BR112016019473B1 - SYK INHIBITOR HETEROARYLS AND PHARMACEUTICAL FORMULATIONS INCLUDING THEM AND INTERMEDIATE COMPOUNDS - Google Patents

Abstract

SIK INHIBITOR HETEROARYLS. The invention relates to novel substituted heteroaryls of formula (1), wherein A is selected from the group consisting of N and CH, D is CH, E is selected from the group consisting of C and N, T is C, G is selected from the group consisting of C and N, and wherein each of the broken (dotted) double bonds in ring 1 is selected from a single bond or a double bond under the condition that all single and double bonds of ring 1 are arranged in such a way manner that they all form together with ring 2 an aromatic ring system, and wherein R1, M and R3 are defined according to claim 1, and to the above compounds for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis.

Description

[001] The invention relates to new substituted heteroaryls of formula 1 on what

[002] A is selected from the group consisting of N and CH

[003] D is CH,

[004] E is selected from the group consisting of C and N,

[005] T is C,

[006] G is selected from the group consisting of C and N,

[007] and wherein each of the broken (dotted) double bonds in ring 1 is selected from a single bond or a double bond under the condition that all single and double bonds of ring 1 are arranged in such a way that they all form together with ring 2 an aromatic ring system, and wherein

[008] M, R3 and R1 are defined as in claim 1. Furthermore, the invention relates to the above compounds of formula 1 or formula 1' for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis.

1. Background to the invention 1.1 SYK inhibitors

[009] The present invention describes new compounds that inhibit protein kinase Syk (spleen tyrosine kinase), the preparation and formulation of the same, its use to prepare a medicine.

[0010] Syk is an intracellular tyrosine kinase that has an important mediator function in signal transduction from different receptors on B cells, mast cells, monocytes, macrophages, neutrophils, T cells, dendritic cells and epithelial cells. The receptors at which Syk plays an important role in signal transduction include, for example, the receptors for IgE (FcεRI) and IgG (FcyR1) on mast cells and B cells, the B cell receptor (BCR) and T cell receptor (TCR) on B and T cells, the ICAM1 receptor (ICAM1R) on respiratory tract epithelial cells, the DAP12 receptor on natural killer cells, dendritic cells and osteoclasts, the dectin 1 receptor on a subpopulation of T-helper cells (Th-17), as well as integrin receptors for βl-, β2- and β3-integrins on neutrophils, monocytes and macrophages ( Wong et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.; Expert Opion. Ther. Target (2005) 9(5);901-921; Wang et al.; J. Immunol.(2006) 177, 6859-6870; Leib und Gut-Landmann et al.; Nature Immunology (2007) 8, 630-638; Slack et al., European J. Immunol.(2007) 37, 1600-1612). Molecular processes are best described for FcεRI signal transduction. On mast cells, binding of IgE to FcεRI causes cross-linking of IgE receptors, and recruitment and activation of Lyn (a tyrosine kinase of the Src family). Active Lyn phosphorylates the so-called ITAM motifs, which are present on many of the listed receptors, and thereby generate binding sites for the SH2 domain of Syk. As a result of binding to the ITAM motif, Syk is activated and then phosphorylates various substrates that are required for the release of allergic and inflammatory mediators such as, for example, histamine and β-hexosamidase (βHA), as well as for the synthesis of lipid mediators, such as, for example, prostaglandins and leukotrienes.

[0011] Due to its central role in the different signal transduction reaction series, Syk has been discussed as a therapeutic target for different diseases such as, for example, allergic rhinitis, asthma, autoimmune diseases, rheumatoid arthritis, osteopenia, osteoporosis, COPD and various leukemias and lymphomas (Wong et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.; Expert Opion Ther Target (2005) 9(5) 901-921 Sigh and Masuda Annual Reports in Medicinal Chemistry (2007) Vol 42 379-391 Bajpai et al. 461-467; Riccaboni et al., Drug Discovery Today (2010) Vol 00(0);517-530; Efremov and Luarenti, Expert Opin Investing Drugs.(2011) 20(5):623-36 ).

[0012] Allergic rhinitis and asthma are diseases associated with allergic reactions and inflammatory processes and involving different cell types such as, for example, Mast cells, eosinophils, T cells and dendritic cells. After exposure to allergens has occurred, high-affinity immunoglobulin receptors for IgE (FcεRI) and IgG (FcyRI) are activated and induce the release of pro-inflammatory and bronchoconstrictor mediators. An inhibitor of Syk kinase activity should therefore be able to inhibit these steps.

[0013] Rheumatoid arthritis (RA) is an autoimmune disease in which the bone and ligament structures surrounding the joints are progressively destroyed. In the pathophysiology of RA, B cells play a significant role, as has been demonstrated, for example, by the therapeutic use of rituximab, a B cell depleting antibody. In addition to Syk's role in BCR signal transduction (which after being stimulated, likewise induces the release of pro-inflammatory mediators), Syk likewise plays an important part in B cell maturation and proliferation (Cheng et al. Nature (1995) 378, 303-306 , Cornall et al., PNAS (2000) 97(4), 1713-1718 ). An inhibitor of Syk kinase activity may therefore offer a therapeutic option for the treatment of autoimmune diseases such as RA and diseases with an increased proliferation of B cells, such as, for example, B-cell lymphomas.

[0014] Chronic obstructive pulmonary disease (COPD) is characterized by a successive deterioration in lung function and chronic inflammation of the airways, which is initiated and produced by harmful substances of all kinds and contributes to maintaining the course of the disease. On a cellular level, in COPD there is, in particular, a multiplication of T lymphocytes, neutrophils, granulocytes and macrophages. In particular, there is an increase in the number of CD8-positive lymphocytes, which are directly connected with impaired lung function. Another feature of COPD is acute deteriorations in lung function (exacerbations), characterized by viral (eg Rhinovirus) or bacterial (eg Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) infections.

[0015] Due to the pro-inflammatory role of Syk in macrophages, T cells and neutrophils as described above (see: Wong et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; and references cited therein) an inhibitor of Syk kinase activity may be a new therapeutic method for treating the inflammatory processes that underpin COPD. Similarly, it has been shown that Syk in respiratory tract epithelial cells is involved in ICAM1R-mediated uptake and subsequent replication of the Rhinovirus and that an si-RNA next to Syk blocks these steps (Wang et al.; J. Immunol. (2006) 177, 6859-6870; Lau et al.; J. Immunol. (2008) 180, 870-880). Thus, an inhibitor of Syk kinase activity can likewise be used therapeutically in exacerbations caused by Rhinovirus.

[0016] Several studies suggest that Syk is involved in the malignant transformation of lymphocytes (summarized in Sigh and Masuda, Annual Reports in Medicinal Chemistry (2007) Vol 42; 379-391). A TEL-Syk fusion protein with a constitutive Syk activity transformed B cells from a patient with myelodysplastic syndrome, a constitutively active ITK-Syk fusion protein was isolated from patients with peripheral T-cell lymphomas (PTCL). In addition, constitutively active Syk has been found in B-cell lymphoma cells from patients, especially in B-lineage acute lymphoblastic leukemia (B-ALL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), lining cell lymphomas and B-cell non-Hodgkin lymphomas (NHLs) as well as in acute myeloid leukemia (AML). Based on these data, it appears that Syk is a proto-oncogene in hematopoietic cells and represents a potential target for the treatment of certain leukemias and lymphomas.

[0017] Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disease in which IgG autoantibodies against antigens present on platelets bind to and destroy platelets. Patients with ITP have an accelerated clearance of circular IgG-coated platelets by macrophages in the spleen and liver. Due to the pro-inflammatory FcyR-mediated role of Syk in macrophages, a Syk inhibitor is considered to have a therapeutic benefit in FcyR-mediated cytopenias such as ITP. Indeed, the Syk inhibitor R788 (R406) improved platelet counts in an open-label, single-center study in patients with ITP (Podolanczuk et al; Blood (2009) 113, 3154-3169).

[0018] Bullous pemphigoid (Ujiie et al. Journal of Dermatology 2010;37:194-204) is a chronic, subdermal, autoimmune, blistering skin disease that rarely involves the mucous membranes. Bullous pemphigoid is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific to the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2). Pemphigus Vulgaris (Venugopal et al. Dermatol. Clin. 2011;29:373-80) is a chronic blistering skin disease with skin lesions that are rarely pruritic but are often painful. Pemphigus Vulgaris is an autoimmune disease caused by IgG autoantibodies directed equally against desmoglein 1 and desmoglein 3 resulting in loss of cohesion between keratinocytes in the epidermis. It is characterized by extensive flaccid blisters and mucocutaneous erosions. In both diseases, IgG autoantibodies bind to the Fc gamma receptor (FcRy) and activate FcRy and downstream signaling by Syk kinase. Thus, an inhibitor of Syk kinase activity that blocks downstream FcRg signaling could be used therapeutically to treat patients with bullous pemphigoid and pemphigus vulgaris.

