1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one derivatives and their use as pde9a modulators

The present invention relates to novel 1,6-disubstituted pyrazolopyrimidinones of formula (I),

Abstract

<img file="MA33152B1_D0001.tif" />

wherein Hc is a tetrahydropyranyl group and R * is the group vw- *, where V and w independently of one another may be an aryl group or a heteroaryl group, which independently of one another may be optionally substituted.

According to one aspect of the invention, the new compounds are used as medicaments or for the manufacture of medicaments, in particular medicaments intended for the treatment of pathologies relating to deficits in perception, concentration, learning or speech. Memory. The novel compounds are also intended for the manufacture of medicaments and / or for use in the treatment of Alzheimer's disease, for example, in particular of cognitive impairment linked to Alzheimer's disease.

186

ة

ΜΑ 33152Β1

NEW COMPOUNDS FOR THE TREATMENT OF CNS DISORDERS

The present invention relates to novel pyrazolopyrimidinones

1,6-disubstituees of formula (I),

2012 ٤١٠

مأ ٦ بلج

بربلآ

RR 'ئ (I) in which Hc is a tetrahydropyranyl group and R ^ is the group vw- *, where V and W independently of one another may be an aryl group or a heteroaryl group, which independently one on the other can be optionally substituted.

According to one aspect of the invention, the new compounds are used as medicaments or for the manufacture of medicaments, in particular medicaments intended for the treatment of pathologies relating to deficits in perception, concentration, learning or speech. Memory. Such pathologies can for example be associated with Alzheimer's disease. The new compounds are also used, for example, for the manufacture of medicaments and / or for use, for example, in the treatment of Alzheimer's disease, in particular of cognitive impairment associated with Alzheimer's disease. The compounds of the invention are inhibitors of PDE9.

Background of the invention

The inhibition of phosphodiesterase 9Α (PDE9A) is one of the current concepts to find new ways of access to the treatment of cognitive impairment due to CNS disorders, such as Alzheimer's disease or any other neurodegenerative process of the brain. By means of the present invention, new compounds which follow this concept are presented.

Phosphodiesterase 9Α is a member of the large family of phosphodiesterases. These enzymes modulate the levels of cyclic nucleotides, cyclic aden٠sine-3 ', 5'-monophosphate (cAMP) and cyclic guanosine3', 5'-monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP) are essential secondary messengers and therefore play a central role in cellular signal transduction cascades. Each of them reactivates among others, 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 in turn capable of phosphorylating a number of cellular effector proteins (eg ion channels, G protein coupled receptors, structural proteins, transcription factors). In this way, the secondary messengers, cAMP and cGMP, are able to control a wide variety of physiological processes in a large number of organs. However, cyclic nucleotides are also able to act directly on effector molecules. It is known, for example, that cGMP is capable of acting directly on the ion channels and therefore of influencing the cellular ionic concentration (described in: Wei et al., Prog. Neurobiol., 1998, 56, 37-54) . Phosphodiesterases (PDE) are a mechanism controlling the activity of cAMP and cGMP and therefore in turn the corresponding physiological processes. PDEs hydrolyze cyclic monophosphates to inactive AMP and GMP monophosphates. To date, 11 PDE families have been defined according to the homology of

ΜΑ 33152Β1 sequence of corresponding genes. Individual PDE genes of the same family are differentiated by letters (eg PDEIA and PDEIB). If splice variants also occur in the same gene, these can then be indicated by an additional number after the letters (for example PDEIAI).

Human PDE9 was cloned and sequenced in 1998. The identity of amino acids with other PDEs does not exceed 34% (PDE8A) and is never less than 28% (PDE5A). With a Michaelis-Menten (Km) constant of 170 nanomoles (nM), PDE9A has a strong affinity for cGMP. Furthermore, PDE9A is selective for cGMP (Km for cAMP = 230 micromoles (μΜ)). PDE9A lacks a cGMP binding domain, suggesting that the enzyme activity is not regulated by cGMP. It has been shown in a Western blot analysis that PDE9A is expressed in the human body, inter alia in the testes, brain, small intestine, skeletal muscle, heart, lungs, thymus and spleen. . The highest expression was observed in the brain, small intestine, kidneys, prostate, colon and spleen (Fisher et al., 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 consists of 21 exons. 4 alternative splicing variants of PDE9A have been identified (Guipponi et al., Hum. Genet., 1998, 103,

386-392). Classical PDE inhibitors do not inhibit human PDE9A. Therefore, 1ΊΒΜΧ, dipyridamole, SKF94120, rolipram and vinpocetine do not show inhibition on the isolated enzyme at concentrations up to 100 micromoles (μΜ). An IC of 35 micromoles (μΜ) has been demonstrated for zaprinast (Fisher et al., J. Biol. Chem., 1998, 273 (25), 15559-15564).

Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (، 7. Biol. Chem., 1998, 273 (19), 15553-15558). This has, like the human form, a strong affinity for cGMP with a Km of 70 nanometers (nM). In particular, elevated expression is observed in the kidneys, brain, lungs and liver of mice. Murine PDE9A is also not inhibited by 1ΊΒΜΧ at concentrations below 200 micromoles; the IC for zaprinast is 29 micromoles (Soderling et al., J. Biol.

Chem., 1998, 273 (19), 15553-15558). It has been observed that PDE9A is highly expressed in certain regions of the brain of rats. These regions include the olfactory bulb, the hippocampus, the cortex, the basal ganglia and the basal forebrain (Andreeva et al., A. Neurosci., 2001, 21 (22), 9068-9076). In particular, the hippocampus, cortex, and basal anterior brain play an important role in learning and memory processes. As already mentioned above, PDE9A is distinguished by a particularly high affinity with cGMP. PDE9A is therefore active even at low physiological concentrations, unlike PDE2A (Krn10 micromoles (μΜ); Martins et al., J.

Biol. Chem., 1982, 25 7, 1973-1979), PDE5A (Km = 4 micromoles (μΜ);

Francis et al., J. Biol. Chem., 1980, 255, 620-626), PDE6A (Km = 17 micromoles; Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17), 81338141) and PDEllA (Km = 0.52 micromoles ; Fawcett et al., Proc. Nat. Acad. Sci., 2000, 97 (7), 3702-3707). Unlike PDE2A (Murashima et al., Biochemistry, 1990, 29, 5285-5292), the catalytic activity of PDE9A is not increased by cGMP because there is no GAF domain (binding domain to cGMP through which PDE activity is allosterically increased) (Beavo et al., Current Opinion in Cell Biology, 2000, 12, 174-179). PDE9A inhibitors can therefore cause an increase in the initial concentration of cGII.

This profile demonstrates that PDE9A is engaged in specific physiological processes in a characteristic and unique way, which differentiates the characteristic role of PDE9A from any other member of the PDE family.

W004099210 describes 6-ary! Methylsubstituted pyrazolopyrimidinones which are inhibitors of PDE9. Compounds do not

ΜΑ 33152Β1 do not contain a non-aromatic heterocyclic moiety at position 1 of pyrazolopyrimidine.

WO004096811 describes heterocyclic bicycles as PDE9 inhibitors for the treatment of diabetes, including type 1 and type 2 diabetes, hyperglycemia, dyslipidemia, glucose intolerance, syndrome. metabolism and / or cardiovascular disease.

Another art technique relates to chemically similar nucleoside derivatives. As examples, we can mention the document

WO002057425, which describes nucleoside derivatives, which are inhibitors of RNA-dependent viral polymerase, or document WO001060315, which describes nucleoside derivatives for the treatment of infection with hepatitis c virus, or document ΕΡ679657 , which describes compounds which serve as ribonucleoside analogs, or US 2002058635, which describes purine L-nucleoside compounds, in which the purine rings and sugar are modified, functionalized and / or both. Accordingly, the sugar must for example comprise at least one esterified OH group.

Document WO06084281 describes inhibitors of the E1 activating enzyme which have a sulfonamide moiety.

WO05051944 describes nucleosides containing an oxetane group for the treatment of disorders related to a nucleoside analogue, such as disorders involving cell proliferation and infection.

Document WO9840384 describes pyrazolopyrimidinones which are inhibitors of PDE1, 2 and 5 and can be used for the treatment of cardiovascular and stroke disorders and of disorders of the urogenital system.

The documents CH396 924, CH396 925, CH396 926, CH396 927, DEH47234, DE1149O13, describe pyrazolopyrimidines which have a coronary dilation effect and which can be used for the treatment of disturbances in myocardial blood flow.

Document US 3732225 describes pyrazolopyrimidines which have an anti-inflammatory and blood sugar lowering effect.

DE24O89O6 describes styrylpyrazolopyrimidinones which can be used as antimicrobial and anti-inflammatory agents for the treatment of edema, for example.

Objective that the invention

Modifications of the substitution pattern of pyrazolopyrimidinones lead to interesting modifications concerning the biological activity, respectively modifications at the level of the affinity towards different target enzymes.

Therefore, an object of the present invention is to provide compounds such as those described herein, in particular in the claims, which effectively modulate ΡΟΕ9Α for the purpose of developing a medicament, in particular for diseases or conditions in which treatment is accessible by modulating PDE9A.

Another object of the present invention is to provide compounds which are useful for the manufacture of a medicament for the treatment of CNS disorders.

Yet another object of the present invention is to provide compounds which exhibit a favorable safety profile.

Another object of the invention is to provide compounds which have a favorable selectivity profile for the inhibition of PDE9A over other members of the PDE family and other pharmacological targets, providing this for therapeutic benefit.

Yet another object is to provide such a medicament which can be used not only for the treatment, but also for the prevention or modification of the disease or the corresponding pathology.

بل

٦٩52Β٩ &lt;؟ 1

The present invention further relates to a pharmaceutical composition comprising a compound as described herein, in particular in the claims, and a pharmaceutically acceptable excipient.

The present invention further relates to a method of treating any of the conditions described herein in a mammal in need of such treatment, preferably in a human, comprising administering by the mammal a therapeutic amount. effective of a compound as described herein, in particular in the claims.

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

Detailed description of the present invention

The compounds of the present invention are characterized by the general formula (I):

<img file="MA33152B1_D0002.tif" />

with the following definitions (the substituents may be printed in bold for easier reading).

The Hc substituent is defined by the following H٠٤ definitions, where the index i describes the order of preference, ranging from Ho ascending to a preferred order (i.e. Hc²) , And so on. Hc *:

Hc is a tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, the groups NC-, F3C-, HFC , FHC-, FC CH-, C٢-alkyl₆, 0-6ء-اء- alkyl, and up to one carbon atom on the ring may be substituted with an oxo group.

H:

Ha is a tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, the groups NC-, F3C-, HFzC-, FHC-, F3C-CH2-, C-alkyl, C 1 -C 6 -alkyl, and up to one carbon atom on the ring may be substituted with an oxo group.

Hc³ :

Ha is an unsubstituted tetrahydropyranyl group.

It is obvious that whatever the type of tetrahydropyranyl group of Hc (unsubstituted or substituted), it will be linked to the backbone (optionally to nitrogen n '1, refer to the definition of "backbone" (= N1). ) by one of the carbon atoms on the ring of said tetrahydropyranyl group.

0 ة The substituent r! is defined by the following definitions R * d, respectively R * '}, where the index j describes the order of preference, going from rU in an ascending manner to more preferred definitions, such as rI'2, and so on. .

ΜΑ 33152Β1

Rl'1:

إلآ being the group vw- * in which

W is a phenyl group or a heteroaryl group;

V is a phenyl group or a heteroaryl group;

V is preferably attached to the position of w, position 1 of w being the point of attachment of w to the CR group²R³ in formula (I);

- * is the bond point by which w is attached to the CRR group in formula (I);

wherein w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, C 1-6 alkyl, HC- , FHC-, F3C-CH2-, F3C-0-, HC-O-, C3-C7 heterocyeloalkyl (preferably a C3C5 heterocyeloalkyl group), Η-Ο-C 1-8 alkyl, C 1-8 alkyl-O-alkyl CCg, C-cycloalkyl₃-VS₇-O-Cc alkyl₆, C3-C cycloalkyl C1-C3_٥-C1C alkyl, phenyl-o-cc-alkyl, benzyl-o-cc-alkyl, Η-Ο-, C1-C alk alkyl, C3-cycloalkyl -C1-O-, C3-Ccycloalkyl₇-alkyl C-C3-0-, phenyl0-, benzyl-o-, N-morpholinyl, and NC-, preferably by a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, the groups C 1 -C alkyl, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, C3-C1 heterocyeloalkyl (preferably C3-C5 heterocyeloalkyl), C1-C625 0- alkyl, C3 cycloalkyl -C6-O-, C3-C8-cycloalkyl-CH2-O-, aryl-CH-O- and NC-.

pl-2.

R * being the group

٧-W-٠ in which

W is a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the Cr2r2 group in formula (I);

- * is the bonding point by which w is attached to the CRR group in formula (I) in which w and V independently of each other may be optionally substituted by one or more substituents selected from a fluorine atom, a chlorine atom, a bromine atom, the alkyl groups in CCg, FjC-, HC-, FHC-, F3C-CH2-, F3C-0-, HC-O-, heterocyeloalkyl in C3-C7 (preferably a group heterocyeloalkyl (C3C5), Η-Ο-C-C6-alkyl, C1-C6-0-alkyl-C1-C8-alkyl, C3-C cycloalkyl₇-O-Cc alkyl, C 3 -C cycloalkyl₇-alkyl-cc-o-C1Ce-alkyl, phenyl-o-alkyl-C1-6, benzyl-o-alkyl-C1-6, Η-Ο-, alkyl-C1C₆50 0-, C3-C-O- cycloalkyl, C3-C cycloalkyl₇-alkyl C-C3-0-, phenyl0-, benzyl-O-, N-morpholinyl, and NC-, preferably by a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, the groups C1-C6 alkyl, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, heterocyeloalkyl C₃-vs₇ (preferably a C3-C5 heterocyeloalkyl group), C٢c alkyl₆55 0-, C3-C6-O- cycloalkyl, C3-C6-CH2-O- cycloalkyl, aryl-CH-Ο- and NC-.

r! '³ :

R¹ being the group

ΜΑ 33152Β1

VW- * in which

W is a heteroaryl phenyl group being selected from pyridazinyl.

or a heteroaryl group, the group pyridyl, pyrimidyl and / or a hetereroaryl group, the group oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the CR group²R³ in formula (I);

-٠ is the bond point by which w is attached to the CR group R

V is a heteroaryl phenyl group being selected from in formula (I) wherein w and V independently of one another may be optionally substituted with one or more substituents selected from a fluorine atom, a chlorine atom, a bromine atom, alkyl groups CC8, F3C-, HC-, FHC-, F3C-CH2-, F3C-0-, HF2C-0-, C3-C7 heterocycloalkyl (preferably a C3C5 heterocycloalkyl group), Η -Ο-C٢c alkyl₆, C-C8-O-C1-C6-alkyl, C3-C7-O-cycloalkyl-C1-C8-alkyl, C3-C7-cycloalkyl-C1-C3-0-alkyl-C1-C1-alkyl₆, phenyl-o-alkyl CfCg, benzyl-o-alkyl C alk, Η-Ο-, alkyl C1-C6-, cycloalkyl C3-C7-O-, cycloalkyl C3-C7-C1-C3alkyl “0-, phenyl0-, benzyl-o-, N-morpholinyl, and NC-, preferably with a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, alkyl groups Cc F3C-, F3C-CH2-, F3C-0-, HC-O-, C3-C7 heterocycloalkyl (preferably a C3-C5 heterocycloalkyl group), ٩-Cg0- alkyl, C3-C6-O- cycloalkyl, C1-cycloalkyl C3-CCH2-O-, aryl-CH-0- and NC-.

Ri'٠:

R being the group

VW- * in which

W is a phenyl group or a pyridinyl group,

V is a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the CR group²r3 in formula (I);

-٠ is the bond point by which w is attached to the CR group²r3 in formula (I) wherein w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, alkyl groups in Ci-Ce, F3C-, HC-, FH2C- F3C-CH2-, F3C-0-, HF2C-0-, C3-C7 heterocycloalkyl (preferably a C3C ؛ heterocycloalkyl group), Η-Ο-C1-alkyl -C6, C-Cg-O-alkyl, Cj-Cg-alkyl, C3-C7-cycloalkyl_O-C1-Cg-alkyl, C3-C7 cycloalkyl-C1C-O-C1C8-alkyl, C1-C8-phenyl-٠-a! C1-C8-benzyl-o-alkyl, Η-Ο-, C1-C6-alkyl, C1-C8-cycloalkyl C3-C7-O-, C3-C cycloalkyl, -C1-C3-Oalkyl, phenyl50O-, benzyl-O-, N-morpholinyl, and NC-, preferably with a substituent chosen from an atom of fluorine, a chlorine atom, a bromine atom, alkyl groups C-C8, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, heterocycloalkyl in C3-C7 (preferably a heterocycloalkyl group in C3-C5), C 1-8 alkyl, C3-CS-0- cycloalkyl, C3_C8 -CH2-O- cycloalkyl, aryl-CH-Ο- and NC-, wherein more preferably w and V independently of each other may be optionally substituted by one or more substituents chosen from a fluorine atom, a chlorine atom, the HC-, F3C-, CH3O-, N-morpholinyl, and NC- groups, more preferably chosen from a fluorine atom, the HC- groups, F3C-, CH3O- and NC-;

ΜΑ 33152Β1

R'5:

Rl being the group

VW- * in which

W is a phenyl group or a pyridyl group,

V is a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, trlazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position IdeW being the point of attachment of w to the group CIR in formula (I);

- * is the bond point by which w is attached to the CR R group in formula (I);

wherein w may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, HC-, F3C-, CHO- and NC- groups, preferably selected from atom fluorine, a chlorine atom and F3C-;

and wherein V can be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, HC-, tert-butyl, F3C-, CHO-, cyclobutyloxy, N-morpholinyl, benzyl-o groups - and NC-.

Rl '⁶ :

R * being the group

V — W— * in which

W is a phenyl group, w being optionally substituted with a fluorine atom, a chlorine atom or F3C-;

V is a heteroaryl group selected from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups, where

V is optionally substituted by 1 to 4, preferably 1 or 2, more preferably 1 substitute, independently of each other selected from fluorine atom, chlorine atom, HC-, tert-butyl, F3C-, CH3O -, cyclobutyloxy, N-morpholinyl, benzyl-o- and NC-,

V is attached to position 2 of w, position IdeW being the point of attachment of w to the Cr2r3 group in formula (I);

- * is the bond point by which w is attached to the CR R group in formula (I).

For each definition of r! (i.e. Ri'٤, Rl, Rl, r! '⁴, rI'5 r! '⁶) :

whenever V may be an oxadiazolyl group, the preferred isomer is 1,2,4-oxadiazol-3-yl;

whenever V may be a triazolyl group, the preferred isomer is 1,2,4-trizaol-1-yl;

whenever V may be a pyrazolyl group, it is preferably a pyrazol-1-yl or pyrazol-4-yl group;

٠ whenever V can be a furanyl group, it is preferably a fun-2-yl group;

whenever V may be a pyridyl group, preferably it may be a 2-, 3- or 4-pyridyl group, more preferably a pyridin-2-yl group;

٠ whenever V can be a pyrimidinyl group, preferably it can be a 5-pyrimidinyl group;

whenever V can be a pyridazinyl group, preferably it can be a 3-or 4-pyridazinyl group.

ΜΑ 33152Β1

R² :

R² is chosen from H-, a fluorine atom, the groups F3C-, HC-, FHC- and C1-C3- alkyl, preferably R² is H.

R³:

R٥ is chosen from H-, a fluorine atom, the groups F3C-, HC-, FHC- and C1-C3- alkyl, preferably R³ is H.

The isoforms, tautomers, stereoisomers, solvates, hydrates and / or possible addition salts of any compounds of the invention, in particular the physiologically acceptable salts thereof with inorganic or organic acids or bases, or combinations thereof are also included in the present invention.

The individual generic embodiments of the compounds of formula (I) are defined by the groups H, rU and R² and R² described above. Therefore, from the definitions given above, the embodiments of the preferred individual compounds of the invention are fully characterized by the terms (H Hi, R * '}) if R² and R² are as defined above and if for each letter i and j an individual figure is given. The indices can vary independently of each other.

The following table (Table 1) shows, gives examples and in order of preference from the first line to the last line of such embodiments Ε-1 to Ε-24 of the invention, which are considered preferred. This means that the embodiment Ε-24, represented by the characteristics of the last line of Table 1, is the preferred embodiment.

Table 1: Preferred generic embodiments Ε-1 to Ε-24 of the invention;

The compounds of the present invention are characterized by the general formula (I):

<img file="MA33152B1_D0003.tif" />

with

<td></td><td>Hc</td><td>r!</td><td>R²</td><td>^-R³</td>

<td>Ε-1</td><td>H</td><td>R¹'!</td><td>defined by the remark</td><td>defined by note 2&gt;</td>

<td>Ε-2</td><td>H</td><td>Rj '²</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-3</td><td>H</td><td>Rl</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-4</td><td>Hc</td><td>Rl, 4</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-5</td><td>Hcr</td><td>م</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-6</td><td>H</td><td>Rl'٥</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-7</td><td>Hcl</td><td>Rl٠٥</td><td>being H</td><td>being H</td>

<td>Ε-8</td><td>Hc</td><td>Ri '⁶</td><td>being H</td><td>being H</td>

<td>Ε-9</td><td>Hc²</td><td>rM</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-10</td><td>Hc²</td><td>r! '²</td><td>defined by the remark</td><td>defined by</td>

ΜΑ 33152Β1

<td></td><td></td><td></td><td> 1</td><td>Note ²</td>

<td>Ε-11</td><td>Hc²</td><td>Ri '³</td><td>defined by the remark ؛ 1</td><td>defined by note 2)</td>

<td>Ε-12</td><td>Hc²</td><td>م</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-13</td><td>Hc²</td><td>م</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-14</td><td>Hc²</td><td>م</td><td>defined by the remark 1)</td><td>defined by Note ²ا</td>

<td>Ε-15</td><td>Hc²</td><td>Rl'b</td><td>being H</td><td>being H</td>

<td>Ε-16</td><td>Hc²</td><td>Rl'6</td><td>being H</td><td>being H</td>

<td>Ε-17</td><td>Hc³</td><td>rI'1</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-18</td><td>H</td><td>r! '²</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-19</td><td>H</td><td>Ri '³</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-20</td><td>H</td><td>R³'م</td><td>defined by the remark 1)</td><td>defined by note 2)</td>

<td>Ε-21</td><td>Hc³</td><td>Rl, 5</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-22</td><td>Hc</td><td>٥ '؛ R</td><td>defined by the remark</td><td>defined by note 2)</td>

<td>Ε-23</td><td></td><td>Ri'5</td><td>being H</td><td>being H</td>

<td>Ε-24</td><td>Hc³</td><td>rI'6</td><td>being H</td><td>being H</td>

R² being chosen from H-, an FHC- atom and C1-C3 alkyl, preferably R²

R³ being chosen from H-, an atom

Notes:

ال the definition refers to fluorine, the groups F3C-, HC being H.

2) the definition refers to fluorine, the groups F3C-, HC-, FHC- and C1-C3 alkyl, preferably r3 being H.

In all of the embodiments of Table 1, it is preferable that R² and R³ each be H.

Where appropriate, the object of the invention also refers to the isoforms, tautomers, stereoisomers, solvates, hydrates and salts of any compounds of the invention, in particular the physiologically acceptable salts thereof with acids. or suitable inorganic or organic bases, or combinations thereof.

Such an embodiment of the invention relates to a compound corresponding to general formula (I)

<img file="MA33152B1_D0004.tif" />

(I)

-2.5 هي being a tetrahydropyranyl group, preferably a 4tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by two substituents independently selected from a fluorine atom, the NC groups -, F3C-, HC-, FHC-, F3C-CH2-, C 1-8 alkyl, C-Cg-O- alkyl, and

ΜΑ 33152Β1 until one carbon atom in the ring can be substituted by a group

٠x٠;

R being the group ح V — W— * in which

W is selected from a phenyl group or a heteroaryl group;

V is selected from a phenyl group or a heteroaryl group;

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the CR2r3 group in formula (I);

-٠ is the bond point by which w is attached to the CR2r3 group in formula (I);

wherein w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, C 1-8 alkyl groups, F₃C-, HC-, FHC-, F3C-CH2-, F3C-0-, HC-O-, C3-C7 heterocycloalkyl (preferably C3-C5 heterocycloalkyl), Η-Ο-alkyl-C-C-C-alkyl o-C 1 -C alkyl₆, C 3 -C cycl cycloalkyl -O-C 1 -C 8 -alkyl, C-C 7 -cycloalkyl-C-C 3 -C -alkyl-C 1 -C 6 -alkyl, pheny! -٥-C 1 -C -alkyl, benzyl-o-C 1 -alkyl C5, Η-Ο-, C1-C،-alkyl _ 0-, C3-C7-O- cycloalkyl, C3-C cycloalkyl, -C1-C3-O-alkyl, phenyl0-, benzyl-o-, N-morpholinyl, and NC-, preferably with a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, C٢c alkyl groups₆, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, heterocycloalkyl en

C3-C7 (preferably a C3-C5 heterocycloalkyl group), cc

0? C3-C-O- cycloalkyl, C3-C6-CH2-O- cycloalkyl, aryl-CHO- and NCR² being chosen from H-, a fluorine atom, the groups F3C-, HC-,

FHC- and C1-C3 alkyl, preferably R² being H;

r3 being chosen from H-, a fluorine atom, the groups F3C-, HC-,

FHC- and C1-C3 alkyl, preferably r3 being H;

and salts thereof, preferably the pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Ha being a tetrahydropyranyl group, preferably a 4tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted with one or - where appropriate - with one or two substituents independently selected from a fluorine atom, NC groups -, F3C-, HC-, FHC- F3C-CH2-, CC alkyl, C1-CO- alkyl, and up to one carbon atom on the ring may be substituted with an oxo group ؛ r! being the group

VW- * in which

W is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position IdeW being the point of attachment of w to the group CR ؛ r3 in formula (I);

wherein w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, groups

ΜΑ 33152Β1 C-Cg alkyl, F3C-, HF₂C-, FH₂C_, F3C-CH2-, F3C-0-, HF₂CO-, C3-C7 heterocycloalkyl (preferably C3-C8 heterocycloalkyl), Η-Ο-C-Cg-alkyl, C-C8-alkyl-O-C-C-alkyl, C-C-C-cycloalkyl, -O-alkyl C1-C6, C3-C7 cycloalkyl-C1-C3-0-alkyl-C1-C6-alkyl, phenyl-o-C1-C6-alkyl, benzyl-o-C1-C8-alkyl, Η-0-, C1-C6-alkyl C ؛ O-, C3-C7-O- cycloalkyl, C3-C7 cycloalkyl-C1-C3-O- alkyl, phenyl0-, benzyl-O-, N-morpholinyl, and NC-, preferably with a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, alkyl groups C1-C6, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, heterocycloalkyl in C3-C7 (preferably a heterocycloalkyl group in C3- C5), C-Cg0- alkyl, C3-C6-O- cycloalkyl, C3-C-CH-0- cycloalkyl, aryl-CH-0- and NCR² being chosen from H-, a fluorine atom, the groups F3C-, HC-, FHC- and C-C3 alkyl, preferably R² being H;

rS being chosen from H-, a fluorine atom, the groups F3C-, HC-, FHC- and C1-C3 alkyl, preferably rS being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Hc being a tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, NC-, F3C-, HF₂C_, FHC-, F3C-CH-, C 1-8 alkyl, C-C8 -alkyl, and up to one carbon atom on the ring may be substituted with an oxo group;

r! being the group

V — W— * in which

W is chosen from a phenyl group or a heteroaryy group, the heteroaryy group being chosen from pyridyl, pyrimidyl and pyridazinyl groups,

V is chosen from a phenyl group or a heteroaryy group, the heteroaryy group being chosen from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position IdeW being the point of attachment of w to group CR²r3 in formula (I);

wherein w and V independently of one another may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, C-C8 alkyl, F3C-, HC-, FHC-, F3C-CH-, F3C-0-, HF₂CO-, C3-C7 heterocycloalkyl (preferably C3-C8 heterocycloalkyl), Η-0-C-Cg-alkyl, C-C-C-O-alkyl-C-C-C, C-C-C-cycloalkyl-C-C-C-alkyl, C3_C7 cycloalkyl-C1-C3_٥-C1C8-alkyl, phenyl-o-C1-C8-alkyl, benzyl-o-C1-alkyl, Η-0-, Cf-Cg0- alkyl, C3-C7-O cycloalkyl -, C3-C7 cycloalkyl, C1-C3-O- alkyl, phenyl0-, benzyl-O-, N-morpholinyl, and NC-, preferably with a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, Cc alkyl groups₆, F3C-, F3C-CH₂-, F3C-0-, HF₂CO-, C3-C7 heterocycloalkyl (preferably C3-C5 heterocycloalkyl), C 1-10 alkyl? C3_C8-O- cycloalkyl, C3-Cg-CH cycloalkyl₂-O-, aryl-CH-0- and NCR² being chosen from H-, a fluorine atom F3C-, HFC-, FHC- and C-C3 alkyl, preferably R² being H;

r3 being chosen from H-, a fluorine atom, the groups F3C-, HF₂C_, FHC- and C-C3 alkyl, preferably r3 being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

د

٦١١52Β٩

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Hc being a, tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, NC-, F3C-, HC- , FHC-, F3C-CH2-, C1-C8-alkyl, C1-C8-alkyl, and up to one carbon atom on the ring may be substituted with an oxo group;

r! being the group

VW- * in which

W is chosen from a phenyl group or a pyridinyl group,

V is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the CR group²R³ in formula (I);

wherein w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, CfC؛ alkyl groups, F3C-, HC -, FHC-, F3C-CH2-, F3C-0-, HF2C-0-, C3-C7 heterocycloaikyie (preferably a C3C5 heterocycloaikyie group), Η-Ο-C-alkyl, C-C8-alkyl-O-alkyl C 1 -C 6 cycloalkyl, C 3 -C 6 -alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 -alkyl-C 1 -C 8 alkyl, phenyl-o-C 1-8 -alkyl, benzyl-o-C 1 -C 8 -alkyl, Η-0-, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 -alkyl, phenyl0- , benzyl-o-, N-morpholinyl, and NC-, preferably with a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, alkyl groups in CCg, F3C-, F3C-CH2-, F3C-0-, HF2C-0-, C3-C7 heterocycloalkyl (preferably a C3-C5 heterocycloalkyl group), CCG0- alkyl, C3-C6-O- cycloalkyl, C3-Cg-CH2_O- cycloalkyl, aryl-CH-0- and NC-, in which preferably w and V independently of each other may be optionally substituted by one or more substituents selected from fluorine atom, chlorine atom, HC- groups , F3C-, CHO-, N-morpholinyl, and NC-, preferably chosen from a fluorine atom, the groups HC-, F3C-, CH3O- and NC-;

R² being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C-C3 alkyl, preferably R² being H;

R³ being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C1-C3 alkyl, preferably R³ being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Ha being a tetrahydropyranyl group,

٥where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, NC-, F3C-, HF2C-, FHC-, F3C-CH2 -, C 1 -C 8 alkyl, C-C 6 -alkyl, and up to one carbon atom on the ring may be substituted by an oxo group;

R³ being the group

VW- * in which

W is selected from a phenyl group or a pyridyl group.

