 273 (19) ), 15553-15558). It has been found that PDE9A is strongly expressed in some areas of the rat brain. Such areas include the olfactory bulb, the hippocampus, the cortical 'basal ganglia, and the basal forebrain (Andreeva et al. 161, 368. doc 201247672, A^wrojci, 2001, (22), 9068-9076). In particular, the hippocampus, cortex and basal forebrain play an important role in learning and memory. As already mentioned above, PDE9A is characterized by a particularly high affinity for cGMP. Therefore, PDE9A is effective even at low physiological concentrations, which is related to PDE2A (Km = 10 micromoles (μΜ); Martins et al., /. Biol. Chem., 1982, 257, 1973-1979), PDE5A (Km= 4 micromoles (μΜ); Francis^ A * J. Biol. Chem., 1980, 255, 620-626) ' PDE6A (Km=17 micromoles (μΜ); Gillespie &Β6&νο,··· 5 ίο/. C/iem., 1988, 2(53 (17), 8133-8141) and PDEllA (Km=0.52 micromoles (μΜ); Fawcett et al., /Voc. ΛΓαί. dcac?. «Sei, 2000 , P7 (7), 3702-3707) contrast. Compared with PDE2A (Murashima et al., Sz'oc/zem/Wry, 1990, 29, 5285-5292), the catalytic activity of PDE9A is not increased by cGMP. Because of its absence of the GAF domain (cGMP binding domain, which is increased ectopically via its PDE activity) (Beavo et al., CwrreW k Ce//仏〇/〇 2000, /2, 174-179). PDE9A inhibitors can cause an increase in baseline cGMP concentrations. This summary indicates that PDE9A participates in specific physiological processes in a unique and unique manner, which distinguishes the effects of PDE9A from any other PDE family members. WO 2004/099210 discloses PDE9 inhibition. Agent 6-aryl fluorenyl substituted hydrazine, biting _. WO 2004/099211 discloses pyrazolopyrimidine substituted by 6-cyclyl methyl- and 6-alkylmethyl groups and their use for improving cognition, Uses of Attention, etc. 0 161368.doc 201247672 DE 102 3 8 722 discloses the use of PDE9A inhibitors for improving cognition and attention. WO 2004/018474 discloses phenyl substituted pyrazolopyrimidines and their use for improved perception Attention 'The use of learning and/or memory. WO 2004/026876 discloses alkyl-substituted pyrazolopyrimidines and their use for improving awareness, attention, learning ability and/or memory performance. WO 2004/096811 discloses heterocyclic bicyclics as PDE9 inhibitors for the treatment of diabetes (including type 1 and type 2 diabetes), hyperglycemia, abnormal dyslipidemia, glucose intolerance, metabolic syndrome and/or cardiovascular disease. WO 2009068617 discloses a derivative derived from the ratio of substituted phenylfluorenyl- or pyridyl-fluorenyl at the 6 position. PDE9 inhibiting compounds that sit and bite the ketone. WO 2010112437 discloses PDE9-inhibiting compounds derived from pyrazolopyrimidinone having an arylmethyl- or heteroaryl-fluorenyl group substituted with a strepto or heteroaryl group at the 6 position. WO 2009/121919 discloses PDE9 inhibitors derived from "bisazolopyrene in a non-aromatic heterocyclic group at the 1-position, one of which is a tetrahydrofuranyl group. WO 2010/026214 discloses a derivative derived from a ratio of having a cycloalkyl or cycloalkenyl group (one of which is 4,4-difluorocyclohexyl) at the 1-position. Sit and shout the ketone PDE9 inhibitor.

Some literature is about nucleoside derivatives. For example, WO 2002/057425 discloses nucleoside derivatives which are inhibitors of RNA-dependent RNA viral polymerase. WO 2001/060315 discloses nucleoside derivatives for the treatment of hepatitis C infections. EP 679657 discloses compounds which act as ribonucleoside analogues. US 161368.doc 201247672 2002058635 discloses 嘌呤L-nucleoside compounds in which anthracyclines and carbohydrates Both rings (pentose rings) are modified, functionalized, or both, so the carbohydrate ring, for example, must exhibit at least one esterified hydroxyl group. WO 2005/05 1944 discloses oxime-containing nucleosides for use in the treatment of nucleoside analog-related disorders, such as those involving cell proliferation and infection. WO 2006/084281 discloses an E1 activating enzyme inhibitor having a sulfonamide moiety. WO 1998/40384 discloses PDE, PDE2 and PDE5 inhibitors and is useful for the treatment of cardiovascular and cerebrovascular disorders as well as urinary and reproductive disorders. Sit and ketone. CH396 924, CH396 925, CH396 926, CH396 927, DE1147234, DE1149013 describe pyrazolopyrimidines which have a coronary dilation effect and which are useful for the treatment of myocardial blood loss. US 3 732225 describes pyrazolopyrimidines having anti-inflammatory and hypoglycemic effects. DE 2408906 describes styrene-based oxime which can be used as an antimicrobial and anti-inflammatory agent for the treatment of, for example, edema. SUMMARY OF THE INVENTION Alterations in the substitution pattern of pyrazolopyrimidinone can lead to interesting changes in biological activity and changes in affinity for different target enzymes. Accordingly, it is an object of the present invention to provide a compound which effectively modulates PDE9(R) as described herein, particularly in the scope of the patent application, for the purpose of developing a pharmaceutical agent, especially in view of diseases which can be modulated by PDE9A Or condition. Another object of the invention is to provide a compound for the manufacture of a medicament for the treatment of CNS disorders. 161368.doc 201247672 A further object of the invention is to provide a combination of advantageous safety properties. Another object of the invention is to provide a selective bias towards PDE9A inhibition (prior to other PDE family members and other pharmacological targets). A compound that is advantageous in nature and that provides advantages. A further object is to provide an agent which can be used not only for the treatment of a corresponding disease or condition but also for preventing or alleviating it. The invention further provides a pharmaceutical composition comprising a compound as described herein, specifically in the scope of the patent application, and a pharmaceutically acceptable carrier. The invention further provides a method of treating any of the conditions described herein in a mammal, preferably a human, in need of such treatment, comprising administering to the mammal a therapeutically effective amount, as described herein, specifically in the scope of the patent application a compound in the middle. The invention further provides a compound as described herein, particularly in the scope of the patent application, for use in a method of treating a human or animal body by therapy. [Embodiment] The compound of the present invention is characterized by the general formula (I):

161368.doc .10- 201247672 X-Series N or CRe,

Ra, Rb, Rc, and Re are each independently selected from the group consisting of hydrazine, Ck-alkyl-, Cw alkyl-hydrazine-, CF3., CHf2, Ch2F, π, and halogen; wherein Cw alkyl · and alkyl _ 〇 _ can be replaced by halogen, preferably by halogen

Rd : is selected from the group consisting of fluorine, NC-, -CF3, _CHF2, -CH2F, and fluorenyl; D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyran. a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group, wherein the cyclopentyl group and the cyclohexyl group are optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from each other selected from the group consisting of Group: fluorine, NC-, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetrahydropentanyl may be substituted by one or two substituents, wherein the substituents may be independently selected from each other selected from the group consisting of a group of: fluorine, NC-, F3C-, HF2C-, and FH2C-; wherein the pyridyl group may be optionally substituted with 1, 2, 3 or 4 substituents, wherein the substituents may be independently selected from the following Group consisting of: fluorine, gas, bromine, NC-, F3C·, FH2C_, p3c-CH2-, C, _6-alkyl- and C3.7-cycloalkyl; m: selected from 1 or 2, compared Preferably, η: is selected from 0, 1 or 2, preferably 0 or 1, more preferably 〇, wherein if η=2, the two groups are selected independently of each other; and salts thereof, Better doctor The acceptable salts, solvates and solvates of the salts thereof described above 161368.doc 201247672. This embodiment is the embodiment 1 of the present invention. Embodiment 2 of the Invention: Another embodiment of the present invention relates to a compound according to the general formula (1), wherein X is N or CRe,

Ra, Rb, RC, and Re are each independently selected from the group consisting of hydrazine, Cn3-alkyl, Cw alkyl-hydrazine-, -CF3, -CHF2, -CH2F, NC-, and halogen; wherein Ci_6_ Hyun- and Cn-based-fluorene-optionally substituted by halogen, preferably by fluorine