[0019] Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can affect basically any organ in the body. It is characterized by a multisystem inflammation of the microvascular and the presence of autoantibodies. FcyR-deficient mice of various aspects of SLE in preclinical disease-related models, suggesting that a Syk inhibitor may have a therapeutic benefit in SLE due to Syk's pro-inflammatory FcyR-mediated role in various cells.

1.2 Prior art

[0020] 1,6-Naphthyridines are known as SYK inhibitors. For example, US Patent Nos. US 3,928,367, US 4,017,500, US 4,115,395 and US 4,260,759 describe 5-amino-1,6-naphthyridines with an antifungal and antibacterial activity. Furthermore, WO 9918077 describes 5-piperazinyl-1,6-naphthyridines as serotonin antagonists. Additionally, US Patent 7,321,041 describes substituted 1,6-naphthyridines as SYK inhibitors, however, these 1,6-naphthyridines have a completely different substitution pattern from the compounds according to the invention. Similarly, WO 2011092128 describes 1,6-naphthyridines which are substituted at position 5 and 7.

[0021] In WO 2012/167733, WO 2012/167423 and in WO 2012/123312, other nathyridine derivatives such as pyrido[3,4-b]pyrazines which were similarly substituted at position 5 and position 7 were described as SYK inhibitors.

[0022] Additionally, WO 01/83485 describes substituted imidazopyrimidines and triazolopyrimidines as SYK inhibitors, whereas WO 2008/113469 describes substituted imidazo- and triazolopyrimidines as GSK 3β inhibitors.

[0023] Similarly, quinolones are known as SYK inhibitors. For example, WO 2006038041 and WO 2013014060 also describe quinoline compounds that are substituted in the 5 and 7 positions, however, the substitution pattern - in particular in the 7 position - is completely different from one of the compounds of formula 1 of the present invention.

[0024] Surprisingly, it has now been found that the compounds of formulas 1 and f and in particular the compounds of formulas 1a, 1a', 1c, 1c', are particularly suitable for the treatment of respiratory diseases, allergic diseases, osteoporosis, gastrointestinal diseases, autoimmune diseases, inflammatory diseases and diseases of the central or peripheral nervous system, particularly for the treatment of asthma, allergic rhinitis, rheumatoid arthritis, allergic dermatitis, lupus and (SLE) and COPD, in particular because all these compounds of the present invention show the following desired capabilities:

[0025] • high SYK inhibition (reflected by "low" IC50 values with respect to SYK inhibition)

[0026] • very low inhibition of Aurora B kinase (reflected by "high" IC50 values with respect to AURB inhibition)

[0027] • low FLT-3 kinase inhibition (reflected by "high" IC50 values with respect to FLT-3 inhibition)

[0028] • low GSK3β kinase inhibition (reflected by "high" IC50 values with respect to GSK3β inhibition)

[0029] This was completely surprising to a person skilled in the art, since the compounds of formula 1 and 1 of the present invention have several significant structural differences compared to previously known prior art compounds. For example, the compounds of formula 1 and 1 of the present invention differ from the 1,6-naphthyridines, quinolones, pyrido[3,4-b]pyrazines, imidazopyrimidines and triazolopyrimidines previously known therein, in that they combine the following aspects:

[0030] • they all have various core modifications in the central bicyclic heteroaromatic ring system (eg core modifications resulting in benzopyrazoles etc.)

[0031] • that they all have a methyl group substitution attached to the E position in formula 1 and/or 1 and

[0032] • that they all have a residue of formula T

2. DESCRIPTION OF THE INVENTION

[0033] The present invention relates to compounds of formula 1 on what

[0034] A is selected from the group consisting of N and CH

[0035] D is CH

[0036] E is selected from the group consisting of C and N,

[0037] T is C

[0038] G is selected from the group consisting of C and N,

[0039] and wherein each of the broken (dotted) double bonds in ring 1 is selected from a single bond or a double bond under the condition that all single and double bonds of ring 1 are arranged in such a way that they all form together with ring 2 an aromatic ring system, and wherein

[0040] M is selected from the group consisting of -CH2-, -O, -NH- and -N(C1-4-alkyl)-;

[0041] R3 is selected from the group consisting of methyl and ethyl;

[0042] Het is selected from the group consisting of

[0043] a five- to six-membered monocyclic heterocycle with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O,

[0044] and a nine- to eleven-membered bicyclic heterocycle with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O;

[0045] Hetarila is selected from the group consisting of

[0046] a five- to six-membered monocyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O;

[0047] and a nine- to eleven-membered bicyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O; and in what

[0048] R1 is selected from the group consisting of

[0049] C6-10-aryl, Het and Hetaryl;

[0050] which is optionally also substituted by one, two or three Z substituents,

[0051] whereby each Z is a substituent selected from the group consisting of

[0052] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[0053] which is optionally also substituted by one, two or three substituents X,

[0054] whereby each X is selected from the group consisting of halogen, -OH, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2,-NH(CH3), -N(CH3)2,

[0055] whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, -OH, halogen and C1-3-alkyl,

[0056] and the pharmaceutically acceptable salts of the aforementioned compounds.

[0057] A preferred embodiment of the present invention relates to the aforementioned compounds of formula 1'

[0058] where residues A, D, E, T, G, Het, Hetaryl, R1 and R3 are defined as mentioned above,

[0059] and the pharmaceutically acceptable salts of the aforementioned compounds.

[0060] In another preferred embodiment, the present invention relates to the aforementioned compounds of formula 1 or formula V, wherein

[0061] D is CH,

[0062] and where E is N

[0063] and in which

[0064] M is -CH2-

[0065] and in which

[0066] R3 is methyl,

[0067] and in which

[0068] G is C (carbon)

[0069] R1 is selected from the group consisting of

[0070] phenyl, Het and Hetaryl;

[0071] which is optionally also substituted by one, two or three Z substituents,

[0072] whereby each Z is a substituent selected from the group consisting of

[0073] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[0074] which is optionally also substituted by one, two or three substituents X,

[0075] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2,

[0076] whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[0077] and the pharmaceutically acceptable salts of the aforementioned compounds.

[0078] In another preferred embodiment, the present invention relates to the aforementioned compounds of formula 1a on what

[0079] R1 is selected from the group consisting of

[0080] phenyl, Het and Hetaryl;

[0081] which is optionally also substituted by one, two or three Z substituents,

[0082] whereby each Z is a substituent selected from the group consisting of

[0083] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[0084] which is optionally also substituted by one, two or three substituents X,

[0085] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2,

[0086] whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[0087] and the pharmaceutically acceptable salts of the aforementioned compounds.

[0088] In another preferred embodiment, the invention relates to compounds of formula 1a or formula 1a' above mentioned, in which R1 is

[0089] a) selected from the group consisting of Het and Hetarila;

[0090] which is optionally also substituted by one, two or three Z substituents,

[0091] whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O- (C1-3-alkyl), -O-Het,

[0092] which is optionally also substituted by one, two or three substituents X,

[0093] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl,

[0094] -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2,

[0095] whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[0096] or where R1 is

[0097] b) phenyl,

[0098] which is optionally also substituted by one, two or three Z substituents,

[0099] whereby each Z is a substituent selected from the group consisting of, -CN, halogen, -C1-6-alkyl, -(C1-3-alkylene)-Hetaryl, -(C1-3-alkylene)-Het, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl,

[00100] which is optionally also substituted by one, two or three substituents X,

[00101] whereby each X is selected from the group consisting of halogen, oxo and -C1-4-alkyl,

[00102] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00103] In another preferred embodiment, the invention relates to compounds of formula 1a or formula 1a' above mentioned, in which

[00104] R1 is

[00105] a five- to six-membered monocyclic heteroaromate with 1, 2 or 3 heteroatoms each independently of one another selected from the group consisting of N, O and S,

[00106] or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently of one another selected from the group consisting of N, O and S,

[00107] in which this residue R1 is connected to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three substituents Z,

[00108] whereby each Z is a substituent selected from the group consisting of

[00109] -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3 -alkylene)-O-(C1-3-alkyl), -O- Het,

[00110] which is optionally also substituted by one, two or three substituents X,

[00111] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2,

[00112] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00113] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00114] In another preferred embodiment, the invention relates to the above compounds of formula 1a or formula 1a' above mentioned, in which

[00115] R1 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl,

[00116] wherein this R1 residue is linked to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three substituents Z,

[00117] whereby each Z is a substituent selected from the group consisting of

[00118] -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-methyl, -O-ethyl, O-propyl, O-butyl, -C1-3-haloalkyl, three-, four-, five- or six-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NH CH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[00119] which is optionally also substituted by one, two or three substituents X,

[00120] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2,

[00121] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00122] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00123] In another preferred embodiment, the invention relates to the above-mentioned compounds of formula 1a or formula 1a' above, wherein

[00124] R1 is phenyl,

[00125] which is optionally also substituted by one, two or three Z substituents,

