WO2015197188A1

WO2015197188A1 - Pyrazolyl-based carboxamides as crac inhibitors

Info

Publication number: WO2015197188A1
Application number: PCT/EP2015/001268
Authority: WO
Inventors: Stefanie RITTER; Sonja Nordhoff; Felix VOSS; Sebastian Wachten; Stefan OBERBÖRSCH
Original assignee: Grünenthal GmbH
Priority date: 2014-06-24
Filing date: 2015-06-24
Publication date: 2015-12-30

Abstract

The invention relates to pyrazolyl-based carboxamide compounds useful as ICRAC inhibitors, to pharmaceutical compositions containing these compounds and to these compounds for the use in the treatment and/or prophylaxis of diseases and/or disorders, in particular inflammatory diseases and/or inflammatory disorders.

Description

201S/001268

Pyrazolyl-based carboxamides VI

FIELD OF THE INVENTION

The invention relates to pyrazol-3-yl-carboxylic acid amides bearing an partially unsaturated heterocycloalkyl substituent, useful for inhibition of the Calcium Release Activated Calcium channel (CRAC) and hence for inhibition of the Calcium Release Activated Calcium current (ICRAC), to pharmaceutical compositions containing these compounds and also to these compounds for the use in immuosupression and in the treatment and/or prophylaxis of conditions, diseases and/or disorders, in particular immune disorders, inflammatory conditions and allergic diseases.

BACKGROUND OF THE INVENTION

Calcium-conducting channels in the plasma membrane can appear very diverse (Parekh & Putney 2005) including voltage-gated ion channels (VOC's), receptor-operated ion channels (ROC's), but also store- operated channels (SOCs; Putney, 1986) that are activated in response to a decrease of the intraluminal Calcium concentration within i.e. the endoplasmic reticulum (ER). The latter have been demonstrated to serve as the main Calcium entry mechanisms in non-excitable cells.

Amongst the distinct SOCs, the CRAC current (ICRAC) is certainly characterized best and displays biophysical features such as high selectivity for Calcium ions, low conductance, and inward rectification (Hoth & Penner, 1992; Hoth & Penner, 1993; Parekh & Penner, 1997; Lepple-Wienhues & Cahalan, 1996; Kerschbaum & Cahalan, 1999). There's substantial evidence that the channels conducting CRAC predominantly rely on two proteins, Orail and Stiml (Roos et al., 2005; Feske et ai, 2006; Peinelt et al., 2006). Orail constitutes the channel pore within the plasma membrane (Prakriya et al., 2006; Vig et al., 2006), whereas Stiml has been demonstrated to function as the sensor of the luminal Calcium concentration (Liou et al, 2005; Zhang et al., 2006).

In a physiological setting, ICRAC is activated in response to the engagement of cell-surface receptors that positively couple to phospholipase C (PLC). PLC increases the concentration of the soluble messenger inositol-1 ,4,5-trisphosphate (IP3), which opens ER membrane-resident IP3-receptors. Thus, IP3 triggers the release of Calcium from internal stores resulting in a drop of the luminal Calcium concentration (Lewis, 1999), which is sensed by Stiml The Stiml molecule undergoes conformational changes inducing clustering with other Stiml molecules just underneath the plasma membrane. At these sites, Stiml can open the Orail pore by bridging the ER-PM gap with its C-terminal tail (Zhang et al., 2005; Luik et al., 2006; Soboloff et al. 2006, Wu et al. 2006; Li et al., 2007).

The above described process serves in signaling pathways of immune cells such as lymphocytes and mast cells. I.e. the activation of antigen or Fc receptors stimulates the release of Calcium from intracellular stores, and subsequent activation of ICRAC that impacts on downstream processes such as gene expression and cytokine release (Feske, 2007; Gwack et al., 2007; Oh-hora & Rao 2008).

The major contribution ICRAC provides to these signaling events has been convincingly demonstrated in patients suffering from severe combined immunodeficiency (SCID) due to a defect in T-cell activation. T cells and fibroblasts from these patients exhibited a strong attenuation of store-operated Calcium entry carried by ICRAC (Feske et al., 2006). This suggests CRAC channel modulators to serve as treatment in disease states caused by activated inflammatory cells. The activation of antigen or Fc receptors stimulates the release of Calcium from intracellular stores and subsequent, sustained activation of ICRAC. Calcium carried by ICRAC activates calcineurin (CaN), which dephosphorylates the transcription factor NFAT. Upon dephosphorylation, NFAT shuttles into the nucleus and regulates gene expression in various ways depending on the nature of the stimulus as well as on the cell/tissue type.

NFAT participates in the transactivation of cytokine genes that regulate T-cell proliferation and other genes that control immune responses. Taking into account that the expression of cytokines such as IL-2, IL-4, IL-5, IL-8, IL-13, tumor necrosis factor alpha (TNFa), granulocyte colony-stimulating factor (G-CSF), and gamma-interferon (INFy) is prone to be controlled via transcriptional elements for NFAT, the impact of the ICRAC/CaN/NFAT signaling pathway on pro-inflammatory processes becomes apparent. The inhibition of this pathway has been demonstrated to be efficacious in patients by the use of drugs such as CsA and FK506, which act by inhibiting CaN.

A hallmark of ICRAC signaling in immune cells is that downstream processes such as gene expression rely on sustained Calcium entry rather than transient signals. However, Calcium entry is essential for other processes that can be independent of CaN/NFAT. Direct, Calcium-mediated release of substances (degranulation) such as histamine, heparin, and TNFa occur in i.e. mast cells, and are of rather acute nature. On the molecular level, this already points towards a differentiation potential for ICRAC blockers from calcineurin inhibitors.

Recent findings suggest that CRAC channel modulators can serve as treatment in disease states caused by the activation of inflammatory cells without side effects observed under treatments with i.e. steroids. Such diseases may include but are not limited to asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases such as multiple sclerosis, and disorders of the immune system.

U.S. Pat. No. 6,958,339, WO 2009/076454 A1 , WO 2009/089305 A1 , and WO 2010/122089 A1 each disclose a series of pyrazole carboxylic acid amide derivatives that are said to possess CRAC channel inhibitory activity which are believed to be useful in the treatment of allergic, inflammatory or autoimmune diseases. Other small molecules possessing structurally different scaffolds as ICRAC inhibtors are known for instance from WO2005/009539, WO 2007/087427 A2 and WO 2007/087441 A2. ICRAC inhibitors bearing a tetrahydropyranyl moiety are known from WO 2007/087443, WO 2008/063504, WO 2009/017831 , WO 2010/039236 and WO 2012/064808. Pyrazole carboxylic acid amides as biologically active compounds are also known in the art, for instance from EP 1 176140 B1 , US 2006/0100208 A1 , WO 2005/016877 A2, WO 2006/076202 A1 , WO 2007/002559 A1 , WO 2007/024744 A2, WO 2009/01 1850 A2 and WO 2009/027393 A2. 8

SUMMARY OF THE INVENTION

The present invention describes a new class of small molecule that is useful for the inhibition of the calcium release activated calcium channel current (thereafter ICRAC inhibitors).

It was therefore an object of the invention to provide novel compounds, preferably having advantages over the prior-art compounds. The compounds should be suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by CRAC channels.

An enhanced solubility in aqueous media, such as water, blood, plasma or water-based formulations, may lead to an improvement of pharmacodynamics and pharmacokinetic properties of small molecules as potentially active ingredients in medical compositions. It is therefore another object of the invention to provide novel compounds, useful as ICRAC inhibitors that possess an improved solubility in aqueous media.

This object is achieved by the subject matter described herein. In particular, the incorporation of partially unsaturated 5- or 6-membered heterocycloalkyl moieties B has been found to have beneficial effects on the solubility in aqueous media of the compounds according to general formula (1).

It has surprisingly been found that the compounds of general formula (I), as given below, display potent inhibitory activity against to CRAC channels and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by CRAC channels.

A first aspect of the present invention therefore relates to a compound of general formula (I),

wherein

R¹ denotes H, C _-4-alkyl or C₃.₆-cycloalkyl;

R² denotes H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl; OH; O-C^-alkyl; OCH₃; OCF₃; OCF₂H;

OCFH₂; NH₂; N(H)C,^-alkyl; N(C_M-alkyl)₂;

A represents phenyl or a 5- or 6-membered heteroaryl,

B represents a partially unsaturated 5- or 6-membered heterocycloalkyl;

wherein said phenyl, said 5- or 6-membered heteroaryl and said partially unsaturated 5- or 6- membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted; wherein said C_1-4-alkyl independently is linear or branched, and

wherein said Ci_₄-alkyl and C₃.₆-cycloalkyl each independently is unsubstituted or mono- or polysubstituted;

optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate thereof. 01268

DETAILED DESCRIPTION

The term "single stereoisomer" preferably means in the sense of the present invention an individual enantiomer or diastereomer. The term "mixture of stereoisomers" means in the sense of this invention mixtures of enantiomers and/or diastereomers in any mixing ratio including racemates.

The term "physiologically acceptable salt" preferably comprises in the sense of this invention a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.

A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid which is physiologically acceptable - in particular when used in human beings and/or other mammals.

A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention as an anion with at least one preferably inorganic cation, which is physiologically acceptable - in particular when used in human beings and/or other mammals.

The term "physiologically acceptable solvate" preferably comprises in the sense of this invention an adduct of one compound according to the present invention and/or a physiologically acceptable salt of at least one compound according to the present invention with distinct molecular equivalents of one solvent or more solvents.

The term "C^-alkyl" comprises in the sense of this invention acyclic saturated, aliphatic hydrocarbon residues, which can be branched or unbranched and also unsubstituted or mono- or polysubstituted, which contain 1 to 4 carbon atoms respectively. Preferred C-|. -alkyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl and tert. -butyl.

The term "C₃.₆-cycloalkyl" means for the purposes of this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms, wherein the hydrocarbons in each case can be unsubstituted or mono- or polysubstituted. The C₃.₆-cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the C₃.₆-cycloalkyl. Preferred C₃.₆-cycloalkyls are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, in particular cyclopropyl.

The terms "3 to 7 membered heterocycloalkyl" or "3-7-membered heterocycloalkyl" mean for the purposes of this invention heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members, in which in each case at least one, if appropriate also two, three or four carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)₂, N, NH and NCd-e-alkyl) such as N(CH₃), wherein the ring members can be unsubstituted or mono- or polysubstituted. The 3 to 7 15 001268 membered heterocycloalkyi can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyi, heterocycloalkyi, aryl or heteroaryl residues, which in each case can in turn be unsubstituted or mono- or polysubstituted. The heterocycloalkyi can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloalkyi if not indicated otherwise.

The term "partially unsaturated 5- or 6-membered heterocycloalkyi" means for the purposes of this invention a heterocycloaliphatic unsaturated (but not aromatic) residue having 5 or 6 ring members, in which in each case at least one, if appropriate also two or three carbon atoms are replaced by a hetero- atom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)₂, N, NH and N(Ci.₆-alkyl) such as N(CH₃), wherein the ring members can be unsubstituted or mono- or polysubstituted. The "partially unsaturated 5- or 6-membered heterocycloalkyi" can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloalkyi if not indicated otherwise. Preferably, partially unsaturated 5- or 6-membered heterocycloalkyls are selected from tetrahydropyridinyl, tetrahydropyranyl, dihydropyrrolidinyl and dihydrofuranyl, preferably from tetrahydropyridinyl.

The term "aryl" means for the purpose of this invention aromatic hydrocarbons containing 6 to 14 carbon atoms. Each aryl residue can be unsubstituted or mono- or polysubstituted, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl. The aryl can be bound to the superordinate general structure via any desired and possible ring member of the aryl residue. The aryl residues can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with a cycloalkyi, heterocycloalkyi, aryl or heteroaryl residue, which can in turn be unsubstituted or mono- or polysubstituted. Examples of condensed aryl residues are benzodioxolanyl and benzodioxanyl. Preferably, aryl is selected from the group consisting of phenyl, 1 - naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can be respectively unsubstituted or mono- or polysubstituted. A particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.

The term "5- to 6-membered heteroaryl" for the purpose of this invention represents a 5 or 6-membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heteroaryl, the substituents can be the same or different and be in any desired and possible position of the heteroaryl. The binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise. It is preferable for the heteroaryl residue to be selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzo- thiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxa- diazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl. 8

In relation to the terms "C_1-4-alkyl, C₃-₆-cycloalkyl, 3 to 7 membered heterocycloalkyi and partially unsaturated 5- or 6-membered heterocycloalkyi", the term "mono- or polysubstituted" refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F; CI; CN; CF₃; CF₂H; CFH₂; CF₂CI; CFCI₂; d-₄-alkyl; C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyi; aryl; heteroaryl; aryl, heteroaryl, C₃-₆-cycloalkyl or 3 to 7 membered heterocycloalkyi, each connected via a d.₄-alkyl; C(=0)-(C₁.₄-alkyl); C(=0)-(C₃.₆-cycloalkyl); C(=0)-(3 to 7 membered heterocycloalkyi); C(=0)-(aryl); C(=0)-(heteroaryl); C(=0)OH; C(=0)-0(C₁.₄-alkyl); C(=0)-0(C₃.₆-cyclo- alkyl); C(=0)-0(3 to 7 membered heterocycloalkyi); C(=0)-0(aryl); C(=0)-0(heteroaryl); C(=0)-NH₂; C(=0)-N(H)(C₁.₄-alkyl); C(=0)-N(H)( C₃.₆-cycloalkyl); C(=0)-N(H)(3 to 7 membered heterocycloalkyi); C(=0)-N(H)(aryl); C(=0)-N(H)(heteroaryl); C(=0)-N(C₁.₄-alkyl)₂; C(=0)-N(C₁.₄-alkyl)(C₃_₆-cycloalkyl); C(=0)-N(C₁.₄-alkyl)(3 to 7 membered heterocycloalkyi); C(=0)-N(C₁.₄-alkyl)(aryl); C(=0)-N(C₁.₄-alkyl)- (heteroaryl); OH; =0; 0-(d-₄-alkyl); 0-(C₃-₆-cycloalkyl); 0-(3 to 7 membered heterocyclic residue); O-

(aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂CI; OCFCI₂; 0-C(=0)-(C₁.₄-alkyl); 0-C(=0)-(C₃.₆-cyclo- alkyl); 0-C(=0)-(3 to 7 membered heterocycloalkyi); 0-C(=0)-(aryl); C(=0)-(heteroaryl); 0-C(=0)-NH₂; O- C(=0)-N(H)(d-₄-alkyl); 0-C(=0)-N(H)(C₃.₆-cycloalkyl); 0-C(=0)-N(H)(3 to 7 membered heterocycloalkyi); 0-C(=0)-N(H)(aryl); 0-C(=0)-N(H)(heteroaryl); 0-C(=0)-N(d.₄-alkyl)₂; 0-C(=0)-N(d-₄-alkyl)(C₃.₆-cyclo- alkyl); 0-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); 0-C(=0)-N(d,₄-alkyl)(aryl); 0-C(=0)- N(d.₄-alkyl)(heteroaryl); NH₂; N(H)(d-₄-alkyl); N(H)(C₃.₆-cycloalkyl); N(H)(3 to 7 membered heterocycloalkyi); N(H)(aryl); N(H)(heteroaryl); N(d.₄-alkyl)₂; N(d.₄-alkyl)(C₃.₆-cycloalkyl); N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)(aryl); N(d_₄-alkyl)(heteroaryl); N(H)-C(=0)-(d.₄-alkyl); N(H)- C(=0)-(C₃.₆-cycloalkyl); N(H)-C(=0)-(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-(aryl); N(H)-C(=0)- (heteroaryl); N(C₁.₄-alkyl)-C(=0)-(Ci.₄-alkyl); N(C₁.₄-alkyl)-C(=0)-(C₃.₆-cycloalkyl); N(C₁.₄-alkyl)-C(=0)-(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-(aryl); N(Ci_₄-alkyl)-C(=0)-(heteroaryl); N(H)-

N(H)-S(=0)₂-(C₃.₆-cycloalkyl); N(H)-S(=0)₂-(3 to 7 membered heterocycloalkyi); N(H)- S(=0)₂-(aryl); N(H)-S(=0)₂-(heteroaryl); N(C,.₄-alkyl)-S(=0)₂-(C₁.₄-alkyl); N(d.₄-alkyl)-S(=0)₂-(C₃.₆-cyclo- alkyl); N(d.₄-alkyl)-S(=0)₂-(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-S(=0)₂-(aryl); N(d.₄-alkyl)- S(=0)₂-(heteroaryl); N(H)-C(=0)-0(C₁.₄-alkyl); N(H)-C(=0)-0(C₃.₆-cycloalkyl); N(H)-C(=0)-0(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-0(aryl); N(H)-C(=0)-0(heteroaryl); N(d.₄-alkyl)-C(=0)-0(d.₄- alkyl); N(d.₄-alkyl)-C(=0)-0(C₃.₆-cycloalkyl); N(C₁.₄-alkyl)-C(=0)-0(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-0(aryl); N(d.₄-alkyl)-C(=0)-0(heteroaryl); N(H)-C(=0)-NH₂; N(H)-C(=0)-N(H)(d.₄- alkyl); N(H)-C(=0)-N(H)(C₃.₆-cycloalkyl); N(H)-C(=0)-N(H)(3 to 7 membered heterocycloalkyi); N(H)- C(=0)-N(H)(aryl); N(H)-C(=0)-N(H)(heteroaryl);

alkyl); N(d.₄-alkyl)-C(=0)-N(H)(C₃._e-cycloalkyl);

to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-N(H)(aryl); N(d.₄-alkyl)-C(=0)-N(H)(heteroaryl); N(H)-C(=0)-N(d.₄-alkyl)₂; N(H)-C(=0)-N(d.₄-alkyl)(C₃.₆-cycloalkyl); N(H)-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-N(d.₄-alkyl)(aryl); N(H)-C(=0)-N(Ci.₄-alkyl)(heteroaryl); N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl)₂; N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl)(C₃.₆-cycloalkyl); N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(C₁.₄-alkyl)-C(=0)-N(C₁.₄-alkyl)(aryl); Nid^-alk -Ci^- iCt^-alkylKheteroaryl); S- (C₃.₆-cycloalkyl); S-(3 to 7 membered heterocycloalkyi); S-(aryl); S-(heteroaryl); SCF₃; S(=0)₂OH; S(=0)- (d-4-alkyl); S(=0)-(C₃-₆-cycloalkyl); S(=0)-(3 to 7 membered heterocycloalkyl); S(=0)-(aryl); S(=0)- (heteroaryl); S(=0)₂-(C₁.₄-alkyl); S(=0)₂-(C₃-₆-cycloalkyl); S(=0)₂-(3 to 7 membered heterocycloalkyl); S(=0)₂-(aryl); S(=0)₂-(heteroaryl);

S(=0)₂-0(3 to 7 membered heterocycloalkyl); S(=0)₂-0(aryl); S(=0)₂-0(heteroaryl); S(=0)₂-N(H)(d.₄-alkyl); S(=0)₂- N(H)(C₃.6-cycloalkyl); S(=0)₂-N(H)(3 to 7 membered heterocycloalkyl); S(=0)₂-N(H)(aryl); S(=0)₂-

N(H)(heteroaryl); S(=0)₂-N(C₁.₄-alkyl)₂; S(=0)₂-N(C₁.₄-alkyl)(C₃-₆-cycloalkyl); S(=0)₂-N(C₁.₄-alkyl)(3 to 7 membered heterocycloalkyl); S(=0)₂-N(C₁.₄-alkyl)(aryl); S(=0)₂-N(C₁.₄-alkyl)(heteroaryl).

The term "polysubstituted" with respect to polysubstituted residues and groups includes the polysub- stitution of these residues and groups either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of CF₃, CH₂CF₃ or 1 ,1 -difluorocyclohexyl, or at various points, as in the case of CH(OH)-CH=CH-CHCI₂ or 1 -chloro-3-fluorocyclohexyl. A substituent can if appropriate for its part in turn be mono- or polysubstituted. The multiple substitution can be carried out using the same or using different substituents.

Preferred substituents of "C₁_₄-alkyl, C₃.₆-cycloalkyl, 3 to 7 membered heterocycloalkyl and partially unsaturated 5- or 6-membered heterocycloalkyl" are selected from the group consisting of F; CI; CF₃; CN; =0; C,.₄-alkyl; C(=0)-H; C(=0)-C₁.₄-alkyl; C(=0)-OH; C(=0)-0-C₁.₄-alkyl; C(=0)-NH₂; C(=0)-N(H)(d.₄- alkyl); C(=0)-N(C₁.₄-alkyl)₂; OH; 0-d.₄-alkyl; 0-C(=0)-d.₄-alkyl; OCF₃; NH₂; N(H)(d.₄-alkyl); N(d.₄- alkyl)₂; N(H)-C(=0)-d.₄-alkyl; N(H)-S(=0)₂-d.₄-alkyl; N(d.₄-alkyl)-S(=0)₂-d.₄-alkyl; N(H)-C(=0)-NH₂;

alkyl)-S(=0)₂-N(C₁.₄-alkyl)₂; SH; SCF₃; S-d.₄-alkyl; S(=0)₂ C_1-4-alkyl; S(=0)₂OH; S(=0)₂0-d.₄-alkyl and S(=0)₂-NH₂; S(=0)₂-N(H)(C₁.₄-alkyl); and S(=0)₂-N(d.₄-alkyl)₂.

