OA16302A

OA16302A - 6-Cycloalkyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as PDE9A inhibitors.

Info

Publication number: OA16302A
Application number: OA1201300022
Authority: OA
Inventors: Niklas Heine; Christian Eickmeier; Marco Ferrara; Riccardo Giovannini; Holger Rosenbrock; Gerhard Schaenzle
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2010-08-12
Filing date: 2011-08-09
Publication date: 2015-04-24

Abstract

The invention relates to novel 6-Cycloalkylpyrazolopyrimidinones according to formula (I)

Description

Such conditions may for example be associated with Alzheimers disease, schizophrenia and other diseases. The new compounds are also for example for the manufacture of médicaments 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 inhibitingproperties.

wherein R¹ is a 5 or 6 membered aromatic heteroaryl-group, R² is an optional substituent, D is optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3- or 4-pyridyl, m= 1 or 2 and n is 0, 1 or 2.

The new compounds are for use as the active entity of médicaments or for the manufacture of médicaments respectively, in particular médicaments for the treatment of conditions concerning déficits in perception, concentration, learning or memory.

O.A.P.I. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 22 20 57 00- Fax: (237) 22 20 57 27- Site web: http:/www.oapi.int - Email: oapi@oapi.int

Boehringer Ingelheim International GmbH

6-Cycloalkyl-pyrazolopyrimidinones for the Treatment of CNS Disorders

The invention relates to novel pyrazolopyrimidinones according to formula (I)

(I),

I 2 wherein R is a 5 or 6 membered aromatic heteroaryl-group, R is an optional substituent, D is optionally substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3or 4-pyridyl, m= 1 or 2 and n is 0, 1 or 2.

The new compounds are for use as the active entity of médicaments or for the manufacture of médicaments respectively, in particular médicaments for the treatment of conditions conceming déficits in perception, concentration, leaming or memory. Such conditions may for example be associated with Alzheimer’s disease, schizophrenia and other diseases. The new compounds are also for example for the manufacture of médicaments and/or for use in the treatment of these diseases, in particular for cognitive impaîrment associated with such disease. The compounds of the invention show PDE9 inhibiting properties.

BACKGROUND OF THE INVENTION

The inhibition of phosphodiesterase 9A (PDE9A) is one of the current concepts to find new access paths to the treatment of cognitive impairments due to CNS disorders like Alzheimer’s disease, schizophrenia and other diseases or due to any other neurodegenerative process of the brain. With the présent invention, new compounds that follow this concept are presented.

Phosphodiesterase 9A is one member of the wide family of phosphodiesterases. These enzymesmodulate the levels of the cyclic nucléotides 5-3’ cyclic adenosine monophosphate (cAMP) and 5'-3' cyclic guanosine monophosphate (cGMP). These cyclic nucléotides (cAMP and cGMP) are important second messengers and therefore play a central rôle in cellular signal transduction cascades. Each of them réactivâtes inter alia, but not exclusively, protein kinases. 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 are able in tum to phosphorylate a number of cellular effector proteins (e.g. ion channels. Gprotein-coupled receptors, structural proteins, transcription factors). It is possible in this way for the second messengers cAMP and cGMP to control a wide variety of physiological processes in a wide variety of organs. However, the cyclic nucléotides are also able to act dîrectly on effector molécules. Thus, it is known, for example, that cGMP is able to act directly on ion channels and thus is able to influence the cellular ion concentration (review in: Wei et al., Prog. Neuroblol., 1998, 56, 37-64). The phosphodiesterases (PDE) are a control mechanism for the activity of cAMP and cGMP and thus in tum for the corresponding physiological processes. PDEs hydrolyse the cyclic monophosphates to the inactive monophosphates AMP and GMP. Currently, 11 PDE families hâve been defined on the basis of the sequence homology of the corresponding genes. Individual PDE genes within a family are differentiated by letters (e.g. PDE1A and PDE1B). If different splice variants within a gene also occur, then this is indicated by an additional numbering after the letters (e.g. PDE1A1).

Human PDE9A was cloned and sequenced in 1998. The amino acid identity with other PDEs does not exceed 34% (PDE8A) and is never less than 28% (PDE5A). With a MichaelisMenten constant (Km) of 170 nanomolar (nM), PDE9A has high affinity for cGMP. In addition, PDE9A is sélective for cGMP (Km for cAMP=230 micromolar (μΜ)). PDE9A has no cGMP binding domain, suggesting that the enzyme activity is not regulated by cGMP. It was shown in a Western blot analysis that PDE9A is expressed in humans inter alia in testes, brain, small intestine, skeletal muscle, heart, lung, thymus and spleen. The highest expression was found in the brain, small intestine, kidney, prostate, colon and spleen (Fisher et al., J. Biol. Chem., 1998, 273 (25), 15559-15564; Wang et al., Gene, 2003, 314, 15-27). The gene for human PDE9A is located on chromosome 21q22.3 and comprises 21 exons. 4 alternative splice variants of PDE9A hâve been identified (Guipponi et al., Hum. Genet., 1998,103, 386- /

-216302

392). Classical PDE inhibitors do not inhibit human PDE9A. Thus, 1BMX, dipyridamole, SKF94120, rolîpram and vinpocetine show no inhibition on the isolated enzyme in concentrations of up to 100 micromolar (μΜ). An IC50 of 35 micromolar (μΜ) has been demonstrated for zaprinast (Fisher et ai, J. Biol. Chem., 1998, 273 (25), 15559-15564).

Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (J. Biol. Chem., 1998, 273 (19), 15553-15558). This has, like the human form, high affinity for cGMP with a Km of 70 nanomolar (nM). Particularly high expression was found in the mouse kidney, braîn, lung and liver. Murine PDE9A is not inhibited by IBMX in concentrations below 200 micromolar either; the IC50 for zaprinast is 29 micromolar (Soderling et al., J. Biol. Chem., 1998, 273 (19), 15553-15558). It has been found that PDE9A is strongly expressed in some régions of the rat brain. These include olfactory bulb, hippocampus, cortex, basal ganglia and basal forebrain (Andreeva et al., J. Neurosci., 2001, 21 (22), 9068-9076). The hippocampus, cortex and basal forebrain in particular play an important rôle in leaming and memory processes. As already mentioned above, PDE9A is distinguished by having particularly high affinity for cGMP. PDE9A îs therefore active even at low physiological concentrations, in contrast to PDE2A (Km=10 micromolar (μΜ); Martins et al., J. Biol. Chem., 1982, 257, 1973-1979), PDE5A (Km=4 micromolar (μΜ); Francis et al., J. Biol. Chem., 1980, 255, 620-626), PDE6A (Km=17 micromolar (μΜ); Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17), 8133-8141) and PDE11A (Km=0.52 micromolar (μΜ); Fawcett et al., Proc. Nat. Acad. Soi., 2000, 97 (7), 3702-3707). In contrast to PDE2A (Murashima et al., Biochemistry, 1990, 29, 5285-5292), the catalytic activity of PDE9A is not increased by cGMP because it has no GAF domain (cGMP-binding domain via which the PDE activity is allosterically increased) (Beavo et al., Current Opinion in Cell Biology, 2000, 12, 174-179). PDE9A inhibitors may therefore lead to an increase in the baseline cGMP concentration.

This outlîne will make it évident that PDE9A engages into spécifie physiological processes in a characteristic and unique manner, which distinguishes the rôle of PDE9A characteristically from any of the other PDE family members.

WO 2004/099210 discloses 6-arylmethyl-substituted pyrazolopyrimidinones which are PDE9 inhibitors.

WO 2004/099211 discloses 6-cyclylmethyl- and 6-alkylmethyl-substituted pyrazolopyrimidines and their use for the improvement of cognition, concentration etc.. /

-316302

DE 102 38 722 discloses the use of PDE9A-inhibitors for the improvement of cognition, concentration.

WO 2004/018474 discloses phenyl-substituted pyrazolopyrimidines and their use for the improvement of perception, concentration leaming and/or memory. /

WO 2004/026876 discloses alkyl-substituted pyrazolopyrimidines which and their use for the improvement of awareness, concentration leaming capacity and/or memory performance. WO 2004/096811 discloses heterocyclic bicycles as PDE9 inhibitors for the treatment of diabètes, including type 1 and type 2 diabètes, hyperglycemia, dyslipidemia, impaired glucose tolérance, metabolic syndrome and/or cardiovascular disease.

W02009068617 discloses PDE9 inhibitîng compounds derived from pyrazolopyrimidinones with a substituted phenylmethyl- or pyridyl-methyl group in the 6-position.

WO2010112437 discloses PDE9 inhibitîng compounds derived from pyrazolopyrimidinones with a phenyl or heteroaryl substituted arylmethyl- or heteroaryl-methyl group in the 6position.

WO 2009/121919 discloses PDE9 inhibitors derived from pyrazolopyrimidinones with a nonaromatic heterocyclyl group in the 1-position, among which is tetrahydropyranyl.

WO 2010/026214 discloses PDE9 inhibitors derived from pyrazolopyrimidinones with a cycloalkyl or a cycloalkenyl group in the 1 -position, among which is 4,4difluorocyclohexyl.

Some prior art is directed to chemically nucleoside dérivatives. As examples it îs referred to WO 2002/057425, which discloses nucleoside dérivatives, which are inhibitors of RNAdependent RNA viral polymerase, or WO 2001/060315, which discloses nucleoside dérivatives for the treatment of hepatitis C infection or EP679657, which discloses compounds that serve as ribonucleoside analogues or US2002058635, which discloses purine L-nucleoside compounds, in which both the purine rings and the carbohydrate ring (pentose ring) are either modified, functionalized, or both. So the carbohydrate ring for example must show at least one esterified hydroxy group.

WO 2005/051944 discloses oxetane-containîng nucleosides, for the treatment of nucleoside analogue related disorders such as disorders involving cellular prolifération and infection. WO 2006/084281 discloses inhibitors ofthe El activation enzyme that hâve a sulfonamide moiety. ^z

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WO 1998/40384 discloses pyrazolopyrimidinones which are PDE1, 2 and 5 inhibitors and can be employed for the treatment of cardiovascular and cerebrovascular disorders and disorders of the urogénital System.

CH396 924, CH396 925, CH396 926, CH396 927, DE1147234, DE1149013, describe pyrazolopyrimidines which hâve a coronary-dilating effect and which can be employed for the treatment of disturbances of myocardial blood flow.

US3732225 describes pyrazolopyrimidines which hâve an anti-inflammatory and blood glucose-lowering effect.

DE2408906 describes styrylpyrazolopyrimidinones which can be employed as antimicrobial and anti-inflammatory agents for the treatment of, for example, oedema.

OBJECTIVE OF THE INVENTION

Changes in the substitution pattern of pyrazolopyrimidinones resuit in interesting changes conceming biological activîty, respectively changes in the affinity towards different target enzymes.

Therefore it îs an objective of the présent invention to provide compounds as herein described, in particular in the claims, that effectîvely modulate PDE9A for the purpose of the development of a médicament, in particular in view of diseases or conditions, the treatment of which is accessible via PDE9A modulation.

It is another objective of the présent invention to provide compounds that are useful for the manufacture of a médicament for the treatment of CNS disorders.

Yet another objective of the présent invention is to provide compounds which show a favourable safety profile.

Another objective of the présent invention is to provide compounds that hâve a favourable selectîvely profile in favour of PDE9A inhibition over other PDE family members and other pharmacological targets and by this may provide an advantage.

Yet another objective is to provide a médicament that may not only serve for treatment but might also be used for the prévention or modification of the corresponding disease or condition. Z

-5 16302

The présent invention further provides a pharmaceutical composition comprising a compound as herein described, in particular in the claims and a pharmaceutically acceptable carrier.

The présent invention further provides a method for the treatment of any of the conditions as described herein in a mammal in need of such treatment, preferably a human, comprising administering to the mammal a therapeutically effective amount of a compound as herein described, in particular in the claims.

The présent invention further provides a compound as herein described, in particular in the claims, for use in a method of treatment of the human or animal body by therapy.

DETAILED DESCRIPTION OFTHE PRESENT INVENTION

The compounds of the présent invention are characterised by general formula (I):

wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1, 2 or 3, of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, whereby said 5 or 6 membered aromatic heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, HO-, NC-, F₃C-, HF₂C-, Fl 1₂C- methyl, H₂N- and (CH₃)₂N-;

R²: is selected from the group consisting of fluorine, NC-, F₃C-, HF₂C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, _✓

-616302 whereby cvclopentyl and cvclohexyl optionally may be substituted by l or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, NC-, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by l or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, NC-, F₃C-, HF₂C- andFH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂-, Cj.

₆-alkyl- and C₃₇-cycloaIkyl;

m: is selected ftom 1 or 2, preferably 1 ;

n: is selected from 0, 1 or 2, preferably, 0 or 1, more preferably 0, whereby if n = 2, these two groups R² are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementioned salts thereof;

with the proviso that the compound is not the following oxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of ail or some thereof or sait thereof or solvaté thereof or a solvaté of a sait thereof.

This embodiment is embodiment 1 of the présent invention.