[00126] whereby each Z is a substituent selected from the group consisting of

[00127] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[00128] which is optionally also substituted by one, two or three substituents X,

[00129] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2,

[00130] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00131] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00132] In a particularly preferred embodiment, the present invention relates to the above compounds of the aforementioned formula 1a or formula 1a', which are selected from the group consisting of

[00133] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00134] In another preferred embodiment, the present invention relates to compounds of formula 1c on what

[00135] R1 is selected from the group consisting of

[00136] phenyl, Het and Hetaryl;

[00137] which is optionally also substituted by one, two or three Z substituents,

[00138] whereby each Z is a substituent selected from the group consisting of

[00139] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[00140] which is optionally also substituted by one, two or three substituents X,

[00141] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2,

[00142] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00143] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00144] In another preferred embodiment, the invention relates to the above compounds of the aforementioned formula 1c or formula 1c', in which R1 is

[00145] selected from the group consisting of Het and Hetarila;

[00146] which is optionally also substituted by one, two or three Z substituents,

[00147] whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O -(C1-3-alkyl), -O-Het,

[00148] which is optionally also substituted by one, two or three substituents X,

[00149] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl,

[00150] -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2,

[00151] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00152] or where R1 is

[00153] b) phenyl,

[00154] which is optionally also substituted by one, two or three Z substituents,

[00155] whereby each Z is a substituent selected from the group consisting of, -CN, halogen, -C1-6-alkyl, -(C1-3-alkylene)-Hetaryl, -(C1-3-alkylene)-Het, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl,

[00156] which is optionally also substituted by one, two or three substituents X,

[00157] whereby each X is selected from the group consisting of halogen, oxo and -C1-4-alkyl,

[00158] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00159] In another preferred embodiment, the invention relates to the above-mentioned compounds of formula 1c or formula 1c' above, wherein

[00160] R1 is

[00161] a five- to six-membered monocyclic heteroaromate with 1, 2 or 3 heteroatoms each independently of one another selected from the group consisting of N, O and S,

[00162] or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently of one another selected from the group consisting of N, O and S,

[00163] wherein this residue R1 is linked to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three Z substituents,

[00164] whereby each Z is a substituent selected from the group consisting of

[00165] -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3 -alkylene)-O-(C1-3-alkyl), -O- Het,

[00166] which is optionally also substituted by one, two or three substituents X,

[00167] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2,

[00168] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00169] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00170] In another preferred embodiment, the invention relates to the above mentioned compounds of formula 1c or formula 1c', wherein

[00171] R1 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl,

[00172] wherein this residue R1 is linked to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three Z substituents,

[00173] whereby each Z is a substituent selected from the group consisting of

[00174] -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-methyl, -O-ethyl, O-propyl, O-butyl, -C1-3-haloalkyl, three-, four-, five-, or six-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NH CH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[00175] which is optionally also substituted by one, two or three substituents X,

[00176] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2,

[00177] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00178] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00179] In another preferred embodiment, the present invention concerns the above-mentioned compounds of formula 1c or formula 1c' above, wherein

[00180] R1 is phenyl,

[00181] which is optionally also substituted by one, two or three Z substituents,

[00182] whereby each Z is a substituent selected from the group consisting of

[00183] -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het,

[00184] which is optionally also substituted by one, two or three substituents X,

[00185] whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2,

[00186] whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl,

[00187] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00188] In a particularly preferred embodiment, the present invention relates to the above compounds of the aforementioned formula 1c or formula 1c', which are selected from the group consisting of

[00189] and the pharmaceutically acceptable salts of the aforementioned compounds.

[00190] In another aspect, the present invention relates to an intermediate compound selected from the group consisting of formula 6

[00191] wherein E, D, G, T and R1 are defined above or as defined in claim 1 and wherein Hal is Cl or Br

[00192] and wherein PG is a protecting group selected from the group consisting of benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl.

[00193] In another aspect, the present invention relates to an intermediate compound selected from the group consisting of formula 5.1

[00194] In another aspect, the present invention relates to one of the aforementioned compounds of formula 1 or 1' (or any of the subformulas 1a, la', 1c, 1c') for the treatment of a disease that can be treated by inhibiting the SYK enzyme.

[00195] In another preferred aspect, the present invention relates to one of the aforementioned compounds of formula 1 or 1' (or any of the subformulas 1a, 1a', 1c, 1c') for the treatment of a disease selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, B-cell lymphoma, contact dermatitis and dermatitis, allergic dermatitis, rhinoconus allergic conjunctivitis, rheumatoid arthritis, antiphospholipid syndrome, Berger's disease, Evans syndrome, ulcerative colitis, allergic antibody-based glomerulonephritis, granulocytopenia, Goodpasture's syndrome, hepatitis, Henoch-Schonlein purpura, hypersensitivity vasculitis, immunoemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematosus lupus nephritis, capsule cell lymphoma, neutropenia, non-familial lateral sclerosis, arteriosclerosis, Crohn's disease, multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis, Sjogren's syndrome, scleroderma, T-cell lymphoma, urticaria/angioedema, Wegener's granulomatosis, and celiac disease.

[00196] In another preferred aspect, the present invention relates to the aforementioned compounds of formula 1 or 1' (or any of the subformulas 1a, 1a', 1c, 1c') for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, allergic dermatitis, contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis , lupus erythematosus, lupus nephritis and allergic rhinoconjunctivitis.

[00197] In another particularly preferred aspect, the present invention relates to the aforementioned compounds of formula 1 or 1' (or any of the subformulas 1a, 1a', 1c, 1c') for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis.

[00198] In another preferred aspect, the present invention relates to pharmaceutical formulations containing one or more of the aforementioned compounds of formula 1 or 1' (or any of the subformulas 1a, 1a', 1c, 1c') and a pharmaceutically acceptable excipient.

[00199] In another preferred aspect, the present invention relates to pharmaceutical formulations containing one or more compounds of the aforementioned compounds of formula 1 or V (or any of the subformulas 1a, 1a', 1c, 1c') in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, LTD4 antagonists, CCR3, iNOS inhibitors, CRTH2 antagonists, HMG-CoA reductase inhibitors and NSAIDs.

3. TERMS AND DEFINITIONS USED

[00200] Unless otherwise stated, all substituents are independent of each other. If, for example, several C1-6-alkyl groups are possible substituents in a group, in the case of three substituents, for example, C1-6-alkyl could independently represent a methyl, an n-propyl and a tert-butyl.

[00201] Within the scope of this application, in the definition of possible substituents, these may still be presented in the form of a structural formula. An asterisk (*) in the structural formula of the substituent should be understood as the point of attachment to the rest of the molecule. Furthermore, the atom of the substituent following the point of attachment is understood to be the atom at position number 1. Thus, for example, the N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl (IV) and 4-tolyl (V) groups are represented as follows:

[00202] If there is no asterisk (*) in the structural formula of the substituent, each hydrogen atom can be removed in the substituent and the valence thereby released can serve as a binding site for the remainder of a molecule. In this way, for example, VI may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

[00203] Alternatively to * within the scope of this application X1 is likewise understood to be the point of attachment of the group R1 to the structure of formula 1 and X2 as being the point of attachment of the group R2 to the structure of formula 1.

[00204] By the term "C1-6-alkyl" (including those that are part of other groups) is meant branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term "C1-3-alkyl" is meant branched and unbranched alkyl groups with 1 to 3 carbon atoms. "C1-4-alkyl" accordingly denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples thereof include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc., can likewise optionally be used for the above mentioned groups. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl and the like.

[00205] By the term "C1-6-alkylene" (including those that form part of other groups) is meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term "C1-4-alkylene" is meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples thereof include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propyl likewise includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

[00206] If the carbon chain is replaced by a group which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes, inter alia, the following examples of the rings:

[00207] By the term "C2-6-alkenyl" (including those forming part of other groups) is meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term "C2-4-alkenyl" is meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl and the like.

[00208] The term "C2-6-alkenylene" (including those forming part of other groups) means branched and unbranched alkenylene groups having 2 to 6 carbon atoms and the term "C2-4-alkenylene" means branched and unbranched alkylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples thereof include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenyl no. Unless otherwise stated, the definitions propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propenyl likewise includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1, 1-dimethylethenylene, 1, 2-dimethylethenylene.

[00209] By the term "aryl" (including those that are part of other groups) is meant aromatic ring systems with 6 or 10 carbon atoms. Examples include: phenyl or naphthyl, the preferred aryl group being phenyl. Unless otherwise stated, aromatic groups may be replaced by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[00210] By the term "aryl-C1-6-alkylene" (including those forming part of other groups) is meant branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl or 1- or 2-naphthylethyl. Unless otherwise stated, aromatic groups may be replaced by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[00211] The term "heteroaryl-C1-6-alkylene" (including those that form part of other groups) means - even if they are already included under "aryl-C1-6-alkylene" - branched and unbranched alkylene groups with 1 to 6 carbon atoms, which are replaced by a heteroaryl.