Rd : is selected from the group consisting of fluorine, NC-, _CF3, -CHF2, -CH2F, and methyl; D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrogen a meridinyl group, a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group, wherein the cyclopentyl group and the cyclohexyl group may be optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from each other by the following a group consisting of: fluorine, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetraarhydropiperidinyl are optionally substituted by 1 or 2 substituents, wherein the substituents may be independently selected from each other selected from the group consisting of Group: fluorine, F3C-, HF2C- and FH2C-; wherein the pyridyl group may be 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2 Substituent substitution wherein the substituents may be independently selected from the group consisting of: fluorine, chlorine, bromine, NC-, F3C_, HF2C_, FH2C_, F3C-CH2-, Ci.6-162368.doc -12 - 201247672 alkyl- and c3.7-cycloalkyl; m. is selected from 1 or 2, preferably m-line 1; η: is selected from 0, 1 or 2, preferably n-system 〇siu, more Goodland n system, where η = 2, the two groups Rd system selected independently of one another; and salts, preferably pharmaceutically acceptable salts, solvates and solvates of such salts. Embodiment 3 of the present invention: Another embodiment of the present invention relates to a compound according to the formula (1), wherein the X-form N or CRe, RR, R, R are independently of each other selected from the group consisting of η, methyl , ethyl, decyloxy, ethoxy, _Cf3, _CHf2, _Ch2F, NC- and dentate; preferably Ra, Rb, rC, Re are independently selected from the group consisting of hydrazine, sulfhydryl, and B. Base, methoxy, ethoxy, -Cf3 and NC-, D: are selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropentanyl, 2-pyridyl, 3-pyridine And a 4-pyridyl group, wherein the cyclopentyl group and the cyclohexyl group are optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetrahydropyranyl are optionally substituted by 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C. Wherein the pyridyl group may be 1, 2, 3 or 4, preferably 161368.doc • 13- 201247672 1 , 2 or 3 More preferably one or two substituent substitutions, wherein the substituents may be independently selected from the group consisting of fluorine, chlorine, bromine, NC-, F3c-, HF2C-, FH2C-, F3C-CH2- , Cw 院基- and C3·? - ring hospital base; m: is selected from 1 or 2, preferably m system 1; η system 0, and its salt, preferably pharmaceutically acceptable salt, solvent combination thereof And a solvate of the above salt. Embodiment 4 of the Invention: Another embodiment of the invention relates to a compound according to formula (I), wherein X is hydrazine or CRe,

Each of Rb, Rd, and Re is H,

Ra is selected from the group consisting of H, methyl, ethyl, methoxy, ethoxy, -CF3, -CHF2, -CH2F, and F; D: is selected from the group consisting of cyclopentyl, Cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-pyridyl, 3-pyridyl and 4-n butyl, wherein cyclopentyl and cyclohexyl may be substituted by one or two substituents. The substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C-; wherein the tetrahydrofuranyl and tetrahydropyranyl groups may be substituted by one or two substituents, where The substituents may be independently of each other selected from the group consisting of fluorine, F3C_, HF2C-, and FH2C-; wherein the pyridyl group may optionally be 1, 2, 3 or 4, preferably 1 or 2 or 3, more preferably 1 or 2 substituent substitutions, wherein 161368.doc • 14- 201247672 the substituents may be independently selected from the group consisting of: gas, bromine, NC-, F3C-, HF2C-, FH2C-, F3c-CH", Γ. B.1-6 alkyl- and c3_7-cycloalkyl; m: selected from 1 or 2, preferably m-line 1; η-system 0, and salts thereof Better doctor An acceptable salt, a solvate thereof, and a solvate of the above salt. Embodiments 5 to 9 of the present invention: Other embodiments of the present invention pertain to compounds according to each of Examples 1 to 4, wherein Claw 1 , and salts thereof, preferably pharmaceutically acceptable salts, solvates thereof, and solvates thereof, in accordance with Examples 10 to 18 of the present invention: Other Embodiments of the Invention According to Examples a compound of each of 1 to 9, wherein D is 4,4-difluorocyclohexyl or tetrahydropyran-4-yl or 4-indolyl-3-pyridyl, and neither of the two groups has Other substituents; and m is 1. Its salt, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof. The examples 19 to 36 of the present invention are based on Example 1 to Compounds of each of 18, wherein χ = Ν. Embodiments 37 to 56 of the present invention pertain to compounds according to each of Examples i to 18, wherein X = Crc. For all Examples 1 to 56: Pyridine The cycloalkyl group at the 6 position of the oxazolopyrimidinone group may be cis or inverse with respect to the pyrazolopyrimidinone group and the substituent R1. Configuration 161368.doc • 15· 201247672 In this aspect, the compounds of the invention may have the following group:

These embodiments, which are defined stereochemically, are yet another bear of the present invention. - Embodiment 57 of the present invention: In the context of the present invention, - or a plurality of compounds selected from the group of the definitions of the types listed in the following Tables are preferred. The compound _, according to the compound of the formula (1), 纟中χ#Νβ left shed contains letters: a family of recognition compounds, if a stereochemistry is not considered, a group of compounds of a chemical structure. The system has the same type of table (1): 16I368.doc 201247672

161368.doc -17- 201247672

Embodiment 58 of the Invention: Another embodiment of the invention pertains to - or a plurality of compounds selected from the group of specifically defined species as listed in Table 2 below. These compounds represent compounds according to formula (1), wherein the paternal line (:1^ and H. left block contains the letter gamma to identify the family of compounds, if the stereochemical properties are not considered, the compounds having the same chemical structure are Group. Eight 161368.doc •18- 201247672 Type Table (2):

