HK1149549B

HK1149549B - 1-heterocyclyl-1,5-dihydro-pyrazolo[3,4-d] pyrimidin-4-one derivatives and their use as pde9a modulators

Info

Publication number: HK1149549B
Application number: HK11103607.6A
Authority: HK
Inventors: Riccardo Giovannini; Cornelia Dorner-Ciossek; Christian Eickmeier; Dennis Fiegen; Thomas Fox; Klaus Fuchs; Niklas Heine; Holger Rosenbrock; Gerhard Schaenzle
Original assignee: 贝林格尔.英格海姆国际有限公司
Priority date: 2008-04-02
Filing date: 2009-04-01
Publication date: 2015-09-25

Description

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 in which i) the nitrogen atom of the pyrazolo group next to the pyrimidinone group is connected to a non-aromatic, organic heterocyclic ring having at least one ring heteroatom selected from O, N and S, and ii) a second substituent is connected to the C-atom between the two nitrogen atoms of the pyrimidinone ring via an optionally substituted methylene bridge. According to one aspect of the invention, the novel compounds are used for the preparation of medicaments, in particular medicaments for the treatment of deficits with respect to perception, concentration, learning or memory. The novel compounds are also useful for the preparation of medicaments for the treatment of alzheimer's disease. Other aspects of the invention relate to processes for the preparation of the compounds and their use for the preparation of medicaments.

Background

Inhibition of phosphodiesterase 9A (PDE9A) is one of the current concepts to find a new avenue of acquisition for the treatment of cognitive impairment due to CNS disorders, such as alzheimer's disease, or due to any other neurodegenerative process of the brain. The novel compounds of the present invention have been proposed based on this concept.

Phosphodiesterase 9A is a member of a large family of phosphodiesterases. These classes of enzymes regulate the levels of cyclic nucleotides 5 '-3' cyclic adenosine monophosphate (cAMP) and 5 '-3' cyclic guanosine monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP) are important second messengers and therefore play an important role in the cell signaling cascade. Each of which (particularly but not exclusively) reactivates protein kinases. Protein kinases activated by cAMP are referred to as protein kinase a (pka), while protein kinases activated by cGMP are referred to as protein kinase g (pkg). In turn, activated PKA and PKG are able to phosphorylate a number of cellular effector proteins (e.g. ion channels, G-protein coupled receptors, structural proteins, transcription factors). In this way, it is possible that the second messengers cAMP and cGMP control a variety of physiological processes in a variety of organs. However, cyclic nucleotides can also act directly on effector molecules. Thus, it is known, for example, that cGMP can act directly on ion channels and can therefore influence the ion concentration of cells (for a review see: Wei et al, prog. neurobiol., 1998, 56, 37-64). Phosphodiesterases (PDEs) are control mechanisms for controlling the activity of cAMP and cGMP, and in turn for the corresponding physiological processes. The PDE hydrolyzes cyclic monophosphates to inactive AMP and GMP monophosphates. Currently, 11 PDE families have been defined based on sequence homology of the corresponding genes. Individual PDE genes within a family are distinguished by letters (e.g., PDE1A versus PDE 1B). If different splice variants also exist within a gene, this is indicated by another number after the letter (e.g., PDE1A 1).

Human PDE9A was cloned and sequenced in 1998. The amino acid identity with other PDEs does not exceed 34% (PDE8A) but is never less than 28% (PDE 5A). PDE9A has a high affinity for cGMP with a Michaelis-Menten constant (Km) of 170 nM. In addition, PDE9A is selective for cGMP (Km 230 μ M for cAMP). PDE9A lacks a cGMP binding domain, indicating that the enzyme activity is not regulated by cGMP. In western blot analysis, PDE9A has been demonstrated to be expressed in humans, particularly in the testis, brain, small intestine, skeletal muscle, heart, lung, thymus and spleen. The highest expression was found in brain, small intestine, kidney, prostate, colon and spleen (Fisher et al, J.biol.chem., 1998, 273(25), 15559-15564; Wang et al, Gene, 2003, 314, 15-27). The gene for human PDE9A is located on chromosome 21q22.3 and includes 21 exons. 4 alternative splice variants of PDE9A have been identified (Guipponi et al, hum. Genet., 1998, 103, 386-392). Typical PDE inhibitors do not inhibit human PDE 9A. Thus, IBMX, dipyridamole, SKF94120, rolipram and vinpocetine showed no inhibition of the isolated enzyme at concentrations up to 100 μ M. The IC of zaprinast has been demonstrated₅₀At 35 μ M (Fisher et al, J.biol.chem., 1998, 273(25), 15559-15564).

Murine PDE9A was cloned and sequenced by Soderling et al in 1998 (J.biol.chem., 1998, 273(19), 15553-15558). It has high affinity for cGMP, as in the human form, with a Km of 70 nM. Particularly high expression is found in kidney, brain, lung and liver of mice. Murine PDE9A was also not inhibited by IBMX at concentrations below 200 μ M; IC of zaprinast₅₀29 μ M (Soderling et al, J.biol.chem., 1998, 273(19), 15553-15558). PDE9A has been found to be strongly expressed in some regions of the rat brain. It includes olfactory bulb, hippocampus, cortex, basal ganglia and basal forebrain (Andreeva et al, j. neurosci, 2001, 21(22), 9068-. The hippocampus, cortex and basal forebrain play important roles, particularly in learning and memory. As already mentioned above, PDE9A is characterized by a particularly high affinity for cGMP. Thus, PDE9A is active even at low physiological concentrations, in comparison with PDE2A (Km 10. mu.M; Martins et al, J.biol. chem., 1982, 257, 1973-. The catalytic activity of PDE9A was not increased by cGMP compared to PDE2A (Murashima et al, Biochemistry, 1990, 29, 5285-. PDE9A inhibitors may therefore result in an increase in baseline cGMP concentrations.

From this summary, it is clear that PDE9A participates in specific physiological processes in a characteristic and unique way, which distinguishes the role of PDE9A from the role of any other PDE family member.

WO04099210 discloses 6-arylmethyl-substituted pyrazolopyrimidinones which are PDE9 inhibitors. The compounds do not have a non-aromatic heterocyclic moiety at the 1-position of the pyrazolopyrimidine.

WO04096811 discloses heterocyclic bicyclic rings which are PDE9 inhibitors for the treatment of diabetes, including type 1 and type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, metabolic syndrome and/or cardiovascular disease.

Other prior art references relate to chemically similar nucleoside derivatives. As an example, reference may be made to WO02057425, which discloses nucleoside derivatives that are inhibitors of RNA-dependent RNA viral polymerase, or WO01060315, which discloses nucleoside derivatives for the treatment of hepatitis c virus infections, or EP679657, which discloses compounds for use as ribonucleoside analogues, or US2002058635, which discloses purine L-nucleoside compounds wherein both the purine ring and the sugar are modified, functionalized or modified and functionalized. The saccharide thus (for example) must exhibit at least one esterified OH group.

WO06084281 discloses inhibitors of the E1 activating enzyme having a sulfonamide moiety.

WO05051944 discloses oxetane-containing nucleosides for the treatment of nucleoside analogue related diseases such as diseases involving cell proliferation and infection.

WO9840384 discloses pyrazolopyrimidinones which are PDE1, 2 and 5 inhibitors and can be used for the treatment of cardiovascular and cerebrovascular conditions and diseases of the urogenital system.

CH396924, CH396925, CH396926, CH396927, DE1147234, DE1149013, GB937726 describe pyrazolopyrimidinones which have a coronary-relaxing effect and which are useful in the treatment of disorders of myocardial blood flow.

US3732225 describes pyrazolopyrimidinones having an anti-inflammatory and blood glucose-lowering effect.

DE2408906 describes styrylpyrazolopyrimidinones which are useful as antimicrobial and anti-inflammatory agents for the treatment of, for example, edema.

Disclosure of Invention

It is clear from the prior art cited above that a change in the substitution pattern of pyrazolopyrimidinones leads to interesting changes with regard to biological activity, respectively a change in the affinity for different target enzymes.

It is therefore an object of the present invention to provide compounds which effectively modulate PDE9A for the purpose of developing medicaments, in particular with regard to diseases which can be treated by PDE9A modulation.

It is another object of the present invention to provide compounds useful for the preparation of medicaments for the treatment of CNS disorders.

It is another object of the present invention to provide compounds that show better side effect characteristics than the compounds of the prior art.

It is a further object of the present invention to provide compounds having advantageous selectivity profiles which favour PDE9A inhibition over other PDE family members and which may therefore provide advantages over the prior art compounds.

It is a further object to provide such a medicament not only for the treatment but also for the prevention or modification of the respective diseases.

Detailed Description

The compounds of the invention are characterized by the general formula I having the following definitions:

(substituents may be printed in bold for better reading):

substituent groupHcBy the following definitionsHc ⁱBy definition, and wherein the index i indicates the order of preference, fromHc ¹Go up to more preferred (i.e. toHc ²) And the like:

Hc ¹：

Hcis a mono-, bi-or tricyclic heterocyclyl group in which the ring members are carbon atoms and at least 1, preferably 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein sulfur is in the form of-S (O)_rA form of (A) wherein r is 0, 1 or 2, and

-the heterocyclyl is or comprises 1 non-aromatic, saturated or partially unsaturated monocyclic ring which comprises at least 1 heteroatom as a ring member, and

-the heterocyclyl group is linked to the backbone via the 1 non-aromatic, saturated or partially unsaturated monocyclic ring, which contains at least 1 heteroatom as a ring member.

Hc ²：

HcIs a heterocyclyl group according to any one of formulae i.1 or i.2 or i.3:

formula I.1:

wherein

n＝1、2、3；

X¹、X²、X³Independently of one another are CH₂、CHR²、CHR³、C(R²)₂、CR²R³、O、NH、NR²Or S (O)_rWherein r is 0, 1, 2, wherein X¹、X²、X³At least one of them is O, NH, NR²Or S (O)_r。

#: means that the ring is not aromatic, and when n ═ 1, one bond in the ring system can optionally be a double bond, and when n ═ 2 or n ═ 3, one bond or two bonds in the ring system can optionally be a double bond, thereby replacing the hydrogen atom to which the ring members are bonded. The double bond is preferably a C-C double bond for each case. Preferably, the ring system is saturated.

Denotes the point of attachment to the nitrogen atom of the pyrazolo ring of formula I.

Formula I.2:

wherein

AIs a ring system of formula I.1;

Bis prepared by reacting withABridged toA) A 3-, 4-, 5-or 6-membered second ring system, and in addition theretoAThe two atoms shared, with the exception of a bond, consist only of carbon atoms and may be saturated, partially saturated, or aromatic; substituent R²And/or R³Can be located in the ring independently of each other and independently of each x, yAOr ringsBThe above step (1);

these two ring systemsAAndBthe two ring atoms shared may both be C-atoms, may both be N-atoms, or one may be C-atom and the other may be N-atom. Preferably both are C-atoms, or one C-atom and one N-atom, and more preferably both are C-atoms. The shared bond may be a single bond or a double bond.

Formula I.3:

wherein

AIs a ring system of formula I.1;

Cis prepared by reacting withAScrewed (screw fused to)A) A 3-, 4-, 5-or 6-membered second ring system, and in addition theretoAExcept for one atom that is shared, it consists only of carbon atoms, and it may be saturated or partially saturated; substituent R²And/or R³Can be located in the ring independently of each other and independently of each x and yAOr ringsCThe above.

Hc ³：

HcIs a heterocyclic group selected from:

Hc ⁴：

Hcas above aboutHc ²Heterocyclyl radicals of the formula I.1 as defined.

Hc⁵：

HcAs above aboutHc ²Heterocyclyl radicals of the formula I.2 as defined.

Hc⁶：

HcAs above aboutHc ²Heterocyclyl radicals of the formula I.3 as defined.

Hc ^7.0：

HcIs a monocyclic, non-aromatic, saturated heterocyclic radical and has 4 to 8, preferably 5, 6 or 7, ring atoms, wherein the ring atoms are carbon atoms and 1, 2 or 3 heteroatoms, preferably 1 heteroatom, selected from the group consisting of oxygen, nitrogen and sulfur, wherein the sulfur is-S (O)_r-wherein r is 0, 1 or 2, wherein r is preferably 0, wherein the heterocyclyl is preferably attached to the backbone via a carbon ring atom that is not directly attached to the ring heteroatom.

Hc ^7.1：

HcSelected from tetrahydropyranyl, tetrahydrofuranyl, piperonylPyridyl, pyrrolidinyl and piperazinyl, wherein preferably the tetrahydropyranyl group is 3-tetrahydropyranyl or 4-tetrahydropyranyl, the tetrahydrofuranyl group is 3-tetrahydrofuranyl, and the piperidinyl group is 3-piperidinyl or 4-piperidinyl.

Hc ⁸：

HcSelected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl, wherein preferably tetrahydropyranyl is 3-tetrahydropyranyl or 4-tetrahydropyranyl, tetrahydrofuranyl is 3-tetrahydrofuranyl, and piperidinyl is 3-piperidinyl or 4-piperidinyl.

Hc ⁹：

HcSelected from the group consisting of piperidinyl and pyrrolidinyl, preferably 3-piperidinyl or 4-piperidinyl and 3-pyrrolidinyl.

Hc ¹⁰：

HcSelected from tetrahydropyranyl and tetrahydrofuranyl, preferably 3-tetrahydropyranyl or 4-tetrahydropyranyl and 3-tetrahydrofuranyl.

Substituent R¹By the following definition of R^1.0.jAre defined as being individually R^1.jAnd wherein the index j illustrates the order of preference, from R^1.0.1Up to a more preferred definition, e.g. R^1.0.2Etc. to R^1.1To R^1.2And the like:

R^1.0.1：

R¹is selected from C_1-8-alkyl-, C_2-8-alkenyl-, C_2-8-alkynyl-, C_1-6alkyl-S-, C_1-6-alkyl-S-C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, aryl-C_2-6-alkenyl-, aryl-C_2-6-alkynyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-C_2-6-alkenyl-and heteroaryl-C_2-6-an alkynyl radical-,

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-6-alkyl-O-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-O-, heteroaryl-C_1-6-alkyl-O-, N-linked-pyridin-2-one-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-O-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-O-, wherein C_3-7-heterocycloalkyl is bound to O, C through one of its ring C-atoms_3-7-heterocycloalkyl-C_1-6-alkyl-O-, wherein C_3-7-heterocycloalkyl is bound to C through one of its ring-C-atoms_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and/or C_1-6-alkyl-SO₂-；

Wherein any of C above_3-7-cycloalkyl-, C_3-7-heterocycloalkyl-, aryl-, heteroaryl-, N-linked-pyridin-2-one-, (R)¹⁰)₂N-CO-C_1-6-the alkyl-group may be optionally substituted with one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、C_3-7-heterocycloalkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-、(R¹⁰)₂N-CO-(R¹⁰)N-、(R¹⁰)₂N-SO₂-(R¹⁰)N-、(R¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and/or C_1-6-alkyl-SO₂-。

R^1.0.2：

R¹Is selected from C_1-8-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl and heteroaryl-C_1-6-an alkyl group-,

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-、R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and/or R¹⁰O-CO-(R¹⁰)N-，

Wherein any of C above_3-7-cycloalkyl-, C_3-7-heterocycloalkyl-, aryl, heteroaryl, N-linked-pyridin-2-one, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl-, (R)¹⁰)₂N-CO-C_1-6-the alkyl-group may be optionally substituted with one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、C_3-7-heterocycloalkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、R¹⁰-CO-、R¹⁰O-CO-, benzyl-O-and/or (R)¹⁰)₂N-CO-, wherein piperidinyl or pyrrolidinyl is preferably substituted by R¹⁰-CO-substitution.

R^1.0.3：

R¹Selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, ethyl, propyl, 1-butyl-, 2-butyl-, 1-pentyl-, 2-pentyl-, 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl,

wherein these groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-3-alkyl-O-, CF₃O-、CF₃-、C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkanesradical-HO-C_1-6-alkyl-,a diazolyl group,Azolyl radical, isoOxazolyl, triazolyl, thiazolyl, pyrrolyl, furyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, (R)¹⁰)₂N-CO-C_1-6-alkyl-, (R)¹⁰)₂N-CO-and/or a phenyl group,

wherein the aboveA diazolyl group,Azolyl radical, isoOxazolyl, triazolyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl and phenyl may optionally be substituted by one or more substituents independently selected from the group consisting of: fluorine, CH₃-、CF₃-、CH₃O-、CF₃O-、H₂NCO-, NC-, morpholinyl and/or benzyl-O-.

R^1.0.4：

R¹Selected from the group consisting of phenyl, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethyl, 1-propyl, 2-propyl, 1-butyl-, 2-butyl-, 1-pentyl-, 2-pentyl-, 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl,

wherein these groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, CF₃O-、CF₃-、Oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl, and/or phenyl,

wherein the aboveOxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridinyl and phenyl may optionally be substituted by one or more substituents which are independently of each other selected from the group consisting of: fluorine, CH₃-、CH₃O-、H₂NCO-and/or NC-.

R^1.1：

R¹Is selected from C_1-8-alkyl-, C_2-8-alkenyl-, C_2-8-alkynyl-, C_1-6alkyl-S-, C_1-6-alkyl-S-C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, heteroaryl and heteroaryl-C_1-6-an alkyl group-,

wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-6-alkyl-O-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-O-, heteroaryl-C_1-6-alkyl-O-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-O-, wherein C_3-7-heterocycloalkyl is bound to O, C through one of its ring C-atoms_3-7-heterocycloalkyl-C_1-6-alkyl-O-, wherein C_3-7-heterocycloalkyl is bound to C through one of its ring-C-atoms_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and C_1-6-alkyl-SO₂-；

Wherein any of C above_3-7-cycloalkyl-, C_3-7The heterocycloalkyl, aryl, heteroaryl radicals may optionally be HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkanesRadical-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-、(R¹⁰)₂N-CO-(R¹⁰)N-、(R¹⁰)₂N-SO₂-(R¹⁰)N-、(R¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-or C_1-6-alkyl-SO₂-substitution.

R^1.2：

R¹Is selected from C_1-8-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, C_3-7-heterocycloalkyl-, aryl and heteroaryl,

wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkanesradical-C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and R¹⁰O-CO-(R¹⁰)N-；

Wherein any of C above_3-7-cycloalkyl-, C_3-7The heterocycloalkyl, aryl, heteroaryl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl groups may optionally be NC-, O-substituted₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、R¹⁰-CO-、R¹⁰O-CO-or (R)¹⁰)₂N-CO-substituted, wherein piperidinyl or pyrrolidinyl is preferably substituted by R¹⁰-CO-substitution.

R^1.3：

wherein these groups may be optionally substituted with one or more substituents selected from: HO-, NC-, C_1-6-alkanesradical-O-, C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-3-alkyl-O-, CF₃O-、CF₃-, fluorine, chlorine, bromine, C_3-7-heterocycloalkyl-and C_3-7-heterocycloalkyl-C_1-6-alkyl-.

R^1.4：

R¹Selected from the group consisting of phenyl, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, ethyl, propyl, 1-butyl-, 2-butyl-, 1-pentyl-, 2-pentyl-, 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl,

wherein these groups may be optionally substituted with one or more substituents selected from: NC-C_1-6-alkyl-O-, C_1-6-alkyl-, CF₃O-、CF₃And halogen (halogen is preferably selected from fluorine, chlorine and bromine).