[00212] If not specifically defined otherwise, a heteroaryl of this type includes five- or six-membered heterocyclic aromatic groups or 5-10-membered bicyclic heteroaryl rings that may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and thus contain many conjugated double bonds in which an aromatic system is formed. The following are examples of five- or six-membered heterocyclic aromatic groups or bicyclic heteroaryl rings:

[00213] Unless otherwise stated, these heteroaryls may be substituted by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[00214] The following are examples of heteroaryl-C1-6-alkylenes:

[00215] By the term "C1-6-haloalkyl" (including those that form part of other groups) is meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, which are replaced by one or more halogen atoms. By the term "C1-4-alkyl" is meant branched and unbranched alkyl groups having 1 to 4 carbon atoms, which are substituted by one or more halogen atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples include: CF3, CHF2, CH2F, CH2CF3.

[00216] By the term "C3-7-cycloalkyl" (including those forming part of other groups) is meant cyclic alkyl groups having 3 to 7 carbon atoms, if not specifically defined otherwise. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, cyclic alkyl groups may be substituted by one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[00217] If not specifically defined otherwise, by the term "C3-10-cycloalkyl" is meant likewise monocyclic alkyl groups having 3 to 7 carbon atoms and likewise bicyclic alkyl groups having 7 to 10 carbon atoms, or monocyclic alkyl groups which are bridged by at least one C1-3-carbon bridge.

[00218] The term "heterocyclic rings" or "heterocycle" means, unless otherwise stated, five-, six- or seven-membered, saturated, partially saturated or unsaturated heterocyclic rings that may contain one, two or three heteroatoms, selected from oxygen, sulfur and nitrogen, while the ring may be attached to the molecule by a carbon atom or a nitrogen atom, if there is one. Although included by the term "heterocyclic rings" or "heterocycles", the term "saturated heterocyclic ring" refers to five-, six-, or seven-membered saturated rings. Examples include:

[00219] Although included by the term "heterocyclic rings" or "heterocyclic group", the term "partially saturated heterocyclic group" refers to partially saturated five-, six- or seven-membered rings that contain one or two double bonds, without so many double bonds being produced that an aromatic system is formed, unless specifically defined otherwise. Examples include:

[00220] Although included by the term "heterocyclic rings" or "heterocycles", the term "heterocyclic aromatic rings", "unsaturated heterocyclic group" or "heteroaryl" refers to five- or six-membered heterocyclic aromatic groups or 5-10-membered bicyclic heteroaryl rings, which may contain one, two, three or four heteroatoms, selected from oxygen, sulfur and nitrogen, and contain as many bonds conjugated doubles in which an aromatic system is formed, unless not specifically defined otherwise. Examples of five- or six-membered heterocyclic aromatic groups include:

[00221] Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may be provided with a keto group. Examples include:

[00222] Although encompassed by the term "cycloalkyl", the term "bicyclic cycloalkyl" generally denotes eight-, nine-, or ten-membered bicyclic carbon rings. Examples include

[00223] Although already included by the term "heterocycle", the term "bicyclic heterocycles" generally denotes eight-, nine- or ten-membered bicyclic rings that may contain one or more heteroatoms, preferably 1-4, more preferably 1-3, even more preferably 1-2, particularly one heteroatom, selected from oxygen, sulfur and nitrogen, unless not specifically defined otherwise. The ring may be attached to the molecule by either a ring carbon atom or a ring nitrogen atom, if there is one. Examples include:

[00224] Although already included by the term "aryl", the term "bicyclic aryl" denotes a 5-10 membered, bicyclic aryl ring that contains sufficient conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl.

[00225] Although already included under "heteroaryl", the term "bicyclic heteroaryl" denotes a 5-10 membered, bicyclic heteroaryl ring that may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contains sufficient conjugated double bonds to form an aromatic system, unless specifically defined otherwise.

[00226] Although included by the term "bicyclic cycloalkyl" or "bicyclic aryl", the term "fused cycloalkyl" or "fused aryl" denotes bicyclic rings in which the bridge separating the rings denotes a direct single bond. The following are examples of a fused, bicyclic cycloalkyl:

[00227] Although included by the term "bicyclic heterocycles" or "bicyclic heteroaryls", the term "fused bicyclic heterocycles" of "fused bicyclic heteroaryls" denotes 5-10 membered bicyclic heterorings containing one, two, three or four heteroatoms, selected from oxygen, sulfur and nitrogen and in which the bridge separating the rings denotes a direct single bond. "Fused bicyclic heteroaryls", moreover, contain enough conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

[00228] "Halogen" within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorine, chlorine and bromine are considered the preferred halogens.

[00229] Compounds of general formula 1 or 1' may have acid groups, mainly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula 1 or 1' may therefore be present as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali metal or metal hydroxides or carbonates. alkaline earth, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine, inter alia.

[00230] As previously mentioned, the compounds of formula 1 or 1' can be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof. These salts can be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids. On the other hand, the compound of formula 1 or 1' when R is hydrogen can be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali and alkaline earth metal cations as counterion. Acid addition salts can be prepared, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is in the same way possible to use mixes of the above-mentioned acids. For preparing the alkali and alkaline earth metal salts of compounds of formulas 1 or 1 in which R denotes hydrogen, it is preferable to use the alkali and alkaline earth metal hydroxides and hydrides of which the hydroxides and hydrides of the alkali metals, particularly sodium and potassium, are preferred, while sodium and potassium hydroxide are particularly preferred.

[00231] The compounds of general formulas 1 or 1 can optionally be converted into salts thereof, particularly for pharmaceutical use into pharmacologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids for this purpose include succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. It is in the same way possible to use mixes of the above-mentioned acids.

[00232] The invention relates to the compounds of formula 1 in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as, for example, acid addition salts with hydroallic acids - for example, hydrochloric or hydrobromic acid - or organic acids - such as, for example, oxalic, fumaric, diglycolic or methanesulfonic acid.

[00233] The compounds of formula 1, 1a and 1c according to the invention can optionally be present as racemates, but can likewise be obtained as pure enantiomers, ie in (R) or (S) form. Preferred are compounds with the specific stereochemistry of formula 1', in particular compounds with the specific stereochemistry of one of formulas 1a' and 1c'.

[00234] The invention relates to the compounds in question, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers or racemates, in the form of tautomers as well as in the form of free bases or corresponding acid addition salts with pharmacologically acceptable acids - such as, for example, acid addition salts with hydroallic acids - for example hydrochloric acid or hydrobromic - or organic acids - such as, for example, oxalic, fumaric, diglycolic or methanesulfonic acid.

[00235] The invention relates to the respective compounds of formulas 1 or 1 in the form of pharmacologically acceptable salts thereof. These pharmacologically acceptable salts of the compounds of formula 1 or 1 can likewise be present in the form of their respective hydrates (for example Monohydrates, dihydrates, etc.) as well as in the form of their respective solvates.

[00236] By a hydrate of the compound according to formula 1 or 1' is meant, for the purpose of the invention, a crystalline salt of the compound according to formula 1 or T, containing water of crystallization.

[00237] A solvate of the compound according to formula 1 or 1' means, for the purpose of the invention, a crystalline salt of the compound according to formula 1 or 1', containing solvent molecules (for example ethanol, methanol etc.) in the crystal lattice.

[00238] The man of skill will be familiar with the standard methods of obtaining hydrates and solvates (eg recrystallization from the corresponding solvent or from water).

4. PREPARATION METHODS

[00239] Examples according to the invention were prepared as shown in Schemes 1, 2 or 3. Scheme 1:

[00240] D is CH,

[00241] G is C or N

[00242] T is C

[00243] E is C or N, preferably N

[00244] Hal is Br or Cl

[00245] with X being -B(OH)2, - boronic acid pinacolester, - trifluoroborate, or - SnBu3

[00246] PG is protecting group (for example, benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl)

[00247] and R1 is as hereinbefore defined. Scheme 2:

[00248] D is CH,

[00249] G is C or N

[00250] T is C

[00251] E is C or N, preferably N

[00252] A is CH or N

[00253] Hal is Br or Cl

[00254] with X being -B(OH)2, -boronic acid pinacholester, -trifluoroborate or -SnBu3

[00255] PG is protecting group (eg benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl)

[00256] and R1 is as hereinbefore defined.

4.1 Starting materials of formula 2, 3, 4, 5 and 10 4.1.1. Synthesis of Lactans 2 from Schemes 1 and 2

[00257] Synthesis of (R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.1 for Examples 1-3, 7 - 13, 17, 50 - 84 and (R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4) -methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.2 for Examples 4 - 6, 14 - 16, 18 - 49.