ΜΑ 33152Β1

V is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the CR group²r3 in formula (I);

wherein w can be optionally substituted by one or more substituents selected from a fluorine atom, a chlorine atom, a bromine atom, the HC-, F3C-, CHO- and NC- groups, preferably selected from an atom of fluorine, a chlorine atom and F3C-;

and wherein V may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, H3C-, tert-butyl, FC, HO-, cyclobutyloxy, N-morpholinyl, benzyl-o- and NC-;

R² being chosen from H-, a fluorine atom, FHC- and C1-C3 alkyl, preferably R² being H; r3 being chosen from H-, a fluorine atom,

FHC- and C1-C3 alkyl, preferably r3 being H;

and salts thereof, preferably the acceptable ones thereof.

groups F3C-, HFC, groups F3C-, HF2C-, pharmaceutically salts

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Hc being a tetrahydropyranyl group, where one or more carbon atoms on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, the groups NC-, FjC-, HFzC -, FHC-, F3C-CH2-, C1-C8 alkyl, C1-C alkyl -O-, and up to one carbon atom on the ring may be substituted by an oxo group;

R * being the group

* —الا in which

W is a phenyl group, w being optionally substituted by a fluorine atom, a chlorine atom or F3C-;

V is a heteroaryl group selected from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups, where

V is optionally substituted by 1 to 4, preferably 1 or 2, more preferably 1 substitute, independently of each other selected from fluorine atom, chlorine atom, HC-, tert-butyl, F3C-, CH3O -, cyclobutyloxy, N-morpholinyl, benzyl-o- and NC-,

V is attached to position 2 of w, position IdeW being the point of attachment of w to the Cr2r3 group in formula (I);

R² being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C1-C3 alkyl, preferably R² being H;

R³ being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C-C3 alkyl, preferably r3 being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Hc being a ، -tetrahydropyranyl group, where each carbon atom on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, the groups NC-, F3C-, HF2C , FHC-٠ F3C-CH2-, C1-C6 alkyl, C1-C6 alkyl, and up to one carbon atom on the ring may be substituted by an oxo group, preferably Hc being a non-، -tetrahydropranyl group. substituted;

د

ΜΑ 33152Β1

R being the group

VW- * in which

W is chosen from a phenyl group or a pyridinyl group,

V is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position 1 of w being the point of attachment of w to the Cr2r3 group in formula (I);

wherein w and V independently of one another may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, bromine atom, C 1-8 alkyl, F3C-, HFC, FHC-, F3C-CH-, F3C-0-, HF2C-0-, C3-C7 heterocycloalkyl (preferably a C3c ؛ heterocycloalkyl group), Η-Ο-C1-C8-alkyl, C1-C6-alkyl- Cc alkyl₆, C3-C7-0-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkyl-CC-O-alkyl-C1-C8-alkyl, phenyl-o-Cj-Cg-alkyl, benzyl-o-Cc-alkyl, Η-Ο -, C 1-10 alkyl, C3-C7-O- cycloalkyl, C3-C3-O- cycloalkyl-C1-C3-O-, phenyl20 O-, benzyl-o-, N-morpholinyl, and NC-, preferably by a substituent chosen from a fluorine atom, a chlorine atom, a bromine atom, alkyl groups C 1 -C 8, F3C-, F3C-CH-, F3C-0-, HF2C-0-, C3-C7 heterocycloalkyl (preferably C3-C5 heterocycloalkyl), CCgO- alkyl, C3-Cg-٥- cycloalkyl, C3_C8-CH2_O- cycloalkyl, aryl-CH-O- and NC-, in which preferably w and V independently of each other may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, HC-, F3C-, CH3O-, N-morpholinyl, and NC-, preferably chosen from a fluorine atom, the groups HC-, F3C-, CHO- and NC-;

R² being chosen from H-, a fluorine atom, the groups F3C-, HF2C-,

FHC- and C1-C3 alkyl, preferably R² being H;

rS being chosen from H-, a fluorine atom, the groups F3C-, HF2C-,

FHC- and C1-C3 alkyl, preferably rS being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Ha being a tetrahydropyranyl group, where each carbon atom on the ring can be optionally substituted by one or - optionally - by one or two substituents independently selected from a fluorine atom, the groups NC-, F3C-, HF ؛ C , ٢H₂C-, F3C-CH2-, C 1-8 alkyl, C-C8 -alkyl, and up to one carbon atom on the ring may be substituted with an oxo group, preferably Hc being an unsubstituted tetrahydropyranyl group;

R² being the group

VW- * in which

W is chosen from a phenyl group or a pyridyl group,

V is chosen from a phenyl group or a heteroaryl group, the heteroaryl group being chosen from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups,

V is preferably attached to position 2 of w, position IdeW 55 being the point of attachment of w to the CR group²r3 in formula (I);

wherein w may be optionally substituted with one or more substituents selected from a fluorine atom, a chlorine atom, a bromine atom, the HC-, F3C-, CH3O- and NC- groups, preferably selected from an atom of fluorine, a chlorine atom and F3C-;

ΜΑ 33152Β1 and wherein V may be optionally substituted with one or more substituents selected from fluorine atom, chlorine atom, HC, tert-butyl, F3C-, CHO-, cyclobutyloxy, N-morpholinyl, benzyl-o groups - and NC-;

R² being chosen from H-, a fluorine atom, the groups F3C-, HF ؛ C-,

FHC- and C1-C3 alkyl, preferably R² being H;

r3 being chosen from H-, a fluorine atom, the groups F3C-, HFzC-,

FHC- and C1-C3 alkyl, preferably r3 being H;

and salts thereof, preferably the pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the invention are compounds corresponding to the general formula (I),

Hc being a ، -tetrahydropyranyl group, where each carbon atom on the ring may be optionally substituted by one or - where appropriate - by one or two substituents independently selected from a fluorine atom, the groups NC-, F3C-, HF2C , FHC-, F3C-CH2-, C1-alkyl, C1-alkyl, and up to one carbon atom on the ring may be substituted with an oxo group, preferably Hc being an unsubstituted ، -tetrahydropyranyl group;

r! being the group

VW— * in which

W is a phenyl group, w being optionally substituted with a fluorine atom, a chlorine atom or F3C-;

V is a heteroaryl group selected from oxadiazolyl, triazolyl, pyrazolyl, pyrrolyl, furanyl, pyridyl, pyrimidyl and pyridazinyl groups, where

V is optionally substituted with 1 to 4, preferably 1 or 2, more preferably 1 substitute, independently of each other selected from fluorine atom, chlorine atom, HC-, tert-butyl, F3C-, CHO groups -, cyclobutyloxy, N-morpholinyl, benzyl-o- and NC-,

V is attached to position 2 of w, position IdeW being the point of attachment of w to group CR²R³ in formula (I);

R² being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C1-C3 alkyl, preferably R² being H;

R² being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C1-C3 alkyl, preferably r3 being H;

and salts thereof, preferably pharmaceutically acceptable salts thereof.

Specifically preferred compounds

Each of the compounds shown in the following table (Table 2) is specifically and individually preferred according to the invention. The listed compounds are described in detail in the section "Examples of embodiments". The following list shows the specific compounds of the invention as "neutral" compounds, ie they are not in the form of salts and the like. The numbering of the examples corresponds to the numbering used in the section "Examples of embodiments". More specific information can be found in the section "Examples of embodiments".

Table 2: Specific preferred embodiments. The reference numbers correspond to those used in the experimental part. The first column refers to the example number / reference number respectively, the second column refers to the structure.

د

ΜΑ 33152Β1

<td> 219</td><td> ٦٩</td><td> 225</td><td>رذ ذ H-</td>

<td> 220</td><td>٩ ث</td><td rowspan="2"> 226</td><td rowspan="2">? ٦ ج</td>

<td rowspan="2"> 221</td><td rowspan="2">: · ؛ ·.: ن</td>

<td rowspan="2"> 227</td><td rowspan="2">رده · ·</td>

<td rowspan="2"> 222</td><td rowspan="2"></td>

<td rowspan="2"> 228</td><td rowspan="2">; -رذد</td>

<td rowspan="2"> 223</td><td rowspan="2">تملآ</td>

<td rowspan="2"> 229</td><td rowspan="2"> .٠٠٩'</td>

<td rowspan="2"> 224</td><td rowspan="2">منم ٦</td>

<td rowspan="2"> 230</td><td rowspan="2">.; رب- '</td>

<td colspan="2"></td>

ΜΑ 33152Β1

ثم

<td> 232</td><td>٦ ي</td>

<td> 234</td><td>ع'٦</td>

<td> 239</td><td>غب</td>

<td> 240</td><td>؟ ي</td>

<td> 241</td><td>ردن</td>

<td> 230-1</td><td>مو ٦ ٠</td>

<td> 230-2</td><td>رد</td>

<td> 230-3</td><td>بم ٦ ةت '</td>

<td> 230-5</td><td>ر:; ي</td>

<td> 231</td><td>ةغب ٠</td>

ΜΑ 33152Β1

<td> 242</td><td> ,; ?..:؟:</td>

<td> 243</td><td>: م: ·</td>

<td> 244</td><td>ني '</td>

<td> 245</td><td>بم ٠ ك ٦</td>

<td> 246</td><td>ني</td>

<td>2ΑΊ</td><td>ني</td>

<td> 248</td><td>خلي</td>

<td> 249</td><td>مع ٠١ ؤحر رد</td>

<td> 250</td><td>نجب</td>

<td> 251</td><td>مم ا ٠</td>

ΜΑ 33152Β1

<td> 252</td><td>د ررد:</td><td rowspan="2"> 257</td><td rowspan="2">ق ٠</td>

<td rowspan="2"> 253</td><td rowspan="2"></td>

<td rowspan="2"> 258</td><td rowspan="2">ف٠-</td>

<td rowspan="2"> 254</td><td rowspan="2"> ٦</td>

<td rowspan="2"> 259</td><td rowspan="2">ر</td>

<td rowspan="2"> 255</td><td rowspan="2">ز^يك ة '</td>

<td rowspan="2"> 260</td><td rowspan="2">; 'يك</td>

<td rowspan="2"> 256</td><td rowspan="2">غ ٠</td>

<td> 261</td><td>خي</td>

<td colspan="2"></td><td> 262</td><td></td>

ΜΑ 33152Β1

<td> 263</td><td> .٩٩</td>

The invention also relates to the compounds of Table 2, in the form of isoforms, tautomers, stereoisomers, solvates, hydrates or salts of any listed compounds, in particular the physiologically acceptable salts thereof with acids or bases. inorganic or organic, or combinations thereof.

The above table (Table 2) further illustrates the general formula (I) and how to read generic embodiments Ε-1 through Ε-24 of Table 1 and Ε-25 through Ε-4 8 of Table 3: for example the compound 261, 6- [2- (5-meth0xy-pyridin-2-yl) -benzyl] -1 (tetrahydro-pyran-4-yl) -1,5-dihydro-pyrazolo [3,4-d ] pyrimidin-4-οηθ, corresponds to the general formula (I) in which Hc is a tetrahydropyran-4-yl group, V and w, which form rI (that is to say VW-٠), are defined as as follows: w = phenyl, wherein said phenyl group is attached through its 1-position to the CIR group of formula (I); V = 5-methoxy-pyridin-2-y! E, where V is attached at position 2 of w (i.e. w has a 1,2 substitution / ortho substitution pattern); and R² and R² are H.

Other embodiments of the invention

Another embodiment of the invention relates to compounds according to general formula (I), the compounds being chosen from the group of compounds in Table 2 having the reference numbers: 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 230-1; 230-2; 2303; 231; 232; 234; and optionally an isoform, tautomer, steroisomer, solvate, hydrate or salt of any one of these compounds, in particular a physiologically acceptable salt thereof with inorganic or organic acids or bases, or combinations thereof. -this.

Another embodiment according to the invention relates to compounds of general formula (I), the compounds being chosen from the group of compounds in Table 2 having the reference numbers: 230-5; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; and optionally an isoform, tautomer, stereoisomer, solvate, hydrate or salt of any of these compounds, in particular a physiologically acceptable salt thereof with inorganic or organic acids or bases, or combinations thereof. -this.

Another series of embodiments of the invention is defined by Table 3.

Table 3: compound characterized by the general formula (I) .٠

<img file="MA33152B1_D0005.tif" />

ΜΑ 33152Β1 with

<td></td><td>Ha</td><td>R *</td><td>R²</td><td>R3</td>

<td>Ε-25</td><td>Here</td><td>rII</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-26</td><td>Hc</td><td>rI'2</td><td>defined by the remark 3)</td><td>defined by note 4 ؛</td>

<td>Έ-2Ί</td><td>H</td><td>Rl'j</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-28</td><td>H</td><td>rI'4</td><td>defined by the remark</td><td>defined by note 4 '</td>

<td>Ε-29</td><td>Η £^γ</td><td>Ri, د</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-30</td><td>H</td><td>Rl, ٥</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-31</td><td></td><td>⁵؛ '؛ R</td><td>being H</td><td>being H</td>

<td>Ε-32</td><td>Hc</td><td>R¹’⁶</td><td>being H</td><td>being H</td>

<td>Ε-33</td><td>Hc²</td><td>rII</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-34</td><td>H</td><td>r! '²</td><td>defined by the remark</td><td>defined by note 4 '</td>

<td>Ε-35</td><td>Hc²</td><td>rI'3</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-36</td><td>Hc²</td><td>rM</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-37</td><td>H</td><td>rI'5</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-38</td><td>H</td><td>Rl, b</td><td>defined by the remark 3)</td><td>defined by note 4)</td>

<td>Ε-39</td><td>Hc²</td><td>٥ '؛ R</td><td>being H</td><td>being H</td>

<td>Ε-40</td><td>Hc²</td><td>Rl, 6</td><td>being H</td><td>being H</td>

<td>Ε-41</td><td>Hc³</td><td>Rl'1</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-42</td><td>Hc³</td><td>Rl '²</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-43</td><td>Hc³</td><td>rI'3</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-44</td><td>H</td><td>rI'4</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-45</td><td>ȳ</td><td>'؛' Rl</td><td>defined by the remark</td><td>defined by note 4 ؛</td>

<td>Ε-46</td><td>H</td><td>Rl '،'</td><td>defined by the remark</td><td>defined by note 4)</td>

<td>Ε-47</td><td>Hc²</td><td>Ri'٥</td><td>being H</td><td>being H</td>

<td>Ε-48</td><td>Hc²</td><td>؛؛ 'Rl</td><td>being H</td><td>being H</td>

provided that the compound is not a compound selected from the group of compounds in Table 2 having reference numbers: 219;

220 ; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 230-1; 230-2; 230-3; 231; 232; 234 or optionally an isoform, tautomer, steroisomer, solvate, hydrate or salt of any of these compounds, in particular not a physiologically acceptable salt thereof with inorganic or organic acids or bases, or combinations of these.

Notes:

^ةل ات definition refers to: R² being chosen from H-, a fluorine atom, the groups ٢₃C-, HC-, FHC- and C1-C3 alkyl, preferably R²

ΜΑ 33152Β1 the definition refers to: R³ being chosen from H-, a fluorine atom, the groups F3C-, HF2C-, FHC- and C1-C3 alkyl, preferably R³being H.

In all of the embodiments of Table 3, it is preferable that each of R² and r3 let H٠

Where appropriate, the object of the invention also refers to an isoform, tautomer, stereoisomer, solvate, hydrate or salt of any of these compounds, in particular a physiologically acceptable salt thereof with acids or inorganic or organic bases, or combinations thereof.

In another embodiment of the invention, it may be preferable that when Hc in any of the embodiments described above is a group defined by the following formula D1

<img file="MA33152B1_D0006.tif" />

position ** (Dl), in which * is the point of attachment to the pyrazole group of the general formula (I), then in position **, there is no substituent which has an integral -CH- group by which it is linked to, or even more preferably, in that position **, there is no substituent at all.

In another embodiment of the invention, it may be preferable in any of the above mentioned embodiments that when Hc is a tetrahydropyranyl group, then there is no CH group bonded in the alpha position to! oxygen atom of the cycle.

In another embodiment of the invention, it may be preferable in any of the above-mentioned embodiments that when Hc is a tetrahydropyranyl group, then there is no C1-C6 alkyl group attached to the above. alpha position at the oxygen atom of the cycle.

Terms and definitions used

The terms not specifically defined here must be given the meanings which would be given to them by those skilled in the art according to the description and the context. Examples include that specific substituents or atoms are shown with 1 or 2 specific coded letters, such as H for hydrogen, N for nitrogen, c for carbon, 0 for oxygen, s for sulfur and analogues. Optionally, but not necessarily, the letter is followed by a hyphen to indicate a link. As used in the application, unless otherwise indicated, the following terms have the meanings indicated and the following conventions are accepted.

In the groups, radicals or fragments defined below, the number of carbon atoms is often specified after the group, for example the term "alkyl in cc" means an alkyl group or an alkyl radical comprising from 1 to 6 carbon atoms. carbon. In general, for groups which are composed of two or more subgroups, the last group named is the point of attachment of the radical, for example the term "alkyl-O-" means a monovalent radical of the formula alkyl-٠_ , which is attached through the oxygen atom (i.e. an alkoxy group). If the term of a substituent begins or ends with a negative sign or a hyphen, that is to say -, this sign marks the point of attachment, as in the "alkyl-O-" example. mentioned above, where "0" is attached to the group for which the group alkyl-O- is a substituent. Unless indicated below

X

ΜΑ 33152Β1 Differently, classical definitions of terms and classical stable atom valences are those assumed and used in all formulas and groups.

In general, if terms are specifically defined with a given context, these specific definitions prevail over the more general definitions, as emphasized in this paragraph.

In general, all "forms and isomeric forms and mixtures thereof", whether individual geometric isomers or optical isomers or racemic or non-racemic mixtures of isomers, of a chemical structure or of a compound, are included, unless the stereochemistry or isomeric form is specifically stated in the name of the compound or in its structure. The specific definitions prevail.

The term "substituted" as used herein explicitly or implicitly, means that one or more hydrogen atoms on the indicated atom are replaced by an element of the substituent group indicates, provided that the normal valence of the atom indicates indicates is not exceeded. In the case where a substituent is linked through a double bond, for example an oxo substituent, each substituent replaces two hydrogen atoms on the indicated atom. The substitution should give a stable compound. The term "stable" in this context preferably means a compound, which from a pharmaceutical point of view is chemically and physically stable enough that it can be used as an active pharmaceutical ingredient in a pharmaceutical composition. If a substituent is not defined, it must be a hydrogen atom.

The term "optionally substituted" means whether the corresponding group is substituted or not substituted.

The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms which are, in medical judgment, suitable for use in contact with tissues of humans and animals without toxicity. excessive irritation, allergic response or any other problem or complication, with a reasonable benefit / risk ratio.

As used herein, the term "pharmaceutically acceptable salt (s)" refers to derivatives of the compounds described in which the parent compound is modified by the preparation of acidic or basic salts thereof, preferably salts thereof. 'addition. Examples of pharmaceutically acceptable salts of a compound according to the invention which has a basic function (for example an amino group) include, without limitation, salts of inorganic or organic acids; and the like. Compounds with acidic properties can form salts with alkaline or organic bases. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid,! tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid,! sulfanilic, 2acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, oxalic acid, isethionic acid, and the like.

Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound with basic or acidic properties by conventional chemical methods. In general, such salts can be prepared by reacting a compound of the present invention which has basic properties with an amount

ΜΑ 33152Β1 stoichiometric of the appropriate acid (respectively, compounds having acidic properties with an appropriate stoichiometric amount of base) in water or in an organic solvent, or in a mixture of both; generally, a non-aqueous mixture such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

"Prodrugs" are considered to be compounds which release an active parent drug of the present invention in vivo when such a prodrug is administered to a mammal. Prodrugs according to the present invention are prepared by modifying the functional groups present in the compound of the invention such that these modifications are converted back to the original functional groups under physiological conditions. Prodrugs include compounds of the present invention in which a hydroxy, amino or sulfhydryl group is bonded to any group which, when the prodrug of the present invention is administered to a mammal, is retransformed to liberate the hydroxy, amino or group. sulfhydryl. Exemplary prodrugs include, without limitation, acetate, formate and benzoate derivatives of alcoholic and amine functional groups in compounds of the present invention.

"Metabolites" are considered to be derivatives of the compounds of the present invention which are formed in vivo. Active metabolites are metabolites that cause a pharmacological effect. It is evident that the metabolites of the compounds of the present invention are also included in the present invention, in particular the active metabolites.

Certain compounds can form "solvates". In the invention, the term “solvates” refers to the forms of the compounds which form, in the solid or liquid state, a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination takes place with water. According to the present invention, the term is preferably used for solid solvates, such as amorphous or more preferably crystalline solvates.

“Skeleton”: the skeleton of the compounds according to the present invention is represented by the following core structure. The numbering of the positions of the atoms of the ring is indicated in bold:

<img file="MA33152B1_D0007.tif" />

It is obvious to those skilled in the art that this skeleton can be described by its tautomeric “enol” shape.

<img file="MA33152B1_D0008.tif" />

In the context of the present invention, the two structural representations of the skeleton should be considered as subject of the present invention, even if only one of the two representations is يد

ΜΑ 33152Β1 presented. Without wishing to be limited or bound by any theory, it is believed that for the majority of compounds under ambient conditions, and therefore under conditions which are the conditions suitable for a pharmaceutical composition comprising said compounds, the balance of the tautomeric forms tilts towards the representation of pyrazolopyrimdin- ، one. Therefore, all embodiments are presented as pyrazolopyrimdin-4-one derivatives or more specifically as pyrazo! O [3,4-d] pyrimidin-4-one derivatives.

"Bonds": if in a chemical formula of a ring system or a defined group, a substituent is directly bonded to an atom or to a group such as "RyR" in the formula below, this means that the substituent is only attached to the corresponding atom. However, from a substituent such as "RxR", if a bond is not specifically linked to an atom in the ring system, but rather drawn towards the center of the ring or group, this means that this "RxR Can be bonded to any useful atom in the ring / group system, unless noted otherwise.

<img file="MA33152B1_D0009.tif" />

The link symbol "-" (= negative sign) or the symbol "-٠" (= negative sign followed by an asterisk) represents the link by which a substituent is linked to the corresponding remaining part of the molecule / backbone. In the event that the negative sign does not seem sufficiently obvious, an asterisk can be added to the symbol "-" in order to determine the point of attachment of said bond with the corresponding main part of the molecule / backbone.

In general, bonding to one of the heterocycloalkyl or heteroaryl groups can be effected through a ring carbon atom or optionally through a ring nitrogen atom of such a heterocycloalkyl or heteroaryl group. .

The term "aryl" used in this application describes a phenyl, biphenyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl or naphthyl group, preferably a phenyl or naphthyl group, more preferably a phenyl group. This definition applies to the use of the term "aryl" in any context of the present description in the absence of any other definition.

The term "CCn alkyl" describes a saturated, branched or unbranched hydrocarbon group comprising from 1 to n carbon atoms, where n is a figure selected from the group consisting of 2, 3, 4, 5 or 6. Examples of these groups include methyl, ethyl, n-propyl, isopropyl, butyl, -iso-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, iso- hexyl, etc.

This definition applies to the use of the term "alkyl" in any reasonable context of this specification in the absence of any other definition.

In the case where the term "C1-Cn-alkyl" is used between two other groups / substituents, such as for example in the term "-cycloalkyl C-Cn-O- alkyl", this means that the "alkyl in c٢c_not Links the other two groups. In the present example, it links the cycloalkyl group in C1-Cn to oxygen as in "cyclopropylmethyl-oxy-". It is evident that in such cases the term "C1-C6 alkyl" has the meaning of a "C-Cn alkylene" spacer, such as methylene (-CH -), ethylene. (for example -CH - CH -), etc. Groups which are linked through a "C1-Cn alkyl" group can be linked to the "CCn alkyl" group at any position. Of

Preferably, the right group is located at the distal right end of the alkyl group and the left group at the distal left end of the alkyl group (e.g. for ΗΟ-C3-: 3-hydroxy-propan) alkyl. l-yle). This also applies to the other substituents.

The term "C-cycloalkyl₃-c “” describes a saturated monocyclic group of 3 carbon atoms, preferably a value of 4 to 7 (= 4, 5, 6 or 7). There are no other atoms on the cycle other than carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. This definition applies to the term "cycloalkyl" in any reasonable context of this specification in the absence of any other definition.

The term “heteroaryl” used in this application describes a heterocyclic, mono- or bicyclic aromatic ring system which comprises in the ring system, in addition to at least one carbon atom, one or more heteroatoms independently selected from N, O , and / or s. A monocyclic ring system preferably comprises 5 to 6 elements on the ring, a bicyclic ring system preferably comprises 8 to 10 elements on the rings. Preferred systems are heteroaryl groups having up to 3 heteroatoms, more preferably up to 2 heteroatoms, more preferably 1 heteroatom. The preferred heteroatom is N. Examples of such moieties are benzimidazolyl, benzisoxazolyl, benzo [1,4] -oxazinyl, benzoxazol-2-onyl, benzofuranyl, benzoisothiazolyl, 1,3-benzodioxolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzoxadiazolyl, benzoxazol, chromanyl, chromanyl, , chromonyl, cinnolinyl, 2,3dihydrobenzo [1,4] dioxinyl, 2,3-dihydrobenzofuranyl, 3,4dihydrobenzo [1,4] oxazinyl, 2,3-dihydroindolyl, 1,3dihydroisobenzofuranyl, 2,3-dihydroisoindolyl, 6,7 -dihydropyrrolizinyl, dihydroquinolin-2-onyl, dihydroquinolein-4-onyl, furanyl, imidazo [1,2_ a] pyrazinyl, imidazo [1,2-a] pyridyl, imidazolyl, imidazopyridyl, imidazo [4,5-d] thiazolyl, indazolyl, indolizinyl , indolyl, isobenzofuranyl, isobenzo-thienyl, isochromanyl, isochromenyl, isoindoyl, isoquinolin-2-onyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthiazolyl, 1,2,4-oxadiazoyl, 1,3,4-oxadiazadoyl, 1,2,5 , oxazolopyridyl, oxazolyl, 2-0X0-2,3-dihydr0benzimidaz0lyl, 2-ΟΧΟ-2,3-dihydroindolyl, 1-oxoindanyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolo [1,5-a] pyridyl, pyrazolo [1,5-a] pyrimidinyl, pyrazolyl, pyridazinyl, pyridopyrimidinyl, pyridyl ( pyridinyl), pyridyl-joxide, pyrimidinyl, pyrimidopyrimidinyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolyl, quinazolinyl, quinolin-4-onyl, guinolinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahinyl, 1,2,3,4-tetrahinyl, 1 , 2,4-thiadia-zolyl, 1,3,4thiadiazolyl, 1,2,5-thiadiazolyl, thiazolyl, thieno [2,3-d] imidazolyl, thieno [3,2-b] pyrrolytic, thieno [3,2-b] thiophenyl, thienyl, triazinyl, or triazolyl.

Preferred heteroaryl groups are defined in the relevant context.

<td></td><td>The definition</td><td>of a</td><td>pyrazole</td><td>includes</td><td>the</td><td>isomers</td><td> ... ,</td><td>3Η-</td><td>and</td><td>4Η-</td>

<td> 50</td><td colspan="2">pyrazole. Preferably</td><td colspan="3">the pyrazolyl group</td><td colspan="2">represents the</td><td colspan="2">group</td><td>IH-</td>

<td></td><td>pyrazolyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>The definition</td><td>of a</td><td>imidazole</td><td>includes</td><td>the</td><td>isomers</td><td>IH-,</td><td>2Η-</td><td>and</td><td>4Η-</td>

<td></td><td colspan="2">imidazole. A definition</td><td>favorite</td><td>of the group</td><td colspan="2">imidazolyl</td><td>is the</td><td colspan="2">group</td><td>IH-</td>

<td></td><td>imidazolyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 55</td><td>The definition</td><td>of a</td><td>triazole</td><td>includes</td><td>the</td><td>isomers</td><td>IH-,</td><td>3Η-</td><td>and</td><td>4Η-</td>

[1,2,4] -triazole as well as the 1H-, 2Η- and 4H- [1,2,3] _triazole isomers. The definition of a triazolyl group therefore includes the groups! - [1,2,4] triazol-1-, -3- and -5-yl, 3H- [1,2,4] -triazol-3- and - 5-yl, 4Η- [1,2,4] _ triazo! -3-, -4- and -5-yl, 1H- [1,2,3] -triazol-1-, -4- and -5 -yl, 2Η60 [1,2,3] -triazo! -2-, -4- and -5-yl as well as the 4H- [1,2,3] tr a ol26 groups

ΜΑ 33152Β1

The term tetrazole includes the isomers 1H-, 2H- and 5H-tetrazo! E. The definition of a tetrazolyl group therefore includes ΙΗ-tetrazol-1et -5-yl, 2H-tetrazol-2- and -5-yl and 5H-tetrazol-5-yl.

The definition of an indole includes the 1H- and 3H-indole isomers. The term indolyl preferably represents a ΙΗ-indol-1-yl group.

The term isoindole includes the isomers 1H- and 2H-isoindole.

This definition applies to the term "heteroaryl" in any reasonable context of this specification in the absence of any other definition.

The term "heterocycloalkyl" in the context of the present invention describes a saturated ring system of 3 to 8 elements, preferably 5-, 6- or 7 elements or a bicyclic ring system of 5 to 12 elements, of which the atoms. of the ring are carbon atoms and 1, 2, 3 or 4 heteroatoms, selected from N, 0, and / or s, s optionally being in the form of so or s٠2, preferably 1, 2, or 3, more preferably 1 heteroatom.

The preferred number of carbon atoms on the ring is 3 to 7, in addition to said 1, 2, 3 or 4 heteroatoms selected from N, O, and / or s. Such heterocycloalkyl groups are termed C3-C7 heterocycloalkyl groups.

Preferred rings are saturated heterocycloalkyl rings comprising 5, 6 or 7 ring atoms, of which 1 or 2 are heteroatoms and the remainder are carbon atoms.

A preferred example of heterocycloalkyl groups include morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxathianyl, dithia-nyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxathiolanyl, imidazolidinyl, thiomorpholinyl, oxathianyl, dithia-nyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, oxathiolanyl, imidazolidinyl, tetrahydropolininyl, homidazolidinyl, homidazolinoidropyranyl, homidazolidinyl, tetrahydropolinidropyranyl, homidazolidinyl, tetrahydropolinidropyranyl, homidazolidinyl, tetrahydropolinidropyranyl, pyrrolidinyl, tetrahydrofuranyl. , azetidinyl, 1,3-diazacyclohexanyl and pyrazolidinyl.