Optional substituents R²By the following definition of R^2.0.kAre defined as being individually R^2.kAnd wherein the index k illustrates the order of preference, from R^2.0.1Up to a more preferred definition (e.g. R)^2.2) And the like:

R^2.0.1：

R²with any other R²Independently of one another, and are selected from H-, fluorine, NC-, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-, carboxy-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_1-6-alkyl-S-, C_1-6-alkyl-S-C_1-3-alkyl-, preferably C_1-6-alkyl-S-C_2-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl radical-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, aryl-C_2-6-alkenyl-, aryl-C_2-6-alkynyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-C_2-6-alkenyl-, heteroaryl-C_2-6-alkynyl-, R¹⁰-O-C_2-3-alkyl-, (R)¹⁰)₂N-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-、(R¹⁰)₂N-CO-(R¹⁰)N-、R¹⁰-O-CO-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-、C_1-6-alkyl-SO₂-and an oxo group,

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, C_1-6-alkyl-O-, C_1-6-alkyl-O-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-，

And if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, and should be: h-, F₃C-CH₂-、HF₂C-CH₂-、C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_1-6-alkyl-S-C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, R¹⁰-O-C_1-3-alkyl-, R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-、R¹⁰-SO₂-or C_1-6-alkyl-SO₂-，

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-。

R^2.1：

R²With any other R²Independently of one another, and are selected from H-, fluorine, NC-, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-, carboxy-, C_1-6-alkyl- (preferably C)_2-6Alkyl), C_2-6-alkenyl-, C_2-6-alkynyl-, C_1-6alkyl-S-, C_1-6-alkyl-S-C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, R¹⁰-O-C_2-3-alkyl-, (R)¹⁰)₂N-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-、(R¹⁰)₂N-CO-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰) N-and C_1-6-alkyl-SO₂-，

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, C_1-6-alkyl-O-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-，

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-。

R^2.2：

R²With any other R²Independently of one another, and are selected from H-, fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、C_1-6-alkyl- (preferably C)_2-6Alkyl group), (R)¹⁰)₂N-CO-and R¹⁰-CO-(R¹⁰)N-，

Wherein the above groups may be optionally substituted with one or more substituents selected from: fluorine, chlorine, bromine, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, C_1-6-alkyl-O-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-，

And if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, and should be: h-, F₃C-CH₂-、HF₂C-CH₂-、C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, R¹⁰-O-C_1-3-alkyl-, R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-or C_1-6-alkyl-SO₂-，

R^2.3：

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine and C_1-6-an alkyl group-,

Wherein the substituents may optionally be substituted independently of one another by one or more substituents selected from fluorine and C_1-6-alkyl-substituted.

R^2.4：

R²With any other R²Independently of each other, and are selected from H-and C_1-6-alkyl- (preferably C)_2-6-an alkyl group),

and if soR²Is connected toHcWhen the ring member is a nitrogen atom, then R²With any other R²Independently of each other, and should be: h-, C_1-6-alkyl-, R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-, phenyl-CO-and phenyl-O-CO-,

wherein the above radicals may optionally be substituted independently of one another by one or more radicals selected from fluorine and C_1-6-alkyl-substituted.

R^2.5：

R²With any other R²Independently of each other, and are selected from H-and C_1-6-an alkyl group-,

and if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, should be H-, C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6-alkyl-, phenyl-CO-, phenyl-O-CO-, (C)_1-6-alkyl groups)₂N-CO-，

Wherein the above groups may be optionally substituted independently of each other by one or more fluoro substituents.

Optionally substituents R³By the following definition of R^3.lDefined, and wherein the index l illustrates the order of preference, from (i.e. R)^3.1) To preferred (i.e. R)^3.2) And the like:

R^3.1：

R³selected from H-, hydroxy and R¹⁰-O-。

R^3.2：

R³Selected from H-, hydroxy and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-.

R^3.3：

R³Is H.

Substituent R⁴And R⁵By the following definition of R^4/5.mDefined, and wherein the index m illustrates the order of preference, from (i.e. R)^4/5.1) To preferred (i.e. R)^4/5.2) And the like:

R^4/5.1：

R⁴and R⁵Independently of one another, from H-, fluorine, F₃C-、HF₂C-、FH₂C-and C_1-3-an alkyl group-,

or

R⁴And R⁵And together with the carbon atom to which they are attached form a 3-to 6-membered cycloalkyl group,

wherein the above groups, including the carbon ring formed, may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-O-and (C)_1-6-alkyl-)₂N-CO-。

R^4/5.2：

R⁴And R⁵Independently of one another, selected from H-, fluorine and methyl.

R^4/5.3：

R⁴And R⁵Is H-.

Substituent R¹⁰By the following definition of R^10.0.nAre defined as being individually R^10.nAnd where the index n illustrates the order of preference. This priority is given from R^10.0.1Up to preferably R^10.0.2Etc. up to R^10.4：

R^10.0.1：

R¹⁰With any other R¹⁰Independently of one another, and are selected from H- (but if they are selected from R)¹⁰O-CO-、R¹⁰-SO₂-or R¹⁰Part of the group-CO-is not H-), F-₃C-CH₂-、C_1-6-alkyl-, C_2-6-alkenyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, aryl-C_1-3-alkyl-, heteroaryl and heteroaryl-C_1-3-an alkyl group-,

and if two of R are¹⁰When the radicals are all bound to the same nitrogen atom, then they may form together with this nitrogen atom a 3-to 7-membered heterocycloalkyl ring, and where the-CH of the heterocycloalkyl ring formed₂One of the-groups may preferably be replaced by-O-, -S-, -NH-, -N (C)_3-6-cycloalkyl) -, -N (C)_3-6-cycloalkyl-C_1-4-alkyl) -or-N (C)_1-4-alkyl) -substitution, and particularly preferably in (R)¹⁰)₂In the case of N-CO-, the two R' s¹⁰Together with the nitrogen atom to which they are bound form a group selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and thiomorpholinyl,

and is

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.0.2：

R¹⁰With any other R¹⁰Independently of one another, and are selected from H- (but if they are selected from R)¹⁰O-CO-、R¹⁰-SO₂-or R¹⁰Part of the group-CO-is not H-), C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl radical-, aryl and heteroaryl radicals,

and if two of R are¹⁰When the radicals are all bound to the same nitrogen atom, then they may form together with this nitrogen atom a 3-to 7-membered heterocycloalkyl ring, and wherein the-CH of the heterocycloalkyl ring formed₂One of the-groups may preferably be replaced by-O-, -NH-, -N (C)_3-6-cycloalkyl) -, -N (C)_3-6-cycloalkyl-C_1-4-alkyl) -or-N (C)_1-4-alkyl) -substitution, and particularly preferably in (R)¹⁰)₂In the case of N-CO-, the two R' s¹⁰Together with the nitrogen atom to which they are bound form a group selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and thiomorpholinyl,

and is

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, NC-F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.0.3：

R¹⁰With any other R¹⁰Independently of one another, and are selected from H- (but if they are selected from R)¹⁰O-CO-、R¹⁰-SO₂-or R¹⁰Part of the group-CO-is not H-), C_1-6-alkyl-, C_3-7Cycloalkyl-, aryl and heteroaryl, aryl preferably being phenyl and heteroaryl preferably being selected fromA diazolyl group,Azolyl radical, isoOxazolyl, triazolyl, thiazolyl, pyrrolyl, furanyl, pyrazolyl, pyridyl, pyridazinyl and pyrimidinyl;

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.0.4：

R¹⁰With any other R¹⁰Independently of each other, and are selected from C_1-6-alkyl-, phenyl and pyridyl, and if R¹⁰When it is a substituent of a nitrogen atom, then R¹⁰Selected from H, C_1-6-alkyl-, phenyl and pyridyl;

R^10.0.5：

R¹⁰With any other R¹⁰Independently of one another, and are selected from methyl-, ethyl-and tert-butyl, and if R¹⁰When it is a substituent of a nitrogen atom, then R¹⁰Selected from H, methyl-, ethyl-, and tert-butyl;

wherein the above groups may optionally be substituted independently of each other by one or more fluoro.

R^10.1：

R¹⁰With any other R¹⁰Independently of one another, and are selected from H- (but if they are selected from R)¹⁰O-CO-、R¹⁰-SO₂-or R¹⁰Part of the group-CO-is not H-), F-₃C-CH₂-、C_1-6-alkyl-, C_2-6-alkenyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, aryl-C_1-3-alkyl-, heteroaryl and heteroaryl-C_1-3-an alkyl group-,

and if two of R are¹⁰When the radicals are all bound to the same nitrogen atom, then they may form together with this nitrogen atom a 3-to 7-membered heterocycloalkyl ring, and wherein the-CH of the heterocycloalkyl ring formed₂One of the-groups may preferably be replaced by-O-, -S-, -NH-, -N (C)_3-6-cycloalkyl) -, -N (C)_3-6-cycloalkyl-C_1-4-alkyl) -or-N (C)_1-4-alkyl) -substitution, and particularly preferably in (R)¹⁰)₂In the case of N-CO-, the two R' s¹⁰The radicals together with the nitrogen atom to which they are bound form a radical selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and thiomorpholinyl,

and is

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.2：

R¹⁰With any other R¹⁰Independently of each other, and are selected from C_1-6-alkyl-, C_3-7-cycloalkyl-, aryl and heteroaryl,

and if two of R are¹⁰When the radicals are all bound to the same nitrogen atom, then they may form together with this nitrogen atom a 3-to 7-membered heterocycloalkyl ring, and wherein the-CH of the heterocycloalkyl ring formed₂One of the-groups may preferably be replaced by-O-, -NH-, -N (C)_3-6-cycloalkyl) -, -N (C)_3-6-cycloalkyl-C_1-4-alkyl) -or-N (C)_1-4-alkyl) -substitution, and particularly preferably in (R)¹⁰)₂In the case of N-CO-, the two R' s¹⁰Together with the nitrogen to which they are bound form a group selected from piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and thiomorpholineThe radical of the radical (I) is,

and is

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, NC-F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.3：

wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-.

R^10.4：

R¹⁰With any other R¹⁰Independently of each other, and are selected from C_1-6-alkyl-, phenyl and pyridyl,

x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2, more preferably x is 0, 1 and more preferably x is 0; if not otherwise specified herein;

y is 0 or 1, preferably y is 0, if not otherwise specified herein;

for each applicable embodiment of formula I of the present invention-e.g., a bagComprisesHc ¹AndHc ³with the proviso that

If it isHcIs oxetanyl and which is attached through the carbon atom of the oxetanyl group immediately adjacent to the oxygen, then nothing is present through-CH₂-a spacer attached to the substituent of the carbon atom.

The values of x and y are independent of each other.

At R^1.i、R^2.jThe index symbols i, j, k, l, m, n in etc. are indices, each of which has an integer: 1.2, 3, etc., such that each R^1.i、R^2.jEtc. represent R^1.i、R^2.jEtc. as characteristic individual embodiments of the corresponding substituents defined.

Thus, under the above definitions, a particular compound according to formula I is to be understood entirely under the term (A)Hc ⁱ R^1.j R^2.k R^3.lR^4/5.m R^10.n) Denotes, if a separate number is given for each letter i, j, k, l, m and n, and wherein-if not otherwise indicated in the text-for each such embodiment (Hc ⁱ R^1.j R^2.k R^3.l R^4/5.mR^10.n) X should be 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2 and y should be 0 or 1, with the proviso that if applicable each of the embodiments of the formula I of the invention is givenHcIs an oxetanyl group and which is attached through the carbon atom of the oxetanyl group immediately adjacent to the oxygen, there are no substituents attached to this carbon atom through a-CH 2-spacer.

In other words, various embodiments (Hc ⁱ R^1.j R^2.k R^3.l R^4/5.m R^10.n) Represents a well characterized collection or subset according to formula I, i.e. a general formula collection of the subject compounds of the present invention. This embodiment defines the variables of formula IHc、R¹、R²、R³、R⁴、R⁵And R where applicable¹⁰And wherein-if not otherwise specified in the textIf it is stated that x should be 0, 1, 2, 3 or 4, preferably 0, 1 or 2, and y should be 0 or 1, and with the proviso that, for each applicable embodiment of the formula I according to the invention, ifHcIs oxetanyl and, when attached through the carbon atom of the oxetanyl group immediately adjacent to the oxygen, no substituent is present through the-CH₂-a group is attached to the carbon atom.

In a1 st general aspect of the invention, one or more compounds of the invention are defined by the following embodiments according to formula I, characterized in that

Hc ¹ R^1.0.1 R^2.0.1 R^3.1 R^4/5.1 R^10.0.1

Wherein

x is independent of any y: x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2

y is independent of any x: y is 0 or 1, and y is a linear or branched,

and pharmaceutically acceptable salts and/or solvates and/or tautomers thereof and the like;

provided that it is

If it isHcIs an oxetanyl group which, when attached through the carbon atom of the oxetanyl group immediately adjacent to the oxygen, is absent through-CH₂-a spacer attached to the substituent of the carbon atom.

According to the above, this means that aspect 1 of the invention relates to compounds according to the general formula I

Wherein

HcSuch asHc ¹Defining;

R¹such as R^1.0.1Defining;

R²such as R^2.0.1Defining;

R³such as R^3.1Defining;

R⁴and R^4/Such as R^4/5.1Defining;

R¹⁰such as R^10.0.1Defining;

x is independent of any y: x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2;

y is independent of any x: y is 0 or 1;

provided that it is

Accordingly, this aspect 1 of the invention is defined as a compound according to formula I

Wherein

HcIs a mono-, bi-or tricyclic heterocyclyl group in which the ring members are carbon atoms and at least 1, preferably 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being in the form of-S (O)_rA form of (A) wherein r is 0, 1 or 2, and

-the heterocyclyl group is linked to the backbone via the 1 non-aromatic, saturated or partially unsaturated monocyclic ring, which monocyclic ring comprises at least 1 heteroatom as a ring member;

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-6-alkyl-O-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-O-, heteroaryl-C_1-6-alkyl-O-, N-linked-pyridin-2-one-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-O-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-O-, wherein C_3-7-heterocycloalkyl is bound to O, C through one of its ring C-atoms_3-7-heterocycloalkyl-C_1-6-alkyl-O-, wherein C_3-7-heterocycloalkyl is bound to C through one of its ring-C-atoms_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and/or C_1-6-alkyl-SO₂-，

Wherein any of C above_3-7-cycloalkyl-, C_3-7-heterocycloalkyl-, aryl-, heteroaryl-, N-linked-pyridin-2-one-, (R)¹⁰)₂N-CO-C_1-6-the alkyl-group may be optionally substituted with one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、C_3-7-heterocycloalkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-、(R¹⁰)₂N-CO-(R¹⁰)N-、(R¹⁰)₂N-SO₂-(R¹⁰)N-、(R¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and/or C_1-6-alkyl-SO₂-；

R²With any other R²Independently of one another, and are selected from H-, fluorine, NC-, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-, carboxy-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_1-6-alkyl-S-, C_1-6-alkyl-S-C_1-3-alkyl-, preferably C_1-6-alkyl-S-C_2-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkanesradical-aryl-C_2-6-alkenyl-, aryl-C_2-6-alkynyl-, heteroaryl-C_1-6-alkyl-, heteroaryl-C_2-6-alkenyl-, heteroaryl-C_2-6-alkynyl-, R¹⁰-O-C_2-3-alkyl-, (R)¹⁰)₂N-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-、(R¹⁰)₂N-CO-(R¹⁰)N-、R¹⁰-O-CO-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-、C_1-6-alkyl-SO₂-and an oxo group,

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-；

R³Selected from H-, hydroxy and R¹⁰-O-；

or

wherein the above groups, including the carbon ring formed, may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-, C_1-6-alkyl-O-and (C)_1-6-alkyl-)₂N-CO-；

and is

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

x is independent of any y: x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2, preferably x is 0 or 1, more preferably x is 0;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and a pharmaceutically acceptable salt thereof,

for each applicable embodiment of the formula I according to the invention, with the proviso that

If it isHcIs oxetanyl and which is attached through the carbon atom of the oxetanyl group immediately adjacent to the oxygen, then nothing is present through-CH₂-a spacer attached to the carbon atom.

Means that the substituents do not contain CH as follows₂A group through which CH₂-a radical substituent is attached to the oxetanyl radical.

The 2 nd aspect of the present invention relates to the compounds of the general formula I according to the 1 st aspect of the present invention, in which

HcIs a heterocyclic group according to a formula selected from the group consisting of formula i.1, i.2 and i.3:

formula I.1:

wherein

n＝1、2、3；

X¹、X²、X³Independently of one another are CH₂、CHR²、CHR³、C(R²)₂、CR²R³、O、NH、NR²Or S (O)_rWherein r is 0, 1, 2, wherein X¹、X²、X³At least one of them is O, NH, NR²Or S (O)_r.；

#: means that the ring is not aromatic, and when n ═ 1, one bond in the ring system optionally can be a double bond, and when n ═ 2 or n ═ 3, one or two bonds in the ring system optionally can be a double bond, thereby displacing the hydrogen atom to which the ring members are bound, and wherein such double bonds are preferably C — C double bonds, more preferably the ring is saturated;

formula I.2:

wherein

AIs a ring system of formula I.1;

Bis prepared by reacting withABridged 3-, 4-, 5-or 6-membered second ring systems, and in addition theretoAThe two atoms and the bond shared-which may be single or double bonds-are other than composed of carbon atoms, and which may be saturated, partially saturated, or aromatic; substituent R²And/or R³Can be located in the ring independently of each other and independently of each x or yAOr ringsBThe above step (1); wherein the two ring systemsAAndBthe two ring atoms shared may both be carbon atoms, may both be nitrogen atoms, or one may be carbon and the other may be nitrogen atoms, and preferably both are carbon atoms or one carbon and one nitrogen atom, and more preferably both are carbon atoms;

formula I.3:

wherein

AIs a ring system of formula I.1;

c is andAa spiro-bound 3-, 4-, 5-or 6-membered saturated or partially saturated second ring system, and in addition theretoAExcept one atom shared by them, consisting only of carbon atoms, and the substituent R²And/or R³Can be located in the ring independently of each other and independently of each x and yAOr on ring C;

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine,Iodine, oxo radical, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and/or R¹⁰O-CO-(R¹⁰)N-，

Wherein any of C above_3-7-cycloalkyl-, C_3-7-heterocycloalkyl-, aryl, heteroaryl, N-linked-pyridin-2-one, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl-, (R)¹⁰)₂N-CO-C_1-6-the alkyl-group may be optionally substituted with one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、C_3-7-heterocycloalkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、R¹⁰-CO-、R¹⁰O-CO-, benzyl-O-and/or (R)¹⁰)₂N-CO-, wherein piperidinyl or pyrrolidinyl is preferably substituted by R¹⁰-CO-substitution;

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine and C_1-6-an alkyl group-,

Wherein the above radicals may optionally be substituted independently of one another by one or more radicals selected from fluorine and C_1-6-alkyl-substituted;

R³selected from H-, hydroxy, C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-;

R⁴and R⁵Independently of one another, selected from H-, fluorine and methyl;

R¹⁰with any other R¹⁰Independently of one another, and are selected from H- (but if they are selected from R)¹⁰O-CO-or R¹⁰Part of the group-CO-is not H-), C_1-6-alkyl-, C_3-7-cycloalkyl-,C_3-7-cycloalkyl-C_1-3-alkyl-, aryl and heteroaryl,

and if two of R are¹⁰When the radicals are all bound to the same nitrogen atom, then they may form together with this nitrogen atom a 3-to 7-membered heterocycloalkyl ring, and wherein the-CH of the heterocycloalkyl ring formed₂One of the-groups may preferably be replaced by-O-, -NH-, -N (C)_3-6-cycloalkyl) -, -N (C)_3-6-cycloalkyl-C_1-4-alkyl) -or-N (C)_1-4-alkyl) -substitution, and particularly preferably in (R)¹⁰)₂In the case of N-CO-, the two R' s¹⁰The radicals together with the nitrogen atom to which they are bound form a radical selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and thiomorpholinyl,

and is

Wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, NC-F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 3 rd aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, wherein

HcIs a monocyclic, non-aromatic, saturated heterocyclic radical having 4 to 8, preferably 5, 6 or 7, ring atoms, and wherein the ring atoms are carbon atoms and 1, 2 or 3 heteroatoms, preferably 1 heteroatom, selected from the group consisting of oxygen, nitrogen and sulfur, wherein the sulfur is-S (O)_r-wherein r is 0, 1 or 2, wherein r is preferably 0, wherein preferably the heterocyclyl is through a carbocyclic ring not directly attached to the ring heteroatomThe atoms are attached to the backbone;

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and/or R¹⁰O-CO-(R¹⁰)N-，

and if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of one another, are: h-, C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6-alkyl-, phenyl-CO-, phenyl-O-CO-, (C)_1-6-alkyl groups)₂N-CO-，

Wherein the above groups may be optionally substituted independently of each other by one or more fluoro substituents;

R³selected from H-, hydroxy and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-;

R⁴and R⁵Independently of one another, selected from H-, fluorine and methyl, preferably both H;

R¹⁰with any other R¹⁰Independently of each other, and are selected from C_1-6-alkyl-, phenyl and pyridyl, and if R¹⁰When it is a substituent of a nitrogen atom, then R¹⁰Selected from H, C_1-6-alkyl-, phenyl and pyridyl,

wherein the above groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof;

provided that

Indicates that none of the substituents contains CH as follows₂A group, the substituent passing through the CH₂The radical is linked to an oxetanyl radical.