[00258] Step 1: Synthesis of (1'R,3R/S)-1-(1'-(4-methoxyphenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid (mixture of diastereoisomers)

[00259] A suspension of 100 g of (R)-1-(4-methoxy-phenyl)-ethylamine and 95 g of itaconic acid in 0.5 L of 1-methyl-2-pyrrolidinone was heated at 80°C for 1 hour. The solution was stirred for an additional 4 hours at 120°C. The reaction mixture was cooled to 25°C and poured into 1.5 L of demineralized water. The precipitate was filtered, washed with demineralized water and dried at 50°C.

[00260] Yield: 195 g (quantitative yield) of solid as a mixture of diastereoisomers Analysis (method G): Rt: 2.6 min and 2.7 min, (M+H)+: 264

[00261] Step 2: Synthesis of (R/S)-N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide as a mixture of diastereoisomers

[00262] 260 g of 1,1'-carbonyldiimidazole (CDI) were added to a solution of 285 g of (1'R,3R/S)-1-(1'-(4-methoxyphenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid (mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran at 20 °C. stirred at 20°C for 80 minutes. 235 ml of ethyldiisopropylamine (DIPEA) and 130 g of N,O-dimethylhydroxylamine hydrochloride were added. The suspension was stirred for 3 hours at 20°C. Under cooling, 850 ml of 4M hydrochloric acid were added. The organic phase was separated and washed twice with 500 ml of 1N hydrochloric acid. The aqueous solution was re-extracted twice with 500 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.

[00263] Yield: 271 g (82% of theory) of (R/S)-N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereoisomers) as an oil. Analysis (H method): Rt: 11.1 min (41% by area) and 13.8 min (59% by area), (M+H)+: 307

[00264] Step 3: Synthesis of (R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one as a mixture of diastereoisomers

[00265] 530 ml of a 3M solution of methylmagnesium bromide in diethyl ether were slowly added to a cooled solution of 271 g of (R/S)-N-methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereoisomers) in 1.4 L of 2-methyltetra -hydrofuran so that the temperature remains below 0°C. After complete addition, the temperature was held for 75 minutes at 0°C, then warmed to 20°C. The suspension was stirred 16 hours at 20°C. Under cooling, 650 mL of a 4M hydrochloric acid was added. The organic phase was separated and washed with 500 ml of saturated sodium carbonate solution and 500 ml of saturated brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.

[00266] Yield: 188 g (81% of theory) of (R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one (mixture of diastereoisomers) as an oil. Analysis (H method): Rt: 7.4 min and 9.6 min, (M+H)+: 262

[00267] Step 4: Crystallization of (R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one under base-induced epimerization conditions

[00268] 103 g of a mixture of diastereomers (R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one were dissolved in 155 ml of 1-butanol at 25°C. 18 mL of benzyltrimethylammonium hydroxide (40% solution in methanol) was added. The solution was stirred for 30 minutes at 25°C. The solution was cooled to 0°C. The precipitation began. The suspension was stirred for 15 minutes at 0°C. 100 mL of n-heptane was added slowly, and the suspension was stirred for 30 minutes at 0°C. The addition of 100 mL portions of n-heptane was repeated 4 times with subsequent stirring of the suspension at 0°C for 30 minutes. The precipitate was isolated, washed with n-heptane and dried at 50°C.

[00269] Yield: 77.1 g of a beige solid (75% of theory) with a diastereomeric purity of ~95: 5 (method H).

[00270] For further purification, the crude product was dissolved in 310 mL of 2-methyl-2-butanol at 40°C (temperature < 50°C). The solution was slowly cooled to 0°C. The precipitation began. At 0°C, 385 mL of n-heptane was added, and the suspension was stirred for 1 hour. The precipitate was filtered, washed with n-heptane and dried at 50°C.

[00271] Yield: 68.7 g (67% of theory) of a colorless solid with a diastereomeric purity of > 99: 1. Analysis (method H): Rt: 6.8 min, (M+H)+: 262

[00272] Step 4: Crystallization of (R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one under base-induced epimerization conditions

[00273] 13.2 g of a mixture of diastereomers (R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one were dissolved in 18 ml of 1-butanol at 25°C. The solution was cooled to 3°C and treated with 100 mg of (R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one. The resulting mixture was stirred for 15 min at 3°C; at which point, 2.3 mL of benzyltrimethylammonium hydroxide (40% solution in methanol) was added. The solution was stirred for 30 minutes at 3°C. 64 mL of n-heptane was added slowly over 1 h at 0 to 3°C, and the suspension was stirred for 60 minutes at 0°C. The precipitate was isolated, washed with n-heptane and dried at 30°C.

[00274] Yield: 10.6 g of a beige solid (80% of theory) with a diastereomeric purity of ~98: 2 (method H). Analysis (H method): Rt: 6.8 min, (M+H)+: 262

[00275] Step 5: Synthesis of (R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.1

[00276] 94.6 mg of dichloro(pentamethylcyclopentadienyl)-iridium(III) dimer and 105 mg of (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine [(R,R)-TsDPEN] were dissolved in 20 mL of acetonitrile and subsequently charged to a suspension of 50 g of (R)-4-a cetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one and 65 g of sodium formate in 500 ml of water at 25°C. The suspension was heated to 60 °C and stirred at this temperature while sparging with nitrogen for 3 h. The reaction was diluted at 60°C with 500 mL of isopropyl acetate and subsequently cooled to room temperature. The layers were separated, and the organic portion was washed twice with 300 mL of water. The organic portion was concentrated to an oily solid. The residual material was crystallized three times from ethyl acetate and hexane followed by drying in a vacuum oven with a nitrogen flow at 30°C. 25.4 g of a beige solid with a diastereomeric purity of >99:1

[00277] Step 5: Synthesis of (R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.2

[00278] 9.46 mg of dichloro(pentamethylcyclopentadienyl)iridium(III) dimer and 10.52 mg of (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine [(R,R)-TsDPEN] were dissolved in 1 ml of acetonitrile and subsequently charged to a suspension of 5 g of (R)-4- acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one and 6.5 g of sodium formate in 50 ml of water at 25°C. The suspension was heated to 60 °C and stirred at this temperature while sparging with nitrogen for 3 h. The reaction was diluted to 60 °C with 50 mL of isopropyl acetate and subsequently cooled to room temperature. The layers were separated, and the organic portion was washed with 20 mL of water. The organic portion was concentrated to an oil. The oil was dissolved in 8 mL of refluxing isopropyl acetate. The solution was cooled to room temperature, at which crystallization took place. The mixture was diluted dropwise with 10 mL of heptane at room temperature. The mixture was stirred for 30 minutes. The solids were collected by filtration, washed with a 20% solution of isopropyl acetate in heptane and dried in a vacuum oven with a nitrogen flow at 55°C. 3.82 g of a beige solid with a diastereomeric purity of 99:1 Analysis (method I): Rt: 12.9 min, (M+H)+: 264 Synthesis of [(1S)-1-[(3R)-1-[(1S)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate 2. 3

[00279] To a mixture of 20.0 g of (R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.2, 21.67 g of p-toluenesulfonyl chloride and 0.92 g of N,N-dimethylpyridin-4-amine were added 42 ml of pyridine and 42 mL of dichloromethane (DCM). The resulting mixture was stirred at 34 °C for 18 h under an argon atmosphere. The reaction mixture was diluted with isopropyl acetate and washed with water and 2M hydrochloric acid. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in isopropyl acetate and n-heptane. The precipitate was filtered, washed with n-heptane/isopropyl acetate and dried to yield 19.83 g of [(1S)-1-[(3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate 2.3 as a solid. Analysis: HPLC-MS: Rt = 0.680 min (J method), M+H = 418

4.1.2. Synthesis of boronic acids, boronic esters, BF3 borate and stananes with formula 4 X.1.2.1. Synthesis of R1-Hal 3 Synthesis of 4-Bromo-1-tert-butyl-pyrazole 3.1 for Examples 2, 18,

[00280] Step 1: Synthesis of 1-tert-Butyl-pyrazole

[00281] To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxypropane and 26.20 g of tert-butylhydrazine hydrochloride in 230 mL of ethanol were added 40.0 mL of conc. dropwise below 50 °C, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was nearly distilled off, and the aqueous residue extracted with diethyl ether. The combined aqueous phases were basified with 10N sodium hydroxide solution and extracted with diethyl ether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as an oil. Analysis: HPLC-MS: Rt = 0.412 min (method A), M+H = 125

[00282] Step 2: Synthesis of 4-Bromo-1-tert-butyl-pyrazole

[00283] To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 ml of DCM were added 31.5 g of N-bromosuccinimide in portions between 0 and 10°C. The resulting mixture was stirred for 30 min. The reaction mixture was allowed to reach room temperature. The precipitate was filtered and washed with DCM. The combined organic extracts were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as an oil. Analysis: HPLC-MS: Rt = 1.35 min (method B), M+H = 203/205 Synthesis of trans 4-[4-(4-Bromo-pyrazol-1-yl)-cyclohexyl]-1-methyl-piperazin-2-one 3.2 for Example 12

[00284] The starting material 1-spiro[7-azoniabicyclo[2.2.1]heptane-7,4'-[1'-methyl-2'-oxo-4'-piperazinium]methanesulfonate] was obtained as described in WO2011092128.