This definition applies to the term "heterocycloalkyl" in any reasonable context of the present description in the absence of any other definition.

oxo ”represents an oxygen atom as a substituent which is bonded by a double bond, preferably it is bonded to a carbon atom.

In the case where an oxo group is used as a substituent, the oxo group replaces two hydrogen atoms of the corresponding atom of the unsubstituted group. The terms "pyridyl" and "pyridinyl" are used equally (in parallel ) to define a pyridine substituent.

The expressions "prevention", "prophylaxis", "prophylactic treatment" or "preventive treatment" used herein are synonymous and in the sense that the risk of the development of a pathology mentioned above is reduced, in particular in a patient with a high risk of developing said pathologies or a corresponding history. Therefore, the term "prevention of 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 aim of prevention is to control the development of the disease, pathology or disorder, and includes the administration of active ingredients to prevent or delay the onset of symptoms or complications and to prevent or delay the development of the disease. apparent diseases, pathologies or disorders. The success of said preventive treatment is statistically reflected by a reduced incidence of said pathology in a population of patients at risk of developing this pathology compared to an equivalent population of patients not receiving preventive treatment.

The expression "treatment" or "therapy" preferably means the therapeutic treatment of patients (for example humans) who have already developed one or more of said pathologies in manifest, acute or chronic form, including symptomatic treatment in order to relieve the symptoms. symptoms of the specific indication or causal treatment in order to reverse or partially reverse the pathology or to delay the

ΜΑ 33152Β1 progression of the indication as much as possible, depending on the pathology and its severity. Therefore, the term "treatment of a disease" used herein means the management and care of a patient who has developed the disease, condition or disorder. The goal of treatment is to combat the disease, pathology, disorder or symptom. Treatment includes administration of the active compounds to eliminate or control the disease, pathology or disorder, as well as to relieve symptoms or complications associated with the disease, pathology or disorder.

The following schemes illustrate the general ways of making the compounds of the present invention in exemplary form. Abbreviated substituents may be as defined in the embodiments of formula (I) if not otherwise defined in the context of the schemes.

ΜΑ 33152Β1

Diagram 1

NC?

CN

٥C₂H₅

HN

Hc

<img file="MA33152B1_D0010.tif" />

HN

Hc

NH

NH,

R٩ R³

Et3N / Et0H heating

R²{R³

عزي ، 1 Xoocy

NaH / EtOH gold

R²\ r

R٦CO₂H activation reagent

NC

H_SNOT

&lt;٢١

Year

Hc

NH₃, H₂O₂Eto HO

Hc the hydrazino group is linked to a carbon atom of the tetrahydropyranyl group step, the 2-ethoxymethyl! Enehydrazines mono-substituted pal

Scheme 1: In a first malononitrile is condensed with heating in a suitable solvent such as ethanol, in the presence of a base (eg triethylamine) to form the corresponding 5-amino-1H-pyraz٠le-4carbonitriles. These compounds are converted in a second step into the corresponding amides, for example by treatment with an ethanolic solution containing ammonia (25% in water) and hydrogen peroxide (35% in water). In a third step, heating with carboxylic esters under basic conditions (eg sodium hydride in ethanol) or carboxylic acids with an activating reagent (eg polyphosphoric acid) gives the pyrazolo [3,4-d] pyrimidin-4-ones as end products [see for example A. Miyashita et al., Heterocycles 1990, 31, 1309ff].

Schemes 2 and 3 illustrate other methods of preparing the final compounds: in these examples of preparation methods, the amides of 5-amino-1H-pyrazole-4-carboxylic acid are condensed in a first step, with a an appropriate ester derivative, this is followed in a second step by alkylation with appropriate electrophiles.

Diagram 2

ΜΑ 33152Β1

<img file="MA33152B1_D0011.tif" />

عز ؛

C00C₂H٠؟ r1

NaHEtOH

<img file="MA33152B1_D0012.tif" />

<img file="MA33152B1_D0013.tif" />

activation reagent

<img file="MA33152B1_D0014.tif" />

O

R

R²

<img file="MA33152B1_D0015.tif" />

ΜΑ 33152Β1

Diagram 3

<img file="MA33152B1_D0016.tif" />

Based,

LG-Hc

<img file="MA33152B1_D0017.tif" />

IG = Br-, CI-, I-, CH3-SO2-O-, p-toluenesulfonyl, which is bonded to. Hc by one of the carbon atonies on the ring of the tetrahydropyranoyl group

Base = N (CH) 3. K ؛ ٠Bu. NaH

Schemes 4 and 5 illustrate other methods of preparing the final compounds: in the examples of preparation methods, the amides of 5-amino-1H-pyrazole-4-carboxylic acid are condensed in a first step, with (2-Bomo-phenl) -acetic acid ester derivatives, which is followed in a second step by substitution of the bromine atom by an aromatic or heteroaromatic residue, for example using reaction conditions of the type Suzuki or Ullmann. Alternatively, as depicted in Scheme 5, the aromatic or heteroaromatic residue is first inserted into a phenyl-acetonitrile residue and then condensed with the amides of 5-amino-1H-pyrazole-4-carboxylic acid in a second step. .

ΜΑ 33152Β1

Diagram 4

<img file="MA33152B1_D0018.tif" />

<img file="MA33152B1_D0019.tif" />

with

٧ '= optionally substituted

<img file="MA33152B1_D0020.tif" />

γΐ = independently selected from each other from the group consisting of CH, O, N, where H of CH may be replaced by a substituent as indicated for formula (I).

ΜΑ 33152Β1

Diagram 5

A. Ullmann

-2 3

<img file="MA33152B1_D0021.tif" />

Ass / N-N'-dlmetnylethylenedlamlne

CSjCODMF

12O٠C

B. Suzuki

VB (0Hfe

PdCPPItyV Na₂CO₃dioxane / HO

14O٠C

٠3 ض

<img file="MA33152B1_D0022.tif" />

٥3 ٠2

<img file="MA33152B1_D0023.tif" />

with

V = optionally substituted

<img file="MA33152B1_D0024.tif" />

NaHEtOH

O

<img file="MA33152B1_D0025.tif" />

Y1 = independently of each other in the group consisting of CH, O, N, where H of CH may be replaced by a substituent as indicated for formula (I).

On the other hand, the synthesis of the final compounds can also be accomplished by the preparation of a boronic acid derivative, followed by Suzuki type cross coupling in a second step (Scheme 6).

ΜΑ 33152Β1

Diagram 6

<img file="MA33152B1_D0026.tif" />

B. Suzuki

Pdi ^ Pha) NaCOg dioxane / HO 14O٠C

<img file="MA33152B1_D0027.tif" />

Scheme 7 illustrates another process for the preparation of the final compounds: in the examples of preparation processes, the amides of 5-amino-1H-pyrazole-4-carboxylic acid are condensed in a first step, with derivatives of (2-CyanO-phenyl) -acetic acid ester, which is followed in a second step by the conversion of the nitrile group to a 5-membered heteroaromatic group.

ΜΑ 33152Β1

Diagram 7

<img file="MA33152B1_D0028.tif" />

Other methods for the preparation of pyrazolo [3,4-d] pyrimidin-4ones are known in the art and can also be used for the synthesis of the compounds of the invention (see for example: p. Schmidt et al. , Helvetica Chimica Acta 1962, 189, 1620ff.).

The mono-substituted hydrazine derivatives, which are used in step 1 of scheme 1 can be prepared by nucleophilic displacement on the corresponding mesylate derivative (scheme 8) or by reduction of the hydrazone intermediate as described in scheme 9. [see for example, Jw Timberlake et al., "Chemistry of Hydrazo-, Azo-, and Azoxy Groups", ٠ Patai, s., Ed., ٠ 1975, Chapter 4; sc Hung et al., Journal of organic Chemistry 1981, 46, 5413-5414].

Figure 8

ΜΑ 33152Β1

<img file="MA33152B1_D0029.tif" />

or

<img file="MA33152B1_D0030.tif" />

OH

<img file="MA33152B1_D0031.tif" />

*· or

<img file="MA33152B1_D0032.tif" />

The tetrahydropyranyl group substitutes as defined.

can optionally be further

Figure 9

<img file="MA33152B1_D0033.tif" />

The tetrahydropyranyl group may further be optionally substituted as defined.

Further information can be found in WO04099210 (in particular page 9, last paragraph on page 14, line 8, incorporated by reference).

The compounds of the invention show an interesting range of pharmacological effects which could not have been predicted. They are characterized in particular by the inhibition of PDE9A.

Preferably, the compounds according to the present invention show a high selectivity profile with regard to the inhibition or modulation of specific elements of the PDE9 family or other PDE families, with a marked preference (selectivity) for. the inhibition of PDE9A.

The compounds of the present invention should have a favorable safety profile for the purpose of medical treatment.

The compounds of the present invention are expected to have a favorable profile with regard to metabolic stability over a period of time for the purpose of medical treatment.

د

ΜΑ 33152Β1

The compounds of the present invention are expected to have a favorable profile with respect to bioavailability for the purpose of medical treatment.

Processing method

The present invention refers to compounds, which are believed to be effective in the treatment of diseases. The compounds according to the invention are effective and selective inhibitors of 9Α phosphodiesterase and can be used for the development of drugs. Such medicaments should preferably be used for the treatment of diseases in which inhibition of PDE9A may result in a therapeutic, prophylactic or disease modifying effect. Preferably, the drugs can be used to improve perception, concentration, cognition, learning or memory, such as those occurring in particular in situations / diseases / syndromes, such as: mild cognitive impairment, age-associated learning and memory impairment, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic dementia, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, body dementia by Lewy, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, progressive supranuclear palsy, dementia with cortico-basal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis , thalamic degeneration, Creutzfeld-Jacob dementia, HIV-associated dementia, epilepsy, temporal lobe epilepsy, schizophrenia or Korsakoff's psychosis.

Another aspect of the present invention relates to the treatment of a disease which is accessible by modulation of PDE9A, in particular sleep disorders such as insomnia or narcolepsy, bipolar disorder, metabolic syndrome, obesity , diabetes mellitus, including type 1 or type 2 diabetes, hyperglycemia, dyslipidemia, glucose intolerance, or disease of the testes, brain, small intestine, skeletal muscle, heart, lungs, thymus or spleen.

Accordingly, the medical aspect of the present invention can be summed up as a compound according to any of the generic embodiments of the invention described herein or a compound selected from the group of compounds specifically described. ("Species") is used as a medicine.

Such a medicament is preferably for the treatment of CNS disease.

In an alternative use, the medicament is for the treatment of CNS disease, the treatment of which is accessible by inhibiting PDE9.

In an alternative use, the medicament is for the treatment of a disease which is accessible by inhibiting PDE9, in particular PDE9A.

In an alternative use, the medicament is for the treatment, amelioration and / or prevention of cognitive impairment which is related to perception, concentration, cognition, learning or memory.

In an alternative use, the medicament is for the treatment, amelioration and / or prevention of cognitive impairment which is related to learning and memory disorders associated with age, loss of memory. memory associated with age, vascular dementia, traumatic brain injury, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic dementia, general disturbance of concentration, disturbance of concentration

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ΜΑ 33152Β1 in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with frontal lobe degeneration, including Pick's syndrome, Parkinson's disease, supranuclear palsy progressive, dementia with cortico-basal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, dementia associated with HIV, epilepsy, temporal lobe epilepsy, schizophrenia with dementia, or Korsakoff's psychosis.

In an alternative use, the medicament is for the treatment of Alzheimer's disease.

In an alternative use, the medicament is for the treatment of sleep disorders, bipolar disorder, metabolic syndrome, obesity, diabetes mellitus, hyperglycemia, dyslipidemia, glucose intolerance, or disease of the testes, brain, small intestine, skeletal muscle, heart, lungs, thymus or spleen.

In another aspect, the present invention relates to a method of treating or preventing a pathology or disease selected from the groups of diseases and conditions indicated above, the method comprising administering a therapeutically amount. of a compound according to the invention to a human being in need thereof.

Pharmaceutical compositions

Medicines for administration, which are also the object of the present invention, comprise a compound according to the present invention in a therapeutically effective amount and a pharmaceutical excipient. The term "therapeutically effective amount" means that if the medicament is applied through an appropriate dosage and adapted to the pathology of the patient, the amount of said compound of formula (I) will be sufficient to treat, prevent or reduce. effectively the progression of the corresponding disease, or otherwise improve the condition of a patient suffering from such disease. It is possible that the "therapeutically effective amount" used in monotherapy is different from the "therapeutically effective amount" used in combination therapy.

The dosage range of the compounds of general formula (I) applicable per day may be 0.1 to 5000 mg, preferably 0.1 to 1000 mg, preferably 2 to 500 mg, more preferably 5 to 250 mg. , ideally from

10 at 100 mg. A dosage unit (eg a tablet) can preferably comprise from 2 to 250 mg, more preferably from 10 to 100 mg of the compounds according to the invention.

The actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art such as the age, weight, sex or other pathologies of the patient, the mode of administration, the severity of the disease. and the like.

The compounds according to the invention can be administered orally, parenterally (intravenously, intramuscularly, etc.), intranasal, sublingual, inhaled, intrathecal, topical or rectal. Preparations suitable for the administration of the compounds according to the present invention include, for example, patches, tablets, capsules, pills, lozenges, dragees, powders, trochisks, suppositories, liquid preparations such as solutions. , suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like. The content of the pharmaceutically active principle (s) should be in the range from 0.5 to 90% by weight, preferably from 0.1 to 50% by weight of the composition as a whole. Appropriate tablets can be obtained, for example, by mixing the active principle (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or

ΜΑ 33152Β1 lactose, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can also have multiple layers.

The coated tablets can therefore be prepared by coating the cores produced in a manner analogous to the tablets with substances generally used for the coatings of tablets, for example collidone or shellac, gum arabic, talc, titanium dioxide or a sugar. To achieve delayed release or prevent incompatibilities, the core can also be made up of a number of layers. Similarly, the tablet coating can be made up of a number of layers to achieve delayed release, optionally using the excipients mentioned above for the tablets.

The syrups or elixirs containing the active ingredients or combinations thereof according to the invention may also contain a sweetener such as saccharin, cyclamate, qlycerol or a sugar and an agent improving the taste, for example an agent. flavoring such as vanillin or orange extract. They can also contain suspending agents or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example the condensation products of fatty alcohols with ethylene oxide, or preservatives such as p- hydroxybenzoates.

The solutions are prepared in the usual way, for example with the addition of isotonic agents, preservatives such as phydroxybenzoates or stabilizers such as the alkali metal salts of ethylenediaminotetraacetic acid, optionally using emulsifiers and / or dispersants, while if water is used as a diluent, for example organic solvents can optionally be used as solubilizing agents or dissolving agent, and solutions can be transferred to injection vials or ampoules or infusion vials.

The capsules containing one or more active principles or combinations of active principles can for example be prepared by mixing the active principles with inert supports such as lactose or sorbitol, and by encapsulating them in gelatin capsules.

Suitable suppositories can, for example, be prepared by mixing them with carriers provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

The excipients which can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (for example petroleum fractions), vegetable oils (for example peanut or sesame oil), mono- or polyfunctional alcohols (for example ethanol or glycerol), supports such as for example natural mineral powders (for example kaolins, clay, talc, chalk), synthetic mineral powders (eg strongly dispersed silicic acid and silicates), sugars (eg cane sugar, lactose and glucose), emulsifiers (eg lignin, waste sulphite liquors, methyl cellulose , starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

For oral use, the tablets may contain, in addition to the specified excipients, additives such as sodium citrate, calcium carbonate and dicalcium phosphate along with various other substances such as starch, preferably apple starch. of earth, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used to produce the tablets. In the case of aqueous suspensions, the principles

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ΜΑ 33152Β1 actives can be combined with various flavor enhancers or coloring agents in addition to the excipients mentioned above.

The dosage of the compounds according to the invention is obviously strongly dependent on the method of administration and on the disease to be treated.

Associations with other active ingredients

According to another aspect, the present invention relates to a therapeutic combination in which a compound according to the present invention is administered with another active principle. Accordingly, the invention also relates to pharmaceutical formulations which provide such a combination of active ingredients, one of the active ingredients of which is a compound of the present invention. Such combinations can be fixed dose combinations (the active ingredients which are to be combined are present in the same pharmaceutical formulation) or free associations (the active ingredients are present in separate pharmaceutical formulations).

Accordingly, another aspect of the present invention refers to an association of each of the compounds of the present invention, preferably of at least one compound according to the present invention, with another compound selected from the group consisting for example of the beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors such as, for example, alzhemed; neuroprotective and / or disease modifying substances acting directly or indirectly; antioxidants such as, for example, vitamin E, ginkgo biloba or ginkqolide; anti-inflammatory substances such as, for example, Cox inhibitors, NSAIDs having in addition or exclusively β reducing properties (Abeta); HMG-CoA reductase inhibitors such as statins; acetylcholine esterase inhibitors such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagonists such as, for example, memantine; AMPA receptor agonists; positive modulators of AMPA receptors, AMkines, inhibitors of type 1 glycine transporters; monoamine receptor reuptake inhibitors; substances modulating the concentration or release of neurotransmitters; substances inducing the secretion of growth hormone such as ibutamorene mesylate and capromorelin; CB-1 receptor antagonists or reverse agonists; antibiotics such as minocycline or rifampicin; PDE1, PDE2, PDE4, PDE5 and / or PDEIO inhibitors; GABAA receptor reverse agonists; GABAA receptor antagonists; positive modulators or partial agonists or nicotinic receptor agonists; positive modulators or partial agonists or nicotinic alpha4beta2 receptor agonists; partial agonists or alpha7 nicotinic receptor agonists; histamine Η3 receptor antagonists; partial agonists or 5-des4 receptor agonists; 5ΗΤ6 receptor antagonists; alpha2 adrenoreceptor antagonists, calcium antagonists; positive modulators or partial agonists or agonists of muscarinic M1 receptors; Μ2 muscarinic receptor antagonists; Μ4 muscarinic receptor antagonists; positive modulators of metabotropic glutamate type 5 receptors; metabotropic glutamate type 2 receptor antagonists, and other substances which modulate receptors or enzymes in such a way that the efficacy and / or safety of the compounds according to the invention is increased and / or the unwanted side effects are reduced.

The present invention further relates to pharmaceutical compositions containing one or more, preferably an active principle. The active principle (s) are chosen from the compounds according to

ΜΑ 33152Β1! 'Invention and / or their corresponding salts. Preferably, the composition comprises only one of these active ingredients. In the event that more than one active principle is present, the other active principle can be chosen from the above mentioned group of association partners such as alzhemed, vitamin E, ginkgolide, donepezil, rivastigmine, tacrine, galantamine, memantine, ibutamorene mesylate, capromorelin, minocycline and / or rifampicin. Optionally, the composition includes other ingredients such as inert excipients and / or diluents.

The compounds according to the invention can also be used in combination with immunotherapies such as, for example, active immunization with Abeta or parts thereof or passive immunization with antibodies or fragments of humanized antiAbeta antibodies for example. the treatment of the diseases and pathologies mentioned above.

The compounds according to the invention can also be combined with dimebon.

The combinations according to the present invention can be used simultaneously in one and the same pharmaceutical form, that is to say in the form of a combination preparation, for example the two components can be incorporated in a tablet, for example example in different layers of said tablet. The combination can also be used separately, in the form of a free combination, i.e. the compounds of the present invention are provided in a pharmaceutical form and one or more of the association partners mentioned above. above are supplied in an alternate dosage form. These two pharmaceutical forms may be equivalent pharmaceutical forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the compound of the present invention and the other containing a therapeutically effective amount of the mentioned combination partner. above. If desired, it is also possible to combine different forms of administration. All types of suitable administration forms can be used.

The compound according to the invention, or a physiologically acceptable salt thereof, and another active principle used in combination can be used simultaneously or in a phased manner, but in particular closely in time. If they are administered simultaneously, the two active ingredients are given to the patient at the same time. If they are administered in a staggered manner, the two active ingredients are administered to the patient successively over a period less than or equal to 12, in particular less than or equal to 6 hours.

The pharmaceutical or administration forms are not limited and within the scope of the present invention any suitable pharmaceutical form can be used. Examples of pharmaceutical forms can be chosen from solid preparations such as patches, tablets, capsules, pills, lozenges, dragees, powders, trochisks, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like.

The pharmaceutical forms are advantageously formulated in the form of dosage units, each dosage unit being suitable for the administration of a single dose of each active principle present. The ingredients are chosen according to the mode of administration and the pharmaceutical form.

The dosage for the combination partners mentioned above is suitably from 1/5 of the lowest generally recommended dose to 1/1 of the generally recommended dose.

The pharmaceutical forms are administered to the patient for example 1, 2, 3, or 4 times a day depending on the nature of the formulation. In the case of delayed or sustained release formulations or other pharmaceutical formulations, what has just been stated may

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ΜΑ 33152Β1 be applied differently (eg once a week or a month, etc.). It is preferable that the compounds of the invention are administered three times or less, more preferably once or twice a day.

Examples

Pharmaceutical compositions

Illustrative examples not intended to be limiting By way of illustration, pharmaceutical formulations will now be described, in which the term "active principle" represents one or more compounds according to the invention, including their salts. In the case of one of the associations mentioned above with one or more other active principles, the term “active principle” can also include the other active principles.

Example A

Tablets containing 100 mg of active ingredient

Composition: compressed active ingredient lactose corn starch polyvinylpyrrolidone magnesium stearate

100.0 mg

80.0 mg

34.0 mg 4.0 mg

<img file="MA33152B1_D0034.tif" />

Example B

Tablets containing 150 mg of active ingredient

Composition: compressed active ingredient powdered lactose corn starch colloidal silica polyvinylpyrrolidone magnesium stearate

150, 89, C 40, C 10, C 1O٠C mg

Example c

Hard gelatin capsules containing 150 mg of active substance

Composition: capsules active ingredient corn starch (dry) approx. lactose approx. magnesium stearate approx.

150.0 mg

80.0 mg 87.0 mg 3.0 mg

320.0 mg

Example D

Composition: suppository active principle polyethylene glycol 1500 polyethylene glycol 6000 polyoxyethylene sorbitan monostearate 840.0 mg

2,000.0 mg

Example E

Composition: ampoules containing 10 mg of active principle 10.0 mg active principle

150.0 mg 550.0 mg 460.0 mg

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ΜΑ 33152Β1 hydrochloric acid 0.01 N qsp

double distilled water up to 2.0 ml

Example F

Composition: ampoules containing 50 mg of active principle active principle 50.0 mg hydrochloric acid 0.01 N qsp

double distilled water up to 10.0 ml

The preparation of any of the formulations mentioned above can be carried out following standard procedures.

Biological dosage

The in vitro effect of the compounds of the invention can be illustrated by the following biological assays.

ΡΡΕ9Α2 assay protocol:

The assay for the enzymatic activity of PDE9A2 is performed as a proximity scintillation (SPA) assay, generally according to the manufacturer's protocol (GE Healthcare, formerly Amersham Biosciences, product number: TRKQ 7100).

As enzymatic source, a lysate (PBS with 1% Triton Χ-100 enriched with protease inhibitors, cell debris removed by centrifugation at 13,000 rpm for 30 minutes) of SF 9 cells expressing human PDE9A2 is used. The amount of total protein included in the assay varies depending on the infection and production efficiency of SF9 cells and ranges from 0.1 to 100 ng.

In general, the assay conditions are as follows:

"Total assay volume: 40 microliters" amount of protein: 0.1 to 50 ng substrate concentration (cGMP): 20 nanomoles; ~ 1 mCi / 1 incubation time: 60 min at room temperature final concentration of DMSO: 0.2 to 1 فأ

The assays are performed with a 384-well format. The reagents to be tested as well as the enzyme and the substrate are diluted in an assay buffer. Assay buffer contains 50 mM Tris, 8.3 mM MgCl, 1.7 mM EGTA, 0.1% bovine albumin serum, 0.05% Tween 20; the pH of the assay buffer is adjusted to 7.5. The reaction is stopped by the application of a specific PDE9 inhibitor (for example the compounds according to document WO004099210 or WO004099211, such as one of the enantiomers of Example 37, for example 1- (2-chlorophenyl). -6 - [(2R) -3,3,3-trifluoro2-methy! -Propyl] -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one) in excess.

5 References .٠

Wunder F, Tersteeqen A, Rebmann A, Erb c, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Molecular Pharmacology. 2005 Dec; 68 (6): 177581.

van der staay FJ, Rutten K, Barfacker L, Devry j, Erb c, Heckroth H,

Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts j, Reymann KG. Schroder UH, Hendrix M. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 2008 Oct; 55 (5): 908-18.

PDEIC assay protocol;

-The assay is carried out in a manner analogous to the assay of PDE9A2, however with the following differences: instead of PDE9A2, PDEIC is used and the assay buffer additionally contains 50 nM of calmodulin, 3 mM of CaCl ؛. The reaction can be stopped by applying the

ΜΑ 33152Β1 same inhibitor as indicated above (1- (2-chlorophenyl) -6 - [(2R) 3,3,3-triflu٠ro-2-methyl-pr٠pyl] -1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin4-one).

Determination of% inhibition:

The activity of the positive control (minus the negative control = background) is set at 100% and the activity in the presence of the compound to be tested is expressed relative to these 100%. Under these conditions, inhibition greater than 100% may be possible due to the nature of the variation of the positive control in the assay. In the following section, the inhibition of PDE9A2 is presented for a concentration of 10 μΜ, unless otherwise indicated.

Determination of the IC:

The IC can be calculated with GraphPadPrism or other suitable software setting the positive control at 100 and the negative control at 0. For the calculation of the IC, the dilutions of the compounds to be tested (substrates) must be chosen and tested according to the mentioned protocol. above.

Data

In the following part, the inhibition data in% (% I) at a concentration of 10 micromoles (at 10 microM) and the IC values ​​for the inhibition of PDE9A2 [nanomoles (nM)] will illustrate that the compounds according to the present invention are suitable for the inhibition of

PDE9, in particular PDE9A2. This shows that the compounds provide useful pharmacological properties (Table 4). The examples are not intended to be limiting.

Under these conditions, inhibition greater than 100% may be possible due to the nature of the variation of the positive control in the assay.

The table also shows selectivity (S) values ​​which show compound preference for PDE9A over PDEIC. Selectivity is the ratio (CI for inhibition of PDEIC) / (CI for inhibition of PDE9A2).

The numbers of the examples refer to the final examples as underlined in the "Embodiment Examples" section.

All data is measured according to the procedure described here.

Table 4

1% (at 10 microM): inhibition at a concentration of 10 micromoles.

IC (nM): IC values ​​for inhibition of PDE9A2 [nanomoles (nM)]

S: selectivity values ​​[= (CI for inhibition of PDEIC) / (CI for inhibition of PDE9A2)]

<td>Example No.</td><td>Go LQ microM)</td><td>THIS (nM)</td><td>S</td>

<td> 219</td><td> 103</td><td> 12</td><td> 179</td>

<td> 220</td><td> 104</td><td> 5</td><td> 526</td>

<td> 221</td><td> 103</td><td> 6</td><td> 98</td>

<td> 222</td><td> 104</td><td> 15</td><td> 131</td>

<td> 223</td><td> 100</td><td> 5</td><td> 1717</td>

<td> 224</td><td> 100</td><td> 12</td><td> 146</td>

<td> 225</td><td> 102</td><td> 6</td><td> 290</td>

<td> 226</td><td> 101</td><td> 9</td><td> 225</td>

<td> 227</td><td> 101</td><td> 8</td><td> 147</td>

<td> 228</td><td> 101</td><td> 6</td><td> 244</td>

<td> 229</td><td> 99</td><td> 14</td><td> 135</td>

<td> 230</td><td> 101</td><td> 12</td><td> 145</td>

<td> 230-1</td><td> 98</td><td> 5</td><td> 197</td>

<td> 230-2</td><td> 102</td><td> 5</td><td> 286</td>

<td>Example No.</td><td>(to 10 microM)</td><td>CIso (nM)</td><td>S</td>

<td> 230-3</td><td> 99</td><td> 11</td><td> 135</td>

<td> 230-5</td><td> 98</td><td> 6</td><td> 274</td>

<td> 231</td><td> 95</td><td> 18</td><td> 245</td>

<td> 232</td><td> 99</td><td> ٦</td><td> 255</td>

<td> 234</td><td> 101</td><td> 3</td><td> &gt; 3333</td>

<td> 239</td><td> 92</td><td> 2</td><td> 400</td>

<td> 240</td><td> 100</td><td> 5</td><td> 126</td>

<td> 241</td><td> 100</td><td> 6</td><td> 368</td>

<td> 242</td><td> 96</td><td> 23</td><td> &gt; 429</td>

<td> 243</td><td> 96</td><td> 18</td><td> 114</td>

<td> 244</td><td> 99</td><td> 26</td><td> 110</td>

<td> 245</td><td> 95</td><td> 21</td><td> 22</td>

<td> 246</td><td> 94</td><td> 55</td><td> 17</td>

<td> 247</td><td> 98</td><td> 21</td><td> 42</td>

٩52Β٩ &lt;؟ ٦ 1

<td>Example No.</td><td>1% (to 10 microM)</td><td>THIS (nM)</td><td>S</td>

<td> 248</td><td>الأ</td><td> 45</td><td> 28</td>

<td> 249</td><td> 101</td><td> 28</td><td> 68</td>

<td> 250</td><td> 99</td><td> 24</td><td> 184</td>

<td> 251</td><td> 101</td><td> 38</td><td> 2.1</td>

<td> 252</td><td> 96</td><td> 11</td><td> 493</td>

<td> 253</td><td> 99</td><td> 34</td><td> 56</td>

<td> 254</td><td> 97</td><td> 20</td><td> 238</td>

<td> 255</td><td> 101</td><td> 41</td><td> 12</td>

<td>Example No.</td><td>1% ل 1٢ ة) microM)</td><td>THIS (nM)</td><td>S</td>

<td> 256</td><td> 103</td><td> 5</td><td> 123</td>

<td> 257</td><td> 103</td><td> 31</td><td> 10</td>

<td> 258</td><td> 100</td><td> ٦</td><td> 122</td>

<td> 259</td><td> 102</td><td> 3</td><td> 942</td>

<td> 260</td><td> 103</td><td> ٦</td><td> 266</td>

<td> 261</td><td> 102</td><td> 4</td><td> 580</td>

<td> 262</td><td> 101</td><td> 20</td><td> 451</td>

<td> 263</td><td> 102</td><td> 8</td><td> 1116</td>

Effect in vivo:

The in vivo effect of the compounds of the present invention can be tested in the Novel Object Recognition test according to the procedure of Prickaerts et al. (Neuroscience 2002, 113,

351-361) or the spontaneous alternation test in the T-maze according to the procedure described by van der staay et al. (Neuropharmacology 2008, 55, 908-918). For more information regarding biological tests, also refer to these two citations.

In addition to the inhibitory property against target PDE9s, the compounds according to the present invention may offer other advantageous pharmacokinetic properties.

For example, the compounds of the present invention may exhibit one or more advantages in the area of ​​balanced metabolism, low risk of drug-drug interaction and / or balanced clearance.