Particularly preferred substituents of "d_₄-alkyl" are selected from the group consisting of F; CI; CF₃; C(=0)-OH; C(=0)-NH₂; C(=0)-N(H)(C₁.₄-alkyl); C(=0)-N(d.₄-alkyl)₂; OH; O-d-4-alkyl; NH₂; N(H)(d.₄- alkyl); N(d.₄-alkyl)₂; N(H)-C(=0)-d_₄-alkyl; N(H)-S(=0)₂-d.₄-alkyl; N(C₁.₄-alkyl)-S(=0)₂-C₁.₄-alkyl; N(H)- S(=0)₂-NH₂; S(=0)₂-d_₄-alkyl, S(=0)₂-NH₂, S(=0)₂-N(d.₄-alkyl)₂ and S(=0)₂-N(H)(d.₄-alkyl).

Particularly preferred substituents of "C₃_₆-cycloalkyl, 3 to 7 membered heterocycloalkyl and partially unsaturated 5- or 6-membered heterocycloalkyl" are selected from the group consisting of F; CI; CF₃; CN; =0; d.₄-alkyl; C0₂H; C(=0)0-d.₄-alkyl; CONH₂; C(=0)N(H)d.₄-alkyl; C(=0)N(C₁.₄-alkyl)₂; OH; 0-C_1-4- alkyl; OCF₃; 0-C(=0)-d.₄-alkyl; NH₂; NH-d.₄-alkyl; N(d.₄-alkyl)₂; NH-C(=0)-d.₄-alkyl; NCC_!^-alkyl)- C(=0)-d.₄-alkyl; S(=0)₂-d.₄-alkyl; S(=0)₂-NH₂, S(=0)₂-N(d.₄-alkyl)₂ and S(=0)₂-N(H)-d.₄-alkyl.

In relation to the terms "phenyl", "aryl" and "heteroaryl", the term "mono- or polysubstituted" refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F; CI; Br; N0₂; CN; CF₃; CF₂H; CFH₂; CF₂CI; CFCI₂; d.₄-alkyl; C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; aryl; heteroaryl; aryl, heteroaryl, C₃._e-cycloalkyl or 3 to 7 membered hetero- cycloalkyi, each connected via a d.₄-alkyl; C(=0)H; C(=0)-( d-4-alkyl); C(=0)-(C₃.₆-cycloalkyl); C(=0)-(3 to 7 membered heterocycloalkyi); C(=0)-(aryl); C(=0)-(heteroaryl); C(=0)OH; C(=0)-0(C₁.₄-alkyl); C(=0)- 0(C₃-₆-cycloalkyl); C(=0)-0(3 to 7 membered heterocycloalkyi); C(=0)-0(aryl); C(=0)-0(heteroaryl);

C(=0)-N(H)(3 to 7 membered hetero- cycloalkyi); C(=0)-N(H)(aryl); C(=0)-N(H)(heteroaryl); C(=0)-N(C₁.₄-alkyl)₂; C(=0)-N(C₁.₄-alkyl)(C₃.₆- cycloalkyl); C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); C(=0)-N(C₁.₄-alkyl)(aryl); C(=0)-N(d.

₄- alkyl)(heteroaryl); OH; =0; 0-(d.₄-alkyl); 0-(C₃.₆-cycloalkyl); 0-(3 to 7 membered heterocycloalkyi); O- (aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂CI; OCFCI₂; 0-C(=0)-(d.₄-alkyl); 0-C(=0)-(C₃.₆-cyclo- alkyl); 0-C(=0)-(3 to 7 membered heterocycloalkyi); 0-C(=0)-(aryl); C(=0)-(heteroaryl); 0-C(=0)-NH₂; O- C(=0)-N(H)(d.₄-alkyl); 0-C(=0)-N(H)(C₃.₆-cycloalkyl); 0-C(=0)-N(H)(3 to 7 membered heterocycloalkyi); 0-C(=0)-N(H)(aryl); 0-C(=0)-N(H)(heteroaryl); 0-C(=0)-N(d.₄-alkyl)₂; 0-C(=0)-N(d.₄-alkyl)(C₃.₆-cyclo- alkyl); 0-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); 0-C(=0)-N(d.₄-alkyl)(aryl); 0-C(=0)- N(d.₄-alkyl)(heteroaryl); NH₂; N(H)(d.₄-alkyl); N(H)(C₃.₆-cycloalkyl); N(H)(3 to 7 membered heterocycloalkyi); N(H)(aryl); N(H)(heteroaryl); N(d.₄-alkyl)₂; N(d.₄-alkyl)(C₃.₆-cycloalkyl); N(d-₄-alkyl)(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl) (aryl); N(d-₄-alkyl)(heteroaryl); N(H)-C(=0)-(C_1-4-alkyl); N(H)- C(=0)-(C₃.₆-cycloalkyl); N(H)-C(=0)-(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-(aryl); N(H)-C(=0)- (heteroaryl); N(C₁.₄-alkyl)-C(=0)-(C₁.₄-alkyl); N(d.₄-alkyl)-C(=0)-(C₃.₆-cycloalkyl); N(d.₄-alkyl)-C(=0)-(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-(aryl); N(d^-alkyl)-C(=0)-(heteroaryl); N(H)- S(=0)₂-(d.₄-alkyl); N(H)-S(=0)₂-(C₃.₆-cycloalkyl); N(H)-S(=0)₂-(3 to 7 membered heterocycloalkyi); N(H)- S(=0)₂-(aryl); N(H)-S(=0)₂-(heteroaryl); N(d.₄-alkyl)-S(=0)₂-(d.₄-alkyl); N(d.₄-alkyl)-S(=0)₂-(C₃._e-cyclo- alkyl); N(d.₄-alkyl)-S(=0)₂-(3 to 7 membered heterocycloalkyi); N(C₁.₄-alkyl)-S(=0)₂-(aryl); N(d.₄-alkyl)- S(=0)₂-(heteroaryl); N(H)-C(=0)-0(d.₄-alkyl); N(H)-C(=0)-0(C₃-₆-cycloalkyl); N(H)-C(=0)-0(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-0(aryl); N(H)-C(=0)-O(heteroaryl); N(C₁.₄-alkyl)-C(=0)-0(C_1-4- alkyl); N(C₁.₄-alkyl)-C(=0)-0(C₃.₆-cycloalkyl); N(C₁.₄-alkyl)-C(=0)-0(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-0(aryl); N(d.₄-alkyl)-C(=0)-0(heteroaryl); N(H)-C(=0)-NH₂; N(H)-C(=0)-N(H)(d_₄- alkyl); N(H)-C(=0)-N(H)(C₃.₆-cycloalkyl); N(H)-C(=0)-N(H)(3 to 7 membered heterocycloalkyi); N(H)- C(=0)-N(H)(aryl); N(H)-C(=0)-N(H)(heteroaryl); N(C₁.₄-alkyl)-C(=0)-NH₂; N(d.₄-alkyl)-C(=0)-N(H)(d.₄- alkyl); N(C₁.₄-alkyl)-C(=0)-N(H)(C₃.₆-cycloalkyl); N(d.₄-alkyl)-C(=0)-N(H)(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-N(H)(aryl); N(d.₄-alkyl)-C(=0)-N(H)(heteroaryl); N(H)-C(=0)-N(C₁.₄-alkyl)₂; N(H)-C(=0)-N(d.₄-alkyl)(C₃.₆-cycloalkyl); N(H)-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(H)-C(=0)-N(d.₄-alkyl)(aryl); N(H)-C(=0)-N(C₁.₄-alkyl) (heteroaryl); N(d-₄-alkyl)-C(=0)-N(d.₄-alkyl)₂; N(C₁.₄-alkyl)-C(=0)-N(C₁.₄-alkyl)(C₃.6-cycloalkyl); N(Ci.₄-alkyl)-C(=0)-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl)(aryl); N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl) heteroaryl); SH;

5- (d.₄-alkyl); S-(C₃.₆-cycloalkyl); S-(3 to 7 membered heterocycloalkyi); S-(aryl); S-(heteroaryl); SCF₃; S(=0)₂OH; S(=0)-(C₁.₄-alkyl); S(=0)-(C₃.₆-cycloalkyl); S(=0)-(3 to 7 membered heterocycloalkyi); S(=0)-

(aryl); S(=0)-(heteroaryl); S(=0)₂-(C₁.₄-alkyl); S(=0)₂-(C₃.₆-cycloalkyl); S(=0)₂-(3 to 7 membered heterocycloalkyi); S(=0)₂-(aryl); S(=0)₂-(heteroaryl); S(=0)₂-0(C_1-4-alkyl); S(=0)₂-0(C₃.₆-cycloalkyl); S(=0)₂-0(3 to 7 membered heterocycloalkyi); S(=0)₂-0(aryl); S(=0)₂-0(heteroaryl); S(=0)₂-N(H)(C₁.₄-alkyl); S(=0)₂- N(H)(C₃.₆-cycloalkyl); S(=0)₂-N(H)(3 to 7 membered heterocycloalkyi); S(=0)₂-N(H)(aryl); S(=0)₂-N(H)- (heteroaryl); S(=0)₂-N(d.₄-alkyl)₂; S(=0)₂-N(d.₄-alkyl)(C₃.₆-cycloalkyl); S(=0)₂-N(d.₄-alkyl)(3 to 7 membered heterocycloalkyi); S(=0)₂-N(d_ -alkyl)(aryl); S(=0)₂-N(C,.₄-alkyl)(heteroaryl). Preferred substituents of "aryl", "phenyl" and "heteroaryl" are selected from the group consisting of F; CI; CF₃; CN; d.₄-alkyl; C(=0)-OH; C(=0)-0-C₁.₄-alkyl; CO-NH₂; C(=0)-N(H)C₁.₄-alkyl; C(=0)-N(C₁.₄-alkyl)₂; OH; 0-C,.₄-alkyl; 0-C(=0)-d.₄-alkyl; OCF₃; OCHF₂; OCH₂F; NH₂; N(H)d.₄-alkyl; N(C₁.₄-alkyl)₂; N(H)- C(=0)-C₁.₄-alkyl; N(C_l.₄-alkyl)-C(=0)C₁.₄-alkyl; N(H)-S(=0)₂-C₁.₄-alkyl; N(C₁.₄-alkyl)-S(=0)₂(C₁.₄-alkyl); N(H)C(=0)NH₂; N(H)C(=0)-N(H)d.₄-alkyl; N(H)-C(=0)-N(C₁.₄-alkyl)₂; N(d.₄-alkyl)-C(=0)-NH₂; N(d.₄- alkyl)C(=0)-N(H)d.₄-alkyl; N(d_₄-alkyl)-C(=0)-N(d.₄-alkyl)₂; S(=0)₂d.₄-alkyl; S(=0)₂-NH₂; S(=0)₂- N(H)d.₄-alkyl and S(=0)₂-N(d.₄-alkyl)₂.

The compounds according to the invention are defined by substituents, for example by R^A, R^B and R^c (1 ^sl generation substituents) which are for their part if appropriate themselves substituted (2^nd generation substituents). Depending on the definition, these substituents of the substituents can for their part be resub- stituted (3^rd generation substituents). If, for example, R^A = a d-₄-alkyl (1 ^st generation substituent), then the d-4-alkyl can for its part be substituted, for example with a N(H)d.₄-alkyl (2^nd generation substituent). This produces the functional group R^A = (d_₄-alkyl-N(H)-d.₄-alkyl). The N(H)-d.₄-alkyl can then for its part be resubstituted, for example with CI (3^rd generation substituent). Overall, this produces the functional group R^A = d^-alkyl-N^-C^-alkyl-CI, wherein the d.₄-alkyl of the NtHJC^-alkyl is substituted by CI.

However, in a preferred embodiment, the 3^rd generation substituents may not be resubstituted, i.e. there are then no 4^th generation substituents.

In another preferred embodiment, the 2^nd generation substituents may not be resubstituted, i.e. there are then not even any 3^rd generation substituents. In other words, in this embodiment, in the case of general formula (I), for example, the functional groups for R¹ to R³ can each if appropriate be substituted;

however, the respective substituents may then for their part not be resubstituted.

If a residue occurs multiply within a molecule, then this residue can have respectively different meanings for various substituents: if, for example, both R^A and R^B denote a 3 to 7 membered heterocycloalkyi, then the 3 to 7 membered heterocycloalkyi can e.g. represent morpholinyl for R^A and can represent piperazinyl for R^B.

Within the scope of the present invention, the symbol

used in the formulae denotes a link of a corresponding residue to the respective superordinate general structure.

It has been found that tetrahydropyridinyl moieties are preferred partially unsaturated 5- or 6-membered heterocycloalkyi B in formula (I). Particularly, 1 ,2,5,6-tetrahydro-pyridin-3-yl residues have been found to be suitable as partially unsaturated 5- or 6-membered heterocycloalkyi B in general formula (I). 01268

In one embodiment of the invention, the compound according to the present invention is characterized in that the compound has general formula (la),

wherein

R³ is selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃-₆-cycloalkyl and 3 to 7 membered heterocycloalkyl;

R⁴ is -L-B\

wherein L is bond, CH₂ or C(=0); and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; Ci. -alkyl; C₃.₆- cycloalkyl; 3 to 7 membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl and OC^-alkyl;

wherein said Ci.₄-alkyl independently is linear or branched, and

wherein said phenyl and said 5- or 6-membered heteroaryl is unsubstituted or mono- or polysubstituted;

wherein said d-4-alkyl, C₃-₆-cycloalkyl and 3 to 7 membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted;

and wherein R¹, R² and A are defined as before,

optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate thereof.

In another embodiment of the invention, the compound according general formula (la) is characterized in that R³ is selected from the group consisting of H; CF₃; CF₂H; CH₂F; d.₄-alkyl and C₃_₆-cycloalkyl;

Preferably R³ is selected from the group consisting of H; CF₃; CF₂H; CH₂F; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl. More preferably, R³ is selected from the group consisting of H; CH₃ and cyclopropyl.

The compound according to general formula (la) is characterized in that L is bond, CH₂ or C(=0).

In another embodiment of the invention, the compound according to general formula (la) is characterized in that L is bond or C(=0).

In yet another embodiment of the invention, the compound according to general formula (la) is characterized in that

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; C^-alkyl; C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl and OC^-alkyl;

wherein said C - -alkyl independently is linear or branched, and

wherein said phenyl and said 5- or 6-membered heteroaryl is unsubstituted or mono- or polysubstituted; wherein said C^-alkyl, C₃.₆-cycloalkyl and 3 to 7 membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted;

Preferably, B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; pyridinyl; pyrimidinyl; pyrazinyl; thiazolyl; oxazolyl; imidazolyl; OCH₃; OCH₂CH₃; OCH₂CH₂CH₃; OCH(CH₃)₂; OCH₂CH₂CH₂CH₃; OCH₂CH(CH₃)₂ and OC(CH₃)₃,

wherein said phenyl, said pyridiny, said pyrimidinyl, said pyrazinyl, said thiazolyl and said oxazolyl is unsubstituted or mono- or independently polysubstituted with F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)CH₃ or N(CH₃)₂.

More preferably, B' is selected from the group consisting of phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl and 2-imidazolyl

wherein said phenyl, said pyridinyl, said pyrimidinyl, said pyrazinyl, said thiazolyl and said oxazolyl is unsubstituted or mono- or independently polysubstituted with F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)CH₃ or N(CH₃)₂.

Even more preferably, B' is selected from the group consisting of phenyl, 2-pyridinyl, 3-pyridinyl, 4- pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl and 2-imidazolyl

wherein said phenyl, said pyridinyl, said pyrimidinyl, said pyrazinyl, said thiazolyl and said oxazolyl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃.

In yet another embodiment of the invention, the compound according to general formula (la) is characterized in that L is bond and

B' is selected from the group consisting of phenyl or 5- or 6-membered heteroaryl,

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted or mono- or independently polysubstituted with F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)CH₃ or N(CH₃)₂.

Preferably, the compound according general formula (la) is characterized in that L is bond and

wherein said 5- or 6-membered heteroaryl is selected from the group consisting of 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- oxazolyl, 4-oxazolyl and 5-oxazolyl,

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃.

In yet another embodiment of the invention, the compound according to general formula (la) is characterized in that L is C(=0) and B' is selected from the group consisting of phenyl or 5- or 6-membered heteroaryl,

Preferably, the compound according to general formula (la) is characterized in that L is C(=0) and

wherein said 5- or 6-membered heteroaryl is selected from the group consisting of 2-pyridinyl, 3-pyridinyl,

4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl and 2-imidazolylwherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃;

CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃.

In yet another embodiment of the invention, the compound according to general formula (la) is characterized in that L is C(=0) and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; OCH₃;

OCH₂CH₃; OCH₂CH₂CH₃; OCH(CH₃)₂; OCH₂CH₂CH₂CH₃; OCH₂CH(CH₃)₂ and OC(CH₃)₃.

Preferably, the compound according to general formula (la) is characterized in that L is C(=0) and B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂;

CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl and cyclohexyl.

In another embodiment of the invention, the compound according to the present invention is

characterized in that R¹ denotes H; Ci_₄-alkyl, unsubstituted or mono- or polysubstituted or C₃.₆-cycloalkyl, unsubstituted or mono- or polysubstituted.

Preferably, R¹ is selected from the group consisting of unsubstituted C^-alkyl or unsubstituted cyclopropyl. More preferably, R¹ is selected from the group consisting of CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl. Even more preferably, R is selected from CH₃ and CH₂CH₃. Most preferably, R¹ denotes CH₃.

In another embodiment of the invention, the compound according to the present invention is characterized in that R² is selected from the group consisting of H; F; CI; unsubstituted C_1-4-alkyl and unsubstituted cyclopropyl.

Preferably, R² is selected from the group consisting of H, CI, CH₃ and CH₂CH₃. Most preferably, R² denotes H.

characterized in that A represents phenyl or 6-membered heteroaryl, each unsubstituted or mono- or polysubstituted. 8

Preferably, A represents phenyl or a 6-membered heteroaryl, containing one 1 , 2 or 3 N-atoms, wherein said phenyl or 6-membered heteroaryl is unsubstituted or mono- or polysubstituted. More preferably, A represents phenyl or a 6-membered heteroaryl, containing one 1 , 2 or 3 N-atoms, wherein said phenyl or 6-membered heteroaryl is unsubstituted or mono- or polysubstituted with substituent(s) independently selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4- alkyl; C_3-e-cycloalkyl; OH; 0-C - -alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)C₁.₄-alkyl; N(C_1-4-alkyl)₂;

NH(C=0)(C₁.₄-alkyl).

Even more preferably, A is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl,

each unsubstituted or mono- or polysubstituted with substituent(s) independently selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C_3-6-cycloalkyl; OH; O-C^-alkyl, OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d.₄-alkyl; N(d_₄-alkyl)₂ and NH(C=0)(C₁.₄-alkyl).

Still more preferably, A is phenyl or pyridinyl,

each unsubstituted or mono- or polysubstituted with substituent(s) independently selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆-cycloalkyl; OH; O-C^-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d.₄-alkyl; N(C,.₄-alkyl)₂ and NH(C=0)(d.₄-alkyl).

A particularly preferred embodiment of the first aspect of the invention is characterized by a certain substitution pattern of the structural element A to enhance affinity to the CRAC channel. Particularly preferred is therefore a compound according the first aspect of the invention, that is characterized in that A has substructure (II),

wherein

K¹ stands for N or CR⁸; K² stands for N or CR⁸ and K³ stands for N or CR⁸;

R⁷ independently is selected from F; CI; Br; CN; CF₃; CF₂H; CFH₂; d.₄-alkyl; C₃.₆-cycloalkyl;, and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl; C₃.₆-cycloalkyl;OH; O-C^-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)C₁.₄-alkyl; N(d-₄-alkyl)₂; NH(C=0)(d.₄-alkyl).

More preferred is a compound according the first aspect of the invention, that is characterized in that A is selected from the group consisting of the substructures (I la) to (llh): 8

(lie), (llh), wherein

R⁷ is selected from F; CI; Br; CN; CF₃; CF₂H; CFH₂; d.₄-alkyl or C₃.₆-cycloalkyl;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; d-4-alkyl; C₃.₆-cycloalkyl; OH; 0-d.₄-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d.₄-alkyl; N(C_1-4-alkyl)₂ and NH(C=0)(C₁.₄-alkyl).

More preferably, R⁷ is independently selected from F; CI; CF₃; CF₂H; CFH₂ and C,.₄-alkyl. Even more preferably, R⁷ is independently selected from F; CI and CH₃. Most preferably, R⁷ is selected from F. More preferably, each R⁸ is independently selected from the group consisting of H; F; CI; CN; CF₃; d_ - alkyl; 0-Ci.₄-alkyl; OCF₃; OCF₂H or OCFH₂. Even more preferably, each R⁸ is independently selected from H; F; CI; CF₃; OCF₃; CH₃ and OCH₃.

Another particularly preferred embodiment of the first aspect of the invention is characterized in that A is selected from the group consisting of

2,6-difluorophenyl, 5-fluoro-4-methyl-pyridin-3-yl, 1 -methyl-pyrazol-5-yl, 3-fluoro-pyridin-4-yl, 2,4-dimethyl- pyridin-5-yl, 3,5-difluoro-pyridin-4-yl, 3,5-difluoro-pyridin-2-yl, 3,5-dichloro-pyridin-4-yl; 3-chloro-5-fluoro- pyridin-4-yl; 3-fluoro-pyridin-2-yl, 4-fluoro-5-methyl-pyridin-3-yl, 2,6-difluoro-4-methoxyphenyl,2-chloro- phenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl and 2,4-difluorophenyl.