[00285] To a solution of 506 mg of 4-bromopyrazole in 7.5 ml of dimethylacetamide (DMA) was added 91 mg of sodium hydride (NaH). The resulting mixture was stirred at room temperature for 10 min, before 1.0 g of 1-spiro[7-azoniabicyclo[2.2.1]heptane-7,4'-[1'-methyl-2'-oxo-4'-piperazinium]methanesulfonate] was added, and the mixture was stirred at 100 °C for 40 min. An additional 70 mg of NaH was added, and the reaction mixture was stirred at 120 °C for 40 min. The solvent was distilled off, and the residue taken up in MeOH and purified by rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to yield after lyophilization, 850 mg of trans 4-[4-(4-bromo-pyrazol-1-yl)-cyclohexyl]-1-methyl-piperazin-2-one as a solid. Analysis: HPLC-MS: Rt = 0.45 min (method C), M+H = 341/343 Synthesis of 5-Bromo-2-(difluoromethyl)pyridine 3.3 for Example 51

[00286] A solution of 1 g of 5-bromopyridine-2-carbaldehyde in 50 mL of DCM was cooled to -70 °C, then 1.55 mL of diethylaminosulfur trifluoride was added dropwise over 20 minutes. The suspension was stirred for 30 minutes at room temperature, then 10 mL of water was added at 0°C followed by slow addition of 20 mL of saturated NaHCO3 (gas formation). The phases were separated and 2 mL of 4M HCl in dioxane was added to the organic phase, which was concentrated in vacuo to give 1.06 g of product as a yellow solid. Analysis: HPLC-MS: Rt = 0.72 min (method D), M+H =208/210

Synthesis of 7-Bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine 3.4 for Example 55

[00287] 7-Bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine can be obtained as described in Shah, Unmesh; Lankin, Claire M.; Boyle, Craig D.; Chackalamannil, Samuel; Greenlee, William J.; Neustadt, Bernard R.; Cohen-Williams, Mary E.; Higgins, Guy A.; Ng, Kwokei; Varty, Geoffrey B.; Zhang, Hongtao; Lachowicz, Jean E., Bioorganic and Medicinal Chemistry Letters, 2008, 18, 4204 - 4209. Synthesis of 6-Bromo-N,N,1-trimethyl-indole-2-carboxamide 3.5 for Example 56

[00288] A mixture of 0.68 g of 6-bromo-1-methyl-indole-2-carboxylic acid, 1.1 g of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 0.55 mL of triethylamine in 2 mL of N-methyl-2-pyrrolidinone (NMP) and 3 mL of tetrahydrofuran (THF) was stirred at room temperature for 2 h, followed by addition of 4.0 mL of 2M solution of dimethylamine in THF. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate solution. The combined organic phases were concentrated in vacuo. The crude material was purified by flash chromatography (DCM ^ DCM: methanol 90:10) to yield 0.66 g of 6-bromo-N,N,1-trimethyl-indole-2-carboxamide 3.5 as an oil. Analysis: HPLC-MS: Rt = 0.85 min (E method), M+H = 281/283

Synthesis of 4-Bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6 for Example 70

[00289] Step 1: Synthesis of [(3R)-Tetrahydrofuran-3-yl]4-methylbenzenesulfonate

[00290] To a solution of 25.43 g of (R)-tetrahydro-furan-3-ol in 60 ml of pyridine and 250 ml of DCM were added 73.0 g of 4-methyl-benzenesulfonyl chloride, followed by 1.0 g of N,N-dimethylpyridin-4-amine. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with 2M hydrochloric acid and water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (DCM ^ DCM: methanol 95:5) to yield 59.46 g of [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate as an oil. Analysis: MS: M+H = 243

[00291] Step 2: Synthesis of 4-Bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6

[00292] A mixture of 650 mg of [(3R)-tetrahydrofuran-3-yl]4-methylbenzenesulfonate, 400 mg of 4-bromo-1H-pyrazole and 1.40 g of cesium carbonate in 10 mL of N,N-dimethylformamide (DMF) was stirred at 65 °C for 6 h. An additional 20 mg of 4-bromo-1H-pyrazole was added, and the reaction mixture was stirred overnight at 65°C. The reaction mixture was diluted with ethyl acetate and washed with brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (cyclohexane/ethyl acetate 9:1 → 1:1) to yield 476 mg of 4-bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazol 3.6 as a solid. Analysis: MS: M+H = 217/219 Synthesis of 4-Bromo-1-[(3R)-tetrahydrofuran-3-yl]pyrazole 3.7 for Example 74

[00293] This intermediate was prepared from (S)-tetrahydro-furan-3-ol in two steps according to the preparation of 4-bromo-1-[(3S)-tetrahydrofuran-3-yl]pyrazol 3.6. Analysis: MS: M+H = 217/219

Synthesis of 4-Bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazol 3.8 for Example 79

[00294] Step 1: Synthesis of 5-methyl-1-tetrahydropyran-4-yl-pyrazol

[00295] To a stirred mixture of 2.26 g of 1-tetrahydropyran-4-ylpyrazole in 20 mL of THF was added 11.14 mL of 1.6M solution of N-butyllithium in hexane dropwise at -50°C under argon atmosphere. The mixture was stirred at -20° to -15°C for 1.5 h before 1.11 mL of methyl iodide was added dropwise. The resulting mixture was stirred at -20° to -15°C for 1.5 h. 10 mL of water was added dropwise, and the mixture was allowed to reach room temperature. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by rpHPLC (basic) to yield after lyophilization, 1.51 g of 5-methyl-1-tetrahydropyran-4-yl-pyrazole as a solid. Analysis: HPLC-MS: Rt = 0.61 min (F method), M+H = 167

[00296] Step 2: Synthesis of 4-Bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazol 3.8

[00297] To a mixture of 1.0 g of 5-methyl-1-tetrahydropyran-4-yl-pyrazole in 20 ml of THF and 20 ml of ethyl acetate were added 1.09 g of bromosuccinimide in portions between 10 and 20°C. The reaction mixture was stirred at room temperature for 30 min, and then quenched with saturated aqueous potassium carbonate solution. The solvent was evaporated, and the residue was purified by rpHPLC (basic) to yield after lyophilization, 1.20 g of 4-bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazol 3.8 as a solid. Analysis: HPLC-MS: Rt = 0.65 min (method F), M+H = 245/247 Synthesis of 4-(4-Bromophenyl)-1-methyl-piperidine 3.9 for Example 80

[00298] To a mixture of 100 mg of 4-(4-bromophenyl)-piperidine hydrochloride and 100 mg of sodium acetate in 3 mL of DCM and 0.5 mL of methanol were added 50 µL of formaldehyde (37% aqueous). The resulting mixture was stirred at room temperature for 10 min before 155 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred for 2 h and quenched with saturated aqueous sodium bicarbonate solution, followed by extraction with DCM. The combined organic phases were concentrated in vacuo to yield 88 mg of 4-(4-bromophenyl)-1-methyl-piperidine 3.9 as a solid. Analysis: HPLC-MS: Rt = 0.38 min (J method), M+H = 254/256 Synthesis of 4-(4-Bromo-3-trifluoromethyl-phenyl)-1-methyl-piperidine 3.10 for Example 32

[00299] To a solution of 640 mg of 4-(4-bromo-3-trifluoromethyl-phenyl)-piperidine in 16.3 mL of DCM and 2.9 mL of methanol was added 6.40 mL of formaldehyde (37% aqueous). The resulting mixture was stirred at room temperature for 1 h, before cooling to 0 °C and 1.02 g of sodium triacetoxyborohydride was added in portions. Then the reaction was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was quenched with saturated aqueous potassium carbonate solution, followed by extraction with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 650 mg of 4-(4-bromo-3-trifluoromethyl-phenyl)-1-methyl-piperidine 3.10 as an oil. Analysis: HPLC-MS: Rt = 1.37 min (K method), M+H = 323/325 Synthesis of 4-(4-Bromo-2-trifluoromethyl-phenyl)-morpholine 3.11 for Example 38

[00300] A mixture of 1.0 g of 4-bromo-2-(trifluoromethyl)aniline, 786 μL of bis(2-bromoethyl)ether and 1.45 mL of diisopropylamine in 3 mL of DMA was stirred in a sealed tube at 140 °C for 2 days. The reaction mixture was poured into water and extracted with TBME. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 833 mg (84% by HPLC) of 4-(4-bromo-2-trifluoromethyl-phenyl)-morpholine 3.11 as an oil. Analysis: HPLC-MS: Rt = 2.37 min (K method), M+H = 310/312

Synthesis of 4-Bromo-1-(4,4-difluorocyclohexyl)pyrazole 3.12 for Example 10

[00301] Step 1: Synthesis of N'-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester

[00302] A solution of 0.99 g of hydrazinecarboxylic acid tert-butyl ester in 5 mL of methanol was added dropwise to a solution of 1.0 g of 4,4-difluoro-cyclohexanone in 5 mL of methanol. The resulting mixture was stirred at room temperature for 1 h. The solvent was distilled off to yield 1.76 g of N'-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester as a solid. Analysis: MS: M+H = 249

[00303] Step 2: Synthesis of N'-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester

[00304] A mixture of 8.0 g of N'-(4,4-difluoro-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester and 800 mg of palladium on carbon in 48 ml of methanol was hydrogenated at 40 °C for 16 h in 10 bar. The catalyst was removed by filtration, and the solvent was evaporated in vacuo to yield 7.82 g of N'-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester. Analysis: MS: M-H = 249

[00305] Step 3: Synthesis of (4,4-Difluoro-cyclohexyl)-hydrazine hydrochloride

[00306] To a mixture of 5.0 g of N'-(4,4-difluoro-cyclohexyl)-hydrazinecarboxylic acid tert-butyl ester in 20 mL of DCM was added 40 mL of 6M hydrochloric acid in isopropanol, and the resulting mixture was stirred at room temperature for 12 h. The solvent was evaporated, and the residue triturated with toluene. The precipitate was filtered and dried to yield 3.72 g of (4,4-difluoro-cyclohexyl)-hydrazine hydrochloride as a solid. Analysis: ESI-MS: M+H = 151

[00307] Step 4: Synthesis of 1-(4,4-difluorocyclohexyl)pyrazole

[00308] To a mixture of 2.04 g of (4,4-difluoro-cyclohexyl)-hydrazine hydrochloride in 15 ml of ethanol were added 3.50 ml of conc. followed by 1.80 g of 1,1,3,3-tetramethoxypropane, then the mixture was refluxed for 1 h. The reaction mixture was diluted with water, ethanol was distilled off. The residue was basified with aqueous sodium hydroxide solution (30%) and extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 2.02 g of 1-(4,4-difluorocyclohexyl)pyrazole as an oil. Analysis: HPLC-MS: Rt = 0.46 min (method C), M+H = 187

[00309] Step 5: Synthesis of hexyl)pyrazole

[00310] To a solution of 2.0 g of 1-(4,4-difluorocyclohexyl)pyrazole in 5 mL of DCM was added 0.55 mL of bromine at 0 °C, and the mixture was stirred at room temperature for 15 min. The solvent was distilled off, and the residue taken up in DCM and washed with half-saturated brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield 2.81 g of 4-bromo-1-(4,4-difluorocyclohexyl)pyrazole 3.12 as a solid. Analysis: HPLC-MS: Rt = 0.60 min (method C), M+H = 265/267

[00311] Synthesis of 4-Bromo-1-(difluoromethyl)imidazole 3.13 for Example 83

[00312] Into a mixture of 10.0 g of 4-bromo-1H-imidazole in 60 mL of DMF was passed 30 g of chlorodifluoromethane under dry ice cooling, then 15.0 g of potassium carbonate were added, and the reaction mixture was heated overnight at 110°C in a sealed tube (19 bar). An additional 30 g of chlorodifluoromethane and 5 g of potassium carbonate were added, and the reaction mixture was heated overnight at 110°C (9 bar). The reaction mixture was allowed to come to room temperature, then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by rpHPLC (SunfireC18, acetonitrile/trifluoroacetic acid water) to yield 3.07 g of 4-bromo-1-(difluoromethyl)imidazole. Analysis: HPLC-MS: Rt = 0.371 min (J method), M+H = 197/199

[00313] The following bromides have been commercially available:

[00314] • 3-Bromoimidazo[1,2-a]pyridine-6-carbonitrile 3.14 for Example 43,

[00315] • 4-Bromo-1-(3,3,3-trifluoro-propyl)pyrazole 3.15 for Example 15, 76,

[00316] • 3-Bromo-1 H-indazole-5-carbonitrile 3.16 for Example 16

[00317] • 2-Bromo-5-fluoro-pyridine 3.17 for Example 41

[00318] • 4-(4-Bromophenyl)-1-methyl-piperidine 3.18 for Example 42

[00319] • 2-(4-Bromo-2-methyl-phenyl)-1,2-thiazolidine 1,1-dioxide 3.19 for Example 71

[00320] • 7-Bromo-2-methyl-3,4-dihydro-1H-isoquinoline 3.20 for Example 75

[00321] • 4-Bromo-1-isopropoxy-2-methoxy-benzene 3.22 for Example 81

[00322] • 5-Bromo-1-methyl-indazol-3-amine 3.23 for Example 36,

[00323] • 2-(4-Bromophenyl)-1,2-thiazolidine 1,1-dioxide 3.24 for Example 33

[00324] • 4-Bromo-1-(difluoromethyl)pyrazole 3.25 for Example 40

[00325] • 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 3.26 for Example 3

[00326] • 1-[(4-Bromophenyl)methyl]-2-methyl-1H-imidazole 3.27 for Example 17 4.1.3. Synthesis of compounds of formula 4 (R1-X) (Scheme 1 and 2) Synthesis of Tributyl-[2-(difluoromethyl)thiazol-4-yl]stannane 4.1 for Example 35

[00327] To a mixture of 500 mg of 4-tributylstannylthiazole-2-carbaldehyde in 5 mL of DCM was slowly added 1.01 mL of 2.7M solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (in toluene) at 0 °C, then the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM and washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 440 mg (82% by HPLC) of tributyl-[2-(difluoromethyl)thiazol-4-yl]stannane 4.1 as an oil. Analysis: HPLC-MS: Rt = 2.72 min (M method), M+H = 425

[00328] The following stannan has been commercially available:

[00329] • Tributyl(thiazol-4-yl)stannane 4.2 for Example 29 Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3-benzazepine 4.3 for Example 55

[00330] 100 mg of 7-bromo-3-methyl-1,2,4,5-tetrahydro-3-benzazepine, 127 mg of bis-(pinacolato)-diboron, 20 mg of 1,1'-bis(diphenylphospine)ferrocenedichloropalladium(II) and 123 mg of potassium acetate were suspended in 2 mL of dioxane, and the mixture stirred at 100 °C for 1.25 h. The mixture was diluted after cooling with dioxane, filtered through Celite, washed with dioxane, and the solvent was evaporated in vacuo to yield 220 mg (92%, 50% content) of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3-benzazepine 4.3 as a solid which was used in the next step without further purification. Analysis: HPLC-MS: Rt = 0.45 min (N method), M+H = 288

[00331] The following boronic esters were synthesized in analogy and were used without further purification:

[00332] • 1-Methyl-4-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-cyclohexyl}-piperazin-2-one 4.4 from 3.2 (for Example 12). Reaction conditions: 4 h, 100 °C. Yield: 81% (36% content). Analysis: HPLC-MS: Rt = 0.41 min (O method), M+H = 389

[00333] • 2-Difluoromethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine 4.5 from 3.3 (for Example 51). Reaction conditions: 45 min, 100°C. Yield: 82% (40% content). Analysis: HPLC: Rt = 0.25 min (N method); MS: M+H = 256

[00334] • N,N,1-Trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxamide 4.6 from 3.5 (for Example 56). Reaction conditions: 3 h, 100 °C. Yield: 84% (50% content). Analysis: HPLC-MS: Rt = 0.69 min (N method), M+H = 329

[00335] • 1-[(3S)-Tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.7 from 3.6 (for Example 70). Reaction conditions: 3 h, 100 °C. Yield: 59% (50% content). Analysis: HPLC-MS: Rt = 0.49 min (N method), M+H = 265

[00336] • 2-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-thiazolidine 1,1-dioxide 4.8 from 3.19 (for Example 71). Reaction conditions: 3 h, 100 °C. Yield: 86% (50% content). Analysis: HPLC-MS: Rt = 0.64 min (N method), M+H = 338

[00337] • 1-[(3R)-Tetrahydrofuran-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.9 from 3.7 (for Example 74). Reaction conditions: 5 h, 100 °C. Yield: 43% (content 38%). Analysis: HPLC-MS: Rt = 0.54 min (J method), M+H = 265

[00338] • 2-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline 4.10 from 3.20 (for Example 75). Reaction conditions: 2 h, 100 °C. Yield: 99% (43% content). Analysis: HPLC-MS: Rt = 0.41 min (J method), M+H = 274

[00339] • 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)pyrazole 4.11 from 3.15 (for Example 76). Reaction conditions: 4 h, 100 °C. Yield: 29% (content 25%). Analysis: HPLC-MS: Rt = 0.61 min (J method), M+H = 291

[00340] • 1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine 4.12 from 3.9 (for Example 80). Reaction conditions: 4 h, 100 °C. Yield: 84% (50% content). Analysis: HPLC-MS: Rt = 0.47 min (J method), M+H = 302