161368.doc 19- 201247672

And a salt thereof, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof. In a compound group according to Tables 1 and 2 (i.e., Examples 57 and 58), a compound having a trans configuration relative to a substitution on a cyclobutyl group may be preferred as compared to a compound having a cis configuration. One of the possible trans-configuration compounds can show an advantage in potency. The more effective the compound, the more preferred it is. Another standard that distinguishes the preferred compounds of the invention is the balance of potency and safety and selectivity relative to other PDE family members (e.g., PDE1C). Different stereoisomers are subject to individual embodiments of the invention: For each of Examples 1 to 56: when d can be a tetrahydrofuranyl group, it is preferably a tetrahydrofuran _3 yl group; In the case of tetrahydropyranyl group, 161368.doc 201247672 is preferably tetrahydropyranyl d 1 + ^ 哚3-yl or tetrahydropyran-4-yl, more preferably tetrahydropyran-4-yl. Terms and Definitions _ Terms not specifically defined herein shall have the meanings given to those skilled in the art in light of this disclosure. Examples include specific substituents or atomic systems represented by their i or 2 letter codes, such as Η for gas, watch for nitrogen, C for carbon, 0 for oxygen, S for sulfur, and the like, but not mandatory. The character is followed by a letter after the letter or before. Unless otherwise stated, the following teachings used in this specification have the meaning indicated and are subject to the following conventions. The number of carbon atoms in the gr〇up, radical or part hereinafter is usually indicated before the group, for example, the meaning means an alkyl group having from 1 to 6 carbon atoms (alkyl g_p, alkyl mi ). Typically, for a group of two or more subgrupups of package 3, the last named group is attached to the group. For example, "hospital base" means A monovalent group attached via its oxygen family (ie, a silk group substituent). If a substituent term begins or ends with a minus sign or a hyphen (ie, _), the symbol emphasizes the attachment point 'as in the above-described example, the group in the oxime is attached to the oxirane substituent. . Unless otherwise stated below, reference to the customary definition of the term and the assumption of a stable valence in all formulas and groups is assumed. In general, if a term is specifically defined in the context of a given context, the more general definitions as outlined in this paragraph shall prevail. In general, all "tautomeric forms and isomeric melons and mixtures" are expected unless specific stereotypes are specified in the compound name or structure. 'A racemic or non-racemic mixture other than the chemical structure or individual isomers or optical isomers or isomers of the compound. The specific definition shall prevail. The term "substituted" as used herein, expressly or implicitly means that any one or more hydrogen radicals on a given atom are replaced by a member of the indicated group of substituents, and the condition does not exceed the normality of the specified atom. price. In the case where a substituent is bonded via a double bond (e.g., a keto substituent), the substituent replaces two hydrogen atoms on the atom. This substitution should result in a stable compound. In this context, "stable" preferably means that the compound is chemically and physically stable from a pharmaceutical standpoint for use as an active pharmaceutical ingredient in a pharmaceutical composition. If no substituent is defined, it should be nitrogen. The term "substituted as appropriate" means that the corresponding group is substituted or unsubstituted. The description that the substituents of the same group can be "selected independently of each other" means that the corresponding substituents may be the same or different. "Pharmaceutically acceptable" as used herein to mean that it is suitable for use in contact with humans and animal tissues within reasonable medical judgment without undue toxicity, irritation, allergic reaction or other problems or complications and reasonable benefits. / risk ratio corresponding to the compound, substance, composition and / or dosage form. The "pharmaceutically acceptable salt" of the compound of the present invention is also the subject of the present invention. By "pharmaceutically acceptable salt" is meant a compound of the invention: a biological compound wherein the parent compound is modified by making an acid salt or a salt thereof (preferably a salt). Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic residues/portions (eg, amine functional groups) of the compounds of the invention or 161368.doc*22-201247672 organic acid salt; within the compounds of the invention The acidic residue/portion can form a salt with an alkali or organic test. Pharmaceutically acceptable salts include the parent non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, amine sulfonic acid 'phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, Propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid (pam〇ic aci (i), maleic acid, keimaic acid, phenylacetic acid, Amino acid, benzoic acid, salicylic acid, sulfamic acid, 2_acetoxybenzoic acid' fumaric acid, toluenesulfonic acid, sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like Physiologically acceptable salts with bases may also include, for example, (as an example and preferably) alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and salt), and Salts and ammonia, such as the following (by way of example and preferred) organic amines having from 1 to 16 C atoms: ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, two Ethanolamine, triethanolamine monocyclohexylamine, monodecylaminoethanol, proca (procaine), dibenzylamine, N-methyl-morpholine, dehydrodiethylamine, arginine, lysine, ethylenediamine, methylhexahydropurine, and the like. The accepted salts can be synthesized by conventional chemical methods from the parent compound having the test or acid character. In general, the salts can be derived from the free acid or base form of the compounds and the stoichiometric amount of the appropriate bite acid in the water. Or an organic solvent or a mixture of the two to prepare a reaction; usually, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is considered to be designed to be in the 161368.doc •23-201247672 prodrug. A compound which releases a biologically active compound of the present invention in vivo when administered to a mammalian subject. The compound of the present invention is prepared by modifying a functional group present in the compound of the present invention such that the modification is Re-conversion to the original functional group under physiological conditions. It is understood that the prodrug of the compound of the present invention is also subordinate to the present invention. "metabolite" is regarded as a derivative of the compound of the present invention formed in vivo" activity Metabolites are metabolites that cause pharmacological effects. It is to be understood that metabolites, in particular active metabolites, of the compounds of the invention may also form "solvates" from some of the compounds of the present invention. For the purposes of the present invention, terms "Solvate" means a form of a compound which forms a complex by coordination with a solvent molecule in a solid or liquid form. The hydrate is in the form of a specific solvate which is coordinated by water. According to the present invention, the term is preferred. For solid solvates, such as amorphous or better crystalline solvates. "Skeleton". The backbone of the compounds of the present invention is represented by the following core structure. The position number of the ring member atoms is indicated in bold:

Those skilled in the art should understand that the framework can be described by its tautomeric "enol" form. 161368.doc •24· 201247672

In the context of the present invention, both structural representations of the skeleton should be considered as

Under the condition, the balance of tautomeric forms is located. Sit and talk than β. Related _ σ related articles -4- ketone representation side. Thus, all examples are given in the form of pyrazolopyrimidine-4-one derivatives or more precisely in the form of pyrazolo[3,4-d]pyrimidin-4-one derivatives. "Key j. If in the ring system or in the chemical formula of the defined group, the substituent

A group such as RyR", which should be directly attached to an atom in the formula or such as means that the substituent is attached only to the corresponding atom. However, if a bond from another substituent such as "RxR" is not specifically bonded to the atom of the ring system, but is drawn toward the center of the ring or group, unless otherwise stated, this means the substituent "RXR" Any atom that can be attached to a ring system/group.

The key symbol "-" (= minus sign) or the symbol "-*j (== minus sign followed by an asterisk) represents the bond by which the substituent is bonded to the corresponding remainder of the numerator/skeleton. The minus sign does not seem clear enough. In the case, an asterisk may be added to the key symbol "_" to determine the attachment point of the key to the corresponding major portion of the numerator/skeleton. 161368.doc -25- 201247672 surgery. . Cl-6_alkyl" means a saturated and branched or unbranched hydrocarbon group having 1 to 6 C atoms. Examples of such groups include methyl, ethyl n-propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, Third amyl, n-hexylisohexyl. This definition is suitable for use in any reasonable context within the specification without any other definition. The term "C3·7-cycloalkyl" means a saturated singlet having 3 to 7 ring atoms. Ring group. Preferably, the 5-member ring burns S. There are no other ring atoms except carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclodecyl, cyclohexyl, cycloheptyl. This definition is suitable for "cycloalkyl" in any reasonable context within the specification without another definition. The term "halogen" means fluorine (F), gas (C1) and bromine (Br) substituents, preferably F and C1 and more preferably F. The term "Pyridy(R)" defines a pyridine substituent, sometimes also referred to as a 0-pyridinyl. As used herein, expressions such as "preventi〇n4pr〇phyUxis" prophylactic treatment or preventive treatment are to be understood as synonymous and mean that the risk of the above mentioned conditions is reduced, especially in Among patients with high risk for these conditions or corresponding past history. Thus, the expression "prevention of disease" as used herein means the control and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the occurrence of a disease, condition or disorder and to include administration of the active compound to prevent or delay the onset of symptoms or complications and to prevent or delay the onset of the associated disease, condition or condition. 161368.doc -26- 201247672 The success of prophylactic treatment is statistically reduced by the incidence of the disease in the same patient population as compared to a patient population who does not have prophylactic treatment at risk of developing the condition To reflect. The expression "treatment" or "therapy" preferably means a therapeutic treatment of a patient (e.g., a better human) who has developed one or more of the conditions in a distinct, acute or k form, including for remission (iv) adaptation. Symptomatic treatment with symptoms of the disease or etiological treatment for reversing or partially reversing the progression of the condition or delaying the indication' as long as it is possible depends on the condition and its severity. Therefore, the expression "treatment of a disease" as used herein means the control and care of a patient who has developed a disease, condition or condition. The purpose of treatment is to treat a disease, condition, condition or symptom thereof. Treatment includes administration of an active compound to eliminate or control a disease, condition or condition and to alleviate symptoms or complications associated with the disease, condition or condition. The following reactions illustrate, by way of example, how the compounds of the invention are typically made. If not otherwise defined in the context of the reaction scheme, the abbreviated substituents may be as defined for the embodiment of formula (I): Reaction Scheme 1