Conceming the proviso définition above: it shall be understood that throughout this description this définition of the compound, specifically /

-716302 “the following oxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of ail or some thereof’ encompasses the following stereoisomers beside the mixtures of these compounds:

Embodiment 2 of the présent invention: Another embodiment of the invention concems a compound according to general formula (I), wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1, 2 or 3, of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, /

-816302 whereby said 5 or 6 membered aromatic heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- methyl, H₂N- and (CH₃)₂N-;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- andFH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂-, C_l6-alkyl- and C₃.₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from the group consisting 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R are selected independently of one another;

with the proviso that the compound is not the following oxadiazolyl-derivative r

-916302

Embodiment 3 of the présent invention: Another embodiment of the invention concems a compound according to general formula (I), wherein

R¹: is a 5 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 2 or 3 of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, whereby said 5 membered aromatic heteroaryl-group optionally may be substituted by

1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-,FH₂C- methyl, H₂N- and (CH₃)₂N-;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyi, tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyi and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected s

- 1016302 independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F’,C-, HF2C-, FH₂C- F₃C-CH₂-, Ci^-alkyl- and C₃_7-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n îs 0, whereby if n = 2, these two groups R are selected independently of one another;

with the proviso that the compound is not the following oxadiazolyl-derivative

Embodiment 4 of the présent invention: Another embodiment of the invention concems a compound according to general formula (I), wherein

R¹: is a 6 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 2 or 3 of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, whereby said 6 membered aromatic heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, methyl, H₂N- and (CH₃)₂N-;

R²: is selected from the group consisting of fluorine, NC-, F₃C-, HF₂C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl; Z

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whereby tetrahydrofuranyl and tetrahvdropyranvl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂-, C].₆-alkyi- and C₃.₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementioned salts thereof.

Embodiment 5 of the présent invention: Another embodiment of the invention concems a compound according to general formula (I), wherein

R¹: is a heteroaryl-group selected from the group consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidînyl, preferably said heteroaryl-group being selected from the group consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidînyl, whereby said heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- methyl, H₂N- and (CH₃)₂N-;

D: îs selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

- 1216302 whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, F₃C-, HHC- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranvl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂-, C, ₆-alkyl- and C₃.₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R² are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementîoned salts thereof;

with the proviso that the compound is not the following oxadîazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of all or some thereof or sait thereof or solvaté thereof or a solvaté of a sait thereof.

Embodiment 6 of the présent invention: Another embodiment of the invention concems a compound according to general formula (I), wherein

R¹: is a heteroaryl-group selected from the group consîsting of thiadiazolyl, 1,2,3oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and

- 13 16302 pyrimidinyl, preferably said heteroaryl-group being selected from the group consisting of thiadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl, whereby said heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, methyl, H₂N- and (CH₃)₂N-;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted independently of one another by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- andFH₂C-;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂-, C^-alkyl- and C₃.₇-cycloalkyl;

m: is selected from 1 or 2, preferably m is 1 ;

and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementioned salts thereof

Embodiment 7 of the présent invention: embodiment 7 of the invention concems a compound that corresponds in ail aspects with embodiment 6, except in that

R¹: îs a heteroaryl-group selected from the group consisting of thiadiazolyl, 1,2,3oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl, preferably said heteroaryl-group being selected from the group consisting of thiadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl,

- 1416302 whereby said heteroaryl-group optionally may be substituted by l, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- methyl, H₂N- and (CH₃)₂N-.

Embodiment 8 of the présent invention: Another embodiment of the invention concerns a compound according to general formula (1), wherein

R¹: is a heteroaryl-group selected from the group consisting of [l,3,4]thiadiazol-2-yl, isoxazol-5-yl, thiazol-5-yl-, oxazol-2-yl, pyridin-2-yl and pyrimidin-2-yl, preferably said heteroaryl-group being selected from the group consisting of [l,3,4]thiadiazol-2-yl, isoxazol5-yl, thîazol-5-yl-, oxazol-2-yl and pyrimidin-2-yl, whereby said heteroaryl-group optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, CN-, methyl and H₂N-;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and4-pyridyl whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- andFH₂C-; preferably by fluorine;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, F₃C-CH₂- and methyl;

whereby preferably D is selected fforn the group consisting of 4,4-difluorocyclohex-lyl, tetrahydropyranyl, thereof preferably tetrahydropyran-4-yl, and 4-methy-3-pyridyl; m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n îs 0, whereby if n = 2. these two groups R² are selected independently of one another; s

- 1516302 and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementioned salts thereof.

Embodiments 9 to 16 of the présent invention:

In any of the above mentioned embodiments 1 to 8 the preferred compounds are represented by formula (II):

Compounds according to formula (II)

with

R¹: as defined in any of the aforementioned embodiments 1 to 8;

D being either 4,4-difluorocyclohexyl or tetrahydropyran-4-yl or 4-methy-3-pyridyl and none of these two groups has further substituents;

with the proviso that the compound is not the following oxadiazolyl-derivative

be it in the form of any possible stereoisomer or a mixture of ail or some thereof or sait thereof or solvaté thereof or a solvaté of a sait thereof. s

- 1616302

The preferred embodiments 9 to 16 according to formula (II) dérivé from embodiments according to formula (I) in that:

m in formula (I) is 1, so that the corresponding cycloalkyl-group is a cyclobutyl;

n in formula (I) is 0;

D in formula (I) is selected from the group of 4,4-difluorocyclohexyl (wîthout further substituents, i.e. unsubstituted) and tetrahydropyran-4-yl (wîthout further substituents, i.e. unsubstituted) and 4-methy-3-pyridyl;

R¹ in formula (I) îs attached to said aforementioned cyclobutyl (m=l) in the 2-position thereof while the 1 position of said cyclobutyl is the attachment point to the 6 position of the D-substituted pyrazolopyrimidinone.

The corresponding embodiments are designated as embodiments 9, 10, 11,12, 13, 14, 15 and 16 respectively.

Embodiment 9 dérivés from embodiment 1, embodiment 10 from embodiment 2, embodiment 11 from embodiment 3, embodiment 12 from embodiment 4, embodiment 13 from embodiment 6, embodiment 14 from embodiment 6, embodiment 15 from embodiment Ί, embodiment 16 from embodiment 7.

Embodiments 17 to 24 of the présent invention:

Within each of the above mentioned embodiments 1 to 16 more preferred compounds are represented by formula (II):

N

with

R¹: as defined in any of the aforementioned embodiments 1 to 8;

- 1716302

D being either 4,4-difluorocyclohexyl or tetrahydropyran-4-yl and none of these two groups has further substituents;

and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the 5 solvatés of the aforementioned salts thereof, with the proviso that the compound is not the following oxadiazolyl-derivatîve

a mixture of ail or some thereof or sait thereof or solvaté thereof or a solvaté of a sait thereof.

For ail embodiments 1 to 24: the configuration of the cycloalkyl group at position 6 of the pyrazolopyrimidinones group with respect to said pyrazolopyrimidinones group and the substituent R¹ may be cis or trans.

In this respect the compounds of the invention may hâve the following configurations:

trans configuration 1	trans configuration 2
	0			0
		Y-
R<	^H 1	N	^R'J	H l	N
.....		\ > Ζγ N
(^R2)n	Y	1 D	(R²)—ί	¥	I D

cis configuration 1

cis configuration 2

- 1816302

whereby R^l, R², m, n and D are as defined in any of embodiments 1 to 8.

These stereochemically defined embodiments are a further aspect of the invention.

Embodiment 25 of the présent invention:

Within the context of the présent invention one or more compound(s) is (are) preferred that are selected from the group of specifically defined species as listed in the following table. The left column contains a letter code to identify the compound family, which is the group of compounds that hâve the same general chemical structural formula if no stereochemical 10 properties are considered. Members of these compound families are exemplified in the section Exemplary embodiments.

Table of species:

- 1916302

-2016302

	Compound family C, covering example 3 ,
c a	0 M in f! ^N, ô
C b	b° fSp. ΆΑ Y ,
C c	0 A/° A ^Hï iPn ^zb ^-o
C d	ο ^ηΛα ^b A

D	γ 0 N=V	0 ^HN^ if A. A N	X / N
			% F	2
	Compound	family	D, covering
	example 4			>
D a	N 0 N=Z	O hAA A J ' N	X _ / N b	\
			b F	^SF
D b	V θ A b	Λ A	X -E b	\
			b F	_F ,
D c	y 0	0 HN^ \|r	X / ~N b	\
			X F

-2116302

-22 16302

Compound family Gl, covering example 7

-2316302

G 2	0 Λ HN Υί	fV Niy
	Compound example 8	family G2, covering
G	0 II
2	ηκΛ	x
	Γ7 ^N	\ /
	H ^Nr	A
G	0 II
2 b	ηνΛ λΑ^ν'	o
	>-<? X	A N--/
G	0 II
2 c	V	»
	y?	H
	U	n=z7
	r	9

-2416302

-2516302

-2616302

-2716302

Μ a	//^Ν Μ ^Ηϊ \yA_NA_N' ζ
Μ b	A -A Α·^Λ^
Μ c	Μ ⁰ A> JA A// ην ΊτΑ ^b y n ^v Z
Μ d	A A» Α-χί

-2816302

N	I Q
V Compound example 20	'y'^x+_J	A / ~N S covering >
famîly	N,
N	l		0
a
	M	HlA I	T	A / 'N

				Λ	<
					/ ’
N	/		0
b			1
	\ // S—Y	HN^X	V	A
	't			-ν'
				Λ	<
					/ ’
N	I		0
c	v>
	M	H A		Λ
		Y-ff N	/ N \
				c	<
					/ ’

N d	/ o
A i	Λ HN A 7' ^N'	A À ·
O	A N=/	0
	^HN^ ιΓ	A
		Aa C- ' N	/ N (b
			A

	Compound example 21	famîly	0, covering
0		0
..-A V o
a	\ !	hiA At AI ' N	A / ''N (b
			h
0		0
b	N 0 N=/	A	A
	b	A?	A
			A ’

-2916302

- 30Boehringer Ingelheim

P01 -2xxx-Prio

--31-16302

-3216302

S	0 [I
d	hnA _ A J a ⁿ	X
	A C ^x>	Q_f
	\=/
T	„Â L	rfx N
	qAN	A a/
	N 7 \=/	0
	Compound family T, covering
	examples 26, 27	and 28
T a	0 „A k	rX N ¹ /
	C/	N X/
	X-n -o	0

Within the latter group of compounds, compounds that show trans configuration with respect to the substitution at the cyclobutyl-group may be preferred over compounds with ois configuration. Of the possible trans configured compounds one thereof may show advantages in efficacy. The more efficacious a compound the more it is among the preferred compounds.

-3316302

Another criterion which may differentiate preferred compounds according to the invention is the balance of efficacy and safety, such as for example selectivity vs. other PDE family members such as PDEIC.

For one pair of trans configured compounds according to the experimental part a single crystal X-ray structure analysis revealed that the absolute stereochemistry of the compound which showed lower efficacy than its enantiomer is R,R. As a conséquence thereof absolute stereochemistry of the compound with the higher efficacy is S,S.

For said compound the S,S-configuration is represented by the following structure according to general formula (II):

In analogy, one may assume that among the compounds according to embodiment 25, such compounds that show the same absolute stereochemistry might be the more active ones compared with the other members of the same compound family. According to the présent invention, within the same compound family the more active compounds are preferred over the less active compounds. The compound family is the group of compounds that differ in their chemical structure only with regard to stereochemical properties.

The different stereoisomers are subject to individual embodiments according to the invention:

embodiment 26 of the présent invention concems a compound according to any one of embodiments l to 25, whereby the compound shows the following stereochemical properties if the compound generally can be represented by formula (I)::

if the compound generally can be represented by formula (II):

(la),

(Ha).

-3416302 embodiment 27 of the présent invention concems a compound according to any one of embodiments 1 to 25, whereby the compound shows the following stereochemical properties:

if the compound generally can be represented if the compound generally can be represented by formula (I):

(Ib), by formula (II):

(Ilb).

embodiment 28 of the présent invention concems a compound according to any one of embodiments 1 to 25, whereby the compound shows the following stereochemical properties:

(le), by formula (II):

(Hc).

embodiment 29 of the présent invention concems a compound according to any one of embodiments 1 to 25, whereby the compound shows the following stereochemical properties: if the compound generally can be represented if the compound generally can be represented by formula (1): by formula (II):

-3516302

(Id),

(Ild).

Embodiment 30 of the présent invention: Another set of preferred embodiment of the présent invention dérivés from each of the aforementioned embodiments conceming compounds according to formula (I) or (II), inclusively the preferences conceming stereochemical properties thereof, in that

R¹ being pyrimidinyl, or pyridyl, preferably pyrimidin-2-yl or pyrdîn-2-yl, m = 1, n = 0 and

D is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, FjC-, HF₂C- and FH2C-; preferably by fluorine; whereby tetrahydrofuranyl, tetrahydronyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F/C-, HF2C- and FH2C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- F₃C-CH₂- and methyl;

whereby preferably D is selected from the group consisting of 4,4-difluorocyclohex-lyl, tetrahydropyranyl and 4-methy-3-pyridyl and salts, preferably pharmaceutically acceptable salts thereof, solvatés thereof and the solvatés of the aforementioned salts thereof

-3616302

For each of the embodiments l to 30: whenever D may be tetrahydrofuranyl, it is preferably tetrahydrofuran-3-yl; whenever D may be tetrahydropyranyl it is préférable tetrahydropyran-

3-yl or tetrahydropyran-4-yl, more preferably tetrahydropyran-4-yl.

