WO2015197187A1

WO2015197187A1 - Pyrazolyl-based carboxamides v

Info

Publication number: WO2015197187A1
Application number: PCT/EP2015/001267
Authority: WO
Inventors: Felix VOSS; Sonja Nordhoff; Sebastian Wachten; Achim Kless; Stefanie RITTER
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 carboxamlde compounds of formula (I) 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

PYRAZOLYL-BASED CARBOXAMIDES V FIELD OF THE INVENTION

The invention relates to pyrazol-3-yl-carboxylic acid amides bearing an 5-membered heteroaryl 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 (SOC's; 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 ai, 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. 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. 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.

This object is achieved by the subject matter described herein.

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^-alky! or Cwrcycloalky!;

R² denotes H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyi; OH; O-C^-alkyl; OCH₃; OCF₃; OCF₂H;

OCFH₂; NH₂; N(H)C_1-4-alkyl; N(C_1-4-alkyl)₂;

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

B represents 5-membered heteroaryl,

wherein said phenyl, said 5- to 6-membered heteroaryl and said 5-membered heteroaryl 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, with the proviso that the compound of general formula (I) is not 5-(2,5-dimethyl-3-thienyl)-1 -ethyl-N-(2- fluorophenyl)-1 H-pyrazole-3-carboxamide, 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. 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 "Ci. -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 Ci_₄-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 NKC^e-alkyl) such as N(CH₃), wherein the ring members can be unsubstituted or mono- or polysubstituted. The 3 to 7 membered heterocycloalkyl 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 "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 furyl (furanyl), imidazolyl, isoxazoyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.

The term "5-membered heteroaryl" for the purpose of this invention represents a 5-membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3 or 4 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 5-membered heteroaryl residue to be selected from the group consisting of furyl (furanyl), imidazolyl, isoxazoyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl and thiadiazolyl.

In relation to the terms "d^-alkyl, C₃.₆-cycloalkyl and 3 to 7 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, tetrasub- stitution, 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; Ci. 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 C_1-4-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-cycloalkyl); C(=0)-0(3 to 7 membered heterocycloalkyi); C(=0)- O(aryl); C(=0)-0(heteroaryl); C(=0)-NH₂; C(=0)-N(H)(d-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(Ci-4-alkyl)(C₃.₆-cycloalkyl); C(=0)-N(C₁.₄-alkyl)(3 to 7 membered heterocycloalkyi); C(=0)-N(d-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; O-

0-C(=0)-(3 to 7 membered heterocycloalkyi); 0-C(=0)- (aryl); C(=0)-(heteroaryl);

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

to 7 membered heterocycloalkyi);

(aryl); N(d.₄-alkyl)-C(=0)-(heteroaryl); N(H)-S(=0)₂-(C,.₄-alkyl); N(H)-S(=0)₂-(d-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-(C₁.₄-alkyl); N(C₁.₄-alkyl)-S(=0)₂-(C₃.₆-cycloalkyl); N(C₁.₄-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(d_₄-alkyl); N(H)- C(=0)-0(d-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(C₁.₄-alkyl)-C(=0)-0(C₁.₄-alkyl); N(Ci.₄-alkyl)-C(=0)-0(C₃.₆-cycloalkyl); N(d.₄- alkyl)-C(=0)-0(3 to 7 membered heterocycloalkyi);

N(C₁.4-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(d.₄-alkyl)-C(=0)-NH₂; N(Ci.4-alkyl)-C(=0)-N(H)(d.4-alkyl); N(d.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(d.₄-alkyl)₂; N(H)-C(=0)-N(C₁.₄-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(C_1-4-alkyl)- (heteroaryl); N(C₁.₄-alkyl)-C(=0)-N(C₁.₄-alkyl)₂; N(C₁.₄-alkyl)-C(=0)-N(C₁.₄-alkyl)(d-6-cycloalkyl); N(d.₄- alkyl)-C(=0)-N(C₁.₄-alkyl)(3 to 7 membered heterocycloalkyi); N(d-₄-alkyl)-C(=0)-N(d.₄-alkyl)(aryl); N(C,. ₄-alkyl)-C(=0)-N(d.₄-alkyl)(heteroaryl); S-(C₃._e-cycloalkyl); S-(3 to 7 membered heterocycloalkyi); S-(aryl); S-(heteroaryl); SCF₃; S(=0)₂OH; S(=0)-(d.₄-alkyl); S(=0)-(d-₆-cycloalkyl); S(=0)-(3 to 7 membered heterocycloalkyi); S(=0)-(aryl); S(=0)-(heteroaryl);

to 7 membered heterocycloalkyi); S(=0)₂-(aryl); S(=0)₂-(heteroaryl); S(=0)₂-0(d.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)(d.4-alkyl); S(=0)₂-N(H)(C₃._e-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(C₁.₄-alkyl)(C₃.₆-cycloalkyl); S(=0)₂- N(C_1-4-alkyl)(3 to 7 membered heterocycloalkyl); S(=0)₂-N(C₁.₄-alkyl)(aryl); S(=0)₂-N(C₁.₄-alkyl)(hetero- aryl).

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 "C_1-4-alkyl, C₃.₆-cycloalkyl and 3 to 7 membered heterocycloalkyl" are selected from the group consisting of F; CI; CN; =0; CF₃; CF₂H; CFH₂; CF₂CI; CFCI₂; C_1-4-alkyl C(=0)-H; C(=0)- d.₄-alkyl; C(=0)-OH; C(=0)-0-C_M-alkyl; C(=0)-N(H)(OH); C(=0)-NH₂; C(=0)-N(H)(d.₄-alkyl); C(=0)- N(d.₄-alkyl)₂; OH; OCF₃; OCF₂H; OCFH₂; OCF₂CI; OCFCI₂; 0-d.₄-alkyl; O-C(=0)-C_1-4-alkyl; 0-C(=0)-0- C_1-4-alkyl; 0-(C=0)-N(H)(C₁.₄-alkyl); 0-C(=0)-N(C₁.₄-alkyl)₂; 0-S(=0)₂-d-₄-alkyl; 0-S(=0)₂-OH; 0-S(=0)₂- 0-d.₄-alkyl;

NH₂; N(H)(d.₄-alkyl); N(d.₄-alkyl)₂; N(H)-C(=0)-d.₄-alkyl; N(H)-C(=0)-0-d.₄-alkyl; N(H)-C(=0)-NH₂; N(H)-C(=0)-N(H)(C₁.₄- alkyl); N(H)-C(=0)-N(d.₄-alkyl)₂; N(C₁.₄-alkyl)-C(=0)-C₁.₄-alkyl; N(d.₄-alkyl)-C(=0)-O-d.₄-alkyl; N(d.₄- alkyl)-C(=0)-NH₂; N(C₁.₄-alkyl)-C(=0)-N(H)(C₁.₄-alkyl); N(d.₄-alkyl)-C(=0)-N(d.₄-alkyl)₂; N(H)-S(=0)₂- OH; N(H)-S(=0)₂-d.₄-alkyl; N(H)-S(=0)₂-0-d.₄-alkyl; N(H)-S(=0)₂-NH₂; N(H)-S(=0)₂-N(H)(d.₄-alkyl); N(H)-S(=0)₂-N(d.₄-alkyl)₂; N(d.₄-alkyl)-S(=0)₂-OH; N(C₁.₄-alkyl)-S(=0)₂-C₁.₄-alkyl; N(d.₄-alkyl)-S(=0)₂- 0-d.₄-alkyl; N(d.₄-alkyl)-S(=0)₂-NH₂; N(d.₄-alkyl)-S(=0)₂-N(H)(d.₄-alkyl); N(d.₄-alkyl)-S(=0)₂-N(d.₄- alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂CI; SCFCI₂; S-d.₄-alkyl; S(=0)-C₁.₄-alkyl; S(=0)₂-C_1-4-alkyl; S(=0)₂-OH; S(=0)₂-0-d.₄-alkyl; S(=0)₂-NH₂; S(=0)₂-N(H)(d.₄-alkyl); and S(=0)₂-N(d.₄-alkyl)₂.

More preferred substituents of "d.₄-alkyl, C₃.₆-cycloalkyl and 3 to 7 membered heterocycloalkyl" are selected from the group consisting of F; CI; CF₃; CN; =0; d_₄-alkyl; C(=0)-C_1-4-alkyl; C(=0)-OH; C(=0)- 0-d.₄-alkyl; C(=0)-NH₂; C(=0)-N(H)(d.₄-alkyl); C(=0)-N(d.₄-alkyl)₂; OH; 0-C_1-4-alkyl; 0-C(=0)-d_₄- alkyl; OCF₃; NH₂; N(H)(d.₄-alkyl); N(Ci.₄-alkyl)₂; N(H)-C(=0)-d_₄-alkyl; N(H)-S(=0)₂-C₁.₄-alkyl; N(C,.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(d.₄-alkyl)₂; N(d.₄- alkyl)-S(=0)₂-NH₂; N(Ci.₄-alkyl)-S(=0)₂-N(H)(d.₄-alkyl); N(d.₄-alkyl)-S(=0)₂-N(d-₄-alkyl)₂; S(=0)₂ d.₄- alkyl; S(=0)₂OH; S(=0)₂0-d.₄-alkyl; S(=0)₂-NH₂; S(=0)₂-N(H)(d.₄-alkyl) and S(=0)₂-N(d.₄-alkyl)₂.

Most 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)(d.₄-alkyl); C(=0)-N(d.₄-alkyl)₂; OH; 0-d.₄-alkyl; NH₂; N(H)(C₁.₄-alkyl); N(d.₄- alkyl)₂; N(H)-C(=0)-C,.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 and 3 to 7 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(d.₄-alkyl)₂; OH; O-C_!^-alk l; OCF₃; 0-C(=0)-d.₄-alkyl; NH₂; NH-C_1-4-alkyl; N(C_1-4- alkyl)₂;

alkyl)₂ and S(=0)₂-N(H)-d-4-alkyl.