161368.doc •27· 201247672 ο ο

Ηη3ι η2ο2 Et0H/H20 Ο

Ν D grass 醯 &&

Methyl decyl diazomethane and then HCI a

Ν Reaction circle 1: In the first step, '2-ethoxymethylene-malononitrile and monosubstituted by heating in the presence of a base such as triethylamine in a suitable solvent such as ethanol The hydrazine is condensed to form the corresponding 5-amino-1 Η-β than sputum-4-carbonitrile. In a second step, the compounds are converted to the corresponding guanamine by, for example, treating the ethanol solution with ammonia (25% in water) and hydrogen peroxide (35% in water). In the third step, the dicarboxylic acid diester is added while heating under the conditions of the test (for example, sodium hydride in ethanol), followed by the addition of 161368.doc •28·201247672 sodium aqueous solution to produce a 4-keto group. _4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substituted carboxylic acid. Successive reaction with chloroform, trimethylsulfonyldiazomethane and hydrochloric acid' followed by reaction with the corresponding 2-aminooxazine or the corresponding 2-amino-pyridine, respectively, yields the final product. Reaction circle 2

among them

Is optionally substituted cyclopentyl or cyclohexyl as defined in formula (I). Thus, n = 1 or 2 reaction circle 2: the monosubstituted indole derivative used in step 1 of the reaction scheme 1 can be borrowed Reducing the aminated ketone with tributyl phthalate for subsequent reduction of the ketone followed by a deprotection step as shown in Figure 4 for the reaction of D, such as cyclopentyl or cyclohexyl as defined in formula (I) [Ref. 'For example, JW Timberlake et al., "C/zemisiry of Hydrazo-, Azo- and Azoxy Groups j; Ραίαί, S1., ed., 1975, Chapter 4, · SC Hung et al., 〇 / Orgam'c C/zew/iir is less 7957, 46,5413-5414]. Additional information can also be found in: • WO 2004/099210 (specifically, the last paragraph on page 9 to the eighth column on page 14 of which is incorporated by reference) ' 161368.doc -29- 201247672 • For general manufacture of compounds of the D-system tetrahydropyranyl group, more information can be found in WO 2009/121919, in particular pages 120 to 125 and its experimental part (by reference) Incorporated herein), • For D for 4,4-difluorocyclohexyl, see www.2010/026214 for more information, specifically pages 59-63 The page and its experimental part (incorporated herein by reference), and the experimental part (exemplary embodiment) of the present specification. The present invention relates to a compound which is considered to be effective for treating a disease. The compound of the present invention effectively inhibits the phosphoric acid Esterase 9A and shows preference for PDE9A compared to other pde family members. Thus 'these compounds are pj' E9A effective selective inhibitors and can be used to develop agents. These agents should preferably be used to treat PDE9A inhibition. A disease that causes a therapeutic, prophylactic or disease mitigating effect. Preferably, the agents are applied to improve (specifically) conditions such as: perception, attention, cognition, learning or memory in the disease/syndromes: mild cognition Injury, age-related learning and memory impairment, age-related a memory loss, vascular dementia, brain trauma, stroke, dementia after stroke (post-stroke dementia), post-traumatic dementia, general attention impairment, Children with learning and memory problems, attention deficit, Alzheimer's disease, Lewy body dementia; frontal degeneration , including Pick's syndrome, Parkins〇nis disease, progressive nuclear paralysis; cortical basal degeneration dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease ( Huntingt〇n, s disease), multiple sclerosis, thalamic degeneration, CJD dementia 161368.doc -30· 201247672 (Creutzfeldt-Jacob dementia), HIV dementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia ( With dementia), Korsakov's psychosis or cognitive impairment associated with depression or bipolar affective disorder. Another aspect of the invention relates to the treatment of diseases which can be affected by modulation of PDE9A, in particular diseases such as sleep disorders, such as insomnia or narcolepsy; bipolar affective disorder; metabolic syndrome; obesity; diabetes, Including type 1 or type 2 diabetes; hyperglycemia; abnormal dyslipidemia; glucose intolerance; or diseased pills, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen. Thus, the medical aspect of the invention can be summarized as the use of a compound of formula (I) or (II) as defined herein, in particular a specifically defined class of compound, for use as a medicament. σ This agent is preferably used to treat CNS diseases. In an alternative use, the agent is used to treat (10) a disease, and the treatment of the cns disease can be affected by inhibition of PDE9. In an alternative use, the agent is for the treatment of a disease that can be affected by inhibition of pDE9, specifically, ancient PDE9A. ° In alternative uses, the agent is used to treat perception, attention, cognition, learning or memorization and/or prevention and intervention. Cognitive impairment associated with the cognitive injury associated with the disease or condition described in this section, which is a preferred alternative in the treatment, improvement, and/or (4) (4) cognitive impairment: age Related learning and age-related memory loss, vascular dementia, cranial and post-stroke insufficiency (post-stroke obstruction), post-traumatic barrier, general: two 161368.doc 31 201247672 Force injury, with learning and memory Problem children's attentional impairment, Alzheimer's disease, Lewy body dementia; frontal degenerative dementia, including Pick's syndrome, Parkinson's disease, progressive nuclear paralysis; basal ganglia degeneration dementia, muscle atrophy Lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, 4 Jay dementia, HIV dementia's epilepsy, temporal lobe epilepsy, mental (quad) (with dementia), Korsakov's psychosis or Cognitive impairment associated with depression or bipolar affective disorder. In an alternative use, the agent is used to treat Alzheimer's disease, schizophrenia, or cognitive impairment associated with Azheimer's disease (4) & schizophrenia. In an alternative use, the medicament is for the treatment of sleep disorders, bipolar affective disorder, metabolic syndrome, obesity, diabetes, hyperglycemia, abnormal dyslipidemia, poor glucosamine or sputum, brain, small intestine, bone road Muscle' disease of the heart, lungs, thymus or spleen. In a further aspect of the invention, the invention relates to a method of treating or preventing a condition or disease selected from the group of diseases and diseases listed above, wherein the method comprises administering to a human in need thereof A therapeutically effective amount of a compound of the invention 0 pharmaceutical composition for administration (which is also subordinate to the invention) comprises a therapeutically effective amount of a compound of the invention and a pharmaceutical carrier. By "therapeutically effective amount" is meant that the amount of the compound of formula (1) will be sufficient to effectively treat, prevent, or slow the progression of the corresponding disease or otherwise ameliorate the disease if the agent is administered via a suitable regimen appropriate to the condition of the patient. The condition of the patient. The possible situation is that the "therapeutically effective amount" in monotherapy will be different from the "therapeutically effective amount" in combination therapy with another agent. The dose of the compound of the formula (I) which can be administered per day may generally range from 1 mg to 5000 mg, preferably from 01 mg to 1 mg, preferably from 2 to mg, more preferably from 5 mg to 250 mg, The best is 1 〇 claw layer to 1 〇〇 mg. Dosage units (e.g., lozenges) may preferably contain between about 11 and 25 mg, especially preferably between 10 and 1 mg. The actual pharmaceutically effective amount or therapeutic dose will depend on factors well known to those skilled in the art, such as the age, weight, sex or other condition of the patient, the route of administration, the severity of the disease, and the like. The compounds of the invention may be administered by the oral, parenteral (intravenous, intramuscular, etc.), intranasal, sublingual, inhalation, intrathecal, topical or rectal routes. Suitable formulations for administration of the compounds of the invention include, for example, patches, troches, capsules, pills, granules, dragees, powders, troches, suppositories; liquid preparations such as solutions, suspensions, emulsions, drops, A syrup, an elixir; or a gaseous preparation such as an aerosol, a spray, and the like. The content of the pharmaceutically active compound should be in the range of from 5% by weight to 9% by weight, preferably from 0.1% by weight to 50% by weight, based on the total composition. Suitable lozenges can be obtained, for example, by mixing the active materials with such well-known excipients as, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose; disintegrating agents such as corn starch or alginic acid; binders For example, starch or gelatin; a lubricant such as magnesium stearate or talc; and/or an agent for delayed release, such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. These tablets may also contain several layers. 