The 4 th aspect of the invention relates to compounds of the general formula I according to the 1 st aspect of the invention, in which

HcSelected from tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl and piperazinyl, wherein preferably tetrahydropyranyl is 3-tetrahydropyranyl or 4-tetrahydropyranyl, tetrahydrofuranyl is 3-tetrahydrofuranyl, and piperidinyl is 3-piperidinyl or 4-piperidinyl; more preferably still, the first and second liquid crystal compositions are,Hctetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and of these 3-tetrahydropyranyl and 4-tetrahydropyranyl, 3-piperidinyl and 4-piperidinyl, and 3-pyrrolidinyl are preferred;

wherein the above radicalsThe groups may optionally be substituted with one or more substituents independently selected from: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_2-6-alkenyl-, C_2-6-alkynyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, N-linked-pyridin-2-one-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and/or R¹⁰O-CO-(R¹⁰)N-，

R²with any other possible R²Independently of each other, and are selected from H-and C_1-6-an alkyl group-,

and if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, and should be: h-, C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6-alkyl-, phenyl-CO-, phenyl-O-CO-, (C)_1-6-alkyl groups)₂N-CO-，

R⁴and R⁵Independently of one another, selected from H-, fluorine and methyl, preferably R⁴And R⁵Are all H;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 5 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, wherein

HcSelected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl and piperazinyl, and wherein preferably tetrahydropyranyl is 3-tetrahydropyranyl or 4-tetrahydropyranyl, tetrahydrofuranyl is 3-tetrahydrofuranyl, and piperidinyl is 3-piperidinyl or 4-piperidinyl; more preferably still, the first and second liquid crystal compositions are,Hctetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and of these 3-tetrahydropyranyl and 4-tetrahydropyranyl, 3-piperidinyl and 4-piperidinyl, and 3-pyrrolidinyl are preferred;

R¹selected from the group consisting of phenyl, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-, pyrimidinyl, pyrazolyl, thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, ethyl, propyl, 1-butyl-, 2-butyl-, 1-pentyl-, 2-pentyl-, 3-pentyl-, tetrahydrofuranyl and tetrahydropyranyl,

wherein these groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, HO-, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-3-alkyl-O-, CF₃O-、CF₃-、C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, HO-C_1-6-alkyl-,a diazolyl group,Azolyl radical, isoAzolyl, triazolyl, thiazolyl, pyrrolyl,Furyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, (R)¹⁰)₂N-CO-C_1-6-alkyl-, (R)¹⁰)₂N-CO-and/or a phenyl group,

R²With any other possible R²Independently of one another, and are selected from H-or C_1-6-an alkyl group-,

R³selected from H-, hydroxy and C_1-6-alkyl-O-, and wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-;

R¹⁰with any other R¹⁰Independently of each other, and is selected from H, C_1-6-alkyl-, phenyl and pyridyl,

independently of the respective other x, x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2.

Preferably x is 0 or 1, more preferably x is 0;

independently of each other y, y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 6 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, wherein

HcSelected from tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl and piperazinyl, preferably tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and preferably 3-tetrahydropyranyl and 4-tetrahydropyranyl, 3-piperidinyl and 4-piperidinyl, and 3-pyrrolidinyl;

wherein these groups may be optionally substituted by one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, CF₃O-、CF₃-、Oxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridyl and/or phenyl,

wherein the aboveOxadiazolyl, triazolyl, pyrazolyl, furanyl, pyridinyl and phenyl may optionally be substituted by one or more substituents which are independently of each other selected from the group consisting of: fluorine, CH₃-、CH₃O-、H₂NCO-and/or NC-;

R²with any other R²Independently of one another, and are selected from H-or C_1-6-an alkyl group-,

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 7 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, in which

HcSelected from piperidinyl and pyrrolidinyl, preferably 3-piperidinyl or 4-piperidinyl and 3-pyrrolidinyl;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 8 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, wherein

wherein these groups may be optionally substituted by one or more substituents independently selected from the group consisting of: NC-C_1-6-alkyl-O-, C_1-6-alkyl-, CF₃O-、CF₃And halogen, preferably selected from fluorine, chlorine and bromine,

R⁴and R⁵Are all H

x is 0 or 1;

y＝0；

and pharmaceutically acceptable salts thereof.

The 9 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, wherein

wherein C is as mentioned above_1-6-the alkyl-groups may be optionally substituted independently of each other by one or more fluoro substituents;

x is independent of any y: x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2, preferably x is 0 or 1, most preferably x is 0;

y is independent of any x: y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 10 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, in which

wherein as hereinbefore describedMentioned as C_1-6-the alkyl-groups may be optionally substituted independently of each other by one or more fluoro substituents;

y is independent of any x: y is 0 or 1, most preferably y is 0;

and pharmaceutically acceptable salts thereof.

The 11 th aspect of the present invention relates to compounds of the general formula I according to the 1 st aspect of the present invention, in which

R⁴and R⁵Are all H

x＝0；

y＝0；

And pharmaceutically acceptable salts thereof.

The 12 th aspect of the present invention relates to compounds according to formula I

Wherein;

Hcis a mono-, bi-or tricyclic heterocyclyl group in which the ring members are carbon atoms and at least 1, preferably 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur is in the form of-S (O)_rA form of (A) wherein r is 0, 1 or 2, and

Wherein any of C above_3-7-cycloalkyl-, C_3-7-heterocycloalkyl-, aryl-, heteroaryl-may optionally preferably be HO-, NC-, O independently of one another₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, R¹⁰-S-C_1-6-alkyl-, C_1-6-alkyl-, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、R¹⁰-S-、R¹⁰-CO-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-CO-O-、R¹⁰O-CO-O-、R¹⁰O-CO-O-C_1-6-alkyl-, R¹⁰O-CO-(R¹⁰)N-、R¹⁰O-CO-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-CO-O-、(R¹⁰)₂N-CO-(R¹⁰)N-、(R¹⁰)₂N-SO₂-(R¹⁰)N-、(R¹⁰)₂N-CO-O-C_1-6-alkyl-, (R)¹⁰)₂N-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰-SO₂-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-(R¹⁰)N-C_1-6-alkyl-, (R)¹⁰)₂N-SO₂-、(R¹⁰)₂N-SO₂-C_1-6-alkyl-and C_1-6-alkyl-SO₂-substitution;

R²with any other R²Independently of one another, and are selected from H-, fluorine, NC-, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-, carboxy-, C_1-6-alkyl- (preferably C)_2-6Alkyl), C_2-6-alkenyl-, C_2-6-alkynyl-, C_1-6-alkyl-S-),C_1-6-alkyl-S-C_1-3-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, C_3-7-cycloalkyl-C_2-6-alkenyl-, C_3-7-cycloalkyl-C_2-6-alkynyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-C_2-6-alkenyl-, C_3-7-heterocycloalkyl-C_2-6-alkynyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, R¹⁰-O-C_2-3-alkyl-, (R)¹⁰)₂N-、R¹⁰O-CO-、(R¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-、(R¹⁰)₂N-CO-(R¹⁰)N-、R¹⁰-SO₂-(R¹⁰) N-and C_1-6-alkyl-SO₂-，

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-、(R¹⁰)₂N-C_1-3-alkyl-and (R)¹⁰)₂N-CO-；

R³Independently selected from H-, hydroxy and R¹⁰-O-；

or

R¹⁰With any other R¹⁰Independently of each other, and are selected fromH- (but if it is selected from R)¹⁰O-CO-、R¹⁰-SO₂-or R¹⁰Part of the group-CO-is not H-), F-₃C-CH₂-、C_1-6-alkyl-, C_2-6-alkenyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-3-alkyl-, aryl-C_1-3-alkyl-, heteroaryl and heteroaryl-C_1-3-an alkyl group-,

and wherein the above groups may be optionally substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、HO-C_1-6-alkyl-, CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

independently of the other individual x, x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2, preferably x is 0 or 1, more preferably x is 0;

independently of each other y, y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salt forms or solvates thereof,

with the following conditions:

if it isHcIs an oxetanyl group and is formed by the direct proximity of the oxetanyl group to oxygenWhen the carbon atom(s) is (are) bonded, then there is no bond via-CH₂-a spacer attached to the substituent of the carbon atom.

The 13 th aspect of the invention relates to compounds of the general formula I according to the 12 th aspect of the invention, in which

formula I.1:

wherein

n＝1、2、3；

formula I.2:

wherein

AIs a ring system of formula I.1;

Bis prepared by reacting withABridged 3-, 4-, 5-or 6-membered second ring systems, and in addition theretoAThe two atoms and the bond shared-other than a single or double bond-consist only of carbon atoms, and may be saturated, partially saturated, or aromatic; substituent R²And/or R³Can be located in the ring independently of each other and independently of each x or yAOr ringsBThe above step (1); and wherein the two ring systemsAAndBthe two ring atoms shared may both be carbon atoms, may both be nitrogen atoms, or one may be carbon and the other may be nitrogen atoms, and preferably both are carbon atoms or one carbon and one nitrogen atom, and more preferably both are carbon atoms;

formula I.3:

wherein

AIs a ring system of formula I.1;

wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl radical-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO- C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and R¹⁰O-CO-(R¹⁰)N-；

Wherein any of C above_3-7-cycloalkyl-, C_3-7The heterocycloalkyl, aryl, heteroaryl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, pyrrolidinyl radicals can optionally be replaced, preferably independently of one another, by NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、R¹⁰-CO-、R¹⁰O-CO-or (R)¹⁰)₂N-CO-substituted, and wherein piperidinyl or pyrrolidinyl is preferably substituted by R¹⁰-CO-substitution;

R²with any other R²Independently of one another, and are selected from H-, fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、C_1-6-alkyl- (preferably C)_2-6Alkyl group), (R)¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-，

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of:fluorine, chlorine, bromine and C_1-6-an alkyl group-,

R³with any other R³Independently of each other, and are selected from H-, hydroxy and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-; preferably R³Is H;

R⁴and R⁵Independently of one another, selected from H-, fluorine and methyl; preferably independently of one another, H-or fluorine, more preferably R⁴And R⁵Is H;

and is

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, NC-F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

independently of the other individual x, x is 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2, preferably x is O or 1, more preferably x is 0;

independently of each other y, y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salt forms or solvates thereof.

The 14 th aspect of the present invention relates to compounds of the general formula I according to the 12 th aspect of the present invention, in which

HcIs a heterocyclic group selected from:

wherein the above radicals may optionally be independently of one another substituted by one or more groups selected fromSubstituted with the following substituents: fluorine, chlorine, bromine, HO-, NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、HO-C_1-6-alkyl-, R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, C_3-7-cycloalkyl-, C_3-7-cycloalkyl-C_1-6-alkyl-, aryl-C_1-6-alkyl-, heteroaryl-C_1-6-alkyl-, C_3-7-heterocycloalkyl-, C_3-7-heterocycloalkyl-C_1-6-alkyl-, tetrahydrofuryl-O-, tetrahydropyranyl-O-, piperidinyl-O-, wherein piperidinyl is bound to O through one of its ring C-atoms, pyrrolidinyl-O-, wherein pyrrolidinyl is bound to O through one of its ring C-atoms, (R)¹⁰)₂N-、(R¹⁰)₂N-C_1-6-alkyl-, R¹⁰-O-、(R¹⁰)₂N-CO-、(R¹⁰)₂N-CO-C_1-6-alkyl-, R¹⁰-CO-(R¹⁰)N-、R¹⁰-CO-(R¹⁰)N-C_1-6-alkyl-, R¹⁰O-CO-O-and R¹⁰O-CO-(R¹⁰)N-；

Wherein any of C above_3-7-cycloalkyl-, C_3-7The heterocycloalkyl, aryl, heteroaryl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, pyrrolidinyl radicals can optionally be replaced, preferably independently of one another, by NC-, O₂N-、F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、F₃C-O-、HF₂C-O-、R¹⁰-O-C_1-6-alkyl-, C_1-6-alkyl-, R¹⁰-O-、R¹⁰-CO-、R¹⁰O-CO-or (R)¹⁰)₂N-CO-substituted, wherein piperidinyl or pyrrolidinyl is preferably substituted by R¹⁰-CO-substitution;

R²with any other R²Independently of one another, and are selected from H-, fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、C_1-6-alkyl- (preferably C)_2-6-alkyl groups),(R¹⁰)₂N-CO-、R¹⁰-CO-(R¹⁰)N-，

R³with any other R³Independently of each other, and are selected from H-, hydroxy and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-;

R⁴and R⁵Independently of one another, selected from H-, fluorine and methyl; preferably independently of each other, selected from H-and fluorine, more preferably R⁴And R⁵Is H;

R¹⁰with any other R¹⁰Independently of each other, and are selected from C_1-6-alkyl-, C_3-7-cycloalkyl-, aryl and heteroaryl

Wherein the above groups may optionally be substituted independently of each other by one or more substituents selected from the group consisting of: fluorine, F₃C-、HF₂C-、FH₂C-、F₃C-CH₂-、CH₃-O-C_1-6-alkyl-, C_1-6-alkyl-and C_1-6-alkyl-O-;

independently of each other y, y is 0 or 1, more preferably y is 0;

and pharmaceutically acceptable salt forms or solvates thereof

Provided that

The 15 th aspect of the present invention relates to a compound according to the 13 th aspect of the present invention, wherein

HcSelected from tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl;

and is

R²With any other R²Independently of one another, and is H-or C_1-6-an alkyl group-,

and is

R⁴And R⁵Is H

And

The 16 th aspect of the present invention relates to a compound according to the 15 th aspect of the present invention, wherein

wherein these groups may be optionally substituted with one or more substituents selected from: HO-, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-3-alkyl-O-, CF₃O-、CF₃-, fluorine, chlorine, bromine, C_3-7-heterocycloalkyl-and C_3-7-heterocycloalkyl-C_1-6-alkyl-.

The 17 th aspect of the present invention relates to a compound according to the 16 th aspect of the present invention, wherein

wherein these groups may be optionally substituted with one or more substituents selected from: NC-C_1-6-alkyl-O-, C_1-6-alkyl-,CF₃O-、CF₃and halogen, preferably selected from fluorine, chlorine and bromine.

Particular aspects of the present invention (aspect 18) are each, independently of and separately from each other, related to each of the following compounds, and/or each of the particular stereoisomers thereof and/or tautomers thereof and/or pharmaceutically acceptable salts thereof, wherever applicable. Each compound is represented and considered as a neutral compound, without indicating its stereochemistry, if any. The left column represents examples from which the compounds are derived. Specific information on stereochemistry may be taken from the experimental part, the exemplary embodiments paragraph. If the final compound according to this exemplary embodiment is in the form of a salt, it may be converted to a neutral compound (free base or acid) by conventional methods.

These 18 main aspects of the invention, their subgroups and some further aspects of the invention are indicated by the elements of the following set (matrix)0 and set I, which set 0 and set I refer to the symbols (a)Hc ⁱR^1.j R^2.k R^3.l R^4/5.m R^10.n) Wherein read is as defined above, i.e. together with general formula I and the remaining features such as x, y, as set 0 or set I as outlined below.

Set 0 and set I show, in the right column, the embodiments of the invention according to the general formula I which are considered to be preferred (Hc ⁱ R^1.j R^2.k R^3.l R^4/5.m R^10.n) Independent and separable from each other, i.e. separate aspects of the invention. The left column provides a reference number for this embodiment. Embodiments or elements are listed in order from less preferred to most preferred, with the priority of the embodiments increasing with reference to the number of references. This means that the last recorded embodiment presented by the set element in the last row of set 0 or set I is the best embodiment, whereas the set I embodiment outperforms the set 0 embodiment.

Aspects 1 to 18 are main aspects of the present invention.

Set 0

The first embodiment of set 0 represents a first general aspect of the present invention. The following embodiments are a subset thereof.

And wherein for each set implementation of set 0:

x is independently of each other 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2; preferably 0 or 1, more preferably x ═ 0:

independently of each other y, y is 0 or 1; more preferably, y is 0, where the specific definition of this set of embodiments prevails;

and pharmaceutically acceptable salts and/or solvates thereof.

And with the proviso that-for each embodiment of the set 0 this proviso is applicable-as for inclusion as byHc ¹OrHc ³As definedHcEmbodiments of (a)

It is clear that if x and/or y is 0, thenHcIs unsubstituted, i.e. the corresponding valency of the ring member atoms is saturated with hydrogen.

If R is¹⁰Not fully defined in set 0, then it is R^10.0.4Or R^10.0.5Preferably R^10.0.5。

Set I

And wherein with respect to each embodiment of set I:

x is independently of each other 0, 1, 2, 3 or 4, preferably x is 0, 1 or 2;

independently of each other y, y is 0 or 1;

and pharmaceutically acceptable salts and/or solvates thereof

With the proviso that-for each embodiment of set 0 the conditions are applicable-as for inclusion as byHc ¹OrHc ²As definedHcEmbodiments of (a)

It is obvious that if x and/or y is 0, thenHcIs unsubstituted, i.e. the corresponding valency of the ring member atoms is saturated with hydrogen.

If R is¹⁰Not fully defined in set I, then it is R^10.4。

Subsets according to further implementations and aspects 1 to 17 of the invention and implementations of set 0 or set I

Hereinafter, other embodiments of the present invention are presented. Each is a separate and separable (i.e., individual) aspect of the present invention.

Also mentioned are embodiments (A)Hc ⁵ R^1.0.1 R^2.0.1 R^3.1 R^4/5.1 R^10.0.1) And (a)Hc ⁶ R^1.0.1 R^2.0.1 R^3.1 R^4/5.1 R^10.0.1) With the remaining features as outlined with respect to the elements of set I.

a.) for R²Subset of aspects 1-17 and implementation of set 0 or I

(a.1.1) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the embodiments of the sets 0 and I, where in the radicalsHc[R²]_x[R³]_yInside ofHcMay be a group defined by the following formula D1

And wherein is the point of attachment to the pyrazolo group in formula I and n is 0, 1, 2 or 3, except that in this subset no embodiment at position x, R is present²comprising-CH₂A group, and R²Through the-CH₂-the groups are attached at positions ·:

this subset is referred to as "subset a.1.1".

(a.1.2) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and each of the embodiments of sets 0 and I, where in the radicalsHc[R²]_x[R³]_yInside ofHcMay be a group defined by the following formula D1

And wherein is the point of attachment to the pyrazolo group in formula I, and n is 0, 1, 2 or 3; except that there are no embodiments at positions in this subset, there are R's other than H²Or R³。

This subset is referred to as "subset a.1.2".