In relation to the terms "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_₆-cycloalkyl or 3 to 7 membered hetero- cycloalkyl, each connected via a d-4-alkyl; C(=0)H; C(=0)-( C^-alkyl); C(=0)-(C₃.₆-cycloalkyl); C(=0)-(3 to 7 membered heterocycloalkyl); C(=0)-(aryl); C(=0)-(heteroaryl); C(=0)OH; C(=0)-0(d-₄-alkyl); C(=0)- 0(C₃.₆-cycloalkyl); C(=0)-0(3 to 7 membered heterocycloalkyl); C(=0)-0(aryl); C(=0)-O(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 heterocycloalkyl); C(=0)-N(H)(aryl); C(=0)-N(H)(heteroaryl);

cycloalkyl);

C(=0)-N(d- -alkyl)(heteroaryl); OH; =0; 0-(d. -alkyl); 0-(C₃.₆-cycloalkyl); 0-(3 to 7 membered heterocycloalkyl); O- (aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂CI; OCFCI₂; 0-C(=0)-(d.₄-alkyl); 0-C(=0)-(C_3-6-cyclo- alkyl); 0-C(=0)-(3 to 7 membered heterocycloalkyl); 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 heterocycloalkyl); 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(C₁.₄-alkyl)(3 to 7 membered heterocycloalkyl); 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 heterocycloalkyl); 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 heterocycloalkyl); N(C,.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 heterocycloalkyl); N(H)-C(=0)-(aryl); N(H)-C(=0)- (heteroaryl); N(d.₄-alkyl)-C(=0)-(d.₄-alkyl); N(C₁.₄-alkyl)-C(=0)-(C₃.₆-cycloalkyl); N(d.₄-alkyl)-C(=0)-(3 to 7 membered heterocycloalkyl); N(d.₄-alkyl)-C(=0)-(aryl); N(C₁.₄-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 heterocycloalkyl); N(H)- S(=0)₂-(aryl); N(H)-S(=0)₂-(heteroaryl); N(d.₄-alkyl)-S(=0)₂-(d.₄-alkyl); N(Ci.₄-alkyl)-S(=0)₂-(C₃.₆-cyclo- alkyl); N(C₁.₄-alkyl)-S(=0)₂-(3 to 7 membered heterocycloalkyl); N(C,.₄-alkyl)-S(=0)₂-(aryl); N(d.₄-alkyl)- S(=0)₂-(heteroaryl);

N(H)-C(=0)-0(3 to 7 membered heterocycloalkyl); N(H)-C(=0)-0(aryl); N(H)-C(=0)-0(heteroaryl);

alkyl); N(C₁.₄-alkyl)-C(=0)-0(C₃.₆-cycloalkyl); N(C₁.₄-alkyl)-C(=0)-0(3 to 7 membered heterocycloalkyl); 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)(d-₆-cycloalkyl); N(H)-C(=0)-N(H)(3 to 7 membered heterocycloalkyl); N(H)-

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

to 7 membered heterocycloalkyi); S(=0)₂-N(C₁.₄-alkyl)(aryl); S(=0)₂-N(C₁.₄-alkyl)(heteroaryl).

Preferred substituents of "aryl" and "heteroaryl" are selected from the group consisting of F; CI; CF₃; CN; Ci-₄-alkyl; C(=0)-OH; C(=0)-0-d-4-alkyl; CO-NH₂; C(=0)-N(H)d_₄-alkyl; C(=0)-N(d-₄-alkyl)₂; OH; O-d. 4-alkyl;

alkyl; N(d.₄-alkyl)-C(=0)d.₄-alkyl; N(H)-S(=0)₂-d.₄-alkyl; N(Ci-₄-alkyl)-S(=0)₂(C₁.₄-alkyl); N(H)C(=0)- NH₂;

N(d_₄-alkyl)- C(=0)-N(H)C_1-4-alkyl; N(C₁.₄-alkyl)-C(=0)-N(C₁-₄-alkyl)₂, S(=0)₂C_M-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 ^st 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 resubstituted (3^ra generation substituents). If, for example, R^A = a C_1-4-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 = (C₁. -alkyl-N(H)-C₁_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 = C₁.₄-alkyl-N(H)-C₁.₄-alkyl-CI, wherein the C_1- -alkyl of the N(H)d. -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. In one embodiment of the first aspect of the invention, the compound according to general formula (I) is charact at B has the substructure (III),

(III),

wherein

X is selected from O, S, N(R^5a), N or CR^6a;

Y is selected from O, S, N(R^5b), N or CR^6b;

Z is selected from O, S, N(R^5c), N or CR^6c;

and

B' is selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C - -alkyl; C₃-₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; phenyl or heteroaryl;

wherein

R^5a, R^5b and R^5c are independently selected from the group consisting of H; CF₃; CF₂H; CFH₂; d^-alkyl;

C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; (C=0)(C₁.₄-alkyl);

R^6a, R^6b, R^6c are independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; d-4-alkyl; C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; OH; O-d-4-alkyl; OCF₃; OCF₂H; OCFH₂;

NH₂; N(H)d.₄-alkyl; N(C₁.₄-alkyl)₂; NH(C=0)(C₁.₄-alkyl);

wherein said C_1-4-alkyl independently is linear or branched, and

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

wherein said C_1-4-alkyl, C₃.₆-cycloalkyl and 3 to 7 membered heterocycloalkyl 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.

It has been found that a certain substitution pattern of B, having substructure (III), even enhances the activity of the compounds as ICRAC inhibitors.

Hence, in one preferred embodiment of the first aspect of the invention, the compound according to general formula (I) is characterized in that

B has the substructure (III), and

X is selected from N(R^5a) or CR^6a; wherein

R^6a is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_n-4-alkyl and C^-cycloalkyl; and

R^5a is selected from the group consisting of C_1-4-alkyl and C₃.₆-cycloalkyl.

Preferably, B has the substructure (III), and X is selected from N(R^5a) or CR^6a; wherein R^5a or R^6a represent C₁.₄-alkyl. More preferably, B has the substructure (III),

wherein the substructure (III) is selected from any of the substructures (Ilia) to (lllo)

(Him), R ^a is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; Ci.₄-alkyl and C₃.₆-cycloalkyl;

R ³ is selected from the group consisting of C^-alkyl and C₃.₆-cycloalkyl; and

R is selected from the group consisting of C_1-4-alkyl and C₃.₆-cycloalkyl.

Even more preferably, B has the substructure (III),

wherein the substructure (III) is selected from any of the substructures (Ilia) to (Hid),

wherein R^6a is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl and C₃_₆- cycloalkyl.

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

B has the substructure (III) and

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃.₆-cycloalk l; 3 to 7 membered heterocycloalkyl; phenyl and 5- or 6- membered heteroaryl,

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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, B has the substructure (III) and B' is selected from the group consisting of CF₃; CF₂H; CFH₂; d.4-alkyl; C₃.₆-cycloalkyl and 5- or 6-membered heteroaryl,

wherein said 5- or 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl,

and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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 has the substructure (III) and B' is selected from the group consisting of CF₃; CH₃; cyclopropyl; oxazolyl; thiazolyl; pyridinyl and pyrimidinyl;

wherein said oxazolyl; thiazolyl; pyridinyl; and pyrimidinyl is unsubstituted und monosubstituted with F; CI; CN; CF₃; CF₂H; CFH₂; CH₃ and cyclopropyl.

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

B has the substructure (III),

wherein the substructure (III) is selected from any of the substructures (Ilia) to (llld)

("la), (1Mb), lc), (Hid), wherein

R^6a is selected from the group consisting of CN; CF₃; CF₂H; CFH₂; C₁_ -alkyl and C₃.₆-cycloalkyl;

and

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; C - -alkyl; C^e-cycloalkyl and 5- or 6-membered heteroaryl,

and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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 to general formula (I) is characterized in that

B has the substructure (III), wherein

R^6a is selected from the group consisting of CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃ and cyclopropyl, and and B' is selected from the group consisting of CF₃; CH₃; cyclopropyl; oxazolyl; thiazolyl; pyridinyl and pyrimidinyl; wherein said oxazolyl; thiazolyl; pyridinyl; and pyrimidinyl is unsubstituted und monosubstituted with F; CI; CN; CF₃; CF₂H; CFH₂; CH₃ and cyclopropyl.

More preferably, the compound according to general formula (I) is characterized in that

B has the substructure (III), wherein

R^6a is CH₃ and

and B' is selected from the group consisting of CF₃; CH₃; cyclopropyl; oxazolyl; thiazolyl; pyridinyl and pyrimidinyl;

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

B has the substructure (III), wherein

R^6a is selected from the group consisting of CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃ and cyclopropyl, and and B' is selected from the group consisting of CF₃; CH₃; cyclopropyl; 2-oxazolyl; 2-thiazolyl; 2-pyridinyl; 2-pyrimidinyl; 4-oxazolyl; 4-thiazolyl; 3-pyridinyl; 4-pyrimidinyl; 5-oxazolyl; 5-thiazolyl; 4-pyridinyl; 5- pyrimidinyl; 4-methyl-oxazol-2-yl; 4-methyl-thiazol-2-yl; 3-methyl-pyridin-2-yl; 4-methyl-pyrimidin-2-yl; 5-methyl-oxazol-2-yl; 5-methyl-thiazol-2-yl; 4-methyl-pyridin-2-yl; 5-methyl-pyrimidin-2-yl; 5-methyl- pyridin-2-yl; 6-methyl-pyridin-2-yl; 2-methyl-oxazol-4-yl; 2-methyl-thiazol-4-yl; 2-methyl-pyridin-3-yl; 2- methyl-pyrimidin-4-yl; 5-methyl-oxazol-4-yl; 5-methyl-thiazol-4-yl; 4-methyl-pyridin-3-yl; 5-methyl- pyrimidin-4-yl; 5-methyl-pyridin-3-yl; 6-methyl-pyridin-3-yl; 2-methyl-oxazol-5-yl; 2-methyl-thiazol-5-yl; 2- methyl-pyridin-4-yl; 2-methyl-pyrimidin-5-yl; 4-methyl-oxazol-5-yl; 4-methyl-thiazol-5-yl; 3-methyl-pyridin-

4- yl; 5-methyl-pyrimidin-4-yl; 4-fluoro-oxazol-2-yl; 4-fluoro-thiazol-2-yl; 3-fluoro-pyridin-2-yl; 4-fluoro- pyrimidin-2-yl; 5-fluoro-oxazol-2-yl; 5-fluoro-thiazol-2-yl; 4-fluoro-pyridin-2-yl; 5-fluoro-pyrimidin-2-yl; 5- fluoro-pyridin-2-yl; 6-fluoro-pyridin-2-yl; 2-fluoro-oxazol-4-yl; 2-fluoro-thiazol-4-yl; 2-fluoro-pyridin-3-yl; 2- fluoro-pyrimidin-4-yl; 5-fluoro-oxazol-4-yl; 5-fluoro-thiazol-4-yl; 4-fluoro-pyridin-3-yl, 5-fluoro-pyrimidin-4-yl;

5- fluoro-pyridin-3-yl; 6-fluoro-pyridin-3-yl; 2-fluoro-oxazol-5-yl; 2-fluoro-thiazol-5-yl; 2-fluoro-pyridin-4-yl; 2- fluoro-pyrimidin-5-yl; 4-fluoro-oxazol-5-yl; 4-fluoro-thiazol-5-yl and 3-fluoro-pyridin-4-yl; 5-fluoro-pyrimidin- 4-yl.