In yet another embodiment of the first aspect of the invention is characterized in that the compound according to general formula (I) is represented by general formula (la),

(la),

wherein

R is selected from the group consisting of CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

R² is selected from the group consisting of H, CI, CH₃ and CH₂CH₃; 15 001268

R³ is selected from the group consisting of H; CF₃; CF₂H; CH₂F; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl; R⁴ is -L-B',

wherein L is bond or C(=0); and

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃;

CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃;

or

L is C(=0);

and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃;

CH₂CH₂CH₃; CH(CH₃)₂; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl amd cyclohexyl;

and

A is selected from the group consisting of substructures (Ha) to (lid);

wherein

R⁷ is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H and OCFH₂;

Preferably, the compound according to general formula (I) is represented by general formula (la), wherein R¹ denotes CH₃;

R² denotes H;

wherein L is bond or C(=0); and

CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃;

or L is C(=0);

and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl amd cyclohexyl;

and

A is selected from the group consisting of substructures (I la) or (lib),

wherein R⁷ is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃;

CH(CH₃)₂ and cyclopropyl;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H and OCFH₂.

R² denotes H;

R³ is selected from the group consisting of H; CH₃; and cyclopropyl;

R⁴ is -L-B',

wherein L is bond or C(=0); and

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃; and

A is selected from the group consisting of substructures (I la) or (lib),

wherein R⁷ is selected from the group consisting of F; CI and CH₃;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; OCH₃; OCF₃; OCF₂H and OCFH₂.

Even preferably, the compound according to general formula (I) is represented by general formula (la), wherein

R¹ denotes CH₃;

R² denotes H;

R³ is selected from the group consisting of H; CH₃; and cyclopropyl;

R⁴ is -L-B',

wherein L is C(=0); and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃; CH(CH₃)₂; CH2CH2CH2CH3; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl amd cyclohexyl;

and

A is selected from the group consisting of substructures (lla) or (lib), wherein R⁷ is selected from the group consisting of F; CI and CH₃;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; OCH₃; OCF₃; OCF₂H and OCFH₂. More preferably, the compound according to general formula (I) is represented by general formula (la), wherein

R¹ denotes CH₃;

R² denotes H;

R³ is selected from the group consisting of H; CH₃; and cyclopropyl;

R⁴ is -L-B',

wherein L is bond or C(=0); and

wherein said 5- or 6-membered heteroaryl is selected from the group consisting of 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2- pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl and 5- oxazolyl,

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und mono- or independently polysubstituted with F; CI; CN; CF₃; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃ or OCF₃;

and

A is selected from the group consisting of 2,6-difluorophenyl, 3,5-difluoro-pyridin-4-yl, 3,5-dichloro- pyridin-4-yl; 3-chloro-5-fluoro-pyridin-4-yl and 3-fluoro-pyridin-2-yl. Even more preferably, the compound according to general formula (I) is represented by general formula (la), wherein

R¹ denotes CH₃;

R² denotes H;

R³ is selected from the group consisting of H; CH₃; and cyclopropyl;

R⁴ is -L-B',

wherein L is C(=0); and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH₂CH₂CH₃;

CH(CH₃)₂; CH₂CH₂CH₂CH₃; CH₂CH(CH₃)₂; C(CH₃)₃; cyclopropyl; cyclobutyl; cyclopentyl amd cyclohexyl;

and

A is selected from the group consisting of 2,6-difluorophenyl, 3,5-difluoro-pyridin-4-yl, 3,5-dichloro- pyridin-4-yl; 3-chloro-5-fluoro-pyridin-4-yl and 3-fluoro-pyridin-2-yl.

In a particular preferred embodiment of the present invention, the compound according to the present invention is selected from the group, consisting of

₁ N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 - methyl-1 H-pyrazole-3-carboxylic acid amide 01268

2 N-(3,5-Difluoro-pyridin-4-yl)-5-[1-(3-fluoro^^

methyl-1 H-pyrazole-3-carboxylic acid amide

2 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2-meth^

3-yl]-1 H-pyrazole-3-carboxylic acid amide

₄ N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-[4-methyl-1 -(2-methyl-pyrimidin-4-yl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₅ N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -oxazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

g N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -oxazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇ N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2-methyl-2H-tetrazol-5-yl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₈ N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-[4-methyl-1 -(2-methyl-2H-tetrazol-5-yl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₉ N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -(1-methyl-1 H-tetrazol-5-yl)-1 ,2,5,6-tetra ydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

_{1 0} 5-(4-Cyclopropyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

^ 4-Chloro-N-(2,6-difluoro-phenyl)-5-[1-(3-fl^

yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

₁2 4-Chloro-N-(3,5-difluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydrc-pyridin- 3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

_{1 3} 5-(4-Cyclopropyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 - methyl-1 H-pyrazole-3-carboxylic acid amide

₁₄ N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 ,4- dimethyl-1 H-pyrazole-3-carboxylic acid amide

₁₅ N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(3-fluoro^^

dimethyl-1 H-pyrazole-3-carboxylic acid amide

_{1 6} N-(3-Fluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 ,4- dimethyl-1 H-pyrazole-3-carboxylic acid amide

_{1 7} N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -pyrazin-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

8 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -pyrimidin-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

9 N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(3-methoxy-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]- 1 -methyl-1 H-pyrazole-3-carboxylic acid amide

0 N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(5-fluoro-pyrimidin-4-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin methyl-1 H-pyrazole-3-carboxylic acid amide

1 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 ^ pyrazole-3-carboxylic acid amide

2 N-(2,4-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide 15 001268 3 N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

4 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridine-3-carbonyl)-1 ,2,5,6-tetrahydrc-pyridin-3- yl]-1 H-pyrazole-3-carboxylic acid amide

5 5-[1 -(Cyclopropanecarbonyl)-4-methyl-1 ,2,5,6-tetrahydro^yridin-3-yl]-N-(2,6-difluoro-phenyl)-1 - methyl-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(py

yl]-1 H-pyrazole-3-carboxylic acid amide

j N-(2,6-Difluoro^henyl)-1 -methyl-5-[4-methyl-1 -(pyridine-2-carbonyl)-1 ,2,5,6-tetrahydro-pyridin-3- yl]-1 H-pyrazole-3-carboxylic acid amide

8 N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -(1 -methyl-1 H-imidazole-2-carbonyl)-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2-methyl-propanoyl)-1 ,2,5,6-tetra ydro-pyridin-3- yl]-1 H-pyrazole-3-carboxylic acid amide

0 N-(2,6-Difluoro-phenyl)-5-[1 -(2-fluoro-benzoyl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 -methyl- 1 H-pyrazole-3-carboxylic acid amide

1 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-met yl-1 -(4-met yl-thiazole-2-carbonyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

2 5-[1 -(2,6-Difluoro-benzoyl)-4-methyl-1 ,2,5,6-tetra ydro-pyridin-3-yl]-N-(2,6-difluoro-phenyl)-1 - methyl-1 H-pyrazole-3-carboxylic acid amide

3 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2,2,2-trifluoro-acetyl)-1 ,2,5,6-tetrahydro-pyridin-^^ yl]-1 H-pyrazole-3-carboxylic acid amide

4 N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridine-2-carbonyl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin 1 -methyl-1 H-pyrazole-3-carboxylic acid amide

5 5-(1 -Acetyl-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H-pyrazole- 3-carboxylic acid amide

6 5-(1 -Benzyl-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H-pyrazole- 3-carboxylic acid amide

7 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridin-2-yl-methyl)-1 ,2,5,6 etrahydro-pyridin^ 1 H-pyrazole-3-carboxylic acid amide

8 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridin-4-yl-methyl)-1 ,2,5,6-tetrahydro-pyridin-3-yl]- 1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-5-[1 -[(2-fluorophe^

methyl-1 H-pyrazole-3-carboxylic acid amide

0 N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -(pyridin-3-yl-methyl)-1 ,2,5,6-tetrahydro-pyridin-3-yl]- 1 H-pyrazole-3-carboxylic acid amide

1 N-(2,6-Difluoro-phenyl)-5-[1 -[(2,6-difluoro

1 -methyl-1 H-pyrazole-3-carboxylic acid amide

2 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -[(3-methyl-3H-imidazol-4-yl)-methyl]-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

3 N-(2,6-Difluoro-phenyl)-5-[1 -[(2,4-dimethyl-thiazol-5-yl)-methyl]-4-methyl-1 ,2,5,6-tetrahydro-pyrid 3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 - ^^

pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

N-(2,6-Difluoro-phenyl)-5-[1 -[(3-fluoro^yridin-2-yl)-methyl]^-methyl-1 ,2,5,6-tetrahydro-pyri 1 -methyl-1 H-pyrazole-3-carboxylic acid amide

N-(2-Chloro-6-methyl-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydrc-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

N-(5-Chloro-2-methyl-phenyl)-1 -methyl-5-(4-methyl-1 hiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-met yl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-phenyl-1 H-pyrazole-3- carboxylic acid amide

N-(4-Methoxyphenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2^6-tetrahydro^^

phenyl]-1 H-pyrazole-3-carboxylic acid amide

N-(2-Methoxyphenyl)-1-methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

N-(2,4-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 _l2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

N-(2-Cyano-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,64etrahydro^yridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

N-(3,5-Dimet oxy-phenyl)-1-methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-1 ^ pyrazole-3-carboxylic acid amide

N-(2,4-Dichlorophenyl)-1 -methyl-5-(4-methyl-1 hiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

N-(2,6-Difluoro-4-methoxy-phenyl)-1 -methyl-5-(4-methyl-14hiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2,6-Difluoro-p enyl)-1-met yl-5-(4-met yl-14 iazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl pyrazole-3-carboxylic acid amide

N-(2-Fluoro-6-methyl-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyM-thiazol-2-yl-1 ,2,5,6-tetrahydro^^

1 H-pyrazole-3-carboxylic acid amide

N-(2-Fluorophenyl)-1-methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-1 H-pyrazole- 3-carboxylic acid amide

N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl^ pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-N-pyridin^-yl-1 H-pyrazole-3- carboxylic acid amide

N-(3,5-Difluoro^yridin-4-yl)-1 -methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridi pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-o-tolyl-1 H-pyrazole-3- carboxylic acid amide 8

₆₅ N-(3-Fluoro-5HTiethyl-pyridin-4-yl)-1-methyl-5-(4-methy^

yl)-1H-pyrazole-3-carboxylic acid amide

₆₆ N-(2-Chloro-6-methyl-phenyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridi

pyrazole-3-carboxylic acid amide

₆₇ N-(5-Chloro-2-methyl-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxyiic acid amide

gg 1- ethyl-N^henyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro^yridin-3-yl)-1H-pyrazole-3-carbox acid amide

₆g N-(4^ethoxyphenyl)-1-methyl-5-(1-thiazol-2-yl-1,2^6-tetrah

carboxylic acid amide

₇₀ 1-Methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro^yridin-3-yl)-N-[2-(trifluoromethyloxy)^heny

pyrazole-3-carboxylic acid amide

₇₁ 1-Methyl-N-o-tolyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro^yridin-3-yl)-1H-pyrazole-3-carboxyN acid amide

₇₂ N-(2-Methoxyphenyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6 etrahydro^yridin-3-yl)-1H^yraz

carboxylic acid amide

₇₃ N-(2,4-Difluoro^henyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,64etrahydro-pyridin-3-yl)-1H-pyrazol^

carboxylic acid amide

₇₄ N-(2-Cyano^henyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6 etrahydro-pyridin-3-yl)-1H^yrazo^

carboxylic acid amide

₇₅ N-(2^-Dichlorophenyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H^yra^

carboxylic acid amide

₇₆ N-(2,6-Difluoro-4-methoxy-phenyl)-1-methyl-5-(1-thiazol-2-yl-1,2_l5,6-tetrahydro-pyridi

pyrazole-3-carboxylic acid amide

_?7 N-(2,6-Difluoro-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H-pyrazole-3- carboxylic acid amide

₇₈ N-(2-Fluoro-6-methyl-phenyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H- pyrazole-3-carboxylic acid amide

?₉ 1-Methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-N-[2-(trifluoro^

pyrazole-3-carboxylic acid amide

8₀ N-(2-Fluorophenyl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazole-3- carboxylic acid amide

g₁ N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazole-3 carboxylic acid amide

₈₂ 1-Methyl-N-pyridin-4-yl-5-(1-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazole

acid amide

₈₃ N-(3,5-Dimethoxy-phenyl)-1-methyl-5-(1 hiazol-2-yl-1,2,5,6-tetrahydro^yridin-3-yl)-1H-pyrazole-3- carboxylic acid amide

optionally in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate thereof. 68

The compounds according to the present invention are useful for calcium release-activated calcium (CRAC) channel regulation, preferably for use in CRAC channel inhibition.

The substances according to the invention hence act, for example, on the CRAC channel relevant in connection with various diseases, so that they are suitable as a pharmacologically active compound in pharamceutical compositions.

In another aspect of the present invention, the invention therefore also provides pharmaceutical compositions, containing at least one compound according to the invention and optionally one or more suitable, pharmaceutically compatible auxiliaries and/or, if appropriate, one or more further pharmacologically active compounds.

The pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.

The pharmaceutical composition according to the invention may be found as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.

In addition to at least one compound according to the invention, if appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemate or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio, or if appropriate in the form of a corresponding salt or respectively in the form of a corresponding solvate, the pharmaceutical composition according to the invention conventionally contains further physiologically compatible pharmaceutical auxiliaries which can for example be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders. Likewise the compound according to the invention, if appropriate in the form of one of its pure stereoisomers, or if appropriate in the form of a corresponding salt or respectively in the form of a corresponding solvate, may also incorporated into the pharmaceutical composition in the form of a prodrug, which releases the active pharmacological agent through normal metabolic processes. The selection of the physiologically compatible auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes. Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application. The compounds according to the invention used in the pharmaceutical composition according to the invention in a repository in dissolved form or in a plaster, agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective compound according to the invention also in a delayed manner.

CRAC channels are believed to be involved in a variety of diseases or disorders in mammals such as humans. These include inflammatory disorders, allergic disorders and disorders of the immune system as well as disorders involving platelet or thrombotic activity.

Examples of allergic disorders include: rhinitis (such as allergic rhinitis), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect sting reactions, latex allergy, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis and food allergies.

Examples of inflammatory disorders include: inflammatory lung disorders (such as asthma, acute respiratory distress syndrome, acute lung injury, chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis); chronic inflammatory disorders of joints (such as arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption); inflammatory bowel diseases (such as Barrett's oesophagus, ileitis, ulcerative colitis and Crohn's disease); inflammatory disorders of the eye (such as corneal dystrophy, trachoma, uveitis, sympathetic ophthalmitis and endophthalmitis); inflammatory diseases of the kidney (such as glomerulonephritis, nephrosis, nephritic syndrome and IgA nephropathy); inflammatory diseases of the liver; inflammatory disorders of the skin (such as psoriasis and eczema); inflammatory diseases of the central nervous system (such as chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimers disease, infectious meningitis, enceophalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis); inflammatory diseases of the muscle (such as polymyositis and polymyalgia rheumatica); inflammatory diseases of the heart (such as myocarditis and cardiomyopathy, ischemic heart disease, myocardial infarction and atherosclerosis); other diseases with significant inflammatory components, including tuberculosis; leprosy; allogeneic or xenogeneic transplantation (cells, stem cells, tissues or organs) graft rejection, graft-versus-host disease; pre-eclampsia; endometriosis, chronic liver failure; brain and spinal cord trauma and cancer; and conditions where systemic inflammation of the body may also be present (such as septic shock, hemorrhagic or anaphylactic shock or shock induced by cancer chemotherapy).

Examples of disorders of the immune system include: autoimmune diseases of the central and peripheral nervous system (such as multiple sclerosis, myasthenia gravis, Eaton-Lambert Myasthenic syndrome); autoimmune neurophathies (such as Guillain-Barre); autoimmune diseases of the eye (such as autoimmune uveitis); autoimmune diseases of the blood (such as autoimmune haemoiytic anemia, pernicious anemia, and autoimmune thrombocytopenia e.g. Idiopathic Thrombocytopaenic Purpura); autoimmune diseases of the vasculature (such as temporal arteritis, anti-phospholipid syndrome, vasculitides e.g. Wegener's granulomatosis and Behcet's disease); autoimmune diseases of the skin (such as alopecia areata, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, bullous pemphigoid and vitiligo); autoimmune disease of the gastrointestinal tract (such as coeliac disease, Crohn's disease, ulcerative colitis, primary biliary cirrhosis and autoimmune hepatitis); autoimmune disorders of the endocrine glands (such 01268 as Typel diabetes mellitus, autoimmune thyroiditis, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis); autoimmune disorder of the adrenal gland (such as Addisons disease); autoimmune disorders of the exocrine glands (such as Sjogren's syndrome); and multi system autoimmune diseases including connective tissue and musculoskeletal system diseases (such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis), spondyloarthropathies (such as ankylosing spondylitis and psoriatic arthritis).

Examples of conditions where anti-platelet or anti-thrombotic activity is useful for treatment and/or prophylaxis include: ischemic heart disease, myocardial infarction, cerebrovascular accident (stroke) and vascular thrombosis (venous, arterial and intra-cardiac).

Further diseases or conditions which may be treated by the compounds of the invention include conditions where mast cells and basophils contribute to pathology, such as mast cell leukaemia, mastocytosis, endometriosis and basophil leukaemia.

The term "disorders and/or diseases which are mediated, at least in part, by CRAC channels", is intended to include each of or all of the above disease states.

It is believed that the compounds of formula (I), having ICRAC inhibitory activity, may inhibit mast cell degranulation and/or inhibit T cell activation. Compounds having such activity may be particularly suitable for the treatment of a number of diseases and conditions, for example asthma; allergies such as allergic rhinitis; and nasal polyposis.

Due to the key role of calcium in the regulation of cellular proliferation in general, calcium channel in- hibitors could act as cytostatic agents which may be useful in the treatment of dieseases of abnormal cellular proliferation, e.g. benign prostatic hyperplasia or familial adenomatosis polyposis. The compounds may be useful for the treatment of a variety of cancers as hematopoietic tumors of lymphoid lineage (such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma and Hodgkin's lymphoma); hematopoietic tumors of myeloid lineage (such as acute and chronic myelgenous leukemias);carcinomas, tumors of mesenchymal origin; tumors of the central and peripheral nervous system (such as astrocytoma and neuroblastoma) and other tumors such as melanoma and sarcoma.

Another aspect of the present invention therefore relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of a or more disorder and/or disease, selected from the group consisting of glomerulonephritis, uveitis, hepatic diseases or disorders, especially hepatitis, renal diseases or disorders, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), multiple sclerosis, inflammatory bowel disease (IBD), especially Barrett's oesophagus, ileitis, ulcerative colitis or Crohn's Disease, vasculitis, dermatitis, dermatomyositis, atopic dermatitis, scleroderma, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, osteoporosis, eczema, psoriasis, allogeneic or xenogeneic transplantation (cells, stem cells, tissues or organs) graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, hepatitis, primary biliary cirrhosis, allergic conjunctivitis, asthma, nasal polyposis; Sjogren's syndrome, cancer and other proliferative diseases, and autoimmune diseases or disorders.

Another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of autoimmune diseases, in particular rheumatoid arthritis and psoriatic arthritis.

Another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of inflammatory disorders of the skin, in particular psoriasis as and/or eczema, most preferably psoriasis.

Another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of chronic inflammatory disorders of the joints, in particular arthritis, rheumatoid arthritis and/or osteoarthritis arthritis, most preferably rheumatoid arthritis (RA).

Yet another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of inflammatory bowel diseases, in particular Barrett's oesophagus, ileitis, ulcerative colitis and Crohn's disease.

Yet another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of allogeneic or xenogeneic transplantation graft rejection, in particluar transplantation grafts of cells, stem cells, tissues and/or organs.

Yet another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of autoimmune diseases of the central and peripheral nervous system, in particular multiple sclerosis, myasthenia gravis and/or Eaton- Lambert Myasthenic syndrome, most preferably multiple sclerosis.

Yet another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of inflammatory lung disorders, in particular asthma, acute respiratory distress syndrome, acute lung injury, chronic obstructive pulmonary disease, bronchiectasis and/or cystic fibrosis, most preferably asthma.

Yet another embodiment of this aspect of the present invention relates to a compound according to the first aspect of the present invention for the treatment and/or prophylaxis of allergies, in particular allergic rhinitis. Another aspect of the present invention provides the use of at least one compound according to the present invention for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of one or more of the above mentioned diseases and/or disorders. One embodiment of the invention provides the use of at least one compound according to the present invention for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of one or more of the diseases and/or disorders, selected from the group consisting of inflammatory disorders and/or autoimmune diseases and/or allergic disorders, preferably selected from the group consisting of psoriasis and/or psoriatic arthritis; rheumatoid arthritis; inflammatory bowel disease; asthma and allergic rhinitis.

Another aspect of the present invention is a method for the treatment and/or prophylaxis, in particular for of one or more of the above mentioned diseases and/or disorders, in a mammal, in particular in a human, in need of treatment and/or prophylaxis of the respective disease and/or disorder, which comprises the administration of an effective amount of at least one compound according the present invention or the administration of a pharmaceutical composition according to the invention to the mammal.

The term "effective amount" according to the present invention means that administered amount of the compound or the pharmaceutical composition that will result in a therapeutically desired biological or medical response of a tissue, system, mammal or human. A therapeutically desired biological or medical response is understood to be an improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder in a mammal, as compared to a corresponding mammal who has not been aministered such amount. The term

"therapeutically desired biological or medical response" includes also the enhancement of a normal physiological function.

The term "compounds according to the first aspect of the present invention" in foregoing aspects of the invention encompasses all possible stereoisomers and tautomers as well as the respective corresponding acids, bases, salts and solvates.