The compounds may also exhibit one or more additional or alternative advantages in the field of bioavailability, a large fraction absorbed, properties of blood transport to the brain, a favorable residence time (mrt) (for example high), favorable exposure in the appropriate compartment, and so on.

Chemical preparations

In this section, the compounds according to the invention will be described, as well as chemically similar compounds which do not show the exact motif as defined for rI. The mode of preparation of the two types of compounds will illustrate the process of preparation of the compounds according to the invention.

Abbreviations:

APCI chemical ionization ق atmospheric pressure

DAD diode array detector

DMSO dimethyl sulfoxide

ESI electrospray ionization (in MS)

Exp. example

Pf. Melting point h hour (sj

HPLC high pressure liquid chromatography

HPLC-MS high pressure liquid chromatography coupled with mass spectroscopy detection

GC-MS gas chromatography coupled with detection by mass spectrometry

MPLC medium pressure liquid chromatography ml milliliter pL microliter min minutes

MS racem mass spectrometry. racemic rt room temperature

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R_t retention time fen HPLC)

Rf iactor of delay (in CCM)

TBTU 2- (ΙΗ-Benzotriazol-1-yl) -1,1,3,3tetramethyluronium tetrafluoroborate

TFA trifluoroacetic acid

TLC thin layer chromatography

2Β٩ &lt;؟ ٩ &lt;؟ &lt;2 UK

LC-MS processes:

Method A

Instrument: HPLC / MS ThermoFinnigan. HPLC Surveyor DAD, LCQduo Ion trap. ; column: Sunryse MS-C18, 5 µm, 4.6 X 100 mm; eluent A: water t 20 mM ammonium formate; eluent B: acetonitrile + 20 mM ammonium formate; gradient: Α / Β (95: 5) for 1 minute, then change to Α / Β (5:95) in 7 minutes for 1.5 minutes; flow rate: 0.85 ml / minute; UV detection: 254 nm; ion source: ESI

Process 1

MS Device Type: Waters Micromass ZQ; HPLC Device Type: Waters Alliance 2695, Waters 2996 Diode Array Detector; column: Varian Microsorb 100 C18, 30 X 4.6 mm, 3.0 µm; eluent A: water t 0.13% TFA, eluent B: acetonitrile; gradient: 0.0 min. 5% B 0.18 min. 5% B ١ 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 / minute; UV detection: 210-380 nm.

Process 2

MS Device Type: Waters Micromass ZQ; HPLC Device Type: Waters Alliance 2695, Waters 2996 Diode Array Detector; column: Merck Chromolith Performance RP18e, 100 xlmm; eluent A: water t 0.13% TFA, eluent B: acetonitrile; gradient: 0.0 min. 5% B * 0.2 min. 5% B * 1.6 min. 98% B * 1.9 min. 98% B * 2.0min. 5% B * 2.2 min. 5% B; flow rate: 3.5 ml / minute; UV detection: 210-380 nm.

ID process

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, MSQ

Quadrupole; column: Sunryse MS-C18, 5 µm, 4.6 X 100 mm; eluent A: 90% water t 10% acetonitrile t 10 mM ammonium formate; eluent B: 90% acetonitrile 10 ؛ % water t 10 mM ammonium formate; gradient: A (100) for 1 minute, then change to B (100) in 7 minutes for 1 minute; flow rate: 1.2 ml / minute; Uv detection: 254 nm; ion source:

APCI.

Process 1Ε

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, MSQ

Quadrupole; column: Symmetry C8, 5 µm, 3 X 150 mm; eluent A: 90% water 10 ؛ % acetonitrile + 10 mM ammonium formate; eluent B: 90% acetonitrile t 10% HO t 10 mM ammonium formate; gradient: A (100) for 1.5 minutes, then change to B (100) in 10 minutes for 1.5 minutes; flow rate: 1.2 ml / minute; Uv detection: 254 nm; ion source:

APCI.

Process 1Ε fusion

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, MSQ Quadrupole; column: Synergi Fusion-RP80A, 4 µm, 4.60 X 100 mm; eluent A: 90% water 10 ؛ % acetonitrile t 10 mM ammonium formate; eluting

B: 90% acetonitrile t 10% HO + 10 mM ammonium formate; gradient: A (100%) for 1.5 minutes, then change to B (100%) in 10 minutes for 1.5 minutes; flow rate: 1.2 ml / minute; Uv detection:

254 nm; ion source: APCI.

1Ε hydro process

ΜΑ 33152Β1

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP80A, 4 µm, 4.60 X 100 mm; eluent A: 90% water ۶ 10% acetonitrile + 10 mM ammonium formate; eluent B: 90% acetonitrile 10 ؛% HO ؛ 10 mM ammonium formate;

gradient: A (100%) for 1.5 minutes, then change to B (100%) in 10 minutes for 1.5 minutes; flow rate: 1.2 ml / minute; Uv detection: 254 nm; ion source: APCI.

2F process

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, Finnigan

LCQduo Ion trap; column: Symmetry-ci8, 5 µm, 3 X 150 mm; eluent A: 95% water 15% acetonitrile + 0.1% formic acid; eluent B: 95% acetonitrile + 5% water + 0.1% formic acid; gradient: Α / Β (95/5) for 1.5 minutes, then change to Α / Β (5/95) in 10 minutes for

1.5 minutes; flow rate: 1 ml / minute; Uv detection: 254 nm; ion source:

ESI.

2L process

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, Finnigan

LCQduo Ion trap; column: Symmetry Shield, 5 µm, 4.6 X 150 mm; eluent A: 90% water 4 10% acetonitrile t 0.1% formic acid; eluent B: 90% acetonitrile t 10% water + 0.1% formic acid; gradient: A / B (70/30) in 1.5 minutes then change to A / B (50/50) then change to B (100%) in 7 minutes for 9.5 minutes; flow rate: 0.85 ml / minute; Uv detection:

254 nm; ion source: ESI.

Process 2Μ

Instrument: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, Finnigan LCQduo Ion trap; column: Symmetry Shield, 5 µm, 4.6 X 150 mm; eluting

A: 90% water 10 ؛ % acetonitrile + 0.1% formic acid; eluent B: 90% acetonitrile + 10% water + 0.1% formic acid; gradient: A / B (90/10) for 1.5 minutes, then change to A / B (5/95) in 10 minutes for 2 minutes; flow rate: 1.2 ml / minute; Uv detection: 254 nm; ion source: APCI.

Grad_C8_acide process

Instrument: HPLC-MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; column: xterra MS-C8, 3.5 µm, 4.6x50mm; eluent A: water + 0.1% TFA + 10% acetonitrile; eluent B: acetonitrile; gradient: A / B (80:20), then change to A / B (10:90) in 3.25 minutes for 0.75 minutes; flow rate: 1.3 ml / minute; Uv detection: 254 nm; ion source: ESI.

GradCISacid process

Instrument: HPLC-MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; Column: Sunfire MS-C18, 3.5 µm, 4.6 X 50 mm; eluent A: water t 0.1% TFA t 10% acetonitrile; eluent B: acetonitrile; gradient: A / B (80:20), then change to A / B (10:90) in 3.25 minutes for 0.75 minutes;

flow rate: 1.3 ml / minute; Uv detection: 254 nm; ion source: ESI.

Grad_90_10_C8_acide process

Instrument: HPLC-MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; column: xterra MS-C8, 3.5 µm, 4.6 X 50 mm; eluent A: water ٠ 0.1% TFA t 10% acetonitrile; eluent B: acetonitrile; gradient: A (100%), then change to Α / Β (10:90) in 3.25 minutes for 0.75 minutes; debit :

1.3 ml / minute; Uv detection: 254 nm; ion source: ESI.

Grad_90_10_C18_acide process

Instrument: HPLC-MS Waters. HPLC Alliance 2695 DAD, ZQ Quadrupole; column: xterra MS-C18, 3.5 µm, 4.6 X 50 mm; eluent A: water + 0.1% of

TFA t 10% acetonitrile; eluent B: acetonitrile; gradient: A (100),

ΜΑ 33152Β1 then switch to A / B (10:90) in 3.25 minutes for 0.75 minutes;

flow rate: 1.3 ml / minute; UV detection: 254 nm; ion source: ESI.

Grad process ce NH COOH

Instrument: HPLC-MS Waters. HPLC Alliance 2695 DAD, ZQ Ouadrupole.

Column: xterra MS-C8, 3.5 µm, 4.6 X 50 mm; eluent A: water t 5 mM ammonium formate + 10% acetonitrile; eluent B: acetonitrile; gradient: at 100%, then change to Α / Β (10:90) in 3.25 minutes for 0.75 minutes; flow rate: 1.3 ml / minute; UV detection: 254 nm; ion source:

ESI.

Process 5

MS Device Type: Waters Micromass ZQ; HPLC Device Type: Waters Alliance 2695, Waters 2996 Diode Array Detector; column :

Varian Microsorb 100 C18, 30 X 4.6 mm, 5.0 µm; eluent A: water t 0.15% of

TFA, eluent B: methanol; gradient: 0.0 min. 5% B »0.15 min. 5% of

B 2.55 ي min. 100% B ”2.70 min. 100% of B 2.80 ي min. 5% of B - "

3.05 min. 5% B; flow rate: 4.8 ml / minute; UV detection: 210-400 nm.

Process 6

MS Device Type: Waters Micromass ZQ; HPLC Device Type: Waters Alliance 2695, Waters 2996 Diode Array Detector; column: Waters Sunfire C18, 20 X 4.6 mm, 5.0 µm; eluent A: water t 0.15% TFA, eluent B: methanol; gradient: 0.0 min. 5% B -0.25 min. 5% of B

1.90 min. 100% B * 2.05 min. 100% B ”2.15 min. 5% of B

2.30 min. 5% B; flow rate: 5.2 ml / minute; UV detection: 210-400 nm.

Procfedfe ٦

MS Device Type: Waters Micromass ZQ; HPLC Device Type: Waters Alliance 2695, Waters 2996 Diode Array Detector; column: Waters Varian Microsorb C18, 20x4.6mm, 5.0 µm; eluent A: water t 0.15% TFA, eluent B: methanol; gradient: 0.0 min. 5% B t 0.25 min. 5% B t 1.90 min. 100% B ”2.05min. 100% B * 2.15 min. 5% of B 2.30 ي min. 5% B; flow rate: 5.2 ml / minute; UV detection: 210-400 nm.

Chiral HPIiC processes

Instrument: Agilent 1100. Column: Chiralpak AS-Η Daicel, 4.6 µm.

<td>4.6 X</td><td>250 mm.</td><td></td><td></td><td></td><td></td>

<td></td><td>Chiral process</td><td>1: eluent:</td><td>hexane / ethanol</td><td> 97/3</td><td>(isocratic);</td>

<td>debit</td><td>: 1.0 ml / minute</td><td>; UV detection</td><td>: 254 nm.</td><td></td><td></td>

<td></td><td>Chiral process</td><td>2: eluent:</td><td>hexane / ethanol</td><td> 98/2</td><td>(isocratic);</td>

<td>debit</td><td>: 1.0 ml / minute</td><td>; UV detection</td><td>: 254 nm</td><td></td><td></td>

<td></td><td>Chiral process</td><td>3: eluent:</td><td>hexane / ethanol</td><td> 80/20</td><td>(isocratic);</td>

<td>debit</td><td>: 1.0 ml / minute</td><td>; UV detection</td><td>: 254 nm</td><td></td><td></td>

GC / MS processes

Process 3Α

Instrument: GC / MS Finnigan. Trace GC, MSQ Quadrupole. Column: DB5MS, 25m X 0.25mm X 0.25 µm; carrier gas: helium, 1 ml / min at constant flow rate; oven program: 50 ٠c (hold for 1 minute), change to 100 ٠c in 10 ٠c / minute, change to 200 ٠c in 20 ٠c / minute, change to 300 ٠c in 30 ° C / minutes, eluent, detection: GC trace , MSQ Quadrupole ion source: El scanning range: 50-450 U.

Process 3Α.1

Instrument: GC / MS Finnigan Thermo Scientific. Trace GC Ultra, DSQ II single Quadrupole. Column: DB-5MS IU, 25m X 0.25mm X 0.25 µm; carrier gas: helium, 1 ml / min at constant flow rate; oven program: 50 ٠c (hold for 1 minute), change to 100 ٠c in 10 ° c / minute, change to

ΜΑ 33152Β1

200 “C in 20 ٠c / minute, change to 300 ٠c in 30 ٠c / minute, eluent, detection: GC trace, single Quadrupole

Microwave heating:

Types of microwave devices:

Discover® CEM instruments, equipped with 10 and 35 ml containers;

Biotage Initiator sixty.

General comment! concerning the presentation of structures

Some compounds have one or more chiral centers. The structure presented will not necessarily show all the possible stereochemistry of the compounds, but only one stereochemistry. However, in such cases, a term such as "cis racemic mixture" is indicated near the structure in order to indicate other stereochemical options.

An example is given for Example 7D below. The structural formula presented is

<img file="MA33152B1_D0035.tif" />

Racemic cis mixture

The added term "cis racemic mixture" indicates the second option stereochemistry:

<img file="MA33152B1_D0036.tif" />

This principle also applies to all other structures.

Synthesis

The following part describes the preparation of the compounds which illustrate the present invention. In the event that the process for preparing a specific compound is not described literally, those skilled in the art will find a description of analogous procedures in these descriptions which he can follow in principle. In some cases, it is said that the examples can be prepared analogously to another example. When referring to such an "analogous process", the reaction conditions are about the same, although the molar ratios of reactants and products have to be adjusted. It is also evident that the starting materials in a described process can be chemically varied to achieve the same results, i.e. if an ester condensation reaction is described in which the alcohol component is a leaving group , but is not the object of the product, this alcoholic component can vary without significant modifications of the procedure as such.

ΜΑ 33152Β1

Starting products

Example IA

<img file="MA33152B1_D0037.tif" />

A solution of 70 g (201 mmol) of carbethoxymethylene triphenylphosphorane in 300 ml of diethyl ether is cooled to 0 ٠c and 25 g (198 mmol) of 1,1,1-trifluorobutanone are added. The solution is warmed to room temperature and stirred overnight. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure (700 mbar and a bath temperature of 40 ° C.). The residue is purified by vacuum distillation (170 mbar and 130 ° C bath temperature, main fraction: 95-96 ° C). 29 g (75%) of the product are obtained in the form of a colorless oil.

HPLC-MS (Method 1): Rt: 1.77 min

MS (ESI pos): m / z = 196 (M ؛ H) ٠

Example 1ΑΑ

400 mg (10.0 mmol) of sodium hydride (60% in mineral oil) are suspended in 10 ml of THF and cooled to 4 ٠c. With stirring, a solution of 1.3 ml (8.99 mmol) of trimethyl phosphonoacetate in 10 ml of THF is added. The mixture is stirred for 1 h at the same temperature. Then, a solution of 4,4-difluorocyclohexanone in 10 ml of THF is added at 0 ٠c. The mixture is left to return to ambient temperature and stirred for 14 h. THF and water are added, then the THF is evaporated. The remainder is diluted with ethyl acetate, washed with water and saturated sodium hydrogencarbonate solution and concentrated to give 1.49 g (95%) of the product.

MS (El): m / z = 190 (M) ٠

The following Examples IB, IC, ID, ΙΕ, 2Α, 2Β, 2C and 2D show how the racemic acids of 3-trifluoromethyl-pentanoic acid and 3-trifluoromethyl-butyric acid can be transformed into both enantiomeric forms of free acid. Resolution can be achieved by separation of the diastereomeric intermediates. The two pure enantiomeric forms of the free acid are called enantiomer A and enantiomer B, respectively. The corresponding diastereomeric intermediates are called diastereoisomer A and diastereomer B respectively.

The same principle can be applied for the enantiomeric resolution of other racemic mixtures if necessary.

Example IB

ΜΑ 33152Β1

FO H

ه '

Diastereoisomer A

A solution of racemic 3-trifluoromethyl-pentanoic acid (8 g, 5 47 mmol), TBTU (16.6 g, 52 mmol) and diisopropylethylamine (24.1 ml,

141 mmol) in dimethylformamide (80 ml) is stirred at 20 ٠c for 1 h, then (s) - (-) -l-phenylethylamine (10 g, 82 mmol) is added and the mixture is stirred for 16 h at 20 ٠c. The solvent is removed and dichloromethane (200 ml) is added. The resulting mixture was washed with 10% citric acid in water (200ml), 20% K2CO3 in water (100ml) and dried over sodium sulfate. Evaporation of the solvent gives a crude solid which is mixed with methanol (10 mL) and filtered through a pad of activated basic alumina. The separation of the diastereoisomers is obtained by flash chromatography on SO eluting with a mixture of cyclohexane / ethyl acetate 85/15.

4.5 g (35.8%) of the title compound are obtained in the form of a white solid.

Rf: 0.25 (cyclohexane / ethyl acetate 85/15, stained with basic KMn٥4)

HPLC-MS (Method 1Ε hydro): Rt: 9.35 min

MS (APCI pos): m / z = 274 (MtH) '.

Chiral HPLC (Chiral Method 1): Rt: 5.58 min of:&gt; 99%

Example IC

٩٩’

Diastereoisomer B

4.4 g (34.2%) of a white solid are obtained in the form of a second product by means of the flash chromatography of Example 1B.

Rf: 0.20 (cyclohexane / ethyl acetate 85/15, stained with ΚΜηΟ₄ basic)

HPLC-MS (Method 1Ε hydro): Rt: 9.33 min MS (APCI pos): m / z = 274 (MH) ٠.

Chiral HPLC (Chiral Method 1): Rt: 6.18 min of:&gt; 99%

Example ID

3-rrifluoromethyl-pentanoic acid, Enantiomer A

<img file="MA33152B1_D0038.tif" />

Enantiomer A

A solution of Example IB (4.6 g, 17 mmol) in dioxane (15 ml) is treated with 70% HSO in water (25 ml) and refluxed for 16 h. The mixture is cooled, made basic to pH 14 with 32% NaOH in water, diluted with water (50 ml) and extracted with dichloromethane (2 X 200 ml). The resulting solution is acidified to pH 1

ΜΑ 33152Β1 with 9 N HCl, extracted with dichloromethane (3 X 500 ml) and the combined organic phases are dried. Evaporation of the solvent gives 2.47 g (85.3%) of a brown oil.

Rf: 0.66 (dichloromethane / methanol 9/1, colored with bromocresol green)

Chiral HPLC (Chiral Method 1): Rt 5.58 min ee:&gt; 99%

Example 1Ε

3-rrifluoromethyl-pentanoic acid, Enantiomer B

<img file="MA33152B1_D0039.tif" />

Enantiomer B

Analogously to the preparation of Example ID, the title compound is obtained using Example IC as a starting material.

Efficiency: 80.3%

Rf: 0.66 (dichloromethane / methanol 9/1, colored with bromocresol green)

Chiral HPLC (Chiral Method 1): Rt: 5.08 min ee:&gt; 99%

Example 2Α

4,4,4-Trifluoro-N - ((R) -2-hydroxy -! - phenyl-ethyl) -3-methyl-butyramide, Diastereoisomer A fk&gt;

OH

A solution of 3- (trifluoromethyl) butyric acid (10 g, 64 mmol) in dimethylformamide (100 ml) is treated with N (3-dimethylamino-propyl) -N'-ethylcarbodiimide hydrochloride (14.7 g, 77 اد), 4dimethyl-aminopyridine (11 g, 89.7 mmol) and (R) - (-) - phenylglycinol (9.9 g, 70.5 mmol). The mixture is stirred at 20 ° C for 16 h, then concentrated to reduce the volume and treated with 10% citric acid in water (300 mL). The mixture is extracted with ethyl ether (2 X 200 ml) and the separated organic phase is washed with 10% NaHCO 3 (150 ml) and brine (150 ml). The organic phase is dried and concentrated to give 13.1 g of a crude white solid.

The separation of the diastereoisomers is obtained by flash chromatography on Si٠2 eluting with a mixture of ethyl acetate / hexane 6/4.

5.32 g (30.2%) of the title compound are obtained in the form of a white solid.

Rf: 0.23 (ethyl acetate / hexane 6/4)

HPLC-MS (1Ε hydro): Rt: 6.97 min

MS (APCI pos): m / z = 276 (M + H) ٠.

Example 2Β

4,4,4-Trifluoro-N - ((R) -2-hydroxy-1-phenyl-ethyl) -3-methyl-butyramide, Diastereoisomer B

ΜΑ 33152Β1

3.08 g (17.5%) of a white solid are obtained in the form of a second product by means of the flash chromatography of Example 2Α.

Rf: 0.16 (ethyl acetate / hexane 6/4)

HPLC-MS (1Ε hydro): Rt 6.92 ؛ min

MS (APCI pos): m / z = 276 (MtH) '.

Example 2C, Enantiomer A

<img file="MA33152B1_D0040.tif" />

OH

<img file="MA33152B1_D0041.tif" />

A solution of Example 2Α (2 g, 7.26 mmol) in tetrahydrofuran (10 ml) is treated with HSO ؛ at 70% in water (10 ml) and refluxed for 16 h. The mixture is cooled, made basic to pH 14 with 32% NaOH in water, diluted with water (50ml) and extracted with dichloromethane (2 x 50ml). The resulting solution is acidified to pH 1 with 9N HCl, extracted with dichloromethane (3 x 50 mL) and the combined organic phases are dried. Evaporation of the solvent gives 0.84 g (74.1%) of a brown oil.

HPLC-MS (1Ε hydro): Rt: 1.73 min

MS (APCI neg): m / z = 155 (Μ-Η) -.

Chiral HPLC (Chiral Method 2): Rt: 6.92 min ee: 99%

Example 2Ρ, Enantiomer B

<img file="MA33152B1_D0042.tif" />

Analogously to the preparation of Example 2C, the title compound is obtained using Example 2Β as the starting material. 1.4 g (8.96 mmol) are obtained

Yield: 82.3%

HPLC-MS (1Ε hydro): Rt: 1.30 min

MS (APCI neg): m / z = 155 (Μ-Η) -.

Chiral HPLC (Chiral Method 2): Rt: 6.49 min ee: 98.6%

Example 3Α

2- (4-Trifluoromethyl-pyridin-2-yl) -malonic acid diethyl ester ، X

ΜΑ 33152Β1

<img file="MA33152B1_D0043.tif" />

A suspension of 60% sodium hydride in mineral oil (1.65 g, 41 mmol) in anhydrous dioxane (36 ml) is treated with diethyl malonate (6.3 ml, 41 mmol) at 25 'c and heat at 60 ٠c for 30 minutes. Cuprous chloride (1.63 g, 17 mmol) is added, the mixture is heated to 80 ٠c and 2-chloro-4- (trifluoromethyl) -pyridine is added and the mixture is gradually heated to 100 ٠c for 16 h .

After cooling to 20 c, the mixture is acidified with 10 to 37% HCl, diluted with water (120 ml) and extracted with dichloromethane (2 X 60 ml). The organic phase is dried and concentrated to give a crude oil which is purified by flash chromatography, eluting with a 95/5 to 60/40 mixture of n-hexane / ethyl acetate,

1.9 g (38%) are obtained in the form of a colorless oil.

HPLC-MS (2F): Rt: 12.24 min

MS (ESI pos): m / z = 306 (MtH) '.

Example 4Α

The following example is synthesized analogously to Preparation 20 of Example 5U, using the corresponding acid (Sinova Inc., Bethesda,

MD 20814, USA) as the starting material.

<img file="MA33152B1_D0044.tif" />

HPLC-MS (Method 1): Rt: 1.47 min

MS (ESI pos): m / z = 194 (M + H-EtOH) ٠

Example 4Β

<img file="MA33152B1_D0045.tif" />

2.0 g (8.6 mmol) of Example 4Α are dissolved in 40 ml of ethanol, Pd (10% on charcoal) is added, and the mixture is hydrogenated at room temperature (2 h, 50 psi) . The reaction mixture is filtered and the residue is washed with ethanol. The solvent is evaporated off under reduced pressure. 1.80 g (100%) of the product are obtained.

HPLC-MS (Method 1): R ،: 0.91 min

MS (ESI pos): m / z = 210 (M ؛ H) ٠

ΜΑ 33152Β1

<img file="MA33152B1_D0046.tif" />

Example 5Α

3-Trifluoromethyl-pentanoic acid methyl ester, Enantiomer A

To a stirred solution of Example ID (250 mg, 1.47 mmol) in dichloromethane (10 ml) and methanol (0.25 ml), under a nitrogen atmosphere, trimethylsilyldiazomethane (solution 2.0 M in diethyl ether (2.1ml, 4.19mmol) at 0 ° C. The reaction mixture is stirred while maintaining the temperature below 5 ٠c for 1 h. The solvent is removed (40 c, 25 bars) giving 250 mg (75.4%) of a yellow oil which is used in the next step without further purification.

GC (Process 3 Procédé): Rt: 3.29 min

MS (El): m / z: 165 (Μ-19) ', 155 (Μ-29)', 153 (Μ-31) '

The following examples are synthesized analogously to the preparation of Example 5Α, using the corresponding acids as starting materials.

<td></td><td>structure</td><td>product of departure : acid carboxylic</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 5 B Enantiomer A</td><td>ا 0 ر٢— F</td><td>Example 2C</td><td>8.01 (Process 3Α)</td><td>170 [El]</td>

<td>Example 5 VS Enantiomer B</td><td>كبر F — r</td><td>2D example</td><td>8.01 (Process 3Α)</td><td>170 [El]</td>

<td>Example 5 D Enantiomer B</td><td>F — r ج— q /</td><td>Example 1Ε</td><td>3.29 (Process 3Α)</td><td>165 (Μ-19) ', 155 (Μ-29) ٠, 153 (Μ-31) ٠ [El]</td>

<td>Example 5 E</td><td> ٦</td><td>ع ك ٦</td><td>7.82 (Process 3Α)</td><td>252 [El]</td>

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : acid carboxylic</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 5 F</td><td>اي</td><td>0 طي</td><td>9.53 (Process 3Α)</td><td>202 [El]</td>

<td>Example 5 G Enantiomer s</td><td>'در</td><td>ارى</td><td>3.92 (Process 3Α)</td><td>130 [El]</td>

<td>Example 5 H</td><td>لحد</td><td>دح</td><td>5.09 (Process 3Α)</td><td>؛ (29-115 (Μ [El]</td>

<td>Example 5 HA cis, racem mix.</td><td>مة</td><td>Example 18Α</td><td>1.22 (Method 1)</td><td>264 [ESI, (MtH) *]</td>

Example 51

[2- (1-Acetyl-piperidin-4-yloxy) -phenyl] acetic acid methyl ester

<img file="MA33152B1_D0047.tif" />

O

Di-tert-butyl azodicarboxylate (305 mg, 1.32 mmol) is added to a solution of 1- (4-hydroxy-piperidin-1-yl) -ethanone (259 mg,

1.8 nmol) in tetrahydrofuran (4 ml) under a nitrogen atmosphere.

Then, (2-hydroxy-phenyl) -acetic acid methyl ester (200 mg, 1.2 mmol) and triphenylphosphine (347 mg, 1.3 اد) are added. The yellow mixture is stirred at 20 c for 16 h. The solvent is evaporated and the residue is purified on silica using a mixture of hexane / ethyl acetate of increasing polarity (from 70% to 100% acetate

جه

Ethyl ΜΑ 33152Β1) as an eluent to give 195 mg (55.6%) of a colorless oil.

HPLC-MS (Grad_C8_NH 00Η process): Rt: 2.67 min

MS (ESI pos): m / z = 292 (MtH) '.

The following examples are synthesized analogously to the preparation of Example 5G, using the corresponding alcohols as starting products.

<td></td><td>Structure</td><td>product of departure : Alcohol</td><td>Rf</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 5J mixed racem.</td><td> ,٠٦</td><td>HO 0 ج</td><td></td><td>2.53 (Grad C8 NHOOH process)</td><td>292 (M + H) ٠</td>

<td>Example 5Κ</td><td>زك</td><td>,-OH ة</td><td>0.35 (hexane / acetate of ethyl 8/2)</td><td></td><td></td>

<td>Example 5L</td><td>0 رغي</td><td>HO „٠C</td><td>2, ه (hexane / ethyl acetate ٦/٦١</td><td></td><td></td>

<td>Example 5Μ</td><td>ك'شل</td><td>H0٣ ر ٦</td><td>0.2 (hexane / ethyl acetate 7/3)</td><td></td><td></td>

<td>Example 50</td><td>د'لرا</td><td>° Ό</td><td>0.25 (hexane / acetate of ethyl 7/3)</td><td></td><td></td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>product of departure : Alcohol</td><td>Rf</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 5Ρ</td><td>خ</td><td>Η٠υ</td><td>0.35 (hexane / acetate of ethyl )</td><td></td><td></td>

Example 5Q

(3-meth٠xy-pyridin-2-yl) -acetic acid methyl ester

<img file="MA33152B1_D0048.tif" />

A mixture of (3-meth٥xy-2-pyridin-2-yl) -acetonitrile (400 mg, 2.7 mmol) in 2 ml of methanol and 96% sulfuric acid (1.8 ml, mmol) is heated in a microwave oven at 120 “C for 1 hour. The mixture is cooled to 0 ° C, made basic with solid NaHO, diluted with water (2 ml) and extracted with dichloromethane. The separated organic phase is dried and concentrated to give 450 mg (92%) of a dark yellow oil which is used in the next step without further purification.

HPLC-MS (Grad process C8.NH OOH): Rt: 1.92 min

MS (ESI pos): m / z = 182 (Μ + Η) '.

Example 5R

(4-Trifluoromethyl-pyridin-2-yl) -acetic acid ethyl ester

<img file="MA33152B1_D0049.tif" />

A solution of Example 3Α (1.0 g, 3.27 mmol) in anhydrous DMSO (θ ml) is treated with water (60 μΐ, 3.27 mmol) and lithium chloride (347 mg , 8.2 mmol). The resulting mixture is heated at 120 ° C for 16 h. After cooling to 20 c, the mixture is treated with brine (12 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phase is dried and concentrated to give a crude oil which is purified by flash chromatography, eluting with an 8/2 mixture of nhexane / ethyl acetate.

390 mg (51%) are obtained in the form of a colorless oil.

HPLC-MS (Method 2F): Rt: 11.09 min

MS (ESI pos): m / z = 234 (M ؛ H) '

Example 5S

(6-trifluoromethyl-pyridin-2-yD-acetic acid ethyl ester

ΜΑ 33152Β1

<img file="MA33152B1_D0050.tif" />

A mixture of cesium carbonate (1.87 g, 5.75 mmol) and tri-t_ 5 butylphosphine (107 μΐ, 0.44 mmol) in anhydrous 1,2 dimethoxyethane (10 ml) is treated with tris- (dibenzylideneacetone) di-palladium (81 mg, 0.09 mmol), 2-bromo-6- (trifluoromethyl) pyridine (Ig, 4.42 mmol) and diethyl malonate (0.8 ml, 5.3 mmol) under a nitrogen atmosphere. The mixture is heated at 150 ° C for 30 minutes in a microwave oven.