In one embodiment of the first aspect of the invention, the compound according to the present invention is characterized in that R¹ denotes H; C^-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 C₁.₄-alkyl or unsubstituted cyclopropyl. More preferably, R is selected from the group consisting of unsubstituted d-4-alkyl. Even more preferably, R is selected from CH₃ and CH₂CH₃. Most preferably, R¹ denotes CH₃.

In one 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; Br; CN; CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; OH; OCH₃; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)CH₃; N(CH₃)₂. Preferably, R² is selected from the group consisting of H, CI, CH₃ and CH₂CH₃. Most preferably, R² denotes H.

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

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

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- - alkyl; C_M-c cloalkyl; OH; O-C^-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)C_M-alkyl; N(C,.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; C₃.₆-cycloalkyl; OH; 0-C,.₄-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)C_1- -alkyl; N(C_1-4-alkyl)₂ and

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)C^-alkyl; N(C^-alkyl)₂ and NH(C=0)(C₁.₄-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; C_1- -alkyl; C₃.₆-cycloalkyl; and each R 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)C₁.₄-alkyl; N(C_1-4-alkyl)₂;

More preferred is a compound according the first aspect of the invention, characterized in that

A is selected from the group consistin of the substruct to 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-Ci.₄-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d.₄-alkyl; N(d.₄-alkyl)₂ and NH(C=0)(d.₄-alkyl).

More preferably, R⁷ is independently selected from F; CI; CF₃; CF₂H; CFH₂ and Ci.₄-alkyl. Even more preferably, R⁷ is independently selected from F; CI and CH₃. Most preferably, R⁷ is selected from F.

Even more preferably, each R is independently selected from the group consisting of H; F; CI; CN; CF₃; d_₄-alkyl; 0-d.₄-alkyl; OCF₃; OCF₂H or OCFH₂. Even more preferably, each R⁸ is independently selected from H; F; CI; CF₃; OCF₃; CH₃ and OCH₃.

Still more preferably,

A is selected from the group consisting of substructures (lla) to (lid), 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; 0-CH₃; OCF₃; OCF₂H and OCFH₂.

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-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl and 2,4-difluorophenyl. Another embodiment of the first aspect of the invention is a compound according to general formula (I) characterized in that the compound has general formula (la):

(la),

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;

substructure (III),

(III), is selected from the group consisting of substructures (Ilia) to (llld)

(Ilia), (Hlb), (lllc), (llld), wherein

R^6a is selected from the group consisting of CF₃; CF₂H; CFH₂. CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyi, thienyl, furanyl, pyrroiyi, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazoiyi, oxadiazolyl, thiadiazolyl and tetrazolyl, and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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;

and

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

(Ha), (lib), (lie), (lid), 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; 0-CH₃; OCF₃; OCF₂H and OCFH₂;

with the proviso that the compound of general formula (la) is not 5-(2,5-dimethyl-3-thienyl)-1 -ethyl-N-(2- fluorophenyl)-1 H-pyrazole-3-carboxamide,

Preferably, the compound according to general formula (la) is characterized in that

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

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

substructure (III) is selected from the group consisting of substructures (Ilia) to (llld), wherein

R^6a is selected from the group consisting of CF₃; CF₂H; CFH_2, CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl; and

B' is selected from the group consisting of

CH₃; cyclopropyl and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl and oxazolyl, and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted with F; CI; CN; CF₃; CF₂H; CFH₂; CH₃; cyclopropyl;

and

A is selected from the group consisting of substructures (I la) to (lid), 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; 0-CH₃; OCF₃; OCF₂H and OCFH₂.

More preferably, the compound according to general formula (la) is characterized in that

R¹ is CH₃;

R² is H;

B' is selected from the group consisting of

and

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-fluorophenyl, 2-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6- fluorophenyl and 2,4-difluorophenyl.

Still more preferably, the compound according to general formula (la) is characterized in that

R¹ is CH₃;

R² is H;

B' is selected from the group consisting of

CH₃; cyclopropyl and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl and oxazolyl, and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted with F; CI; CN; CF₃; CF₂H; CFH₂; CH₃ or cyclopropyl;

and

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

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)-1-methyl-5-(5-methyl-2-oxazol-2-yl-thiazol-4-yl)-1 H-pyrazole-3-carboxylic acid amide

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

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

4 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(2-methyl-5^yridin-2-yl-thiophen-3-yl)-1 H-pyrazole-3- carboxylic acid amide

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

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

7 5-(2-Cyclopropyl-5-methyl-thiazol-4-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

8 5-(2-Cyclopropyl-5-methyl-thiazol-4-yl)-N-(3,5-difluoro-pyridin-4-yl)-1-methyl-1 H-pyrazole-3- carboxylic acid amide

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

10 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

11 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H-pyrazole-3- carboxylic acid amide 12 N-(2,6-Difluoro-phenyl)-1-methyl-5-(5-m

acid amide

13 N-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(5-methyl-2-pyridin-3-yl-thiazol-4-yl)-1 H-pyrazole-^

carboxylic acid amide

14 N-(2,6-Difluoro-phenyl)-1-methyl-5-(2-methyl-5-oxa2ol-2-yl hiophen-3-yl)-1 H-pyrazole-3-carboxylic acid amide

15 5-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H-pyrazole-3- carboxylic acid amide

16 5-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H-pyrazole-3 carboxylic acid amide

17 N-(2,6-Difluoro-phenyl)-5-(2,5-dimethyl-thiophen-3-yl)-1 -methyl-1 H-pyrazole-3-carboxylic acid amide

18 N-(3,5-Difluoro-pyridin-4-yl)-5-(2,5-dim^ acid amide

19 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[2-methyl-5-(2-oxo-oxazolidin-3-yl)-thiophen-3-yl]-1 H-py

carboxylic acid amide

20 N-(2,6-Difluoro~phenyl)-1 -methyl-5-(4-methyl-2-py

acid amide

21 N-(2,6-Difluoro-phenyl)-1 -methyl-5-[2-methyl-5-(6-methyl-pyridin-3-yl)-thiophen-3-yl]-^

carboxylic acid amide

22 N-(2,6-Difluoro^henyl)-5-[5-(5-fluoro-pyridin-3-yl)-2-methyl-thiophen-3-yl]-1-methyl-1 H

carboxylic acid amide

23 N-(3-Fluoro-pyridin-4-yl)-1-methyl-5-(2-methyl-5-oxazol-2-yl-thiophen-3-yl)-1 H-pyrazole-3-carboxylic acid amide

24 N-(3-Fluoro-pyridin-4-yl)-1 -methyl-5-(2-methy^

acid amide

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

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, intradermal^, 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 haemolytic 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 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, lupus nephritis, 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 inhibitors 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 6 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 a glyoxalate diester as diethyl glyoxalate yields a β- 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, 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, as shown in Scheme 2 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.

Alternatively, the B-ring moiety may be incorporarted by direct coupling through a Palladium catalyzed C- H-activation reaction of the 5-unsubstituted pyrazoie ester with a 5-membered heteroaryl halogenide. Subsequent steps may then follow the route depicted in Scheme 1. In particular cases a protecting group may be employed.

As shown in Scheme 4 and 5 alternatively Pd-catalyzed coupling methods may be used to obtain compounds of the invention. Scheme 4 illustrates the synthesis via a pyrazoie bromide or triflate employed in a Suzuki cross coupling with an appropriate boronic acid or ester. The coupling may also be performed on a pyrazoie ester intermediate. Scheme 5 provides an example how a 5-unsubstituted pyrazoie ester is converted into a boronic ester in the presence of an iridium catalyst and bispinacolatodiborane. Suzuki coupling with an appropriate aryl halogenide or triflate subsequently gives aryl pyrazoie esters that can be converted to compounds of the invention as shown in Scheme 1 .

Alternatively, synthesis of compounds of the present invention can be accomplished starting from B-ring substitutetd alkynes (Int 19) wich can be, mediated by cooper(l) salts, transformed to intermediates Int 20 which are than condensed with apropiate hydrazines to intermediates of typ Int 3 which can be converted to compounds of the invention as shown in Scheme 1 (Scheme 6). Scheme 6

Exemplified Compounds

The following examples of the invention were prepared according to reaction schemes 1 to 6.

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 ¹ H- 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.

Further abbreviations: AIMe₃ = trimethylaluminium; Cy = cyclohexane; DMF = Λ/,/V-dimethylformamide; EtOH = ethanol; EtOAc = ethyl acetate; LHMDS = Lithium hexamethyldisilazide; eOH = methanol; NEt₃ = triethyl amine; PdOAc₂ - palladium(ll)acetate; Pd(dppf)CI₂-CH₂CI₂ = [1 , 1 '-bis(diphenylphosphino)- ferrocene]dichloropalladium(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: 1.39 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; Detection: UV, 220 and 260 nm; Column: Zorbax Extend C18 4.6 x 50 mm, 5 micron; Column temperature: 30°C; Flow rate: 1.2 mL/min; Runtime: 5 min.

Eluent: A: Water with 0.05 vol-% formic acid; B: CH₃CN; Gradient: t = 0 min: 90 / 10 (A / B); t = 1.50 min: 70 / 30 (A / B); t = 3.00 min: 10 / 90 (A / B); t = 4.00 min: 10 / 90 (A / B); t = 5.00 min: 90 / 10 (A / B).