(a.2.1) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and each of the embodiments of sets 0 and I, where in the radicalsHc[R²]_x[R³]_yInside ofHcMay be a group defined by the following formula D1-2

Wherein is the point of attachment to the pyrazolo group in formula I, and n is 1, 2 or 3, and wherein Z is¹Selected from N, O and S (O)_rWherein r is 0, 1, 2, and Z²Selected from C, N, O and S (O)_rWherein r is 0, 1, 2, in all cases, wherein Z¹Or Z²Is saturated with H or, as the case may be, by the last remaining valence bond of

R²Or R³The reaction mixture is saturated and then is subjected to a reaction,

r is present except that there are no embodiments at positions in this subset²Containing optionally substituted-CH₂A group, and R²By the optionally substituted-CH₂-the groups are attached at positions ·:

this subset is referred to as "subset a.2.1".

(a.2.2) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and each of the embodiments of sets 0 and I, where in the radicalsHc[R²]_x[R³]_yInside ofHcMay be a group defined by the following formula D1-2

And wherein is the point of attachment to the pyrazolo group in formula I, and n is 1, 2 or 3, and wherein Z is¹Selected from N, O, S (O)_rWherein r is 0, 1, 2, and Z²Selected from C, N, O, S (O)_rWherein r is 0, 1, 2, in all cases, wherein Z¹Or Z²Is saturated with H or, optionally, R²Or R³The reaction mixture is saturated and then is subjected to a reaction,

except that there are no embodiments at positions in this subset, there are R's other than H²Or R³：

This subset is referred to as "subset a.2.2".

(a.3) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydrofuranyl, except that there is no embodiment within this subset, R²Is CH₃-a group bound to the alpha-position of the epoxy atom.

This subset is referred to as "subset a.3".

(a.4) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the embodiments of set 0 and set I, whereinHcIs or may be tetrahydrofuranyl, except that there is no embodiment within this subset, R²To have CH₂R of the radical¹⁰-O-C_2-6-alkyl-through the CH₂-a group which is bound to the C-atom alpha to the epoxy atom of the tetrahydrofuranyl group.

This subset is referred to as "subset a.4".

(a.5.1) in an individual and independent subset of embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydrofuranyl, except that there is no embodiment within this subset, R²Is C bound in the alpha-position of the epoxy atom_1-6-alkyl-.

This subset is referred to as "subset a.5.1".

(a.5.2) in an individual and independent subset of embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydrofuranyl, except that there is no embodiment within this subset, R²Is C bound in the alpha-position of the epoxy atom_2-6-alkenyl-.

This subset is referred to as "subset a.5.2".

(a.5.3) in an individual and independent subset of embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydrofuranyl, except that there is no embodiment within this subset, R²Is C bound in the alpha-position of the epoxy atom_2-6-alkynyl-.

This subset is referred to as "subset a.5.3".

(a.6) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydrothienyl, except that within this subset there is no embodiment, R²Being CH bound in the alpha-position to the ring sulfur atom₃-a group.

This subset is referred to as "subset a.6".

(a.7) in an individual and independent subset of embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and each of the embodiments of set 0 and set I, wherein Hc is or may be tetrahydrothienyl, except that no embodiment within this subset, R²To have CH₂R of the radical¹⁰-O-C_2-6-alkyl-through the CH₂-a group which is bound to the C-atom alpha to the ring sulfur atom of the tetrahydrothienyl group.

This subset is referred to as "subset a.7".

(a.8) in an individual and independent subset of embodiments according to the invention, the embodiments correspond to each of aspects 1 to 17 and to each of the embodiments of set 0 and set I, whereinHcIs or may be tetrahydrothienyl, except that within this subset there is no embodiment, R²To have CH₂-C of a radical_1-6-alkyl-through the CH₂-a group bound in a-position to the ring sulfur atom.

This subset is referred to as "subset a.8".

(a.9) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be tetrahydropyranyl or tetrahydrothiopyranyl, with the exception of no embodiment within this subset, R²Is CH bound to the alpha-position of the epoxy or sulfur atom respectively₃-a group.

This subset is referred to as "subset a.9".

(a.10) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the embodiments of set 0 and set I, whereinHcIs or may be tetrahydropyranyl or tetrahydrothiopyranyl, with the exception of no embodiment within this subset, R²To have CH₂R of the radical¹⁰-O-C_2-6-alkyl-through the CH₂-a group bound to a C-atom of the tetrahydropyranyl or tetrahydrothiopyranyl group, wherein the C-atom is in the alpha-position to the epoxy or sulphur atom, respectively.

This subset is referred to as "subset a.10".

(a.11) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the embodiments of set 0 and set I, whereinHcIs or may be tetrahydropyranyl or tetrahydrothiopyranyl, with the exception of no embodiment within this subset, R²To have CH₂-C of a radical_1-6-alkyl-through the CH₂-a group bound in alpha-position to the epoxy or sulphur atom, respectively.

This subset is referred to as "subset a.11".

(a.12) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcCan be an oxetanyl group, except as used hereinThere is no implementation outside of the subset,Hcis oxetanyl-.

This subset is referred to as "subset a.12".

(a.13) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be a cyclohexylglycosyl group (group), wherein, in respect of any hydroxyl group, hydrogen may optionally be replaced by any other group and/orHcIs or may be a cyclic mono-or di-deoxyhexosyl group, wherein hydrogen for any remaining hydroxyl groups may optionally be replaced by any other group, except that in this subset there is no embodiment for R²Is CH bound in the alpha-position to the epoxy atom₃-a group.

This subset is referred to as "subset a.13".

(a.14) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be a cyclohexosyl group, wherein with respect to any hydroxyl group, hydrogen may optionally be replaced by any other group, and/orHcIs or may be a cyclic mono-or di-deoxyhexosyl group, wherein hydrogen for any remaining hydroxyl groups may optionally be replaced by any other group, except that in this subset there is no embodiment for R²Is C bound in the alpha-position of the epoxy atom_1-6-alkyl-.

This subset is referred to as "subset a.14".

(a.15) in an individual and independent subset of the embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and to the respective embodiments of set 0 and set I, whereinHcIs or may be a cyclohexosyl group, wherein with respect to any hydroxyl group, hydrogen may optionally be replaced by any other group, and/orHcIs or may be a cyclic mono-or di-deoxyhexosyl group, wherein the hydrogen may optionally be replaced by any other group with respect to any remaining hydroxyl groups, except inWithin this subset, R is not outside the embodiment²Is R bound in the alpha-position of the epoxy atom¹⁰-O-C_2-6-alkyl-.

This subset is referred to as "subset a.15".

(a.16) in an individual and independent subset of embodiments according to the invention, embodiments thereof correspond to each of aspects 1 to 17 and each of the embodiments of the sets 0 or I, wherein R²Is defined as comprising a compound selected from (R)¹⁰)₂N-and (R)¹⁰)₂N-C_1-3-alkyl-radicals, R being absent of embodiments within this subset²Is (R)¹⁰)₂N-or (R)¹⁰)₂N-C_1-3-alkyl-, and R²All remaining definitions of (a) remain unchanged.

This subset is referred to as "subset a.16".

b.) for R^4/5Set 0 or set I of embodiments

(b.1) in an individual and independent subset of the embodiments according to the invention, the embodiments thereof correspond to the embodiments of set 0 or set I, in which R^4/5Is R^4/5.2Embodiments of this subset

R^4/5.2-2Is denoted by R⁴And R⁵Independently of one another, H-or fluorine.

This subset is referred to as "subset b.1".

c.) for R¹⁰Subset of embodiments of set I

(c.1) in an individual and independent subset according to embodiments of the invention, relates to each embodiment selected from set I, wherein R¹⁰By R^10.2、R^10.3Or R^10.4Defined as follows: for the embodiments of this subset, each definition R^10.2、R^10.3And R^10.4Is extended so that if R¹⁰Is bound to a nitrogen atom, then this R¹⁰Or may be H.

This subset is referred to as "subset c.1".

It is clear that within this section "subsets and set 0 or set I implementations according to other implementations/aspects 1-17 of the invention", the subsets defined in a.) and b.) correspond to the implementations of aspects 1-17 and set 0, set I, respectively, with the scope of the particular definitions being varied. If these changes are limited, the new definitions may be considered to include the incidental conditions. Thus, these embodiments are considered "subsets" of the embodiments of aspects 1-17 and set 0, set I, respectively.

Each embodiment of the general formula I as defined by aspects 1 to 18, and any element of set 0, set I, or by subsets a), b) or c) above, is to be considered as an independent and separable aspect of the invention, i.e. as a separate aspect of the invention.

Terms and definitions used

Terms not explicitly defined herein shall be given their meanings to those skilled in the art in light of the disclosure and context. Examples include specific substituents or atoms presented in their 1 or 2 letter codes, e.g., H is hydrogen, N is nitrogen, C is carbon, O is oxygen, S is sulfur, and the like. Optionally but not mandatorily, the letters are followed by hyphens, which represent keys. However, unless specified to the contrary, the following terms have the indicated meanings and adhere to the following conventional usage when used in this patent specification.

In a group, radical or moiety, as defined hereinafter, the number of carbon atoms is generally specified before the group, e.g. C_1-6Alkyl means an alkyl group or an alkyl radical having from 1 to 6 carbon atoms. In general, for a group containing two or more sub-groups, the last-named group is the point of attachment of the group, e.g., "thioalkyl" refers to a monovalent group of the formula HS-alkyl-. If a substituent term begins or terminates with a negative sign or hyphen (i.e. -), then the notation emphasizes the point of attachment, thenAs in the example HS-alkyl-mentioned hereinbefore, HS-alkyl-is a substituent wherein an "alkyl" is attached to the group. Unless otherwise indicated below, the conventional definitions and conventional stable valencies specified by the term are assumed and achieved in all formulae and groups.

In general, unless a specific stereochemistry or isomeric form is explicitly indicated in the name or structure of a compound, the present invention includes all "tautomeric forms and isomeric forms and mixtures" of chemical structures or compounds, whether individual geometric or optical isomers, or racemic or non-racemic mixtures of isomers.

The term "substituted" as used herein (explicitly or implicitly) means that any one or more hydrogens on the designated atom is replaced with a member of the indicated group of substituents, provided that the designated atom's normal valency is not exceeded. If a substituent is bonded by a double bond, such as an oxo substituent, such substituent replaces two hydrogen atoms on the designated atom. Substitution will yield a stable compound. "Stable" in its sense preferably means a compound that is sufficiently chemically and physically stable from a medical point of view to be used as an active pharmaceutical ingredient of a pharmaceutical composition.

If a substituent is not defined, it is hydrogen.

By "optionally substituted" is meant that the corresponding group is substituted or unsubstituted. Thus, in each instance in which this term is used, the unsubstituted instance is a more significant aspect of the present invention, i.e., preferably without such optional substituents.

The expression "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; an alkali metal salt or an organic salt of an acidic group such as a carboxylic acid, and the like. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed 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, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothiocarboxylic, and the like. While the compounds of the present invention may have both acidic as well as basic groups, these compounds may also be present as internal salts as a result.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, in water or in an organic solvent, or a mixture of the two; generally, nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

"prodrug" is considered to be a compound which when such prodrug is administered to a mammalian patient, releases the active parent drug of the present invention in vivo. Prodrugs according to the present invention are made by modifying functional groups present in the compound in such a way that the modifications are reconverted to the original functional group under physiological conditions. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a mammalian patient, converts to the free hydroxy, amino, or sulfhydryl group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

"metabolites" are to be understood as derivatives of the compounds according to the invention which are formed in vivo. The active metabolite is such that it causes a pharmacological effect. It should be clear that metabolites of the compounds according to the invention are also subject to the invention, in particular active metabolites.

Some compounds may form "solvates". For the purposes of the present invention, the term "solvate" refers to a compound in the form of a complex formed in solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvate, where the coordination is carried out using water. According to the present invention, this term is preferably applied to solid solvates, such as amorphous or more preferably crystalline solvates.

"skeleton": the backbone of the compounds according to the invention is represented by the following core structure, wherein the numbering is shown in bold:

it will be appreciated by those skilled in the art that this backbone can be described by its tautomeric "enol" form

In the context of the present invention, the two structural representations of the skeleton are to be regarded as the subject of the invention, even if only one of the two representative examples is presented. It is believed that for most compounds under ambient conditions and under the relevant conditions for pharmaceutical compositions comprising the compounds, the equilibrium of the tautomeric forms depends on the side of the pyrazolopyrimidin-4-one diagram. All embodiments are therefore presented as pyrazolo pyrimidin-4-one-derivatives or more precisely as pyrazolo [3,4-d ] pyrimidin-4-one-derivatives.

"Key": if within the ring system or the formula of a defined group, a substituent is directly attached to an atom or group, such as "RyR" in the formula below, it means that the substituent is attached only to its corresponding atom. However, if a bond is not specifically attached to an atom of the ring system from another substituent, such as "RxR", but is drawn toward the center of the ring or group, it is intended that this substituent "RxR" may be attached to any atom of interest of the ring system/group, unless otherwise stated.

The bond symbol "-" (═ minus) or "-" (- ═ minus followed by an asterisk) denotes the bond through which a substituent is bound to the respective rest of the molecule/backbone. If the sign does not appear clear enough due to the minus sign, an asterisk is added to the bond symbol "-" to determine the point of attachment of the bond to the corresponding major portion of the molecule/backbone.

In general, a bond to one of the heterocycloalkyl, heterocyclyl or heteroaryl groups defined herein may be through a C atom or an optional N atom.

The term "aryl" as used in this application denotes phenyl, biphenyl, indanyl, indenyl, 1, 2, 3, 4-tetrahydronaphthyl or naphthyl, preferably phenyl or naphthyl, more preferably phenyl. This definition applies, without further definition, to "aryl" in any context within the present specification.

The term "C_1-n-alkyl "denotes a saturated, branched or straight chain hydrocarbon radical having 1 to n C atoms, wherein n is 2, 3,4, 5, 6, 7, 8, 9 or 10, preferably selected from 2, 3,4, 5 or 6, more preferably selected from 2, 3 or 4. Examples of such groups include methylEthyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl and the like. As is clear from this context, such C_1-n-alkyl optionally may be substituted.

This definition applies, without further definition, to "alkyl" in any reasonable context within the present specification.

If wherein the term "C_1-nAlkyl "being used intermediate to two other groups/substituents, e.g. at" C_1-n-cycloalkyl-C_1-nin-alkyl-O- ", then this means" C_1-nThe-alkyl "-moiety bridges the two other groups. In this example it bridges C_1-nCycloalkyl groups are reacted with oxygen, for example in "cyclopropyl-methyl-oxy-". In this case, it is obvious that "C" is_1-nThe alkyl radical "having" C_1-nBy alkylene "spacer, e.g., methylene, ethylene, and the like. Is covered with "C_1-nThe-alkyl "bridged group may be bonded to" C "at any of its positions_1-n-an alkyl group ". Preferably, the right group is located at the distal right end of the alkyl group and the left group is located at the distal left end of the alkyl group. The same applies to the other substituents.

The term "C_2-n-alkenyl "denotes a branched or straight chain hydrocarbon group having 2 to n C atoms and at least one C ═ C group (i.e. a carbon-carbon double bond), wherein n is preferably selected from 3,4, 5, 6, 7 or 8, more preferably from 3,4, 5 or 6, more preferably from 3 or 4. Examples of such groups include ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like. As is clear from this context, such C_2-n-alkenyl optionally may be substituted.

This definition applies to "alkenyl", unless otherwise defined, in any reasonable context within this specification.

If wherein the term "C_2-nAlkenyl "is used intermediate to two other groups/substituents, and is analogous to C_1-n-definition of alkyl.

The term "C_2-n-alkynyl "denotes a branched or straight chain hydrocarbon radical having 2 to n C atoms and at least one C ≡ C (i.e. carbon-carbon triple bond), wherein n is preferably selected from 3,4, 5, 6, 7 or 8, more preferably from 3,4, 5 or 6, more preferably from 3 or 4. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. As is clear from this context, such C_2-n-alkynyl optionally may be substituted.

This definition applies, without further definition, to "alkynyl" in any reasonable context within this specification.

If wherein the term "C_2-nAlkynyl "is used in the middle of two other groups/substituents, and is analogous to C_1-n-definition of alkyl.

The term "C_3-n-cycloalkyl "denotes a saturated monocyclic group having 3 to n C ring atoms. n preferably has a value of 4 to 8(═ 4, 5, 6, 7, or 8), more preferably 4 to 7, such C_3-nCycloalkyl is more preferably 5 or 6 membered. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. This definition applies, without further definition, to "cycloalkyl" in any reasonable context within the present specification.

The term "halogen" denotes an atom selected from F, Cl, Br and I.

The term "heteroaryl" as used in the present application denotes a heterocyclic, mono-or bicyclic aromatic ring system which, in addition to at least one C atom, contains one or more C atoms in the ring system itselfAnd (b) a heteroatom independently selected from N, O and/or S. Monocyclic ring systems preferably consist of 5 to 6 ring members and bicyclic ring systems preferably consist of 8 to 10 ring members. Preferably a heteroaryl group having up to 3 heteroatoms, more preferably up to 2 heteroatoms, more preferably having 1 heteroatom. Preferably the heteroatom is N. Examples of such moieties are benzimidazolyl, benzisoxazolylAzolyl, benzo [1, 4]]-Azinyl radicals, benzoOxazol-2-onyl, benzofuranyl, benzisothiazolyl, 1, 3-benzodioxolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenylDiazolyl, benzoAzolyl, chromanyl, chromenyl, chromonyl, cinnolinyl, 2, 3-dihydrobenzo [1, 4]]Dioxadienyl, 2, 3-dihydrobenzofuranyl, 3, 4-dihydrobenzo [1, 4]]Oxazinyl, 2, 3-dihydroindolyl, 1, 3-dihydroisobenzofuranyl, 2, 3-dihydroisoindolyl, 6, 7-dihydropyrrolizinyl (pyrrolizinyl), dihydroquinolin-2-onyl, dihydroquinolin-4-onyl, furanyl, imidazo [1, 2-a ] group]Pyrazinyl, imidazo [1, 2-a ]]Pyridyl, imidazolyl, imidazopyridyl, imidazo [4, 5-d]Thiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothiophenyl, isochromanyl, isochromenyl, isoindolyl, isoquinolin-2-yl, isoquinolinyl, isothiazolylAzolyl, naphthyridinyl, 1, 2, 4-Oxadiazolyl, 1, 3,4-Oxadiazolyl, 1, 2, 5-A diazolyl group,An azolopyridinyl group,Azolyl, 2-oxo-2, 3-dihydrobenzimidazolyl, 2-oxo-2, 3-dihydroindolyl, 1-oxoindanyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolo [1, 5-a ]]Pyridyl, pyrazolo [1, 5-a]Pyrimidinyl, pyrazolyl, pyridazinyl, pyridopyrimidinyl, pyridinyl (pyridinyl), pyridinyl-N-oxide, pyrimidinyl, pyrimidopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolyl, quinazolinyl, quinolin-4-one, quinolinyl, quinoxalinyl, 1, 2, 3, 4-tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, tetrazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, thiazolyl, thieno [2, 3-d ] diazolyl]Imidazolyl, thieno [3, 2-b ]]Pyrrolyl, thieno [3, 2-b ]]Thienyl, triazinyl or triazolyl.

Preferred heteroaryl groups are furyl, iso-furylOxazolyl, pyrazolyl, pyridyl, pyrimidinyl, thienyl and thiazolyl.

More preferably heteroaryl isOxadiazolyl, triazolyl, pyrazolyl, furanyl and pyridyl, more preferably pyrazolyl and pyridyl.

Pyrazole definitions include the isomers 1H-, 3H-, and 4H-pyrazole. Pyrazolyl preferably denotes 1H-pyrazolyl.

The imidazole definition includes the isomers 1H-, 2H-, and 4H-imidazole. A preferred definition of imidazolyl is 1H-imidazolyl.