After cooling to 20 c, the mixture is treated with a saturated solution of ammonium chloride (120 ml) and extracted with ethyl ether (3 X 80 ml). The organic phase is dried and concentrated to give a crude oil which is purified by flash chromatography, eluting with a 6/1 mixture of n-hexane / ethyl ether.

460 mg (81%) are obtained in the form of a colorless oil.

GC (Process 3Α): Rt: 8.28 min MS (El): m / z = 233 (M) '

Example 5Τ, Racemic mixture

<img file="MA33152B1_D0051.tif" />

g (148 mmol) of Example IA are combined with 2 g of Pd / C (10%) and hydrogenated at room temperature (6 hrs, 15 psi). The reaction mixture is filtered and washed with diethyl ether. The solvent is evaporated off under reduced pressure (500 mbar, bath temperature of 40 C). 27.6 g (94%) of the product are obtained in the form of a colorless liquid.

HPLC-MS (Method 1): Rt: 1.65 min

Example 5ΤΑ

شذ

1.49 g (95%, 7.43 mmol) are dissolved in 20 ml of ethanol and hydrogenated over 150 mg of Pd / c (10%) at atmospheric pressure for 14 h. The mixture is filtered and the solvent is removed to give 1.27 g (89%) of the product.

Example 5U / 5 ،

ΜΑ 33152Β1

Br

<img file="MA33152B1_D0052.tif" />

A solution of 15 g (69.8 mmol) of (2-bromo-phenyl) -acéti٩ue acid in 50 ml of ethanol is cooled to 0 ° C and 8 ml (110 mmol) of thionyl chloride are added dropwise. drop. The reaction mixture is heated at 50 ٠c overnight. After cooling to room temperature, the solvent is removed under reduced pressure. The residue is mixed with ethyl acetate and filtered through 30 g of basic aluminum oxide. The filtrate is concentrated under reduced pressure. 18 g (92%) of the product are obtained.

HPLC-MS (Method 1): Rt: 1.62 min

MS (ESI pos): m / z = 243/45 (Br) (MtH) '

The following examples are synthesized analogously to the preparation of Example 5U, using the corresponding acids as starting materials.

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI m / z)</td>

<td>Exp. 5V</td><td>Λλ</td><td>0 ٢٨OH</td><td></td><td>185 (MtH) ٠</td>

<td>Exp. 5Υ</td><td>لي ٦ له ٠</td><td></td><td>1.56 (Process 1)</td><td>199/201 (Cl) (MtH) ٠</td>

<td>Exp. 5W</td><td> ٦٦٢٦</td><td> ٦٦٣٠</td><td>1.53 (Process 1)</td><td>201 (MtH) *</td>

<td>Exp. 5Χ</td><td> ٦</td><td>H</td><td></td><td>171 (MtH) *</td>

ΜΑ 33152Β1

<td>Exp. 5Ζ</td><td> ۴</td><td>٠٧٢ Cl</td><td>1.74 (Process 1)</td><td>233/235 / 237 (2C1) (MtH) *</td>

<td>Exp. 5AA mixed racem.</td><td>لك 0 د ١</td><td>ه</td><td></td><td>133 (MtH) ا</td>

<td>Exp. 5AB</td><td> 0</td><td>خء</td><td></td><td>201 (MtH) ا</td>

<td>Exp. 5AC</td><td>لمم</td><td>ع</td><td>1.65 (Process 1)</td><td>157/58 (MtH) *</td>

<td>Exp. 5AD</td><td>مئ</td><td>مئ</td><td>1.36 (Process 1)</td><td>195 (MtH) *</td>

<td>Exp. 5ΑΕ</td><td>؛ 'Ό ؛:</td><td>ي</td><td>1.69 (Process 1)</td><td>249/50 (MtH) *</td>

<td>Exp. 5AF mixed racem.</td><td>رض</td><td>٠ ض</td><td></td><td>Available in trade</td>

يك

ΜΑ 33152Β1

<td>Exp. 5AG</td><td>ي</td><td>د ي</td><td>1.46 (Process 1)</td><td></td>

<td>Exp. 5AH</td><td>ر</td><td>0 0Η دإد ٦٩</td><td>1.63 (Process 1)</td><td></td>

<td>Exp. 5 AI</td><td>تمره FF</td><td>0Η FF</td><td></td><td>185 (Μ + Η) ا</td>

<td>Exp. 5AJ</td><td>ل الملح 0</td><td>0Η لمللح 0</td><td>1.43 (Process 1)</td><td>213 (Μ + Η) ٠</td>

<td>Exp. 5AK</td><td>غ ١</td><td>“حم ١ ى ٠</td><td></td><td></td>

laughed

ΜΑ 33152Β1

<td>Exp. 5AL</td><td>٨٩ ي</td><td colspan="2">د ي</td><td>1.58 (Process 1)</td><td>235/237 (Cl) (MtH) '</td>

<td>Exp. 5ALA</td><td>دع</td><td>ر</td><td>٠Η ٠ د ل</td><td>1.29 (Process 1)</td><td>129 (MtH) *</td>

<td>Exp. 5ALB</td><td> ؟·</td><td colspan="2">زتئ</td><td>1.54 (Process 1)</td><td>229/231 (Cl) (MtH) '</td>

<td>Exp. 5ALC</td><td>لمررم</td><td></td><td>٦ رم</td><td>1.62 (Process 1)</td><td>157 (MtH) '</td>

<td>Exp. 5ALD</td><td></td><td colspan="2">Λ٨Λ</td><td>1.56 (Process 1)</td><td>209 (MtH) '</td>

<td>Exp. 5ALE</td><td> ٧٦</td><td>r ١</td><td>٧١۴٥ OH رك</td><td>1.59 (Process 1)</td><td>291 (MtH) '</td>

ΜΑ 33152Β1

<td>Exp. 5ALF</td><td> ٨/١ ٦</td><td>ب ٦</td><td>1.86 (Process 5)</td><td>/ لآ 2٦٦/2٦ 281 (Μ٠Η) ٠ (Cl / Br)</td>

<td>Exp. 5ALG</td><td>ج دا</td><td>ب ك ٦</td><td>1.60 (Process 1)</td><td>261/263 (Br) (MtH) '</td>

Example 5ΑΜ

The following example is synthesized analogously to the preparation of Example 5U, using the corresponding acid as the starting material and methanol as the solvent.

<img file="MA33152B1_D0053.tif" />

HPLC-MS (Method 1): Rt: 1.04 min 10 MS (ESI pos): m / z = 167 (MtH) '

The following example is synthesized analogously to the preparation of Example 5AM, using the corresponding acid as the starting material.

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 5ΑΜΑ</td><td>يب</td><td>يب</td><td>1.52 (Process 1)</td><td>236 (MtH) '</td>

Example 5ΑΝ

ΜΑ 33152Β1

م '.,

6.0 g (88.5 mmol) of pyrazole are dissolved in 60 ml of DMSO, then 10.4 g (93 mmol) of potassium tert-butoxide are added portion by portion, maintaining the temperature between 20 and 25 ٠c . The reaction mixture is stirred for 10 minutes at room temperature. 10.8 ml (98 mmol) of ethyl bromacetate are added dropwise, maintaining the temperature between 25 and 35 ° C. The reaction mixture is stirred for 2 h at room temperature. The reaction mixture is added to saturated aqueous NaCl solution and extracted with ethyl acetate. The organic phase is dried, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by preparative MPLC (SO, eluent: mixture of dichloromethane / methanol 95/5). 10.4 g (38%) of the product are obtained.

Example 5ΑΟ

<img file="MA33152B1_D0054.tif" />

<img file="MA33152B1_D0055.tif" />

٥٧

1.83 g (7.7 mmol) of Example 4Β are mixed with 60 ml of 4N HCl and cooled in an ice bath. A solution of 1.15 g (16.4 mmol) of sodium nitride in 13.5 ml of water is added dropwise. After 10 minutes, a solution of 3.9 g (39.5 mmol) of copper (I) chloride in 20 ml of conc. is added dropwise. The reaction mixture is allowed to come to room temperature and is stirred for 30 minutes. The mixture is extracted with ethyl acetate. The organic phase is neutralized with potassium carbonate, filtered through celite and the filtrate is extracted with water. The organic phase is dried, filtered and the filtrate is concentrated under reduced pressure. 1.24 g (62%) of the product are obtained.

HPLC-MS (Method 1): Rt: 1.60 min MS (ESI pos): m / z = 229/231 (Cl) (M٠H) ٠

Example 5ΑΡ

<img file="MA33152B1_D0056.tif" />

Under argon 1.00 g (4.11 mmol) of Example 5U, 540 mg (4.95 mmol) of

3-methylpyridone and 80 mg (0.42 mmol) of copper (I) iodide are mixed with 5 ml of DMSO, then 1.14 g (8.25 mmol) of potassium carbonate and

2Β٩ &lt;؟ ٩ &lt;؟ &lt;2 1

120 mg (0.82 mmol) of 8-hydroxyquinoleine are added. The mixture is stirred for 48 h at 120 ٠c. After cooling to room temperature, the mixture is dissolved in ethyl acetate and washed with 1 M HCl and saturated sodium chloride solution. The organic phase is separated, dried and concentrated. The residue is purified by HPLC (eluent A: water f 0.13% TFA, eluent B: acetonitrile). The acetonitrile is evaporated and the remainder is extracted with ethyl acetate. The organic phase is dried and concentrated to give 633 mg (57%) of the desired product.

HPLC-MS (Method 1): Rt: 1.56 min 10 MS (ESI pos): m / z = 272 (MtH) '

Example 6Α

<img file="MA33152B1_D0057.tif" />

g (54 mmol) of lN-Boc-3-pyrrolidinone are dissolved in 50 ml of ethanol, then 7.3 g (55.2 mmol) of tert-butyl carbazate are added. The reaction mixture is stirred at room temperature for 2 h. The solvent is evaporated off under reduced pressure. The residue is purified by preparative MPLC (Si٥2, eluent: mixture of dichloromethane / methanol 95/5). 18 g (89%) of the product are obtained in the form of an oil.

HPLC-MS (Method 1): Rt: 1.35 min

MS (ESI neg.): M / z = 298 (Μ-Η) 25 Example 6Β

The following example is synthesized analogously to the preparation of Example 6 de, using Ι-Ν-Βοο-3-piperidone as the starting material.

<img file="MA33152B1_D0058.tif" />

HPLC-MS (Method 1): Rt: 1.45 min Example 7Α, Racemic mixture

ΜΑ 33152Β1

<img file="MA33152B1_D0059.tif" />

g (48 mmol) of Example 6Α are dissolved in 300 ml of methanol, then 2.5 g of Pd / C (10%) are added, and the mixture is hydrogenated at room temperature (8 h, 50 psi). The reaction mixture is filtered and the residue is washed with methanol. The solvent is evaporated off under reduced pressure. 16 g of product are obtained in the form of a colorless oil which is used without further purification.

HPLC-MS (Method 1): Rt: 1.36 min

Example 7Β, Racemic mixture

The following example is synthesized analogously to the preparation of Example 7Α, using Example 6Β as the starting material.

<img file="MA33152B1_D0060.tif" />

HPLC-MS (Method 1): Rt: 1.42 min

MS (ESI pos): m / z = 316 (MtH) '

Example 7C

<img file="MA33152B1_D0061.tif" />

g (100 mmol) of tetrahydropyran-4-one are dissolved in 100 ml of methanol and 14.5 g (110 mmol) of tert-butyl carbazate are added. The reaction mixture is stirred at room temperature for 2 h. The solvent is evaporated off under reduced pressure. The residue is mixed with 140 ml of acetic acid (50%), then 6.9 g (110 mmol) of sodium cyanoborohydride are added and the mixture is stirred at room temperature overnight. The reaction mixture is neutralized with 4 Met NaOH extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. 19 g (88%) of the product are obtained in the form of a white solid.

MS (ESI pos): m / z = 217 (M + H) ٠

لح

ΜΑ 33152Β1

The following examples are synthesized analogously to the preparation of Example 7C using the corresponding ketones as starting materials.

Example 7Ρ

<td></td><td>Structure</td><td>product of start: cetone</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 70 A cis, racem mix.</td><td>لإ ٢٠ ي</td><td>ά</td><td>11.12 (Process 3Α)</td><td>174 [El, (Μ-56) *]</td>

<td>Example 70 B trans, mixed racem.</td><td></td><td>0 مه</td><td>11.22 - (Process 3Α)</td><td>174 [El, (Μ-56) ']</td>

<td>Example 70 VS</td><td>٥٢٥۴ ΗΝ'ΝΗ٢ ٠</td><td>oh</td><td>0.99 (Method 1)</td><td>177 [ESI, [؛ ((M-56tH</td>

<img file="MA33152B1_D0062.tif" />

Racemic mixture cis

A solution of 2-methyl-tetrahydro-pyran-4-one (2.2 g, 19.7 mmol) in methanol (30 ml) is treated with tert-butyl carbazate (2.6 g, 19.7 mmol) and stirred for 3 11-20 ٠c. Evaporation of the solvent gives a white solid which is mixed with 30 ml of acetic acid (50% in water), and the mixture is treated with sodium cyanoborohydride (1.2 g, 19.7 mmol). portion by portion. The mixture is stirred at 20 ° C. for 16 h, then neutralized with 5Ν NaOH and extracted with dichloromethane. The organic phase is washed with saturated NaHO solution and brine, dried, filtered and concentrated to give a crude solid. The separation of the diastereoisomers is obtained by flash chromatography on SO eluting with a mixture of

ΜΑ 33152Β1 cyclohexane / ethyl acetate with increasing polarity (from 7/3 to 1/1) to give 1.85 g (41%) of a white solid.

Rf: 0.29 (hexane / ethyl acetate 1: 1)

HPLC-MS (Grad 90 10 C8 acidic process): Rt: 1.79 min

MS (ESI pos): m / z = 131 (M-100tHJ

The cis configuration between methyl and carbazyl groups is implied by the ROESY correlation for Η-2 / Η-4.

Example 7Ε

<img file="MA33152B1_D0063.tif" />

Racemic mixture trans

0.7 q (15%) of a colorless oil is obtained in the form of a second product by means of the flash chromatography of Example 7D.

Rf: 0.29 (mixture of hexane / ethyl acetate 1: 1 stained with Pancaldi's reagent)

HPLC-MS (Grad_90_10_C8_acide process): Rt: 1.96min MS (ESI pos): m / z = 131 (Μ-100 + Η) '

Example 8Α, Racemic mixture

<img file="MA33152B1_D0064.tif" />

g (46.5 mmol) of Example 7Α are dissolved in 50 ml of dichloromethane, cooled with an ice bath and 25 ml (325 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred for 3 h at room temperature. The solvent is evaporated off under reduced pressure. The residue is purified by preparative MPLC (Si٠2, eluent: dichloromethane / methanol mixture 8/2). 12 g (78%) of the product are obtained.

Example 8Β

The following example is synthesized analogously to the preparation of Example 8 de, using Example 7C as the starting material.

laughed

ΜΑ 33152Β1

<img file="MA33152B1_D0065.tif" />

MS (ESI pos): m / z = 117 (Μ + Η) '5 Example 8C, Racemic mixture

<img file="MA33152B1_D0066.tif" />

13.0 g (37.1 mmol) of Example 7Β are dissolved in 5 ml of dioxane, then 93 ml (371 mmol) of hydrochloric acid in dioxane (4M) are added. The reaction mixture is stirred overnight at room temperature. 40 ml of diethyl ether are added and the mixture is stirred for 15 minutes at room temperature. The reaction mixture is filtered. 7.0 g (100%) of the product are obtained in the form of a white solid.

The following examples are synthesized analogously to the preparation of Example 80 using the corresponding Boc-hydrazines as starting materials.

<td></td><td>Structure</td><td>starting material: Bochydrazine</td><td>MS m / z</td>

<td>Example 8C A cis, racem mix.</td><td>- ™ ا ٠: ت ٧</td><td>Example 7CA</td><td>131 (MtH) *</td>

<td>Example 8C B trans, mixed racem.</td><td>لآي</td><td>Example 7CB</td><td>131 (Μ + Η) '</td>

<td>Example 80 VS</td><td>عنه</td><td>Example 7CC</td><td>133 (MtH) ا</td>

ΜΑ 33152Β1

<img file="MA33152B1_D0067.tif" />

Racemic mixture trans

A solution of Example 7Ε (700 mg, 3 mmol) in dioxane (5 ml) is treated with 4 N HCl in dioxane (15 ml, 60 mmol) and the mixture is stirred at 20 ٠c for 18 h. The solvent is concentrated to give 560 mg (91%) of a sticky solid which is used in the next step without further purification.

HPLC-MS (Grad C8 NH OOH Low mass): Rt: 0.67 min

MS (ESI pos): m / z = 131 (MtH) ٠

<img file="MA33152B1_D0068.tif" />

Racemic mixture cis

Analogously to the preparation of Example 8D, the title compound is obtained using Example 7D as a starting material.

Yield: 68.3%

HPLC-MS (GradCNH OOH Low mass method): Rt: 0.70 min MS (ESI pos): m / z = 131 (MtH) '

Example 9Α, Racemic mixture

<img file="MA33152B1_D0069.tif" />

32.0 g (77.8 mmol) of Example 8Α are mixed with 12.0 g (98.3 mmol) of ethoxymethylene-malonodinitrile in 250 ml of ethanol, then ml (288 mmol) of triethylamine are added. The reaction mixture is heated at 50 ٠c for 2 h. After cooling to room temperature, the solvent is removed under reduced pressure. The residue is purified by preparative MPLC (Si٥2, eluent: mixture of dichloromethane / methanol

8/2).

HPLC-MS (Method 1): Rt: 0.29 min

ΜΑ 33152Β1

The following examples are synthesized analogously to the preparation of Example 9Α, using the corresponding hydrazines as starting materials.

<td></td><td>structure</td><td>product of departure</td><td>Rttmin]</td><td>MS (ESI, m / z)</td>

<td>Exp. 9Β Mixed racem.</td><td>٠. „حجر. ق</td><td>Example 8C</td><td>0.59 (Method 1)</td><td>192 (MtH) *</td>

<td>Exp. 9C</td><td>هي</td><td>Example 8Β</td><td>٠,٦6 (Method 1)</td><td>193 (MtH) ٠</td>

<td>Exp. 9D</td><td>٠ د ό</td><td>بري</td><td>0.32 (Method 1)</td><td>192 (MtH) *</td>

<td>Exp. 9Ε</td><td>ظ, " Q</td><td>برع</td><td>0.40 (Method 1)</td><td>206 (MtH) *</td>

ΜΑ 33152Β1

<td>Example 9ΕΑ cis, racem mixture.</td><td>يق</td><td>Example 8CA</td><td>1.90 Grad C8- NHCCOH</td><td>207 (M + H)⁺</td>

<td>Example 9ΕΒ trans, mixed racem.</td><td>دد</td><td>Example 8CB</td><td>1.87 Grad CB- NHCCOH</td><td>2٢٢٦ (MtH) ♦</td>

<td>Example 9EC</td><td>زد ه</td><td>Example 8CC</td><td>1.01 (Method 1)</td><td>209 (M + H)⁺</td>

Example 9F

<img file="MA33152B1_D0070.tif" />

٧

A mixture of 4.4 g (38 mmol) of (tetrahydro-pyran-4-yl) -hydrazine and 4.7 g (38 mmol) of ethoxymethylene-malononitrile in 90 ml of ethanol and 10.5 ml ( 103 mmol) of triethylamine is stirred at 50 ٠c for 30 minutes. After cooling to 20 ٠c, the solvent is removed under reduced pressure and the residue is treated with a water / dichloromethane mixture = 1/1. The resulting suspension is stirred for 15 minutes, then filtered to give a yellow solid which is then washed with dichloromethane, water and dichloromethane. The solid is dried at 45 ° C under reduced pressure. 2.7 g (37%) of the title compound are obtained as a yellow solid which is used in the next step without further purification.

The following examples are synthesized analogously to the preparation of Example 9F, using the corresponding hydrazines as starting materials.

ΜΑ 33152Β1

<td></td><td>Structure</td><td>product of start: hydrazine</td><td>Rt [min]</td><td>MS m / z</td>

<td>Example 9 G mixed racem.</td><td>قد</td><td>لابع ύ</td><td>1.31 (Process Grad 90 10 C8 aci de)</td><td>179 (MtH) ٠ ل</td>

<td>Example 9 H mixed racem.</td><td>ؤ</td><td>^Η2^Ν١νη ة</td><td>4.97 (Method 1Ε hydro)</td><td>193 (MtH) *</td>

<td>Example 9 I trans; racem mix.</td><td>لآ</td><td>Example 8D</td><td>2.14 (Process Grad 10 90 C8 aci de)</td><td>207 (Μ٠Η) ٠</td>

<td>Example 9 ل cis; mixed racem.</td><td>لآ</td><td>Example 8Ε</td><td>1.91 (Process Grad 10 90 C8 aci de)</td><td>207 (MtH) '</td>

Example 9GA (Enantiomer A)

<img file="MA33152B1_D0071.tif" />

ΜΑ 33152Β1

Example 9G is subjected to chiral separation to isolate its enantiomers. The brand A enantiomer, of unknown, but unique stereochemistry, is isolated using the following conditions.

Enantiomer A

<td>Amount used</td><td>5g</td>

<td>Chiral column</td><td>Daicel chiralpak AD 50 X 300 mm</td>

<td>Mobile phase</td><td>n-Hexane (60%) / methyl-tert- ether butyl (40%) / ethanol (5%) v / v</td>

<td>Debit</td><td>20 ml / min</td>

<td>Detection</td><td>UV at 254 nm</td>

<td>Fashion injection</td><td>continued</td>

We obtain Igde the enantiomer A.

Enantiomeric excess: 99.3%; retention time: 27.83 min; (analytical method: Chiral 3)

Example 9GB (Enantiomer B)

<img file="MA33152B1_D0072.tif" />

Enantiomer B

It is isolated using the same conditions as for enantiomer A, giving 0.5 g; Enantiomeric excess: 96.7%; Rt: 30.94min; (analytical method: Chiral 3).

Example 10Α, Racemic mixture

<img file="MA33152B1_D0073.tif" />

ΜΑ 33152Β1

4.0 g (22.6 mmol) of Example 9Α are mixed with 60 ml of tetrahydrofuran, then 5.7 g (30 mmol) of di-tert-butyl dicarbamate are added. The reaction mixture is heated at 60 ٥c for 5 h. After cooling to room temperature, the solvent is removed under reduced pressure. The residue is purified by preparative MPLC (Sic&gt; 2, eluent: mixture of dichloromethane / methanol 9/1).

HPLC-MS (Method 1): Rt: 1.28 min

MS (ESI pos): m / z = 278 (MtH) '

The following examples are synthesized analogously to the preparation of Example 10Α, using the corresponding pyrazoles as starting materials.

<td></td><td colspan="2">structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 10Β</td><td>١ VS /</td><td>زل ٥ 0 دل \</td><td>Example 9D</td><td>1.30 (Process 1)</td><td>292 (Mt-H) '</td>

<td>Exp. lOC Mixed racem.</td><td colspan="2">حد ٧٢</td><td>Example 9Β</td><td>1.33 (Process 1)</td><td>292 (MtH) *</td>

Example 11Α, Racemic mixture

ΜΑ 33152Β1

<img file="MA33152B1_D0074.tif" />

2.4 g (8.96 mmol) of Example 10Α are dissolved in 30 ml of ethanol. At room temperature, a solution of 10 ml (120 mmol) of hydrogen peroxide (35% in water) and 50 ml of ammonia (25% in water) is added slowly over a period of 10 minutes. The reaction mixture is stirred at room temperature for 2 h. The solution is carefully concentrated to a volume of 50 ml under reduced pressure. The precipitate formed is collected by filtration. 1.3 g (50%) of the product are obtained in the form of a solid.

HPLC-MS (Method 1): Rt: 1.08 min

MS (ESI pos): m / z = 296 (MtH) '

The following examples are synthesized analogously to the preparation of Example 11Α, using the corresponding pyrazoles as starting materials.

<td></td><td colspan="2">structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 11Β</td><td colspan="2"> ٦٥.</td><td>Example 9C</td><td>0.44 (Process 1)</td><td>211 (MtH) ٠</td>

<td>Exp. lie</td><td>H₂nJ ع /</td><td>~ ح 0 0 دل \</td><td>Example 10Β</td><td>1.12 (Process 1)</td><td>308 (Μ-Η) -</td>

ΜΑ 33152Β1

<td>Exp. HD mixed racem.</td><td>NOT- HN</td><td>ج</td><td>LOC example</td><td>1.13 (Process</td><td>310/311 (M + H) ٠ HPLC-MS</td>

<td></td><td> ۴٢</td><td>ة.</td><td></td><td></td><td></td>

<td>Exp. 11Ε mixed racem.</td><td>NH, أح</td><td>Example 9G</td><td>2.39 (Process 2 F)</td><td>197 (MtH) ٠</td>

<td>Exp. HF mixed racem.</td><td>NH, حدك هر ١</td><td>Example 9Η .</td><td>0.95 (Process Grad C8-NHC OOH)</td><td>211 (M + H) ٠</td>

<td>Exp. IIG mixed racem.</td><td>NH, أح ه</td><td>NC ۴١٠ Η, Ν٦ at</td><td>1.57 (Process Grad_C8_NH ، C OOH)</td><td>339 (M + H)⁺</td>

<td>Exp. 11Η trans, racem mixture.</td><td>NH, أ</td><td>Example 91</td><td>1.27 (Process Grad 90 10 c 8 acid)</td><td>225 (M + H) ٠</td>

ΜΑ 33152Β1

<td></td><td></td><td></td><td></td><td></td>

<td>Exp. 111 cis, racem mixture.</td><td>NH, ٠١</td><td>Example 9 ل</td><td>1.27 (Process Grad 90 10 c 8 acid)</td><td>225 (MtH) '</td>

<td>Example 1 1ΙΑ cis, racem mixture.</td><td>كفي</td><td>Example 9ΕΑ</td><td>1.11 (Process Grad C8 HC OOH)</td><td>225 (Μ + Η</td>

<td>Example 1 1ΙΒ trans, mixed racem.</td><td>تميي</td><td>Example 9ΕΒ</td><td>1.14 (Process Grad C8 NH c OOH)</td><td>225 (M + H) ٠</td>

<td>Example 1 CU</td><td>لكدت</td><td>Example 9EC</td><td></td><td>227 (MtH) ا</td>

Example HJ, racemic mixture

<img file="MA33152B1_D0075.tif" />

2.30 g (11.2 mmol) of Example 9Ε are dissolved in 6 ml of dimethylsulfoxide. Under cooling in ice, 8 ml (77.6 mmol) of hydrogen peroxide and 1.7 g (12.3 mmol) of potassium carbonate are added. Then the reaction mixture is stirred for

ΜΑ 33152Β1 minutes at room temperature. The reaction mixture is cooled with an ice bath, 100 ml of water are added and the mixture is extracted with dichloromethane. The aqueous phase is concentrated under reduced pressure. The residue is mixed with dichloromethane and the mixture is filtered. 2.8 g (52%) of the product are obtained in the form of a white solid.

HPLC-MS (Method 1): Rt: '0.24 min

Example 12Α

<img file="MA33152B1_D0076.tif" />

660 mg (2.13 mmol) of Example UC are dissolved in 15 ml of absolute ethanol. 1.85 g (10.7 mmol) of Example 5AC and 430 mg (10.7 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 150 ٠c for 30 minutes in a microwave oven. Cooling to room temperature is followed by evaporation of the solvent under reduced pressure. The residue is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile). 320 mg (38%) of the product are obtained in the form of a white solid.

HPLC-MS (Method 1): Rt: 1.61 min

MS (ESI pos): m / z = 402 (MH) '

The following examples are synthesized analogously to the preparation of Example 12Α, using pyrazoles and the corresponding esters as starting materials.

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 12Β</td><td>at</td><td>Exp. UC</td><td>د</td><td>1.52 (Process 1)</td><td>410 ٠ (H ؛ M)</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI p٥s / neg, m / z)</td>

<td>Exp. 12C</td><td> .٦٦٩</td><td>Exp. lie</td><td>Example 5Α E</td><td>1.66 (Process 1)</td><td>492 (Μ-Η) -</td>

<td>Exp. 12D mixed of stereo- isomers</td><td>at</td><td>Exp. HJ</td><td>Example 5Α C</td><td>1.02 (Process 1)</td><td>332 (MtH) ا</td>

<td>Exp. 12Ε mixed of stereo- isomers</td><td> ٠٦</td><td>Exp. HJ</td><td></td><td>0.96 (Process 1)</td><td>340 (MtH) *</td>

<td>Exp. 12F mixed of stereo- isomers</td><td> ٦؟</td><td>Exp. HJ</td><td>Example 5Α E</td><td>1.12 (Process 1)</td><td>424 (MtH) *</td>

<td>Exp. 12G mixed racem.</td><td> ۶.</td><td>Exp. 11Α</td><td>يم</td><td>1.49 (Process 1)</td><td>396 (MH) *</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 12Η mixed racem.</td><td></td><td>Exp. 11Α</td><td>Example 5Α E</td><td>1.62 (Process 1)</td><td>480 (Μ + Η) '</td>

<td>Exp. 121 mixed racem.</td><td>لآت-</td><td>Exp. 11Α</td><td>Example 5Α D</td><td>1.52 (Process 1)</td><td>426 (Μ + Η) '</td>

<td>Exp. 12J mixed racem.</td><td>٦ ب</td><td>Exp. 11Α</td><td>غ</td><td>1.49 (Process 1)</td><td>374 (MH *</td>

<td>Exp. 12Κ mixed of stereo- isomers</td><td> ١٦٦٠:.'</td><td>Exp. 11Α</td><td>Example 5Τ</td><td>1.58 (Process 1)</td><td>428 (M- H) -</td>

يك

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 12L mixed racem.</td><td>٦ ض رب</td><td>Exp. HD</td><td>Example 5Α VS</td><td>1.55 (Process 1)</td><td>402 (MtH) *</td>

<td>Exp. 12Μ mixed racem.</td><td>٦ حمله د ري</td><td>Exp. HD</td><td>ز</td><td>1.55 (Process 1)</td><td>408 (MH *</td>

<td>Exp. 12Ν mix racem.</td><td>ا كفه ٠ يأ م</td><td>Exp. HD</td><td>Example 5Α E</td><td>1.67 (Process 1)</td><td>494 (Μ + Η) '</td>

<td>Example 1 20 mixed racem.</td><td>٦٠ ص ب</td><td>Exp. HD</td><td> ٠</td><td>1.13 (Process 1)</td><td>411 (M + H) ٠</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 12Ρ mixed of stereo- isomers</td><td>١ كفه جده ٠ ب</td><td>Exp. HD</td><td>Example 5Τ</td><td>1.63 (Process 1)</td><td>444 (Μ + Η) '</td>

<td>Exp. 12Q mix racem.</td><td>.خزلي لام 0 رم</td><td>Exp. HD</td><td>Example 5Α G</td><td>1.53 (Process 1)</td><td>428 (MtH) '</td>

<td>Exp. 12R mixed racem.</td><td>ت? ' تي هم</td><td>Exp. HD</td><td>Example 5Α H</td><td>1.66 (Process</td><td>478 (MH *</td>

<td>Exp. 12s mixed racem.</td><td>٠ رأ تي ب</td><td>Exp. HD</td><td>AT</td><td>1.51 (Process 1)</td><td>376 (MtH) '</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI i ؛؟ pos / born (m / z</td>

<td>Exp. 12Τ mixed racem.</td><td>جه ني ب</td><td>Exp. HD</td><td>Example 5Α K</td><td>1.63 (Process 1)</td><td>454 (MtH) *</td>

<td>Exp. 12U mixed racem.</td><td>لم لالم كض 0١ ري</td><td>Exp. HD</td><td>٠ ؛, م</td><td>1.56 (Process 1)</td><td>388 (MtH) '</td>

<td>Exp. 12V</td><td>ض</td><td>NH ïR NH '} و ؛ ho 'oh</td><td>ه-</td><td>1.77 (Process 2 F)</td><td>228 (MtH) *</td>

<td>Exp. 12W</td><td>حلاتم</td><td>NHj ? ج NH, iR ر Oh</td><td>AT</td><td>6.96 (Process 2 F)</td><td>193 (MtH) *</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material: pyrazole</td><td>starting material: ester</td><td>Rt [min]</td><td>MS (ESI pos / neg, m / z)</td>

<td>Exp. 12Χ</td><td>شم</td><td>NH, ٥٦ NH ، R 0؟ ho</td><td>Example 5Α C</td><td>8.28 (Process 2 F)</td><td>219 (MtH) ٠</td>

<td>Exp. 12Υ</td><td>خمع</td><td>NH, ٢ و ؛ NH ) ٠ ؛ Oh? ؟ Ho</td><td>Example 5Α MA</td><td>9.15 (Process 2 F)</td><td>295 (MtH) ٠</td>

<td>Example 1 2Ζ</td><td>~ ير شم</td><td>NH, ٠١ NH أد- Oh? ؟ Ho</td><td>Example 5Α H</td><td>9.54 (Process 2 F)</td><td>295 (MtH) *</td>

<td>Example 1 2ΑΑ</td><td>حم</td><td>NH, ض NH ٠١ Oh? ؟ Ho</td><td>Example 5Α LA</td><td>6.48 (Process 2 F)</td><td>191 (MtH) *</td>

Example 13Α, Racemic mixture

ΜΑ 33152Β1

<img file="MA33152B1_D0077.tif" />

400 mg (1.35 mmol) of example 11Α are dissolved in 8 ml of absolute ethanol, then 840 mg (5.4 mmol) of example 5AC and 220 mg (5.5 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 150 ٠c for 30 minutes in a microwave oven. After cooling to room temperature, the reaction mixture is acidified with 4N hydrochloric acid. The solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile). 250 mg (46%) of the product are obtained in the form of a white solid.