Chromatography

Biichi MPLC system; Stationary phase: silica gel, 40-50μ or

PuriFlash 430; Stationary phase: InterchimO-cartridges.

NMR spectroscopy

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

Building Block 1 : 5-Bromo-W-(2,6-difluorophenyl)-1 -methyl-1 H-pyrazole-3-carboxamide

^NN-N_v -

BB-1

Step 1 : To a solution of methyl 5-hydroxy- -methyl-1 H-pyrazole-3-carboxylate (2.0 g) in CH₃CN (47 mL) was added phosphorus(V)oxybromide (18.3 g) and the RM was heated to 80°C for 18 h. The RM was chilled in an ice bath and saturated Na₂C0₃ solution was added. The mixture was extracted with EtOAc, the combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired product.

LC-MS {Method 2): m/z [M+H]⁺ = 219.0 (MW calc. = 219.04); R, = 0.45 min.

Step 2: A solution of the intermediate of step 1 (506 mg) in dioxane (10 mL) was treated with LiOH solution (2 M, 1 mL) and the mixture was stirred at 70°C for 1 h. HCI (1 M) was added and the mixture was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound (84%).

LC-MS (Method 2): m/z [M+H]⁺ = 205.0 (MW calc. = 205.01 ); R, = 0.31 min.

Step 3: A solution of the intermediate of step 2 (2.5 g, 12.2 mmol) in SOCI₂ (21 mL, 293 mmol) was heated to 60°C for 1 h. The volatiles were removed under reduced pressure to yield the desired compound (2.5 g, 99%).

Step 4: To a solution of the intermediate of step 3 (800 mg, 3.58 mmol) in CH₂CI₂ (58 mL) were consecutively added NEt₃ (0.98 mL, 7.16 mmol) and 2,6-difluoro-aniline (508 mg, 3.94 mmol) and the RM was stirred at RT overnight. Saturated NH₄CI was added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Interchim® cartridge50SiHP / 25 g, Cy/EtOAc) to yield the desired compound (260 mg, 23%). LC-MS (Method 2): mlz [M+Hf = 316.0 ( W calc. = 316.10); R, = 0.77 min. H-NMR (DMSO-d₆): δ = 9.91 (s, 1 H), 7.44-7.33 (m, 1 H), 7.22-7.12 (m, 2H), 6.95 (s, 1 H), 3.95 (s, 3H) ppm.

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

4,4'-Di-ferf-butyl-2,2'-dipyridyl (194 mg) was added to a solution of (1 ,5-Cyclooctadiene)- (methoxy)iridium(l) dinner (241 mg) and pinacolborane (4.13 g) in pentane (21 mL) and the RM was stirred for 20 min at RT. Then a solution of 1 -methyl-1 H-pyrazole-3-carboxylate (3.05 g) 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 chromatography (Si0₂, CH₂CI₂ / eOH) to yield the desired product (78%).

¹H-NMR (DMSO-de): δ = 7.00 (s, 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 2a: Methyl 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole-3- carboxylate

BB-2a was prepared in analogy to the synthesis of BB-2 starting from methyl 1 -methyl-1 /-/-pyrazole-3- carboxylate (80%). l)oxazole

Step 1 : A solution of NaN0₂ (5.70 g, 61.0 mmol) in water (10 mL) was added at 0°C to a solution of 5- methylthiazol-2-amine (3.00 g, 26.4 mmol) in cone. H₃P0₄ (30 mL) and cone. HN0₃ (15 mL) and the mixture was stirred at 0°C for 20 min. The RM was then added to mixture of Cu(l)Br (3.9 g, 26.4 mmol) in HBr (46%, 30 mL) and the RM was stirred at RT for 2 h. The mixture was chilled in an ice bath and NaOH (5M) followed by NaHC0₃ were added. The mixture was extracted with EtOAc, the combined organic layers were washed with sodium thiosulfate and brine, were dried and the volatiles were removed under reduced pressure. The residue was recrystallized (Cy) to yield the desired compound (4.78 g, 73%).

LC-MS (Method 1): m/z: [M+H]⁺ = 256.0 (MW calc. = 254.84), R, = 3.3 min.

Step 2: 2-(Tributylstannyl)oxazole (1.07 g, 3.00 mmol) was added to a solution of the intermediate of step 1 (770 mg, 3.00 mmol) and Pd(PPh₃)₄ (347 mg, 300 prnol) in dry CH₃CN (4 mL) and the RM was stirred at 90°C for 20 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield BB-3 (570 mg, 78%).

LC-MS (Method 1): m/z: [M+H]⁺ = 245.1 (MW calc. = 254.84), R, = 3.1 min. ¹ H-NMR (CDCI₃): δ = 7.76 (d, J = 0.8 Hz, 1 H), 7.27 (d, J = 0.8 Hz, 1 H), 2.48 (s. 3H) ppm. )pyridine

Step 1 : /PrMgCI LiCI (1.3M in THF, 3.61 mL, 4.68 mmol) was added under N₂ to a solution of 2,4-di- bromo-2-methyl-thiophene (1 .00 g, 3.91 mmol) in dry THF (10 mL) at 0°C and the RM was stirred for 40 min. Trimethyl borate (0.85 mL, 7.62 mmol) was added and the RM was stirred at 0°C for 30 min. Aqueous HCI (2M, 8 mL) was added, the mixture was stirred for 10 min and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound (757 mg) as crude that was used without further purification in the next step.

Step 2: A mixture of the crude product of step 1 (750 mg, 3.40 mmol), 2-bromo pyridine (804 mg, 496 pmol) and Pd(dppf)CI₂-CH₂CI₂ (124 mg, 170 μιτιοΙ) in THF (22 mL) and aqueous Na₂C0₃ (2M, 4.7 mL) was heated in a microwave to 100°C for 2h. Saturated NH₄CI was added and the organic phase was separated. The volatiles were removed and the residue was purified by chromatography (Interchim® cartridge50SiHP / 25 g, Cy/EtOAc) to yield BB-4 (454 mg, 53%).

¹ H-NMR (DMSO-d₆): δ = 8.51 (d, J = 5.0 Hz, 1 H), 7.95-7.89 (dd, J = 7.5 Hz, 1 ,5 Hz, 1 H), 7.75 (s, 1 H), 7.31 -7.26 (m, 1 H), 2.40 (s, 3H) ppm.

Building Block 5: 3-(4-bromo-5-methylthiophen-2-yl)pyridine

A mixture of 3,5-dibromo-2-methylthiophene (500 mg, 1 .95 mmol), pyridin-3-ylboronic acid (266 mg, 2.17 mmol) and Pd(PPh₃)₄ (229 mg, 196 Mmol) in a mixture of THF (6 mL) and aqueous Na₂C0₃ (2M, 3.5 mL) was heated under N₂ to 80°C for 4 h. Water was added and the mixture was extracted with CH₂CI₂. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Interchim® cartridge50SiHP / 25 g, Cy/EtOAc) to yield BB-5 (380 mg, 77%).

1 H-NMR (DMSO-d₆): δ = 8.88-8.84 (m, 1 H), 8.53-8.49 (m, 1 H), 8.03-7.98 (m, 1 H), 7.60 (s, 1 H), 7.46-7.42 (m, 1 H), 2.41 (s, 3H) ppm.

Building Block 6: 5-(4-bromo-5-methylthiophen-2-yl)-2-methylpyrimidine

BB-6 was prepared in analogy to BB-5 through the reaction of 3,5-dibromo-2-methylthiophene (250 mg, 976 pmol) with (2-Methylpyrimidin-5-yl)boronic acid (148 mg, 1.07 mmol) (36 mg, 14%).

LC-MS (Method 2): m/z: [M+H]⁺ = 269.1 (MW calc. = 269.16), R, = 0.86 min. yclopropyl-5-methylthiazole

Cyciopropyl zinc bromide (0.5m in THF, 17 mL, 8.5 mmol) was added under a nitrogen atmosphere to a mixture of the step 1 intermediate of BB-3 (1.09 g, 4.25 mmol) and Pd(PPh₃)₄ (491 mg, 430 pmol) in THF and the mixture was heated to 75°C for 1 h. The volatiles were removed under reduced pressure, water was added, and the mixture was extracted with CHCI₃. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield BB-7 (403 mg, 43%). LC-MS (method 1): m/z: [M+H]⁺ = 218.1 (MW calc. = 218.1 1 ), R, = 3.5 min. ¹H-NMR (CDCI₃): δ = 2.32 (s, 3H), 2.21 (m, 1 H), 1.10 (m, 4H) ppm. hiophen-2-yl)pyridine

A solution of 3,5-dibromo-2-methylthiophene (935 mg, 3.65 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine (750 mg, 3.65 mmol), K₂C0₃ (1.64 g, 11 .9 mmol) and Pd(PPh₃)₄ (256 mg, 230 μηιοΙ) in a mixture of DME (25 mL) and water (5 mL) was heated under Ar to 80°C for 3 h. The mixture was chilled, brine was added and was extracted with CH₂CI₂. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield BB-8 (606 mg, 65%).

LC-MS (method 1 ): m/z: [M+Hf = 254.1 (MW calc. = 254.11 ), R, = 2.7 min. ¹H-NMR (CDCI₃): δ = 8.58 (dd, J = 4.4 Hz, 2 Hz), 7.38 (dd, J = 4.4 Hz, 2 Hz), 7.32 (s, 1 H), 2.45 (s, 3H) ppm.

Building Block 9: 3-bromo-5-chloro-2-methylthiophene

A solution of bromine (470 μί, 9.00 mmol) in CHCI₃ (5 mL) was added to a solution of 2-chloro-5- methylthiophene (1.00 g, 7.5 mmol) in CHCI₃ (15 mL) at 0°C and the mixture was stirred at RT for 2 h. The mixture was treated with saturated NaHC0₃ and was extracted with CHCI₃. The volatiles were removed under reduced pressure to yield the desired compound (1.38 g, 87%).