161368.doc •33· 201247672 Therefore 'coated record: the agent can be used by using the substances usually used for tablet coating (such as 'could steel (c〇llid〇ne) or shellac, gum gum (gum blC) Stone, titanium dioxide or sugar) is prepared by applying a coating in a core similar to that produced by a bonding agent. To achieve delayed release or to prevent incompatibility, the core can also be composed of many layers. Similarly, a drag coating may be composed of a plurality of layers to achieve delayed release 'the above-mentioned excipients which can be used for tablets, 0 3 having the active substance of the present invention or a combination thereof may additionally contain unsynchronized For example, saccharin, cyclamate, glycerin or sugar; and flavor enhancers, such as flavoring agents, such as vanillin or citrus extract. It may also contain a suspension adjuvant or thickening agent such as sodium mmethylcellulose; a wetting agent' such as a condensation product of a fatty alcohol with ethylene bromide; or a preservative such as a paraben. / The liquid mixture can be prepared in a conventional manner, for example, adding an isotonic agent preservative (for example, p-hydroxybenzoic acid vinegar) or a stabilizer (for example, a metal salt of ethylenediaminetetraacetic acid, optionally using an emulsifier and/or a dispersant) At the same time, for example, if water is used as a diluent, the organic solvent may optionally be used as a solubilizer or dissolution aid, and the solution may be transferred to an injection vial or vial or vial. Capsules containing one or more active substances or a combination of active substances can be prepared, for example, by mixing the active materials with an inert carrier such as lactose or sorbitol and filling them in gelatin capsules. It can be prepared, for example, by mixing with a carrier provided for this purpose, such as 'neutral fat or polyethylene glycol or a derivative thereof. 161368.doc -34 - 201247672 Excipients that can be used include (for example) water; pharmaceutically acceptable agents such as stone, for example, petroleum oil (for example, peanut oil = sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerol); carriers such as ' Natural mineral powder (for example, Ridge, clay, talc, chalk), alpha into minerals (eg, highly dispersed tannins and citrates), sugars (eg, sucrose, lactose, and glucose), emulsifiers (eg, lignin, Tellurite waste, methyl cellulose, starch and polyethylene bitumen) and lubricants (for example, magnesium stearate, talc, stearic acid and sodium lauryl sulfate). For oral use, in addition to the carrier described, the tablet may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various such as starch (preferably horse starch), gelatin and the like. Add substances. Lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc) can also be used to produce lozenges. In the case of an aqueous suspension, in addition to the above-mentioned excipients, the active substance may be combined with various flavoring agents or coloring agents. Naturally, the dosage of the compound of the invention will depend to a large extent on the method of administration and the condition being treated. Combination with other active substances In another aspect, the invention relates to combination therapies wherein the compounds of the invention are administered with another active compound. Accordingly, the present invention is also directed to a pharmaceutical formulation which provides a combination of such active ingredients and wherein one of the active ingredients is a sigma compound of the present invention. Such combinations may be in a fixed dose combination (the active ingredient to be combined is the subject of the same pharmaceutical formulation) or a free-dose combination (the active ingredient is present in a separate pharmaceutical formulation). Thus, a further aspect of the invention pertains to each of the compounds of the invention 161368.doc-35-201247672 (preferably, at least one compound of the invention) and another activity selected from the group consisting of, for example, Combination of compounds: β-secretase inhibitor; γ-secretase inhibitor; γ-secretase modulator; amyloid aggregation inhibitor, such as azhmed (alzhemed); direct or indirect neuroprotection and / Or disease-modifying substances; antioxidants such as vitamin E, ginkgo or ginkgolides; anti-inflammatory substances such as Cox inhibitors, NSAIDs additionally or exclusively having Αβ (Abeta) reducing properties; HMG-CoA reductase inhibitors, for example Statin; acetaminophen esterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptors Antagonists, such as memantine; AMPA receptor agonists; AMPA receptor positive regulators, AMPakines; glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; modulation of neurotransmitter concentration or release Substance; substances that induce growth hormone secretion, such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics such as minocycline (minocyclin) or rifampicin; PDE1, PDE2, PDE4, PDE5 and/or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA α5 receptor inverse agonists; GABΑΑ receptor antagonists; nicotinic receptors An agonist or partial agonist or positive modulator; an α4β2 nicotinic receptor agonist or partial agonist or positive regulator; an α7 nicotinic receptor agonist or partial agonist; a histidine receptor Η3 antagonist; 5-ΗΤ4 receptor agonist or partial agonist; 5-ΗΤ6 receptor antagonist; cx2-adrenoreceptor antagonist, calcium antagonist; muscarinic receptor M1 agonist or partial agonist or positive regulator ; muscarinic receptor M2 antagonist 161368.doc -36- 201247672 agent; scorpion venom receptor M4 antagonist; metabolic lysine is regulated by positive ectopic effector; metabotropic glutamate is antagonized by Metabotropic glutamate receptor 2/3 agonist; metabotropic face acid 2 ectopic positive response modifiers and so that the efficacy of the compounds of the present invention and / or enhanced safety and / or to reduce the side effects of unexpected manner Wang receptors or enzymes regulating other substances. The present invention is directed to pharmaceutical compositions containing one or more, preferably one, active substance. At least one active substance is selected from the compounds of the invention and/or their corresponding salts. Preferably, the composition comprises only one such active compound. In the case of more than one active compound, the other active compound may be selected from the group of the above-mentioned combination partners, such as azemadide vitamin E, ginkgolides, donepez, lissamine, tacrine, garland Hemin, memantine, Ibumolar mesylate, caprelin, minocycline and/or rifampicin. The composition optionally contains other ingredients such as inert carriers and/or diluents. The compounds of the invention may also be used in combination with immunotherapy (e.g., by active immunization with A (or a portion thereof) or by passive immunization with a humanized anti-Αβ antibody or antibody fragment to treat the above diseases and conditions. It can be used in combination with Dimeb〇n. The compounds of the invention may also be combined with antidepressants, such as amitriptyline, imipramine hydrochloride (TOFRANIL), imipramine. Maleic acid salt (SURM〇NTIL), lofepramine, desipraniine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (trirpramine) (SURMONTIL 16l368.doc -37· 201247672 Alternatively, the compounds of the invention may also be combined with serotonin (5-HT) reuptake inhibitors, such as alaproclate, citalopram (CELEXA, CIPRAMIL). , escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine ( Fenflurami Ne) (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), 0 indpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR) ), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), brasofensme, and tesofensine The combinations of the invention may be provided in the same dosage form (i.e., in the form of a combined preparation), for example, the two components may be included in a tablet, for example, in separate layers of the tablet. The combination may also be provided separately in a free combination, i.e., the compound of the invention is provided in one dosage form and one or more of the above combination partners are provided in another dosage form. The two dosage forms can be in the same dosage form, e.g., a total of two pharmaceutically active agents, one containing a therapeutically effective amount of a compound of the invention and the other containing a therapeutically effective amount of the above combination. Different forms of administration can also be combined if needed. Any type of suitable form of administration can be provided. 161368.doc -38 - 201247672 The combination of a compound of the invention or a physiologically acceptable salt thereof with another active substance can be used simultaneously or at interleaved times (but particularly close in time). If administered simultaneously, the two active substances are administered to the patient together; if administered at the staggered time, the two active substances are sequentially administered for a period of less than or equal to 12 hours, specifically less than or equal to 6 hours. patient. The dosage or form of administration is not limited. In the context of the present invention, any suitable dosage form can be employed. For example, the dosage form may be selected from solid preparations such as patches, troches, capsules, pills, granules, sugar-coated bonds, powders, buccal bonds, suppositories; liquid preparations such as solutions, suspensions, emulsions, drops, sugar schigging Agents, or gaseous preparations, such as aerosols, sprays, and the like. These dosage forms can be advantageously formulated into dosage units, each dosage unit being suitable for the supply of a single-dose per active ingredient. Therefore, depending on the route and dosage form, the ingredients are selected. The dose of the upper combination can be conveniently recommended as 1/5 of the lowest dose to 1/1 of the normal recommended dose. For example, the dosage form is administered to the patient i, 2, 3, or 4 times a day, and the pressure is measured by the nature of the formulation. In the case of delayed or prolonged release of the formulation or other j formulation, the @ dosage form can be administered in different ways (e.g., weekly or monthly). Preferably, the compounds of the invention are administered three times or less per day, more preferably once or twice per day. EXAMPLES Pharmaceutical compositions and lower examples may illustrate possible pharmaceutical formulations, but are not intended to be limiting: 161368.doc -39- 201247672 The term "active substance" is meant to include one or more of the compounds of the present invention. In the case of one of the above combinations with one or more other active substances, the term "active substance" may also include other active substances.