The triazole definition includes the isomers 1H-, 3H-, and 4H- [1, 2, 4] -triazole, as well as 1H-, 2H-, and 4H- [1, 2, 3] -triazole. Triazolyl definitions thus include 1H- [1, 2, 4] -triazol-1-, 1H- [1, 2, 4] -triazol-3-and 1H- [1, 2, 4] -triazol-5-yl, 3H- [1, 2, 4] -triazol-3-and-5-yl, 4H- [1, 2, 4] -triazol-3-, 4H- [1, 2, 4] -triazol-4-and 4H- [1, 2, 4] -triazol-5-yl, 1H- [1, 2, 3] -triazol-1-, 1H- [1, 2, 3] -triazol-4-and 1H- [1, 2, 3] -triazol-5-yl, 1H- [1, 2, 4] -triazol-5-yl, 2H- [1, 2, 3] -triazol-2-, 2H- [1, 2, 3] -triazol-4-and 2H- [1, 2, 3] -triazol-5-yl, and 4H- [1, 2, 3] -triazol-4-and-5-yl.

The term tetrazole includes the isomers 1H-, 2H-, and 5H-tetrazole. The tetrazolyl definition thus includes 1H-tetrazol-1-and-5-yl, 2H-tetrazol-2-and-5-yl, and 5H-tetrazol-5-yl.

The definition of indole includes the isomers 1H-indole and 3H-indole. The term indolyl preferably denotes 1H-indol-1-yl.

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

This definition applies, without further definition, to "heteroaryl" in any reasonable context within the specification.

The term "N-linked-pyridin-2-one" as used in this application means:

and tautomeric forms thereof

The term "heterocycloalkyl" in the context of the present invention denotes a saturated 3-to 8-membered, preferably 5-, 6-or 7-membered ring system, or a 5-to 12-membered bicyclic ring system comprising 1, 2, 3 or 4 heteroatoms selected from N, O and/or S. Preferably 1, 2 or 3 heteroatoms.

Preferably the number of carbon atoms is 3 to 7 and has 1, 2, 3 or 4 heteroatoms selected from N, O and/or S. Such heterocycloalkyl radicals are designated C_3-7-heterocycloalkyl.

Preference is given to saturated heterocycloalkyl rings having 5, 6 or 7 ring atoms, of which 1 or 2 are heteroatoms and the remainder are C atoms.

Wherever C is mentioned_3-7-heterocycloalkyl-substituents, which in preferred embodiments are 5-, 6-or 7-membered rings, more preferably monocyclic. It contains 1, 2, 3 or 4 heteroatoms selected from N, O and/or S, and of these preferably 1 or 2 such heteroatoms, more preferably 1 such heteroatom.

Preferred examples of the heterocycloalkyl group include a morpholinyl group, a piperidinyl group, a piperazinyl group, a thiomorpholinyl group, an oxathienylalkyl group, a dithianyl group, a dioxanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a dioxolanyl group, an oxathienylpentyl group, an imidazolidinyl group, a tetrahydropyranyl group, a pyrrolinyl group, a tetrahydrothienyl group, a,Oxazolidinyl, homopiperazinyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, azetidinyl, 1, 3-diazocyclohexane or pyrazolidinyl.

This definition applies to "heterocycloalkyl" in any reasonable context within this specification in the absence of further specific definitions.

The term "heterocyclyl" is used in particular to define the radicals in formula I and derivatives thereofHcAnd are therefore used independently of the definition of "heterocycloalkyl". However, the definition of "heterocycloalkyl" should be included within the definition of "heterocyclyl".HcIs a group which is or at least comprises a non-heteroaromatic alkyl group bound to the backbone.

In the context of the present invention and as used herein, in particular inHcIn the context of (A), a "heterocyclyl" refers to a non-aromatic monocyclic, bicyclic or tricyclic ring system wherein the ring members are carbon atoms and at least one, preferably 1 to 3, heteroatoms selected from nitrogen, oxygen or sulfur, wherein the sulfur is a group-S (O)_r-wherein r is 0, 1 or 2. This ring system can be further bridged. This system is also referred to in the context of the present invention as a heteromonocyclic, heterobicyclic or heterotricyclic ring system.

The heterocyclic group may be saturated or partially unsaturated, wherein in systems with more than one ring system at least one of them is not aromatic. At least one non-aromatic ring system contains at least one heteroatom.

The heterocyclic group may be attached to the backbone in more than one way. If no specific bonding method is specified, all possible methods are included. For example, the term "tetrahydropyranyl" includes 2-, 3-, or 4-tetrahydropyranyl and the like. In the case of more than one ring system, the bonding to the backbone is via at least one ring atom of a non-aromatic ring system comprising at least one heteroatom. This heterocyclyl-group is preferably attached to the backbone through one of the nitrogen atoms or saturated carbon atoms in the ring system. It is more preferably attached to the backbone via a carbon atom of the non-aromatic heterocyclic ring system.

Such heterocyclic groups may be fused with, bridged separately with, or may be part of a spiro ring system, a cycloalkyl group, another heterocyclic group, an aromatic ring system such as phenyl. In fused or bridged systems, two ring systems share a chemical bond between two adjacent ring atoms. In the spiro form, the two ring systems share a common ring atom.

Mono-heterocyclic systems within this definition areNon-aromatic monocyclic ring systems in which at least one, preferably 1 to 3, carbon atoms has been replaced by a heteroatom, such as nitrogen, oxygen or sulfur, wherein the sulfur is a radical-S (O)_r-wherein r is 0, 1 or 2, preferably comprising 4 to 8 ring atoms. In this context, preference is given to 5-, 6-or 7-membered saturated or at least partially unsaturated heterocyclic rings.

Heterobicyclic ring systems within this definition are bicyclic ring systems in which at least one, preferably 1 to 3, carbon atoms have been replaced by a heteroatom, such as nitrogen, oxygen or sulfur, where the sulfur is a group-S (O)_r-wherein r is 0, 1 or 2; the ring system has at least one non-aromatic ring which contains the at least one heteroatom, and the bicyclic ring system preferably contains 7 to 12 ring atoms. In this context, preference is given to 8-, 9-or 10-membered saturated or at least partially unsaturated heterocyclic rings.

The tricyclic ring system within this definition is a bridged monocyclic tricyclic ring system in which at least one, preferably 1 to 3, carbon atoms have been replaced by a heteroatom (e.g. nitrogen, oxygen or sulfur), wherein the sulfur is a group-S (O)_r-wherein r is 0, 1 or 2; the ring system has at least one non-aromatic ring which contains the at least one heteroatom, and the tricyclic ring system preferably contains 7 to 14 ring atoms.

The term spiro ring system as referred to in this definition preferably means a 5-to 10-membered spirocyclic ring which may optionally contain 1, 2 or 3 heteroatoms selected from oxygen, sulphur and nitrogen. Such systems optionally may be bridged with aromatic ring systems such as phenyl.

The order of preference of the heterocyclic ring systems is: monocyclic ring systems are preferred over bicyclic ring systems, and bicyclic ring systems are preferred over tricyclic ring systems.

Such heterocycles according to the inventionHcExamples of radicals are the following radicals:

wherein-represents the chemical bond by which said group is linked to the nitrogen atom of the skeleton, numbered 1.

The above definitions apply to "heterocyclyl" in any reasonable context within this specification, unless defined further.

The term "oxo" denotes an oxygen atom as a substituent, which is bonded via a double bond, which is preferably bonded to a C-atom. If oxo is used as a substituent, the oxo replaces two hydrogen atoms of the corresponding atom of the unsubstituted compound.

The following reaction equations illustrate by way of example the method of making the compounds of the present invention:

reaction equation 1

Reaction equation 1: in the first step, 2-ethoxymethylene-malononitrile (2-ethoxymethylene-malononitrile) is condensed with monosubstituted hydrazine by heating in a suitable solvent (e.g. ethanol) in the presence of a base (e.g. triethylamine) to form 5-amino-1H-pyrazole-4-carbonitrile. These compounds are converted in a second step into the corresponding amides, for example by treating an ethanol solution with ammonia (25% in water) and hydrogen peroxide (35% in water). In a third step, heating with a carboxylic acid ester under basic conditions (e.g. sodium hydride in ethanol) or with a carboxylic acid and an activating reagent (e.g. polyphosphoric acid) gives pyrazolo [3,4-d ] pyrimidin-4-one as the final product [ see, e.g. a. miyashita et al, Heterocycles 1990, 31, 1309ff ].

Equations 2 and 3 illustratively illustrate alternative methods of preparing the final compound: in these exemplary preparation processes, 5-amino-1H-pyrazole-4-carboxylic acid amides are condensed in a first step with suitable ester derivatives and subsequently alkylated in a second step with suitable electrophiles.

Reaction equation 2

Reaction equation 3

Equation 4 illustrates an alternative method of preparing the final compound: in an exemplary preparation process, 5-amino-1H-pyrazole-4-carboxylic acid amide is condensed in a first step with a (2-bromophenyl) -acetate derivative, followed by substitution of the bromine atom in a second step by an aromatic or heteroaromatic moiety, for example using Suzuki or Ullmann-type reaction conditions.

Reaction equation 4

Equation 5 illustrates an alternative method of preparing the final compound: in an exemplary preparation method, 5-amino-1H-pyrazole-4-carboxylic acid amide is condensed with a (2-cyano-phenyl) -acetate derivative in a first step, followed by conversion of the nitrile group to a 5-membered heteroaromatic group in a second step.

Reaction equation 5

Other alternative methods for the preparation of pyrazolo [3,4-d ] pyrimidin-4-ones are known in the art and can likewise be utilized for the synthesis of the compounds of the present invention (see, e.g., P.Schmidt et al, Helvetica Chimica Acta 1962, 189, 1620 ff.).

The monosubstituted hydrazine derivatives used in step 1 of reaction equation 1 can be prepared by nucleophilic displacement on the corresponding mesylate derivative (reaction equation 6) or by reduction of the hydrazone intermediate as depicted in reaction equation 7 [ see, e.g., j.w. timberland et al, "Chemistry of hydrazo-, Azo-, and Azoxy Groups"; patai, s., ed.; 1975, chapter 4; hung et al, Journal of organic Chemistry 1981, 46, 5413-5414.

Reaction equation 6

Reaction equation 7

Further information can also be found in WO04099210 (especially page 9 last paragraph through page 14 line 8, which is hereby incorporated by reference).

The compounds of the present invention show a valuable range of pharmacological effects which cannot be expected. They are characterized inter alia by the inhibition of PDE 9A.

Preferably, the compounds of the invention show a highly selective profile for inhibiting or modulating a specific member of the PDE9 family or other PDE families, with a clear preference (selectivity) for PDE9A inhibition.

The compounds of the present invention are believed to exhibit advantageous safety profiles.

Method of treatment

The present invention relates to compounds which are considered to be potent and selective inhibitors of phosphodiesterase 9A and which are useful in the development of medicaments. Such a medicament is preferably used for the treatment of a disease in which inhibition of PDE9A is involved in the treatment, prevention or amelioration of the disease. Preferably, the medicament is for improving perception, concentration, cognition, learning or memory, such as those which occur in particular in conditions/diseases/symptoms such as mild cognitive impairment, age-associated learning and memory impairment (age-associated impairment and memory), age-associated memory loss (age-associated memory), vascular dementia (vascular dementia), craniocerebral trauma (mental trauma), stroke, dementia following stroke (post-stroke dementia), post-traumatic dementia, general attention deficit impairment (attention deficit impairment), attention deficit in children with learning and memory problems (cognitive in mental deterioration and memory), alzheimer's disease, dementia with Lewy bodies, dementia with leaves including the syndrome of dementia, and the like, Parkinson's disease, progressive nuclear palsy (progressive nuclear palsy), dementia with corticobasal degeneration (dementia with Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration (thalamic degeneration), Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis.

Another aspect of the invention relates to the treatment of diseases which can be achieved by PDE9A modulation, in particular sleep diseases such as insomnia or narcolepsy, bipolar disorders, metabolic syndrome, obesity, diabetes, including type 1 or type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, or diseases of the testis, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

Thus, summarizing the medical aspects of the present invention, compounds of any of the characteristic embodiments of the invention as outlined herein, in particular compounds according to formula I as defined by each element/embodiment of aspects 1-17, set 0 or set I, or selected from the exemplified final compounds (see aspects 18 or the section exemplified embodiments), are considered for use as medicaments.

Such medicaments are preferably used for the treatment of CNS disorders.

In an alternative use, the medicament is for the treatment of CNS disorders, the treatment of which is achieved by inhibition of PDE 9.

In an alternative use, the medicament is for the treatment of a disease accessible by inhibition of PDE 9.

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

In an alternative use, the medicament is for the treatment, amelioration and/or prevention of cognitive impairment associated with age-related learning and memory impairment, age-related memory loss, vascular dementia, cranial and cerebral trauma, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic dementia, impaired general attention, impaired concentration 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, progressive nuclear palsy, dementia with corticobasal degeneration, Amyotrophic Lateral Sclerosis (ALS), huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, 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, hyperglycemia, dyslipidemia, impaired glucose tolerance, or a disorder of the testis, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

Pharmaceutical composition

Medicaments for pharmaceutical use comprise a compound according to the invention in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of the compound of formula (I) which is sufficient to effectively treat, prevent or slow the progression of the corresponding disease, or to improve the condition of a patient suffering from such a disease, if the drug is administered by an appropriate regimen appropriate to the symptoms of the patient. It is also possible that a "therapeutically effective amount" in monotherapy is different from a "therapeutically effective amount" in combination therapy with another drug.

The dose range of the compound of formula (I) which may be applied daily is generally from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, preferably from 2 to 500 mg, more preferably from 5 to 250 mg, optimally from 10 to 100 mg. Dosage units (e.g. tablets) preferably contain 2 to 250 mg, particularly preferably 10 to 100 mg, of a compound according to the invention.

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

The compounds according to the invention may be administered by the oral, parenteral (intravenous, intramuscular, etc.), intranasal, sublingual, inhalation, intrathecal, topical or rectal routes. Suitable formulations for administration of the compounds according to the invention include, for example, patches, tablets, capsules, pills, pellets, dragees, powders, tablets, 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 compound should be in the range of 0.05 to 90 weight-%, preferably 0.1 to 50 weight-%, of the composition as a whole. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for delaying release, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

Coated tablets may thus be prepared by coating cores, made like tablets, with substances conventionally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of a plurality of layers for delayed release or to prevent incompatibilities. Likewise, the tablet coating may be composed of a number of layers to achieve delayed release, and excipients as mentioned above with respect to the tablets may be used.

A syrup or elixir containing an active substance or a combination thereof according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a flavour enhancer, for example a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoic acid esters.

Solutions are prepared in a customary manner, for example by adding isotonic agents, preservatives, such as p-hydroxybenzoate, or stabilizers, such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whereas if water is used, for example, as diluent, organic solvents may optionally be used as solubilizers or dissolution aids, and the solutions may be transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can be produced, for example, by mixing the active substances together with inert carriers, such as lactose or sorbitol, and filling them into gelatin capsules.

Suitable suppositories may be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono-or polyhydric alcohols (e.g. ethanol or glycerol), carriers, such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly disperse silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquors, methylcellulose, starch and polyvinylpyrrolidone), and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

For oral use, the tablets may obviously contain, in addition to the indicated carrier, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various other substances such as starch, preferably potato starch, gelatin and the like. Lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, may also be used to make tablets. In the case of aqueous suspensions, the active substance may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

The dosage of the compounds according to the invention is of course highly dependent on the method of administration and the affliction to be treated. When administered by inhalation, the compounds of formula (I) are characterized by high efficacy, even at doses in the microgram range. The compounds of formula (I) may also be used effectively in the range of micrograms above. Thus the dosage may be, for example, in the gram range.

In combination with other active substances

In another aspect, the invention relates to the pharmaceutical preparation as mentioned above, characterized in that it contains a compound according to the invention.

A further aspect of the invention refers to the combination of each compound of the invention, preferably at least one compound according to the invention, with another compound selected from, for example, the following, inhibitors of β -secretase; gamma-secretase inhibitors; a gamma-secretion modulator; amyloid aggregation inhibitors such as alzhemed (alzhemed); neuroprotective and/or disease-modifying substances acting directly or indirectly; antioxidants, such as vitamin E, ginkgo biloba, or bilobalide; anti-inflammatory substances such as Cox inhibitors, NSAIDs additionally or exclusively having a β -lowering properties; HMG-CoA reductase inhibitors such as statins; acetylcholinesterase inhibitors such as donepezil (donepezil), rivastigmine (rivastigmine), tacrine (tacrine), galantamine; NMDA receptor antagonists, such as memantine (memantine); AMPA receptor agonists; AMPA receptor positive modulators, AMPkines-monoamine receptor reuptake inhibitors; substances that regulate the concentration or release of neurotransmitters; substances that induce secretion of growth hormone, such as ibutemoren (ibutamoren) methanesulfonate and capromorelin (capromorelin); a CB-1 receptor antagonist or inverse agonist; antibiotics, such as minocycline (minocycline) or rifampin (rifampicin); PDE1, PDE2, PDE4, PDE5 and/or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA receptor antagonists; a nicotinic receptor agonist or partial agonist; an α 4 β 2 nicotinic receptor agonist or partial agonist; an alpha 7 nicotinic receptor agonist or partial agonist; histamine receptor H3 antagonists; a 5-HT4 receptor agonist or partial agonist; 5-HT6 receptor antagonists; alpha 2-adrenoceptor antagonists, calcium antagonists; a muscarinic receptor M1 agonist or positive modulator; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; metabotropic glutamate receptor 5 positive modulators; metabotropic glutamate receptor 2 antagonists, and other substances that modulate the receptor or enzyme in such a way that the efficacy and/or safety of the compounds according to the invention is increased, and/or unwanted side effects are reduced.

The invention further relates to pharmaceutical compositions containing one or more, preferably one, active substance selected from the compounds according to the invention and/or the corresponding salts thereof, and one or more, preferably one, active substance selected from the group consisting of zizanide (alzhemed), vitamin E, bilobalide, donepezil (donepezil), rivastigmine (rivastigmine), tacrine (tacrine), galantamine, memantine (memantine), ibutoman (ibutomane) methanesulfonate, capromorelin (capromorelin), minocycline (minocycline) and/or rifampicin (rifampicin), optionally together with one or more inert carriers and/or diluents.

The compounds according to the invention may also be used in combination with immunotherapy, such as active immunization with a β or a part thereof, or passive immunization with humanized anti-a β antibodies or antibody fragments or nanobodies, to treat the above mentioned diseases and conditions.

The combination according to the invention may be provided simultaneously in one and the same dosage form, i.e. in the form of a combined preparation, e.g. the two ingredients may be incorporated in one tablet, e.g. in different layers of the tablet. Combinations may also be provided individually in free combination, i.e. the compounds of the invention are provided in one dosage form and one or more of the above combination partners are provided in another dosage form. The two dosage forms may be the same dosage form, e.g., co-administration of two tablets, one containing a therapeutically effective amount of a compound of the present invention and one containing a therapeutically effective amount of the above-described combination partner. If desired, different administration forms can also be combined. Any type of suitable administration form may be provided.

The compounds according to the invention or their physiologically acceptable salts and with another active substance can be used simultaneously or at staggered times, but in particular close together in time. If administered simultaneously, the two active substances are administered together to the patient; if administration is carried out at staggered times, the two active substances are administered to the patient continuously over a period of less than or equal to 12, in particular less than or equal to 6 hours.

The dosage or administration form is not limited and any suitable dosage form may be used within the scope of the invention. Exemplary dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, tablets, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or gaseous preparations such as aerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to provide a single dose of each active ingredient present. The ingredients are selected accordingly, depending on the route of administration and the dosage form.