1H-NMR (CDCI₃): δ = 6.73 (s, 1 H), 2.32 (s, 3H) ppm. -3-yl)thiazole

Step 1 : A solution of thionicotinamide (10.0 g, 72.5 mmol) and 2-bromo propionaldehyde diethyl acetal (12.8 ml_, 72.5 mmol) in acetic acid (100 mL) was stirred at 100°C for 16 h. The volatiles were removed under reduced pressure and the residue was diluted with saturated NaHC0₃ and was extracted with EtOAc. The combined organic layers were washed with water and brine, were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (5.5 g, 43%).

Step 2: Bromine (6.2 mL, 124.3 mmol) was added to a solution of step 1 intermediate (5.5 g, 31 .1 mmol) in a mixture of CHCI₃ (60 mL) and CH₃CN (60 ml) at 0°C. The resulting RM was stirred at 80°C for 80h. The mixture was poured into a solution of sodium thiosulphate at 0°C and was extracted with EtOAc. The combined organic layers were washed with water and brine, were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield BB-10 (2.4 g, 30%).

¹H-NMR (CDCI3): δ = 9.06 (d, J = 4.8 Hz, 1 H), 8.64 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 8.18 (td, J = 8.0 Hz, 1.8 Hz, 1 H), 7.39-7.35 (m, 1 H), 2.47 (s, 3H) ppm. methylthiophen-2-yl)oxazole

A solution of 3,5-dibromo-2-methylthiophene (2.55 g, 10.0 mmol), oxazole (2.84 g, 20.0 mmol), Pd(PPh₃)₄ (240 mg, 1.00 mmol) and LiOr-Bu (1.58 g, 20.0 mmol) in dioxane (32 mL) was heated under Ar to 140°C for 3 h. The volatiles were removed under reduced pressure, saturated NH₄CI was added and the mixture was extracted with EtOAc. The combined organic layers were dried, the volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to give BB-1 1 (1 .20 g, 49 %).

LC-MS (Method 1): m/z: [M+Hf = 244.1 (MW calc. = 244.1 1 ), R, = 3.7 min. ¹H-NMR (CDCI₃): δ = 7.62 (d, J = 0.8 Hz, 1 H), 7.46 (s, 1 H), 7.16 (d, J = 0.8 Hz, 1 H), 2.44 (s, 3H) ppm.

Building Block 12: Ethyl S'-cyclopropyl^^'-dimethyl^H^'H-tS.S'-bipyrazolel-S-carboxylate

Step 1 : A solution of 1 ,4-bis(trimethylsilyl)buta-1 ,3-diyne (4.54 g, 23.4 mmol) in dry CH₂CI₂ was treated at 0°C with AICI₃ (3.42 g, 25.7 mmol) and cyclopropanecarbonyl chloride (2.34 g, 25.7 mmol) and the mixture was stirred at RT for 45 min. Aqueous HCI (1 M) and water were added and the mixture was extracted with CH₂CI₂. The volatiles were removed to yield the desired compound (4.42 g, 99%).

Step 2: A solution of step 1 intermediate (3.99 g, 21.0 mmol) in EtOH (20 mL) was treated with methyl hydrazine (1.08 mL, 21 mmol) and the mixture was stirred at 80°C for 1 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desried compound (2.78 g, 61 %).

Step 3: A solution of step 2 intermediate (2.78 g, 12.7 mmol) in MeOH (26 mL) was treated with aqueous NaOH (2M, 26 mL, 52.0 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (1 .13 g, 61 %).

Step 4: A solution of step 3 intermediate (1.13 g, 7.73 mmol) in dry THF (26 mL) was treated with Cu(l)l (77 mg, 400 pmol) and NEt₃ (1.12 mL, 15.5 mmol) and the mixture was stirred at RT for 10 min. Ethyl 2- chloro-2-oxoacetate (1.74 mL, 15.5 mmol) was added and the mixture was stirred at RT for 17 h. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (1.59 g, 84%).

Step 5: A solution of step 4 intermediate (1.59 g, 6.46 mmol) in EtOH (13 mL) was treated with methyl hydrazine (0.77 mL, 14.2 mmol) and the mixture was stirred at 80°C for 3 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield BB-12 (1.31 g, 73%).

¹H-NMR (CDCI₃): δ = 6.87 (s, 1 H), 6.05 (s, 1 H), 4.43 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1 .94 (m, 1 H), 1.41 (t, J = 7.1 , 3H), 0.95 (m, 2H), 0.75 (m, 2H) ppm.

Building Block 13: 3-(4-bromo-5-methylthiophen-2-yl)oxazolidin-2-one

A degassed mixture of 3,5-dibromo-2-methylthiophene (2.00 g, 7.81 mmol), oxazolidin-2-one (220 mg, 2.58 mmol), Cu(!)l (480 mg, 2.58 mmol), K₂C0₃ (720 mg, 5.24 mmol) and ethylene diamine (140 mg 2.58 mmol) in dioxane (5 mL) was heated to 100°C overnight. The volatiles were removed and the residue was purified by chromatography (Interchim® cartridge50Si^'HP / 12 g, Cy/EtOAc) to yield the desired compound (728 mg, 36%).

H-NMR (DMSO-d₆): δ = 6.49 (s, 1 H), 4.54-4.49 (m, 2H), 4.03-3.97 (m, 2H), 2.27 (s, 3H), ppm. Building Block 14: 5-(4-bromo-5-methylthiophen-2-yl)-2-methylpyridine

A mixture of 3,5-dibromo-2-methylthiophene (250 mg, 976 ymol), (6-methylpyridin-3-yl)boronic acid (141 mg, 1 .07 mmol), Pd(PPh₃)₄ (1 15 mg, 98 pmol) in Na₂C0₃ (2M, 0.9 mL), EtOH (0.9 mL) and toluene (4.7 mL) was heated under N₂ to 100 C for 1 h. The layers were separated, the organic layer was dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Interchim® cartridge50SiHP / 25 g, Cy/EtOAc) to yield the desired compound.

LC-MS (Method 2): m/z: [M+Hf = 268.1 (MW calc. = 268.17), R, = 0.70 min.

Building Block 15: 3-(4-Bromo-5-methylthiophen-2-yl)-5-fluoropyridine

BB-15 was prepared in analogy to BB-14 starting from 3,5-dibromo-2-methylthiophene (250 mg, 976 mmol) (265 mg, 99%).

LC-MS (Method 2): m/z: [M+Hf = 272.1 (MW calc. = 272.14), R, = 0.97 min. Representative Examples

Example 1 : A -(2,6-Difluoro-phenyl)-1 -methyl-5-(5-methyl-2-oxazol-2-yl-thiazol-4-yl)-1 H-pyrazole-3- carboxylic acid amide

Step 1 : A solution of BB-3 (570 mg, 2.33 mmol), BB-2a (620 mg, 2.33 mmol), LiOH (56 mg, 2.33 mmol) and bis(tri-fert-butylphosphine)palladium(0) (1 18 mg, 230 pmol) in dry DMF (10 mL) was heated under N₂ to 80°C for 1 h. The volatiles were removed under reduced pressure and the residue was treated with water and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, CH₂CI₂/MeOH) to yield the title compound of example 1 (227 mg, 32%).

¹H-NMR (CDCI₃): δ = 7.79 (s, 1 H), 7.31 (s, 1 H), 6.97 (s, 1 H), 4.12 (s, 3H), 3.96 (s, 3H), 2.59 (s, 3H) ppm. Step 2: A solution of the intermediate of step 1 (120 mg, 390 μιτιοΓ) and 2,6-difluoroaniline (71 mg, 550 pmol) in dry THF was treated with LHMDS (1 M in hexane, 550 pL, 550 pmol) and the mixture was stirred at 70°C for 1 h. The mixture was chilled and MeOH was added. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (89 mg, 56%).

LC-MS (Method 2): m/z: [M+H]⁺ = 402.1 (MW calc. = 401.08), R, = 0.69 min. ¹H-NMR (CDCI₃): δ = 8.27 (s, 1 H), 7.80 (s, 1 H), 7.32 (s, 1 H), 7.24 (m, 1 H), 7.00 (m, 2H), 4.13 (s, 3H), 2.62 (s, 3H) ppm.

Example 2: W-(3,5-Difluoro-pyridin^-yl)-1 -methyl-5-(5-methyl-2-oxazol-2-yl-thiazol-4-yl)-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 2 was prepared in analogy to example 1 through the reaction of step 1 intermediate (107 mg, 350 pmol) with 3,5-difluoropyridin-4-amine (64 mg, 490 pmol) (60 mg, 43%).

LC-MS {Method 2): m/z: [M+H]⁺ = 403.1 (MW calc. = 402.07), R, = 0.63 min. ¹H-NMR (CDCI₃): δ = 8.53 (s, 1 H), 8.42 (s, 2H), 7.80 (d, J = 0.8 Hz, 1 H), 7.32 (d, J = 0.8 Hz, 1 H), 7.06 (s, 1 H), 4.14 (s, 3H), 2.62 (s, 3H) ppm.

Example 3: W-(2,6-Difluoro-phenyl)-1 -methyl-5-(2-methyl-5-pyridin-2-yl-thiophen-3-yl)-1 H-pyrazole- 3-carboxylic acid amide

The title compound of example 3 was prepared in analogy to example 1 starting from BB-4 (380 mg, 1.50 pmol) (57 mg, 33% over 2 steps).

LC-MS (Method 2): m/z: [M+H]⁺ = 41 1 .2 (MW calc. = 410.10), R, = 0.77 min. H-NMR (DMSO-d₆): δ = 9.88 (s, 1 H), 8.54 (d, J = 5.3 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.88 (s, 1 H), 7.87-7.82 (m, 1 H), 7.42-7.36 (m, 1 H), 7.29 (dd, J = 7.2 Hz, 5.6 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 2H), 6.88 (s, 1 H), 3.90 (s, 3H), 2.44 (s, 3H) ppm.

Example 4: A/-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(2-methyl-5-pyridin-2-yl-thiophen-3-yl)-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 4 was prepared in analogy to example 1 starting from step 1 intermediate of example 3 (1 12 mg, 342pmol) (22 mg, 9%).

LC-MS (Method 2): m/z: [M+Hf = 412.2 (MW calc. = 411.10), R, = 0.72 min. ¹H-NMR (DMSO-d₆). δ = 10.38 (s, 1 H), 8.60 (s, 2H), 8.55-8.52 (m, 1 H), 7.96-7.93 (m, 1 H), 7.88 (s, 1 H), 7.87-7.83 (m, 1 H), 7.30- 7.27 (m, 1 H), 6.93 (s, 1 H), 3.92 (s, 3H), 2.45 (s, 3H) ppm.