Example A Lozenge composition containing 100 mg of active substance: Bond active substance 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 ms 220.0 mg Example B Key containing 150 mg of active substance Composition: Nar: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal cerium oxide 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 me 300.0 mg Example C Hard food containing 150 mg of active substance Gelatin capsule active substance 150.0 mg Lactose 87.0 mg Corn starch (dry) 80.0 mg Magnesium stearate 3.0 me 320.0 mg 161368.doc -40· 201247672

Example D Composition: Suppository Active substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

Example E Composition: Anxun active substance containing 10 mg of active substance 10.0 mg 0.01 N hydrochloric acid

Secondary steaming water to make up to 2.0 mL

Example F Composition: Ampoule containing 50 mg of active substance Active substance 50.0 mg 0.01 N hydrochloric acid

Re-distilled water to 10.0 mL The preparation of any of the above formulations can be carried out according to standard procedures. Biological Analysis The in vitro effects of the compounds of the invention can be visualized by the following biological assays. PDE9A2 Assay Protocol: PDe9A2 Enzyme Activity Assay is typically performed by Scintillation Proximity Analysis (SPA) according to the manufacturer's protocol (GE Healthcare, former Amersham Biosciences, product number: TRKQ 7 100). 161368.doc • 41 - 201247672 The lysate of SF 9 cells expressing human PDE9A2 (PBS containing 1% Triton X-100 supplemented with protease inhibitors, removed by centrifugation at 13.000 rpm for 30 min) ) as a source of enzymes. The amount of total protein included in the assay varied after infection and the potency of SF9 cells ranged from 0.1 ng to 100 ng. Generally, the analytical conditions are as follows: • Total analytical volume: 40 μl • Protein amount: 0.1 ng to 50 ng • Substrate concentration (cGMP): 20 nmer; about 1 mCi/1 • Incubation time: at room temperature Lower 60 min • Final DMSO concentration: 0.2% to 1% These analyses were performed in a 384-well format. Test reagents and enzymes and receptors are diluted in assay buffer. The assay buffer contained 50 mM Tris, 8.3 mM MgCl2, 1.7 mM EGTA, 0.1% BSA, 0.05% Tween 20; and the pH of the assay buffer was adjusted to 7.5. By applying an excess of a PDE9-specific inhibitor (for example, a compound of WO 2004/099210 or WO 2004/099211, such as one of the enantiomers of Example 37, such as 1-(2-phenylphenyl)-6-[ (2R)-3,3,3-trifluoro-2-indolyl-propyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) to terminate the reaction . references:

Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using cGMP reporter cell line. Molecular Pharmacology. 2005 December; 68(6): 1775-81. 161368.doc -42- 201247672 van der Staay FJ, Rutten K, Barfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schroder UH, Hendrix M. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. TV'ewrop/iarmaco/ogy. October 2008; 55(5): 908-18 ° PDE1C analysis protocol: The analysis is similar The analysis was performed in the manner of PDE9A2 analysis with the following differences: PDE1C was used instead of PDE9A2, and the assay buffer additionally contained 50 nM calmodulin, 3 mM CaCl2. By applying the same inhibitor (1-(2-phenylphenyl)-6-[(2R)-3,3,3-trifluoro-2-methyl-propyl]-1 as described above, 5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) was used to terminate the reaction. Determination of IC5〇: IC5G can be calculated using GraphPadPrism or other suitable software, setting the positive control to 100 and the negative control to zero. To calculate IC5G, the dilution of the test compound (substrate) was selected and tested according to the protocol above. Data In the following, the IC50 value of PDE9A2 inhibition [Nemo (nM)] indicates that the compounds of the present invention inhibit PDE9, especially PDE9A2. This shows that these compounds provide useful pharmacological properties. These examples are not intended to be limiting. The table also provides selectivity values (selectivity) which show that these compounds prefer PDE9A relative to PDE1C. Selectivity ratio (IC5 P [Namole (nM)] for PDE1C inhibition / IC5 P [Nemo 161368.doc -43- 201247672 (nM)] for PDE9A2 inhibition) ° Example number refers to example The final examples outlined in the Examples section. All data can be measured in accordance with the procedures described herein. The definition of enantiomer 1 or enantiomer 2 is related to the order of dissolution of the palmitic SFC and the enantiomers in the palmitic HPLC. Compound Family Example No. IC5〇PDE9A2 [Nemo] Selective A 1* 1 288 A 2 (trans enantiomer 1) 0.5 532 A 3 (trans enantiomer 2) 19 85 C 4* 6 123 D 5* 10 40 * Trans-racemic mixture in vivo effect: It is believed that the positive in vitro potency results of the compounds of the invention are converted to positive in vivo efficacy. The in vivo effects of the compounds of the invention can be tested in novel object recognition tests (according to the procedures of Prickaerts et al. 2002, 113, 351-361), social identification tests or T-maze spontaneous alternating tests (as described by van der Staay et al. The test was performed in the program (TVewrop/zarmaco/ogy 2008, 55, 908-918). See also the two citations for more information on biological testing. In addition to the inhibitory properties of the target PDE9, the compounds of the invention provide other advantageous pharmacokinetic properties. 161368.doc -44- 201247672 For example, the compounds of the invention may exhibit one or more advantages in terms of safety, balanced metabolism, lower risk of drug-drug interactions, and/or balanced clearance. The compound may also exhibit one or more additional or alternative advantages in terms of bioavailability, high absorption fraction, blood brain transport characteristics, favorable (e.g., high) mean residence time (mrt), beneficial exposure in the effector, and the like. Abbreviation of chemical manufacturing: APCI atmospheric pressure chemical ionization ACN acetonitrile DCM di-methane methane DEA diethylamine DIPEA diisopropylethylamine DME 1,2-dimethoxyethane DMF dimethylformamide EI electron impact ESI EFI Fog ionization (in MS) EtOH Ethanol Exp. Example GC-MS gas chromatography and mass spectrometry h h (S) HPLC Southern liquid chromatography HPLC-MS high performance liquid chromatography-mass spectrometry Using M Moore (mol/L) 161368.doc -45- 201247672

MeOH sterol min min MS mass spectrometry NMP 1-mercapto-2-pyrrolidone Rt retention time (in HPLC) TFA trifluoroacetic acid THF tetrahydro-β-propan TLC thin layer chromatography UPLC ultra-high performance liquid chromatography Method UPLC-MS Method • • Method 1 (NH4COOH) Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole. Column: BEH C18 1.7 μπι, 2.1 mm><50 mm; eluent A: water + 5 mM ammonium citrate + 10% acetonitrile; eluent B: acetonitrile; gradient: A 100%, then 1.20 min To B 100% for 0.25 min; flow rate: 0.7 mL/min; UV detection: 254 nm; ion source: ESI. LC-MS method: Method 1

MS device type: Waters Micromass ZQ; HPLC device type: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb 100 C18, 30 mm ><4.6 mm, 3.0 μιη; Eluent A: Water +0.13°/. TFA, lysate B: ACN; gradient: 0·0 min 5% B - 0.18 min 5% B - 2.0 min 98% B - 2.2 min 98% B - > 2.3 min 5% B - > 2.5 min 5 % B ; flow rate · · 3.5 mL / min ; UV 161368.doc -46- 201247672 Detection : 210 nm to 380 nm 0 Method IE hydro Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole ; Column: Synergi Hydro- RP80A, 4 μιη, 4.60 mm x lOO mm; Eluent A: 90% water + 10% acetonitrile + 10 mM ammonium formate; eluent B = 90% ACN + 10% H2O + 10 mM NH4COOH; Gradient: A (100) For 1.5 min, then 10 min to B (100) for 1.5 min; flow rate: 1.2 mL/min; UV detection: 254 nm; ion source: APCI. Method 3 MS device type: Waters Micromass ZQ; HPLC device type: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb C18, 20 mm ><4.6 mm, 5.0 μιη; Eluent A: Water + 0.15% TFA, Eluent B: MeOH; Gradient: 0.0 min 5% B - > 0.25 min 5% B - > 1.90 min 100% B - > 2.05 min 100% B - 2.15 min 5% B - 2.25 min 5% B; flow rate: 5.2 mL/min; UV detection: 210 nm to 400 nm. GC/MS Method Method 3A.2