For each of the embodiments 1 to 30: the heteroaryl-group R¹ preferably is bound via a carbon ring atom thereof to the cycloalkyl-group that is attached to the 6-position of the pyrazolopyrimidinone-scaffold. According to general formula (I) said cycloalkyl-group may be a cyclobutyl- or cyclopentyl-group, according to general formula (II) said cycloalkylgroup is a cyclobutyl-group.

TERMS AND DEFINITIONS

Ternis not specifically defined herein should be given the meanings that would be given to them by a person skilled in the art in light of the disclosure and the context. Examples include that spécifie substituents or atoms are presented with their 1 or 2 letter code, like H for hydrogen, N for nitrogen, C for carbon, O for oxygen, S for sulphur and the like. Optionally but not mandatory the letter is followed by a hyphen to indicate a bond. As used in the spécification, unless specified to the contrary, the following ternis hâve the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C|.6 alkyl means an alkyl group or alkyl radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for exampïe, (CH₃)₂N- means a monovalent radical of the formula (CH₃)₂N-, which is attached via the nitrogen atom thereof (i.e. a dimethylamino-substituent). If the terni of a substituent starts or ends with a minus sign or hyphen, i.e. -, this sign emphasises the attachment point as in the aforementioned example (CH₃)₂N-, where the N is linked to the group of which the dimethylamino-group is a substituent. Unless otherwise specified below, conventional définitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.

-3716302

In general, if terms are specifically defined with a given context, such spécifie définitions shall prevail over the more general définitions as outlined in this paragraph.

In general, ail “tautomeric forms and isomeric forms and mixtures”, whether individual géométrie isomers or optical isomers or racemic or non-racemic mixtures of isomers, of a chemical structure or compound are intended, unless the spécifie stereochemistry or isomeric form is specifically indicated in the compound name or structure. Spécifie définitions prevail.

“Substitution”: The term substituted*' as used herein explicitly or implicitly, means that any one or more hydrogen(s) on the designated atom is replaced with a member of the indicated group of substituents, provided that the designated atom's normal valence is not exceeded. In case a substituent is bound via a double bond, e.g. an oxo substituent, such substituent replaces two hydrogen atoms on the designated atom. The substitution shall resuit in a stable compound. “Stable” in this context preferably means a compound that from a pharmaceutical point of view is chemically and physically sufficiently stable in order to be used as an active pharmaceutical ingrédient of a pharmaceutical composition. If a substituent îs not defined, it shall be hydrogen. By the term optionally substituted is meant that either the corresponding group is substituted or it is not. A characterisation that substituents of the same group may be “selected independently of one another” shall mean, that the corresponding substituents may be the same or may be different.

The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of Sound medical judgment, suitable for use in contact with the tissues of human beings or as the case may be of animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonablebenefit/risk ratio.

pharmaceutically acceptable salt(s) of the compounds according to the invention are subject of the présent invention as well. The term pharmaceutically acceptable salt(s) refers to dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, preferably addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic residues/parts of the compounds of the présent invention such as aminofonctions; acidic

-3816302 residues/parts within compounds of the présent invention may form salts with alkali or organic bases. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quatemary ammonium salts of the parent compound formed, for example, from nontoxic inorganîc or organic acids. For example, such conventional non-toxic salts include those derived from inorganîc acids such as hydrochloric acid, hydrobromic acid, suliuric acid, sulfamic acid, phosphoric acid, ni trie acid and the like; and the salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartane acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acîd, sulfanilic acid, 2acetoxybenzoic acid, fiimaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethîonic acid and the like.

Physiologically acceptable salts with bases also may include salts with conventional bases such as, by way of example and preferably, alkali métal salts (e.g. sodium and potassium salts), alkaline earth métal salts (e.g. calcium and magnésium salts) and ammonia, organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, Nm ethyl -morpho line, dehydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine and the like.

The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound with basic or acidic properties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acîd or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile are preferred.

A “Prodrug” is considered a compound that is designed to release a biologically active compound according to the présent invention in-vivo when such prodrug is administered to a mammalian subject. Prodrugs of compounds according to the présent invention are prepared by modifying functional groups présent în the compound of the invention in such a way that these modifications are retransformed to the original functional groups under physiological x

-3916302 conditions. It will be appreciated that prodrugs of the compounds according to the présent inventions are subject to the présent invention as well.

“Métabolites” are considered dérivatives of the compounds according to the présent invention that are formed in-vivo. Active métabolites are such métabolites that cause a pharmacological effect. It will be appreciated that métabolites of the compounds according to the présent inventions are subject to the présent invention as well, in particular active métabolites.

Some of the compounds may form “solvatés”. For the purposes of the invention the term “solvatés” refers to those forms of the compounds which form, in the solid or liquid state, a complex by coordination with solvent molécules. Hydrates are a spécifie form of solvatés in which the coordination takes place with water. According to the présent invention, the term preferably is used for solid solvatés, such as amorphous or more preferably crystalline solvatés.

“Scaffold”: The scaffold of the compounds according to the présent invention is represented by the following core structure. The numération of the positions of the ring member atoms is indicated in bold:

It will be évident for the skilled person in the art, that this scaffold can be described by its tautomeric “enol” form s

-4016302

In the context of the présent invention both structural représentations of the scaffold shall be considered the subject of the présent invention, even if only one of the two représentatives îs presented. Without meant to be limiting or bound, it îs believed that for the majority of compounds under ambient conditions and therewith under conditions which are the relevant conditions for a pharmaceutical composition comprising said compounds, the equilibrium of the tautomeric forms lies on the side of the pyrazolopyrimdin-4-one représentation. Therefore, all embodiments are presented as pyrazolopyrimdin-4-one-derivatives or more precisely as pyrazolo[3,4-d]pyrimidin-4-one dérivatives.

“Bonds”: If within a chemical formula of a ring system or a defined group, a substituent is directly linked to an atom or a group like “RyR” in the formula below, this shall mean that the substituent îs only attached to the corresponding atom. If however from another substituent like “RxR” a bond is not specifically linked to an atom of the ring system but drawn towards the center of the ring or group this means that this substituent “RxR” may be linked to any meaningful atom of the ring system / group unless stated otherwise.

The bond symbol (= minus sign) or the symbol *” (= minus sign followed by an asterisk sign) stands for the bond through which a substituent is bound to the corresponding remaining part of the molécule / scaffold. In cases in that the minus sign does not seem to be sufficiently clear, there may be added an asterisk to the bond symbol in order to détermine the point of attachment of said bond with the corresponding main part of the molécule / scaffold. s

-4l 16302

The term “CX,-alkyl” dénotés a saturated, branched or unbranched hydrocarbon group with 1 to 6 C atoms. Examples of such groups include methyl, ethyl, «-propyl, zso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, «-pentyl, iso-pentyl, «eo-pentyl, ter/-pentyl, «-hexyl, iso-hexyl. This définition applies for the use of “alkyl” in any reasonable context within the présent description in the absence of a further définition.

The term “Ci-v-cycloalkyl” dénotés a saturated monocyclic group with 3 to 7 C ring atoms. Preferred are 5 or 6 membered cycloalkyl-groups. There are no other ring atoms than carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. This définition applies for “cycloalkyl” in any reasonable context within the présent description in the absence of a further définition.

The term “heteroaryl” used in this application dénotés a heterocyclic, monocyclic aromatic ring System which includes within the ring system itself in addition to at least one C atom one or more heteroatom(s) which are independently selected from N, O and/or S. Preferred are heteroaryls with 1 to 3 heteroatoms or 1 to 2 heteroatoms, or 1 heteroatom. Preferred heteroatom is N.

The terms “pyridyl” defines a pyridine-substituent, sometimes also called pyridinyl.

Expressions like prévention, prophylaxis, prophylactic treatment or préventive treatment used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis. Thus the expression prévention of a disease as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prévention is to combat the development of the disease, condition or disorder and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said préventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an équivalent patient population without préventive treatment. r

-42 16302

The expression treatment or therapy preferably means therapeutic treatment of (e.g. preferably human) patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve 5 symptoms of the spécifie indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression treatment of a disease as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition, 10 disorder or a symptom thereof. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

The following schemes shall illustrate generally how to manufacture the compounds of the présent invention by way of example. The abbreviated substituents may be as defined for the embodiments offormula (I) ifnot defined otherwise within the context ofthe schemes: x .1 8 JAN 2013 ’

ROUN

53

-4316302

Scheme 1

NH₃, H₂O₂

EtOH/H₂O

see Scheme 2 (path 2)

u NaH/EtOH

Scheme 1 : In a first step 2-ethoxymethylene-malononitrile is condensed with mono5 substituted hydrazines by heating in an appropriate solvent like éthanol in the presence of a base (e.g. triethylamine) to form the corresponding 5-amino-lH-pyrazole-4-carbonitriles. These compounds are converted in a second step to the corresponding amides, e.g. by treatment of an ethanolic solution with ammonia (25 % in water) and hydrogen peroxide (35 % in water). In a third step, heating with dicarboxylic acid diesters under basic conditions (e.g. sodium hydride in éthanol) followed by the addition of aqueous sodium hydroxide leads /

-4416302 to 4-oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl substituted carboxylic acids (path 1). The carboxylic acid functional group thereof is converted to a heteroaryl group as described în Scheme 2 yieldîng pyrazolo[3,4-d]pyrimidin-4-ones as final products. Altematively, 4oxo-4,5-dihydro-l 1l-pyrazolo[3,4-d]pyrimidîn-6-yl substituted nîtriles can be synthesized from dinitriles by heating under basic conditions (e.g. sodium hydride in éthanol) in the third step (path 2). The nitrile functional group is further converted to heteroaryl substituents as described in Scheme 3 yieldîng pyrazolo[3,4-d]pyrimidin-4-ones as final products. [cf., for example, A. Miyashîta et al., Heterocycles 1990, 31, 1309ff|.

Scheme 2

Scheme 2: 4-Oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl substituted carboxylic acids are treated under conditions listed in the table below to form heteroaryl substituted 15 pyrazolo[3,4-d]pyrimidin-4-ones as final products. R^a is a substituent of R¹.

conditions as mentioned in scheme 2	R¹	R^a
1. ) Reaction with HATU and DIPEA followed by a carboxylic acid hydrazide. 2. ) Treatment with Lawesson’s reagent in THF at elevated températures.	_Da__Z N	H-, F₃C-, HF₂C-, FH₂C-, methyl
1.) Reaction with oxalylchloride in THF followed by treatment with trimethylsilydiazomethane followed by	O *	H-, F₃C-, HF₂C-, FH₂C-, methyl

-4516302

hydrochloric acid in dioxane. 2.) Reaction with a thioamide in EtOH.
1. ) Reaction with oxalylchloride in THF followed by treatment with trimethylsilydiazomethane followed by hydrochloric acid în dioxane. 2. ) Reaction with a thiourea in EtOH.	H) s V	H-, FjC-, HF₂C-, FH₂C-_t methyl
3. ) Reaction with oxalylchloride in THF followed by treatment with trimethylsilydiazomethane and hydrochloric acid in dioxane. 4. ) Reaction with a thiourea in EtOH.	S V	H₂N-, (CH₃)₂N-
1. ) Reaction with TBTU and D1PEA followed by a 2-amino-alkohol. 2. ) Oxîdation with Dess-Martin- Periodinane in dichloromethane. 3. ) Treatment with Burgess-reagent in DME at elevated températures.	V oK	H-, NC-, F₃C-, hf₂c-, fh₂c-, methyl
1. ) Reaction with TBTU and DIPEA followed by a 2-amino-ketone hydrochloride. 2. ) Treatment with Burgess-reagent in DME at elevated températures.	oV	H-, NC-, F₃C-, hf₂c-, fh₂c-, methyl
1. ) Reaction with TBTU and DIPEA followed by a 2-amino-alkohol. 2. ) Oxîdation with Dess-Martin-		H-, NC-, F₃C-, hf₂c-, fh₂c-, methyl

-4616302

Periodinane in dichloromethane. 3.) Treatment with Lawesson’s reagent in THF at elevated températures.
1. ) Reaction with TBTU and DIPEA followed by a 2-amino-ketone hydrochloride. 2. ) Treatment with Lawesson’s reagent in THF at elevated températures.	A S-'A	H-, NC-, F₃C-, hf₂c-,fh₂c-, methyl
1. ) Reaction with TBTU and DIPEA followed by 1,2-dimethylhydroxylamine hydrochloride. 2. ) Reaction with a mixture prepared separately from propan-2-one oxime and n-buthyllithium followed by treatment with sulfuric acid in THF / water.	k
1. ) Reaction with TBTU and DIPEA followed by hydrazîne hydrate. 2. ) Treatment with triethoxymethane at elevated températures.	An <. Jl o-\

-4716302

Scheme 3

with

R^x - Me, Et

R^y = NC-, F₃C-,

HF₂C-, fh₂c-, methyl, HScheme 3: 4-Oxo-4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl substituted nîtriles are mixed with methanol and treated with acetylchloride or, altematively, mixed with a saturated 5 solution of hydrochloric acid in éthanol. The intermediates are treated in a second step with a solution of ammonia in methanol to form the corresponding amidînes. Reaction with a

1,1,3,3-tetraalkoxypropane yields pyrimidin-2-yl substituted pyrazolo[3,4-d]pyrimîdin-4-ones as final products.