Example 5: W-(2,6-Difluoro-phenyl)-1 -methyl-5-(2-methyl-5-pyridin-3-yl-thiophen-3-y l)-1 H-pyrazole- 3-carboxylic acid amide

The title compound of example 5 was prepared in analogy to example 1 starting from BB-5 (380 mg, 1 .50 pmol) (57 mg, 32% over 2 steps).

LC-MS {Method 2): m/z: [M+H]⁺ = 41 1 .1 (MW calc. = 410.10), R, = 0.67 min. ¹H-NMR (DMSO-d₆): δ = 9.88 (s, 1 H), 8.93 (d, J = 2.3 Hz, 1 H), 8.52 (d, J = 5.3 Hz, 1 H), 8.07-8.03 (m, 1 H), 7.74 (s, 1 H), 7.49-7.44 (m, 1 H), 7.42-7.36 (m, 1 H), 7.18 (t, J = 7.9 Hz, 2H), 6.89 (s, 1 H), 3.91 (s, 3H), 2.47 (s, 3H) ppm.

Example 6: W-(2,6-Difluoro-phenyl)-1 -methyl-5-[2-methyl-5-(2-methyl-pyrimidin-5-yl)-thiophen-3-yl] 1 H-pyrazole-3-carboxylic acid amide

The title compound of example 6 was prepared in analogy to example 1 starting from BB-5 (74 mg, 279 pmol) (32 mg, 40% over 2 steps).

LC-MS (Method 2): m/z: [M+H]⁺ = 426.3 (MW calc. = 425.1 1 ), R, = 0.74 min. ¹H-NMR (DMSO-d₆): δ = 9.88 (s, 1 H), 9.00 (s, 2H), 7.79 (s, 1 H), 7.42-7.36 (m, 1 H), 7.22-7.14 (m, 2H), 6.89 (s, 1 H), 3.90 (s, 3H), 2.65 (s, 3H), 2.47 (s, 3H) ppm. Example 7: 5-(2-Cyclopropyl-5-methyl hiazol-4-yl)-/V-(2,6-difluoro-phenyl)-1-methyl-1 H-pyrazole-3- carboxylic acid amide

BB-7 BB-2a Example 7

Step 1 : Step 1 was performed in analogy to step 1 of example starting from BB-7 (342 mg, 1.49 mmol) (241 mg, 58%).

¹H-NMR (DMSO-d₆): δ = 6.86 (s, 1 H), 4.04 (s, 3H), 3.94 (s, 3H), 2.43 (s, 3H), 2.24 (m, 1 H), 1 .12 (m, 2H), 1.05 (m, 2H) ppm.

Step 2: Step 2 was performed in analogy to step 2 of example starting from step 1 intermediate (120 mg, 430 pmol) (98 mg, 62% yield).

LC-MS (Method 2): m/z: [M+H]⁺ = 375.1 (MW calc. = 374.10), R, = 0.79 min. ¹H-NMR (CDCI₃): δ = 8.26 (s, 1 H), 7.21 (m, 1 H), 6.99 (m, 2H), 6.94 (s, 1 H), 4.04 (s, 3H), 2.45 (s, 3H), 2.26 (m, 1 H), 1 .10 (m, 4H) ppm.

Example 8: 5-(2-Cyclopropyl-5-methyl-thiazol-4-yl)-A -(3,5-difluoro-pyridin-4-yl)-1 -methyl-1H- pyrazole-3-carboxylic acid amide

The title compound of example 8 was prepared in analogy to example 1 starting from step 1 intermediate of example 7 (120 mg, 430 pmol) (44 mg, 33%).

LC-MS (Method 2): m/z: [M+H]⁺ = 376.1 (MW calc. = 375.10), R, = 0.73 min. 'H-NMR (CDCI₃): δ = 8.52 (s, 1 H), 8.41 (s, 2H), 6.96 (s. 1 H), 4.05 (s, 3H), 2.45 (s, 3H), 2.26 (m, 1 H), 1.10 (m, 4H) ppm.

Example 9: A/-(2,6-Difluoro-phenyl)-1-methyl-5-(2-methyl-5-pyridin-4-yl-thiophen-3-yl)-1H-pyrazole- 3-carboxylic acid amide

Step 1 : A solution of ethyl 1 -methyl-1 H-pyrazole-3-carboxylate (300 mg, 2.00 mmol), BB-8 (508 mg, 2.00 mmol), KOAc (390 mg, 4.00 mmol) and di(1 -adamantyl)-n-butylphosphine (72 mg, 200 pmol) in dry DMF (5 mL) was degassed through purging with Ar. PdOAc₂ (22 mg, 100 prnol) was added and the mixture was heated to 140°C for 18 h. The volatiles were removed under reduced pressure and the residue was treated with water and was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, EtOAc/MeOH) to yield the desired compound (108 mg, 17%).

LC-MS (method 1 ): m/z: [M+H]⁺ = 328.2, (MW calc. = 327.40), R, = 3.0 min. ¹H-NMR (CDCI₃): δ = 8.61 (dd, J = 4.8, 2 Hz), 7.45 (dd, J = 4.8, 1.6 Hz, 2H), 7.34 (s, 1 H), 6.81 (s, 1 H), 4.44 (q, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.43 (s, 3H), 1.42 (t, J = 6.8 Hz, 3H) ppm.

Step 2: A solution of the intermediate of step 1 (108 mg, 0.33 mmol) in dry toluene (3 mL) was treated with 2,6-difluoroaniline (52 mg, 400 pmol) and AIMe₃ (2M in heptane, 0.2 mL, 400 pmol) and the mixture was heated to 1 10°C for 1 h. The mixture was chilled and aqueous HCI (1 M, 3 mL) was carefully added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, CH₂CI₂/MeOH) to yield the desired compound (94 mg, 69%).

LC-MS (Method 2): m/z: [M+H]⁺ = 41 1.1 (MW calc. = 410.10), R, = 0.55 min. ¹H-NMR (CDCI₃): δ = 8.61 (dd, J = 4.8, 1.6 Hz, 2H), 8.26 (s, 1 H), 7.45 (dd, J = 4.8, 2 Hz, 2H), 7.35 (s, 1 H), 7.23 (m, 1 H), 6.97-7.03 (m, 2H), 6.90 (s, H), 3.86 (s, 3H), 2.46 (s, 3H) ppm.

Example 10: 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-N-(2,6-difluoro-phenyl)-1-methyl-1 H- pyrazole-3-carboxylic acid amide

Step 1 : A solution of BB-9 (150 mg, 710 pmol), BB-2 (239 mg, 850 pmol), LiOH (20 mg, 850 pmol) and Pd(PPh₃)₂ (36 mg, 70 μιηοΙ) in dry DMF (5 mL) was heated under Ar to 80°C for 2 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (153 mg, 76%).

LC-MS (method 1 ): m/z: [M+Hf = 285.2 (MW calc. = 284.76), R, = 3.8 min. ¹H-NMR (CDCI₃): δ = 6.75 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.31 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H) ppm.

Step 2: A solution of the intermediate of step 1 (153 mg, 540 pmol), potassium cyclopropyl trifluoroborate (96 mg, 650 Mmol), PdOAc₂ (11 mg, 50 pmol), di(1 -adamantyl)-A?-butylphosphine (39 mg, 1 10 pmol) and Cs₂C0₃ (528 mg, 1.62 mmol) in toluene (10 mL) was treated with a few drops of water and the mixture was stirred under an nitrogen atmosphere at 90°C for 20 h. Water was added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Si0₂, Cy/EtOAc) to yield the desired compound (100 mg, 64%).

LC-MS (method 1 ): m/z: [M+H]⁺ = 291.2, (MW calc. = 290.38), R, = 3.9 min. ¹H-NMR (CDCI₃): δ = 6.72 (s, 1 H), 6.57 (s, 1 H), 3.81 (s, 3H), 2.28 (s, 3H), 2.01 (m, 1 H), 1.41 (t, J = 7.2 Hz, 3H), 0.99 (m, 2H), 0.70 (m, 2H) ppm. Step 3: The title compound of example 10 was prepared in analogy to example 1 starting from step 2 intermediate (100 mg, 340 prriol) (78 mg, 61 %).

LC-MS (method 2): m/z: [M+Hf = 374.1 (MW calc. = 373.11 ), R, = 0.82 min. ¹H-NMR (DMSO-d₆): δ = 9.82 (s, 1 H), 7.42-7.36 (m, 1 H), 7.22-7.18 (m, 2H), 6.86 (s, 1 H), 6.76 (s, 1 H), 3.82 (s, 3H), 2.32 (s, 3H), 2.16-2.04 (m, 1 H), 1 .03-0.94 (m, 2H), 0.72-0.65 (m, 2H) ppm.

Example 11 : 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-W-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 11 was prepared in analogy to example 1 starting from step 2 intermediate of example 10 (120 mg, 410 pmol) (48 mg, 41 %).

LC-MS (method 2): m/z: [M+H]⁺ = 375.1 (MW calc. = 374.10), R, = 0.79 min. H-NMR (CDCI₃): δ = 8.50 (s, 1 H), 8.41 (s, 2H), 6.83 (s, 1 H), 6.59 (s, 1 H), 3.81 (s, 3H), 2.31 (s, 3H), 2.04 (m, 1 H), 0.99 (m, 2H), 0.71 (m, 2H) ppm.

Example 12: /V-(2,6-Difluoro-phenyl)-1 -methyl-5-(5-methyl-2-pyridin-3-yl-thiazol-4-yl)-1H-pyrazole- 3-carboxylic acid amide

Step 1 : Step 1 was performed in analogy to step 1 of example starting from BB-10 (100 mg, 392 pmol) (116 mg, 94%).

Step 2: Step 2 was performed in analogy to step 2 of example 1 starting from step 1 intermediate (69 mg, 222 pmol) (23 mg, 25%).