Instrument: GC/MS Finnigan Thermo Scientific. Trace GC Ultra, DSQ II single phase quadrupole. Column: DB-5MS, 25 mx 〇.25 mmx 〇.25 μηι ; carrier gas: 氦, 1 mL/min constant flow; oven program: 50 ° C (for 1 minute), l 〇 ° C / min To 100 ° C, from 20 ° C / min to 200 ° C, from 30 ° C / min to 300 ° C solution, detection: trace DSQ 161368.doc • 47- 201247672 II 'single quadrupole; ion source: EI. Scanning range: 50 a to 45 0a for palmar HPLC method: for palmity method 1: HPLC device type: Agilent 1100; column: Daicel chiralcel OJ-H, 250 mnix 4.6 mm, 5.0 μιη; eluent: Burning / EtOH 80:20; Flow rate: 1 mL/min, Temperature: 25 ° C; UV detection: changeable (200 nm to 500 nm) ° Microwave heating: • Discover® CEM instrument equipped with 1 mL and 35 mL container. General notes on structural displays Some compounds have a stereocenter. The structure depicted in the experimental section below may not necessarily show all possible stereochemical possibilities of the compound, but only one. However, in such cases, terms such as "trans-racemic mixture" or "cis-racemic mixture" are added after the depicted structure to indicate other stereochemical choices. Examples are given below. The structural formula shown, 'Xx ^Yy trans-racemic compound > Χχ >y Therefore, the compound produced is 161368.doc •48· 201247672 ^Xx ,,,'Xx

A mixture of Yy and Yy. This principle also applies to other structures shown. Example 1A (cis-racemic mixture)

2.00 g (13.9 mmol) of cis-cyclobutane-1,2-dioxanoic acid was mixed with 15.5 mL of EtOH at 〇 ° C, and 2.15 mL (29.5 mmol) of sulfite was slowly added. The mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure and the product was filtered with a pad of activated basic alumina and then rinsed with DCM. 2.70 g of product was obtained. GC (Method 3A.2): Rt: 8.42 min MS (El): m/z: 155 (M-45)+, 127 (M-73)+ The following examples are used in a similar manner to the preparation of Example 1A. The acid is synthesized as a starting material. Example Structure Starting Material Rt [min] MS (ESI pos, m/z) Example 1B Trans-racemic mixture λ wide \^〇X〇H V0H 0 1.34 (Method 1) 201 (M+H)+ Example 2A (trans-racemic mixture) 161368.doc • 49- 201247672

1.17 g (5.5 mmol) of 5-amino-1-(tetrahydro-pyran-4-yl)-1 Η-pyr.曱-4-曱 醯 醯 醯 ( (see pct patent application WO 09-121919) was mixed with 15 mL of anhydrous EtOH, adding 2.7 g (13.8 mmol) of Example 1A and 0·89 g (22.2 mmol) of sodium hydride (existing 60% suspension in mineral oil The reaction mixture was heated to 14 Torr in a microwave oven (power: 150 W) (:, for 40 min. The mixture was cooled to room temperature) The solvent was removed under reduced pressure and used Citric acid (5 m) in 1/0 solution in water) absorbs the residue; DCM is added and the organic phase is separated by means of a phase separation cartridge. The crude material obtained after evaporation of the solvent (2.18 g) is passed through a flash layer. Analytical procedure [Solution: (j) CM / MeOH / AcOH 90: 10: 1) / DCM] was purified from DCM and eluted with a 1/1 ratio of the above-mentioned solution to yield the final product to obtain 1.14 g (64). %) Product. UPLC-MS (Method 1): Rt=〇.54 MS (ESI pos): m/z=319 (M+H) + Example 3A (trans-racemic mixture)

0.50 g (1.76 mmol) of Example 2A was dissolved in THF (5 161368.doc • 50· 201247672 ml) under an inert atmosphere; the temperature was lowered to 0 ° C, then DMF (1 drop) and grass brewing gas (0.167) were added. Ml, 1.94 mmol). The reaction mixture was stirred at 0<0>C for 2 h and then trimethyl-methyl s-triazane (2M solution in diethyl ether) (1.76 ml; 3.52 mmol). After 2 h, hydrochloric acid (stored in dioxane 4 Μ solution) (0.88 ml; 3.52 mmol) was added and the temperature was raised to room temperature. The mixture was diluted with DCM and washed with a saturated NaHC[rho]3 solution, and the aqueous phase was extracted with dcm. The organic phase was collected and washed with a saturated solution of NaCl; the residue obtained after evaporation of the organic phase and evaporation of solvent (0.54 g) was used for the next step. UPLC-MS (Method 1): Rt=0.82 MS (ESI pos): m/z = 351, 353 (M+H) + Example 4A (trans-racemic mixture)

The trans-racemic mixture will be 1.00 g (4.09 mmol) of 5-amino-1-(4,4-difluoro-cyclohexyl)·1Η·carbazole _4·decanoic acid decylamine (see PCT patent application) WO 2010/026214, Example 8A) was mixed with 15 mL of anhydrous EtOH, adding 2.46 g (12 3 mm 〇1) of Example 1B and 0.66 g (16.4 mmol) of sodium hydride (6 〇 % suspension in mineral oil) . The reaction mixture was heated to M (rc for 3 Torr in a microwave oven. The mixture was cooled to room temperature and a solution of sodium hydroxide (4] water 161368.doc -51 - 201247672) was added. The solvent was removed. The residue was purified by preparative HpLC (eluent a: solvant B: MeOH) to give 〇7 〇 water + 0.13% TFA ' lysate b: Me g (49%) product. -MS (Method 1): Rt=i, 24 min MS (ESI pos): m/z=353 (M+H)4 Example 5A (trans-racemic mixture)

Trans-racemic mixture 0.250 g (0.71 mmol) of Example 4A was mixed with 2 mL of THF. The mixture was cooled using an ice bath and 0.060 mL (0.71 mmol) of grass brewed gas and - DMF were added. The reaction mixture was stirred at 0 °C for 1 h. To the reaction mixture was added 4 mL of CAN and 0.710 mL of trimethylsulfonyldiazomethane (2.0 Μ, 1.42 mmol in the hospital). The mixture was stirred at 0 ° C for 2 h, then 0.355 mL of HCl (4.0 M in 2° smoldering) was slowly added. The reaction was searched for 15 min. Ethyl acetate and a saturated sodium hydrogencarbonate solution were added to the mixture. The organic layer was washed with water and brine and partially evaporated. The product was used in the next reaction without further purification. HPLC-MS (Method 1): Rt = 1.40 min MS (ESI s): m/z = 385 / 387 (CI) s s s s s s s s s s s s s s s s s s s s s s s s s s s s s

Example 3A (lg, 2.85 mmol) was suspended in dimethyloxyethane in a 50 ml Schlenk tube; 3-amino-6-mercaptopyridazine was added; sealed with a stopper

The Schlenk tube was heated at 95 ° C for μ h. Lower the temperature' remove the solvent under reduced pressure and pass the crude material through Spe

"STRATA" 10 g SCX cartridge, eluted with MeOH and then with NH3 solution in MeOH; by flash chromatography [solvent s: cyclohexane /

The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) HPLC-MS (Method 1Eh): Rt = 7.62 MS (APCI): m/z = 406 (M+H) + Separation of the enantiomer e of Example 1 by semi-preparative versus palm chromatography HPLC for semi-preparation Method for separation of enantiomers: Semi-preparative conditions: HPLC semi-preparative system: waters 600 pump; column: Daicel chiralcel OJ-Η, 5·0 μηι, 250 mm><20 mm; elution Liquid: hexane / EtOH 80:20; flow rate: 15 mL/min, temperature: 25 ° C; UV detection: 161368.doc • 53· 201247672

Example 4 (trans-racemic mixture)

To Example 5A (crude product synthesized from 0.250 g (0.71 mmol) of Example 4A), 0.118 g (1·24 mmol) was added dropwise to 4 mL of Εΐ:ΟΗψ2π ratio -2-ylamine. The reaction mixture was stirred overnight. EtOH was evaporated and the residue 161368.doc -54 - 201247672 was mixed with 2 ml DMF and heated to 50 ° C for 2 h. The residue was purified by preparative HPLC (eluent A: water + <RTI ID=0.0>> After lyophilization, the residue was diluted with 2 mL of aq. The solvent was evaporated and lyophilized from ACN / water to give a product. HPLC-MS (method 3): Rt = 1.20 min; MS (ESI ESI): m/z = 425 (M+H) + The following example was synthesized in a similar manner to the preparation of Example 4 using the corresponding amine as starting material. .