Further alternative processes for preparing pyrazolo[3,4-d]pyrimidin-4-ones are known in the art and can likewise be employed for synthesizing the compounds of the invention (see, for example: P. Schmidt et al., Helvetica Chimica Acta 1962,189, 1620ff.). /

-4816302

Scheme 4

H NNH

O

reducing agent

is cyclopentyl or cyclohexyl optionally substited as defined in formula (I). Consequently, n = 1 or 2

Scheme 4: The mono-substituted hydrazine dérivatives, that are used in step 1 of scheme 1 can be prepared by reductive amination of a ketone with hydrazinecarboxylic acid tert-butyl ester followed by a deprotection step as shown in scheme 4 for an D being cyclopentyl or cyclohexyl as defined in general formula (I) [c£, for example, J.W. Timberlake et al., “Chemistry of Hydrazo-, Azo- and Azoxy Groups; Patai, S., Ed.; 1975, Chapter 4; S. C. Hung et al., 10 Journal of Organic Chemistry 1981, 46, 5413-5414].

-4916302

Scheme 5

oc₂h₅	NH / 2	ELN/EtOH
+	HN 1	----►
1 CN	D	heat

NH₃, HaOg

EtOH/H₂O

Scheme 5: As described in scheme 1, in a first step 2-ethoxymethylene-malononitrile is condensed with mono-substituted hydrazines by heating in an appropriate solvent like éthanol in the presence of a base (e.g. triethylamine) to form the corresponding 5-amino-lHpyrazole-4-carbonitriles. These compounds are converted in a second step to the corresponding amides, e.g. by treatment of an ethanolic solution with ammonîa (25 % in water) and hydrogen peroxide (35 % in water). In a third step, heating with R¹ and R²10 substituted cyclobutyl or cyclopentyl carboxylic acid ester under basic conditions (e.g.

sodium hydride în éthanol) leads to the final pyrazolo[3,4-d]pyrimidin-4-ones as final products. [cf„ for example, A. Miyashita et al., Heterocycles 1990, 31, 1309ff]. This procedure is described in more detail for R¹ being pyridniyl, m being 1 and n being 0 in the experimental section (examples 29 to 32).

Further information also can be found în:

WO 2004/099210 (in particular page 9, last paragraph to page 14, line 8, incorporated by reference),

- 5016302

- with respect to the general manufacture of compounds with D being tetrahydropyranyl more information can be found in W02009/121919, particularly on page 120 to 125 and the experimental part thereof (herewith incorporated by reference),

- with respect to D being 4,4-difluorocyclohexyl more information can be found in WO 2010/026214, particularly on page 59 to 63 and the experimental part thereof (herewith incorporated by reference), and in the experimental part (exemplary embodiments) of this description. The letter in particular with respect to the manufacture of the two building blocks:

METHOD OF TREAMENT

The présent invention refers to compounds, which are considered effective in the treatment of diseases. The compounds according to the invention are effective and sélective inhibitors of phosphodiesterase 9A and can be used for the development of médicaments. Such médicaments shall preferably be used for the treatment of diseases in which the inhibition of PDE9A can provide a therapeutic, prophylactic or disease modifying effect. Preferably the médicaments shall be used to improve perception, concentration, cognîtion, leaming or memory, like those occurring in particular in situations/diseases/syndromes such as: mild cognitive împairment, age-associated leaming and memory impairments, age-associated memory fosses, vascular dementia, craniocerebral trauma, stroke, dementîa occurring after strokes (post stroke dementia), post-traumatic dementia, general concentration impairments, concentration impairments in children with leaming and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with cortîcobasal degeneration, amyotropic latéral sclerosis (ALS), Huntington’s disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobe

-51 16302 epîlepsy, schizophrenia, schizophrenia (with dementia), Korsakoff s psychosis or cognitive impairment associated with dépréssion or bipolar disorder.

Another aspect of the présent invention may concem the treatment of a disease which is accessible by PDE9A modulation, in particular sleep disorders like insomnia or narcolepsy, bipolar disorder, metabolic syndrome, obesity, diabètes mellitus, including type 1 or type 2 diabètes, hyperglycemia, dyslipidemia, impaired glucose tolérance, or a disease of the testes, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

Thus the medical aspect of the présent invention can be summarised in that it is considered that a compound according to formula (I) or (II) as herein defined, in particular the specifically defined species compounds is used as a médicament.

Such a médicament preferably is for the use in a method for the treatment of a CNS disease.

In an alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment of a CNS disease, the treatment of which is accessible by the inhibition of PDE9.

In an alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment of a disease that is accessible by the inhibition of PDE9, specifically PDE9A.

In the most preferred alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment, amelioration and / or prévention of cognitive impairment being related to perception, concentration, cognition, leamîng or memory, preferably if such cognitive impairment is associated with a disease or condition as described in this section.

In an alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment or the amelioration or prévention of cognitive impairment being related to age-associated leamîng and memory impainnents, ageassociated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic dementia, general concentration împairments, concentration impairments in children with leamîng and memory problems,

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Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotropic latéral sclerosis (ALS), Huntington’s disease, multiple sclerosîs, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia (with dementia), Korsakoff s psychosis or cognitive impairment associated with dépréssion or bipolar disorder.

In an alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment of Alzheimer’s disease, schizophrenia or cognitive impairment associated with Alzheimer’s disease or associated with schizophrenia.

In an alternative use, the médicament is for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment of sleep disorders, bipolar disorder, metabolic syndrome, obesity, diabètes mellitus, hyperglycemia, dyslipidemia, impaired glucose tolérance, or a disease of the testes, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

In a further aspect of the invention, the présent invention relates to the method of treatment or prévention of a condition or disease selected from the above listed groups of conditions and diseases, whereby the method comprises the administration of a therapeutically effective amount of a compound according to the invention in a human being in need thereof.

Another aspect of the invention concems the compounds of the inventions for use as a médicament in a therapeutic or prophylactic method, preferably a therapeutic method. If indicated the therapeutic method or the médicament is preferably for the treatment of a condition or a disease selected from the group of conditions or a diseases as outlined above in this section which is entitled “METHOD OF TREATMENT”.

PHARMACEUTICAL COMPOSITIONS

Médicaments for administration, which are also subject to the présent invention, comprise

- a compound according to the présent invention as a or the pharmaceutically active ingrédient in a therapeutically effective amount and

- a pharmaceutical carrier, x

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By therapeutically effective amount it is meant that if the médicament is applied via the appropriate regîmen adapted to the patient’s condition, the amount of said compound of formula (I) will be suffi oient to effectively treat, to prevent or to decelerate the progression of the corresponding disease, or otherwise to ameliorate the state of a patient suffering from such a disease. It may be the case that the therapeutically effective amount in a monotherapy will differ from the therapeutically effective amount in a combination therapy with another médicament.

The dose range of the compounds of general formula (I) applicable per day may be usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, preferably from 2 to 500 mg, more preferably from 5 to 250 mg, most preferably from 10 to 100 mg. A dosage unit (e.g. a tablet) preferably may contain between 2 and 250 mg, particularly preferably between 10 and 100 mg of the compounds according to the invention.

The actual pharmaceutically effective amount or therapeutic dosage will dépend on factors known by those skilled in the art such as âge, weight, gender or other condition of the patient, route of administration, severity of disease and the like.

The compounds according to the invention may be administered by oral, parentéral (intravenous, intramuscular etc.), intranasal, sublingual, inhalatîve, intrathecal, topical or rectal route. Suitable préparations for administering the compounds according to the présent invention include for example patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid préparations such as solutions, suspensions, émulsions, drops, syrups, élixirs, or gaseous préparations such as aérosols, sprays and the like. The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixîng the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disîntegrants such as corn starch or alginic acid, binders such as starch or gélatine, lubricants such as magnésium stéarate or talc and/or agents for delayîng release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

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Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxîde or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or élixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanîllin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatîves such as p-hydroxybenzoates.

Solutions may be prepared in the usual way, e.g. with the addition of isotonie agents, preservatîves such as p-hydroxybenzoates or stabilisers such as alkali métal salts of ethylenediamine-tetra-acetic acid, optionally using emulsificrs and/or dispersants, while if water shall be used as diluent, for example, organic solvents may optionally be used as solubilisers or dissolving aids and the solutions maybe transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gélatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the dérivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. éthanol or glycerol), carriers such as e.g. natural minerai powders (e.g. kaolins, clays, talc, chalk), synthetic minerai powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), y

-5516302 emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnésium stéarate, talc, stearic acid and sodium lauryl sulphate).

For oral use the tablets may contain, in addition to the carriers specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various addîtional substances such as starch, preferably potato starch, gélatine and the like. Lubricants such as magnésium stéarate, sodium laurylsulphate and talc may also be used to produce the tablets. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the abovementioned excipients.

The dosage of the compounds according to the invention is naturally highly dépendent on the method of administration and the complaint which is being treated.

COMBINATIONS WITH OTHER ACTIVE SUBSTANCES

In another aspect the présent invention relates to a combination therapy in which a compound according to the présent invention is administered together with another active compound. Accordingly, the invention also refers to pharmaceutical formulations that provide such a combination of pharmaceutically active ingrédients, whereby one of which is a compound of the présent invention. Such combinations may be fixed dose combinations (the pharmaceutically active ingrédients that are to be combined are subject of the same pharmaceutical formulation) or free dose combinations (the pharmaceutically active ingrédients are in separate pharmaceutical formulations).

Consequently, a further aspect of the présent invention refers to a combination of each of the compounds of the présent invention, preferably at least one compound according to the présent invention, with another active compound for example selected from the group of beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors such as e.g. alzhemed; directly or indirectly acting neuroprotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E , ginko biloba or ginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors, NSAIDs additionally or exclusively having AB (Abeta) lowering properties; HMG-CoA reductase inhibitors, such as statîns; acétylcholine esterase inhibitors, such as donepezil, rivastigmine, tacrine, z

-5616302 galantamine; NMDA receptor antagonists such as e.g, memantine; AMPA receptor agonists; AMPA receptor positive modulators, AMPkines, glycine transporter l inhibitors; monoamine receptor reuptake inhibitors; substances modulating the concentration or release of neurotransmitters; substances inducing the sécrétion of growth hormone such as ibutamoren mesylate and capromorelin; CB-l receptor antagonists or inverse agonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2, PDE4, PDE5 and / or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA aipha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or positive modulators; alpha7 nicotinic receptor agonists or partial agonists; histamine receptor H3 antagonists; 5HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists, calcium antagonists; muscarinic receptor Ml agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; metabotropic glutamate receptor 5 positive allosteric modulators; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate receptor 2/3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the compounds according to the invention is increased and/or unwanted side effects are reduced.

This invention further relates to pharmaceutical compositions contaîning one or more, preferably one active substance. At least one active substance is selected from the compounds according to the invention and/or the corresponding salts thereof. Preferably the composition comprises only one such active compound. In case of more than one active compound the other one can be selected fforn the aforementioned group of combination partners such as alzhemed, vitamin E, ginkolide, donepezil, rivastigmine, tacrine, galantamine, memantine, ibutamoren mesylate, capromorelin, minocyclin and/or rifampicin. Optionally the composition comprises further ingrédients such as inert carriers and/or diluents.

The compounds according to the invention may also be used în combination with immunothérapies such as e.g. active immunisation with Abeta or parts thereof or passive immunisation with humanised anti-Abeta antibodîes or antibody fragments for the treatment of the above mentioned diseases and conditions. s

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The compounds according to the invention also may be combined with Dimebon.

The compounds according to the invention also may be combined with antidepressants like amitriptyline imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL).

Or the compounds according to the invention also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL) escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetîne (MALEX1L), fenfluramine (PONDIMIN), norfenfluramine, fluoxetîne (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicîfadine, desvenlafaxine (PRISTIQ), brasofensme and tesofensine.

The combinations according to the présent invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination préparation, for example the two components may be incorporated in one tablet, e. g. in different layers of said tablet. The combination may be also provided separately, in form of a free combination, i.e. the compounds of the présent invention are provided in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form. These two dosage forms may be equal dosage forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the compound of the présent invention and one containing a therapeutically effective amount of the above mentioned combination partner. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be provided.

The compound according to the invention, or a physiologically acceptable sait thereof, in combination with another active substance may be used simultaneously or at staggered times, but particularly close together in time. If administered simultaneously, the two active substances are given to the patient together; if administered at staggered times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours. /

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The dosage or administration forms are not limited, in the context of the présent invention any suitable dosage form may be used. For example, the dosage forms may be selected from solid préparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid préparations such as solutions, suspensions, émulsions, drops, syrups, élixirs, or gaseous préparations such as aérosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being présent. Depending from the administration route and dosage form the ingrédients are selected accordingly.

The dosage for the above-mentioned combination partners may be expediently l/5 of the normally recommended lowest dose up to l/l of the normally recommended dose.