LC-MS (Method 2): m/z: [M+H]⁺ = 412.1 (MW calc. = 41 1 .10), R, = 0.70 min. ¹H-NMR (DMSO-d₆): δ = 9.92 (s, 1 H), 9.17 (d, J = 1.5 Hz, 1 H), 8.70 (dd, J - 5.5 Hz, 1 .5 Hz, 1 H), 8.35-8.30 (m, 1 H), 7.59-7.55 (m, 1 H), 7.44-7.35 (m, 1 H), 7.23-7.15 (m, 2H), 7.09 (s, 1 H), 4.12 (s, 3H), 2.61 (s, 3H) ppm.

Example 13: W-(3,5-Difluoro-pyridin-4-yl)-1 -methyl-5-(5-methyl-2-pyridin-3-yl-thiazol-4-yl)-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 13 was prepared in analogy to example 1 starting from step 2 intermediate of example 12 (85 mg, 270 μηιοΙ) (25 mg, 23%).

LC-MS (method 2): m/z: [M+H]⁺ = 413.1 ( W calc. = 412.09), R, = 0.65 min. ¹H-NMR (DMSO-d₆): δ = 10.43 (s, 1 H), 9.17 (d, J = 1.9 Hz, 1 H), 8.69 (dd, J = 4.9 Hz, 1.5 Hz, 1 H), 8.61 (s, 2H), 8.33 (td, J = 8.7 Hz, 1 .5 Hz, 1 H), 7.57 (dd, J = 4.5 Hz, 3.0 Hz, 1 H), 7.14 8s, 1 H), 4.13 (s, 3H), 2.61 (s, 3H) ppm.

Example 14: N-(2,6-Difluoro-phenyl)-1 -rnethyl-5-(2-methyl-5-oxazol-2-yl-thiophen-3-yl)-1 H-pyrazole- 3-carboxylic acid amide

Step 1 : Step 1 was performed in analogy to step 1 of example starting from BB-1 1 (229 mg, 940 pmol) (213 mg, 79%).

Step 2: Step 2 was performed in analogy to step 2 of example 1 starting from step 1 intermediate (75 mg, 250 μηηοΙ) (86 mg, 87%).

LC-MS {Method 2): m/z: [M+Hf = 401.1 (MW calc. = 400.08), R, = 0.72 min. Ή-NMR (DMSO-d₆): δ = 8.26 (s, 1 H), 7.65 (s, 1 H), 7.51 (s, 1 H), 7.22 (m, 1 H), 7.19 (s, 1 H), 7.00 (t, J = 8 Hz, 2H), 6.90 (s, 1 H), 3.86 (s, 3H), 2.46 (s, 3H) ppm.

Example 15: 5-(5-Cy clopropy l-2-methy l-2H-py razol-3-y l)-W-(2,6-difluoro-phenyl)-1 -methy 1-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 15 was prepared in analogy to example 1 starting from BB-12 (160 mg, 850 μιηοΙ) (124 mg, 60%).

LC-MS (Method 2): m/z: [M+H]⁺ = 358.1 (MW calc. = 357.14), R, = 0.66 min. ¹H-NMR (CDCI₃): δ = 8.23 (s, 1 H), 7.23 (m, 1 H), 7.02-6.97 (m, 3H), 6.07 (s, 1 H), 3.87 (s, 3H), 3.75 (s, 3H), 1 .95 (m, 1 H), 0.95 (m, 2H), 0.77 (m, 2H) ppm. Example 16: 5-(5-Cyclopropyl-2-methyl-2H^yrazol-3-yl)-/V-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 16 was prepared in analogy to example 1 starting from BB-12 (195 mg, 710 pmol) (168 mg, 66%).

LC-MS (Method 2): m/z: [M+H]⁺ = 359.1 (MW calc. = 358.14), R, = 0.60 min. ¹H-NMR (CDCI₃): δ = 8.48 (s, 1 H), 8.42 (s, 2H), 6.98 (s, 1 H), 6.08 (s, 1 H), 3.88 (s, 3H), 3.75 (s, 3H), 1 .95 (m, 1 H), 0.96 (m, 2H), 0.77 (m, 2H) ppm. Example 17: W-(2,6-Difluoro-phenyl)-5-(2,5-dimethyl-thiophen-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylic acid amide

A mixture of 2,5-dimethylthiophen-3-ylboronic acid (100 mg, 641 pmol), BB-1 (203 mg, 641 pmol) and Pd(dppf)CI₂-CH₂CI₂ (24 mg, 32 pmol) in THF (4 mL) and aqueous Na₂C0₃ (2M, 0.9 mL) was heated in a microwave to 100°C for 3 h. Saturated NH₄CI was added and the organic phase was separated. The volatiles were removed and the residue was purified by chromatography (Interchim® cartridge50SiHP / 12 g, Cy/EtOAc) to yield example 17 ( 70 mg, 76%).

LC-MS (Method 2): m/z: [M+Hf = 348.1 (MW calc. = 347.09), R, = 0.79 min. ¹H-NMR (DMSO-d₆): δ = 9.83 (s, 1 H), 7.41 -7.35 (m, 1 H), 7.20-7.15 (m, 2H), 6.85 (s, 1 H), 6.76 (s, 1 H), 3.82 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H) ppm.

Example 18: V-(3,5-Difluoro-pyridin^-yl)-5-(2,5-dimethyl-t iophen-3-yl)-1-methyl-1 H-pyrazole-3- carboxylic acid amide

Step 1 : Step 1 was performed in analogy to example 17 through reaction of 2,5-dimethylthiophen-3- ylboronic acid (100 mg, 641 pmol) with ethyl 5-bromo-1 -methyl-1 H-pyrazole-3-carboxylate (138 mg, 641 pmol) (185 mg, >99%).

Step 2: The title compound of example 18 was prepared in analogy to example 1 starting from step 1 intermediate (185 mg, 565 pmol) (120 mg, 61 %). LC-MS (Method 2): m/z: [M+H]⁺ = 349.1 (MW calc. = 348.09), R, = 0.73 min. ¹H-NMR (DMSO-d₆): δ = 8.02 (s, 2H), 6.80 (s, 1 H), 6.46 (s, 1 H), 3.68 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H) ppm (note: NH not detected).

Example 19: W-(2,6-Difluoro-phenyl)-1 -met yl-5-[2-methyl-5-(2-oxo-oxazolidin-3-yl)-thiophen-3-yl]-

The title compound of example 19 was prepared in analogy to example 1 starting from BB-13 (99 mg, 382 pmol) (34 mg, 15% over 2 steps).

LC-MS (Method 2): m/z: [M+H]⁺ = 419.1 (MW calc. = 418.09), R, = 0.64 min. ¹H-NMR (DMSO-d₆): δ = 9.84 (s, 1 H), 7.43-7.36 (m, 1 H), 7.22-7.13 (m, 2H), 6.79 (s, 1 H), 6.63 (s, 1 H), 5.57-4.50 (m, 2H), 4.09-4.02 (m, 2H), 3.85 (s, 3H), 2.33 (s, 3H) ppm.

Example 20: A -(2,6-Difluoro-phenyl)-1 -methy l-5-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-1 H-pyrazole- 3-carboxylic acid amide

The title compound of example 20 was prepared in analogy to example 1 starting from commercially available 5-bromo-4-methyl-2-(pyridin-3-yl)thiazole (149 mg, 587 pmol) (60 mg, 31 % over 2 steps).

LC-MS (Method 2): m/z: [M+Hf = 412.1 (MW calc. = 41 1.1 ), R, = 0.67 min. ¹H-NMR (DMSO-d₆): δ = 9.97 (s, 1 H), 9.16 (d, J = 2.3 Hz, 1 H), 8.71 (dd, J = 4.5 Hz, 1.5 Hz, 1 H), 8.34 (dt, = 7.9 Hz, 2.1 Hz, 1 H), 7.58 (dd, J = 7.5 Hz, 4.5 Hz, 1 H), 7.43-7.36 (m, 1 H), 7.22-7.15 (m, 2H), 7.05 (s, 1 H), 3.92 (s, 3H), 2.43 8s, 3H) ppm.

Example 21 : A -(2,6-Difluoro-p enyl)-1-methyl-5-[2-methyl-5-(6-methyl-pyridin-3-yl)-thiophen-3-yl]- 1 H-pyrazole-3-carboxylic acid amide

The title compound of example 21 was prepared in analogy to example 1 starting from BB-14 (140 mg, 522 μιτιοΙ) (90 mg, 38% over 2 steps).

LC-MS {Method 2): m/z: [M+Hf = 425.2 (MW calc. = 424.12), R, = 0.64 min. ¹H-NMR (DMSO-d₆): δ = 9.88 (s, 1 H), 8.77 (d, J = 1.5 Hz, 1 H), 7.94 (dd, J = 8.3 Hz, 2.3 Hz, 1 H), 7.67 (s, 1 H), 7.42-7.35 (m, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.21-7.15 (m, 2H), 6.87 (s, 1 H), 3.90 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H) ppm.

Example 22: A/-(2,6-Difluoro-phenyl)-5-[5-(5-fluoro-pyridin-3-yl)-2-methyl-thiophen-3-yl]-1-methyl-

Step 1 : Step 1 was done in analogy to step 1 of example 1 starting from BB-15 (265 mg, 974 μηιοΙ). Step 2: Step 1 intermediate (290 mg, 840 μιηοΙ) was dissolved in dioxane (4.5 mL) and was treated with aqueous LiOH (2M, 2 mL) at 80°C overnight. Aqueous HCI ( ) was added and the mixture was extracted with CH₂CI₂. The combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound (245 mg, 92%).

Step 3: Step 2 intermediate (800 mg, 2.52 mmol) was dissolved in SOCI₂ (8.2 mL) and the mixture was stirred at 70°C for 4 h. The volatiles were removed under reduced pressure and the residue was dissolved in CH₂CI₂ (15 mL). 2,6-Difluorobenzenamine (126 mg, 981 pmol) and NEt₃ (0.26 mL,

1.87 mmol) were added and the mixture was stirred at RT overnight. The volatiles were removed and the residue was purified by chromatography (Interchim® cartridge50SiHP / 12 g, Cy/EtOAc) to yield the desired compound (55 mg, 13%).