The embodiments and in particular the preferred embodiments of any aspect of the present invention apply to all other aspects of the inventions respectively.

Compounds of the invention may be made by the methods depicted in the reaction schemes below and described for examples of the invention. The following reaction schemes 1 to 4 are illustrative only and various modifications of the methods may be made by those skilled in the art in order to obtain compounds of the invention.

Condensation of an appropriate aryl alkyl ketone with an oxalate diester as diethyl oxalate yields a β- (beta-)ketone intermediate that readily cyclises upon treatment with a suitably substituted hydrazine to afford the aryl pyrazole ethyl ester as a mixture of isomers. After separation of the isomers, for instance by flash chromatography, modifications on B' to form moiety B of the invention may be performed. Transformation of the ester into compounds of the invention can be performed via saponification and amide coupling by one of the various methods known to those skilled in the art or a conventional one step method (Scheme 1 ). Alternatively, cyclisation of the β-ketone intermediate can be performed with unsubstituted hydrazine. Alkylation with suitable halogenides or equivalents again leads to substituted aryl pyrazole ethyl ester derivatives. Separation of isomers and subsequent steps follow the route depicted in Scheme 1.

Substitutions R²≠ H may be introduced on stage of the ketone starting material (as shown in Scheme 1 , e.g. R² = CH₃), the β-ketone intermediate or the aryl pyrazole ester (e.g. R² = CI, N0₂) or at any other suitable stage of the synthesis optionally followed by further modifications (e.g. reduction of N0₂ to NH₂ with an appropriate reagent on this or later stage). Subsequent steps may then follow the route depicted in Scheme 1 . In particular cases a protecting group may be employed.

In general, the order of steps may be changed in order to obtain compounds of the invention.

As shown in Scheme 2 alternatively Pd-catalyzed coupling methods may be used to obtain compounds of the invention. Scheme 2 provides an example how a direct coupling of a 5-unsubstituted pyrazole with a suitable halogenide gives 5-substituted pyrazole esters that can be transformed into compounds of the invention. Alternatively, 5-unsubstituted pyrazole ester is converted into a boronic ester in the presence of an iridium catalyst and bispinacolatodiborane. Suzuki coupling with an appropriate halogenide or triflate subsequently gives 5-substituted pyrazole esters. A synthesis route via a 5-pyrazole bromide or triflate employed in a Suzuki cross coupling with an appropriate boronic acid or ester may provide an alternative synthesis strategy. The coupling may also be performed on a suitable pyrazole amide intermediate. Modifications on B' to form moiety B of the invention may be performed on various stages of the route depicted in Scheme 2.

In particular, compounds of the invention according formula la can be synthesized according Scheme 3. A 5-unsubstituted pyrazole ester is reacted in a Pd-catalyzed coupling with an appropriate pyridine halogenide to form intermediate 1 (int-1 ). Activation of the pyridine as benzylation followed by reduction with a suitable reagent delivers the partially unsaturated intermediate 2 (int-2). Transformation into compounds of the invention is then performed by benzyl cleavage followed by introduction of R⁴ in one or 01268 more steps and subsequent amide formation. The order of synthesis steps from intermediate 2 can be changed as described for instance in Scheme 4. Modifications of R² may be made on intermediate 1 e.g. R² = CI or any other step. In addition other routes to intermediate 1 as described above may be used.

The following examples of the invention were prepared according to the reaction schemes 1 to 4. These examples are, however, not construed to limit the scope of the invention in any manner

Experimental Procedures

Starting materials and reagents are available from commercial suppliers such as for example Acros, Aldrich, Apollo, Fluka, FluoroChem, Lancaster, Manchester Organics, MatrixScientific, Maybridge, Merck, TCI, Oakwood, etc., or the synthesis has been described as such in the literature or the materials may be prepared by conventional methods known to those skilled in the art.

All the intermediate products and exemplary compounds were analytically characterized by means of ¹H- NMR spectroscopy. In addition, mass spectrometry tests (MS, m/z for [M+H]⁺) were carried out for all the exemplary compounds and selected intermediate products.

Abbreviations:

The indication "CC" means column (flash) chromatography, ..equivalents" ("eq." or "eq" or "equiv.") means molar equivalents,„RT" or "rt" means room temperature (23 ± 7 °C), "RM" means reaction mixture,„M" are indications of concentration in mol/l,„aq." means aqueous,„sat." means saturated,„sol." means solution, "cone." means concentrated. 68

Further abbreviations: Cy = cyclohexane; DIPEA = diisopropylethylamine; DMA = Λ/,/V-dimethyl- acetamide; DMF = Λ ,/V-dimethylformamide; DMS = dimethylsulfide; EDCI = A -(3-Dimethylaminopropyl)- Λ/'-ethylcarbodiimide hydrochloride; Et₂0 = diethyl ether; EtOH = ethanol; EtOAc = ethyl acetate; HATU = 1-[bis(dimethylamino)rnethylene]-1 - -1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HOBT = 1 -hydroxybenzotriazole; Hex = hexane; MeOH = methanol; NEt₃ = triethyl amine; PAd₂Bu: Di(1 - adamantyl)-butylphosphine; PEPPSI™-lpr: [1 ,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloro- pyridyl)palladium(ll) dichloride; Pd(dppf)CI₂-CH₂CI₂ = [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro- palladium(ll), complex with CH₂CI₂; THF = tetrahydrofuran. Analytical and purification methods:

Liquid chromatography with mass spectrometry detection: LC-MS

Method 1:

Agilent LC-MS 1200 Rapid Resolution with detector MSD6140; Detection: MM-ES + APCI + DAD (254 nm); Fragmentation: 50 V [pos / neg]; Column: Agilent SB-C18, 2.1 ^χ 30 mm, 3.5 micron; Column temperature: 30°C; Flow rate: 0.8 mL/min;

Runtime: 4 min; Eluent: A: Water; B: MeOH with 1 vol-% formic acid

Gradient: t = 0 min: 95 / 5 (A / B); t = 1 .00 min: 95 / 5 (A / B); t = 4.00 min: 0 / 100 (A / B).

Method 2:

Agilent 1290 Infinity UHPLC-TOF system; Detection: Agilent G4212A DAD (190 - 400 nm) + Agilent 6224 TOF; Column: Zorbax SB-C18 Rapid Resolution HD, 2.1 x 50 mm; Column temperature: 80°C; Flow rate: 2.3 mL/min;

Runtime: 1 .38 min; Eluent: A: Water with 0.1 vol-% formic acid; B: CH₃CN with 0.1 vol-% formic acid; Gradient: t = 0 min: 98 / 2 (A / B); t = 1 .20 min: 0 / 100 (A / B); t = 1.29 min: 0 / 100 (A / B); t = 1 .31 min: 98 / 2 (A / B); t = 1.39 min: 98 / 2 (A / B).

Method 3:

Applied Biosystem LCMS/MS API 2000; Column: Zodiac C-18 (100 X 4.6), 3 μιη; Column temperature: 30°C; Flow rate: 0.7 mL/min;

Runtime: 8.1 min; Eluent: A: Water with 0.1 vol-% formic acid; B: CH₃CN;

Gradient: t = 0 min: 60 / 40 (A / B); t = 4.0 min: 10 / 90 (A / B); t = 8.0 min: 10 / 90 (A / B); t = 8.1 min: 60 / 40 (A / B).

Chromatography

Buchi MPLC system; Stationary phase: silica gel, 40-50μ or PuriFlash 430; Stationary phase: Interchim®- cartridges.

NMR spectroscopy

Bruker Advance II 400 MHz and Bruker Advance II 600 MHz spectrometer. Building block synthesis:

Building Block 1 : Ethyl 1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate 5 001268

Step 1 : A suspension of ethyl 1 -methyl-1 H-pyrazole-3-carboxylate (1.5 g, 9.73 mmol), 3-bromo-4- methylpyridine (1 .67 g, 9.73 mmol), PAd₂Bu (523 mg, 1.46 mmol), pivalic acid (200 mg, 1 .95 mmol) and K₂C0₃ (2.69 g, 19.5 mmol) in dry DMA (14 ml) was purged with inert gas and subsequently Pd(OAc)₂ (218 mg, 0.97 mmol) was added. The RM was stirred for 5 h at 150°C. The volatiles were removed under reduced pressure, the residue dissolved in water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (PF- 50SIHP/120G, MeOH/CH₂CI₂ (5:95)) to yield the desired compound (640 mg, 27%).

LC-MS (Method 1): m/z [M+H]⁺ = 246.2 (MW calc. = 245.28); R, = 2.5 min. ¹H-NMR (CDCI₃): δ = 1.41 (t, J = 7.2 Hz, 3H); 2.20 (s, 3H); 3.74 (s, 3H); 4.42 (q, J = 7.2 Hz, 2H); 6.81 (s, 1 H); 7.26 (d, J = 5.2 Hz, 1 H); 8.42 (s, 1 H); 8.55 (d, J = 5.2 Hz, 1 H). ¹³C-NMR (CDCI₃): δ = 14.4; 19.4; 37.6; 61 .1 ; 110.3; 125.3; 126.0; 140.3; 143.1 ; 147.0; 150.3; 150.4; 162.2.

Step 2: To a solution of the intermediate of step 1 (630 mg, 2.57 mmol) in dry CH₂CI₂ (20 mL) was added benzyl bromide (1.32 g, 7.71 mmol) and the mixture was stirred at rt for 16 h. All volatiles were removed under reduced pressure and the residue was washed with Et₂0 to yield the desired compound (1 .05 g, 99%).

LC-MS (Method 1): m/z [M]⁺ = 336.2 (MW calc. = 336.41 ); R, = 2.4 min. H-NMR (CDCI₃): δ = 1.37 (t, J = 7.2 Hz, 3H); 2.43 (s, 3H); 3.92 (s, 3H); 4.37 (q, J = 7.2 Hz, 2H); 6.38 (s, 2H); 6.88 (s, 1 H); 7.37-7.40 (m, 3H); 7.68 (m, 2H); 8.00 (d, J = 6.4 Hz, 1 H); 9.21 (s, 1 H); 9.59 (d, J = 6.4 Hz, 1 H). ¹³C-NMR (CDCI₃): δ = 14.3; 20.8; 39.1 ; 61.3; 63.8; 1 1 1.5; 129.5, 129.7; 129.9; 130.0; 130.1 ; 132.6; 135.4; 143.4; 144.4; 144.6; 158.6; 161.6.

Step 3: To a solution of the intermediate of step 2 (1 .05 g, 2.52 mmol) in MeOH (15 mL) was added a solution of sodium borohydride (95 mg, 2.52 mmol) in water (2 mL) at -78°C. The RM was allowed to reach rt in 1 h before further sodium borohydride (95 mg, 2.52 mmol) in water (1 mL) was added and stirring continued for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (PF-30SIHP/40G, EtOAc/Cy (7:3)) to yield the desired compound (621 mg, 72%).

LC-MS (Method 1): m/z [M+H]⁺ = 340.2 (MW calc. = 339.19); R, = 2.5 min. ¹H-NMR (CDCI₃): δ = 1.33 (t, J = 7.2 Hz, 3H); 1 .47 (s, 3H); 2.21 (br s, 2H); 2.61 (m, 2H); 2.94 (br s, 2H); 3.56 (br s, 2H), 3.69 (s, 3H);

4.33 (q, J = 7.2 Hz, 2H); 6.53 (s, 1 H); 7.18-7.28 (m, 5H). ³C-NMR (CDCI₃): δ = 14.4; 20.0; 31 .6; 37.1 ;

49.6; 56.5; 60.8; 62.4; 108.5; 119.8; 127.3; 128.3; 129.1 ; 136.0; 137.7; 142.6; 143.4; 162.4.

Step 4: To a solution of the intermediate of step 3 (620 mg, 1 .83 mmol) in dry CH₂CI₂ (4 mL) was added chloroethyl chloroformate (392 mg, 2.74 mmol). The RM was stirred at rt for 1 h. All volatiles were removed under reduced pressure and the residue was dissolved in EtOH and stirred at 70°C for 1 h.

Again, the volatiles were removed under reduced pressure and the residue was purified by CC (Si0₂ /

100 g, NH₃/MeOH/CHCI₃) to yield BB-1 (366 mg, 80%).

LC-MS (Method 1): m/z [M+H]⁺ = 250.3 (MW calc. = 249.15); R, = 1 .9 min. ¹H-NMR (CDCI₃): δ = 1 .39 (t, J = 7.2 Hz, 3H); 1.57 (s, 3H); 2.35 (br s, 2H); 3.20 (m, 2H); 3.51 (br s, 2H); 3.82 (s, 3H); 4.39 (q, J = 7.2 Hz, 2H); 6.62 (s, 1 H). ¹³C-NMR (CDCI₃): δ = 14.4; 20.5; 30.4; 37.2; 42.5; 48.3; 60.9; 108.5; 120.0; 136.5; 142.7; 142.8; 162.4.

Building Block 2: Ethyl 5-(1 -cyano^-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylate

To a solution of the intermediate of step 3 of BB-1 (1 g, 2.95 mmol) in dry CH₂CI₂ (10 mL) was added cyanogen bromide (937 mg, 8.85 mmol) and the resulting mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was purified by CC ((PF-50SIHP/ 20G, EtOAc) to yield BB-2 (665 mg, 82%).

LC-MS (Method 1): m/z [M+H]⁺ = 275.3 (MW calc. = 274.32); R, = 3.1 min. ¹H-NMR (CDCI₃): δ = 1.38 (t, J = 7.2 Hz, 3H); 1.59 (s, 3H); 2.37 (m, 2H); 3.40 (m, 2H); 3.73 (m, 2H); 3.78 (s, 3H); 4.78 (q, J = 7.2 Hz, 2H); 6.63 (s, 1 H). ¹³C-NMR (CDCI₃): δ = 14.3; 20.5; 29.1 ; 37.2; 45.9; 50.8; 61.0; 108.9; 1 17.3; 1 17.5; 136.7; 140.8; 143.1 ; 162.1.

Building Block 3: Ethyl l -methyl-S^^.S.S-tetramethyl-l.a.a-dioxaborolan^-ylJ-I H-pyrazole-S- carboxylate

4,4'-D tert-butyl-2,2'-dipyridyl (194 mg, 722 pmol) was added to a solution of (1 ,5-Cyclooctadiene)- (methoxy)iridium(l) dimer (241 mg, 363 pmol) and pinacolborane (4.13 g, 32.2 mmol) in pentane (21 mL) and the mixture was stirred for 20 min at rt. Then, a solution of 1 -methyl-1 H-pyrazole-3-carboxylate (3.05 g, 19.8 mmol) in pentane (14 mL) and THF (7 mL) was added and the solution was stirred at rt for 3 d. The volatiles were removed under reduced pressure and the residue was purified by CC (Si0₂, CH₂CI₂ /CH₃OH) to yield the desired product (78%).

¹H-NMR (DMSO-d6): δ = 7.00 (s, 1 H), 4.25 (q, J = 8 Hz, 2H), 4.04 (s, 3H), 1.31 (s, 3H), 1 .28 (t, J = 8 Hz, 3H) ppm.

Building Block 3a: Methyl 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-3- carboxylate

BB-3a was prepared in analogy to BB-3 starting from methyl 1 -methyl-1 H-pyrazole-3-carboxylate (80%). 15 001268

Building Block 4: Methyl 5-(1 -cyano-4-cyclopropyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H- pyrazole-3-carboxylate

Step 1 : A solution of cyclopropyl zink bromide (0.5 M, 12 mL, 6.0 mmol) was added to ethyl 3,4- dibromopyridine (1.42 g, 6.0 mmol) and Pd(PPh₃)₄ (347 mg, 0.6 mmol) and the RM was stirred at 90 ⁶C under an inert atmosphere for 2.5 h. Subsequently, the volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CH₂CI₂. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (Si0₂, EtOAc/Cy (1 :2)) to yield the desired compound (600 mg, 51 %).

LC-MS (Method 1): m/z [M+Hf = 198.1 (MW calc. = 196.98); R, = 2.6 min. ¹H-NMR (CDCI₃): δ = 0.79 (m, 2H); 1 .15 (m, 2H); 2.20 (m, 1 H); 6.72 (d, J = 5.2 H, 1 H); 8.85 (d, J = 5.2 Hz, 1 H); 8.63 (s, 1 H). ³C-NMR (CDCI₃): δ = 9.7; 1 5.2; 1 19.9; 123.9; 148.1 ; 151 .3; 152.1 .

Step 2: A solution of the intermediate from step 1 (600 mg, 3.03 mmol), BB-3a (1 .01 g, 3.79 mmol), LiOH (72 mg. 3.03 mmol) and Bis-(tri-tert-butyl phosphine)palladium (156 mg, 0.3 mmol) in dry DMF was degassed and subsequently heated to 90°C under an inert atmosphere for 1 h. The volatiles were removed under reduced pressure, the residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (Si0₂, EtOAc) to give the desired compound (630 mg, 81 %).

LC-MS (Method 1): m/z [M+Hf = 258.2 (MW calc. = 257.12); R, = 2.6 min. ¹ H-NMR (CDCI₃): δ = 0.86 (m, 2H); 1 .10 (m, 2H); 1 .62 (m, 1 H); 3.81 (s, 3H); 3.96 (s, 3H); 6.78 (d, J = 5.6 Hz, 1 H); 6.90 (s, 1 H); 8.40 (d, J = 0.8 Hz, 1 H); 8.55 (dd, J = 0.8,5.6 Hz, 1 H).

Step 3: To a solution of the intermediate of step 2 (630 mg, 2.45 mmol) in dry CH₃CN (20 mL) was added benzyl bromide (1 .25 g, 7.35 mmol) and the mixture was stirred at 80°C for 1 h. All volatiles were removed under reduced pressure and the residue was washed with Et₂0 to yield the desired compound (0.81 g, 77%).

LC-MS (Method 1): m/z [M]⁺ = 348.3 (MW calc. = 348.17); R, = 2.5 min. ¹ H-NMR (CDCI₃): δ = 1 .18 (m, 2H); 1 .39 (m, 2H); 1 .77 (m, 1 H); 3.92 (s, 3H); 3.94 (s, 3H); 6.23 (s, 2H); 6.97 (s, 1 H); 7.33-7.40 (m, 4H); 7.66 (m, 2H); 8.69 (s, 1 H); 9.55 (d, J = 5.6 Hz, 1 H).

Step 4: To a solution of the intermediate of step 3 (805 mg, 2.31 mmol) in MeOH (60 mL) was added sodium borohydride (439 mg, 1 1 .6 mmol) and the RM was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was dissolved in sat. NaHC0₃ solution and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (PF-30SIHP/25G, EtOAc/Cy) to yield the desired compound (380 mg, 47%). LC-MS (Method 1): mlz [M+H]⁺ = 352.3 (MW calc. = 351.19); R, = 2.5 min. ¹H-NMR (CDCI₃): δ = 0.54 (d, J = 6.8 Hz, 4H); 1.22 (quint, J = 6.8 Hz, 1 H), 1 .88 (m, 2H); 2.62 (m, 2H); 6.04 (br s, 2H); 3.61 (br s, 2H); 3.83 (s, 3H); 3.90 (s, 3H); 6.56 (s, 1 H); 7.26-7.33 (m, 5H).

Step 5: To a solution of the intermediate of step 4 (380 mg, 1 .08 mmol) in 1 ,2-dichloroethane (12 mL) was added cyanogen bromide (344 mg, 3.24 mmol) and the RM was stirred at 90°C for 6 h. The volatiles were removed under reduced pressure and the residue was taken up in water and extracted with EtOAc. The combined organic layers were dried, all volatiles were removed under reduced pressure and the residue was purified by CC (PF-50SIHP/25G, EtOAc/Cy) to yield BB-4 (275 mg, 89%).

LC-MS (Method 1): mlz [M+H]⁺ = 287.2 (MW calc. = 286.14); R, = 3.1 min. H-NMR (CDCI₃): δ = 0.55- 0.67 (m, 4H); 1.28 (m, 1 H); 2.00 (m, 2H); 3.37 (t, J = 6.4 Hz, 2H); 3.78 (t, J = 2.4 Hz, 1 H); 3.86 (s, 3H); 3.92 (s, 3H); 6.71 (s, 1 H).

Building Block 5: Methyl 1-methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate

Step 1 : A suspension of methyl 1 -methyl-1 H-pyrazole-3-carboxylate (2.1 g, 15 mmol), 3-bromo-4-methyl- pyridine (3.08 g, 18 mmol) and KOAc (2.95 g, 30 mmol) in dry DMA (40 ml) was purged with inert gas. Then, Pd(OAc)₂ (336 mg, 1.5 mmol) was added. The RM was stirred for 7 h at 160°C. The volatiles were removed under reduced pressure, the residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by CC (Si0₂, MeOH/ CH₂CI₂) to give the desired compound (964 mg, 28%).

1H-NMR (CDCI₃): δ = 2.20 (s, 3H); 3.75 (s, 3H); 3.95 (s, 3H); 6,82 (s, 1 H); 7.27 (d, J = 5 Hz, 1 H); 8.44 (s, 1 H); 8.57 (d, J = 5 Hz, 1 H). ¹³C-NMR (CDCI₃): δ = 19.4; 37.6, 52.1 ; 1 10.3; 125.3; 125.9; 140.4; 142.7; 146.9; 150.3; 150.5; 162.6.