The dosage forms are administered to the patient for example 1, 2, 3, or 4 times daily depending on the nature of the formulation. In case of retardîng or extended release formulations or other pharmaceutical formulations, the same may be applied differently (e.g. once weekly or monthly etc.). It is preferred that the compounds of the invention be administered either three or fewer times, more preferably once or twice daily.

EXAMPLES

PHARMACEUTICAL COMPOSITIONS

Examples which might illustrate possible pharmaceutical formulations, without being meant to be limitîng:

The term active substance dénotés one or more compounds according to the invention including the salts thereof. In the case of one of the aforementioned combinations with one or more other active substances the term active substance may also include the additional active substances.

Example A ✓

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Tablets containing 100 mg of active substance

Composition: tabiet

active substance	100.0 mg
lactose	80.0 mg
corn starch	34.0 mg
polyvinylpyrrolîdone	4.0 mg
magnésium stéarate	2.0 mg
	220.0 mg

Example B

Tablets containing 150 mg of active substance

Composition: tabiet

active substance	150.0 mg
powdered lactose corn starch	89.0 mg 40.0 mg
colloïdal silica	10.0 mg
polyvinylpyrrolîdone magnésium stéarate	10.0 mg 1.0 mg 300.0 mg

Examnle C

Hard gélatine capsules containing 150 mg of active substance

active substance	150.0 mg
lactose	87.0 mg
corn starch (dried)	80.0 mg

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magnésium stéarate

3.0 mg 320.0 mg

Example D

Composition: suppository

active substance	150.0 mg
polyethyleneglycol 1500 polyethyleneglycol 6000 polyoxyethylene sorbitan monostearate	550.0 mg 460.0 mg 840.0 mg

2000.0 mg

Example E

Composition: ampoules containing 10 mg active substance

active substance 0.01 N hydrochloric acid q.s. double-distilled water ad

10.0 mg 2.0 mL

Example F

Composition: ampoules containing 50 mg of active substance active substance 50.0 mg

0.01 N hydrochloric acid q.s.

double-distîlled water ad 10.0 mL

The préparation of any the above mentioned formulations can be done following standard procedures. /

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BIOLOGICAL ASSAY

The in-vitro effect of the compounds of the invention can be shown with the following biological assays.

PDE9A2 assay protocol:

The PDE9A2 enzymatic activity assay was run as scintillation proximity assay (SPA), in general according to the protocol of the manufacturer (GE Healthcare, former Amersham Biosciences, product number: TRKQ 7100).

As enzyme source, lysate (PBS with 1 % Triton X-100 supplemented with protease inhibitors, cell débris removed by centrifugation at 13.000 rpm for 30 min) of SF 9 cell expressing the human PDE9A2 was used. The total protein amount included in the assay varied upon infection and production efficacy of the SF9 cells and lay in the range of 0.1 100 ng.

In general, the assay conditions were as follows:

• total assay volume: 40 microlitre • protein amount: 0.1-50 ng • substrate concentration (cGMP): 20 nanomolar; ~1 mCi/1 • incubation time: 60 min at room température • final DMSO concentration: 0.2 -1 %

The assays were run in 384-well format. The test reagents as well as the enzyme and the substrate were diluted in assay buffer. The assay buffer contained 50 mM Tris, 8.3 mM MgC12, 1.7 mM EGTA, 0.1 % BSA, 0.05 % Tween 20; the pH of assay buffer was adjusted to 7.5. The reaction was stopped by applying a PDE9 spécifie inhîbîtor (e.g. compounds according to WO 2004/099210 or WO 2004/099211, like one of the enantiomeres of example 37, e.g. 1 -(2-ChI orophenyl)-6-[(2R)-3,3,3-tri fiuoro-2-methyl-propyl]-1,5-dihydro-4Hpyrazolo[3,4-d]pyrimidine-4-one) in excess.

References: ^x

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Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and sélective PDE9 inhibitor using a cGMP reporter cell line. Molecular Pharmacology. 2005 Dec;68(6): 1775-81.

van der Staay FJ, Rutten K, Bârfacker 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 sélective PDE9 inhibitor BAY 73-6691 improves leaming and memory in rodents. Neuropharmacology. 2008 Oct;55(5):908-18.

PDE1C assay protocol:

The assay was run in an analogous manner to the PDE9A2 assay, with the following différences: instead of PDE9A2, PDE1C was used and the assay buffer contained in addition 50 nM Calmodulin, 3 mM CaCU. The reaction can be stopped by applying the same inhibitor than the one that is outlined above (l-(2-Chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-l,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one).

Détermination of Κ\η*.

IC50 can be caiculated with GraphPadPrism or other suited software setting the positive control as 100 and the négative control as 0. For calculation of IC₅o dilutions of the test compounds (substrates) are to be selected and tested following the aforementioned protocol.

Data

In the following IC50 values for PDE9A2 inhibition [nanomolar (nM)] illustrate that the compounds according to the présent invention inhibit PDE9, specifically PDE9A2. This évidences that the compounds provide useful pharmacological properties. The examples are not meant to be limiting.

The table also provides selectivity values (Selectivity) that show a preference of the compounds for PDE9A versus PDE1C. Selectivity is the ratio (IC50 for PDE1C inhibition [nanomolar (nM)]) / (IC50 for PDE9A2 inhibition [nanomolar (nM)]). z-6316302

The example numbers refer to the final examples as outlined in the section Exemplary embodiments and as defined by the above compound family table (embodiment 25).

Ail data can be measured according to the procedure described herein. The définition enantîomer l or enantiomer 2 is related to the elution orders of enantiomers in chiral SFC and 5 chiral HPLC.

Compound family	Example No.	IC₅₀ PDE9A2 [nanomolar]	Selectivity
A	1*	450	3
B	2*	5	143
C	3*	23	34
D	4*	242	22
E	5*	60	14
F	6*	58	15
G1	7*	31	15
G2	8*	85	63
Hl	g*	19	46
H2	10*	13	120
I	11*	233	>43
J	12*	80	38
K	13*	Ί	328
K	14 (enantiomer 1)	473	4,3
K	15 (enantiomer 2)	4	424
L	16*	5	245
M	17*	16	78
M	18 (enantiomer 1 )	5	255
M	19 (enantiomer 2)	1345	0.61
N	20*	31	68
0	21*	433	10
P	22*	21	49
Q	23	23	187
Q	24 (enantiomer 1)	218	8.9

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Compound famîly	Example No.	IC₅o PDE9A2 [nanomolar]	Selectivity
Q	25 (enantiomer 2)	7	197
R	29*	11	117
R	30 (enantiomer 1)	304	4.95
R	31 (enantiomer 2)	7	186
S	32*	7	117
S	33 (enantiomer 1)	4	181
S	34 (enantiomer 2)	388	1.68
T	26*	32	>400
T	27 (enantiomer 1)	11	250
T	28 (enantiomer 2)	360	7

* trans racemic mixture

In-vivo effect:

It is believed that the positive in-vitro efficacy results of the compounds of the présent invention translate in positive in-vivo efficacy.

The in-vivo effect of the compounds of this invention can be tested in the Novel Object Récognition test according to the procedure of Prickaerts et al. (Neuroscience 2002,113, 351-361), the social récognition test or the T-maze spontaneous alternation test according to 10 the procedures described by van der Staay et al. (Neuropharmacology 2008, 55, 908-918).

For further information conceming biological testing one is also referred to these two citations.

Besides the inhibition property toward the target PDE9, compounds according to the présent invention may provide further advantageous pharmacokinetic properties.

E.g. compounds according to the invention may show one or more advantages in the area of safety, balanced metabolism, low risk of causing drug - drug interaction and/or balanced clearance. /

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Compounds also might show one or more additional or alternative advantages in the area of bioavailability, high fraction absorbed, blood brain transport properties, a favourable (e.g. high mean) résidence time (mrt), favourable exposure in the effect compartment and so on.

CHEMICAL MANUFACTURE

Abbreviations:

Burgess-reagent (methox ycarbonylsulfamoyl)-tri ethyl ammonium-N-betain

Lawesson’s reagent 2,4-bis-(4-methoxy-phenyl)-[ l ,3,2,4]dithiadiphosphetane 2,4-

APCI	disulfide Atmospheric pressure chemical ionization
ACN	acetonitrile
CDI	1,1 ’-carbonyldiîmidazole
DEA	diethylamîne
DIPEA	diisopropylethylamine
DME	1,2-dimethoxyethane
DMF	dimethylformamide
ESI	electrospray ionization (in MS)
EtOH	éthanol
Exp.	example
h	hour(s)
HATU	O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
HPLC	hexafluorophosphate high performance liquid chromatography

HPLC-MS	coupled high performance liquid chromatography-mass spectrometry
M	molar (mol/L)
MeOH	methanol
min	minutes
MS	mass spectrometry
NMP	l-methyl-2-pyrrolidinone '

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R*	rétention time (in HPLC)
SFC	supercrtîcial fluid chromatography
TBTU	O-(benzotriazol-l -yl)-N,N,N',N -tetramethyluronium tetrafluoroborate
TFA	trifluoroacetic acid
THF	tetrahydrofuran
TLC	thin-layer chromatography

LC-MS methods:

Method 1

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb 100 Cl8, 30 x 4.6 mm, 3.0 μιη; eluent A: water + 0.13 % TFA, eluent 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 détection: 210-380 nm.

Method 2

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb 100 Cl8, 30 x 4.6 mm, 3.0 μιη; eluent A: water + 0.13 % TFA, eluent B: MeOH; gradient: 0.0 min 5 % B -> 0.35 min 5 % B —> 3.95 min 100 % B -> 4.45 min 100 % B -> 4.55 min 5 % B > 4.9 min 5 % B; flow rate: 2.4 mL/min; UV détection: 210-380 nm.

Method 3

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb Cl8, 20 x 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 détection: 210-400 nm. /

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Method 1E hydro

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP80A, 4 um, 4.60 x 100 mm; eluent A: 90% water + 10% acetonitrile + ammonium formate 10 mM; eluent B = ACN 90%+10% H₂O + NH4COOH 10 mM; gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5 min; flow rate: 1.2 mL/min; UV Détection: 254nm; Ion source: APCI.

Chiral SFC methods:

Method 4

SFC apparatus type: Berger “Analytix”; column: Daicel IC, 250 mm x 4.6 mm, 5.0 μτη; eluent: CO₂ / 25 % MeOH / 0.2 % DEA (isocratic); flow rate: 4.0 mL/min, 10 min; température: 40°C; (JV détection: 210/220/254 nm.

Method 5

SFC apparatus type: Berger “Analytix”; column: Daicel ADH, 250 mm x 4.6 mm, 5.0 μτη; eluent: CO₂ / 25 % MeOH / 0.2 % DEA (isocratic); flow rate: 4.0 mL/min, 10 min; température: 40°C; UV détection: 210/220/254 nm.

Chiral HPLC methods:

Method 6:

HPLC apparatus type: Agilent 1100; column: Daicel chiralcel OJ-H, 250 mm x 4.6 mm, 5.0 μην; eluent: hexane/EtOH80:20; flow rate: 1 mL/min, Température: 25°C; UV Détection: variable (200- 500 nm).

Method 6.1:

HPLC apparatus type: Agilent 1100; column: Daicel chiralcel OJ-H, 250 mm x 4.6 mm, 5.0 pm,; eluent: hexane/EtOH 85:15; flow rate: 1 mL/min, Température: 25°C; UV Détection: variable (200- 500 nm).

Method 7: ^z

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HPLC apparatus type: Agilent 1100; column: Chiralpak AD-H, 250 mm x 4.6 mm, 5.0 pm,; eluent: hexane/isopropanol 80:20; flow rate: l mL/min, Température: 25°C; UV Détection: variable (200- 500 nm).

HPLC apparatus type: Agilent 1100; column: Chiralpak AD-H, 250 mm x 4.6 mm, 5.0 pm,; eluent: hexane/isopropanol 80:20; flow rate: 1 mL/min, Température: 25°C; UV Détection: variable (200- 500 nm).

Microwave heating:

• Discover® CEM instruments, equipped with 10 and 35 mL vessels;

• Biotage Initiator Sîxty.

General comment concerning the présentation of the structures

Compounds with stereogenic centre(s): The structures depicted in the experimental section below will not necessarily show ail the stereochemical possibilities of the compounds but only one. However, in such cases a term like “trans - racemic mixture” or “cîs-racemic mixture” is added next to the depicted structure in order to indicate the other stereochemical options.

An example is given below. The presented structural formula is ,,.Χχ trans - racemic mixture

The added term “trans-racemic mixture” points to the second stereochemical option:

-6916302 __χΧχ ^γν

Thus, the manufacturée! compound is a mixture of

This principle applies to other depicted structures as well.

Starting compounds:

Example 1A (trans - racemic mixture)

trans - racemic mixture

2.00 g (13.9 mmol) trans-cyclobutan-l,2-dicarboxylîc acid were mixed with 16 mL EtOH at

0°C and 2.21 mL (30.5 mmol) thionylchloride were slowly added. The mixture was allowed to warm to room température and stirred for lh. The solvent was removed under reduced pressure and the product was filtered through a pad of activated basic alumina. 2.71 g (98 %) of the product were obtained.