The dosages for the combination partners mentioned above are conveniently 1/5 which is the lowest normally recommended dose to 1/1 which is the normally recommended dose.

The dosage form is administered to the patient, for example 1, 2, 3 or 4 times daily, depending on the nature of the formulation. In the case of a slow or extended release formulation or other pharmaceutical agent, it may be applied in a different manner (e.g., once per week or month, etc.). The compounds of the present invention are preferably administered three or less times daily, more preferably once or twice daily.

Examples

Pharmaceutical composition

The following pharmaceutical formulations are illustrative of the present invention and are not intended to be limiting:

some examples of formulations will now be described in which the term "active substance" denotes one or more compounds according to the invention, including salts thereof. In the case of one of the aforementioned combinations with one or more other active substances, the term "active substance" also includes other active substances.

Example A

Tablet containing 100 mg of active substance

Consists of the following components:

1 tablet contained:

active substance 100.0 mg

Lactose 80.0 mg

Corn starch 34.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate2.0 mg

220.0 mg

Diameter: 10mm, biplanar, faceted on both sides and indented on one side.

Example B

Tablet containing 150 mg of active substance

Consists of the following components:

1 tablet contained:

150.0 mg of active substance

Powdered lactose 89.0 mg

Corn starch 40.0 mg

Colloidal silica 10.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium stearate1.0 mg

300.0 mg

Diameter: 10mm, flat

Example C

Hard gelatin capsules containing 150 mg of active substance

1 capsule contains:

150.0 mg of active substance

Corn starch (dry) about 80.0 mg

Lactose (as powder) about 87.0 mg

Magnesium stearate3.0 mg

About 320.0 mg

Capsule shell: no. 1 hard gelatin capsule

Example D

Suppository containing 150 mg of active substance

1 suppository contains:

150.0 mg of active substance

1500550.0 mg of polyethylene glycol

6000460.0 mg of polyethylene glycol

Polyoxyethylene sorbitan monostearate840.0 mg

2,000.0 mg

Example E

Ampoules containing 10 mg of active substance

Consists of the following components:

active substance 10.0 mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to 2.0 ml

Example F

Ampoule containing 50 mg of active substance

Consists of the following components:

active substance 50.0 mg

Proper amount of 0.01N hydrochloric acid

Double distilled water to 10.0 ml

Preparation of any of the above-indicated formulations can be accomplished according to standard procedures.

Biological assay

The in vitro effects of the compounds of the invention can be demonstrated using the biological assays described above

PDE9a2 test protocol:

PDE9A2 enzyme activity assays were performed according to the Scintillation Proximity Assay (SPA), generally according to the manufacturer's protocol (Amersham Biosciences, product No.: TRKQ 7100).

As an enzyme source, a lysate of SF9 cells expressing human PDE9a2 (PBS with 1% triton x-100, supplemented with protease inhibitors, cell debris was removed by centrifugation at 13.000rpm for 30 minutes) was used. The total protein amount contained in the assay varied according to infection and production efficacy of SF9 cells, and ranged from 0.1 to 100 ng.

In general, the test conditions are as follows:

total test volume: 40 microliter

Protein amount: 0.1-50ng

Substrate concentration (cGMP): 20 nM; 1mCi/l

Culture time: room temperature for 60 minutes

Final DMSO concentration: 0.2 to 1 percent

The test was run in 384-well format. The test reagents as well as the enzyme and substrate are diluted in the test buffer. The test buffer contained 50mM Tris, 8.3mM MgCl₂1.7mM EGTA, 0.1% BSA, 0.05% Tween 20; the pH of the test buffer was adjusted to 7.5. The reaction is stopped by applying an excess of a PDE9 specific inhibitor (e.g. a compound according to WO 04099210).

Determination of% inhibition:

the activity of the positive control (minus negative control-background) is set at 100%, and the activity in the presence of the test compound is expressed relative to these 100%. Within this setting, inhibition above 100% was possible due to the variability properties of the positive control within this test, however, in this case the reported% inhibition had been adjusted to 100%.

IC₅₀The determination of (1):

IC₅₀the positive control can be set to 100 and the negative control to 0 as calculated by GraphPadPrism or other suitable software. About IC₅₀Dilutions of test compounds (substrates) were selected and tested according to the protocol described above.

Data of

Hereinafter,% inhibition data will exemplarily illustrate that the compounds of the present invention are suitable for inhibiting PDE9 and may therefore provide useful pharmacological properties. This embodiment is not intended to be limiting. The table also provides the IC₅₀The value is obtained. This value is provided in a nanomolar range (nM), i.e., between 1 nanomolar to 100 nanomolarIn the range of 101 nanomolar to 1200 nanomolar. Specific IC₅₀Values fall within the stated ranges. Example numbers refer to the final examples as outlined in the partially exemplified embodiment (see also aspect 18 of the invention).

All data were measured according to the methods described herein.

The in vivo effect is as follows:

the in vivo effects of the compounds of the present invention can be tested in a Novel object recognition test (Novel object recognition test) according to the procedures of Prickaerts et al (Neuroscience, 2002, 113, 351-361).

For further information on biological assays for compounds of the invention, see also Neuropharmacology, 2008, 55, 908-918.

Chemical preparation

Abbreviations:

APCI atmospheric pressure chemical ionization mass spectrum

DAD diode array detector

DMSO dimethyl sulfoxide

ESI electrospray ionization (in MS)

Exp. examples

Fp. melting Point

h hours

HPLC high performance liquid chromatography

HPLC-MS high performance liquid chromatography combined mass spectrum

GC-MS gas chromatography combined mass spectrum

MPLC Medium pressure liquid chromatography

mL of

Microliter of μ L

min for

MS Mass Spectrometry

racemization of ram

rt Room temperature

R_tRetention time (in HPLC)

Rf Retention coefficient (in TLC)

TBTU 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaTetrafluoroborate salt

TFA trifluoroacetic acid

TLC thin layer chromatography

LC-MS method:

method A

The instrument comprises the following steps: HPLC/MS ThermoFinnigan. HPLC Surveyor DAD, LCQduo ion trap; column: sunryse MS-C18, 5 micron, 4.6x100 mm; eluent A: water +20mM ammonium formate; eluent B: acetonitrile +20mM ammonium formate; gradient liquid: A/B (95: 5) for 1 minute, then within 7 minutes to A/B (5: 95) for 1.5 minutes; flow rate: 0.85 ml/min; and (4) UV detection: 254 nm; an ion source: ESI

Method 1

MS device type: waters Micromass ZQ; HPLC apparatus type: waters Alliance2695, Waters 2996 diode array detector; column: varian Microsorb 100C 18, 30x 4.6 mm, 3.0 micron; eluent A: water + 0.13% TFA, eluent B: acetonitrile; gradient liquid: 0.0 min 5% B → 0.18 min 5% B → 2.0 min 98% B → 2.2 min 98% B → 2.3 min 5% B → 2.5 min 5% B; flow rate: 3.5 ml/min; and (4) UV detection: 210-.

Method 2

MS device type: waters Micromass ZQ; HPLC apparatus type: waters Alliance2695, Waters 2996 diode array detector; column: merck chromosome performance rp18e, 100x 1 mm; eluent A: water + 0.13% TFA, eluent B: acetonitrile; gradient liquid: 0.0 min 5% B → 0.2 min 5% B → 1.6 min 98% B → 1.9 min 98% B → 2.0 min 5% B → 2.2 min 5% B; flow rate: 3.5 ml/min; and (4) UV detection: 210-.

Method 1D

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, MSQ

Quadrupole; column: sunryse MS-C18, 5 micron, 4.6x100 mm; eluent A: 90% water + 10% acetonitrile + ammonium formate 10 mM; eluent B: acetonitrile 90% + 10% water + ammonium formate 10 mM; gradient liquid: a (100) for 1 minute, then within 7 minutes to B (100) for 1 minute; flow rate: 1.2 ml/min; and (4) UV detection: 254 nm; an ion source: APCI.

Method 1E

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, msqquadrupupole; column: symmetry C8, 5 μm, 3 × 150 mm; eluent A: 90% water + 10% acetonitrile + ammonium formate 10 mM; eluent B: acetonitrile 90% + 10% H₂O + ammonium formate 10 mM; gradient liquid: a (100) for 1.5 minutes, then within 10 minutes to B (100) for 1.5 minutes; flow rate: 1.2 ml/min; and (4) UV detection: 254 nm; an ion source: APCI

Method 1E fusion

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, msqquadrupupole; column: synergi Fusion-RP80A, 4 microns, 4.60X 100 mm; eluent A: 90% water + 10% acetonitrile + ammonium formate 10 mM; eluent B: acetonitrile 90% + 10% H₂O + ammonium formate 10 mM; gradient liquid: a (100%) for 1.5 min, then within 10 min to B (100%) for 1.5 min; flow rate: 1.2 ml/min; and (4) UV detection: 254 nm; an ion source: APCI

Method 1E hydro

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, msqquadrupupole; column: synergi Hydro-RP80A, 4 μm, 4.60 × 100 mm; eluent A: 90% water + 10% acetonitrile + ammonium formate 10 mM; eluent B: acetonitrile 90% + 10% H₂O + ammonium formate 10 mM; gradient liquid: a (100%) for 1.5 min, then within 10 min to B (100%) for 1.5 min; flow rate: 1.2 ml/min; and (4) UV detection: 254 nm; an ion source: APCI

Method 2F

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, finnigan lcqduo ion trap; column: Symmetry-C18, 5 microns, 3x 150 mm; eluent A: 95% of water, 5% of acetonitrile and 0.1% of formic acid; eluent B: acetonitrile 95% + 5% water + formic acid 0.1%; gradient liquid: A/B (95/5) for 1.5 minutes, then within 10 minutes to A/B (5/95) for 1.5 minutes; flow rate: 1 ml/min; and (4) UV detection: 254 nm; an ion source: ESI

Method 2L

The instrument comprises the following steps: HPLC-MS ThermoFinnigan. HPLC Surveyor DAD, finnigan lcqduo ion trap; column: symmetry Shield, 5 micron, 4.6x 150 mm; eluent A: 90% of water, 10% of acetonitrile and 0.1% of formic acid; eluent B: acetonitrile 90% + 10% water + formic acid 0.1%; flow rate: 0.85 ml/min; and (4) UV detection: 254 nm; an ion source: ESI

Method Grad _ C8_ acidic

The instrument comprises the following steps: HPLC-MS Waters. HPLC Alliance2695 DAD, ZQ Quadrupole; column: xterra MS-C8, 3.5 microns, 4.6x 50 millimeters; eluent A: water + 0.1% TFA + 10% acetonitrile; eluent B: acetonitrile; gradient liquid: A/B (80: 20) then in 3.25 minutes to A/B (10: 90) for 0.75 minutes; flow rate: 1.3 ml/min; and (4) UV detection: 254 nm; an ion source: ESI

Method Grad _ C18_ acidic

The instrument comprises the following steps: HPLC-MS Waters. HPLC Alliance2695 DAD, ZQ Quadrupole; column: sunfire MS-C18, 3.5 microns, 4.6x 50 mm; eluent A: water + 0.1% TFA + 10% acetonitrile; eluent B: acetonitrile; gradient liquid: A/B (80: 20) then in 3.25 minutes to A/B (10: 90) for 0.75 minutes; flow rate: 1.3 ml/min; and (4) UV detection: 254 nm; an ion source: ESI.

Method Grad _90_10_ C8_ acidic

The instrument comprises the following steps: HPLC-MS Waters. HPLC Alliance2695 DAD, ZQ Quadrupole; column: xterra MS-C8, 3.5 microns, 4.6x 50 millimeters; eluent A: water + 0.1% TFA + 10% acetonitrile; eluent B: acetonitrile; gradient liquid: a (100%) then went to A/B (10: 90) in 3.25 minutes for 0.75 minutes; flow rate: 1.3 ml/min; and (4) UV detection: 254 nm; an ion source: ESI.

Method Grad _90_10_ C18_ acidic

The instrument comprises the following steps: HPLC-MS Waters. HPLC Alliance2695 DAD, ZQ Quadrupole; column: xterra MS-C18, 3.5 microns, 4.6x 50 millimeters; eluent A: water + 0.1% TFA + 10% acetonitrile; eluent B: acetonitrile; gradient liquid: a (100) then to A/B (10: 90) in 3.25 minutes for 0.75 minutes; flow rate: 1.3 ml/min; and (4) UV detection: 254 nm; an ion source: ESI.

Method Grad _ C8_ NH₄COOH

The instrument comprises the following steps: HPLC-MS Waters. HPLC Alliance2695 DAD, ZQ Quadrupole. Column: xterra MS-C8, 3.5 microns, 4.6x 50 millimeters; eluent A: water + ammonium formate 5mM + 10% acetonitrile; eluent B: acetonitrile; gradient liquid: a100%, then within 3.25 minutes to A/B (10: 90) for 0.75 minutes; flow rate: 1.3 ml/min; and (4) UV detection: 254 nm; an ion source: ESI.

Chiral HPLC method

The instrument comprises the following steps: agilent 1100. Column: chiralpak AS-H Daicel, 4.6 microns, 4.6x 250 mm;

method chirality 1: eluent: hexane/ethanol 97/3 (constant composition); flow rate: 1.0 ml/min; and (4) UV detection: 254 nm

The method is chiral 2: eluent: hexane/ethanol 98/2 (constant composition); flow rate: 1.0 ml/min; and (4) UV detection: 254 nm

Method chirality 3: eluent: hexane/ethanol 80/20 (constant composition); flow rate: 1.0 ml/min; and (4) UV detection: 254 nm

GC/MS method

Method 3A

The instrument comprises the following steps: GC/MS Finnigan. Trace GC, MSQ Quadrupole. Column: DB-5MS, 25 meters x 0.25 mm x 0.25 micron; carrier gas: helium, 1 ml/min constant flow; oven procedure: 50 ℃ (hold for 1 minute), 10 ℃/min to 100 ℃, 20 ℃/min to 200 ℃, 30 ℃/min eluent to 300 ℃, assay: tracking MSQ, Quadrupole

An ion source: IE scanning range: 50-450 u.

Method 3A.1

The instrument comprises the following steps: GC/MS Finnigan Thermo Scientific. Trace GC Ultra, DSQ II single quadrupole. Column: DB-5MS UI, 25 meters x 0.25 mm x 0.25 micron; carrier gas: helium, 1 ml/min constant flow; oven procedure: 50 ℃ (hold for 1 minute), 10 ℃/min to 100 ℃, 20 ℃/min to 200 ℃, 30 ℃/min eluent to 300 ℃, assay: tracking DSQ, single quadrupole

Microwave heating:

microwave device type:

·DiscoverCEM instruments with 10 and 35 ml containers;

microwave device type: biotage Initiator six.

General discussion of structural presentation

Some compounds have one or more centers of oppositivity. The depicted structures do not necessarily show all possible stereochemical realizations of the compound, but only one. However, in this case, the term "cis-racemic mixture", for example, immediately follows the structural description, with other stereochemistry indications.

Example 7D is given, for example, as follows. It has a structural formula of

Cis-racemic mixtures

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

this principle is also applicable to the other depicted structures.

Synthesis of

In the following, the description illustrates the preparation of the compounds of the invention. If the method by which a particular compound is made has not been literally disclosed, then those skilled in the art will seek a description of similar methods within the specification to which it may in principle follow. In some of the positions described, some embodiments may be prepared similarly to other embodiments. If reference should be made to this "analogous process", the reaction conditions are substantially the same, even though the molar ratio of reagents to educts may be adjusted. It is also clear that the starting materials in one such process can be chemically altered to achieve the same result, i.e. if the condensation reaction of the ester is described, the alcoholic component can be altered without significantly altering the process itself, since this alcoholic component is the leaving group and not the subject of the product.

Starting compounds:

example 1A

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

HPLC-MS (method 1): r_t: 1.77 minutes

MS (ESI positive): 196(M + H) is equal to M/z⁺

Example 1AA

400 mg (10.0 mmol) of sodium hydride (60% in mineral oil) are suspended in 10 ml of THF and cooled to 4 ℃. With stirring, a solution of 1.3 ml (8.99 mmol) of trimethylphosphonoacetate (trimethy phosphoacetate) in 10 ml of THF is added. The mixture was stirred at the same temperature for 1 hour. Then, a solution of 4, 4-difluorocyclohexanone in 10 ml of THF is added at 0 ℃. The mixture was warmed to room temperature and stirred for 14 hours. THF and water were added and THF was evaporated. The residue was diluted with ethyl acetate, washed with water and saturated sodium bicarbonate solution and evaporated to yield 1.49 g (95%) of product.

MS(EI)：m/z＝190(M)⁺

The following examples 1B, 1C, 1D, 1E, 2A, 2B, 2C and 2D show how the racemic acids 3-trifluoromethyl-pentanoic acid and 3-trifluoromethyl-butanoic acid can be converted into the two enantiomeric forms of the free acid. Resolution can be achieved by separation of diastereomeric intermediates. The two pure enantiomeric forms of the free acid are referred to as enantiomer a, enantiomer B, respectively. The corresponding diastereoisomeric intermediates are designated diastereomer A and diastereomer B, respectively.

The same principle can be applied, if appropriate, to the enantiomeric resolution of other racemic mixtures.

Example 1B

Diastereomer A

A solution of racemic 3-trifluoromethyl-pentanoic acid (8 g, 47 mmol), TBTU (16.6 g, 52 mmol) and diisopropylethylamine (24.1 ml, 141 mmol) in dimethylformamide (80 ml) was stirred at 20 ℃ for 1 hour, then (S) - (-) -1-phenylethylamine (10 g, 82 mmol) was added and the mixture was stirred at 20 ℃ for 16 hours. The solvent was removed and dichloromethane (200 ml) was added. The resulting mixture was diluted with 10% aqueous citric acid (200 ml), 20% K₂CO₃The aqueous solution (100 ml) was washed and dried over sodium sulfate. The solvent was evaporated to give a crude solid, which was mixed with methanol (10 ml) and filtered through a pad of activated basic alumina. Separation of diastereomers from SiO₂This was achieved by flash chromatography eluting with a mixture of cyclohexane/ethyl acetate 85/15.

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

Rf: 0.25 (cyclohexane/Ethyl acetate 85/15, using basic KMnO₄Color development)

HPLC-MS (method 1E hydro): r_t: 9.35 minutes

MS (APCI positive): 274(M + H) is defined as M/z⁺。

Chiral HPLC (method chiral 1): r_t: 5.58 min, de: more than 99 percent

Example 1C

Diastereomer B

4.4 g (34.2%) of a white solid was obtained as the second product from flash chromatography of example 1B.

Rf: 0.20 (cyclohexane/Ethyl acetate 85/15, using basic KMnO₄Color development)

HPLC-MS (method 1E hydro): r_t: 9.33 minutes

MS (APCI positive): 274(M + H) is defined as M/z⁺。

Chiral HPLC (method chiral 1): r_t: 6.18 min, de: more than 99 percent

Example 1D

3-trifluoromethyl-pentanoic acid, enantiomer a

Enantiomer A

Example 1B (4.6 g, 17 mmol) was added in twoSolution in alkane (15 ml) with 70% H₂SO₄Aqueous solution (25 ml) was treated and refluxed for 16 hours. Will be mixed withThe compound was cooled, basified with 32% aqueous NaOH to pH 14, diluted with water (50 ml) and extracted with dichloromethane (2 × 200 ml). The resulting solution was acidified to pH1 using 9n hcl, extracted with dichloromethane (3 × 500 ml) and the combined organic phases dried. The solvent was evaporated to give 2.47 g (86.3%) of a brown oil.

Rf: 0.66 (methylene chloride/methanol 9/1, color development Using bromocresol green)

Chiral HPLC (method chiral 1): r_t5.58 min, ee: more than 99 percent

Example 1E

3-trifluoromethyl-pentanoic acid, enantiomer B

Enantiomer B

In analogy to the preparation of example 1D, the title compound was obtained using example 1C as starting material.