LC-MS (Method 2): m/z: [M+Hf = 429.1 (MW calc. = 428.09), R, = 0.76 min. ¹H-NMR (DMSO-d₆): δ =

9.88 (s, 1 H), 8.79 (s, 1 H), 8.52 (d, J = 2.3 Hz, 1 H), 8.08 (dt, J = 9.8 Hz, 1 .5 Hz, 1 H), 7.84 (s, 1 H), 7.42- 7.36 (m, 1 H), 7.21 -7.16 (m, 2H), 6.89 (s, 1 H), 3.91 (s, 3H), 2.48 (s, 3H) ppm.

Example 23: N-(3-Fluoro-pyridin-4-yl)-1 -methy!-5-(2-met yl-5-oxazol-2-yl-thiophen-3-yl)-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 23 was prepared in analogy to example 1 starting from step 1 intermediate of example 14 (65 mg, 210 μιτιοΙ) (60 mg, 73%).

LC-MS (Method 2). m/z: [M+Hf = 384.1 (MW calc. = 383.09), R, = 0.69 min. ¹H-NMR (DMSO-d₆): δ = 9.81 (s, 1 H), 8.59 (d, J = 2.3 Hz, 1 H), 8.39 (d, J = 5.3 Hz, 1 H), 8.19 (s, 1 H), 8.09 (t, J = 5.3 Hz, 1 H), 7.78 (s, 1 H), 7.35 (s, 1 H), 7.01 (s, 1 H), 3.89 (s, 3H), 2.46 (s, 3H) ppm. Example 24: /V-(3-Fluoro^yridin-4-yl)-1 -methyl-5-(2-methyl-5-pyridin-4-yl-thiophen-3-yl)-1 H- pyrazole-3-carboxylic acid amide

The title compound of example 24 was prepared in analogy to example 1 through the reaction of step 1 intermediate of example 9 (73 mg, 220 μηιοΙ) with 3-fluoropyridin-4-amine (30 mg, 260 prnol) (60 mg, 57%).

LC-MS (Method 2): m/z: [M+Hf = 394.1 (MW calc. = 393.1 1 ), R, = 0.51 min. ¹H-NMR (CDCI₃): δ = 9.18 (s, 1 H), 8.61 (dd, J = 4.8 Hz, 1 .6 Hz, 2H), 8.52 (m, 1 H), 8.47 (d, J = 2.4 Hz, 1 H), 8.38 (d, J = 5.2 Hz, 1 H), 7.44 (dd, J = 4.8 Hz, 1 .6 Hz, 2H), 7.35 (s, 1 H), 6.90 (s, 1 H), 3.88 (s, 3H), 2.45 (s, 3H) ppm.

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 [Ca²⁺] 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 Ca²⁺-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 100 μΜ EGTA during store-depletion. Intracellular changes in [Ca ⁺] 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 Ca ⁺ signal measured from 9.5-10 min post-administration. Zero percent inhibition (MAX) was defined as the Ca²⁺ 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 Ca²⁺ 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 DM EM/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 g/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 (n.d.). or % inhibition @ 10 μΜ < 50 (C), 50 - 70 (B), > 70 (A).

10 A A 22 A C

11 A A 23 B C

12 B C 24 B C

Claims

Patent Claims:

1 . (I),

wherein

R¹ denotes H, C_1-4-aIkyl or C₃.₆-cycloalkyl;

R² denotes H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; d -alkyl; OH; 0-C_1-4-alkyl; OCH₃; OCF₃;

OCF₂H; OCFH₂; NH₂; N(H)C₁.₄-alkyl; N(C_1-4-alkyl)₂;

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

B represents 5-membered heteroaryl,

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

wherein said Ci_₄-alkyl and C₃.₆-cycloalkyl each independently is unsubstituted or mono- or polysubstituted, with the proviso that the compound of general formula (I) is not

5-(2,5-dimethyl-3-thienyl)-1 -ethyl-N-(2-fluorophenyl)-1 H-pyrazole-3-carboxamide, 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 B has the substructure (III),

(IN),

wherein

X is selected from O, S, N(R^5a), N or CR^6a;

Y is selected from O, S, N(R^5b), N or CR^6b;

Z is selected from O, S, N(R^5c), N or CR^6c;

and

B' is selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C - -alkyl; C₃.₆- cycloalkyl; 3 to 7 membered heterocycloalkyl; phenyl or heteroaryl;

R ^a, R⁵ and R⁵° are independently selected from the group consisting of H; CF₃; CF₂H; CFH₂; C^ 4-alkyl; C₃.₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; (C=0)(C₁.₄-alkyl); R , R , R^6c are independently selected from the group consisting of H; F; CI; Br; CN; CF₃; CF₂H; CFH₂; C _-4-alkyl; C₃-₆-cycloalkyl; 3 to 7 membered heterocycloalkyl; OH; 0-Ci.₄-alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)C₁.₄-alkyl; id^-alkyl^; NH(C=0)(C₁.₄-alkyl); wherein said Ci_₄-alkyl independently is linear or branched, and

wherein said C_1-4-alkyl, C₃.6-cycloalkyl and 3 to 7 membered heterocycloalkyl each independently is unsubstituted or mono- or polysubstituted,

A compound according to claim 2, characterized in

X is selected from N(R^5a) or CR^6a; wherein

R^6a is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl and C^- cycloalkyl; and

R^5a is selected from the group consisting of C - -alkyl and C₃.₆-cycloalkyl;

preferably R^5a or R^6a represents C^-alkyl.

A compound according to one or more of claims 2 or 3, characterized in that B represents substructure (III)

(Ilia), (lllb), (Nlc), (llld),

(Hie), (III , (Nig), (Nlh),

(lllk), (lllm),

(llln) (lllo);

wherein

R^6a is selected from the group consisting of F; CI; Br; CN; CF₃; CF₂H; CFH₂; C_1-4-alkyl and C3-6- cycloalkyl;

R^5a is selected from the group consisting of C_n.₄-alkyl and C₃.₆-cycloall<yl; and

R^5b is selected from the group consisting of C_1-4-alkyl and C₃-₆-cycloalkyl.

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

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; Ci_-4-alkyl;

C₃_6-cycloalkyl;

3 to 7 membered heterocycloalkyl;

phenyl and 5- or 6-membered heteroaryl,

wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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.

6. A compound according to one or more claims 2 to 5, characterized in that B represents

substructure (III)

(Ilia), (Mb), (lllc), (Hid), wherein

R^6a is selected from the group consisting of CN; CF₃; CF₂H; CFH₂; C^-alkyl and C₃.₆-cycloalkyl; and

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; C_1-4-alkyl; C₃__e-cycloalkyl and 5- or 6-membered heteroaryl,

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 R denotes CH₃ or CH₂CH₃; more preferably R¹ denotes CH₃.

8. 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, pyrimindinyl, 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^-alkyl; C_3-6-cycloalkyl; OH; O-C^- alkyl; OCF₃; OCF₂H; OCFH₂; NH₂; N(H)d -alkyl; Nid^-alkyl);,; NH(C=0)(C₁.₄-alkyl).

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

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

wherein

R⁷ is selected from F; CI; Br; CN; CF₃; CF₂H; CFH₂; C^-alkyl; C₃.₆-cycloalkyl;

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

0. 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-fluorophenyl, 2-chloro-4- fluorophenyl, 2-chloro-6-fluorophenyl and 2,4-difluorophenyl. 1. A compound according to one or more of claims 2 to 1 1 , characterized in that the compound rmula (la),

wherein

R² is selected from the group consisting of H, CI, NH₂, CH₃ and CH₂CH₃;

substructure (III),

(Ilia), (lllb), (lllc), (Hid), wherein

R^6a is selected from the group consisting of CF₃; CF₂H; CFH_2, CH₃; CH₂CH₃; CH(CH₃)₂ and cyclopropyl;

B' is selected from the group consisting of

CF₃; CF₂H; CFH₂; CH₃; CH₂CH₃; CH(CH₃)₂; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl, and wherein said 5- or 6-membered heteroaryl is unsubstituted und monosubstituted 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;

and

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

(Ha),

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; 0-CH₃; OCF₃; OCF₂H and OCFH₂; with the proviso that the compound of general formula (la) is not 5-(2,5-dimethyl-3-thienyl)-1 - ethyl-N-(2-fluorophenyl)-1 H-pyrazole-3-carboxamide, 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.

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

1 N-(2,6-Difluoro-phenyl)-1-methyl-5-(5-methyl-2-oxazol-2-yl-thia2ol-4-yl)-1 H-pyrazole-3- carboxylic acid amide

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

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

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

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

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

7 5-(2-Cyclopropyl-5-methyl-thiazol-4-yl)-N-(2,6-difluoro-phenyl)-1-methyl- H-pyrazole- 3-carboxylic acid amide

8 5-(2-Cyclopropyl-5-methyl-thiazol-4-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

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

10 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-N-(2,6-difluoro-phenyl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

11 5-(5-Cyclopropyl-2-methyl-thiophen-3-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide 12 N-(2,6-Difluoro-phenyl)-1 -methyl-5-(5-methyl-2-py ridin-3-yl-thiazol-4-yl)-1 H-pyrazole- 3-carboxylic acid amide

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

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

15 5-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N-(2,6-difluoro-prienyl)-1-metriyl-1 H- pyrazole-3-carboxylic acid amide

16 5-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-N-(3,5-difluoro-pyridin-4-yl)-1 -methyl-1 H- pyrazole-3-carboxylic acid amide

17 N-(2,6-Difluoro-phenyl)-5-(2,5-dimethyl-thiophen-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylic acid amide

18 N-(3,5-Difluoro^yridin-4-yl)-5-(2,5-dimethyl-thiophen-3-yl)-1 -methyl-1 H-pyrazole-3- carboxylic acid amide

19 N-(2,6-Difluoro-phenyl)-1 -methyl-5- ^

1 H-pyrazole-3-carboxylic acid amide

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

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

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

23 N-(3-Fluoro-pyridin-4-yl)-1 -methyl-5-(2-methyl-5-oxazol-2-yl-thiophen-3-yl)-1 H- pyrazole-3-carboxylic acid amide

24 N-(3-Fluoro-pyridin-4-yl)-1 -methyl-5-(2-methyl-5-pyridin-4-yl-thiophen-3-yl)-1 H- pyrazole-3-carboxylic acid amide

A pharmaceutical composition comprising at least one compound according to one or more of claims 1 to 12 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 12 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.