HPLC-MS (Method 1): Rt: 0.93 min MS (ESI pos): m / z = 288 (MtH) '

Example 13Β

<img file="MA33152B1_D0078.tif" />

330 mg (0.82 mmol) of Example 12Α are dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid is added. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated off under reduced pressure. The resulting product is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile).

240 mg (70%) of the product are obtained.

HPLC-MS (Method 1): Rt: 0.96min

MS (ESI pos): m / z = 302 (Μ + Η) '

The following examples are synthesized analogously to the preparation of Example 13Β, using the corresponding Boc-protected amines as starting materials.

ممه

ΜΑ 33152Β1

<td></td><td>Structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 13C mixed racem.</td><td>خ</td><td>Exp. 12L</td><td>1.01 (Process 1)</td><td>302 (MtH) *</td>

<td>Exp. 13D mixed racem.</td><td>ج</td><td>Exp. 12Μ</td><td>0.93 (Process 1)</td><td>310 (MH) ٠</td>

<td>Exp. 13Ε mixed racem.</td><td>غتلاب '٥ لا</td><td>Exp. 12Ν</td><td>1.09 (Process 1)</td><td>394 (MtH) ٠</td>

ΜΑ 33152Β1

<td>Exp. 13F mixed racem.</td><td>١ ت Ο٢ΟΗ</td><td>Exp. 12G</td><td>0.92 (Process 1)</td><td>296 (Μ + Η)</td>

<td>Exp. 13G mixed racem.</td><td> ٦٥١٠</td><td>Exp. 12Η</td><td>1.08 (Process 1)</td><td>٠ (H ؛ 380 (M</td>

<td>Exp. 13Η mixed racem.</td><td>. · ؛ · 0٢٠Η زه ؛</td><td>Exp. 121</td><td>0.96 crossbreed ؟،) (1</td><td>326 (M + H) ٠</td>

<td>Exp. 131 mixed racem.</td><td>ذف ·. ٢٨</td><td>Exp. 12J</td><td>0.89 (Process 1)</td><td>٠ (H ؛ 274 (M</td>

ΜΑ 33152Β1

<td>Exp. 13 ل mixed racem.</td><td>; -ي; زد ؛</td><td>Εχρ. 12Κ</td><td>1.0 (Process 1)</td><td>330 (MH) '</td>

<td>Exp. 13Κ</td><td>دت</td><td>Exp. 12Β</td><td>0.92 (Process 1)</td><td>310 (Μ + Η) '</td>

<td>Exp. 13L</td><td>همببء "نم:</td><td>Exp. 12c</td><td>1.07 (Process 1)</td><td>394 (MtH) *</td>

د

ΜΑ 33152Β1

<td>Exp. 13Μ mixture of stereoisomers</td><td>at ع ٢ حع</td><td>Exp. 12Ρ</td><td>1.04 (Process 1)</td><td>344 (Μ + Η)</td>

<td>Exp. 13Ν mixed racem.</td><td></td><td>Exp. 120</td><td>٠٠٦٦ (Process 1)</td><td>319 (Μ + Η) *</td>

<td>Exp. 130 mixed racem.</td><td>أي. لمح</td><td>Exp. 12s</td><td>0.89 (Process 1)</td><td>276 (Μ + Η) *</td>

(λ

ΜΑ 33152Β1

<td>Exp. 13Ρ mixed racem.</td><td> -٦۶ ^Ρ٢Λ</td><td>Exp. 12Τ</td><td>1.04 (Process 1)</td><td>354 (MtH) '</td>

<td>Exp. 13Q mixed racem.</td><td>لآه</td><td>Exp. 12U</td><td>0.94 (Process 1)</td><td>288 (MH) '</td>

Example 15Α:

<img file="MA33152B1_D0079.tif" />

Enantiomer A

200 mg (1.12 mmol) of Example 9GA are mixed with 4.5 ml of an ammonia solution (30% in water). The reaction mixture is heated at 130 ٠c for 30 minutes in a microwave oven. Cooling to room temperature is followed by evaporation of the solvent under reduced pressure. 180 mg (82%) of the product are obtained.

GC-MS (Process 3Α. 1): Rt: 12.62 min

[M] '= 196

Example 16Α:

د

ΜΑ 33152Β1

<img file="MA33152B1_D0080.tif" />

150 mg (0.84 mmol) of Example 9GB are mixed with 2.10 ml of an ammonia solution (30% in water). The reaction mixture is heated at 130 ٠c for 30 minutes in a microwave oven. Cooling to room temperature is followed by evaporation of the solvent under reduced pressure. 100 mg (60%) of the product are obtained.

GC-MS (Process 3Α. 2): Rt: 12.59 min 10 [M] '= 196

Example 17Α, Mixture of Stereoisomers

<img file="MA33152B1_D0081.tif" />

A solution of 1.00 g (5.32 mmol) of 2-methoxy-5-bromopyridine in 10 ml of anhydrous THF is cooled to -78 ٠c and η-BuLi (3.66 ml, 5.85 mmol, 1 , 6 M in hexane) is added. After 10 minutes at 78 ٠c, 1.18 g (6.38 mmol) of 2-oxo-cyclohexylacetic acid ethyl ester are added and the mixture is warmed to 25 ٠c. Water is added (1 ml) and the mixture is concentrated under reduced pressure. The residue is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile). 370 mg (28%) of the product are obtained in the form of an oil.

HPLC-MS (Method 1): Rt: 1.23 min

MS (ESI pos): m / z = 248 (MtH) '

Example 18Α, cis. Racemic mixture

<img file="MA33152B1_D0082.tif" />

د

ΜΑ 33152Β1

380 mg (1.54 mmol) of Example 17Α are mixed with 5 ml of methanol, then 50 mg of Pd / C (10%) are added, and the mixture is hydrogenated at room temperature (8 h, 50 psi). The reaction mixture is filtered and the residue is washed with methanol. The solvent is evaporated off under reduced pressure. 340 mg (89%) of product are obtained in the form of a colorless oil which is used without further purification.

HPLC-MS (Method 1): Rt: 1.01 min

MS (ESI pos): m / z = 250 (MtH) '

Example 19Α

<img file="MA33152B1_D0083.tif" />

100 mg (0.48 mmol) of Example 11Β are dissolved in 2 ml of absolute ethanol, then 346 mg (1.43 mmol) of [2- (4,4,5,5-tetramethyl_ [1,3, 2] dioxaborolan-2-yl) -phenyl] -acetonitrile and 25.3 mg (0.63 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 130 ٠c for 40 minutes in a microwave oven. Cooling to room temperature is followed by the addition of 25.3 mg (0.63 mmol) of sodium hydride (60% suspension in mineral oil) and a second microwave radiation (130 ٠c; 40 minutes). Cooling to room temperature is followed by the addition of ammonium chloride and dichloromethane. The two phases are separated and the residue is purified by flash chromatography on so. 55 mg (26%) of the product are obtained in the form of a solid,

HPLC-MS (Method 1Ε hydro): Rt: 9.98 min

MS (APCI pos): m / z = 331 (M + H) ٠ Example 20Α

[2- (3-Methy! -Pyrazol-1-yl) -phenyl] -acetonitrile

<img file="MA33152B1_D0084.tif" />

A round flask is charged under an inert atmosphere with copper iodide (760 mg, 4 mmol), cesium carbonate (3.91 g, 12 mmol) then dimethylformamide (20 ml), previously degassed, is added. , followed by 2-bromophenylacetonitrile (519 μΐ, 4 mmol), 3-methylpyrazole (3.32 ml, 40 mmol) and N, N'-dimethylethylene diamine (425.86 μΐ, 4 mmol). The reaction mixture is heated at 120 ٠c for 2.5 hours. After cooling, the reaction mixture is filtered through a plug of céüte which is rinsed with dimethylformamide. The volume is reduced under reduced pressure, a saturated aqueous solution of ammonium chloride is added and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of H Cl and brine, then dried over NaO ، and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on Si٥2 in

د

ΜΑ 33152Β1 using an increasing polarity cyclohexane / ethyl acetate mixture (from 100% cyclohexane to 100% ethyl acetate) as the eluent. The oil obtained is further purified by SPE Stratosphere “PL-THIOL MP” to completely eliminate copper salts. The title compound is obtained as a thick dark oil (300 mg, 38%).

GC-MS (Process 3Α.1): Rt: 10.47 min MS: 197 [M] * Example 21Α (2-pyrrol-1-yl-phenyl) -acetonitrile

<img file="MA33152B1_D0085.tif" />

Under an inert atmosphere, a solution of 500 mg (3.783 mmol) of 2 aminophenylacetonitrile and 1 ml (7.566 mmol) of 2.515 dimethoxytetrahydrofuran in 5 ml of acetic acid is heated at 60 ٠c for 2 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is purified by flash chromatography on Si٥2 using a mixture of cyclohexane / ethyl acetate with increasing polarity (from 100% cyclohexane to 100% ethyl acetate) as eluent. The title compound is obtained as a slightly yellow oil (470 mg, 68.2%).

GC-MS (Process 3Α): Rt: 9.75 min MS: 182 [M]

Examples of embodiments

The following section presents illustrative compounds which possess PDE9 inhibitory properties, either to illustrate the compounds of the invention or to provide a process for their preparation. Among these examples, the compounds which are the object of the present invention are present. More details regarding the scope of the present invention are given in the description.

<img file="MA33152B1_D0086.tif" />

100 mg (0.48 mmol) of example 11Β are dissolved in 5 ml of absolute ethanol, then 400 mg (2.17 mmol) of example 5V and 100 mg (2.5 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 150 ° C for 30 minutes in a microwave oven. Cooling to room temperature is followed by evaporation of the solvent under reduced pressure. The residue is purified by preparative HPLC (eluent A: water 4-0.13% TFA, eluent B: acetonitrile). 29 mg (18%) of the product are obtained in the form of a solid.

ΜΑ 33152Β1

HPLC-MS (Method 1): Rt: 1.08 min MS (ESI pos): m / z = 331 (MtH) +

The following examples are synthesized analogously to the preparation of Example 1, using pyrazoles and corresponding esters or nitriles as starting materials.

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 2</td><td>at</td><td>Example 11Β</td><td>ي</td><td>1.27 (Process 1)</td><td>325 (MtH) *</td>

<td>Exp. 3</td><td>ه</td><td>Example 11Β</td><td>\ ه ٢ مد 0</td><td>1.22 (Process 1)</td><td>291 (M + H) ٠</td>

<td>Exp. 4</td><td>at</td><td>Example 11Β</td><td>Example 5Υ</td><td>1.23 (Process 1)</td><td>345/347 (Cl) (MtH) *</td>

<td>Exp. 5</td><td>..at</td><td>Example 11Β</td><td>Example 5U</td><td>1.29 (Process 1)</td><td>389/91 (Br) (MtH) *</td>

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 6</td><td> ٩</td><td>Example 11Β</td><td>تغ</td><td>1.28 (Process 1)</td><td>363/65 (Cl) (MtH) ا</td>

<td>Exp. 7</td><td> ٩,</td><td>Example 11Β</td><td>Example 5W</td><td>1.22 (Process 1)</td><td>345 (M- H) -</td>

<td>Exp. 8</td><td>حلام</td><td>Exp. 11Β</td><td> ٠١٢٨٧١/ ٠</td><td>1.14 (Process 1)</td><td>277 (MH) '</td>

<td>Exp. 9</td><td>؟ ر</td><td>Exp. 11Β</td><td>Example 5Χ</td><td>1.37 (Process 1)</td><td>317 (MtH) '</td>

ΜΑ 33152Β1

<td></td><td>Structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Εχρ. 10</td><td>ό لآ</td><td>Exp. 11Β</td><td>ί</td><td>1.30 (Process 1)</td><td>361/63 (Cl) (Μ + Η) ♦</td>

<td>Exp. 11</td><td>لآي</td><td>Exp. 11Β</td><td>٣ م</td><td>1.18 (Process 1)</td><td>341 (MH) *</td>

<td>Εχρ. 12 mixed racem.</td><td>وة</td><td>Exp. 11Β</td><td>Example 5AA</td><td>1.44 (Process 1)</td><td>329 (MtH) ٠</td>

<td>Exp. 13</td><td>وف</td><td>Exp. 11Β</td><td>Example 5AB</td><td>1.26 (Process 1)</td><td>347 (MH *</td>

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 14 mixed racem.</td><td> ٥</td><td>Exp. 11Β</td><td>Example 5AF</td><td>1.28 (Process 1)</td><td>325 (MtH) '</td>

<td>Exp. 15 mixed racem.</td><td> .٢٦</td><td>Exp. 11Α</td><td>vs</td><td>1.49 (Process 1)</td><td>396 (MtH) '</td>

<td>Exp. 16 mixed racem.</td><td>Λ,</td><td>Exp. 11Α</td><td>ا 0 AT ٠</td><td>1.49 (Process 1)</td><td>374 (Μ + Η) '</td>

<td>Exp. 17 mixed racem.</td><td>مللان ٠٥</td><td>Exp. HD</td><td>Example 5AC</td><td>1.65 (Process 1)</td><td>402 (MtH) '</td>

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 18 mixed racem.</td><td>جلاداً ة</td><td>Exp. HD</td><td>vs</td><td>1.55 (Process 1)</td><td>408 (MtH) '</td>

<td>Exp. 19 mixed racem.</td><td>٠ ا ٦ ة رش</td><td>Exp. HD</td><td>Example 5ΑΕ</td><td>1.67 (Process 1)</td><td>494 (MtH) *</td>

<td>Exp. 20 mixed racem.</td><td>ابى ملان</td><td>Exp. HD</td><td> 0'</td><td>1.13 (Process 1)</td><td>411 (Μ + Η) *</td>

100

ΜΑ 33152Β1

<td></td><td colspan="2">structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 21 mixed racem.</td><td>ح ( vs ح</td><td>ملالا لاي 0 د &lt; \</td><td>Exp. HD</td><td>Example 5Τ</td><td>1.63 (Process 1)</td><td>444 (MtH) '</td>

<td>Exp. 22 mixed racem.</td><td colspan="2">مبلج لا ؛ ٠ خ 0 ب</td><td>Exp. HD</td><td>Example 5AH</td><td>1.66 (Process 1)</td><td>478 (MtH) *</td>

<td>Exp. 23 mixed racem.</td><td>VS ا</td><td>ملات ن</td><td>Exp. HD</td><td>يك ٦</td><td>1.53 (Process 1)</td><td>428 (MtH) *</td>

<td>Exp. 24</td><td colspan="2">لاي</td><td>Exp. 11Β</td><td>لأ</td><td>0.91 (Process 1)</td><td>346 (Μ- + Η) *</td>

101 rk

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 25</td><td> ٨.</td><td>Exp. 11Β</td><td>Example 5AI</td><td>1.17 (Process 1)</td><td>331 ٠ (H ؛ M)</td>

<td>Exp. 26</td><td>غ 0 ٥</td><td>Exp. 11Β</td><td>Example 5AN</td><td>0.87 (Process 1)</td><td>301 (MtH) '</td>

<td>Exp. 27</td><td>ع غ ه</td><td>Exp. 11Β</td><td>Example 5AJ</td><td>1.17 (Process 1-)</td><td>359 (MH) *</td>

<td>Exp. 28</td><td>رأتج</td><td>Exp. 11Β</td><td>Example 5AM</td><td>1.08 (Process 1)</td><td>327 (MtH) ٠</td>

102

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 29</td><td>وثر دح</td><td>Exp. 11Β</td><td> ٧٥۴٧ 0</td><td>1.02 (Process 1)</td><td>263 (MtH) *</td>

<td>Exp. 30 mixed racem.</td><td>٠٦٥٢ تم</td><td>Exp. HD</td><td>Example 5AK</td><td>1.63 (Process 1)</td><td>454 (MtH) *</td>

<td>Exp. 31 mixed racem.</td><td>مج ص</td><td>Exp. HD</td><td>AT</td><td>1.51 (Process ؛ 1</td><td>376 (MH *</td>

ينم

103

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 32 mixed racem.</td><td>٦ ص \ ك</td><td>Exp. HD</td><td>ع اب</td><td>1.56 (Process 1)</td><td>388 (MtH) *</td>

<td>Exp. 33</td><td>له ٠</td><td>Exp. 11Β</td><td>Example 5ΑΟ</td><td>1.29 (Process 1)</td><td>(Cl) (Μ + Η) '</td>

<td>Exp. 34</td><td>Λ</td><td>Exp. 11Β</td><td>ممح</td><td>1.11 (Process 1)</td><td>317 (MtH) '</td>

<td>Exp. 35</td><td> ١٥</td><td>Exp. 11Β</td><td>٢ تخ ١</td><td>1.17 (Process 1)</td><td>366 (Μ + Η) *</td>

104

ΜΑ 33152Β1

<td></td><td>structure</td><td>product departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 36</td><td>ه.</td><td>Exp. 11Β</td><td></td><td>1.36 (Process 1)</td><td>339 (MtH) *</td>

<td>Exp. 37</td><td>جي</td><td>Exp. 11Β</td><td>Example 5AL</td><td>1.3 (Process 1)</td><td>381/383 (Cl) (MtH) '</td>

<td>Exp. 38</td><td>وف.</td><td>Exp. 11Β</td><td>Example 5Ζ</td><td>1.44 (Process 1)</td><td>379/381/383 (Cl (MtH) ٠</td>

<td>Exp. 39</td><td>٠ فت</td><td>Exp. 11Β</td><td>çnr</td><td>1.28 (Process 1)</td><td>345/347 (Cl) (MtH) '</td>

105

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 40</td><td>لا</td><td>Exp. 11Β</td><td>١ دعه ٨</td><td>1.16 (Process 1)</td><td>311 (Μ + Η) '</td>

<td>Exp. 40-1</td><td>حم</td><td>Exp. 11Β</td><td>Exp. 5ALC</td><td>1.30 (Process 1)</td><td>303 (MtH) ٠</td>

<td>Exp. 40-2</td><td>ه زح م ٦ 0 ك</td><td>Exp. 11Β</td><td>Example 5ALB</td><td>1.31 (Process 1)</td><td>375 (M + H) ٠</td>

<td>Exp. 40-3</td><td>0 حب حم</td><td>Exp. 11Β</td><td>Example 5ALD</td><td>1.25 (Process 1)</td><td>355 ٠ (H ؛ M)</td>

<td>Exp. 40-4 cis, mixed racem.</td><td>لالأ ό</td><td>Exp. 11Β</td><td>Exp. 5HA</td><td>1.18 (Process 1)</td><td>424 (M + H)⁺</td>

106

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 40-5</td><td>لآي</td><td>Exp. HIC</td><td>Exp. 5ALA</td><td>1.24 (Process 1)</td><td>291 (MtH) '</td>

<td>Exp. 40-6</td><td>لآص</td><td>Exp. 11Β</td><td>Example 5ΤΑ</td><td>1.22 (Process 1)</td><td>353 (MtH) *</td>

<td>Exp. 40-7</td><td>٠٢٠٧٦١١ مآم \ 1 ا ™</td><td>Exp. 11Β</td><td>Example 5AP</td><td>1.35 (Process 1)</td><td>418 (MtH) *</td>

<td>Exp. 40-8</td><td>AT</td><td>Exp. 11Β</td><td>Example 5ALF</td><td>1.78 (Process 5)</td><td>423/425 / 427 (MtH) * (Cl / Br)</td>

107

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure : pyrazole</td><td>product of departure : ester or nitrile</td><td>Rt [min]</td><td>MS (ESIAPCI pos / neg, m / z)</td>

<td>Exp. 40-9</td><td>٠ ةلى مه</td><td>Exp. 11Β</td><td>ل</td><td>1.81 (Process 5)</td><td>458/460 (MtH) ' (Br)</td>

<td>Exp. 40-10</td><td>دأي</td><td>Exp. 11Β</td><td>Example 5ALG</td><td>1.33 (Process 1)</td><td>407/409 (MtH) ' (Br)</td>

Example 41

<img file="MA33152B1_D0087.tif" />

mg (0.38 mmol) of example 11Β are dissolved in 1 ml of absolute ethanol, then 262 mg (1.52 mmol) of ethyl tetrahydropyran-4-yl-acetate and 45.1 mg (1, 10 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 150 ° C for 401 minutes in a microwave oven. Cooling to 20 ٠c is followed by evaporation of the solvent under reduced pressure. The residue is treated with water (10 ml), acidified with HCl (10% in water) and extracted twice with dichloromethane (2 ml). The organic phase is dried over sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is triturated with ether to give 65 mg (53.7%) of the product as a white solid.

HPLC-MS (GradC8NH OOH method): Rt: 1.89 min

MS (ESI pos): m / z = 319 (MtH) '.

The following examples are synthesized analogously to the preparation of Example 41, using pyrazolyl-carboxamides and the corresponding esters as starting materials.

108

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Εχρ٠ 42 mixed racem.</td><td> ٦'</td><td>Exp. 11Β</td><td> ٩٢</td><td>2.02 (Grad C8 NH4COOH process)</td><td>305 (MtH) *</td>

<td>Exp. 43</td><td></td><td>Exp. 11Β</td><td> '١</td><td>2.40 (Grad C8 NHOOH process)</td><td>289 (MtH) *</td>

<td>Exp. 44</td><td> $٩٠:</td><td>Exp. 11Β</td><td>.ماحمء</td><td>3.06 (Grad C8 NHCOOH process)</td><td>379 (MtH) *</td>

<td>Exp. 45</td><td> ٦;;'</td><td>Exp. 11Β</td><td>٠ مي</td><td>3.04 (Grad C8 NHCOOH process)</td><td>379 (MtH) *</td>

<td>Exp. 46 mixed racem.</td><td>ردم</td><td>Exp. 11Β</td><td>ر 0 رب^٢</td><td>٦٦, 2 (Grad C8 NHCOOH process)</td><td>331 (MtH) *</td>

vs/

109

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 47</td><td>ري</td><td>Exp. 11Β</td><td></td><td>2.21 (Grad C8 process NH COOH)</td><td>275 (Μ + Η) *</td>

<td>Exp. 48 mixed racem.</td><td> ٦</td><td>Exp. 11Β</td><td>Exp. 5Τ</td><td>2.84 (Grad C8 NHCOH process)</td><td>345 (Μ + Η) *</td>

<td>Exp. 49</td><td>مجب ة</td><td>Exp. 11Β</td><td>OoMe MeO٢١d \ ٠</td><td>2.57 (Grad C8 NHOOH process)</td><td>341 (Μ + Η) '</td>

<td>Exp. 50</td><td>مجج : ٦</td><td>Exp. 11Β</td><td>Exp. 5Ε</td><td>3.02 (Grad C8 NHOOH process)</td><td>413 (MtH) '</td>

<td>Exp. 51</td><td></td><td>Exp. 11Β</td><td>ماع</td><td>5.97 (Process 1Ε hydro)</td><td>312 (MtH) ٠</td>

110

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 52</td><td>ريص ٦٠</td><td>Exp. 11Β</td><td>Exp. 5AK</td><td>2.75 (Grad C8 NHOOH process)</td><td>355 (Μ + Η) '</td>

<td>Exp. 53</td><td>نبر HN ، ٠ NC</td><td>Exp. 11Β</td><td>QoMe NC٦— &lt;</td><td>2.15 (Grad C8 HCOOH process)</td><td>336 (M + H) ٠</td>

<td>Exp. 54</td><td>ة</td><td>Exp. 11Β</td><td> ١٢٠٦١</td><td>3.15 (Grad 08 NHOOH process)</td><td>369 (MH). *</td>

<td>Exp. 55</td><td>زبي خ</td><td>Exp. 11Β</td><td>Exp. 5Κ</td><td>3.21 (Grad C8 NHOOH process)</td><td>381 (MH *</td>

<td>Exp. 56</td><td> ,?؛1-</td><td>Exp. 11Β</td><td>٩٦Me O</td><td>6.52 (Process 1Ε hydro)</td><td>326 (MtH) *</td>

111

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 57 In year- tiomer R</td><td>٠٩١٠ ئ ه</td><td>Exp. 11Β</td><td>Exp. 5Μ</td><td>2.64 (Process Grad 08 NH 00Η)</td><td>397 (MH) '</td>

<td>Exp. 58 In year- tiomer S</td><td>أ ۵</td><td>Exp. 11Β</td><td>Exp. 5L I</td><td>2.64 (Process Grad_C8_ NHCOOH)</td><td>397 (MtH) '</td>

<td>Exp. 60</td><td>نلآ ه</td><td>Exp. 11Β</td><td>Exp. 50</td><td>2, Ίη (Grad C8 process NH OOH) -</td><td>411 (MtH) '</td>

<td>Exp. 61 Enantiomer A</td><td>ج: ٦ ٢ '</td><td>Exp. 11Β</td><td>Exp. 5Α</td><td>2.68 (Grad C8 NHCOOH process) 15.32 (Chiral 1)</td><td>345 (MtH) '</td>

112

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 62 Enantiomer B</td><td>ئبي</td><td>Exp. 11Β</td><td>Exp. 5D</td><td>2.68 (Process Grad_C8_ NHCOOH) 18.74 (Chiral 1)</td><td>345 (MtH) '</td>

<td>Exp. 63</td><td>هع</td><td>Exp. 11Β</td><td> ٩٦٦٠</td><td>9.37 (Process 2 F)</td><td>380 (MtH) *</td>

<td>Exp. 64</td><td> ·١١'</td><td>Exp. 11Β</td><td>Exp. 5S</td><td>٦5, &lt;؟ (Process 1Ε hydro)</td><td>380 (MtH) *</td>

<td>Exp. 65</td><td>؛ ح</td><td>Exp. 11Β</td><td>Exp. 5R</td><td>9.45 (Process 2 F)</td><td>380 (MtH) *</td>

<td>Exp. 66</td><td>جلاه</td><td>Exp. 11Β</td><td>not * ١٥ ”</td><td>٦٠, &lt;؟ (Process 2 F)</td><td>313 (MtH) *</td>

113

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 67</td><td>نبب لآ</td><td>Exp. 11Β</td><td>Exp. 5Q</td><td>2.38 (Grad C8 process NH OOH)</td><td>342 (MtH) *</td>

<td>Exp. 68</td><td>٠ HN ٦١٠ ه / ، Ο</td><td>Exp. 11Β</td><td>Exp. 51</td><td>1.95 (Grad C8 NHOOH process)</td><td>452 (MtH) *</td>

<td>Exp. 69 mixed racem.</td><td> .١.</td><td>Exp. 11Ε</td><td>Exp. 5AC</td><td>&lt;؟ Ί, Β Process) (1Ε</td><td>289 (MtH) '*</td>

<td>Exp. 70 mixed racem.</td><td>هبب HN١١٣ □ هث</td><td>Exp. 11Ε</td><td>Exp. 5ΑΕ</td><td>Ί, Ίΰ (Process 1Ε fusion)</td><td>381 (MtH) *</td>

114

0&lt;

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 71 mixed racem.</td><td>ه</td><td>Exp. 11Ε</td><td>Exp. 5F</td><td>7.68 (Process 1Ε fusion)</td><td>349 (MtH) *</td>

<td>Exp. 72 mixed of stereo- isomers</td><td> ؟؟</td><td>Exp. 11Ε</td><td>ك 0 ك ١ ب^ع ٦</td><td>9.82 (Process 2 F)</td><td>317 (MtH) *</td>

<td>Exp. 73 mixed racem.</td><td>;؟ دب</td><td>Exp. 11Ε</td><td> ·٦٠</td><td>9.44 (Process 2 F)</td><td>275 (MtH) *</td>

<td>Exp. 74 mixed racem.</td><td>٦ يذ.</td><td>Exp. 11Ε</td><td>ه</td><td>8.89 (Process 2 F)</td><td>263 (MtH) *</td>

<td>Exp. 75 mixed racem.</td><td> ٦؟</td><td>Exp. 11Ε</td><td> ٩٠٢</td><td>10.69 (Process 2 F)</td><td>303 (MtH) *</td>

به

115

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 76 mixed racem.</td><td>د</td><td>Exp. 11Ε</td><td>Exp. 5Η</td><td>10.57 (Process 2 F)</td><td>291 (MH '</td>

<td>Exp. 77 mixed stereo- isomers</td><td></td><td>Exp. 11Ε</td><td>Exp. 5Τ</td><td>10.55 (Process 2 F)</td><td>331 (Μ + Η) '</td>

<td>Exp. 78 mixed racem.</td><td>at</td><td>Exp. 11Ε</td><td>No. ٦ OEt M</td><td>4.83 (Process 1Ε Hydro)</td><td>298 (M + H) ٠</td>

<td>Exp. 79 mixed racem.</td><td>جيي</td><td>Exp. 11Ε</td><td>? بخ OMe M</td><td>7.10 (Process 1Ε fusion)</td><td>315 (MtH) *</td>

<td>Exp. 80 mixed racem.</td><td>لآدي</td><td>Exp. 11Ε</td><td> ٦٠</td><td>5.97 (Process 1Ε fusion)</td><td>261 (MH *</td>

116 (L.