HPLC-MS (Method 1): R_t = L34 min

MS (ESI pos): m/z = 201 (M+H)⁺

The following example was synthesized in analogy to the préparation of Example 1 A, using the corresponding dîaeid as starting material.

Example

structure

starting material

R_t [min]

MS (ESI pos, m/z)

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Example 2A (racemic mixture)

8.00 g (89.7 mmol) 2-amino-propîonic acid were mixed with 88.0 mL (0.93 mol) acetic anhydride and 88.0 mL pyridine. The reaction mixture was stirred at 100°C for 135 min. The solvent was removed under reduced pressure. Toluene was added to the residue and the solvent was removed under reduced pressure, then 204 mL (816 mmol) HCl (4 M aqueous solution) was added and the mixture was refluxed for 3h. The solvent was removed under reduced pressure. 1-Butanol (20 mL) was added to the residue and the solvent was removed under reduced pressure. 11.6 g of the title compound were obtained as hydrochloride sait. MS (ESI pos): m/z = 88 (M+H)⁺

Example 3A (trans - racemic mixture)

1.00 g (4.09 mmol) 5-Amino-l-(4,4-difluoro-cyclohexyl)-lH-pyrazole-4-carboxylîc acid amide (see PCT patent application WO 2010/026214, example 8A) was mixed with 15 mL of /

-71 16302 anhydrous EtOH, 2.46 g (12.3 mmol) of Example IA and 0.66 g (16.4 mmol) of sodium hydride (60 % suspension în minerai oil) were added. The reaction mixture was heated to 140°C for 30 min in a microwave oven. The mixture was cooled to room température and sodium hydroxide solution (4 M aqueous solution) was added. The solvent was removed under reduced pressure. The residue was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 0.70 g (49 %) ofthe product were obtained.

HPLC-MS (Method 1 ): R, =-1.24 min

MS (ESI pos): m/z = 353 (M+H)⁺

The following examples were synthesized in analogy to the préparation of Example 3A, using 10 the corresponding amide and ester as starting materials (for starting materials it is referred to

PCT patent publications WO 2010/026214, WO 2009/121919 and WO 2004/09921 ).

Example	structure	starting material: amide	starting material: ester	R. [min]	MS (ESI pos, m/z)
Exp. 3 B (trans racemic mixture)	'-'O	5-amino-l(tetrahydropyran-4-yl)-lHpyrazole-4carboxylic acid amide (see WO 2009/121919, example 11 B)	Exp. IB	1.07 (Meth od 3)	319 (M+H)⁺
Exp. 3C (trans racemic mixture)	^η°Ύ ^hO0ⁿ ^x k	5-amino-l-(4methyl-pyridin3-yl)-lHpyrazole-4carboxylic acid amide (see WO 2004/099211, example 3 5A)	Exp. IA	0.81 (Meth od 1):	326 (M+H)⁺

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0.200 g (0.568 mmol) Example 3A were mixed with 0.157 mL (1.14 mmol) triethylamine and 5 mL DMF. To the mixture were added 0.237 g (0.624 mmol) HATU, then the réaction mixture was stirred at room température for 10 min. To the mixture were added 0.042 g (0.568 mmol) acetîc acid hydrazide and the reaction mixture was stirred at room température for lh. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 30 mg of the product were obtained.

HPLC-MS (Method 1): R_t = 1.03 min

MS (ESI pos): m/z = 409 (M+H)⁺

Example 5A (trans - racemic mixture)

trans - racemic mixture

0.150 g (0.426 mmol) of Example 3A were mixed with 2 mL THF. The mixture was cooled to 0°C and 0.036 mL (0.426 mmol) oxalylchloride and one drop of DMF were added. The reaction mixture was stirred at 0°C for lh. To the reaction mixture were added 2 mL ACN and 0.426 mL (0.851 mmol) trimethylsilyldiazomethane (2 M in hexane). The mixture was stirred for 2h, then 0.213 mL HCl (4 M in dioxane) was slowly added. The reaction was /

-73 16302 stirred for 3h. To the mixture were added ethylacetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water and brine and dried over sodium sulfate. The solvents were partially evaporated until volume of approximately 2 mL was reached. The mixture was taken to the next step without further purification.

HPLC-MS (Method l): R_t = 1.40 min

MS (ESI pos): m/z = 385/387 (Cl)

The following example was synthesized in analogy to the préparation of Example 5A, using the corresponding acid as starting material.

Example	structure	starting material	R, [min]	MS (ESI pos, m/z)
Exp. 5B trans- racemic mixture	T b 0 Cl o	Exp. 3 B	I.l2 (Method 1)	351/353 (Cl)

Example 6A (trans - mixture of stereoisomers)

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0.200 g (0.628 mmol) of Example 3B were mixed with l mL DMF. 0.261 mL (1.89 mmol) triethylamine and 0.222 g (0.691 mmol) of TBTU were added. The reaction mixture was stirred at room température for 10 min. Then 0.078 g (0.628 mmol) of Example 2A was added and the mixture was stirred at room température for lh. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 190 mg of the product were obtained.

HPLC-MS (Method 3): R_t = 1.03 min

MS (ESI pos): m/z = 388 (M+H)⁺

0.200 g (0.628 mmol) of Example 3B were mixed with 1 mL DMF. 0.174 mL ( 1.26 mmol) triethylamine and 0.222 g (0.691 mmol) of TBTU were added. The reaction mixture was stirred at room température for 10 min. Then 0.066 g (0.628 mmol) 2,2-dimethoxyethylamine was added and the mixture was stirred at room température for lh. Then HCl (2 M aqueous solution) was added and the mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). The residue was mixed with 5 mL acetone and 1 mL HCl (2 M aqueous solution) and stirred overnight under nitrogen. Then the mixture was extracted with DCM. The organic layer was evaporated and purified by préparative HPLC (eluent A: water +0.13 % TFA, eluent B: MeOH). 170 mg of the product was obtained.

HPLC-MS (Method 3): R, = 1.01 min

MS (ESI pos): m/z = 360 (M+H)⁺

Example 8A (trans - mixture of stereoisomers) s

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0.200 g (0.568 mmol) of Example 3A was mixed with l.O mL DMF. 0.432 mL (2.84 mmol) DIPEA and 0.200 g (0.624 mmol) TBTU were added. The reaction mixture was stirred at room température for 10 min. Then 0.140 g ( l. 14 mmol) of Example 2A were added and the mixture was stirred at room température for 2h. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 70 mg (29 %) of the product was obtained.

HPLC-MS (Method l): R_t = 1.23 min

MS (ESI pos): m/z = 422 (M+H)⁺

The following examples were synthesized in analogy to the préparation of Example 8A, using the corresponding nucleophiles as starting materials..

Example	structure	starting material	R_t [min]	MS (ESI pos, m/z)
Exp. 8B trans - racemic mixture	A z°	H hydrochloride	1.31 (method n	396 (M+H)⁺

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Exp. 8C trans - mixture of stereoisomers	Q F	x'X^NH, HO		410 (M+H)⁺
Exp. 8D trans - mixture of stereoisomers	Q F	X».	1.12 (method 1)	410 (M+H)⁺
Exp. 8E trans - racemic mixture	GcV Q F ^h	hydrazine hydrate	0.99 (method 1)	367 (M+H)⁺

Example 9A (trans - racemic mixture)

trans - racemic mixture

0.182 g (0.430 mmol) Dess-Martin periodinane were mixed with 2.5 mL DCM. 0.160 g (0.391 mmol) Example 8D in 2.5 mL DCM was added at room température. The reaction /

-7716302 mixture stirred at room température for 30 min and at 30°C for 30 min. To the mixture were added 10 mL sodium thiosulfate solution (10 % in water) and 10 mL saturated sodium hydrogen carbonate solution and the mixture was stirred for 20 min. The organic layer was separated and the aqueous layer was extracted with DCM. The organic layer was washed with saturated sodium hydrogen carbonate solution, dried and evaporated. 93 mg (58 %) of the product were obtained.

HPLC-MS (Method 1): R_t = 1.18 min

MS (ESI pos): m/z - 408 (M+H)⁺

The following example was synthesized in analogy to the préparation of Example 9A, using the corresponding alcohol as starting material.

Example	structure	starting material
Exp. 9B trans - mixture of stereoisomers	VF Q F	Exp. 8C

Example 10A (trans - mixture of stereoisomers)

0.450 g of Example 3C was mixed with 3.5 mL DMF and 0.273 g (2.21 mmol) Example 2A.

1.00 mL (6.64 mmol) DIPEA and 0.390 g (1.22 mmol) TBTU were added and the mixture

-7816302 was stirred for lh. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 360 mg (83 %) of the product was obtained.

HPLC-MS (Method 1): R_t = 0.85 min

MS (ESI pos): m/z = 395 (M+H)⁺

Example 11A (trans - racemic mixture) trans - racemic mixture

300 mg (1.23 mmol) of 5-amino-l-(4,4-difluoro-cyclohexyl)-lH-pyrazole-4-carboxylic acid amide (see WO 2010/026214, example 8A) were mixed with 4 mL anhydrous EtOH, 326 mg (3.07 mmol) trans-cyclobutane-l,2-dicarbonitrile and 0.197 g (4.91 mmol) of sodium hydride (60 % suspension în minerai oil) under nitrogen. The reaction mixture was heated to 140°C for 45 min in a microwave oven. The solvent was removed under reduced pressure. The residue was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH).

210mg(51 %)ofthe title compound were obtained.

HPLC-MS (Method 3): R_t = 1.19 min

MS (ESI pos): m/z = 334 (M+H)⁺

Example 1 IB (trans - racemic mixture) '

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trans - racemic mixture

To a solution of 0.8 g (3.805 mmol) of 5-amino-l-(tetrahydro-pyran-4-yl)-l-H-pyrazole-4carboxylic acid amide (see PCT patent application WO2010/026214) in 8 mL anhydrous EtOH , 0.457 g (19.6 mmol) of sodium hydride (60 % suspension in minerai oil) were added 5 at room température under nitrogen. After 1 h under stirring, 1.2g (11.42mmol) of transcyclobutane-l,2-dicarbonîtrile were added and the reaction mixture was heated to 140°C for 45 min in a microwave oven. The solvent was removed under reduced pressure. The residue was dissolved in DCM, water was added and phases were separated. Organic layers were dried over sodium sulphate and evaporated under reduced pressure. The crude was purified 10 by flash cromatography (Cy/EtOAc from 80/20 to 100%) to obtain the title compound as yellow solid. (0.64g, 55%)

HPLC-MS(MethodlEh):R_t=6.21min

MS (APCI): m/z = 300 (M+H)⁺

trans - racemic mixture s

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To a solution of 0.85 g (3.91 mmol) of 5-amino-l-(4-methyl-pyridin-3-yl)-lH-pyrazole-4carboxylic acid amide (see PCT patent application WO 2004/09921) in 10 mL anhydrous EtOH , 0.47 g (11.74 mmol) of sodium hydride (60 % suspension in minerai oil) were added at room température under nitrogen. After 1 h under stirring, 1.28g (11.74 mmol) of transcyclobutane-l,2-dicarbonitrile were added and the reaction mixture was heated to I40°C for 45 min in a microwave oven. The reaction mixture was then loaded on SCX cartridge, ammonia fractions were collected and evaporated and the residue was purified by flash cromatography ( DCM/MeOH 90:10) to obtain the title compound as white solid. (0.63g, 52%).

HPLC-MS (Method lEh): R₍ = 5.92 min

MS (APCI pos): m/z = 307 (M+H)⁺

Example 12A (trans - racemic mixture)

HN trans - racemic mixture

190 mg (0.570 mmol) of Example 11A were mixed with 0.281 mL toluene and 0.093 mL (2.30 mmol) anhydrous MeOH. 0.103 mL (1.45 mmol) acetylchloride were added slowly at 0°C. The mixture was stirred at room température for 12h. The solvent was removed under reduced pressure. To the residue 0.5 mL MeOH were added. Then 0.407 mL (2.85 mmol) ammonia (7 M in MeOH) were added at 0°C and the mixture was allowed to warm to room température. After 30 min the reaction mixture was treated with water and the pH was adjusted to pH=l by addition of TFA. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH) yielding 110 mg (42 %) of the product were as trifluoroacetic acid sait, ,

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HPLC-MS (Method 3): R, = 1.04 min

MS (ESI pos): m/z = 351 (M+H)⁺

trans - racemic mixture

To a mixture of dry EtOH (5mL) and dry CHC1₃ (5mL) cooled at 0°C, acetylchloride (2.27mL, 30.82mmol) was added slowly and mixture left under stirring for 20min. 0°C. A solution of Example 1 IB (0.410g, 1.027mmol) in dry CHC1₃ (5mL) was added dropwise and the mixture stirred at room température overnight. Solvents were evaporated under reduced 10 pressure, residue dissolved in dry EtOH (5mL) and 6.4mL of a 7.0M solution of ammonia in

MeOH (30.82mmol) were added. The mixture was stirred at room température for 12h. The solvent was removed under reduced pressure. The final product was obtained as hydrochloride and used for the next step wîthout further purification. (0.37g, content 50% estimated by HPLC-MS).