Yield: 80.3 percent

Chiral HPLC (method chiral 1): r_t: 5.08 min, ee: more than 99 percent

Example 2A

4, 4, 4-trifluoro-N- ((R) -2-hydroxy-1-phenyl-ethyl) -3-methyl-butyramide, diastereomer a

A solution of 3- (trifluoromethyl) butyric acid (10 g, 64 mmol) in dimethylformamide (100 ml) was treated with N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (14.7 g, 77 mmol), 4-dimethyl-aminopyridine (11 g, 89.7 mmol) and (R) - (-) -phenylglycinol (9.9 g, 70.5 mmol). The mixture was stirred at 20 ℃ for 16 hours, then concentrated to reduce the volume and treated with 10% aqueous citric acid (300 ml). The mixture was extracted with ether (2 × 200 ml) and the separated organic phase was extracted with 10% NaHCO₃(150 ml) and brine (150 ml). The organic phase was dried and evaporated to give 13.1 g of a crude white solid. Separation of diastereomers at SiO₂This was done by flash chromatography, eluting with a mixture of ethyl acetate/hexane 6/4.

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

Rf: 0.23 (Ethyl acetate/Hexane 6/4)

HPLC-MS(1E hydro)：R_t: 6.97 minutes

MS (APCI positive): m/z 276(M + H)⁺。

Example 2B

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

3.08 g (17.5%) of a white solid was obtained as the second product from flash chromatography of example 2A.

Rf: 0.16 (Ethyl acetate/Hexane 6/4)

HPLC-MS(1E hydro)：R_t: 6.92 pointsClock (CN)

MS (APCI positive): m/z 276(M + H)⁺。

Example 2C, enantiomer A

A solution of example 2A (2 g, 7.26 mmol) in tetrahydrofuran (10 mL) was taken up at 70% H₂SO₄Aqueous solution (10 ml) was treated and refluxed for 16 hours. The mixture was cooled, basified to pH 14 with 32% aqueous NaOH, diluted with water (50 ml) and extracted with dichloromethane (2 × 50 ml). The resulting solution was acidified to pH1 using 9N HCl, extracted with dichloromethane (3 × 50 ml), and the combined organic phases were dried. The solvent was evaporated to give 0.84 g (74.1%) of a brown oil.

HPLC-MS(1E hydro)：R_t: 1.73 minutes

MS (APCI negative): 155(M-H)^-。

Chiral HPLC (method chiral 2): r_t: 6.92 min, ee: 99 percent

Example 2D, enantiomer B

In analogy to the preparation of example 2C, the title compound was obtained using example 2B as starting material. 1.4 g (8.96 mmol) were obtained.

Yield: 82.3 percent of

HPLC-MS(1E hydro)：R_t: 1.30 minutes

MS (APCI negative): 155(M-H)^-。

Chiral HPLC (method chiral 2): r_t: 6.49 min, ee: 98.6 percent

Example 3A

2- (4-trifluoromethyl-pyridin-2-yl) -malonic acid diethyl ester

60% sodium hydride (1.65 g, 41 mmol) in mineral oil was added to anhydrous mineral oilThe suspension in alkane (36 ml) was treated with diethyl malonate (6.3 ml, 41 mmol) at 25 ℃ and heated to 60 ℃ for 30 minutes. Cuprous chloride (1.63 g, 17 mmol) was added, the mixture was heated to 80 ℃ and 2-chloro-4- (trifluoromethyl) -pyridine was added and heated to 100 ℃ for 16 hours.

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

1.9 g (38%) were obtained as a colorless oil.

HPLC-MS(2F)：R_t: 12.24 minutes

MS (ESI positive): 306(M + H)⁺。

Example 4A

The following examples were prepared analogously to example 5U, synthesized using their corresponding acids (Sinova, Bethesda, MD 20814, USA) as starting materials.

HPLC-MS (method 1): r_t: 1.47 minutes

MS (ESI positive): m/z 194(M + H-EtOH)⁺

Example 4B

2.0 g (8.6 mmol) of example 4A 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 was filtered, and the residue was washed with ethanol. The solvent was evaporated under reduced pressure. 1.80 g (100%) of product are obtained.

HPLC-MS (method 1): r_t: 0.91 minute

MS (ESI positive): m/z 210(M + H)⁺

Example 5A

3-trifluoromethyl-pentanoic acid methyl ester, enantiomer a

Enantiomer A

To a stirred solution of example 1D (250 mg, 1.47 mmol) in dichloromethane (10 ml) and methanol (0.25 ml) was added dropwise trimethylsilyldiazomethane (2.0M ether solution) (2.1 ml, 4.19 mmol) under a nitrogen atmosphere at 0 ℃. The reaction mixture was stirred for 1 hour while maintaining the temperature below 5 ℃. The solvent was removed (40 ℃, 25 bar) to give 250 mg (75.4%) of a yellow oil which was used in the next step without further purification.

GC (method 3A): r_t: 3.29 minutes

MS(EI)：m/z：165(M-19)⁺，155(M-29)⁺，153(M-31)⁺

The following examples were prepared analogously to example 5A, using their corresponding acids as starting materials:

example 5I

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

Di-tert-butyl azodicarboxylate (305 mg, 1.32 mmol) was added dropwise to a solution of 1- (4-hydroxy-piperidin-1-yl) -ethanone (259 mg, 1.8 mmol) 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 mmol) were added. The yellow mixture was stirred at 20 ℃ for 16 hours. The solvent was evaporated and the residue was purified on silica gel using a hexane/ethyl acetate mixture of increasing polarity (from 70% to 100% ethyl acetate) as eluent to give 195 mg (55.6%) of a colorless oil.

HPLC-MS (method Grad _ C8_ NH)₄COOH)：R_t: 2.67 minutes

MS (ESI positive): 292(M + H) M/z⁺。

The following examples were prepared analogously to example 5G, using their corresponding alcohols as starting materials:

example 5Q

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

A mixture of (3-methoxy-2-pyridin-2-yl) acetonitrile (400 mg, 2.7 mmol) in 2 ml methanol and 96% sulfuric acid (1.8 ml, 32 mmol) was heated in a microwave oven at 120 ℃ for 1 hour. The mixture was cooled to 0 ℃ as solid NaHCO₃Basified, diluted with water (2 ml) and extracted with dichloromethane. The separated organic phase was dried and evaporated to give 450 mg (92%) of a dark yellow oil which was used in the next step without further purification.

HPLC-MS (method Grad _ C8_ NH)₄COOH)：R_t: 1.92 minutes

MS (ESI positive): m/z 182(M + H)⁺。

Example 5R

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

A solution of example 3A (1.0 g, 3.27 mmol) in anhydrous DMSO (8 ml) was treated with water (60 μ l, 3.27 mmol) and lithium chloride (347 mg, 8.2 mmol). The resulting mixture was heated at 120 ℃ for 16 hours. After cooling to 20 ℃, the mixture was treated with brine (12 ml) and extracted with ethyl acetate (3 × 20 ml). The organic phase was dried and evaporated to give a crude oil which was purified by flash chromatography eluting with n-hexane/ethyl acetate 8/2.

390 mg (51%) were obtained as a colorless oil.

HPLC-MS (method 2F): r_t: 11.09 minutes

MS (ESI positive): 234(M + H) M/z⁺

Example 5S

(6-trifluoromethyl-pyridin-2-yl) -acetic acid ethyl ester

A mixture of cesium carbonate (1.87 g, 5.75 mmol) and tri-tert-butylphosphine (107 μ l, 0.44 mmol) in dry 1, 2-dimethoxyethane (10 ml) was treated with tris (dibenzylideneacetone) dipalladium (81 mg, 0.09 mmol), 2-bromo-6- (trifluoromethyl) pyridine (1 g, 4.42 mmol) and diethyl malonate (0.8 ml, 5.3 mmol) under a nitrogen atmosphere. The mixture was heated to 150 ℃ in a microwave oven for 30 minutes. After cooling to 20 ℃, the mixture was treated with saturated ammonium chloride solution (120 ml) and extracted with ether (3 × 80 ml). The organic phase was dried and evaporated to give a crude oil which was purified by flash chromatography eluting with n-hexane/diethyl ether 6/1.

460 mg (81%) was obtained as a colorless oil.

GC (method 3A): r_t: 8.28 minutes

MS(EI)：m/z＝233(M)⁺

Example 5T, racemic mixture

29 g (148 mmol) of example 1A were combined with 2 g Pd/C (10%) and hydrogenated at room temperature (6 h, 15 psi). The reaction mixture was filtered and washed with diethyl ether. The solvent was evaporated under reduced pressure (500 mbar, 40 ℃ bath temperature). 27.6 g (94%) of product were obtained as a colorless liquid.

HPLC-MS (method 1): r_t: 1.65 minutes

Example 5TA

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

Example 5U

A solution of 15 g (69.8 mmol) of (2-bromo-phenyl) -acetic acid in 50 ml of ethanol is cooled to 0 ℃ and 8 ml (110 mmol) of thionyl chloride are added dropwise. The reaction mixture was heated to 50 ℃ overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was mixed with ethyl acetate and filtered over 30 g of basic alumina. The filtrate was evaporated under reduced pressure. 18 g (92%) of product are obtained.

HPLC-MS (method 1): r_t: 1.62 minutes

MS (ESI positive): m/z 243/45(Br) (M + H)⁺

The following examples were synthesized analogously to the preparation of example 5U, using their corresponding acids as starting materials.

Example 5AM

The following example is prepared analogously to example 5U, using its corresponding acid as starting material and methanol as solvent.

HPLC-MS (method 1): r_t: 1.04 minutes

MS (ESI positive): 167(M + H)⁺

The following examples were synthesized analogously to the preparation of example 5AM, using their corresponding acids as starting materials.

Example 5AN

6.0 g (88.5 mmol) of pyrazole are dissolved in 60 ml of DMSO and 10.4 g (93 mmol) of potassium tert-butoxide are added in portions while maintaining the temperature between 20 ℃ and 25 ℃. The reaction mixture was stirred at room temperature for 10 minutes. 10.8 ml (98 mmol) of ethyl bromoacetate are added dropwise while maintaining the temperature between 25 and 35 ℃. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a saturated aqueous NaCl solution and extracted with ethyl acetate. The organic layer was dried, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative MPLC (SiO)₂Eluent dichloromethane/methanol 95/5). 10.4 g (38%) of product are obtained。

Example 5AO

1.83 g (7.7 mmol) of example 4B are mixed with 60 ml of 4N HCl and cooled with an ice bath. A solution of 1.15 g (16.4 mmol) of sodium nitrite 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 concentrated HCl is added dropwise. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The mixture was extracted with ethyl acetate. The organic layer was neutralized with potassium carbonate, filtered over celite, and the filtrate was extracted with water. The organic layer was dried, filtered and the filtrate was evaporated under reduced pressure. 1.24 g (62%) of product were obtained.

HPLC-MS (method 1): r_t: 1.60 minutes

MS (ESI positive): m/z 229/231(Cl) (M + H)⁺

Example 5AP

1.00 g (4.11 mmol) of example 5U, 540 mg (4.95 mmol) of 3-methylpyridinone and 80 mg (0.42 mmol) of copper (I) iodide are mixed with 5 ml of DMSO under argon, and 1.14 g (8.25 mmol) of potassium carbonate and 120 mg (0.82 mmol) of 8-hydroxyquinoline are added. The mixture was stirred at 120 ℃ for 48 hours. After cooling to room temperature, the mixture was dissolved in ethyl acetate and washed with 1M HCl and saturated sodium chloride solution. The organic phase was separated, dried and evaporated. The residue was purified by HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). Acetonitrile was evaporated and the residue was extracted with ethyl acetate. The organic phase was dried and evaporated to give 633 mg (57%) of the desired product.

HPLC-MS (method 1): r_t: 1.56 minutes

MS (ESI positive): m/z 272(M + H)⁺

Example 6A

10 g (54 mmol) of 1-N-Boc-3-pyrrolidone were dissolved in 50 ml of ethanol and 7.3 g (55.2 mmol) of tert-butyl carbazate were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative MPLC (SiO)₂Eluent dichloromethane/methanol 95/5). 18 g (89%) of product were obtained as oil.

HPLC-MS (method 1): r_t: 1.35 minutes

MS (ESI negative): 298(M-H) M/z^-

Example 6B

The following examples were synthesized analogously to the preparation of example 6A, using 1-N-Boc-3-piperidone as starting material.

HPLC-MS (method 1): r_t: 1.45 minutes

Example 7A, racemic mixture

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

HPLC-MS (method 1): r_t: 1.36 minutes

Example 7B, racemic mixture

The following examples were synthesized analogously to the preparation of example 7A, using example 6B as starting material.

HPLC-MS (method 1): r_t: 1.42 minutes

MS (ESI positive): m/z 316(M + H)⁺

Example 7C

10 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 was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was mixed with 140 ml of acetic acid (50%), 6.9 g (110 mmol) of sodium cyanoborohydride was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 4M NaOH and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 19 g (88%) of product were obtained as a white solid.

MS (ESI positive): 217(M + H)⁺

Example 7D

Cis-racemic mixtures

A solution of 2-methyl-tetrahydro-pyran-4-one (2.2 g, 19.7 mmol) in methanol (30 ml) was treated with tert-butyl carbazate (2.6 g, 19.7 mmol) and stirred at 20 ℃ for 3 hours. The solvent was evaporated to give a white solid, which was mixed with 30 ml of acetic acid (50% in water) and treated in portions with sodium cyanoborohydride (1.2 g, 19.7 mmol). The mixture was stirred at 20 ℃ for 16 hours, then neutralized with 5N NaOH and extracted with dichloromethane. The organic phase was washed with saturated NaHCO₃The solution was washed with brine, dried, filtered, and evaporated to give a crude solid. Separation of diastereomers at SiO₂Obtained by flash chromatography eluting with a mixture of cyclohexane/ethyl acetate mixtures of increasing polarity (from 7/3 to 1/1) to yield 1.85 g (41%) of a white solid.

Rf: 0.29 (Hexane/EtOAc 1: 1)

HPLC-MS (method Grad-90-10-C8-acid): r_t: 1.79 minutes

MS (ESI positive): 131(M-100+ H)⁺

The cis configuration between methyl and t-butyl carbazate is obtained by the H-2/H-4 correlation of ROESY.

Example 7E

Trans-racemic mixtures

0.7 g (16%) of a colorless oil were obtained as a second product from flash chromatography of example 7D.

Rf: 0.29 (Hexane/EtOAc 1: 1, color development Using Pancaldi's reagent)

HPLC-MS (method Grad-90-10-C8-acid): r_t: 1.96 minutes

MS (ESI positive): 131(M-100+ H)⁺

Example 8A, racemic mixture

14 g (46.5 mmol) of example 7A 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 was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was purified by preparative MPLC (SiO)₂Eluent dichloromethane/methanol 8/2). 12 g (78%) of product are obtained.

Example 8B

The following examples were synthesized analogously to the preparation of example 8A, using example 7C as starting material.

MS (ESI positive): 117(M + H) M/z⁺

Example 8C, racemic mixture

13.0 g (37.1 mmol) of example 7B are dissolved in 5 ml of twoTo the mixture was added 93 ml (371 mmol) of hydrochloric acid in bis (ethyl acetate)Alkane solution (4M). The reaction mixture was stirred at room temperature overnight. 40 ml of diethyl ether were added, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered. 7.0 g (100%) of product are obtained as a white solid.

The following examples were synthesized analogously to the preparation of example 8C, using their corresponding Boc-hydrazines as starting materials.

Example 8D

Trans-racemic mixtures

Example 7E (700 mg, 3 mmol) was added in twoSolution in alkane (5 ml) with 4N HCl bisThe alkane solution (15 ml, 60 mmol) was treated and the mixture was stirred at 20 ℃ for 18 hours. The solvent was evaporated to give 560 mg (91%) of a sticky solid, which was used in the next step without further purification.

HPLC-MS (gradient _ C8_ NH)₄COOH_Lowmass)：R_t: 0.67 minute

MS (ESI positive): 131(M + H) M/z⁺

Example 8E

Cis-racemic mixtures

In analogy to the preparation of example 8D, the title compound was obtained using example 7D as starting material.

Yield: 68.3 percent of

HPLC-MS (method Grad _ C8_ NH)₄COOH_Lowmass)：R_t: 0.70 min

MS (ESI positive): 131(M + H) M/z⁺

Example 9A, racemic mixture

32.0 g (77.8 mmol) of example 8A are mixed with 12.0 g (98.3 mmol) of ethoxymethylene-malononitrile (ethoxymethylene-malononitrile) in 250 ml of ethanol, and 40 ml (288 mmol) of triethylamine are added. The reaction mixture was heated to 50 ℃ for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by preparative MPLC (SiO)₂Eluent dichloromethane/methanol 8/2).

HPLC-MS (method 1): r_t: 0.29 minute

The following examples were synthesized analogously to the preparation of example 9A, using the corresponding hydrazines as starting materials.

Example 9F

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

The following example is prepared in analogy to the preparation of example 9F, using the corresponding hydrazines as starting materials.

Example 9GA (enantiomer A)

Enantiomer A

Example 9G chiral resolution was performed to isolate its enantiomer. Was isolated using the following conditions

A known but single stereochemistry identifies an enantiomer of a.

Amount supplied	5g
		Chiral column	Daicel Chiralpak AD 50x 300 mm
Mobile phase	N-hexane (60%)/methyl-tert-butyl ether (40%)/ethanol (5%) v/v
		Flow rate of flow	20 ml/min
Detection of	UV 254 nm
		Injection mode	Continuous

1 g of enantiomer A is obtained.

Enantiomeric excess 99.3%; retention time 27.83 minutes; (analytical method: chirality 3)

Example 9GB (enantiomer B)

Enantiomer B

Separation was carried out using the same conditions for enantiomer a, obtaining 0.5 g; enantiomeric excess 96.7%; rt: 30.94 minutes; (analytical method: chirality 3).

Example 10A, racemic mixture

4.0 g (22.6 mmol) of example 9A are mixed with 60 ml of tetrahydrofuran and 5.7 g (30 mmol) of di-tert-butyl dicarbamate are added. The reaction mixture was heated to 60 ℃ for 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by preparative MPLC (SiO)₂Eluent dichloromethane/methanol 9/1).

HPLC-MS (method 1): r_t: 1.28 minutes

MS (ESI positive): 278(M + H) M/z⁺

The following examples are prepared analogously to example 10A, using their corresponding pyrazoles as starting materials.

Example 11A, racemic mixture

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

HPLC-MS (method 1): r_t: 1.08 minutes

MS (ESI positive): 296(M + H)⁺

The following examples are prepared analogously to example 11A, using their corresponding pyrazoles as starting materials.

Example 11J, racemic mixture

2.30 g (11.2 mmol) of example 9E are dissolved in 6 ml of dimethyl sulfoxide. Under ice-cooling, 8 ml (77.6 mmol) of hydrogen peroxide and 1.7 g (12.3 mmol) of potassium carbonate were added. Then, the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled with an ice bath, 100 ml of water was added, and extracted with dichloromethane. The aqueous phase was evaporated under reduced pressure. The residue was mixed with dichloromethane and filtered. 2.8 g (52%) of product were obtained as a white solid.

HPLC-MS (method 1): r_t: 0.24 minute

Example 12A

660 mg (2.13 mmol) of example 11C 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) were added. The reaction mixture was heated to 150 ℃ in a microwave oven for 30 minutes. Cooled to room temperature, followed by evaporation of the solvent under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 320 mg (38%) of product were obtained as a white solid.

HPLC-MS (method 1): r_t: 1.61 minutes

MS (ESI positive): m/z 402(M + H)⁺

The following examples are prepared analogously to example 12A, using their corresponding pyrazoles and esters as starting materials.