Step 2: To a solution of the intermediate of step 1 (890 mg, 3.85 mmol) in dry CH₃CN (14 mL) was added /V-chlorosuccinimide (1 .03 mg, 7.7 mmol) and the mixture was stirred at 80°C for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with saturated NAHC0₃ solution, dried and the volatiles were removed under reduced pressure. The residue was purified by CC (PF-30SIHP/40G, MeOH/CH₂CI₂) to yield the desired compound (666 mg, 65%).

LC-MS (Method 1): mlz [M]⁺ = 266.2 (MW calc. = 265.06); R, = 2.7 min. ¹H-NMR (CDCI₃): δ = 2.20 (s, 3H); 3.73 (s, 3H); 3.97 (s, 3H); 7.31 (d, J = 5.2 Hz, 1 H); 8.42 (s, 1 H); 8.61 (d, J = 5.2, 1 H).

1³C-NMR (CDCI₃): δ = 19.1 ; 38.6; 52.2; 113.5, 123.4; 125.3; 138.3; 138.5; 147.7; 150.7; 151 .2; 161 .1 . Step 3: The synthesis was performed in analogy to step 2 in the synthesis of BB-1 (1 .18 g, 100%). LC-MS (Method 1): mlz [Mf = 356.2 (MW calc. = 356.12); R, = 2.5 min. ¹ H-NMR (CDCI₃): δ = 2.43 (s, 3H); 3.93 (s, 3H); 3.99 (s, 3H); 6.35-6.43 (m, 2H); 7.37-7.41 (m, 3H); 7.65-7.67 (m, 2H); 8.03 (d, J = 6.4 Hz, 1 H); 9.22 (d, J = 1 .2 Hz, 1 H); 9.59 (dd, J = 1.2 und 6.4 Hz, 1 H).

Step 4: The synthesis was performed in analogy to step 3 in the synthesis of BB-1 (463 mg, 51 %).

LC-MS (Method 1). mlz [M+H]⁺ = 360.2 (MW calc. = 359.14); R, = 2.5 min. ¹H-NMR (CDCI₃): δ = 1.53 (s, 3H); 2.31 (m, 2H); 2.71 (m, 2H); 2.98 (m, 2H); 3.63 (m, 2H); 3.73 (s, 3H); 3.93 (s, 3H); 7.23-7.37 (m, 5H). ¹³C-NMR (CDCI₃): δ = 19.8; 31 .5; 38.0; 49.6; 52.0; 54.5; 62.1 ; 111.9; 117.5; 127.2; 128.3; 129.0; 137.8; 137.8; 138.8; 141.0; 161.4.

Step 5: The synthesis was performed in analogy to step 4 in the synthesis of BB-1 to yield BB-5 (339 mg, 97%).

LC-MS (Method 1): mlz [M+Hf = 270.2 (MW calc. = 269.09); R, = 1.9 min. ¹H-NMR (CDCI₃): δ = 1.62 (s, 3H); 2.45 (m, 1 H); 2.74 (m, 1 H); 3.25 (m, 1 H); 3.57 (m, 1 H); 3.69 (m, 2H); 3.88 (s, 3H); 3.94 (s, 3H).

Building Block 6: Ethyl 1 ,4-dimethyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate

Step 1 : A solution of ethyl 4-bromo-1 -methyl-1 H-pyrazole-3-carboxylate (2.98 mg, 12.9 mmol), tetramethyltin (4.56 g, 25.6 mmol), LiCI (1.09 g, 25.6 mmol) and dichlorobis(tri-o-tolylphosphino)palladium (1.01 g, 1.29 mmol) in dry DMA (20 ml) was purged with inert gas and subsequently stirred for 1 h at 1 10°C. The volatiles were removed under reduced pressure and the residue was dissolved in water and Et₂0. The mixture was filtered and the organic layer was washed with water and dried. The volatiles were removed under reduced pressure and the residue was purified by CC (PF-30SIHP/80G, EtOAc/Cy) to give the desired compound (1.1 g, 51 %).

LC-MS (Method 1): mlz [M+H]⁺ = 169.2 (MW calc. = 168.09); R, = 2.8 min. ¹H-N R (CDCI₃): δ = 1 .39 (t, J = 7.2 Hz, 3H); 2.27 (s, 3H); 3.90 (s, 3H); 4.38 (q, J = 7.2 Hz, 2H); 7.17 (s, 1 H). ¹³C-NMR (CDCI₃): δ = 9.6; 14.4; 39.4; 60.5; 121.2; 130.8, 140.8; 162.9.

Step 2: The synthesis was performed in analogy to step 1 in the synthesis of BB-1 to yield the desired compound (793 mg, 64%).

LC-MS (Method 1): mlz [M+H]⁺ = 260.3 (MW calc. = 259.13); R, = 2.8 min. ¹H-NMR (CDCI₃): δ = 1 .42 (t, J = 7.2 Hz, 3H); 2.09 (s, 3H); 2.13 (s, 3H); 3.67 (s, 3H); 4.43 (q, J = 7.2 Hz, 2H); 7.28 (d, J = 5.2 Hz, 1 H); 8.37 (s, 1 H); 8.58 (d, J = 5.2 Hz, 1 H). ¹³C-NMR (CDCI₃): δ = 9.5; 14.4; 19.0; 37.6, 60.7; 120.4; 125.2; 125.5; 138.7; 140.6; 147.6; 150.5; 150.9; 162.8.

Step 3: The synthesis was performed in analogy to step 2 in the synthesis of BB-1 to yield the desired compound (1 .19 g, 95%). LC-MS (Method 1): m/z [M]⁺ = 350.3 (MW calc. = 350.16); R, = 2.5 min. ¹H-N R (CDCI₃): δ = 1 .40 (t, J = 7.2 Hz, 3H); 2.01 (s, 3H), 2.36 (s, 3H); 3.84 (s, 3H); 4.40 (q, J = 7.2 Hz, 2H); 6.40 (s, 2H); 7.35-7.41 (m, 3H); 7.64-7.66 (m, 2H); 8.03 (d, J = 6.8 Hz, 1 H); 9.01 (d, J = 1.2 Hz, 1 H); 9.63 (dd, J = 1 .2, 6.8 Hz, 1 H). Step 4: The synthesis was performed in analogy to step 3 in the synthesis of BB-1 to yield the desired compound (752 mg, 75%).

LC-MS (Method 1): m/z [M+H]⁺ = 354.3 (MW calc. = 353.21 ); R, = 2.7 min. ¹H-NMR (CDCI₃): δ = 1 .39 (t, J = 7 Hz, 3H); 1.48 (s, 3H); 2.1 1 (s, 3H); 2.28 (m, 2H); 2.69 (m, 2H); 2.90 (s, 2H); 3.62 (m, 2H); 3.70 (s, 3H); 4.38 (q, J = 7 Hz, 2H); 7.23 (m, 5H).

Step 5: The synthesis was performed in analogy to step 4 in the synthesis of BB-1 to yield BB-6 (502 mg, 91 %).

LC-MS (Method 1): m/z [M+H]⁺ = 264.3 (MW calc. = 263.16); R, = 2.2 min. ¹H-NMR (CDCI₃): δ = 1.39 (t, J = 7.2 Hz, 3H); 1.56 (s, 3H); 2.58 (m, 2H); 3.39 (m, 2H); 3.61 (s, 2H); 3.83 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H). ¹³C-NMR (CDCI₃): δ = 9.3; 14.4; 20.0; 27.6; 37.7; 40.7; 44.0; 60.7; 77.2; 1 14.7; 1 19.4; 138.4; 140.5; 162.8.

Building Block 7: N-(3,5-difluoropyridin-4-yl)-1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-

1 H-pyrazole-3-carboxamide

Step 1 : To a solution of 3-acetyl pyridine (130 g, 1.07 mol) in dry THF (2L), Cul (10.2 g, 52.5 mmol) and DMS (440 g, 7.09 mol) were added at rt and the resulting mixture was stirred for 15 min. A solution of phenyl chloroformate (143 g, 914mmol) in THF (250mL) was added followed by dropwise addition of ethyl acetoacetate (185 g, 1.18 mol) at rt over a period of 45 min. The RM was cooled to -20°C, methyl magnesium bromide (1 .6M solution in THF; 671 mL, 1.07 mol) was added at 0°C and the RM was stirred at RT overnight. The RM was quenched with sat. aq. NH₄CI (500 mL) and the aqueous layer was extracted with EtOAc The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by column CC (Si0₂: EtOAc-Pet Ether) to give phenyl 3-acetyl-4-methylpyridine-1 (4H)-carboxylate (180 g, 65%).

LC-MS (Method 3): m/z [M+H]⁺ = 258 (MW calc. = 257.1 1 ). 01268

Step 2: To a solution of sulfur (37.3 g, 1 .16 mol) in decalin (800 mL), phenyl 3-acetyl-4-methylpyridine- 1 (4H)-carboxylate (150 g, 584 mmol) was added at rt and the RM was slowly heated to 190°C and stirred for 5 h. The RM was brought to rt and loaded on a column of Si0₂; (EtOAc/Pet Ether) to afford 1 -(4- Methylpyridin-3-yl)ethanone (42 g, 53%).

LC-MS (Method 3): m/z [M+H]⁺ = 136 (MW calc. = 135.07)

Step 3: Under argon atmosphere, sodium ethoxide (42.3 g, 622 mmol) was added to dry EtOH (1 L) at rt and stirred for 15 min. Diethyl oxalate (90.8 g, 622mmol) was added at 10°C and stirred for 15 min. A solution of 4-methyl-3-acetyl pyridine (10 g, 74 mmol) in EtOH (100 mL) was then added at the same temperature and the RM was stirred at rt overnight. The pH of the RM was adjusted to ~7 using 1 aq. HCI. The solvent was evaporated under reduced pressure and the aqueous residue diluted with toluene (100 mL) and evaporated under reduced pressure to give ethyl 4-(4-methylpyridin-3-yl)-2,4- dioxobutanoate (73 g). The material was directly used for the next step without any further purification. LC-MS (Method 3): m/z [M+Hf = 236 (MW calc. = 235.08)

Step 4: To ethyl 4-(4-methylpyridin-3-yl)-2,4-dioxobutanoate (73 g, 31 mmol) in dry EtOH (500 mL), methyl hydrazine sulfate (89.7 g, 622 mmol) was added at rt. The RM was heated to 60°C and stirred for

5 h. The solvent was evaporated under reduced pressure and the pH of the residue was adjusted to ~7 using saturated aqueous NaHC0₃ solution. The neutral aqueous layer was extracted with ethyl acetate.

The organic layer was washed with water, brine, dried and then concentrated under reduced pressure.

The residue was purified by CC (Si0₂: EtOAc-Pet Ether) to afford ethyl 1 -methyl-5-(4-methylpyridin-3-yl)- 1 H-pyrazole-3-carboxylate (20 g, 26%).

LC-MS (Method 3): m/z [M+H]⁺ = 246 (MW calc. = 245.12)

Step 5: To a solution of Ethyl 1 -methyl-5-(4-methylpyridin-3-yl)-1 H-pyrazole-3-carboxylate (1 g, 4.08 mmol,) in dry CH₂CI₂ (30 mL), benzylbromide (1.04 g, 6.12 mmol) was added at 50°C and the RM was stirred for 16 h. The solvent was evaporated under reduced pressure and the residue was triturated with Et₂0 to give the corresponding benzyl salt (1.6 g). The solid was dissolved in dry MeOH (30 mL), NaBH₄ (145 mg, 3.83 mmol) was added at 0°C and the RM was brought to rt and stirred for 2 h. The solvent was evaporated under reduced pressure and the residue diluted with water and EtOAc. The layers were separated, the organic layer was washed with water, brine, dried and concentrated under reduced pressure. The residue was purified by column CC (Si0_2, EtOAc-Pet Ether to give ethyl 5-(1-benzyl-4- methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3-carboxylate (800 mg, 58% over two steps). LC-MS (Method 3): mlz [M+Hf = 340 (MW calc. = 339.19).

Step 6: To a solution of ethyl 5-(1-benzyl-4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole- 3-carboxylate (10 g, 29.5 mmol) in THF/MeOH/water (40ml/20ml/10ml), LiOH H₂0 (2.21 g, 44.2 mmol), was added and the RM was stirred at rt for 16 h. The solvent was evaporated and the aqueous residue was washed with EtOAc. The pH of the aqueous layer was adjusted to ~5 using 1 HCI and extracted with MeOH/CH₂CI₂ (5:95). The combined organic layers were dried and concentrated under reduced pressure. The residue was co-evaporated with toluene to afford 5-(1 -benzyl-4-methyl-1 ,2,5,6- tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3-carboxylic acid (7 g, 77%).

LC-MS (Method 3): mlz [M+Hf = 312 (MW calc. = 31 1.16).

Step 7: To a solution of 5-(1 -benzyl-4-methyl-1 , 2,5, 6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylic acid (1.5 g, 4.82 mmol) in dry CH₂CI₂ (100 mL), oxalyl chloride (0.92 g, 7.23 mmol) and DMF (0.2 mL) was added at 0°C and the RM was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure. The residue was diluted in dry CH₂CI₂ (100 mL), Et₃N (1.46 g, 14.46 mmol) and a solution of 3,5-difluoro,4-amino pyridine (689 mg, 5.30 mmol) in dry CH₂CI₂ (10 mL) was added at 0°C. The RM was stirred at rt overnight. The RM as quenched with sat. aq. NaHC0₃ solution , extracted with CH₂CI₂. The layers were separated, the organic layer was dried and concentrated under reduced pressure. The residue was purified by CC (Si0₂: EtOAc-Pet Ether) to afford compound 5-(1 -benzyl-4- methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-N-(3,5-difluoropyridin-4-yl)-1 -methyl-1 H-pyrazole-3-carboxamide (1.9 g, 46%).

LC-MS (Method 3): m/z [M+H]⁺ = 425 (MW calc. = 423.1 9).

Step 8: To a solution of 5-(1 -benzyl-4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-N-(3,5-difluoropyridin-4-yl)-1 - methyl-1 H-pyrazole-3-carboxamide (1 g, 2.36 mmol) in dry CH₂CI₂ (30 mL), 1 -chloroethyl chloroformate (675 mg, 4.73 mmol) was added and the RM was stirred at rt overnight. The solvent was evaporated, EtOH (30 mL) was added and the RM was heated at reflux for 4 h. The solvent was evaporated and the residue was diluted with CH₂CI₂ (200 mL) and washed with saturated aqueous NaHC0₃ solution. The layers were separated, the organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by CC (neutral aluminium oxide, MeOH/CH₂CI₂) to afford BB-7 (230 mg, 33%).

LC-MS (Method 3): m/z [M+H]⁺ = 334.1 (MW calc. = 333.14). ¹ H-NMR (400MHz, CDCI₃): δ = 1 .57 (s, 3H); 2.19 (t, J = 6.0 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H), 3.39 (q, J = 2.0 Hz, 2H), 3.79 (s, 3H), 6.70 (s, 1 H), 8.34 (s, 2H).

Building Block 8: N-(2,6-difluorophenyl)-1 -methyl-5-(4-methy 1-1 ,2, 5,6-tetrahydropyridin-3-yl)-1 H- pyrazole-3-carboxamide

Step 1 : To a solution of the intermediate from step 6 in the synthesis of BB-7, 5-(1 -benzyl-4-methyl- 1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3-carboxylic acid (1.5 g, 4.8 mmol) in dry CH₂CI₂ (70 mL), oxalyl chloride (0.92 g, 7.23 mmol) and DMF (0.2 mL) were added and stirred at rt for 1 h. The Volatiies were evaporated under reduced pressure. The residue was diluted with dry CH₂CI₂ (70mL), Et₃N (1 .46 g, 14.45 mmol) and 2,6-difluoroaniline (0.683 g, 5.29 mmol) was added at 0°C. The RM was stirred at rt for 2 h. This reaction was carried out in two batches of 1 .5 g each and a combined workup was carried out for the two reactions. The RM was quenched with saturated aqueous NaHC0₃ solution and extracted with CH₂CI₂. The layers were separated, the combined organic layers were dried and concentrated under reduced pressure. The residue was purified by CC (Si0₂; EtOAc-Pet Ether) to afford 5-(1 -benzyl-4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-N-(2,6-difluorophenyl)-1 -methyl-1 H-pyrazole-3- carboxamide (2.5 g, 61 %).

LC-MS (Method 3): m/z [M+H]⁺ = 423 (MW calc. = 422.19).

Step 2: To a solution of -(1 -benzyl-4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-N-(2,6-difluorophenyl)-1 - methyl-1 H-pyrazole-3-carboxamide (3 g, 7.1 1 mmol) in dry CH₂CI₂ (60 mL), 1 -chloroethyl chloroformate 1268

(2.03 g, 14.22 mmol) was added and the RM was stirred at rt overnight. The solvent was evaporated, EtOH (60 mL) was added and the RM heated at reflux for 4 h. The solvent was evaporated and the residue was diluted with CH₂CI₂ and washed with saturated aqueous NaHC0₃. The layers were separated and the organic layer was washed with brine, dried and then concentrated under reduced pressure. The residue was purified by CC (neutral aluminium oxide, MeOH/CH₂CI₂) to afford N-(2,6- difluorophenyl)-1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxamide (BB-8) (1.3 g, 56%).

LC-MS (Method 3): m/z [M+Hf = 333.1 (MW calc. = 332.14). ¹H-NMR (400MHz, DMSO-d₆): δ = 1.50 (s, 3H); 2.05 (br, 2H); 2.85 (t, J = 6.0 Hz, 2H), 3.22 (s, 2H), 3.74 (s, 3H), 6.54 (s, 1 H); 7.15 (m, 2H), 7.36 (m, 1 H), 9.82 (s, 1 H).

Building Block BB-9: 1-Methyl-5-(1-(thiazol-2-yl)-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylic acid

Step 1 : Under Ar, sodium (5.1 g, 248 mmol) was added in portions to dry EtOH (150 mL) at rt and stirred until complete dissolution. Diethyl oxalate (36.2 g, 248 mmol) was added at rt and the RM stirred for 30 min. A solution of 3-acetyl pyridine (30 g, 248 mmol) in Et₂0 (50 mL) was then added at rt and the RM was stirred at for 24 h. The pH of the RM was adjusted to ~7 using aq. HCI. The aqueous layer was extracted with EtOAc and the combined organic layers were dried and then concentrated under reduced pressure to give ethyl 2,4-dioxo-4-(pyridin-3-yl)butanoate (48 g). The material was directly used for the next step without any further purification.

Step 2: To Ethyl 2,4-dioxo-4-(pyridin-3-yl)butanoate (48 g) in dry EtOH (150 mL), methyl hydrazine sulfate (31.3 g, 217 mmol) was added at rt, the RM was heated to 80°C and stirred for 7 h. The solvent was evaporated under reduced pressure and the pH of the residue was adjusted to ~7 using saturated aqueous NaHC0₃. The neutral aqueous layer was extracted with EtOAc and the combined organic layers were washed with water brine, were dried and concentrated under reduced pressure. The residue was purified by CC (Si0₂, EtOAc-Pet Ether) to afford ethyl 1 -methyl-5-(pyridin-3-yl)-1 H-pyrazole-3-carboxylate (17 g, 34%).

LC-MS (Method 3): m/z [M+Hf = 232 (MW calc. = 231.10).

Step 3: To a solution of Ethyl 1 -methyl-5-(pyridin-3-yl)- H-pyrazole-3-carboxylate (40 g, 173 mmol) in dry CH₂CI₂ (500 mL), benzylbromide (38.4 g, 27 mL, 225 mmol) was added at rt and the RM was heated at reflux for 24h. The solvent was evaporated under reduced pressure and the residue was triturated with Et₂0 (100 mL) to give the corresponding N-benzyl salt (70 g). The above N-benzyl salt (70 g) was dissolved in dry MeOH (300 mL) and a solution of NaBH₄ (11.7 g, 346 mmol) in water (100 mL) was added at -78°C. The RM was brought to 0°C and stirred for 30 min. The solvent was evaporated under reduced pressure and the residue was diluted with brine and EtOAc. The layers were separated; the aqueous layer was extracted with EtOAc, the combined organic layers were dried and concentrated under reduced pressure. The residue was purified by CC (Si0₂, EtOAc-Pet Ether) to afford ethyl 5-(1 - benzyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3-carboxylate (27.1 g, 48% over two steps). LC-MS (Method 3): m/z [M+H]⁺ = 326 (MW calc. = 325.18).

Step 4: To a solution of ethyl 5-(1 -benzyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylate (5 g, 15.4 mmol) in CH₂CI₂ (50 ml_), chloroethyl chloroformate (3.27 g, 23.1 mmol) was added and the RM was stirred at rt overnight. The solvent was evaporated and dry MeOH (50 mL) was added. The RM was heated at reflux for 1 h. The RM was brought to rt and neutralized with saturated aqueous NaHC0₃; filtered and concentrated under reduced pressure. The residue was purified by CC (Si0₂, MeOH-CH₂CI₂-aq. NH₄OH) to afford methyl 1 -methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate (2.1 g, 64%).

LC-MS (Method 3): m/z [M+H]⁺ = 222 (MW calc. = 221.12).

Step 5: To a solution of methyl 1 -methyl-5-(1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxylate (9 g, 40.7 mmol) in 1 ,4-dioxane (150 mL) in a sealed tube K₃P0₄ (17.3 g, 81.4 mmol) was added and Ar was purged through the mixture for 10 min. Then, Pd₂(dba)₃ (1.86 g, 2.03 mmol) and X-phos (1 .93 g, 4.06 mmol) were added and the RM was further purged with Ar for 10 min. Then, 2-bromothiazole (10.1 g, 61.1 mmol) was added and the RM was heated to 1 10°C for 30 h. The RM was brought to rt and filtered over a plug of celite. The filtrate was concentrated under reduced pressure. The residue was purified by CC (Si0₂, EtOAc-Pet Ether) to afford methyl 1-methyl-5-(1 -(thiazol-2-yl)-1 ,2,5,6- tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxylate (8.1 g, 63%).