HPLC-MS (Method lEh): R_t = 5.38 min

MS (APCI pos): m/z = 317 (M+H)⁺

Example 12 C (trans - racemic mixture)

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trans - racemic mixture

To a mixture of dry EtOH (4mL) and dry CHCl₃ (lOmL) cooled at 0°C, acetylchloride (4.38 mL, 61.7 mmol) was added slowly and mixture left under stirring for 20min. 0°C. A solution of Example 11C (0.63g, 2.057 mmol) in dry CHCI3 (5mL) was added dropwise and the mixture stirred at room température overnight. Solvents were evaporated under reduced pressure, residue dissolved in dry MeOH (lOmL) and 10.3 mL of a 7.0M solution of ammonia in MeOH (72 mmol) were added. The mixture was stirred at room température for 12h. The solvent was removed under reduced pressure. The final product, obtained as hydrochloride sait, was used as such in the next step without further purification. (0.85g, content 84%, estimated by 1 H-NMR).

HPLC-MS (Method lEh): R_t = 5.15 min

MS (APC1 pos): m/z = 324 (M+H)⁺

Example 13A (trans - racemic mixture)

To a solution of 1.6 g (10.24 mmol) of 2-acetyl-cyclobutanecarboxylic acid methyl ester (prepared as described in J. Med. Chem, 25, 109, 1982) in dry EtOH (12mL), propargylamine (1.4mL, 20.4mmmol) was added followed by 0.122g (0.307mmol) of sodium gold trichloride. The reaction mixture was heated to 140°C for 45 min in a microwave oven, solid was filtered and the organic evaporated. Crude was purified by flash cromatography (Cy/EtOAc 70:30) to obtaîn the title compound as yellow green oil. (0.18g, 9.2%). '

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HPLC-MS (Method 1 Eh): R_t = 0.87 min

MS (APCI pos): m/z = 192 (M+H)⁺

Exemplary embodiments

Example 1 (trans - racemic mixture)

trans - racemic mixture

22.0 mg (0.306 mmol) of propan-2-one oxime were mixed with 2 mL anhydrous THF and 0.471 mL (1.22 mmol) n-butyllithium (2.6 mol/L in toluène) was added carefully to the mixture. The reaction mixture was stirred at room température for 30 min. 0.110 g (0.278 mmol) of Example 8B in 1 mL anhydrous THF were carefully added during 10 min. After 30 min the reaction mixture was added to a mixture of 0.28 mL H2SO4 and 4 mL THF/water (4:1). The mixture was refluxed for 1.5h. Saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethylacetate. The organic layer was dried and the solvents were evaporated. The residue was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 8 mg(8 %) of the product were obtained.

HPLC-MS (Method 1): R_t = 1.40 min

MS (ESI pos): m/z = 390 (M+H)⁺

Examnle 2 (trans - racemic mixture) x

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0.190 g of Example 6A were mixed with 3 mL DME and 0.273 g (1.14 mmol) Burgess reagent. The reaction mixture was heated to 130°C for 1 h in a microwave oven. The solvent was evaporated and the residue purifîed by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 70 mg (55 %) of the product were obtained.

HPLC-MS (Method 1): R_t = 1.11 min

MS (ESI pos): m/z = 370 (M+H)⁺

The following examples were synthesized in analogy to the préparation of Example 2, using the corresponding amides as starting materials.

Example	structure	starting material	R, [min]	MS (ESI pos, m/z)
Exp. 3 transracemic mixture	A X-, AÇQ Q	Exp. 7A	1.17 (Method 3)	342 (M+H)⁺

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Exp. 4 trans racemic mixture	î ^N=v Xj3	Exp. 4A	1.20 (Method 1 )	391 (M+H)⁺
Exp. 5 transracemic mixture	î'c- v /	Exp. 8A	1.38 (method 1)	404 (M+H)⁺
Exp. 6 transracemic mixture	XJ> F	Exp. 9A	1.37 (method 1)	390 (M+H)⁺
Exp. 7 trans racemic mixture		Exp. 9B	1.42 (method 3)	390 (M+H)⁺

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Example 9 (trans - racemic mixture)

trans - racemic mixture

To a solution of Example 5A, synthesized starting from 0.426 mmol of Example 3A as described above, was added dropwise 0.062 g (0.832 mmol) thioacetamide in 2 mL EtOH. The reaction mixture was stirred ovemight. The mixture was purified by préparative HPLC (eluent A: water + O.l3 % TFA, eluent B: MeOH). 62 mg of the title compound were obtained.

HPLC-MS (Method 1): R_t = 1.37 min

MS (ESI pos): m/z = 406 (M+H)⁺

The following examples were synthesized in analogy to the préparation of Example 9, using the corresponding starting materials.

Example

structure

starting material: nucleophile

starting material: chloroketon

R, [min]

MS (ESI pos,

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			m/z)
Exp. 10 trans racemic mixture	IjO¹h ^N A	thioacetamide	Exp. 5B	1.21 (Method 3)	372 (M+H)⁺
Exp. 11 trans racemic mixture	Ά, x	1,1-dîmethylthiourea	Exp. 5A	1.15 (Method 3)	435 (M+H)⁺
Exp. 12 trans racemic mixture	^H\| JPN V À	thiourea	Exp. 5A	1.15 (Method 3)	407 (M+H)⁺

Example 13 (trans - racemic mixture)

Z

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ÎOO mg (0.215 mmol) of Example 12A were mixed with 1.00 mL(6.07 mmol) 1,1,3,3tetramethoxypropane. The reaction mixture was heated to 175°C for Ih using a microwave oven. The reaction mixture was treated with DCM/MeOH and one drop of triethylamine. The solvents were removed under reduced pressure. The mixture was purified by préparative

HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH) yielding 45 mg (54 %) of the title compound.

HPLC-MS (Method 3): R_t = 1-36 min

MS (ESI pos): m/z = 387 (M+H)⁺

The enantiomers of the title compound were separated by HPLC using a chiral stationary phase.

Method for enantioseparation:

HPLC apparatus type: Berger Minigram; column: Daicel IC, 5.0 pm, 250 mm x 10 mm; method: eluent CO? / 30 % MeOH / 0.2 % DEA (isocratic); flow rate: 10 mL/min, Température: 40°C; pressure: 100 bar; UV Détection: 210 nm

Example	structure	R, [min]
Exp. 14 trans enantiomer 1	t h	3.15 (Method 4)

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The following example was synthesized in analogy to the préparation of Example 13, using the corresponding dialdehydediacetal as starting material.

Example	structure	starting material	R_t [min]	MS (ESI pos, m/z)
Exp. 16 trans racemic mixture	^h£jCⁿ M	1,1,3,3tetraethoxy-2methylpropane	1.42 (Method 3)	401 (M+H)⁺

Example 17 (trans - racemic mixture)

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176 mg (0.431 mmol) of Example 4A were mixed with 3 mL THF and 122 mg (0.302 mmol) Lawesson’s reagent at room température. Then the mixture was stirred for 6h at 60°C. The reaction mixture was treated with water and diluted with DCM. The mixture was filtered over basic alumia and eluted with DCM und EtOH. The solvents were removed under reduced pressure. The residue was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 45 mg (26 %) of the product were obtaîned.

HPLC-MS (Method 3): R_t = 1.37 min

MS (ESI pos): m/z = 407 (M+H)⁺

The enantiomers of the tîtle compound were seperated by HPLC using a chiral stationary phase.

Method for enantioseparation:

HPLC apparatus type: Berger Minigram; column: Daicel ADH, 5.0 pm, 250 mm x 10 mm; method: eluent CO2 / 30 % MeOH / 0.2 % DEA (isocratic); flow rate: 10 mL/min,

Température: 40°C; pressure: 100 bar; UV Détection: 210 nm

Example	structure	R, [min]
Exp. 18 trans enantiomer 1 (S,S)	Q	2.47 (Method 5)

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2.96 (Method

5)

Single crystals of example 19 hâve been prepared by recrystallisation from ethylacetate and subjected to X-ray crystal analysis. The data allowed to détermine the absolute configuration of example 19 to be (R,R).

Experimental: Data collection and réduction: Data collected on Satum 944 CCD mounted on AFC11K goniometer, Radiation: Cu Ka from RU200 rotating anode and RIGAKU

VARIMAX optics, Température: 100K.

Suinmary of data collection statistîcs

Spacegroup Unit cell dimensions	P2₍ 8.560(2) 6.844(1) 15.603(3) 90.00 98.82(3) 90.00
Resolution range Total number of reflections	15.42-0.85 (0.88-0.85) 10857
Number of unique reflections	1588
Average redundancy % completeness	6.84 (2.46) 95.7 (79.1)
Rmerge Output <l/sigl>	0.064 (0.118) 27.7 (7.9)

Values in () are for the last résolution shell.

Refinement statîstics:

Final Structure Factor Calculation for example 19 in P2|

Total number of l.s. parameters = 255

GooF = S = 1.154

Weight = 1 / [ sigma^A2(Fo^A2) + ( 0.0421 * P )^Λ2 + 0.38 * P] where P = ( Max ( Fo^A2, 0 ) + 2 * Fc^A2 ) / 3

RI = 0.0695 for 2207 Fo > 4sig(Fo)and 0.0829 for ail 2334 data, wR2 = 0.1646,

Flack x parameter = 0.09(3). χ

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Example 20 (trans - racemic mixture)

0.060 g of Example 10A were mixed with 4 mL anhydrous dioxane and 0.074 g (0.180 mmol) Lawesson’s reagent. The reaction mixture was heated to 12O°C for lh in a microwave oven. The mixture was filtered over basic alumina and eluted with DCM and MeOH. The solvents were removed under reduced pressure. The residue was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH). 22 mg of the product were obtained as sait with TFA.

HPLC-MS.· (Method l): R_t = 0.94 min

MS (ESI pos): m/z = 393 (M+H)⁺

Example 21 (trans - racemic mixture)

trans - racemic mixture

0.190 g (0.519 mmol) Example 8E were mixed with 1.38 mL (8.31 mmol) triethoxymethane.

The mixture was stirred for 1.5h at 150°C. The reaction mixture was allowed to cool to room

-93 16302 température and purified by préparative HPLC (eluent A: water +0.13 % TFA, eluent B: MeOH). 90 mg (46 %) of the product were obtained.

HPLC-MS (Method 1 ): R_t = 1.19 min

MS (ESI pos): m/z = 377 (M+H)⁺

Example 22 (trans - racemic mixture) trans - racemic mixture mg (0.10 mmol) CuCl₂, 26 mL (0.22 mmol) tert-butyl-nitrite were mixed with ACN. A mixture of 22 mg (0.05 mmol) Example 12 in ACN was carefully added at 0°C. The mixture was stirred for lh at 25°C. Additional 9 mg (0.07 mmol) CuCl₂ and 13 mL (0.11 mmol) tertbutyl-nitrite was added and stirred another 20 min. The solvents were removed under reduced pressure. The residue was taken up in DCM and extracted with HCl and water. The mixture was purified by préparative HPLC (eluent A: water + 0.13 % TFA, eluent B: MeOH) yieldîng2.1 mg (9 %) of the product..

HPLC-MS: (Method 3): R_t = 1.46 min

MS (ESI pos): m/z = 426/428 (Cl) (M+H)⁺

Example 23 (trans - racemic mixture)

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trans - racemic mixture

180 mg (0.26 mmol, content 50%, estimated by HPLC-MS) of Example 12b were mixed with 1.00 mL (6.07 mmol) 1,1,3,3-tetramethoxypropane. The reaction mixture was heated to 175°C for lh using a microwave oven. The reaction mixture was treated with DCM, washed with water. Organic layers were dried over sodiumsulphate and evaporated under reduced pressure. The crude was purified by flash cromatography (Cy/EtOAc from 80/20 to AcOEt/MeOH 96/4) and then with a second flash cromatography (DCM 100% to DCM/EtOH 96/4) to obtain the title compound as beige solid. (0.034g).

HPLC-MS (Method lEh): R_t = 6.57 min

MS (APC1 pos): m/z = 353 (M+H)⁺

The enantiomers of the title compound were seperated by HPLC using a chiral stationary phase.

Method for enantioseparation:

Semipreparative conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chiralcel OJ-H, 250 mm x 20 mm, 5.0 pm; eluent: hexane/EtOH80:20; flow rate: 15 mL/min, Température: 25°C; UV Détection: 254 nm

Example

structure

R_t [min]

-9516302

Exp. 24 trans enantiomer 1	V ô o X	15.604 (Method 6)
Exp. 25 trans enantiomer 2	V ô	20.119 (Method 6)

Analytical conditions

HP LC apparatus type: Agilent 1100; Method 6; column: Daicel chiralcel OJ-H, 250 mm x 4.6 mm, 5.0 pm; eluent: hexane/EtOH80:20; flow rate: 1 mL/min, Température: 25°C; UV

Détection: 254 nm

trans - racemic mixture

-9616302

140 mg (content 84%, 0.33 mmol) of Example 12C were mixed with 1.4 mL of 1,1,3,3tetramethoxypropane and L4mL of NMP. The reaction mixture was heated to 175°C for lh using a microwave oven. The reaction mixture was then diluted with MeOH and loaded on SCX cartridge. Ammonia fractions were collected and the residue was purifîed by flash 5 cromatography (Cy/EtOAc from 90/10 to 100%) to obtain the title compound as white solid (30mg).