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 81 mixed of stereo- isomers</td><td>غ</td><td>Exp. 11Ε</td><td> '٠٩</td><td>4.73 (Process 1Ε hydro)</td><td>291 (Μ + Η) '</td>

<td>Exp. 82 mixed racem.</td><td> ٥٢١^ΝΌ I</td><td>Exp. 11Ε</td><td>Exp. 5ΑΚ</td><td>1.31 (Process 1Ε hydro)</td><td>341 (MtH) '</td>

<td>Exp. 83 mixed racem.</td><td>..ن:</td><td>Exp. 11Ε</td><td>Exp. 5AD</td><td>6.85 (Process 1Ε hydro)</td><td>32Ί (MtH) *</td>

<td>Exp. 84 mixed of stereo- isomers</td><td>AT</td><td>Exp. 11Ε</td><td></td><td>6.88 (Process 1Ε hydro)</td><td>2ΊΊ (M + H) ٠</td>

<td>Exp. 85 mixed racem.</td><td>ص ؤب ق;</td><td>Exp. 11Ε</td><td>Exp. 5AH</td><td>7.93 (Process 1Ε hydro)</td><td>365 (MtH) *</td>

117

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 86 mixed racem.</td><td>i بن</td><td>Exp. 11Ε</td><td>F١۶٦٠٠OMe FFO</td><td>10.93 (Process 2 F)</td><td>365 (MtH) '</td>

<td>Exp. 87 mixed racem.</td><td>؛؟ - م. 5</td><td>Exp. 11Ε</td><td>ل ٦ إ 0</td><td>5.43 (Process 1Ε hydro)</td><td>312 (MtH) *</td>

<td>Exp. 88 mixed racem.</td><td> ٩٩</td><td>Exp. 11Ε</td><td>QoMe NC٦٩</td><td>5.43 (Process 1Ε hydro)</td><td>312 (MtH) *</td>

<td>Exp. 89 mixed racem.</td><td>١٥٦٧ كع</td><td>Example 11Ε</td><td> ٩ 0</td><td>5.28 (Process 1Ε hydro)</td><td>322 (MtH) *</td>

<td>Exp. 90 mixed racem.</td><td>هيلى</td><td>Exp. HF</td><td>Exp. 5AC</td><td>(Process 1Ε hydro)</td><td>303 (MtH) *</td>

118

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 91 mixed racem.</td><td>منم اه</td><td>Exp. IIF</td><td>Exp. 5ΑΕ</td><td>8.45 (Process IE hydro)</td><td>395 (MH) '</td>

<td>Exp. 92 mixed racem.</td><td>الائد</td><td>Exp. HF</td><td>اهه 0</td><td>6.93 (Process IE hydro)</td><td>21Ί (Μ + Η) ب</td>

<td>Exp. 93 mixed racem.</td><td>عليه</td><td>Exp. IIF</td><td>Exp. 5AK</td><td>8.20 (Process IE hydro)</td><td>355 (Μ + Η) *</td>

<td>Exp. 94 mixed racem.</td><td>| لاع ٠</td><td>Exp. IIF</td><td>(\ ٦0Me 0</td><td>6.28 (Process IE hydro)</td><td>312 (Μ + Η) ٠</td>

<td>Exp. 95 mixed of stereo- isomers</td><td> ٩</td><td>Exp. IIF</td><td>OMe ، إك 0</td><td>٦,٦٠ (Process IE hydro)</td><td>291 (Μ + Η) '</td>

119

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt- [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 96 mixed racem.</td><td>مه</td><td>Exp. IIF</td><td>. OMe M٠</td><td>Ί, Β (Process 1Ε hydro)</td><td>289 (MtH) *</td>

<td>Exp. 97 mixed racem.</td><td>ή</td><td>Exp. IIF</td><td>٦ ز ٢ OMe ^FF 0</td><td>8.17 (Process 1Ε hydro)</td><td>379 (MtH) *</td>

<td>Exp. 98 mixed racem.</td><td>ؤتج</td><td>Exp. IIF</td><td>: صاحلى ١ 0</td><td>6.80 (Process 1Ε hydro)</td><td>336 (MtH) *</td>

<td>Exp. 99 mixed racem.</td><td> ٩</td><td>Exp. IIF</td><td>OMe ؛&gt; M</td><td>6.43 (Process 1Ε hydro)</td><td>275 (MtH) *</td>

<td>Exp. 100 mixed racem.</td><td>مع “1“</td><td>Exp. IIF</td><td>ل ١ ج OMe يع 0</td><td>2.38 (Process 2 F)</td><td>326 (MtH) *</td>

120

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 101 mixed racem.</td><td>ودخ</td><td>Exp. HF</td><td>٢ ^^ OMe 0</td><td>3.52 (Process 1Ε hydro)</td><td>329 (MtH) ٠</td>

<td>Exp. 102 mixed racem.</td><td>لآ</td><td>Exp. IIF</td><td>Exp. 5F</td><td>8.28 (1Ε hydro)</td><td>363 (MtH</td>

<td>Exp. 103 mixed racem.</td><td></td><td>Exp. IIF</td><td>C جح 0</td><td>8.70 (Process 1Ε hydro)</td><td>317 (MH *</td>

<td>Exp. 104 mixed racem.</td><td> .';-,</td><td>Exp. IIG</td><td>Exp. 5AC</td><td>8.57 (Process 1Ε hydro)</td><td>331 (MtH) '</td>

<td>Exp. 105 mixed racem.</td><td>٧ ج ٠٢ ٦ ة ى</td><td>Exp. IIG</td><td>Exp. 5AK</td><td>8.62 (Process 1Ε hydro)</td><td>383 (Mt-H) ٠</td>

121

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 106 mixed racem.</td><td> .٦</td><td>Exp. IIG</td><td>Methyl isovalerate __i ، OMe 0</td><td>7.58 (Process 1Ε hydro)</td><td>305 (MtH) *</td>

<td>Exp. 108 mixed racem.</td><td>٧, A دد 0 ٠</td><td>Exp. IIG</td><td>Ester methyl cyclobutylacetic acid ساحا M</td><td>7.93 (Process 1Ε)</td><td>317 (Μ + Η) *</td>

<td>Exp. 111 trans; racem mixture.</td><td>مه •</td><td>Exp. 11Η</td><td>(y ٦٠Me 0</td><td>2.05 (Process 2 F)</td><td>326 (MtH) '</td>

<td>Exp. 112 trans; racem mixture.</td><td>مح مده ة</td><td>Exp. 11Η</td><td>Exp. 5AC</td><td>8.25 (Process 2 F)</td><td>317 (MtH) *</td>

122

ΜΑ 33152Β1

<td></td><td>structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 113 trans; racem mixture.</td><td>ردجرو لآه هف</td><td>Exp. UH</td><td>ماب ؛</td><td>8.42 (Process 1Ε hydro)</td><td>393 (Μ + Η) *</td>

<td>Exp. 114 trans; racem mixture.</td><td>لأع</td><td>Exp. 11Η</td><td>- (oEt ٦</td><td>7.15 (Process 1Ε hydro)</td><td>291 (MtH) '</td>

<td>Exp. 115 mixed racem.</td><td>ل ٦ ي</td><td>Exp. 111</td><td> ’٥</td><td>9.90 (Process 2 F)</td><td>291 (MH) *</td>

<td>Exp. 116 cis; mixed racem.</td><td></td><td>Exp. 111</td><td>٦ ي OMe</td><td>(Process 1Ε hydro)</td><td>393 (Μ4Η) '</td>

<td>Exp. 117 cis; mixed racem.</td><td> ٠١</td><td>Exp. 111</td><td>Exp. 5AC</td><td>7.98 (Process 1Ε hydro)</td><td>317 (MtH) '</td>

123

ΜΑ 33152Β1

<td></td><td>structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 118 cis; mixed racem.</td><td> ٠٩٠</td><td>Exp. 111</td><td>ς OMe 0</td><td>5.80 (Process 1Ε hydro)</td><td>326 (M + H) ٠</td>

<td>Exp. 119 cis; mixed racem.</td><td>ردجتم ٥٦٠ at</td><td>Exp. 111</td><td>Exp. 5Η</td><td>8.42 (Process 1Ε hydro)</td><td>319 (M + H) ٠</td>

<td>Exp. 120 cis; mixed racem.</td><td>ردجتر لآه</td><td>Exp. 111</td><td>نماح 0</td><td>1.3 (Process 1Ε hydro)</td><td>303 (MtH) *</td>

<td>Exp. 121 cis; mixed racem.</td><td>ودجي لآه مع</td><td>Exp. 111</td><td>١ ء OMe NCU O</td><td>9.91 (Process 2 F)</td><td>350 (MH) ♦</td>

124

Λ

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 122 mixed racem.</td><td>ثم ١ •</td><td>Exp. IIF</td><td>هيرهك</td><td>6.95 (Process 2 F)</td><td>342 (MtH) t</td>

<td>Exp. 123</td><td>٦: ت</td><td>Exp. 11Β</td><td>مم</td><td>2.12 (Grad C8 NHCOOH process)</td><td>312 (MtH) *</td>

<td>Exp. 124 mixed racem.</td><td>أشم</td><td>Exp. 11Ε</td><td>ك ٢ Λο ٧</td><td>4.98 (Process 1Ε hydro)</td><td>298 (MtH) *</td>

<td>Exp. 125</td><td>مك 1٠</td><td>Exp. 11Β</td><td>Εχρ. 5Ρ</td><td>12, &lt;؟ (Process 1Ε hydro)</td><td>395 (MtH) *</td>

<td>Exp. 126 mixed racem.</td><td>.. ؛؛ ب '</td><td>Exp. IIF</td><td>ي</td><td>9.12 (Process 2 F)</td><td>336 (MtH) *</td>

تم

125

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>Exp. 127 mixed racem.</td><td>. ;؛ هم</td><td>Exp. HF</td><td>Exp. 5AB</td><td>7.62 (Process 1Ε hydro)</td><td>341 (MtH) *</td>

<td>Exp. 128 Enantiomer s</td><td>AT</td><td>Exp. 11Β</td><td>Exp. 5G</td><td>9.83 (Process 2 F)</td><td>291 (MtH) *</td>

<td>Exp. 129 mixed racem.</td><td>; هم.</td><td>Exp. HF</td><td>Exp. 5AF</td><td>11.56 (Process 2 F)</td><td>379 (MtH) *</td>

<td>Exp. 130 mixed racem.</td><td>غلادد</td><td>Exp. 11F</td><td>Exp. 5Η</td><td>8.38 (Process 1Ε hydro)</td><td>305 (MtH) *</td>

<td>Exp. 131 Enantiomer A</td><td></td><td>Exp. 11Β</td><td>Exp. 5Β</td><td>9.93 (Process 2 F)</td><td>331 (MtH) *</td>

126

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 132 Enantiomer B</td><td> ٠٦٩</td><td>Exp. 11Β</td><td>Exp. 5C</td><td>9.93 (Process 2 F)</td><td>331 (Μ + Η) '</td>

<td>Exp. 132-1 mixed racem.</td><td> ٩</td><td>Exp. 11ΙΑ</td><td>مدا</td><td>9.83 (Process 2 F)</td><td>291 (MtH) '</td>

<td>Exp. 132-2 cis, mixed racem.</td><td></td><td>Exp. 11ΙΑ</td><td>Exp. 5AC</td><td>10.96 (Process 2 F)</td><td>317 (MtH) '</td>

<td>Exp. 132-3 Enantiomer A</td><td>اد.</td><td>Exp. 15Α</td><td> ٦٦٠٧</td><td>8.84 (Process 2 F)</td><td>263 (Mt-H) *</td>

<td>Exp. 132-4 Enantiomer B</td><td> ٨٩</td><td>Exp. 16Α</td><td>٢ï٥٧</td><td>8.96 (Process 2 F)</td><td>263 (MtH) '</td>

127

ΜΑ 33152Β1

<td></td><td>Structure</td><td>pyrazoly 1- carbox- amide</td><td>Ester</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 132-5 trans, mixed racem.</td><td>جعلايرن</td><td>Exp. 11ΙΒ</td><td>Exp. 5AC</td><td>10.21 (Process 2 F)</td><td>317 (MtH) '</td>

<td>Exp. 132-6 Enantiomer B</td><td>أم</td><td>Exp. 16Α</td><td>'دم</td><td>7.15 (Process 1Ε Hydro)</td><td>275 (M + H) ٠</td>

<td>Exp. 132-7 Enantiomer B</td><td>أحم</td><td>Exp. 16Α</td><td> ٥</td><td>5.68 (Process 1Ε Hydro)</td><td>298 (MtH) *</td>

<td>Exp. 132-8 trans, mixed racem.</td><td>كأيود</td><td>Exp. 11ΙΒ</td><td>مم</td><td>9.23 (Process 2 F)</td><td>291 (MtH) *</td>

<td>Exp. 132-9 Enantiomer A</td><td>أشم</td><td>Exp. 15Α</td><td> ٠٠</td><td>8.83 (Process 2L)</td><td>275 (MtH) *</td>

Example 133

6- (2-Ethy! -Butyl) -1- (tetrahydro-pyran-4-yl) -1,5-dihydro-pyrazolo [3,4d] pyrimidin-4-one

ΜΑ 33152Β1

<img file="MA33152B1_D0088.tif" />

Example 11Β (0.1 g, 0.48 mmol) is mixed with polyphosphoric acid (1.0 g), then 2- (trifluoro5 methoxy) phenylacetic acid (248 mg, 1.9 mmol) is added. The mixture is heated at 120 ٠c for 16 hours. The temperature is reduced to 20 ٠c and the pH is adjusted to 7 by adding ammonia (30% solution in water). The aqueous phase is extracted with dichloromethane (2 X 20 ml) and the organic phase is dried over sodium sulfate. The crude mixture is purified by flash chromatography. Eluent: mixture of hexane / ethyl acetate 40/60.

23.5 mg (16%) are obtained in the form of a white solid.

HPLC-MS (1Ε) Rt: 6.77 min MS (APCI pos): m / z = 305 (M + H) ٠

The following examples are synthesized analogously to the preparation of Example 133, using the corresponding carboxylic acids as starting materials.

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Example 134</td><td> .١١</td><td>٩ OH ٩</td><td>6.37 (Method 1Ε)</td><td>303 (MtH) *</td>

<td>Example 135 mixed racem.</td><td>مد</td><td>-?OH ٦٩</td><td>5.95 (Method 1Ε)</td><td>291 (MtH) *</td>

رم

129

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Example 136</td><td>حئه</td><td> ٩</td><td>51, ة (Method 1Ε)</td><td>407 (MtH) *</td>

<td>Example 137</td><td>Λ-Ο زب S</td><td> ٩</td><td>6.48 (Method 1Ε)</td><td>363 ٠ (H ؛ M)</td>

<td>Example 138</td><td>، هس</td><td> ٧٩;</td><td>5.12 (Method 1Ε)</td><td>395 (Μ + Η) *</td>

<td>Example 139</td><td></td><td>„ي</td><td>2.71 (Process Grad C8 NH 0 OH)</td><td>329 (MtH) *</td>

رم

130

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Example 140</td><td></td><td> ٩٠</td><td>٦٦.2 (Process Grad C8 NH 0 OH)</td><td>329 ٠ (H ؛ M)</td>

<td>Example 141</td><td>.: عي</td><td>, R {</td><td>2.90 (Process Grad C8 NH 0 OH)</td><td>329 (MtH) ٠</td>

<td>Example 142</td><td>ذرق</td><td>هب '</td><td>3.07 (Process Grad C8 NH 0 OH)</td><td>347 (MtH) ٠</td>

<td>Example 143</td><td></td><td>ه</td><td>2.71 (Process Grad C8 NH 0 OH)</td><td>211 (MtH) ٠</td>

<td>Example 144</td><td> .؛٢٩٦'</td><td> 0</td><td>3.28 (Grad_C8 NH O OH process)</td><td>317 (MtH) *</td>

رك

131

ΜΑ 33152Β1

Example 145, Racemic mixture

<img file="MA33152B1_D0089.tif" />

106 mg (0.47 mmol) of Example 12V are mixed with 4 ml of ethyl acetate, then 0.5 ml of dimethylformamide, 51 mg (0.61 mmol) of 3,4dihydroH-pyrane and 88.4 mg (0.51 mmol) of p-toluenesulfonic acid are added. The reaction mixture is heated to 60 ٠c and stirred for 2 h. After cooling to room temperature, ethyl acetate is added and the mixture is washed with saturated sodium hydrogencarbonate solution and with saturated sodium chloride solution. The organic phase is concentrated under reduced pressure. The residue is purified by preparative HPLC-MS. 31.5 mg (21.7%) are obtained.

MS (APCI pos): m / z = 312 (MtH) '

HPLC-MS (Method 2F) Rt: 8.26 min

The following examples are synthesized analogously to the preparation of Example 145, using the corresponding pyrazolopyrimidinones as starting materials.

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESL- APCI, m / z)</td>

<td>Exp. 146 mixed racem.</td><td></td><td>Example 12W</td><td>9.99 (Process 2 F)</td><td>٦ 21 (M + H) ٠</td>

<td>Exp. 147 mixed racem.</td><td> ٦١٦</td><td>Example 12Χ</td><td>10.98 (Process 2 F)</td><td>303 (MtH) *</td>

132 ل

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI- APCI, m / z)</td>

<td>Exp. 1471 mixed racem.</td><td></td><td>Example 12Υ</td><td>10.98 (Process 2 F)</td><td>303 (MtH) *</td>

<td>Example 1 47-2 racem mixture.</td><td>لاددد</td><td>Example 12ΑΑ</td><td>9.56 (Process 2 F)</td><td>275 (Μ + Η) *</td>

<td>Example 1 47-3 racem mixture.</td><td>ه:,</td><td>Example 12Ζ</td><td>11.62 (Process 2 F)</td><td>379 (Μ + Η) *</td>

Example 148

<img file="MA33152B1_D0090.tif" />

160 mg (470 mmol) of Example 12Ε are dissolved in 10 ml of methanol, then 350 mg of Raney nickel are added. The reaction mixture is hydrogenated at room temperature for 6 hours, filtered and the selvant is evaporated off under reduced pressure. 100 mg (65%) of the product are obtained.

HPLC-MS (Method 1): Rt: 0.95 min

MS (ESI pos): m / z = 324 (Μ + Η)

133

ΜΑ 33152Β1

The following examples are synthesized analogously to the preparation of Example 148, using the corresponding N-oxides as starting materials.

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 149</td><td>٠٣ h</td><td>Example 12D</td><td>0.95 (Method 1)</td><td>316 (MtH) *</td>

<td>Exp. 150</td><td>.'دت '</td><td>Example 12F</td><td>1.11 (Method 1)</td><td>408 (MtH) '</td>

Example 151

<img file="MA33152B1_D0091.tif" />

mg (150 mmol) of! Example 13Β are dissolved in 4 ml of dichloromethane, then 22.5 μΐ (300 mmol) of ethyl chloride and 42 μΐ (300 mmol) of triethylamine are added. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water 0.13 ؛% TFA, eluent B: acetonitrile). 28 mg (55%) of the product are obtained.

HPLC-MS (Method 1): Rt: 1.18 min MS (ESI pos): m / z = 344 (M + H) ٠

The following examples are synthesized analogously to the preparation of Example 151, using the starting materials.

134

ΜΑ 33152Β1 correspondents. Obviously, as an acylating agent, but not for all compounds, acetyl chloride is introduced. However, other acylating agents, such as commercially available methoxychloroformate, substituted or non-substituted aminocarbonyl chloride, substituted or non-substituted phenoxycarbonyl chloride, substituted or non-substituted benzoyl chloride, are used.

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 152</td><td>.م</td><td>Example 13Κ</td><td>1.09 (Method 1)</td><td>352 (M + H)⁺</td>

<td>Exp. 153</td><td>زحتيدبء ة لا</td><td>Example 13L</td><td>1.25 (Method 1)</td><td>436 (Μ + Η) *</td>

<td>Exp. 154 mixed racem.</td><td>... '; ر</td><td>Example 13C</td><td>1.38 (Method 1)</td><td>360 (Μ + Η) *</td>

<td>Exp. 155 mixed racem.</td><td> :^غب</td><td>Example 13D</td><td>1.30 (Method 1)</td><td>368 (Μ + Η) ٠</td>

135

ل

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 156 mixed racem.</td><td>ة;, ·, &lt;-&gt;</td><td>Example 13Ε</td><td>1.44 (Method 1)</td><td>452 (MtH) *</td>

<td>Exp. 157 mixed racem.</td><td>..ذب.</td><td>Example 13C</td><td>1.20 (Method 1)</td><td>344 (MtH) *</td>

<td>Exp. 158 mixed racem.</td><td>... دوح</td><td>Example 13D</td><td>1.16 (Method 1)</td><td>352 (MtH) *</td>

<td>Exp. 159 mixed racem.</td><td>رب</td><td>Example 13D</td><td>1.25 (Method 1)</td><td>381 (MtH) *</td>

<td>Exp. 160 mixed racem.</td><td>: · .خ.</td><td>Example 13C</td><td>1.30 (Method 1)</td><td>373 (MtH) *</td>

136

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 161 mixed racem.</td><td> ٥٢٩ ٨١ :.-؛٠</td><td>Example 13Ε</td><td>1.38 (Method 1)</td><td>465 (MtH) '</td>

<td>Exp. 162 mixed racem.</td><td>؛ .. رذت</td><td>Example 13C</td><td>1.62 (Method 1)</td><td>440 (MtH) '</td>

<td>Exp. 163 mixed racem.</td><td>للع ٠١ م ا</td><td>Example 13Ε</td><td>1.48 (Method 1)</td><td>498 (MtH) '</td>

<td>Exp. 164 mixed racem.</td><td></td><td>Example 13G</td><td>1.23 (Method 1)</td><td>422 (MtH) '</td>

137

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 165 mixed racem.</td><td>AT</td><td>Example 13Α</td><td>1.14 (Method 1)</td><td>330 (MtH) '</td>

<td>Exp. 166 mixed racem.</td><td> ٠١</td><td>Example 13F</td><td>1.28 (Method 1)</td><td>400 (MtH) '</td>

<td>Exp. 167 mixed racem.</td><td> ٥٩</td><td>Example 13Α</td><td>1.36 (Method 1)</td><td>392 (MtH) '</td>

<td>Exp. 168 mixed racem.</td><td>.: م-</td><td>Example 13Η</td><td>1.1 (Method 1)</td><td>368 (MtH) '</td>

138

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 169 mixed racem.</td><td>.,؟ ي</td><td>Example 13G</td><td>1.44 (Method 1)</td><td>484 (MtH) *</td>

<td>Exp. 170 mixed racem.</td><td>.بغلا</td><td>Example 13Η</td><td>1.32 (Method 1)</td><td>430 (MtH) *</td>

<td>Exp. 171 mixed racem.</td><td> ٠٦</td><td>Example 131</td><td>1.29 (Method 1)</td><td>٠ (ت</td>

<td>Exp. 172 mixed racem.</td><td>أك</td><td>Example 13F</td><td>1.07 (Method 1)</td><td>338 (MtH) *</td>

139

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 173 mixed stereo- isomers</td><td> : ٦-٠7</td><td>Example 13Μ</td><td>1.25 (Method 1)</td><td>386 (MtH) *</td>

<td>Exp. 174 mixed stereo- isomers</td><td>بن ص ٩ •</td><td>Example 13Μ</td><td>1.44 (Method 1)</td><td>448 (MtH) *</td>

<td>Exp. 175 mixed racem.</td><td>Ογ٠ ص 0 ة</td><td>Example 13Ν</td><td>1.04 (Method 1)</td><td>415 (MtH) *</td>

140 )

33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 176 mixed racem.</td><td> .۶٦</td><td>Example 13Ν</td><td>0.84 (Method 1)</td><td>353 (MtH) '</td>

<td>Exp. 177 mixed racem.</td><td>۴٠ ن م ٠٩</td><td>Example 130</td><td>1.31 (Method 1)</td><td>380 (MH) *</td>

<td>Exp. 178 mixed racem.</td><td>ين ٧٠ ة ٠</td><td>Example 13Ρ</td><td>1.43 (Method 1)</td><td>458 (MtH) *</td>

<td>Exp. 179 mixed racem.</td><td>ί تيما »ه</td><td>Example 13Ρ</td><td>1.24 (Method 1)</td><td>396 (Μ + Η) '</td>

141

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 180 mixed racem.</td><td>... 'ي ،</td><td>Example 13Q</td><td>1.14 (Method 1)</td><td>330 (MtH) *</td>

<td>Exp. 181 mixed racem.</td><td>٠ ر ٦ هم لآده</td><td>Example 13Q</td><td>1.34 (Method 1)</td><td>392 ! Μ + ΗΓ</td>

<td>Exp. 182 mixed racem.</td><td>هم لآده</td><td>Example 13D</td><td>1.35 (Method 1)</td><td>414 (MtH) *</td>

<td>Exp. 183 mixed racem.</td><td>ح</td><td>Example 13C</td><td>1.41 (Method 1)</td><td>406 (MtH) *</td>

142

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 184 mixed racem.</td><td> ٧٦</td><td>Example 205</td><td>1.30 (Method 1)</td><td>420 (MtH) ٠</td>

<td>Exp. 185 mixed racem.</td><td>٠; يك</td><td>Example 13D</td><td>1.53 (Method 1)</td><td>448 (MtH) '</td>

<td>Exp. 186 mixed racem.</td><td>١ σ٠٧ ٠٦٠</td><td>Example 204</td><td>1.35 (Method 1)</td><td>432 (MtH) '</td>

143 nZ

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 187 mixed racem.</td><td>مر ا</td><td>Example 204</td><td>1.15 (Method 1)</td><td>370 (Μ + Η) '</td>

<td>Exp. 188 mixed racem.</td><td>ردم ب</td><td>Example 13Ε</td><td>1.29 (Method 1)</td><td>436 (MtH) ا</td>

<td>Exp. 189 mixed racem.</td><td>ثم ٠٩</td><td>Example 130</td><td>1.08 (Method 1)</td><td>318 (Μ + Η) '</td>

<td>Exp. 190 mixed racem.</td><td>أر</td><td>Example 13F</td><td>1.18 (Method 1)</td><td>367 (MtH) '</td>

144

رم

ΜΑ 33152Β1

Example 191, Racemic mixture

<img file="MA33152B1_D0092.tif" />

60 mg (0.2 mmol) of Example 13C are dissolved in 5 ml of xylene and mg (0.2 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate are added dropwise. The reaction mixture is heated to 140 ٠c and stirred for 5 h. The solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent

B: acetonitrile). 24.8 mg (32%) of the product are obtained.

HPLC-MS (Method 1): Rt: 1.45 min MS (ESI pos): m / z = 384 (MH *

The following examples are synthesized analogously to the preparation of Example 191, using the corresponding starting materials.

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / Z)</td>

<td>Exp. 192 mixed racem.</td><td>د R</td><td>Example 13Q</td><td>1.35 (Method 1)</td><td>370 (M + H) ٠</td>

<td>Exp. 193 mixed racem.</td><td>خ ، رم</td><td>Example 13C</td><td>1.07 (Method 1)</td><td>366 (MtH) *</td>

يبم

145

ΜΑ 33152Β1

Example 194, Racemic mixture

<img file="MA33152B1_D0093.tif" />

400 mg (1.35 mmol) of example 11Α are dissolved in 8 ml of absolute ethanol, then 840 mg (5.4 mmol) of example 5AC and 220 mg (5.5 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture is heated at 150 ٠c for 30 minutes in a microwave oven. After cooling to room temperature, the reaction mixture is acidified with 4N hydrochloric acid. The solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile). 250 mg (46%) of the product are obtained in the form of a white solid.

HPLC-MS (Method 1): Rt: 0.93 min

MS (ESI pos): m / z = 288 (MtH) '

Example 195

<img file="MA33152B1_D0094.tif" />

330 mg (0.82 mmol) of Example 12Α are dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid is added. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated off under reduced pressure. The residue is purified by preparative HPLC (eluent A: water 0.13 ؛% TFA, eluent B: acetonitrile). 240 mg (70%) of the product are obtained.

HPLC-MS (Method 1): Rt: 0.96 min

MS (ESI pos): m / z = 302 (MtH) '

The following examples are synthesized analogously to the preparation of Example 195, using the corresponding Boc-protected amines as starting materials.

146

بك

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Εχρ٠ 196 mixed racem.</td><td> ؟٢٢</td><td>Example 12L</td><td>1.01 (Process 1)</td><td>302 (M + H) ٠</td>

<td>Exp. 197 mixed racem.</td><td> ؟؟</td><td>Example 12Μ</td><td>0.93 (Process 1)</td><td>310 (MtH) *</td>

<td>Exp. 198 mixed racem.</td><td>هلي ' ئ غأ اجء</td><td>Example 12Ν</td><td>1.09 (Process 1)</td><td>394 (MtH) '</td>

147

با

ΜΑ 33152Β1

296 (MtH)

0.92 (Process

1)

Example 12G

O

<img file="MA33152B1_D0095.tif" />

WHERE

٨

380 (MtH) '

1.08 (Process

1)

Example 12Η

274 (MtH)

0.89 (Process

1)

Example 12J

١٩.

٠٢٠Η

ة

310 (MtH) '

0.92 (Process

1)

Example 12Β

O

<img file="MA33152B1_D0096.tif" />

H لمت:

Exp. 199 racem mixture.

Exp. 200 racem mixture.

Exp. 201 racem mixture.

Exp. 202

148

ΜΑ 33152Β1

<td>Exp. 203</td><td>Q ك^٠اج</td><td>Example 12C</td><td>1.07 (Process 1)</td><td>394 (MtH) *</td>

<td>Exp. 204 mixed racem.</td><td>.٦٦ خح '</td><td>Example 12٠</td><td>0.95 (Process 1)</td><td>328 (MtH) '</td>

<td>Exp. 205 mixed racem.</td><td>-. '؛ ر</td><td>Example 12R</td><td>1.13 (Process 1)</td><td>378 (Μ + Η) '</td>

<td>Exp. 206 mixed racem.</td><td>زه</td><td>Example 12υ</td><td>0.94 (Process 1)</td><td>288 (MtH) '</td>

Example 207, Racemic mixture

149

رم

ΜΑ 33152Β1

<img file="MA33152B1_D0097.tif" />

mg (120 mmol) of Example 13Α are dissolved in 5 ml of dichloromethane and 15 mg (500 mmol) of formaldehyde are added. The reaction mixture is stirred at room temperature for 1 h. 15 μΐ (260 mmol) of acetic acid and 35 mg (160 mmol) sodium triacetoxyborohydride are added. The reaction mixture is stirred for 2 h at room temperature. The solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water ٠ 0.13% TFA, eluent B: acetonitrile). 34 mg (65%) of the product are obtained.