LC-MS (Method 3): m/z [M+H]⁺ = 305 (MW calc. = 304.10).

Step 6: To a solution of methyl 1 -methyl-5-(1 -(thiazol-2-yl)-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate (8.1 g, 26.3 mmol) in THF-water (1 :1 , 240 mL), LiOH (2.23 g, 53.3 mmol), was added and the RM was stirred at rt for 5 h. The solvent was evaporated and the aqueous residue was washed with EtOAc (20 mL). The pH of the aqueous layer was adjusted to ~4 using 1 N HCI and extracted with MeOH- CH₂CI₂ (5:95). The organic layer was separated, dried and was concentrated under reduced pressure to give a solid. The residue was dissolved in MeOH, treated with charcoal (2 g) and then heated to reflux for 15 min and was filtered hot. The filtrate was concentrated under reduced pressure to afford BB-9 (5.7 g, 73%).

LC-MS (Method 3): m/z [M+H]⁺ = 291 (MW calc. = 290.08). ¹H-NMR (400MHz, DMSO-d₆): δ = 2.94 (br, 2H); 3.65 (m, 2H), 3.82 (s, 3H), 4.13 (br, 2H), 6.24 (m, 1 H), 6.76 (s, 1 H); 6.84 (d, 1 H), 7.20 (d, 1 H). Building Block BB-10: 1 -Methyl-5-(4-methyl-1 -(thiazol-2-yl)-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H- pyrazole-3-carboxylic acid

01268

Step 1 : To a solution of ethyl 5-(1 -benzyl-4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 -methyl-1 H-pyrazole- 3-carboxylate (2.5 g, 7.37 mmol, synthesis as described above) in CH₂CI₂ (15 mL), chloroethyl chloroformate (1.58 g, 1 1.0 mmol) was added and the RM was stirred at rt overnight. The solvent was evaporated, EtOH (10 mL) was added and the RM was heated at reflux for 1 h. The solvent was evaporated and the residue was diluted with CH₂CI₂ and washed with saturated aqueous NaHC0₃. The layers were separated and the organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by CC (Si0₂. MeOH-CHCI₃-aq. NH₄OH) to afford ethyl 1 - methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxylate (1 g, 55%).

LC-MS (Method 3): m/z [M+H]⁺ = 250 (MW calc. = 249.15).

Step 2: To a solution of ethyl 1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxylate (500 mg, 2 mmol) in 1 ,4-dioxane (20 mL) in a sealed tube, K₃P0₄ (850 mg, 4 mmol) was added and the mixture was purged with Ar for 10 min. Then, Pd₂(dba)₃ (92 mg, 0.1 mmol) and X-phos (96 mg, 0.2 mmol) were added and the mixture was purged with Ar for further 10 min. A solution of 2- bromothiazole (490 mg, 3 mmol) in 1 ,4-dioxane (1 mL) was added and the RM was heated to 1 10°C for 24 h. The RM was brought to rt and filtered over a plug of celite. The filtrate was concentrated under reduced pressure. The residue was purified by CC (Si0_2, EtOAc-Pet Ether) to afford ethyl 1 -methyl-5-(4- methyl-1 -(thiazol-2-yl)-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxylate (240 mg, 36%).

LC-MS (Method 3): m/z [M+H]⁺ = 333 (MW calc. = 332.13).

Step 3: To a solution of ethyl 1 -methyl-5-(4-methyl-1 -(thiazol-2-yl)-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H- pyrazole-3-carboxylate (240 mg, 0.72 mmol) in THF-water (1 :1 , 6 mL), LiOH (60 mg, 1.43 mmol), was added and the RM was stirred at rt overnight. The solvent was evaporated and the aqueous residue was washed with EtOAc. The pH of the aqueous layer was adjusted to ~4 using 1 N HCI (~5 mL) and extracted with MeOH-CH₂CI₂ (1 :9). The organic layer was separated, dried and concentrated under reduced pressure to give a solid. This was dissolved in MeOH (15 mL) treated with charcoal ( 5 mg), refluxed for 15 min and filtered hot. The filtrate was concentrated under reduced pressure to afford BB-10 (130 mg, 60%).

LC-MS (Method 3): m/z [M+H]^* = 305 (MW calc. = 304.10). ¹H-NMR (400MHz, DMSO-d₆): δ = 1.55 (s, 3H), 2.35 (br, 2H); 3.68 (m, 2H), 3.74 (s, 3H), 3.95 (br, 2H), 6.64 (s, 1 H), 6.86 (d, 1 H); 7.18 (d, 1 H). Synthesis of representative examples

Synthesis example 1 : N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6- tet

Step 1 : A solution of BB-1 (150 mg, 0.6 mmol), 2,3-difluoropyridine (83 mg, 0.72 mmol) and DIPEA (387 mg, 3 mmol) in dry DMF (3 mL) was stirred at 100°C for 24 h. The volatiles were removed under reduce pressure and the residue was purified by CC (PF-30SIHP/25G / MeOH/ CH₂CI₂) to yield the desired compound (83 mg, 40%). LC-MS (Method 1): m/z [M+Hf = 345.3 (MW calc. = 344.16); R, = 3.8 min. ¹H-NMR (CDCI₃): δ = 1.39 (t, J = 7.2 Hz, 3H); 1.57 (s, 3H); 2.35 (m, 2H); 3.71 (m, 2H); 3.83 (s, 3H); 4.02 (m, 2H); 4.40 (q, J = 7.2 Hz, 2H); 6.67 (s, 1 H); 6.75 (m, 1 H); 7.24 (m, 1 H); 7.98 (m, 1 H). ³C-NMR (CDCI₃): δ = 14.4; 20.2; 31.0; 37.2; 44.8 (d, J = 7 Hz); 50.1 (d, J = 5 Hz); 60.8; 108.7; 115.7 (d, J = 3 Hz); 1 19.9; 123.2 (d, J = 19 Hz); 136.4; 142.6 (m); 142.7; 142.8; 149.2 (d, J = 7 Hz); 149.8 (d, J = 255 Hz); 162.4.

Step 2: To a solution of the intermediate from step 1 (83 mg, 0.24 mmol) and 2,6-difluoroaniline (37 mg, 0.29 mmol) in dry THF (6 mL) was added a solution of lithium bis(trimethylsilyl)amide (1 M in hexane, 0.36 mL, 0.36 mmol) and the RM was stirred at 60°C for 2 h. MeOH was added, the volatiles were removed under reduce pressure and the residue was purified by CC (PF-30SIHP/25G / Cy/EtOAc) to yield the desired compound (73 mg, 71 %).

LC-MS (Method 2): m/z [M+Hf = 428.2 (MW calc. = 427.43); R, = 0.78 min. H-NMR (CDCI₃): δ = 1 .61 (s, 3H); 2.38 (m, 2H); 3.75 (m, 2H); 3.85 (s, 3H); 4.06 (m, 2H); 6.77 (m, 1 H); 6.78 (s, 1 H); 7.27 (m, 1 H); 7.93 (m, 1 H), 8.40 (s, 2H); 8.48 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.3; 30.9, 37.1 , 44.8 (d, J = 8 Hz); 50.0 (d, J = 4 Hz); 107.5; 1 15.8 (d, J = 2 Hz); 1 19.9; 121.5 (t, J = 13 Hz); 123.2 (d, J = 19 Hz); 132.9 (m); 134.7 (m); 136.8; 142.7 (d, J = 5 Hz); 143.9 (d, J = 5 Hz); 149.2 (d, J = 7 Hz); 149.9 (d, J = 256 Hz); 153.2 (d, J = 263 Hz); 158.9.

Synthesis example 2: N-(3,5-Dif luoro-pyridin-4-yl)-5-[1 -(3-f luoro-py ridin-2-yl)-4-methyl-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to step 2 in the synthesis of example 1 using 4-amino-3,5- difluoropyridine as starting material (46 mg, 45%).

LC-MS (Method 2): m/z [M+H]⁺ = 429.2 (MW calc. = 428.42); R, = 0.74 min. ¹H-NMR (CDCI₃): δ = 1.61 (s, 3H); 2.38 (m, 2H); 3.75 (m, 2H); 3.85 (s, 3H); 4.06 (m, 2H); 6.77 (m, 1 H); 6.78 (s, 1 H); 7.27 (m, 1 H); 7.93 (m, 1 H); 8.40 (s, 2H); 8.48 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.3; 30.9; 37.1 ; 44.8 (d, J = 8 Hz); 50.0 (d, J = 4 Hz); 107.5; 1 15.8 (d, J = 2 Hz); 1 19.9; 121 .5 (t, J = 13 Hz); 123.2 (d, J = 19 Hz); 132.9 (m); 134.7 (m); 136.8; 142.7 (d, J = 5 Hz); 143.9 (d, J = 5 Hz); 149.2 (d, J = 7 Hz); 149.9 (d, J = 256 Hz); 153.2 (d, J = 263 Hz); 158.9.

Synthesis example 3: N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1-(2-methyl-pyrimidin-4-yl)- 1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

Step 1 : A solution of BB-1 (400 mg, 1.6 mmol), 4-chloro-2-methylpyrimidine (248 mg, 1.92 mmol) and DIPEA (1.02 g, 8 mmol) in dry DMF (14 mL) was stirred at 110°C for 3 h. The volatiles were removed under reduce pressure and the residue was purified by CC (PF-30SIHP/25G / MeOH/ CH₂CI₂) to yield the desired compound (202 mg, 37%).

LC-MS (Method 1): m/z [M+H]⁺ = 342.3 (MW calc. = 341.41 ); R, = 2.7 min. H-NMR (CDCI₃): δ = 1 .39 (t, J = 7.2 Hz, 3H); 1.59 (s, 3H); 2.33 (m, 2H); 2.50 (s, 3H); 3.81 (s, 3H); 3.85 (m, 2H); 4.40 (q, J = 7.2 Hz, 2H); 6.32 (d, J = 6 Hz, 1 H); 6.68 (s, 1 H); 8.14 (d, J = 6 Hz; 1 H). ¹³C-NMR (CDCI₃): δ = 14.4; 20.3; 26.0; 30.3; 37.2; 40.4; 47.0; 60.9; 100.0; 108.8; 1 19.0; 137.0; 142.1 ; 142.9; 155.6; 161.3; 162.3; 167.3.

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 (53 mg, 43%).

LC-MS (Method 2): m/z [M+H]⁺ = 425.2 (MW calc. = 424.45); R, = 0.45 min. ¹H-NMR (CDCI₃): δ = 1.64 (s, 3H); 2.36 (m, 2H); 2.53 (s, 3H); 3.81 (s, 3H); 3.88 (m, 2H); 4.12 (m, 2H); 6.35 (d, J = 6.4 Hz, 1 H); 6.78 (s, 1 H); 6.99 (m, 2H); 7.24 (m, 1 H); 8.16 (d, J = 6 Hz, 1 H); 8.22 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.4; 25.9; 30.3; 37.1 ; 40.5; 47.0; 100.0; 107.4; 1 1 1 .7 (m); 1 13.8 (t, J = 16 Hz); 119.1 ; 127.3 (t, J = 10 Hz); 137.1 ; 142.8; 144.8; 155.1 ; 158.0 (dd, J = 5, 250 Hz); 159.8; 161 .3; 167.1 .

Synthesis example 4: N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-[4-methyl-1-(2-methyl-pyrimidin-4- yl)-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 (92 mg, 35%).

LC-MS (Method 2): m/z [M+H]⁺ = 426.2 (MW calc. = 425.44); R, = 0.43 min. ¹H-NMR (CDCI₃): δ = 1.63 (s, 3H); 2.36 (m, 2H); 2.51 (s, 3H); 3.82 (s, 3H); 3.88 (m, 2H); 4.12 (m, 2H); 6.34 (d, J = 6 Hz, 1 H); 6.79 (s, 1 H); 8.16 (d, J = 6 Hz, 1 H); 8.40 (s, 2H); 8.49 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.4; 26.0; 30.3; 37.2; 40.5; 46.9; 100.0; 107.6; 1 19.0; 121 .4 (t, J = 13 Hz); 134.7 (m); 137.3; 143.2; 144.1 ; 153.3 (d, J = 261 Hz); 155.5; 158.8; 161.3; 167.3.

Synthesis example 5: N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -oxazol-2-yl-1 ,2,5,6-tetra- hydro-pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

Step 1 : A solution of BB-2 (250 mg, 0.91 mmol) and para toluene sulfonic acid monohydrate (519 mg, 2.73 mmol) in dry CH₂CI₂ (10 mL) was stirred at RT for 30 min. The RM was washed with saturated NaHC0₃ solution and water, dried and the volatiles were removed under reduce pressure. The residue was dissolved in 1 ,2-dichloroethane and stirred in the microwave at 120°C for 20 min. The volatiles were removed under reduced pressure and the residue purified by CC (PF-30SIHP/25G / MeOH/ CH₂CI₂) to yield the desired compound (260 mg, 90%).

LC-MS (Method 1): m/z [M+H]⁺ = 317.3 (MW calc. = 316.15); R, = 3.2 min. ¹H-NMR (CDCI₃): δ = 1.39 (s, J = 7.2 Hz, 3H); 1 .58 (s, 3H); 2.34 (m, 2H); 3.72 (m, 2H); 3.79 (s, 3H); 4.01 (m, 2H); 4.39 (q, J = 7.2 Hz, 2H); 6.66 (s, 1 H); 6.82 (d, J = 1.6 Hz, 1 H); 7.22 (d, J = 1.2 Hz, 1 H). ¹³C-NMR (CDCI₃): δ = 14.4; 20.4; 29.9; 37.2; 42.5; 48.5; 60.9; 108.8; 118.6; 126.8; 132.7; 136.5; 142.0; 142.8; 161.4; 162.3.

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 to yield example 5 (99 mg, 61 %).

LC-MS {Method 2): m/z [M+H]⁺ = 400.2 (MW calc. = 399.40); R, = 0.61 min. ¹H-NMR (CDCI₃): δ = 1.61 (t, J = 7.2 Hz, 3H); 2.35 (m, 2H); 3.74 (m, 2H); 3.79 (s, 3H); 4.03 (m, 2H); 6.75 (s, 1 H); 6.84 (d, J = 0.8 Hz, 1 H); 6.98 (m, 2H); 7.21 (m, 1 H); 7.23 (d, J = 0.8 Hz, 1 H); 8.21 (br s, 1 H). ³C-NMR (CDCI₃): δ = 20.5; 29.9; 37.0; 42.6; 48.4; 107.4; 1 1 1.7 (m); 113.8 (t, J = 17 Hz); 118.7; 126.8; 127.2 (t, J = 10 Hz); 132.7; 136.6; 142.6; 144.7; 158.0 (dd, J = 5,250 Hz); 159.8; 161 .4. Synthesis example 6: N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1-oxazol-2-yl-1 , 2,5,6- tetrahydro-pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 to yield the title compound (61 mg, 37%).

LC-MS (Method 2): m/z [M+H]⁺ = 401.2 (MW calc. = 400.39); R, = 0.55 min. ¹H-NMR (CDCI₃): δ = 1 .62 (t, J = 7.2 Hz, 3H); 2.37 (m, 2H); 3.75 (m, 2H); 3.83 (s, 3H); 4.04 (m, 2H); 6.77 (s, 1 H); 6.85 (d, J = 0.8 Hz, 1 H); 7.24 (d, J = 0.8 Hz, 1 H); 8.40 (s, 2H); 8.46 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.5; 29.9; 37.2; 42.6; 48.4; 107.6; 1 18.5; 121.5 (t, J = 13 Hz); 126.7; 132.8; 134.7 (m); 136.9; 143.0; 144.1 ; 153.2 (d, J = 261 Hz); 158.8; 161.3. Synthesis example 7: N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -(2-methyl-2H-tetrazol-5-yl)- 1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

mmol) in dry DMF (10 mL) was stirred at 100°C for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in dry CH₂CI₂. A solution of trimethylsilyldiazomethane in Et₂0 (2 M, 0.84 ml, 1.67 mmol) was added and the RM stirred at rt for 20 min. The volatiles were removed under reduced pressure and the residue was purified by CC (PF-30SIHP/40G / EtOAc) to yield the desired compound (291 mg, 63%: polar isomer / 67 mg, 5 %: less polar isomer).

Polar isomer

LC-MS (Method 1): mlz [M+Hf = 332.2 (MW calc. = 331.17); R, = 3.4 min. ¹H-NMR (CDCI₃): δ = 1.39 (t, J = 7.2 Hz, 3H); 1.38 (t, J = 7.2 Hz, 3H); 1 .56 (s, 3H); 2.33 (m, 2H); 3.72 (m, 2H); 3.79 (s, 3H); 3.97 (m, 2H); 4.15 (s, 3H); 4.39 (q, J = 7.2 Hz, 2H); 6.66 (s, 1 H). ¹³C-NMR (CDCI₃): δ = 14.3; 20.4; 29.5; 37.2; 39.3; 43.3; 49.5; 60.9; 108.8; 118.9; 136.4; 142.2; 142.8; 162.3; 169.1.

Less polar isomer

LC-MS (Method 1): mlz [M+H]⁺ = 332.2 (MW calc. = 331.17); R, = 3.1 min. ¹H-NMR (CDCI₃): δ = 1.39 (t, J = 7.2 Hz, 3H); 1.59 (s, 3H); 2.37 (m, 2H); 3.54 (m, 2H); 3.85 (s, 3H); 3.89 (m, 2H); 3.91 (s, 3H); 4.39 (q, J = 7.2 Hz, 2H); 6.65 (s, 1 H). ¹³C-NMR (CDCI₃): δ = 14.4; 20.3; 29.7; 33.8; 37.4; 46.5; 51 .9; 60.9; 108.8; 1 18.6; 136.5; 141.7; 142.9; 158.6; 162.3.

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 to give the title compound (102 mg, 63% yield).

LC-MS (Method 2): mlz [M+Hf = 415.2 (MW calc. = 414.42); R, = 0.68 min. ¹H-NMR (CDCI₃): δ = 1.60 (s, 3H); 2.34 (m, 2H); 3.75 (m, 2H); 3.79 (s, 3H); 4.00 (m, 2H); 4.17 (s, 3H); 6.75 (s, 1 H); 6.98 (m, 2H); 7.21 (m, 1 H); 8.21 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.5; 29.4; 37.0; 39.3; 43.4; 49.5; 107.4; 1 1 1.7 (m); 1 13.8 (t, J = 16 Hz); 1 19.1 ; 127.2 (t, J = 10 Hz); 136.5; 142.9; 144.7; 158.0 (dd, J = 5, 249 Hz); 159.8; 169.1 .

Synthesis example 8: N-(3,5-Difluoro-pyridin^-yl)-1-methyl-5-[4-methyl-1-(2-methyl-2H-tetrazol-5- yl)-1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 employing the intermediate from step 1 in example 7 to yield the title compound (71 mg, 44%).

LC-MS (Method 2): mlz [M+H]⁺ = 416.2 (MW calc. = 415.41 ); R, = 0.61 min. ¹H-NMR (CDCI₃): δ = 1 .61 (s, 3H); 2.35 (m, 2H); 3.75 (m, 2H); 3.81 (s, 3H); 4.00 (m, 2H); 4.17 (s, 3H); 6.77 (s, 1 H); 8.40 (s, 2H); 8.48 15 001268

(br s, 1 H). C-NMR (CDCI₃): δ = 20.5; 29.4; 37.1 ; 39.3; 43.4; 49.5; 107.6; 118.9; 121.6 (t, J = 13 Hz); 134.6 (m); 136.8; 143.3; 144.0; 153.2 (d, J = 261 Hz); 158.8; 169.1 .

Synthesis example 9: N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(1-methyl-1 H-tetrazol-5-yl)- 1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to step 2 in the synthesis of example 1 to give the title compound (52 mg, 62% yield).

LC-MS (Method 2): m/z [M+Hf = 415.2 (MW calc. = 414.42); R, = 0.61 min. ¹H-NMR (CDCI₃): δ = 1 .63 (s, 3H); 2.37 (m, 2H); 3.56 (m, 2H); 3.86 (s, 3H); 3.91 (m, 2H); 3.92 (s, 3H); 6.73 (s, 1 H); 6.98 (m, 2H); 7.21 (m, 1 H); 8.21 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 20.4; 29.6; 33.9; 37.2; 46.4; 51 .8; 107.2; 1 11.7 (m); 1 13.8 (t, J = 16 Hz); 118.7; 127.3 (t, J = 10 Hz); 136.6; 142.3; 144.8; 157.9 (dd, J = 5, 249 Hz); 158.6; 159.7.

Synthesis example 10: 5-(4-Cyclopropyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6- difluoro-phenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid amide

Step 1 : Hydrogen sulfide was bubbled into a solution of BB-4 (275 mg, 0.96 mmol) and NEt₃ (1.32 mL, 9.6 mmol) in dry EtOH (35 mL) at rt for 30 min. The volatiles were removed under reduced pressure. The residue was dissolved in acetone (10 mL) and subsequently concentrated. HCI (2 mL) and chloroacetaldehyde dimethylacetal (330 μΙ, 2.88 mmol) were added and the RM was stirred at reflux for 1 h. The volatiles were removed under reduced pressure and saturated NaHC0₃ solution was added followed by extraction with EtOAc. The combined organic layers were dried and the residue was purified by CC (PF-30SIHP/12G, EtOAc/Cy) to yield the desired compound (158 mg, 48%).