HPLC-MS (Method lEh): R_t = 6.72 min

MS (APClpos): m/z = 370 (M+H)⁺

The enantiomers of the title compound were seperated by HPLC using a chiral stationary 10 phase.

Method for enantioseparation:

Semipreprative conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chîralcel OJ-H, 250 mm x mm, 5.0 pm; eluent: hexane/EtOH80;20; flow rate: 15 mL/min, Température: 25°C; UV

Détection: 230 nm

Example	structure	R_t [min]
Exp. 27	b b	17.748
trans enantiomer 1	(Method 6)

-9716302

Anal yti cal conditions

HPLC apparatus type: Agilent 1100; Method 6; column: Daicel chiralcel OJ-H, 250 mm x 4.6 mm, 5.0 pm; eluent: hexane/EtOH80:20; flow rate: 1 mL/min, Température: 25°C; UV

Détection: 254 nm

trans - racemic mixture

To a suspension of 0.132 g (0.63mmol) of 5-amino-l-(tetrahydro-pyran-4-yl)-l-H-pyrazole10 4-carboxylic acid amide (see PCT patent application WO2010/026214) in dry EtOH (1.5mL),

0.066 g (1-66 mmol) of sodium hydride (60 % suspension in minerai oil) were added at room température under nitrogen. After 10min, 0.181mg(0.945mmol) of Example 13A were added and the reaction mixture was heated to 140°C for 40 min in a microwave oven (Power 100W). The reaction mixture was then diluted with DCM, water was added, organics 15 separated and dried over sodiumsulphate. Organics were evaporated under reduced pressure

-98 16302 and the crude purified by flash cromatography (DCM/IPA 98:2) to obtain the title compound as a white solid. (54mg, 32%).

HPLC-MS (Method 1 Eh): R_t = 8.01 min

MS (APCI pos): m/z = 352 (M+H)⁺

Method for enantioseparation:

Semipreprative conditions:

HPLC semipreparative System: Waters 600 pump; column: Daicel chiralcel OJ-H, 250 mm x 10 20 mm, 5.0 pm; eluent: hexane/EtOH85:15; flow rate: 15 mL/min, Température: 25°C; UV

Détection: 254 nm

Example	structure	Rt [min]
Exp. 30	J	I	%	14.754
		N^Z
trans enantiomer	Γι ^N		X	(Method
1	O	1	Q	6.1)
Exp. 31	J-	I	%	16.834

trans enantiomer	Γι ⁿ	(	V	(Method
2		1	A?	6.1)
	\=/

Analytical conditions z

-9916302

HPLC apparatus type: Agilent 1100; Method 6.1; column: Daicel chîralcel OJ-H, 250 mm x

4.6 mm, 5.0 pm; eluent: hexane/EtOH85:15; flow rate: 1 mL/min, Température: 25°C; UV Détection: 254 nm

Example 32 (trans - racemic mixture)

F trans - racemic mixture

To a suspension of 0.135 g (0.553 mmol) of 5-amino-l-(4,4-dîfluoro-cyclohexyl)-l-Hpyrazole-4-carboxylic acid amide (see PCT patent application W02010/026214) in dry EtOH (1.5mL), 0.066 g (1.66 mmol) of sodium hydride (60 % suspension in minerai oil) were added at room température under nitrogen. After 10min, O.lôlmg (0.837mmol) of Example 13A were added and the reaction mixture was heated to 140°C for 40 min in a microwave oven (Power 100W). The reaction mixture was then diiuted with DCM, water was added, organics separated and dried over sodium sulphate. Organics were evaporated under reduced pressure and the crude purified by flash cromatography (Cy/EA from 50:50 to 10:90) to obtain the title compound as a white solid. (54mg, 25%).

HPLC-MS (Method lEh): R, = 9.63 min

MS (APCI pos): m/z = 386 (M+H)⁺

Method for enantioseparation:

-10016302

Semipreprative conditions:

HPLC semipreparative System: Waters 600 pump; Column: Daicel chiralpak AD-H, 250 mm x 20 mm, 5.0 pm; eluent: hexane/Isopropanol 80:20; flow rate: 10 mL/min, Température: 25°C; UV Détection: 260 nm

Example	structure	R_t [min]
Exp. 33	ïS			14.80
	Av
trans -	il ^N	A
		/—		(Method
enantiomer			\
1		7	t	7)
		F
Exp. 34				20.40
	AO
trans -	n
	—/	/—		(Method
enantiomer		(	\
2		7	ζ	7)
	\=/	F

Analytical conditions

HPLC apparatus type: Agilent 1100; Method 7; column: Daicel chiralcel AD-H, 250 mm x

4.6 mm, 5.0 pm; eluent: hexane/Isopropanol 80:20; flow rate: 1 mL/min, Température: 25°C;

UV Détection: 260 nm. /

Claims

Claims

l. A compound of formula (I) wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4, preferably 1, 2 or 3 of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, whereby said 5 or 6 membered aromatic heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, HO-, NC-, F₃C-, HF;C-, FIfC- methyl, IFN- and (CH₃)2N-;

R : is selected from the group consisting of fluorine, NC-, F₃C-, HF2C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another fforn the group consisting of fluorine, NC-, F₃C-, HF2C- and FH2C-;

whereby tetrahydrofuranyl and tetrahydronvranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, NC-, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH2C-, F₃C-CH₂-, Ci.

6-alkyl- and C₃_7-cycloalkyl, m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R are selected independently of one another;

- 10216302 and salts, preferably pharmaceutically acceptable salts thereof;

with the proviso that the compound is not mixture of ail or some thereof.

be it in the form of any possible stereoisomer or a
2. A compound according to claim 1, wherein

R¹: is a 5 or 6 membered heteroaryl-group whereby 1, 2, 3 or 4 preferably 1, 2 or 3 of the ring atoms are heteroatoms that are selected independently of each other from N, O or S, whereby said 5 or 6 membered aromatic heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, methyl, H₂N- and (CH₃)₂N-;

R²: is selected from the group consisting of fluorine, NC-, F₃C-, HF₂C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C- ;

- 103 16302 whereby pyridyl optionally may be substituted by l, 2, 3 or 4 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- F3C-CH2-, Ci_

6-alkyl- and Cv.-cycloalkyl.

m: îs selected from l or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n îs 0, whereby if n 2. these two groups R are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof;

with the proviso that the compound is not mixture of ail or some thereof be it in the form of any possible stereoisomer or a
3. A compound according to claim 2, wherein

R': îs a heteroaryl-group selected from the group consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl, whereby said heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- methyl, H₂N- and (CH₃)₂N-.
4. A compound according to claim 1, wherein /

- 10416302

R¹: is a heteroaryl-group selected from the group consîsting of thiadiazolyl, 1,2,3oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidînyl, preferably said group consîsting of thiadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl, whereby said heteroaryl-group optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C-, methyl, H₂N- and (CH₃)₂N-;

R²: is selected from the group consîsting of fluorine, NC-, F₃C-, HF₂C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl;

D: is selected from the group consîsting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, F₃C-, HF₂C- and FH₂C-;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4, preferably 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consîsting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂CF₃C-CH₂-, C_{t 6}-alkyl- and C₃.₇-cycloalkyl.

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R² are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof.
5. A compound according to any of ciaims 1 to 4, whereby R¹ is no oxadiazolyl, neither unsubstituted nor substituted.
6. A compound according to claim 4, wherein /

- 10516302

R^l: is a heteroaryl-group selected from the group consisting of [l,3.4]thiadiazol-2-yl, isoxazol-5-yl, thiazol-5-yl-, oxazol-2-yl, pyridin-2-yl and pyrimidin-2-yl, whereby said heteroaryl-group optionally may be substituted by l or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, CN-, methyl and H₂N-;

R²: is selected from the group consisting of fluorine, NC-, F₃C-, HF₂C-, FH₂C- and methyl, preferably fluorine, NC-, F₃C- and methyl;

D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, thereof preferably tetrahydrofuran-3yl, tetrahydropyranyl, thereof preferably tetrahydropyran4yl, 2-, 3- and 4-pyridyI, whereby cyclopentyl and cyclohexyl optionally may be substituted by l or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C-; preferably fluorine;

whereby tetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by 1 or 2 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, F₃C-, HF₂C- and FH₂C- ;

whereby pyridyl optionally may be substituted by 1, 2, 3 or 4 substituents, whereby said substituents may be selected independently of one another from the group consisting of fluorine, chlorine, bromine, NC-, F₃C-, HF₂C-, FH₂C- F₃C-CH₂- and methyl;

whereby preferably D is selected from the group of 4,4-dîfluorocyclohex-l-yl, tetrahydropyranyl, preferably tetrahydropyran-4-yl, and 4-methy-3-pyridyl;

m: is selected from 1 or 2, preferably m is 1 ;

n: is selected from 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0, whereby if n = 2, these two groups R are selected independently of one another;

and salts, preferably pharmaceutically acceptable salts thereof.
7. A compound according to claim 1, characterised in that it is a compound according to formula (II)

- 10616302 (il), wherein

R¹ : is as defined in any of claims 1, 2, 3,4, 5 or 6;

5 D: is selected from the group consisting of 4,4-difluorocyclohexyl, tetrahydropyran-4-yl and

4-methy-3-pyridyl whereby neither 4,4-difluorocyclohexyl nor tetrahydropyran-4-yl has additional substituents;

and salts, preferably pharmaceutically acceptable salts thereof.
8. A compound according to claim 7, wherein the compound is selected from the group

- 10716302

- 108 16302

- 10916302

-no16302

- Ill 16302

- U216302

- 11316302

- Il416302

- 115 16302

-11616302

- 117 16302

- us16302

-11916302 and salts, preferably pharmaceutically acceptable salts thereof.

- 120 16302
9. A compound according to any one of claims l-6, whereby the compound îs selected from the group of a compound according to formula (la), formula (Ib), formula (le) and formula (Id) (la), (le), (Id), with R¹, R², D, n and m as defined or presented in any of claims l to 6

5 and salts, preferably pharmaceutically acceptable salts thereof.
10. A compound according to any one of claims 7 and 8, whereby the compound is selected from the group of a compound according to formula (Ha), formula (Ilb), formula (lie) and formula (Ild) (Ha), (Hb), (Ile), (Ild), with R¹ and D as defined in any of claims 7 to 8 /

- 121 16302 and salts, preferably pharmaceutically acceptable salts thereof.
11. A compound according to any one of daims 1 to 10 for use as a médicament or for the use as pharmaceutically active ingrédient in a médicament, preferably a médicament for use in a therapeutic or prophylactic method, preferably in a therapeutic method.
12. A compound according to any one of daims 1 to 10 for use in a therapeutic or prophylactic, preferably a therapeutic method (a) for the treatment of a CNS disease, more preferably a CNS disease, the treatment of which is accessible by the inhibition of PDE9, (b) for the treatment of a disease that is accessible by the inhibition of PDE9, (c) for the treatment of or for the amelioration of or for the prévention of, preferably for the treatment of a condition being selected from the group consisting of cognitive impairment being related to a disease or condition selected from the group of perception, concentration, cognition, leaming or memory, whereby preferably the treatment, amelioration or prévention of cognitive impairment is related to ageassociated leaming and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic dementia, general concentration impairments, concentration impairments in children with leaming and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pîck's syndrome, Parkinson’s disease, progressive nuclear palsy, dementia with cortîcobasal degeneration, amyotropic latéral sclerosis (ALS), Huntîngton's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, epîlepsy, temporal lobe epilepsy, schizophrenia, schîzophrenia (with dementia), Korsakoff s psychosis or cognitive impairment associated with dépréssion or bîpolar disorder, (d) for the treatment of Alzheimer’s disease or cognitive impairment associated with Alzheimer’s disease, _x

- 12216302 (e) for the treatment of schizophrenia or cognitive impairment associated with schizophrenia, (f) for the treatment of epilepsy or cognitive impairment associated with epilepsy, (g) for the treatment of a disease or condition being selected from the group consisting of sleep disorders, bipolar disorder, metabolic syndrome, obesity, diabètes mellitus, hyperglycemia, dyslipidemia, impaired glucose tolérance, or a disease of the testes, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.
13. A compound according to any one of claims 1 to 10 for use în a method for the treatment or prophylaxis of cognitive impairment, préférable cognitive impairment related to perception, concentration, leaming or memory.
14. A compound according to any one of claims 1 to 10 for use in a method for the treatment or prophylaxis of cognitive impairment, préférable cognitive impairment related to perception, concentration, leaming or memory, as symptoms of anther base laying disease.
15. A compound according to any one of claims 1 to 10 for use in a method for the improvement of cognitive skills related to perception, concentration, leaming or memory.
16. Pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutical carrier.
17. Use of a compound according to any one of claims 1 to 10 for the manufacture of a médicament for the treatment of a disease or condition as defined în any of claims 12 to 15.
18. Combination of a compound according to any one of claims 1 to 10 with another active agent, whereby /

- 123 16302

- said combination preferably îs useful for the treatment of a disease or condition as defined in any of claims 12 to 15 or

- said combination preferably being for the use in a therapeutic or prophylactic method, preferably a therapeutic method, for the treatment of a condition or disease as defined in any

5 of claims 12 to 15 or

- said combination being for the manufacture of a médicament which preferably is for the treatment of a condition or disease as defined in any of claims 12 to 15. —