HPLC-MS (Method 1): Rt: 0.99 min

MS (ESI pos): m / z = 302 (M + H) ٠

The following examples are synthesized analogously to the preparation of Example 207 using the corresponding amines as starting materials.

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 208 mixed racem.</td><td></td><td>Example 13C</td><td>1.02 (Method 1)</td><td>316 (MtH) *</td>

<td>Exp. 209 mixed racem.</td><td>خليلا ميل</td><td>Example 13Ε</td><td>1.13 (Method 1)</td><td>408 (MtH) '</td>

150

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 210 mixed racem.</td><td>٠٩ Ο٢ΟΗ F٨</td><td>Example 13F</td><td>0.93 (Method 1)</td><td>310 (MtH) *</td>

<td>Exp. 211 mixed racem.</td><td>٥٦ WHERE ة</td><td>Example 13G</td><td>1.11 (Method 1)</td><td>394 (MtH) '</td>

<td>Exp. 212 mixed racem.</td><td>Ο٢ΟΗ F٨</td><td>Example 13Η</td><td>0.98 (Method 1)</td><td>340 (MtH) '</td>

<td>Exp. 213 mixed of stereo- isomers</td><td> ٢٠١'</td><td>Example 13J</td><td>1.02 (Method 1)</td><td>344 (MtH) '</td>

151

نيم

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 214 mixed racem.</td><td>0٢0Η ذة ؛</td><td>Example 131</td><td>0.91 (Method 1)</td><td>288 (MtH) *</td>

<td>Exp. 215 mixed racem.</td><td></td><td>Example 13D</td><td>0.97 (Method 1)</td><td>324 (MtH) *</td>

<td>Exp. 216 mixed racem.</td><td></td><td>Example 205</td><td>1.16 (Method 1)</td><td>392 (MtH) '</td>

<td>Exp. 217 mixed racem.</td><td></td><td>Example 204</td><td>0.98 (Method 1)</td><td>342 (MtH) ٠</td>

152

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Exp. 218 mixed racem.</td><td>AT.</td><td>Example 13Q</td><td>0.95 (Method 1)</td><td>302 (MtH) '</td>

Example 219

<img file="MA33152B1_D0098.tif" />

Under an argon atmosphere, 100 mg (0.26 mmol) of Example 5, 95 mg (0.77 mmol) of pyridine-3-boronic acid, 310 μΐ (2.41 mmol) of a solution aqueous sodium carbonate (2Μ), 5 ml of dioxane and 20 mg (0.02 mmol) of tetrakis- (triphenylphosphine) -palladium (O) are combined. The reaction mixture is heated at 140 ٠c for 35 minutes in a microwave oven. After cooling to room temperature, the reaction mixture is filtered through celite. The filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC. 82 mg (83%) of the product are obtained.

HPLC-MS (Method 1): Rfc: 1.00 min

MS (ESI pos): m / z = 388 (Μ + Η) '

The following examples are synthesized analogously to the preparation of Example 219 using the corresponding boronic acids as starting materials.

<td></td><td>structure</td><td>product</td><td>of</td><td>Rt [min]</td><td>MS (ESI,</td>

<td></td><td></td><td>departure</td><td></td><td></td><td>m / z)</td>

153

ΜΑ 33152Β1

<td></td><td>structure</td><td colspan="2">product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Example 2 20</td><td>٠ ت ؛ ي</td><td colspan="2">HOyOH شه</td><td>1.01 (Process 1)</td><td>418 (MtH) *</td>

<td>Example 2 21</td><td>مخل ب NOT</td><td>و , ٥١ ζ I r</td><td>ا ٥'3 S / Ν 1 .1</td><td>1.24 (Process 1)</td><td>413 (MtH) *</td>

<td>Example 2 22</td><td>لآغ ٠ لا</td><td>Η٥١ [ ζ 1 Γ</td><td>/ ΟΗ إ</td><td>1.34 (Process 1)</td><td>412 (MtH) *</td>

154

٨

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Example 2 23</td><td>لأر</td><td> ?</td><td>1.03 (Process 1)</td><td>473 (MtH) *</td>

<td>Example 2 24</td><td>Ό٠ ٠٢٠ ردتد لأ</td><td>ΗΟ \_θ/ ΟΗ ؤ</td><td>0.96 (Process 1)</td><td>388 (MtH) *</td>

<td>Example 2 25</td><td>أد</td><td>ΗΟ١ OH ة</td><td>1.18 (Process 1)</td><td>418 (Μ + Η) *</td>

155

عاً

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Example 2 26</td><td>ح ري</td><td>HO OH ¢. ة</td><td>1.57 (Process 1)</td><td>494 ٠ (H ؛ M)</td>

<td>Example 2 27</td><td>مغ ت</td><td>HO OH ق 0 /</td><td>1.19 (Process 1)</td><td>419 (Μ + Η) ٠</td>

<td>Example 2 28</td><td>لأخل</td><td>HOyOH , ة</td><td>1.26 (Process 1)</td><td>406 (Μ + Η) ٠</td>

156

Π \

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Example 2 29</td><td> ٠٩</td><td>HO١ OH ب</td><td>1.40 (Process 1)</td><td>417 (MtH) '</td>

<td>Example 2 30</td><td>طغل نلم ٠١ با 0</td><td>ΗΟ \ OH Λ</td><td>1.06 (Process 1)</td><td>389 (MtH) '</td>

<td>Example 2 30-1</td><td>:: ؛ ٦, ة</td><td>دا νΛν ب عذب</td><td>1.24 (Process 1)</td><td>474 (MtH) '</td>

157

٩

ΜΑ 33152Β1

<td></td><td>structure</td><td>product of departure</td><td>Rt [min]</td><td>MS (ESI, m / z)</td>

<td>Example 2 30-2</td><td>مثو ٠١ ا</td><td>١Ν-Ν V ١0 ا 0 زبر</td><td>1.16 (Process 1)</td><td>391 (MtH) *</td>

<td>Example 2 30-3</td><td> 1 ٢</td><td>ج OH</td><td>1.25 (Process 1)</td><td>404 (MtH) *</td>

<td>Example 2 30-4</td><td></td><td>ه عثم ١ ي Κ لآ '</td><td>1.28 (Process 1)</td><td>367 (MtH) *</td>

<td>Example 2 30-5</td><td>هت ٦ ة ٠١ ١٩</td><td>ة H0-R ΟΗ</td><td>1.27 (Process 1)</td><td>3.11 (MtH) *</td>

Example 231

158

ΜΑ 33152Β1

<img file="MA33152B1_D0099.tif" />

A vial is charged under an inert atmosphere with Example 5 (175 mg, 0.45 mmol), pyrazole (306 mg, 4.49 mmol), copper iodide (85 mg, 0.45 mmol) and cesium carbonate (439 mg, 1.35 mmol). Dimethylformamide (5 ml), degassed beforehand, is then added, followed by Ν, Ν'-dimethylethylene diamine (47.87 μΐ; 0.45 mmol). The reaction mixture is heated at 120 ٠c for hours. The suspension is then filtered through a pad of celite. Celite is washed with DMF. The volume of the organic phase is reduced under reduced pressure, then a saturated solution of ammonium chloride is added, followed by ethyl acetate. The phases are separated and the organic phase is washed with brine, then dried. The crude product is purified by an SPE cartridge and the product obtained is further purified by SPE Stratosphere “PLTHIOL MP” in order to completely eliminate the copper salts. The solid obtained is triturated with diethyl ether. 15.5 mg of the desired product are obtained (yield = 9.2%).

HPLC-MS (Method 1Ε hydro): Rt: 7.80 min

MS (APCI pos): m / z = 377 (MtH) '

Example 232

<img file="MA33152B1_D0100.tif" />

Example 53 (100 mg, 0.298 mmol) and hydroxylamine (0.073 ml,

1.19 mmol) are mixed together in absolute ethanol (4 ml) in a 50 ml flask. The reaction mixture is brought to reflux for 3 hours before being treated. The solvent is then removed under reduced pressure to obtain 120 mg (70% yield, 0.228 mmol) of N-hydroxy-2_ [4-ΟΧΟ-1- (tetrahydro-pyran-4-yl) -4,5-dihydro- 1H-pyrazolo [3,4-d] pyrimidin-630 ylmethylj-benzamidine in the form of a solid which is used as such in the next step.

N-hydroxy-2_ [4-ΟΧΟ-1- (tetrahydro-pyran-4-yl) -4,5-dihydro-! Hpyrazolo [3,4-d] pyrimidin-6-ylmethyl] -benzamidine (120 mq, 70% yield; 0.228 mmol) is suspended in trimethyl orthoacetate (5 ml) and acetic acid is then added (1 ml). The mixture is heated at 100 ٠c for 1 hour. The mixture is cooled to room temperature and the precipitation of a solid is observed. The filtrate is concentrated under reduced pressure. The crude product is purified by flash chromatography. The product is then triturated with diethyl ether. 24 mg of the desired compound are obtained (yield 26.6%).

HPLC / MS (1Ε hydro process)

MS (APCI pos): m / z = 393 (MtH) '

159

ل

ΜΑ 33152Β1

Example 233

<img file="MA33152B1_D0101.tif" />

Example 12Χ (250 mg, 1.14 mmol) is dissolved in 20 ml of hot methanol. Alumina (neutral) is added and the solvent is then removed to give a white powder which is transferred to a 2 ml Wheaton vial. 5,6-Dihydro-2H-pyran-2-oxo is added, followed by DMFe (1 ml) and the vial is tightly closed. The suspension is heated to 80 ٠c with orbital shaking for 4 days. The reaction is then filtered and the alumina is washed with methanol, ethyl acetate and dichloromethane. The organic phases are combined and the solvents are removed under reduced pressure. The crude product is purified by flash chromatography. Eluent: (starting with a gradient of n15 hexane / ethyl acetate 9/1 to ethyl acetate (100%) followed by ethyl acetate / methanol 99/1 to 94/6). 70 mg of the desired compound are obtained in the form of a solid (19.3%).

HPLC-MS (Method 2F): Rt: 9.06 min

MS (ESI pos): m / z = 317 (M + H)⁺

Example 234

<img file="MA33152B1_D0102.tif" />

Example 53 (160 mg, 80% yield, 0.38 mmol) and hydrated hydrazine (0.186 ml, 3.81 mmol) are mixed together in absolute ethanol (4 ml) in a flask of. 25 ml. The reaction mixture is brought to reflux for 6 hours before being treated. The solvent is removed under reduced pressure to obtain 200 mg (70% yield, 0.38 mmol) of the desired product used as such in the next step. The product (200 mg, 70% yield, 0.38 mmol) is suspended in trimethyl orthoacetate (6 ml). Acetic acid is added (0.6ml) and the solution is heated at 80 ٠c for 30 minutes. Trimethyl orthoacetate and acetic acid are removed under reduced pressure and the crude product is partitioned between water and dichloromethane. The organic phase is dried and the crude product is purified by flash chromatography. (gradient: starting with a mixture of dichloromethane / methanol 98/2 and ending with a mixture of dichloromethane / methanol 90/10). The product is further purified by trituration with diethyl ether. 8 mq of the desired compound (4%) are obtained.

HPLC-MS (Method 1Ε hydro): Rt: 6.82 min MS (APCI pos): m / z = 392 (MtH) *

160

عه

ΜΑ 33152Β1

Example 235

<img file="MA33152B1_D0103.tif" />

mg (0.06 mmol) of Example 230-4 in 3 ml of methanol are hydrogenated over Pd / C (10%) at atmospheric pressure. The catalyst is removed. The solvent is evaporated off and the residue is chromatographed by HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile) to give 15.7 mg (71%) of the product.

HPLC-MS (Method 1): Rt: 1.35 min

MS (ESI pos): m / z = 369 (M٠H) ٠

<img file="MA33152B1_D0104.tif" />

100 mg (73%, 0.251 mmol) of Example 40-5 are dissolved in 2 ml of acetic acid and 30 μΐ (0.35 mmol) of hydrogen peroxide dissolved in water (35%) are add. The mixture is stirred for 3 h and a mixture of acetonitrile / water is added. The mixture is chromatographed by HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile) to give 50.3 mg (65%) of the product.

HPLC-MS (Method 1): Rt: 0.88 min

MS (ESI pos): m / z = 307 (MH) '

Example 237

161

لى

ΜΑ 33152Β1

<img file="MA33152B1_D0105.tif" />

100 mg (73%, 0.251 mmol) of Example 40-5 are dissolved in 2 ml of acetic acid and 200 μΐ (2.33 mmol) of hydrogen peroxide dissolved in water (35%) are add. The mixture is stirred for 3 days and an acetonitrile / water mixture is added. The mixture is chromatographed by HPLC (eluent A: water t 0.13% TFA, eluent B: acetonitrile) to give 21.5 mg (27%) of the product.

HPLC-MS (Method 1): Rt: 0.93 min

MS (ESI pos): m / z = 323 (MtH) '

Example 239

<img file="MA33152B1_D0106.tif" />

Under a nitrogen atmosphere, 50.0 mg (0.12 mmol) of Example 40-10 and 51 mg (0.25 mmol) of 1-methyl-4- (4,4,5,5-tetramethyl) -1, 3,2-dioxaborolan2-y!) - 1H-pyrazole are dissolved in 2 ml of DMF. 156 mg (0.74 mmol) of potassium phosphate, 0.78 mg (2.45 pmmol) of tris (dibenzylideneacetone) dipalladium and 2.85 mg of tri (tert-butylphosphonium) tetrafluoroborate are added. The reaction mixture is heated at 150 ° C for 30 minutes in a microwave oven. The mixture is evaporated under reduced pressure. The residue is purified by preparative HPLC. 29 mg (58%) of the product are obtained.

HPLC-MS (Method 1): Rt: 1.23 min

MS (ESI pos): m / z = 409 (MtH) '

Example 240

<img file="MA33152B1_D0107.tif" />

162

ΜΑ 33152Β1

Step A:

1.00 g (6.33 mmol) of 2-bromo-pyridine and 1.53 ml (6.46 mmol) of triisopropyl borate are dissolved in 10 ml of THF under a nitrogen atmosphere. The mixture is cooled to -30 ٥c. 6.76 ml (10.8 mmol) of nbutyllithium are added dropwise. After stirring for 1.5 h, the mixture is allowed to return to room temperature over 1 h. The precipitate is filtered and dried to give 0.84 g of the solid compound.

Step B:

To 100 mg (0.26 mmol) of Example 5 and 213 mg of the product obtained in step A, 3 ml of DMF, 436 mg (2.05 mmol) of potassium phosphate and 26.7 mg are added. (0.02 mmol) of tetrakis- (triphenylphosphine) palladium (0). The reaction mixture is heated at 145 ° C for 90 minutes in a microwave oven. The mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane and washed with water and brine. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by preparative HPLC (eluent A: water + 0.1% conc. Ammonia, eluent B: methanol). The resulting product is further purified by a 3-step procedure: (1) conversion to the corresponding hydrochloride salt by adding dichloromethane followed by hydrochloric acid (6Μ in isopropanol) followed by evaporation of the volatiles under reduced pressure; (2) trituration with acetonitrile followed by removal of the solvent by filtration; and (3) liberation of the free base by addition of dichloromethane and extraction with an aqueous solution of potassium carbonate followed by phase separation and removal of the solvent from the organic phase under reduced pressure. 9.1 mg (9.1%) of the product are obtained.

HPLC-MS (Method 4): Rt = 2.57 min

MS (ESI pos): m / z = 388 (MtH) '

The following examples are synthesized analogously to the preparation of Example 240, using the corresponding starting materials.

<td></td><td>structure</td><td>starting material: bromopyridine</td><td>Rt</td><td>MS (ESI pos, m / z)</td>

<td>Example 24 1</td><td>ث؟ ٠</td><td>Q</td><td>3.04 min (Method 4)</td><td>406 (MtH) '</td>

163

لاك

ΜΑ 33152Β1

<td></td><td>structure</td><td>starting material: bromopyridine</td><td>Rt</td><td>MS (ESI pos, m / z)</td>

<td>Example 24 2</td><td>مع وغد</td><td> ٩</td><td>3.29 min (Method 4)</td><td>456 (MtH) *</td>

<td>Example 24 3</td><td>مجج ا ١ ج ٢ ^ ا</td><td>ي</td><td>3.10 min (Method 4)</td><td>456 (Μ + Η) *</td>

<td>Example 24 4</td><td>للمه م ٠ b</td><td>'ب</td><td>3.37 min (Method 4)</td><td>456 (MtH) *</td>

Example 245

<img file="MA33152B1_D0108.tif" />

164

٠٩

ΜΑ 33152Β1

A microwave vial is loaded with Example 5 (100 mg,

0.257 mmol), 5-methylfuran-2-boronic acid (161.75 mg, 1.285 mmol), tetrakis (triphenylphosphine) -palladium (O) (118.84 mg, 0.104 mmol) in dioxane (1 ml ). Then 1.02 ml (2.056 mmol) of an aqueous solution of

NO 2 M are added. The reaction mixture is heated at 130 ٠c for 4 hours in a microwave oven. Cooling to 20 ° C is followed by acidification with 37% HCl until an acidic pH is obtained, then the mixture is extracted with dichloromethane (2x2 ml). The organic phase is dried over Na2S٠4, filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by flash chromatography on SO2 using a mixture of cyclohexane / ethyl acetate with increasing polarity (from 100% cyclohexane to 100% ethyl acetate) as the eluent. The product obtained is further purified by preparative TLC (mixture of ethyl acetate / cyclohexane 80/20 as eluent). The solid is lyophilized with a 1: 1 water / acetonitrile mixture giving the title compound as a white solid (23 mg, 22.9%).

HPLC-MS (Method 1Ε hydro): Rt: 8.93 min MS (APCI pos): m / z = 391 (MtH) '

Example 246

<img file="MA33152B1_D0109.tif" />

A 0.231 mmol) vial of for microwave is charged with Example 5 (90 mg, 2-furanboronic acid (77.74 mg, 0.694 mmol), tetrakis- (triphenylphosphine) palladium (0) (40 , 74 mg, 0.035 mmol) in dioxane (1 ml). Then 0.46 ml (0.925 mmol) of an aqueous solution of

Na ؛ CO3 2 M are added. The reaction mixture is heated at 130 ٠c for 80 minutes in a microwave oven. Cooling to 20 ° C is followed by dilution with water and acidification with 10% aqueous HCl solution followed by extraction with dichloromethane (2 x 2 ml). The organic phase is dried over Na₂SO₄, filtered and the filtrate is concentrated under reduced pressure. The remaining residue is purified by preparative HPLC (eluent A: water + 5 mM NH 0OH, eluent B: acetonitrile). After lyophilization, the title compound is obtained in the form of a white solid (28 mg, 32.2%).

HPLC-MS (Method 1Ε hydro): Rt: 8.42 min MS (APCI pos): m / z = 377 (MtH) '

Example 247

<img file="MA33152B1_D0110.tif" />

165

ر

ΜΑ 33152Β1

A vial is charged under an inert atmosphere with Example 5 (100 mg, 0.514 mmol) and 4- (tributylstannyl) -pyridazine (227.6 mg,

0.617 mmol) in previously degassed toluene (7 ml), then tetrakis (triphenyl-phosphine) palladium (0) (59.37 mg, 0.051 mmol) and

Copper iodide (9.79 mg, 0.051 mmol) is added. The reaction mixture is heated at 120 ٠c for 2 hours in a microwave oven. The reaction mixture is diluted with a saturated aqueous solution of NH Cl and extracted with dichloromethane. The organic phase is dried over Na2S٠4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on Sio ؛ using a mixture of dichloromethane / methanol 98/2 as the eluent. The solid obtained is further purified by preparative HPLC (eluent A: water + 5 mM NH 0OH, eluent B: acetonitrile). The title compound is obtained in the form of a white solid (22 mg, 11%).

HPLC-MS (Method 1Ε hydro): Rt: 6.33 min

MS (APCI pos): m / z = 389 (MtH) '

Example 248

<img file="MA33152B1_D0111.tif" />

A balloon is charged under an inert atmosphere with copper iodide (97.86 mg, 0.514 mmol), cesium carbonate (502.23 mg, 1.541 mmol), Example 5 (200 mg, 0.514 mmol). , 1,2,4-triazole (384.56 mg, 5.138 mmol) and dimethylformamide (12ml), degassed beforehand, followed by Ν, Ν'-dimethylethylene diamine (109.4 μΐ, 1.028 mmol). The reaction mixture is heated at 120 ٥c for 3 hours. After cooling, the reaction mixture is filtered through a rib pad which is rinsed with dimethylformamide, then a saturated aqueous NHC solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NHCl, brine, then dried over Na2S0 ، and the solvent is removed under reduced pressure. The crude product is purified by preparative HPLC (eluent A: water t 5 mM NHOOH, eluent B: acetonitrile). The title compound is obtained as a solid (7.2 mg, 3.7%).

HPLC-MS (Method 1Ε hydro): Rt: 6.37 min

MS (APCI pos): m / z = 378 (Μ + Η) ♦

The following examples are synthesized analogously to the preparation of Example 248, using the corresponding bromides and heterocycles as starting materials.

<td></td><td>Structure</td><td>Product of</td><td>Rt [min]</td><td>MS</td>

<td></td><td></td><td>departure :</td><td></td><td>(APCI</td>

<td></td><td></td><td>heterocycle</td><td></td><td>pos,</td>

<td></td><td></td><td></td><td></td><td>m / z)</td>

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<td></td><td>Structure</td><td>Product of start: heterocycle</td><td>Rt [min]</td><td>MS kASCI. pos, m / z)</td>

<td>Example 249</td><td>مم لأ °</td><td>,NOT^notvnh</td><td>6.52 (1Ε hydro process)</td><td>392 (Mt-H) ٠</td>

<td>Example 250</td><td>ي</td><td>٨ ' Ν-Ν</td><td>8.75 1Ε hydro process</td><td>445 (M٠H) ٠</td>

<td>Example 251</td><td>! حدلا</td><td>٦ Vn</td><td>8.63 1Ε hydro process</td><td>445 (MtH) '</td>

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<img file="MA33152B1_D0112.tif" />

79.89 mg (0.380 mmol) of Example 11Β are dissolved in absolute ethanol (2ml), then 76 mg (1.9 mmol) of sodium hydride (suspension of

60 % in mineral oil) are added. The mixture is stirred for minutes before adding 300 mg (1.521 mmol) of [2- (3-methyl-pyrazol-lyl) -phenyl] acetonitrile (Example 20Α). The reaction mixture is then heated at 140 ٠c for 40 minutes in a microwave oven. Cooling to 20 ٠c is followed by evaporation of the solvent under reduced pressure. The residue is dissolved in a strong 10% citric acid solution (2 ml) and then extracted with dichloromethane (2x2 ml). The organic phase is dried over Na₂SO₄, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent A: water 0.05 ؛% of TFA, eluent B: acetonitrile). The solid obtained is triturated with diisopropyl ether to give the title compound as a solid (50.8 mg, 34.2%).

HPLC-MS (Method 2Μ): Rt = 8.41 min MS (APCI pos): m / z = 391 (MH) '

The following example is synthesized analogously to the preparation of Example 252, using the corresponding ester or nitrile as starting materials.

<td></td><td>Structure</td><td>pyrazolyl- carboxamide</td><td>nitrile</td><td>Rt [min]</td><td>MS (ESI pos, m / z)</td>

<td>Example 253</td><td>ص '٠</td><td>Example 11Β</td><td>ولؤ Example 21Α</td><td>10.09 Process 2 F</td><td>376 (MtH) ٠</td>

<img file="MA33152B1_D0113.tif" />

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A microwave vial is loaded with example 19Α (50 mg,

0.115 mmol), 3-bromopyridazine (15 mg, 0.094 mmol) and 1,2dimethoxyethane (2.5 ml). The mixture is degassed, then tetrakis (triphenylphosphine) palladium (0) (16.35 mg, 0.014 mmol) and

165.11 μΐ (0.33 mmol) of a 2 M aqueous solution of Na2C٥3 are added. The reaction mixture is heated at 120 ° C for 1 hour in a microwave oven. After cooling to 20 ٠c, the reaction mixture is diluted with a saturated aqueous solution of HCl and extracted with dichloromethane, dried over Na₂SO4 and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on SiC&gt; 2 using a mixture of dichloromethane / methanol 98/2 as eluent. The title compound is obtained as a solid (12 mg, 32.8%).

HPLC-MS (Method 1Ε hydro): Rt: 7.12 min

MS (APCI pos): m / z = 389 (MtH) '

Example 255

<img file="MA33152B1_D0114.tif" />

Example 53 (200 mg, 0.596 mmol) and 50% hydroxylamine in water (146.18 μΐ, 2.385 mmol) are mixed together in absolute ethanol (6 ml). The reaction mixture is brought to reflux for 5 hours. The solvent is then removed under reduced pressure to obtain 229 mg (0.621 mmol) of N-hydroxy-2- [4-oxo-l-8tetrahydro-pyran-4-yl) -4,5-dihydroΙΗ-pi ^ razolo [3 , 4-d] pyrimidin-6-ylmethyl] -benzamidine as a yellow solid which is used as such in the next step.

N-hydroxy-2_ [4-oxo-1-8tetrahydro-pyran-4-yl) -4,5-dihydro-! Hpyrazolo [3,4-d] pyrimidin-6-ylmethyl] -benzamidine (225 mg, 0.611 mmol) is suspended in anhydrous dichloromethane (4.5ml), then N, Ndiisopropylethylamine (0.79 ml, 4.616 mmol) is added and the reaction mixture is cooled to 0 ° C before the addition of trifluoroacetic anhydride ( 0.402 ml, 2.89 mmol). The mixture is stirred at 0 ° C. for 5 hours before being diluted with dichloromethane and washed with water and brine. The organic phase is dried over Na₂SO₄, filtered and the solvent is removed under reduced pressure. The remaining residue is purified by flash chromatography on Si٥2 using a mixture of dichloromethane / methanol with increasing polarity (from 100% dichloromethane to 99/1 of a mixture of dichloromethane / methanol) as eluent. The product is obtained as a slightly yellow solid (55 mg, 20.2%).

HPLC-MS (Method 1Ε hydro): Rt: 9.22 min MS (APCI pos): m / z = 447 (MtH) '

Example 256

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<img file="MA33152B1_D0115.tif" />

A microwave vial is charged under an inert atmosphere with copper (I) oxide (5.1 mg, 0.04 mmol), cesium carbonate (154 mg, 0.47 mmol), 2-hydroxy-benzaldehyde oxime (9.7 mg,

0.07 mmol), example 40-8 (100 mg, 0.24 mmol) and pyrazole (32.1 mg,

0.47 mmol). Acetonitrile (5 ml), degassed beforehand, is added. The reaction mixture is heated at 80 ٠c for 2 hours using a microwave oven. After cooling, the reaction mixture is diluted with dichloromethane and filtered through a pad of celite. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC (A: water 0.05% TFA, eluent B: methanol). The resulting product is further purified by a 3-step procedure: (1) conversion to the corresponding hydrochloride salt by adding ethyl acetate followed by hydrochloric acid (6 M in isopropanol) followed by evaporation of the products. volatiles under reduced pressure; (2) trituration with ethyl acetate followed by removal of the solvent by filtration; and (3) liberation of the free base by addition of ethyl acetate and extraction with an aqueous solution of potassium carbonate followed by phase separation and removal of the solvent from the organic phase under reduced pressure. 30 mg (31%) of the product are obtained.

HPLC-MS (Method 6): Rt = 1.45 min

MS (ESI pos): m / z = 411/413 (Μ + Η) '(Cl)

The following examples are synthesized analogously to the preparation of Example 256, using the corresponding bromides and heterocycles as starting materials.

<td></td><td>Structure</td><td>product of start: bromide</td><td>product of departure : hetero- cycle</td><td>Rt [min]</td><td>MS (ESI pos, m / z)</td>

<td>Example 25Ί</td><td> ٠</td><td>Example 40-9</td><td>VS Ü١H</td><td>1.50 (Process 6)</td><td>445 (MtH) '</td>

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<td></td><td>Structure</td><td>product start: bromide</td><td>product departure : hetero- cycle</td><td>Rt [min]</td><td>MS (ESI pos, m / z)</td>

<td>Example 257</td><td> '1'</td><td>Example 40-9</td><td>لام</td><td>1.50 (Process 6)</td><td>445 (M + H)⁺</td>

<td>Example 258</td><td> 1</td><td>Example 40-8</td><td>k</td><td>1.46 (Process 7)</td><td>425/42٦ (Μ + Η) ' (Cl)</td>

Example 259

<img file="MA33152B1_D0116.tif" />

A microwave vial is loaded with example 19Α (70 mg,

0.16 mmol), 2-bromo-6-tert-butyl-pyridine (69 mg, 0.32 mmol) and DMF (2.0ml). The mixture is degassed, then tetrakistiphenylphosphine) palladium (0) (9.2 mg, 0.01 mmol) and potassium acetate (55.1 mg, 0.56 mmol) are added. The reaction mixture is heated at 145 ٠c for 45 minutes in a microwave oven. After cooling to 20 ٠c, the solvent is removed under reduced pressure. The crude product is purified by preparative HPLC (A: water t 0.05% TFA, eluent B: methanol). The resulting product is further purified by a two-step procedure: (1) conversion to the corresponding hydrochloride salt by adding dichloromethane and then hydrochloric acid (6Μ in isopropanol) followed by evaporation of the volatiles under reduced pressure; and (2) trituration with ethyl acetate followed by removal

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HPLC-MS (Method 7): Rt = 1.42 min

MS (ESI pos): m / z = 444 (MtH) '

The following examples are synthesized analogously to the preparation of Example 259, using the corresponding bromopyridines as starting materials.

<td></td><td>structure</td><td>product of start: bromopyridine</td><td>Rt</td><td>MS (ESI pos, m / Z)</td>

<td>Example 26 0</td><td>نببه I fo ٠١ο</td><td>.ه. ه</td><td>1.62 min (Process ٦١</td><td>458 (MtH))</td>

<td>Example 26 1</td><td>مع ك '_: .ت ٦٦۶</td><td>لأ</td><td>1.38 min (Process ٦١</td><td>418 (M + H) ⁺</td>

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<td></td><td>structure</td><td>product of start: bromopyridine</td><td>Rt</td><td>MS (ESI pos, m / z)</td>

<td>Example 26 2</td><td>٢ مغل Cl</td><td> .٠</td><td>1.53 min (Process 7)</td><td>422 (MtH) *</td>

<td>Example 26 3</td><td>ران شو</td><td> ,١٧١٠</td><td>1.22 min (Process ٦١</td><td>402 (MtH) *</td>

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