LC-MS (Method 1): m/z [M+H]⁺ = 345.2 (MW calc. = 344.13); R, = 3.2 min. ¹H-NMR (CDCI₃): δ = 0.58- 0.64 (m, 4H); 1.29 (m, 1 H); 2.02 (m, 2H); 3.71 (t, J = 6 Hz, 2H); 3.89 (s, 3H); 3.93 (s, 3H); 4.00 (t, J = 2 Hz, 1 H); 6.59 (d, J = 3.6 Hz, 1 H); 6.77 (s, 1 H); 7.21 (d, J = 3.6 Hz, 1 H).

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 to yield example 10 (54 mg, 53%).

LC-MS (Method 2): m/z [M+Hf = 442.2 (MW calc. = 441.50); R, = 0.70 min. ¹H-NMR (CDCI₃): δ = 0.60- 0.67 (m, 4H); 1 .36 (m, 1 H); 2.02 (m, 2H); 3.74 (t, J = 5.6 Hz, 2H); 3.88 (s, 3H); 4.00 (t, J = 2 Hz, 1 H); 6.59 (d, J = 3.6 Hz, 1 H); 6.85 (s, 1 H); 6.99 (m, 2H); 7.18-7.25 (m, 2H); 8.21 (s, 1 H). ³C-NMR (CDCI₃): δ = 4.2; 14.3; 22.9; 37.3; 44.9; 51.7; 107.4; 107.6; 111.7 (m); 113.8 (t, J = 16 Hz); 118.1, 127.2 (t, J = 10 Hz); 139.6; 140.1; 142.8; 144.8; 158.0 (dd, J = 250, 5 Hz); 159.8; 171.1.

Synthesis example 11: 4-Chloro-N-(2,6-difluoro-phenyl)-5-[1-(3-fluoro-pyridin-2-yl)-4-methyl- 1,2,

Step 1: The synthesis was performed in analogy to step 1 in the synthesis of example 1 to yield the desired compound (82 mg, 19%).

LC-MS (Method 2): m/z [M+H]⁺ = 365.2 (MW calc. = 364.80); R, = 3.7 min.¹H-NMR (CDCI₃): δ = 1.57 (s, 3H); 2.39 (s, 2H); 3.65 (m, 1H); 3.85 (m, 1H); 3.86 (s, 3H); 3.95 (s, 3H); 4.03 (m, 2H); 6.76 (m, 1H); 7.25 (m, 1H); 7.98 (m, 1H).¹³C-NMR (CDCI₃): δ = 20.1; 30.9; 38.2; 44.8 (d, J = 8 Hz); 48.4 (d, J = 4 Hz); 52.0; 112.1; 115.8 (d, J = 2 Hz); 117.6; 123.2 (d, J= 19 Hz); 137.9; 139.2; 140.6; 142.7 (d, J = 5 Hz); 148.2 (d, J = 7 Hz); 149.9 (d, J = 255 Hz); 166.4.

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 to yield example 11 (44 mg, 43%).

LC-MS {Method 2): m/z [M+H]⁺ = 462.1 (MW calc. = 461.87); R, = 0.82 min.¹H-NMR (CDCI₃): δ = 1.61 (s, 3H); 2.39 (s, 2H); 3.66 (m, 1H); 3.86 (s, 3H); 3.88 (m, 1H); 4.06 (m, 2H); 6.76 (m, 1H); 6.98 (m, 2H); 7.23 (m, 2H); 7.98 (m, 1H); 8.15 (brs, 1H).¹³C-NMR (CDCI₃): δ = 20.2; 30.9; 38.0; 44.8 (d, J = 8 Hz); 48.5 (d, J = 4 Hz); 111.0; 111.6 (m); 113.6 (t, J = 16 Hz); 115.7 (d, J = 3 Hz); 117.7; 123.2 (d, J= 19 Hz); 127.3 (t, J= 10 Hz); 139.2; 141.0; 142.7 (d, J = 5 Hz); 149.2 (d, J = 7 Hz); 149.9 (d, J = 255 Hz); 158.0 (dd, ,7 = 5, 249 Hz); 158.5.

Synthesis example 12: 4-Chloro-N-(3,5-difluoro-pyridin-4-yl)-5-[1-(3-fluoro-pyridin-2-yl)-4-methyl- 1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 employing the intermediate from step 1 in the synthesis of example 11 to yield the title compound (54 mg, 26%).

LC-MS {Method 2): m/z [M+H]⁺ = 463.1(MW calc. = 462.86); R, = 0.78 min.¹H-NMR (CDCI₃): δ = 1.61 (s, 3H); 2.40 (s, 2H); 3.65 (m, 1H); 3.87 (s, 3H); 3.88 (m, 1H); 4.06 (m, 2H); 6.76 (m, 1H); 7.26 (m, 1H); 7.98 (m, 1H); 8.40 (s, 2H); 8.42 (s, 1H).¹³C-NMR (CDCI₃): δ = 20.2; 30.9; 38.1; 44.8 (d, J = 8 Hz); 48.4 (d, J = 4 Hz); 111.5; 115.9 (d, J = 2 Hz); 117.5; 121.2 (t, J= 13 Hz); 123.2 (d, J= 19 Hz); 134.7 (dd, J= 5,22 Hz); 138.6; 139.5; 141.5; 142.7 (d, J = 5 Hz); 149.1 (d, J = 7 Hz); 149.9 (d, J = 255 Hz); 153.2 (d, J = 261 Hz); 157.5.

Synthesis example 13: 5-(4-Cyclopropyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(3,5- difluoro-pyridin-4-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 to give the title compound (64 mg, 40%).

LC-MS (Method 2): m/z [M+H]⁺ = 443.1 (MW calc. = 442.49); R, = 0.64 min. ¹H-NMR (CDCI₃): δ = 0.61- 0.66 (m, 4H); 1 .33 (m, 1 H); 2.02 (m, 2H); 3.74 (t, J = 5.6 Hz, 2H); 3.89 (s, 3H); 4.02 (t, J = 2 Hz, 2H); 6.60 (d, J = 3.6 Hz, 1 H); 6.87 (s, 1 H); 7.22 (d, J = 3.6 Hz, 1 H); 8.41 (s, 2H); 8.45 (s, 1 H). ³C-NMR (CDCI₃): δ = 4.3; 14.3; 22.9; 37.4; 45.0; 51 .6; 107.5; 107.9; 1 17.9; 121.5 (t, J = 16 Hz); 134.7 (m); 139.5; 140.3; 143.1 ; 144.1 ; 153.2 (d, J = 261 Hz); 158.8; 171.0.

Synthesis example 14: N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetra- hydro-pyridin-3-yl]-1 ,4-dimethyl-1 H-pyrazole-3-carboxylic acid amide

Step 1 : A solution of BB-6 (502 mg, 1.91 mmol) in 2,3-difluoropyridine (1.4 ml, 15.5 mmol) was stirred at 130°C for 48 h. The volatiles were removed under reduce pressure and the residue was purified by CC (PF-30SIHP/40G / MeOH/ CH₂CI₂) to yield the desired compound (356 mg, 52%).

LC-MS {Method 2): m/z [M+H]⁺ = 359.3 (MW calc. = 358.18); R_t = 3.9 min. ¹H-NMR (CDCI₃): δ = 1.41 (t, J = 7.2 Hz, 3H); 1.52 (s, 3H); 2.17 (s, 3H); 2.37 (m, 2H); 3.72 (m, 2H); 3.79 (s, 3H); 3.96 (m, 2H); 4.40 (q, J = 7.2 Hz, 2H); 6.75 (m, 1 H); 7.24 (m, 1 H); 7.98 (m, 1 H). ¹³C-NMR (CDCI₃): δ = 9.3; 14.5; 19.9; 31 .0; 37.2; 44.9 (d, J = 8 Hz); 49.3 (d, J = 5 Hz), 1 15.6 (d, J = 3 Hz); 119.2 (d, J = 18 Hz); 123.2 (d, J = 18 Hz); 137.4; 140.1 ; 140.9; 142.7 (d, J = 5 Hz); 149.3; 149.9 (d, J = 255 Hz); 163.1.

Step 2: The synthesis was performed in analogy to step 2 in the synthesis of example 1 to yield example 14 (90 mg, 73% yield).

LC-MS {Method 2): mlz [M+Hf = 442.2 (MW calc. = 441.46); R, = 0.87 min. ¹H-NMR (CDCI₃): δ = 1 .57 (s, 3H); 2.24 (s, 3H); 2.39 (m, 2 H); 3.75 (m, 2H); 3.80 (s, 3H); 3.99 (m, 2H); 6.75 (m, 1 H); 6.98 (m, 2H); 7.19 (m, 1 H); 7.25 (m, 1 H); 7.99 (m, 1 H); 8.25 (s, 1 H). ¹³C-NMR (CDCI₃):□ = 9.0; 20.0; 31.0; 37.1 ; 44.9 (d, J = 8 Hz); 49.3 (d, J = 5 Hz), 1 1 1 .7 (m); 1 14.1 (t, J = 16 Hz); 1 15.7 (d, J = 2 Hz); 1 18.3; 1 19.3; 123.2 (d, J = 19 Hz); 127.0 (t, J = 10 Hz); 137.4; 141.4 (d, J = 14 Hz); 142.7 (d, J = 5 Hz); 149.3 (d, J = 7 Hz); 149.9 (d, J = 255 Hz); 158.0 (dd, J = 5, 249 Hz); 161 .0.

Synthesis example 15: N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 ,4-dimethyl-1 H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 to give the title compound (61 mg, 35%).

LC-MS (Method 2): m/z [M+H]⁺ = 443.2 (MW calc. = 442.44); R, = 0.83 min. ¹ H-NMR (CDCI₃): δ = 1 .56 (s, 3H); 2.24 (s, 3H); 2.39 (m, 2 H); 3.75 (m, 2H); 3.81 (s, 3H); 3.98 (m, 2H); 6.76 (m, 1 H); 7.25 (m, 1 H); 7.99 (m, 1 H); 8.39 (s, 2H), 8.52 (s, H). ¹³C-NMR (CDCI₃):□ = 9.0; 20.0; 31.0; 37.2; 44.9 (d, J = 8 Hz); 49.3 (d, J = 5 Hz); 115.7 (d, J = 2 Hz); 1 18.6; 119.1 ; 121.7 (t, J = 13 Hz); 123.2 (d, J = 19 Hz); 134.6 (m); 137.7; 140.8; 141.8; 142.7 (d, J = 5 Hz); 149.2 (d, J = 6 Hz); 149.9 (d, J = 255 Hz); 153.2 (d, J = 259 Hz); 159.9.

Synthesis example 16: N-(3-Fluoro-pyridin-4-yl)-5-[1-(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 ,4-dimethyM H-pyrazole-3-carboxylic acid amide

The synthesis was performed in analogy to example 2 employing 4-amino-3-fluoropyridine to give the title compound (75 mg, 64%).

LC-MS (Method 2): m/z [M+H]⁺ = 425.2 (MW calc. = 424.45); R, = 0.86 min. ¹H-NMR (CDCI₃): δ = 1 .55 (s, 3H); 2.26 (s, 3H); 2.39 (m, 2 H); 3.74 (m, 2H); 3.81 (s, 3H); 3.98 (m, 2H); 6.76 (m, 1 H); 7.25 (m, 1 H); 7.99 (m, 1 H); 8.34 (m, 1 H), 8.43 (m, 1 H); 8.52 (m, 1 H), 9.20 (br s, 1 H). ¹³C-NMR (CDCI₃): δ = 9.1 ; 20.0; 31.0; 37.2; 44.9 (d, J = 7 Hz); 49.3 (d, J = 4 Hz); 1 14.2; 115.8 (d, J = 3 Hz); 118.4; 119.1 ; 123.2 (d, J = 19 Hz); 133.8 (d, J = 8 Hz); 136.9 (d, J = 21 Hz); 137.7; 141.2; 141.9; 142.7 (d, J = 5 Hz); 146.8 (d, J = 5 Hz); 149.2 (d, J = 250 Hz); 149.3 (d, J = 7 Hz); 149.9 (d, J = 255 Hz); 161.3.

Synthesis example 7: N-(3,5-difluoropyridin-4-yl)-1 -methyl-5-(4-methyl-1 -(pyrazin-2-yl)-1 ,2,5,6- tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxamide

A solution of BB-7 (79 mg, 0.24 mmol), 2-bromopyrazine (48 mg, 0.319 mmol), f-BuOK (8 mg, 0.72 mmol, as 1.0 M solution in dry THF) and iPr-PEPPSI catalyst (9 mg, 0.014 mmol) in toluene (3 mL) was heated at 70°C in a microwave reactor for 1 h. Then, water was added and the RM was extracted with EtOAc. The volatiles were removed under reduced pressure and the residue was purified by CC (PF-30SIHP/4G / Cy /EtOAc) to yield the desired compound (23 mg, 23%).

LC-MS (Method 2): m/z [M+Hf = 412.3 (MW calc. = 411 .16); R, = 0.662 min. ¹H-NMR (600MHz, DMSO- d₆): δ = 1.59 (s, 3H); 2.33 (m, br, 2H); 3.82 (s, 3H); 3.86 (t, J = 6.0 Hz, 2H), 4.12 (m, 2H); 6.78 (s, 1 H); 7.85 (d, J = 2.4 Hz, 1 H), 8.10 (m, 1 H), 8.37 (d, J = 2.4 Hz, 1 H), 8.59 (s, 2H), 10.32 (s, 1 H).

Synthesis example 18: N-(3,5-difluoropyridin-4-yl)-1-methyl-5-(4-methyl-1-(pyrimidin

tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxamide

The synthesis was performed in analogy to example 17 employing 2-bromopyrimidine (22 mg, 22%). LC-MS (Method 2): m/z [M+H]⁺ = 412.2 (MW calc. = 41 1.16); R, = 0.684 min. ¹H-NMR (600MHz, DMSO- d₆): δ = 1.58 (s, 3H); 2.29 (s, br, 2H); 3.81 (s, 3H); 3.98 (t, J = 6.0 Hz, 2H), 4.20 (s, 2H); 6.66 (t, J = 6.0 Hz, 1 H), 6.73 (s, 1 H), 8.40 (d, J = 6.0 Hz, 2H); 8.59 (s, 2H); 10.32 (s, 1 H).

Synthesis example 19: N-tS.S-difluoropyridin^-y -S-iS'-methoxy^-methyl-S.e-dihydro^H-II ^'- bipyridin]-3-yl)-1-methyl-1 H-pyrazole-3-carboxamide

The synthesis was performed in analogy to example 17 employing 2-bromo-3-methoxypyridine (29 mg, 27%).

LC-MS (Method 2). m/z [M+H]⁺ = 441.1 8 (MW calc. = 440.18); R, = 0.584 min. ¹H-NMR (600MHz, DMSO- d₆): δ = 1.56 (s, 3H); 2.28 (br, 2H); 3.59 (t, J =■ 6.0 Hz, 2H); 3.82 (s, 3H); 3.84 (s, 3H); 3.92 (br, 2H); 6.69 (s, 1 H); 6.88 (m, 1 H); 7.26 (m, 1 H); 7.77 (m, 1 H); 8.58 (s, 2H); 10.30 (s, 1 H). Synthesis example 20: N-(3,5-difluoropyridin^-yl)-5-(1 -(5-fluoropyrimidin-4-yl)-4-methyl-1 ,2,5,6- tetrahydropyri

The synthesis was performed in analogy to example 17 employing 4-bromo-5-fluoropyrimidine (25 mg, 24%).

LC-MS (Method 2): mlz [M+H]⁺ = 430.16 (MW calc. = 429.15); R, = 0.606 min. H-NMR (600MHz, DMSO- d₆): δ = 1.58 (s, 3H); 2.36 (br, 2H); 3.82 (s, 3H); 3.94 (t, J = 6.0 Hz, 2H), 4.28 (br, 2H); 6.75 (s, H); 8.30 (m, 1 H), 8.41 (m, 1 H); 8.58 (s, 1 H); 10.33 (s, 1 H).

Synthesis example 21 : N-(3,5-difluoropyridin-4-yl)-1 -methyl-5-(4-methyl-1 -(thiazol-2-yl)-1 ,2,5,6- tetrahydropyridin-3-yl)-1 H-pyrazole-3-carboxamide

To a suspension of BB-10 (100 mg, 1 eq) in CH₂CI₂, DIPEA (3 eq) was added and the RM was stirred at rt for 10 min. EDCI (1.5 eq) and HOBT (1.2 eq) were added and the RM was stirred for 10 more min. Then, 3,5-difluoropyridin-4-amine (1.2 eq) was added and the RM was stirred at rt overnight. The RM was diluted with water, extracted with CH₂CI₂. Then, the layers were separated, the aqueous layer was extracted with CH₂CI₂ and the combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (Si0₂, G- G254; MeOH/ CHCI₃) to give the target compound (28 mg, 21 %).

LC-MS (Method 2): mlz [M+H]⁺ = 417.1 (MW calc. = 416.12); R, = 0.565 min. ¹H-NMR (600MHz, DMSO- d₆): δ = 1 .59 (s, 3H); 2.37 (br, 2H); 3.70 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 4.00 (br, 2H); 6.76 (s, 1 H); 6.87 (d, J = 6.0 Hz, 1 H), 7.19 (d, J = 6.0 Hz, 1 H), 8.59 (s, 2H); 10.32 (s, 1 H).

Synthesis example 22: N-(2,4-difluorophenyl)-1 -methyl-5-(4-methyl-1 -(thiazol-2-yl)-1 ,2,5,6- tetrahydropyridin-3

The synthesis was performed in analogy to examp LC-MS (Method 2): m/z [M+H]⁺ = 416.2 (MW calc. = 415.13); R, = 0.729 min. ¹H-NMR (600MHz, DMSO- d_e): δ = 1 .58 (s, 3H); 2.37 (br, 2H); 3.69 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.99 (br, 2H); 6.72 (s, 1 H); 6.87 (d, J = 6.0 Hz, 1 H), 7.10 (m, 1 H), 7.19 (d, J = 6.0 Hz, 1 H), 7.27 (m, 1 H), 7.72 (m, 1 H), 9.67 (s, 1 H).

Synthesis example 23: N-(2,6-difluorophenyl)-1 -methyl-5-(4-methyl-1 -(thiazol-2-yl)-1 ,2,5,6-tetra- hydropyridin-3-yl)-1 H-pyrazole-3-carboxamide

The synthesis was performed in analogy to example 21.

LC-MS (Method 2): m/z [M+H]⁺ = 416.2 (MW calc. = 415.13); R, = 0.634 min. ¹H-NMR (600MHz, DMSO- d₆): δ = 1.59 (s, 3H); 2.37 (br, 2H); 3.70 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.99 (br, 2H); 6.71 (s, 1 H); 6.87 (d, J = 6.0 Hz, 1 H), 7.18 (m, 3H), 7.38 (m, 1 H), 9.82 (s, 1 H).

Synthesis examples 24 - 83:

Method A:

To a solution of N-(2,6-difluorophenyl)-1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxamide (BB-8, 1 10 μηηοΙ, 1.1 eq) in 1 mL of CH₂CI₂ was added the corresponding carboxylic acid (100 pmol, 1.0 eq) in 1 mL of CH₂CI₂. Then, 0.5 mL of a 1.0M solution of Et₃N in CH₂CI₂ was added, followed by addition of T₃P (1 -Propylphosphonic acid cyclic anhydride; 200 μιτιοΙ, 2.0 eq, 50% sol in EtOAc). The RM was stirred at rt for 2 h. Then, water (2 mL) was added and the RM was extracted with CH₂CI₂ (3 x 2 mL). The volatiles were removed under reduce pressure and the residue was purified by HPLC (Preparative Waters HPLC-MS System / Column. Macherey-Nagel Nucleodur C18 Gravity 5μηο 100x21 mm / Runtime 32 min / Flow Rate 35 mL/min / Eluent: A: Water; B: MeOH with 0.1 vol-% formic acid / Gradient: t = 0 min.: 75 / 25 (A / B), t = 1.0 min.: 75 / 25 (A / B), t = 21.0 min.: 35 / 65 (A / B), t = 30.0 min.: 0 / 100 (A / B), t = 32.0 min.: 75 / 25 (A / B))

Method B:

To a solution of N-(2,6-difluorophenyl)-1 -methyl-5-(4-methyl-1 ,2,5,6-tetrahydropyridin-3-yl)-1 H-pyrazole-3- carboxamide (BB-8, 100 pmol, 1 .0 eq) in 1 mL of MeOH was added the corresponding aldehyde (100 μιηοΙ, 1.0 eq) in 1 mL of MeOH. The mixture was stirred at 50°C for 1 h. Then, the RM was allowed to cool to rt and Boran-Pyridin-complex (100 pmol, 1 .0 eq, 0.2M solution in MeOH) was added. After 16 h at 50°C, the RM was carefully quenched with water and extracted with EtOAc (3 x 2 mL). The volatiles were removed under reduce pressure and the residue was purified by HPLC (Preparative Waters HPLC-MS System / Column: Macherey-Nagel Nucleodur C18 Gravity 5pm 100x21 mm / Runtime 20 min / Flow Rate 35 mL/min / Eluent: A: Water; B: MeOH with 0.1 vol-% formic acid / Gradient: t = 0 min.: 60 / 40 (A / B), t = 1.0 min.: 60 / 40 (A / B), t = 17.0 min.: 20 / 80 (A / B), t = 18.0 min.: 0 / 100 (A / B), t = 19.5 min.: 60 / 40 (A / B)). Method C:

A solution of BB-9 or BB-10 (1 .1 eq), HATU (1.5 eq) and DIPEA (3 eq) in CH₂CI₂/DMF (3:1 ), was stirred with the corresponding amine (1 eq) at 60°C for 18 h. Then, brine was added and the mixture was extracted with CH₂CI₂ (3 x 2 mL). The volatiles were removed under reduce pressure and the residue was purified by flash CC.