161368.doc 55-

Claims (1)

201247672 VII. Patent application scope: 1 · A compound of formula (I), Wherein X system N or CRe, R, Rb, Rc, Re are independently selected from the group consisting of: Η, C丨·6-alkyl-, C丨·6-alkyl·〇_, _Cf3, _CHf2 And _CH2F, NC- and halogen; wherein G.6-alkyl- and 仏6-alkyl-〇_ may be optionally substituted by halogen, preferably by fluorine. R is selected from the group consisting of: defeat, NC- , -CF3, _CHF2, -CH2F and fluorenyl; D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-pyridyl, 3-pyridyl and 4 a pyridyl group, wherein the cyclopentyl group and the cyclohexyl group are optionally substituted by 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, NC-, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetrahydropyranyl are optionally substituted by 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of 161368.doc 201247672: fluorine, NC-, F3C -, HF2C- and FH2C-; wherein the pyridyl group may be optionally substituted with 1, 2, 3 or 4 substituents, wherein the substituents may be independently selected from Group of lower constituents: fluorine, gas, bromine, NC-, F3C-, HF2C-, FH2C-, f3c-ch2-, c,.6-alkyl- and C3-7-cycloalkyl; m: selected from 1 or 2, preferably 1; η: is selected from 〇, 1 or 2, preferably 〇 or 1, more preferably 〇, wherein if η = 2 ', the two Rd groups are selected independently of each other And a salt thereof, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof. 2. The compound of claim 1, wherein the X-form N or CRe, Ra, Rb, Re, Re are independently of each other selected from the group consisting of: H, Cw-alkyl-, (:, .3-alkane) Bases _〇_, _CF3, -CHF2, -CH2F, NC- and _ 素; wherein C, · 6 · alkyl - and ^ 6 - alkyl - fluorene - optionally substituted by halogen, preferably by fluorine The group consisting of fluorine, NC-, -CF3, -CHF2, -CH2F and sulfhydryl is selected; D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, wherein cyclopentyl and cyclohexyl are optionally taken by i or 2 substituents 161368.doc 201247672, wherein the specific substituents may be selected independently of each other a group consisting of fluorine, F3C-, HF2C-, and FH2C-; wherein the tetrahydrofuranyl and tetrahydropyranyl groups may be optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from each other selected from the group consisting of Groups: fluorine, F3C-, HF2C- and FH2C-; wherein the guanidinyl group may be 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 Or 2 take a substituent, wherein the substituents may be independently selected from the group consisting of fluorine, gas, bromine, NC_, F3C_, HF2C_, FH2C_, F3C-CH2-, Cw alkyl, and c3-7-cycloalkyl; Is selected from 1 or 2, preferably ^1; η: is selected from the group consisting of 0, 1 or 2, preferably η 〇 or 1, more preferably η 0, wherein η = 2 And the two Rd groups are selected independently of each other; and a salt thereof, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof, as described in claim 2 a compound wherein X-form N or CRe, R, R, R<:' Re-systems are independently selected from the group consisting of H, methyl, ethyl, decyloxy, ethoxy, CF3-, -CHF2 , -CH2F, NC- and dentate; preferably Ra, Rb, rC, Re are independently selected from the group consisting of Η, methyl, ethyl, methoxy, ethoxy, 161368. Doc 201247672 CF3- and NC-, D: are selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropentanyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, wherein Cyclopentane The group and the cyclohexyl group may be optionally substituted by 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetrahydroperylene The thio group may be optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C-; wherein the pyridyl group may be subjected to one, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2 substituents, wherein the substituents may independently of one another are selected from the group consisting of: fluorine , gas, bromine, NC-, F3C-, HF2C·, FH2C_, F3C-CH2-, C丨·6-alkyl- and c3.7-cycloalkyl; m: selected from 1 or 2' preferably m system 1 ; η system 0, and a salt thereof, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof. 4. The compound of claim 1, wherein X is hydrazine or CRe, each of Rb, Re, Rd, and Re is H, and Ra is selected from the group consisting of H, thiol, ethyl, methoxy. , ethoxy, -CF3, _CHF2, and F; preferably the core is selected from the group consisting of 161368.doc -4- 201247672: hydrazine, fluorenyl, ethyl, decyloxy, ethoxy, and cf3- D : is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, wherein cyclopentyl And the cyclohexyl group may be optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C-, HF2C- and FH2C-; wherein tetrahydrofuranyl and tetrahydropyran The group may be optionally substituted with 1 or 2 substituents, wherein the substituents may be independently selected from the group consisting of fluorine, F3C., HF2C- and FH2C-; wherein "pyridyl can be viewed as 1 , 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2 substituents, wherein the substituents may independently of one another Selected from the following groups: fluorine, gas, bromine, NC-, F3C-, HF2C-, FH2C-, F3C-CH2-, Cw alkyl and c3_7_ cycloalkyl; m. selected from 1 or 2, compared Preferably, η system 0, and a salt thereof, preferably a pharmaceutically acceptable salt, a solvate thereof, and a solvate thereof. 5. If the request is made to any of the compounds in the bucket, where the paw is =1. 6. The compound of any one of claims 1 to 4, wherein χ=Ν. The compound of any one of claims 1 to 4, wherein x = CRe. The compound according to any one of claims 1 to 4, wherein the oxime is 4, cardifluorocyclohexyl or tetrahydropyran-4-yl or 4-methyl-3-. Bipyridyl, and both groups are 161368.doc 201247672 does not have other substituents, and m = l. 9. The compound of claim 1 wherein the compound is selected from the group consisting of: 161368.doc 201247672 And a salt thereof, preferably a pharmaceutically acceptable salt. 10. The compound of claim 1 wherein the compound is selected from the group consisting of: 161368.doc 201247672 And a salt thereof, preferably a pharmaceutically acceptable salt. The compound of any one of claims 1 to 4 wherein the compound is selected from the group consisting of compounds according to formula (la), formula (lb), formula (Ic) and formula (Id) (10), (lb), \n/nid R d), u, m and n, as defined in any of X, Ra, Rb, Rc 7, and salts thereof, preferably pharmaceutically acceptable salts. The compound according to any one of claims 1 to 4, which is used or used as a medicament, wherein the medicament is used or the medicament is used for (a) treatment of CNS diseases, (b) inhibition by PDE9 (c) The treatment of a condition of a group consisting of the following treatments, amelioration or prevention of cognitive impairment associated with a disease condition selected from the group consisting of perception, attention, cognition, learning or memory, Preferably, the cognitive improvement (4) is about age-related learning and memory impairment, age 161368.doc 201247672 related memory loss vascular dementia, craniocerebral trauma, stroke, dementia after stroke (post-stroke dementia) ), post-traumatic dementia, general attentional impairment, attentional impairment in children with learning and memory problems, Alzheimer's disease, Lewy body dementia; frontal degeneration dementia, Including Pickis syndrome, Parkinson's disease, progressive nuclear pruritus, degenerative cortical basal ganglia degeneration, muscle atrophic spinal cord side Disease (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jacob dementia, HIV dementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia With dementia), K〇rsak〇ffs psychosis or cognitive impairment associated with (4) or bipolar, clearing disorder, (d) Alzheimer's disease or with Alzheimer's Treatment of cognitive impairment related to illness, treatment (4) treatment of schizophrenia or cognitive impairment associated with schizophrenia (1) treatment of epilepsy or cognitive impairment associated with epilepsy, ω selected from the group consisting of diseases or conditions Obstruction, bipolar affective disorder, metabolic syndrome: · sleep disorder hyperglycemia, abnormal dyslipidemia, glucose intolerance urinary disease, 13. small intestine, (four) muscle, heart, lung, thymus or spleen. A brain, a medical composition comprising 'the compound of claim (1) and a pharmaceutical carrier. Any of the claims 1 to 11 for the manufacture of a compound as defined in claim 12 t for use in a combination of agents 0 If the claim item can be used to treat, for example, the request box, the terminology, the disease or condition defined by the object and the sword, the combination is used for Λ/D therapy as in claim 2 A defined condition or disease or a combination of diseases or treatments is used to treat the disease as defined in claim 12. 161368.doc -11· 201247672 IV. Designated representative map: ( a) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R N \—/ I /IV 161368.doc