Example 13A, racemic mixture

400 mg (1.35 mmol) of example 11A are dissolved in 8 ml of absolute ethanol, and 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 was heated to 150 ℃ in a microwave oven for 30 minutes. After cooling to room temperature, the reaction mixture was acidified with 4N hydrochloric acid. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 250 mg (46%) of product were obtained as a white solid.

HPLC-MS (method 1): r_t: 0.93 min

MS (ESI positive): 288(M + H)⁺

Example 13B

330 mg (0.82 mmol) of example 12A are dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid are added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residual product was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 240 mg (70%) of product are obtained.

HPLC-MS (method 1): r_t: 0.96 min

MS (ESI positive): 302(M + H) M/z⁺

The following examples were synthesized analogously to the preparation of example 13B, using their corresponding Boc-protected amines as starting materials.

Example 15A:

enantiomer A

200 mg (1.12 mmol) of example 9GA were mixed with 4.5 ml ammonia solution (30% in water). The reaction mixture was heated to 130 ℃ in a microwave oven for 30 minutes. Cooled to room temperature, followed by evaporation of the solvent under reduced pressure. 180 mg (82%) of product are obtained.

GC-MS (method 3 A.1): r_t: 12.62 minutes

[M]⁺＝196

Example 16A:

enantiomer B

150 mg (0.84 mmol) of example 9GB were mixed with 2.10 ml ammonia solution (30% in water). The reaction mixture was heated to 130 ℃ in a microwave oven for 30 minutes. Cooled to room temperature, followed by evaporation of the solvent under reduced pressure. 100 mg (60%) of product are obtained.

GC-MS (method 3 A.2): r_t: 12.59 minutes

[M]⁺＝196

Example 17A, mixture of stereoisomers

A solution of 1.00 g (5.32 mmol) of 2-methoxy-5-bromopyridine in 10 mL of anhydrous THF was cooled to-78 deg.C and n-BuLi (3.66 mL, 5.85 mmol, 1.6M in hexane) was added. After 10 min at-78 ℃, 1.18 g (6.38 mmol) of ethyl 2-oxo-cyclohexyl-acetate were added and the mixture was warmed to 25 ℃. Water (1 ml) was added and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 370 mg (28%) of product were obtained as an oil.

HPLC-MS (method 1): r_t: 1.23 minutes

MS (ESI positive): m/z 248(M + H)⁺

Example 18A, cis, racemic mixture

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

HPLC-MS (method 1): r_t: 1.01 minutes

MS (ESI positive): 250(M + H) M/z⁺

Exemplary embodiments:

example 1

100 mg (0.48 mmol) of example 11B are dissolved in 5 ml of absolute ethanol, and 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 was heated to 150 ℃ in a microwave oven for 30 minutes. Cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 29 mg (18%) of product were obtained as a white solid.

HPLC-MS (method 1): r_t: 1.08 minutes

MS (ESI positive): 331(M + H) for M/z⁺

The following examples are prepared analogously to example 1, using their corresponding pyrazoles and esters as starting materials.

EXAMPLE 41

80 mg (0.38 mmol) of example 11B are dissolved in 1 ml of absolute ethanol, and 262 mg (1.52 mmol) of tetrahydropyran-4-yl-acetic acid ethyl ester and 45.1 mg (1.10 mmol) of sodium hydride (60% suspension in mineral oil) are added. The reaction mixture was heated to 150 ℃ in a microwave oven for 40 minutes. Cooled to 20 ℃ and the solvent was evaporated under reduced pressure. The residue was treated with water (10 ml), acidified with HCl (10% in water) and extracted twice with dichloromethane (2 ml). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 65 mg (53.7%) of the product as a white solid.

HPLC-MS (method Grad _ C8_ NH)₄COOH)：R_t: 1.89 minutes

MS (ESI positive): 319(M + H) M/z⁺。

The following examples are prepared analogously to example 41, using their corresponding pyrazolyl-carboxamides and esters as starting materials.

Example 133

6- (2-ethyl-butyl) -1- (tetrahydro-pyran-4-yl) -1, 5-dihydro-pyrazolo [3,4-d ] pyrimidin-4-one

Example 11B (0.1 g, 0.48 mmol) and polyphosphoric acid (1.0 g) were mixed together and 2- (trifluoromethoxy) phenylacetic acid (248 mg, 1.9 mmol) was added. The mixture was heated to 120 ℃ over a period of 16 hours. The temperature was reduced to 20 ℃ and the pH was adjusted to 7 by adding ammonia (30% solution in water). The aqueous phase was extracted with dichloromethane (2 × 20 ml) and the organic phase was dried over sodium sulfate. The crude mixture was purified by flash chromatography. Eluent: hexane/ethyl acetate 40/60. 23.5 mg (16%) was obtained as a white solid.

HPLC-MS(1E)R_t: 6.77 minutes

MS (APCI positive): m/z 305(M + H)⁺

The following examples are prepared analogously to example 133, using their corresponding carboxylic acids as starting materials for the synthesis:

example 145, racemic mixture

106 mg (0.47 mmol) of example 12V are mixed with 4 ml of ethyl acetate and 0.5 ml of dimethylformamide, and 51 mg (0.61 mmol) of 3.4-dihydro-2H-pyran and 88.4 mg (0.51 mmol) of p-toluenesulfonic acid are added. The reaction mixture was heated to 60 ℃ and stirred for 2 hours. After cooling to room temperature, ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate and with saturated sodium chloride. The organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC-MS. Yield 31.5 mg (21.7%).

MS (APCI positive): 312(M + H) M/z⁺

HPLC-MS (method 2F) R_t: 8.26 minutes

The following examples were synthesized in a similar manner to the preparation of example 145, using the corresponding pyrazolopyrimidinones as starting materials.

Example 148

160 mg (470 mmol) of example 12E are dissolved in 10 ml of methanol and 350 mg of Raney nickel are added. The reaction mixture was hydrogenated at room temperature for 6 hours, filtered, and the solvent was evaporated under reduced pressure. 100 mg (65%) of product are obtained.

HPLC-MS (method 1): r_t: 0.95 minute

MS (ESI positive): 324(M + H) M/z

The following examples were synthesized analogously to the preparation of example 148, using the corresponding N-oxides as starting materials.

Example 151

62 mg (150 mmol) of example 13B are dissolved in 4 ml of dichloromethane and 22.5. mu.l (300 mmol) of acetyl chloride and 42. mu.l (300 mmol) of triethylamine are added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 28 mg (55%) of product were obtained.

HPLC-MS (method 1): r_t: 1.18 minutes

MS (ESI positive): 344(M + H) is given M/z⁺

The following examples were synthesized in a similar manner to the preparation of example 151, using the corresponding starting materials. It is obvious that when acetyl chloride has not been introduced as an acylating agent for all compounds, other acylating agents are used, for example commercially available methoxy chloroformates, substituted or unsubstituted carbamoyl chlorides, unsubstituted or substituted phenoxyformyl chlorides, unsubstituted or substituted benzoyl chlorides.

Example 191, racemic mixture

60 mg (0.2 mmol) of example 13C are dissolved in 5 ml of xylene and 57 mg (0.2 mmol) of 2, 2, 2-trifluoroethyl trichloromethane sulfonate are added dropwise. The reaction mixture was heated to 140 ℃ and stirred for 5 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 24.8 mg (32%) of product were obtained.

HPLC-MS (method 1): r_t: 1.45 minutes

MS (ESI positive): 384(M + H) M/z⁺

The following examples were prepared analogously to example 191, using their corresponding starting materials for the synthesis.

Example 194 racemic mixture

HPLC-MS (method 1): r_t: 0.93 min

MS (ESI positive): 288(M + H)⁺

Example 195

330 mg (0.82 mmol) of example 12A are dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid are added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 240 mg (70%) of product are obtained.

HPLC-MS (method 1): r_t: 0.96 min

MS (ESI positive): 302(M + H) M/z⁺

The following examples were synthesized analogously to the preparation of example 195, using their corresponding Boc-protected amines as starting materials.

Example 207, racemic mixture

50 mg (120 mmol) of example 13A are dissolved in 5 ml of dichloromethane and 15 mg (500 mmol) of formaldehyde are added. The reaction mixture was stirred at room temperature for 1 hour. 15 μ l (260 mmol) of acetic acid and 35 mg (160 mmol) of sodium triacetoxyborohydride are added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile). 34 mg (65%) of product are obtained.

HPLC-MS (method 1): r_t: 0.99 min

MS (ESI positive): 302(M + H) M/z⁺

The following examples were prepared in analogy to example 207, using the corresponding amines as starting materials for the synthesis

Example 219

100 mg (0.26 mmol) of example 5, 95 mg (0.77 mmol) of pyridine-3-boronic acid (boronic acid), 310. mu.l (2.41. mu.l) were introduced under argonMmol) aqueous sodium carbonate solution (2M), 5 ml of twoAlkane and 20 mg (0.02 mmol) tetrakis- (triphenylphosphine) palladium (0) were mixed. The reaction mixture was heated to 140 ℃ in a microwave oven for 35 minutes. After cooling to room temperature, the reaction mixture was filtered over celite. The filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC. 82 mg (83%) of product are obtained.

HPLC-MS (method 1): r_t: 1.00 minute

MS (ESI positive): 388(M + H)⁺

The following examples were synthesized analogously to the preparation of example 219, using the corresponding boronic acids as starting materials.

Example 231

In a vial under an inert atmosphere, 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) were added. Then dimethylformamide (5 ml), degassed beforehand, was added, followed by N-N' -dimethylethylenediamine (47.87. mu.l; 0.45 mmol). The reaction mixture was heated to 120 ℃ for three hours. Then, the suspension was filtered over a pad of celite; celite was washed with DMF. The volume of the organic phase was reduced under reduced pressure, then a saturated solution of ammonium chloride was added, followed by the addition of ethyl acetate. The phases were separated and the organic phase was washed with brine and then dried. The crude product was purified by SPE cartridge and the resulting product was further purified by SPE Stratosphere "PL-THIOL MP" to completely remove the copper salt. The solid obtained was triturated with diethyl ether. 15.5 mg of the desired compound were obtained (yield ═ 9.2%).

HPLC-MS (method 1E hydro): r_t: 7.80 minutes

MS (ESI positive): m/z 377(M + H)⁺

Example 232

Example 53(100 mg, 0.298 mmol) and hydroxylamine (0.073 ml, 1.19 mmol) were mixed together in dry ethanol (4 ml) in a 50 ml flask. The reaction mixture was refluxed for 3 hours and then worked up. The solvent was then removed under reduced pressure to yield 120 mg (content 70%, 0.228 mmol) of N-hydroxy-2- [ 4-oxo-1- (tetrahydro-pyran-4-yl) -4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-6-ylmethyl ] -benzamidine as a solid, which was used as such in the next step.

N-hydroxy-2- [ 4-oxo-1- (tetrahydro-pyran-4-yl) -4, 5-dihydro-1H-pyrazolo [3,4-d ] pyrimidin-6-ylmethyl ] -benzamidine (120 mg, content 70%; 0.228 mmol) was suspended in trimethyl orthoacetate (5 ml) and acetic acid (1 ml) was added; the mixture was heated to 100 ℃ for one hour. The mixture was cooled at room temperature and precipitation of the solid was found. Evaporating the filtrate under reduced pressure; the crude product was purified by flash chromatography. The product was then triturated with ether. 24 mg of the desired compound were obtained (26.6% yield).

HPLC/MS (method 1E hydro)

MS (ESI positive): 393(M + H)⁺

Example 233

Example 12X (250 mg, 1.14 mmol) was dissolved in 20 ml of hot methanol. Alumina (neutral) was added, then the solvent was removed to give a white powder which was transferred to a2 ml Wheaton vial; 5, 6-Dihydro-2H-pyran-2-one (5, 6-Dihydro-2H-pyran-2-oxo) was added followed by DMF (1 ml) and the vial was closed tightly. The suspension was heated to 80 ℃ with orbital shaking during 4 days. Then, the reaction was filtered and the alumina was washed with methanol, ethyl acetate and dichloromethane; the organic solutions were combined and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography.

Eluent: (gradient, starting with n-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 were obtained as a solid (19.3%).

HPLC-MS (method 2F): r_t: 9.06 minutes

MS (ESI positive): 317(M + H) with M/z⁺

Example 234

Example 53(160 mg, content 80%, 0.38 mmol) and hydrazine hydrate (0.186 ml, 3.81 mmol) were mixed together in dry ethanol (4 ml) in a 25 ml flask. The reaction mixture was refluxed for 6 hours and then worked up. The solvent was removed under reduced pressure to obtain 200 mg (content 70%, 0.38 mmol) of the desired substance, which was used as such in the next step. This material (200 mg, 70% content, 0.38 mmol) was suspended in trimethyl orthoacetate (6 ml). Acetic acid (0.6 ml) was added and the solution was heated to 80 ℃ for 30 minutes. Trimethyl orthoacetate and acetic acid were removed under reduced pressure and the crude product was partitioned between water and dichloromethane. The organic phase was dried and the crude product was purified by flash chromatography. (gradient: start with dichloromethane/methanol 98/2 and end with dichloromethane/methanol 90/10). The product was further purified by trituration with ether. 8 mg of the desired compound (4%) were obtained.

HPLC-MS (method 1E hydro): r_t: 6.82 minutes

MS (ESI positive): 392(M + H) M/z⁺

Example 235

22 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 was evaporated and the residue was chromatographed by HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile) to give 15.7 mg (71%) of the product.

HPLC-MS (method 1): r_t: 1.35 minutes

MS (ESI positive): m/z 369(M + H)⁺

Example 236

100 mg (73%, 0.251 mmol) of example 40-5 are dissolved in 2 ml of acetic acid and 30. mu.l (0.35 mmol) of hydrogen peroxide solution in water (35%) are added. The mixture was stirred for 3 hours and acetonitrile/water was added. The mixture was 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): r_t: 0.88 min

MS (ESI positive): 307(M + H) M/z⁺

Example 237

100 mg (73%, 0.251 mmol) of example 40-5 are dissolved in 2 ml of acetic acid and 200. mu.l (2.33 mmol) of hydrogen peroxide solution in water (35%) are added. The mixture was stirred for 3 days and acetonitrile/water was added. The mixture was chromatographed by HPLC (eluent A: water + 0.13% TFA, eluent B: acetonitrile) to give 21.5 mg (27%) of the product.

HPLC-MS (method 1): r_t: 0.93 min

MS (ESI positive): m/z 323(M + H)⁺

Claims

1. Compounds of the general formula I

Wherein

HcSelected from tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl;

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

wherein these radicals areThe group 2-pyridyl-, 3-pyridyl-, 4-pyridyl-may be optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, HO-, oxo, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, C_3-7-cycloalkyl-O-, C_3-7-cycloalkyl-C_1-3-alkyl-O-, F₃CO-and F₃C-，

and if R is²Is connected toHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, and selected from: h-, C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6Alkyl-, phenyl-CO-, phenyl-O-CO-and (C)_1-6-alkyl groups)₂N-CO-，

Wherein the above-mentioned group C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6Alkyl-, phenyl-CO-, phenyl-O-CO-and (C)_1-6-alkyl groups)₂N-CO-may be optionally substituted independently of each other with one or more fluoro substituents;

R³selected from H-, HO-and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more of fluoro, chloro, bromo and HO-;

x is 0, 1, 2, 3 or 4;

y is 0 or 1;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein

HcSelected from piperidinyl and pyrrolidinyl;

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

wherein these groups 2-pyridyl-, 3-pyridyl-, 4-pyridyl-may be optionally substituted by one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo,NC-、C_1-6-alkyl-O-, C_1-6-alkyl-, F₃CO-and F₃C-，

R³selected from H-, hydroxy and C_1-6-alkyl-O-, wherein C_1-6-alkyl-O-may be optionally substituted by one or more fluoro, chloro, bromo or HO-;

x is 0 or 1;

y is 0 or 1;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 1, wherein

Hc is selected from 3-piperidinyl or 4-piperidinyl and 3-pyrrolidinyl;

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

wherein these groups 2-pyridyl-, 3-pyridyl-, 4-pyridyl-may be optionally substituted by one or more substituents independently from each other selected from the group consisting of: NC-C_1-6-alkyl-O-, C_1-6-alkyl-, F₃CO-、F₃C-, fluorine, chlorine and bromine;

and if R is²Connection ofToHcWhen the ring member is a nitrogen atom, then R is²With any other R²Independently of each other, and selected from: h-, C_1-6alkyl-CO-, C_1-6alkyl-O-CO-, C_1-6Alkyl-, phenyl-CO-, phenyl-O-CO-and (C)_1-6-alkyl groups)₂N-CO-，

R⁴and R⁵Are all H;

x is 0 or 1;

y＝0；

and pharmaceutically acceptable salts thereof.

4. The compound of claim 1, wherein

HcSelected from tetrahydropyranyl and tetrahydrofuranyl;

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

wherein these groups 2-pyridyl-, 3-pyridyl-, 4-pyridyl-may be optionally substituted by one or more substituents independently from each other selected from the group consisting of: fluorine, chlorine, bromine, iodine, oxo, NC-, C_1-6-alkyl-O-, C_1-6-alkyl-, F₃CO-and F₃C-，

wherein C is as defined above_1-6-the alkyl-groups may be optionally substituted independently of each other by one or more fluoro substituents;

x is independent of any y: x is 0 or 1;

y is independent of any x: y is 0 or 1;

and pharmaceutically acceptable salts thereof.

5. The compound of claim 1, wherein

HcSelected from 3-tetrahydropyranyl or 4-tetrahydropyranyl and 3-tetrahydrofuranyl;

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

x is 0 or 1;

y is 0 or 1;

and pharmaceutically acceptable salts thereof.

6. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein

R¹selected from 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,

wherein these groups 2-pyridyl-, 3-pyridyl-, 4-pyridyl-may be optionally substituted by one or more substituents independently from each other selected from the group consisting of: NC-C_1-6-alkyl-O-, C_1-6-alkyl-, F₃CO-、F₃C. Fluorine, chlorine and bromine;

R⁴and R⁵Are all H

x＝0；

y＝0。

7. The compound of any one of claims 1-6 and pharmaceutically acceptable salts thereof, wherein

R⁴And R⁵Is H;

x＝0；

y＝0。

8. the compound of claim 1 selected from the group consisting of:

and a tautomer of each thereof, or a pharmaceutically acceptable salt of each thereof.

9. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

10. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

11. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

12. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

13. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

14. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

15. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

16. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

17. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

18. A compound according to claim 1, characterized in that it has the formula:

and tautomers thereof, or pharmaceutically acceptable salts thereof.

19. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of a disease treatable by inhibition of PDE 9.

20. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment, amelioration or prevention of cognitive impairment associated with perception, concentration, cognition, learning or memory.

21. Use according to claim 20, characterized in that the medicament is for the treatment, amelioration or prevention of cognitive impairment associated with: age-related memory impairment of learning, age-related memory loss, vascular dementia, head trauma, stroke, dementia following stroke, post-traumatic dementia, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration, dementia with corticobasal degeneration, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jakob disease, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis.

22. The use of claim 21, wherein the dementia with frontal lobe degeneration includes pick's syndrome, parkinson's disease, and progressive nuclear palsy.

23. Use according to claim 20, characterized in that the medicament is for the treatment, amelioration or prevention of impaired concentration in children with learning and memory problems.

24. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for the treatment of alzheimer's disease.

25. Use of a compound according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of cognitive impairment due to alzheimer's disease.

26. Use of a compound according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of sleep disorders, bipolar disorders, metabolic syndrome, or diseases of the testis, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

27. The use of claim 26, wherein the metabolic syndrome comprises obesity, diabetes, hyperglycemia, dyslipidemia, and impaired glucose tolerance.

28. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, and a pharmaceutical carrier.

29. A combination of a compound according to any one of claims 1 to 18 and another agent useful for the treatment of alzheimer's disease.