Table 1 :

N-(2,6-difluorophenyl)-5-(1 -(2- method 2

fluorobenzoyl)-4-methyl-1 ,2,5,6- m/z: [M+Hf = tetrahydropyridin-3-yl)-1 -methyl- A 455.1

1 H-pyrazole-3-carboxamide MWoaic = 454.16

R, = 0.70 min

N-(2,6-difluorophenyl)-1 -methyl- method 2 5-(4-methyl-1 -(4-methylthiazole- m/z: [M+H]⁺ = 2-carbonyl)-1 ,2,5,6-tetrahydro- A 458.2 pyridin-3-yl)-1 H-pyrazole-3- MW_cai_o = 457.14 carboxamide R, = 0.722 min

5-(1 -(2,6-difluorobenzoyl)-4- method 2 methyl-1 ,2,5,6-tetrahydro- m/z: [M+H]⁺ = pyridin-3-yl)-N-(2,6- A 474.1 difluorophenyl)-1 -methyl-1 H- MW_calc = 472.15 pyrazole-3-carboxamide R, = 0.706 min

N-(2,6-difluorophenyl)-1 -methyl- method 2 5-(4-methyl-1 -(2,2,2-trifluoro- m/z: [M+H]⁺ = acetyl)-1 ,2,5,6-tetrahydro- A 429.1 pyridin-3-yl)-1 H-pyrazole-3- MW_calc = 428.13

carboxamide R, = 0.709 min

N-(2,6-difluorophenyl)-5-(1-(3- method 2 fluoropicolinoyl)-4-methyl- m/z: [M+Hf = 1 ,2,5,6-tetrahydropyridin-3-yl)- A 456.2

1 -methyl-1 H-pyrazole-3- MW_calc = 455.16 carboxamide R, = 0.620 min

5-(1 -acetyl-4-methyl-1 ,2,5,6- method 2 tetrahydropyridin-3-yl)-N-(2,6- m/z: [M+Hf = difluorophenyl)-1 -methyl-1 H- A 375.1

N pyrazole-3-carboxamide MW_calc = 374.16

R, = 0.60 min

5-(1 -benzyl-4-methyl-1 ,2,5,6- method 2 tetrahydropyridin-3-yl)-N-(2,6- m/z: [M+Hf = difluorophenyl)-1 -methyl-1 H- B 423.3 pyrazole-3-carboxamide MW_ca,c = 422.19

R, = 0.54 min

N-(2,6-difluorophenyl)-1 -methyl- method 2 5-(4-methyl-1 -(pyridin-2-yl- m/z: [M+H]⁺ = methyl)-1 ,2,5,6-tetrahydro- B 424.3 pyridin-3-yl)-1 H-pyrazole-3- MW_calc = 423.19 carboxamide R( = 0.499 min

pyrazole-3-carboxamide R, = 0.513 min

\=J R, = 0.704 min 1268

R, = 0.602 min

R, = 0.644 min

Pharmacological methods

Compounds of the invention have been tested for their effects on CRAC channels according to the following or similar procedures. HEK Calcium influx assay

The effect of compounds of the invention on intracellular [Ca ⁺] was tested in the HEK293 cell line (ECACC). HEK293 cells were cultured in DMEM/F12/Glutamax (Gibco) containing 10%FCS (Gibco), and maintained at 37°C, 5% C0₂. Cell were split twice a week [3^*10⁶ (Mon-Thu) and 1 ^*10⁶ (Thu-Mon) cells/50ml medium in T-175 ZK culture flasks, respectively]. Twenty four hours pre-experiment, cells were seeded on 96 well plates (Poly-D-Lysine 96well Black/Clear Plate, BD Biocoat REF 356640) at a density of 40,000 cells / well in DMEM/F12 (Gibco) containing 10%FCS (Gibco), and maintained at 37°C, 5% C0₂. Prior to store-depletion, cell culture medium was removed and cells were loaded with the a Calcium-sensitive fluorescent dye comprised within the Calcium-4-assay kit (Molecular Devices) in nominally Ca²⁺-free HBS buffer (140 mM NaCI, 4 mM KCI, 0.2 mM MgCI₂, 1 1 mM D-glucose, and 10 mM HEPES, pH 7.4) according to manufacturer's instruction for 60 min at 37°C, 5% C0₂. Passive depletion of intracellular Ca^2*-stores was then triggered by employing the SERCA inhibitor thapsi- gargin (2 μΜ final) for 10 min in the dark (RT). To prevent immediate Ca²⁺- entry via the activated Store-operated channels (SOCs), cells were maintained in Ca²⁺-free HBS buffer comprising 00 μΜ EGTA during store-depletion. Intracellular changes in [Ca²⁺] were subsequently monitored with the FLIPR device (Molecular Devices). In brief, baseline imaging post-store depletion was allowed for 1 min before adjusting the extracellular buffer to 3 mM CaCI₂. Increases in intracellular [Ca²⁺] due to pre-activated SOC channels were monitored for 15 min until intracellular Ca²⁺ levels had declined into a steady-state. Finally, compounds were administered and Ca²⁺ signals were recorded for additional 10 min. Inhibition of endogenous SOC in HEK293 cells was quantified employing the average Ca²⁺ signal measured from 9.5-10 min post-administration. Zero percent inhibition (MAX) was defined as the Ca ⁺ signal recorded from wells to which DMSO-only had been added instead of compound. Hundred percent inhibition (MIN) was defined as the signal obtained from wells in which cells haven't been treated with TG prior to Ca ⁺ addition and to which DMSO-only had been added instead of compound. For routine IC50 determinations of compounds, 8 concentrations of a serial dilution (1 :3.16) were tested, starting off from 10 μΜ. Reliable IC50's could consequently be determined only, if they were at least sub 2.5-3 μΜ.

Jurkat IL-2 production assay

The effect of compounds of the invention on lnterleukin-2 (IL-2) production/release was tested in the Jurkat T cell line (ECACC) clone E6-1 . Jurkat T cells were cultured in DMEM/F12/Glutamax (Gibco) containing 10%FCS (Gibco), and maintained at 37°C, 5% C0₂. Cell were split twice a week [5^*10⁶ (Mon-Thu) and 1 ^*10⁷ (Thu-Mon) cells/50ml medium in T-175 ZK culture flasks, respectively]. Prior to experiment, cells were seeded on 96 well plates (Cellstar 96 Well; Cat No. 655180, Greiner bio-one) at a density of 5*10⁵ cells/well in DMEM/F12/ Glutamax (Gibco) containing 10%FCS (Gibco), and incubated for 60 min at 37°C, 5% C0₂. Subsequently, compounds were added and cells were allowed to incubate for 30 min at 37°C, 5% C0₂. Cells were then stimulated with 15 pg/ml Phytohemagglutinin (PHA; Sigma) for 22 hours at 37°C, 5% C0₂. Before sampling of the supernatants, cells were spun down (200^*g / 5 min / RT). The amount of IL-2 released into the supernatant was quantified with the human IL-2 AlphaLisa kit (Perkin Elmer) according to manufacturer's instructions. Luminescence proximity measurements were carried out in the Synergy H4 reader (BioTek) employing the fluorescence setting of the reader (ex: 680/30 nm; em: 620/40 nm). Inhibition of IL-production/release in/from Jurkat T cells cells was quantified as follows: Zero percent inhibition (MAX) was defined as the [IL-2] determined in supernatants derived from cells to which PHA & DMSO-only had been added instead of compound. Hundred percent inhibition (MIN) was defined as the [IL-2] determined in supernatants derived from cells that had been pre-treated with 1 μΜ CyclosporineA (Sigma) before the addition of 15 μg/ml PHA. For routine IC50 determinations of compounds, 8 concentrations of a serial dilution (1 :3.16) were tested, starting off from 10μΜ.

Exemplary compounds of the invention exhibit inhibition of the CRAC channel and inhibition of the IL- 2 production in these assays within the following ranges: IC₅₀ values from < 0.5 μΜ (A); 0.5 - 1.0 μΜ (B); > 1 .0 - 5.0 μΜ (C) and full IC₅₀ not determined (nd). or % inhibition @ 10 μΜ < 50 (C), 50 - 70 (B), > 70 (A).

Claims

Claims:

A compound according to general formula (I),

wherein

R¹ denotes H, C _-4-alkyl or C₃.₆-cycloalkyl;

R² denotes H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl; OH; 0-C,.₄-alkyl; OCH₃; OCF₃;

OCF₂H; OCFH₂; NH₂; N(H)C₁.₄-alkyl; N(d.₄-alkyl)₂;

A represents phenyl or a 5- or 6-membered heteroaryl,

B represents a partially unsaturated 5- or 6-membered heterocycloalkyl;

wherein said phenyl, said 5- or 6-membered heteroaryl and said partially unsaturated 5- or 6- membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted; wherein said d. -alkyl independently is linear or branched, and

wherein said C_1-4-alkyl and C₃.₆-cycloalkyl each independently is unsubstituted or mono- or polysubstituted; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate thereof.

2. A compound according to claim 1 , characterized in that the compound has general formula (la),

(la),

wherein

R³ is selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆- cycloalkyl and 3 to 7 membered heterocycloalkyl;

R⁴ is -L-B',

wherein L is bond, CH₂ or C(=0); and

B' is selected from the group consisting of CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆- cycloalkyl; 3 to 7 membered heterocycloalkyl; phenyl; 5- or 6-membered heteroaryl and OC-|.₄-alkyl;

wherein said C^-alkyl independently is linear or branched, and

wherein said phenyl and said 5- or 6-membered heteroaryl is unsubstituted or mono- or polysubstituted; wherein said Ci_₄-alkyl, C₃.₆-cycloalkyl and 3 to 7 membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted;

3. A compound according to claim 2, characterized in that

R³ is selected from the group consisting of H; CF₃; CF₂H; CH₂F; C - -alkyl and C^e-cycloalkyl; preferably R³ is H; CF₃; CF₂H; CH₂F; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl.

4. A compound according to claim 2 or 3, characterized in that L is bond or C(=0).

5. A compound according one or more of the claims 2 to 4, characterized in that

L is bond and

6. A compound according to one or more of the claims 2 to 4, characterized in that

L is C(=0) and

7. A compound according to one or more of the preceding claims, characterized in that R¹ is

selected from the group consisting of unsubstituted C-^-alkyl and unsubstituted cyclopropyl, preferably R¹ denotes CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

more preferably R¹ denotes CH₃.

8. A compound according to one or more of the preceding claims, characterized in that R² is

selected from the group consisting of H; F; CI; unsubstituted C^-alkyl and unsubstituted cyclopropyl;

preferably R² denotes H; CI; CH₃ or CH₂CH₃;

more preferably R² denotes H.

9. A compound according to one or more of the preceding claims, characterized in that A is selected from the group consisting of

phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl, each unsubstituted or mono- or polysubstituted with substituent(s) independently selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆-cycloalkyl; OH; 0-d.₄- alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d_₄-alkyl; N(d.₄-alkyl)₂ and NH(C=0)(C₁.₄-alkyl).

A compound according to one or more of the preceding claims, characterized in that

A is selected from he group consisting of the substructures (lla) to (llh);

wherein R⁷ is selected from F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl or C₃_₆-cycloalkyl;

and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆-cycloalkyl; OH; 0-d.₄-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d.₄-alkyl; N(d.₄-alkyl)₂ and NH(C=0)(C₁.₄-alkyl).

1 1. A compound according to one or more of the preceding claims, characterized in that A is selected from the group consisting of 2,6-difluorophenyl, 5-fluoro-4-methyl-pyridin-3-yl, 1 -methyl-pyrazol-5- yl, 3-fluoro-pyridin-4-yl, 2,4-dimethyl-pyridin-5-yl, 3,5-difluoro-pyridin-4-yl, 3,5-difluoro-pyridin-2-yl, 3,5-dichloro-pyridin-4-yl; 3-chloro-5-fluoro-pyridin-4-yl; 3-fluoro-pyridin-2-yl, 4-fluoro-5-methyl- pyridin-3-yl, 2,6-difluoro-4-methoxyphenyl,2-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6- fluorophenyl and 2,4-difluorophenyl.

12. A compound according one or more of the preceding claims, characterized in that the compound according to formula (I) has general formula (la),

a),

wherein

R¹ is selected from the group consisting of CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

R² is selected from the group consisting of H, CI, CH₃ and CH₂CH₃;

R³ is selected from the group consisting of H; CF₃; CF₂H; CH₂F; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl; L is bond or C(=0); and

or

L is C(=0);

and

A is selected from the group consisting of substructures (lla) to (lid);

(lib), (He), ("Id),

wherein

R⁷ is selected from F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl; and each R⁸ is independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H and OCFH₂;

13. A compound according to one or more of the preceding claims, selected from the group consisting of

₁ N-(2,6-Difluoro-phenyl)-5-[1-(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3- yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

₂ N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

₃ N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2-methyl-pyrimidin-4-yl)-1 ,2,5,6-tetra- hydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₄ N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-[4-methyl-1 -(2-methyl-pyrimidin-4-yl)-1 , 2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

, N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -oxazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

6 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -oxazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

₇ N-(2,6-Difluoro-phenyl)-1-methyl-5 4-methyl-1 -(2-methyl-2H-tetrazol-5-yl)-1 ,2,5,6-tetra- hydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₈ N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-[4-methyl-1 -(2-methyl-2H-tetrazol-5-yl)-1 ,2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

₉ N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(1 -methyl-1 H-tetrazol-5-yl)-1 ,2,5,6-tetra- hydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

_{1 0} 5-(4-Cyclopropyl-1-thiazol-2-yl-1 ,2,5,6-tetraty^

methyl-1 H-pyrazole-3-carboxylic acid amide

^ 4-Chloro-N-(2,6-difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

1₂ 4-Chloro-N-(3,5-difluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetra- hydro-py ridin-3-y l]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

^ j 5-(4-Cyclopropyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(3,5-difluoro-pyridin-4- yl)-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

₁₄ N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3- yl]-1 ,4-dimethyl-1 H-pyrazole-3-carboxylic acid amide

_{1 5} N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 ,4-dimethyl-1 H-pyrazole-3-carboxylic acid amide

₁₆ N-(3-Fluoro-pyridin-4-yl)-5-[1 -(3-fluoro-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin- 3-yl]-1 ,4-dimethyl-1 H-pyrazole-3-carboxylic acid amide

₁₇ N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -pyrazin-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

8 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -pyrimidin-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

9 N-(3,5-Difluoro-pyridin-4-yl)-5-[1-(3-methoxy-pyridin-2-yl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

0 N-(3,5-Difluoro-pyridin-4-yl)-5-[1 -(5-fluoro-pyrimidin-4-yl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

1 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

2 N-(2,4-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

3 N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

4 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridine-3-carbonyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

5 5-[1 -(Cyclopropanecarbonyl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-N-(2,6-difluoro- phenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridine-4-carbonyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide ₇ N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridine-2-carbonyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(1 -methyl-1 H-imidazole-2-carbonyl)-

1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

9 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2-methyl-propanoyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

0 N-(2,6-Difluoro^henyl)-5-[1 -(2-fluoro-benzoyl)-4-met yl-1 ,2,5,6-tetrahydro-pyridin-3-yl]- 1 -methyl-1 H-pyrazole-3-carboxylic acid amide

1 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(4-methyl-thiazole-2-carbonyl)-1 , 2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

2 5-[1 -(2,6-Difluoro-benzoyl)-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl]-N-(2,6-difluoro- phenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid amide

3 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(2,2,2-trifluoro-acetyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

4 N-(2,6-Difluoro-phenyl)-5-[1 -(3-fluoro-pyridine-2-carbonyl)-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

g 5-(1 -Acetyl-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6-difluoro-phenyl)-1-methyl- 1 H-pyrazole-3-carboxylic acid amide

6 5-(1 -Benzyl-4-methyl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl- 1 H-pyrazole-3-carboxylic acid amide

7 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridin-2-yl-methyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-1 -methyl-5-[4-methyl-1 -(pyridin-4-yl-methyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

g N-(2,6-Difluoro-phenyl)-5-[1 -[(2-fluorophenyl)-methyl]- -methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

0 N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -(pyridin-3-yl-methyl)-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

1 N-(2,6-Difluoro-phenyl)-5-[1-[(2,6-difluoro-phenyl)-methyl]-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

2 N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1 -[(3-methyl-3H-imidazol-4-yl)-methyl]- 1 ,2,5,6-tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

3 N-(2,6-Difluoro-phenyl)-5-[1 -[(2,4-dimethyl-thiazol-5-yl)-methyl]-4-methyl-1 ,2,5,6-tetra- hydro-pyridin-3-yl]-1-methyl-1 H-pyrazole-3-carboxylic acid amide

4 N-(2,6-Difluoro-phenyl)-1-methyl-5-[4-methyl-1-[(2-pheny!-thiazol-4-yl)-methyl]-1 , 2,5,6- tetrahydro-pyridin-3-yl]-1 H-pyrazole-3-carboxylic acid amide

5 N-(2,6-Difluoro-phenyl)-5-[1 -[(3-fluoro-pyridin-2-yl)-methyl]-4-methyl-1 ,2,5,6-tetrahydro- pyridin-3-yl]-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

6 N-(2-Chloro-6-methyl-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

N-(5-Chloro-2-methyl-phenyl)-1 -methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide ₈ 1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-phenyl-1 H- pyrazole-3-carboxylic acid amide

g N-(4-Methoxyphenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

0 1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetra ydro-pyridin-3-yl)-N 2-(trifluoromethyl- oxy)-phenyl]-1 H-pyrazole-3-carboxylic acid amide

1 N-(2-Methoxyphenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

2 N-(2,4-Difluoro-phenyl)-1-methyl-5-(4-methyl-1-thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

3 N-(2-Cyano-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

N-(3,5-Dimethoxy-p enyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin- 3-yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2,4-Dichlorophenyl)-1-methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetra ydro^yridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2,6-Difluoro-4-methoxy-p enyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetra- hydro-pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2,6-Difluoro-phenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3- yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2-Fluoro-6-methyl-phenyl)-1 -met yl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6 etrahydro^yridin-3-yl)-N-[2-(trifluoromethyl)- p enyl]-1 H-pyrazole-3-carboxylic acid amide

N-(2-Fluorophenyl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

N-(3-Fluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin- 3-yl)-1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-pyridin-4-yl-1 H- pyrazole-3-carboxylic acid amide

N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro- pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-o-tolyl-1 H- pyrazole-3-carboxylic acid amide

N-(3-Fluoro-5-methyl-pyridin-4-yl)-1 -methyl-5-(4-methyl-1 -thiazol-2-yl-1 ,2,5,6-tetra- hydro-pyridin-3-yl)-1 H-pyrazole-3-carboxylic acid amide

N-(2-Chloro-6-methyl-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

N-(5-Chloro-2-methyl-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

1 -Methyl-N-phenyl-5-(1-thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1H-pyrazole-3- carboxylic acid amide ₆₉ N-(4-Methoxyphenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇₀ 1 -Methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-N-[2-(trifluoromethyloxy)- phenyl]-1 H-pyrazole-3-carboxylic acid amide

₇₁ 1 -Methyl-N-o-tolyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H-pyrazole-3- carboxylic acid amide

₇₂ N-(2-Methoxyphenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇₃ N-(2,4-Difluoro^henyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇₄ N-(2-Cyano^henyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,64etrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇₅ N-(2,4-Dichlorophenyl)-1-methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro^yridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₇g N-(2,6-Difluoro-4-methoxy-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin- 3-yl)-1 H-pyrazole-3-carboxylic acid amide

₇₇ N-(2,6-Difluoro-phenyl)-1 riethyl-5-(1 -thiazol-2-yM

pyrazole-3-carboxylic acid amide

₇₈ N-(2-Fluoro-6-methyl-phenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6 etrahydro^yridin-3-yl)- 1 H-pyrazole-3-carboxylic acid amide

₇₉ 1 -Methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-N-[2-(trifluoromethyl)-phenyl]- 1 H-pyrazole-3-carboxylic acid amide

₈₀ N-(2-Fluorophenyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

₈₁ N-(3-Fluoro-pyridin-4-yl)-1 -methyl-5-(1 hiazol-2-yl-1 ,2,5,6-tetrahydro-pyridin-3-yl)-1 H- pyrazole-3-carboxylic acid amide

g₂ 1 -Methyl-N-pyridin^-yl-5-(1 -thiazol-2-yl-1 ,2,5,6-tetrahy^

carboxylic acid amide

₈₃ N-(3,5-Dimethoxy^henyl)-1 -methyl-5-(1 -thiazol-2-yl-1 ,2,5^ etrahydro-pyridin-3-yl)-1 H pyrazole-3-carboxylic acid amide

optionally in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate thereof.

A pharmaceutical composition comprising at least one compound according to one or more of claims 1 to 13 and optionally one or more suitable, pharmaceutically compatible auxiliaries and/or, if appropriate, one or more further pharmacologically active compounds.

A compound according to one or more of claims 1 to 13 for the treatment and/or prophylaxis of one or more disorders selected from the group consisting of inflammatory disorders and/or autoimmune diseases and/or allergic disorders, in particular psoriasis and/or psoriatic arthritis and/or rheumatoid arthritis and/or inflammatory bowel disease and/or asthma and/or allergic rhinitis.