[00341] • 2-(4-Isopropoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.13 from 3.22 (for Example 81). Reaction conditions: 3 h, 100°C. Yield: 87% (40% content). Analysis: HPLC-MS: Rt = 0.75 min (J method), M+H = 293

[00342] • 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-thiazolidine 1,1-dioxide 4.14 from 3.24 (for Example 33). Reaction conditions: 2.5 h, 80°C, in DMF. Yield: 68% (95% content). Analysis: HPLC-MS: Rt = 2.04 min (K method), M+H = 324

[00343] The following examples were synthesized in analogy to the example described, but using bis(triphenylphosphine)palladium(II) chloride (0.05 eq.) instead of 1,1'-bis(diphenylphospine)ferrocenedichloropalladium(II) as catalyst (see description above):

[00344] • 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-amine 4.15 from 3.23 (for Example 36). Reaction conditions: 1 h, 95°C. Yield: 89% (content 85%). Analysis: HPLC-MS: Rt = 1.76 min (K method), M+H = 274

[00345] • 1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]piperazine 4.16 from 3.10 (for Example 32). Reaction conditions: 1.5 h, 95 °C. Yield: 61% (95% content). Analysis: HPLC-MS: Rt = 1.66 min (K method), M+H = 371

[00346] • 1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.17 from 3.25 (for Example 40). Reaction conditions: 2.5 h, 95 °C. Yield: 70% (95% content). Analysis: HPLC-MS: Rt = 1.97 min (K method), M+H = 245

[00347] • 4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]morpholine 4.18 from 3.11 (for Example 38). Reaction conditions: 1 h, 95 °C. Yield: 99% (78% content). Analysis: HPLC-MS: Rt = 2.67 min (K method), M+H = 358 Synthesis of 1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.19 for Examples 2,18,

[00348] To a stirred mixture of 50 g of 4-bromo-1-tert-butylpyrazole 3.1 in 230 mL of THF was added dropwise 100 mL of 2.5M solution of N-butyllithium in hexane under argon atmosphere below -60°C, then the mixture was stirred at this temperature for 5 min, before 52 mL of 2-isopropoxy-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane were added dropwise below -60°C. The reaction mixture was allowed to reach room temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer solution and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was distilled off, and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 44.26 g of 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole as a solid. Analysis: HPLC-MS: Rt = 0.904 min (method F), M+H = 251 Synthesis of 5-Methyl-1-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.20 for Example 79

[00349] This intermediate was prepared from 4-bromo-5-methyl-1-tetrahydropyran-4-yl-pyrazol 3.8 according to the preparation of 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.19. Yield: 94% of 4.20 Analysis: HPLC-MS: Rt = 0.58 min (J method), M+H = 293 Synthesis of 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine 4.21 for Example 49

[00350] A mixture of 250 mg of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester 4.51 and 0.5 mL of trifluoroacetic acid in 2 mL of DCM was stirred at room temperature for 1 h. The solvent was distilled off, and the residue taken up in 10 mL of DCM, followed by addition of 494 µL of formaldehyde (37% aqueous). The reaction mixture was stirred at room temperature for 1 h before 421 mg of sodium triacetoxyborohydride was added. The resulting mixture was stirred at room temperature for 30 min, diluted with saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to yield 99 mg of 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine 4.21 as a solid. Analysis: HPLC-MS: Rt = 1.25 min (K method), M+H = 292

[00351] The following boronic acids, boronic esters and BF3 borate were commercially available:

[00352] • (3,4-dimethoxyphenyl)boronic acid 4.22 for Example 1

[00353] • 2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4.23 for Example 50

[00354] • 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4.24 for Examples 8, 73

[00355] • (3,4,5-trimethoxyphenyl)boronic acid 4.25 for Example 52

[00356] • tert-Butyl-5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate 4.26 for Example 53

[00357] • 1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.27 for Example 57

[00358] • 1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.28 for Example 58

[00359] • [6-(Trifluoromethyl)-3-pyridyl]boronic acid 4.29 for Examples 4, 61

[00360] • (1-methylindazol-5-yl)boronic acid 4.30 for Example 62

[00361] • 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.31 for Example 63

[00362] • 1-Tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.32 for Examples 47, 64

[00363] • 1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.33 for Example 65

[00364] • 4-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]morpholine 4.34 for Example 66

[00365] • 1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine 4.35 for Examples 26, 67

[00366] • 1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol 4.36 for Example 68

[00367] • 1,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.37 for Example 69

[00368] • (1-methylindazol-6-yl)boronic acid 4.38 for Example 72

[00369] • 7-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole 4.39 for Examples 48, 77

[00370] • 1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.40 for Example 78

[00371] • tert-Butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate 4.41 for Examples 9, 45, 82,

[00372] • Potassium 5-methyl-2-thiophenetrifluoroborate 4.42 for Example 54

[00373] • Potassium 6-methoxy-3-pyridyltrifluoroborate 4.43 for Example 59

[00374] • Potassium 4-(Trifluoromethyl)phenyltrifluoroborate 4.44 for Example 60

[00375] • 5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4.45

[00376] • (4-morpholinophenyl)boronic acid 4.46 for Example 22

[00377] • (1-methylindazol-5-yl)boronic acid 4.47 for Examples 28

[00378] • 2-Isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4.48 for Example 27

[00379] • 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4.49 for Example 14

[00380] • 1-Cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazole 4.50 for Example 7

[00381] • 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester 4.51 for Example 49 4.1.4. Synthesis of 5 and 10 Heterocyclics from Schemes 1 and 2 Synthesis of 4,6-Dichloro-2-methyl-pyrazolo[4,3-c]pyridine (5.1) for Examples 1-3, 7 - 13, 17, 50 - 83

[00382] To a mixture of 9.5 g of trimethyloxonium tetrafluoroborate in 300 mL of DCM was added 10.0 g of 4,6-dichloro-3aH-pyrazolo[4,3-c]pyridine (commercially available from Sphinx Scientific Laboratory Corporation) under argon atmosphere. The reaction mixture was stirred overnight at room temperature. An additional 2.7 g of trimethyloxonium tetrafluoroborate and 2.0 mL of ethyldiisopropylamine (DIPEA) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, filtered, and the organic phase was concentrated in vacuo. The raw material was trapped in semi-saturated aqueous sodium bicarbonate solution. The precipitate was filtered, washed with water and dried to yield 8.2 g of 4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine 5.1 as a solid. Analysis: HPLC-MS: Rt = 0.45 min (method C), M+H = 202/204 Synthesis of 6-Bromo-2-methyl-indazol-4-ol 10.2 for Examples 14 - 16, 18, 22, 26 - 29, 32, 33, 35, 36, 38, 40 - 43, 45, 4 7 - 49

[00383] Step 1: Synthesis of 6-Bromo-4-methoxy-2-methyl-indazole

[00384] To a solution of 5.0 g of 6-bromo-4-methoxy-1H-indazole in 50 mL of 1,4-dioxane was added 4.23 g of trimethyloxonium tetrafluoroborate at room temperature. The reaction mixture was stirred at 40 °C for 3 h and allowed to stand overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried to yield 4.26 g of 6-bromo-4-methoxy-2-methyl-indazole as a solid. Analysis: HPLC-MS: Rt = 1.78 min (K method), M+H = 241/243

[00385] Step 2: Synthesis of 6-Bromo-2-methyl-indazol-4-ol 10.2

[00386] To a suspension of 4.26 g of 6-bromo-4-methoxy-2-methyl-indazole in 42.6 ml of DCM was added 53.06 ml of boron tribromide solution (1M in DCM) at 0°C. The reaction mixture was allowed to reach room temperature and stirred for 3 days. An additional 10 mL of boron tribromide solution (1M in DCM) was added, and the reaction mixture was stirred at room temperature for 8 h. The mixture was poured into water. The precipitate was filtered and triturated with acetonitrile to yield 2.8 g of 6-bromo-2-methyl-indazol-4-ol 10.2 as a solid. The acetonitrile filtrate was combined with the DCM layer and concentrated in vacuo. The residue was triturated with acetonitrile to afford 1.08 g of 6-bromo-2-methyl-indazol-4-ol 10.2 as a solid. The two solids were combined to yield 3.88 g of 6-bromo-2-methyl-indazol-4-ol 10.2 as a solid. Analysis: HPLC-MS: Rt = 1.49 min (K method), M+H = 227/229 4.2. Synthesis of Intermediates 6, 7, 8 and 11 from Scheme 1 and 2

Synthesis of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one (7.1) for Examples 1-3, 7 - 13, 17, 50 - 83

[00387] Step 1: Synthesis of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

[00388] To a mixture of 20.0 g of 4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine 5.1 and 30.1 g of (R)-4-[(R)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.1 in 1 L of dioxane were added 4.5 1 g of NaH in mineral oil (60%). The resulting mixture was stirred at 100 °C for 15 h. The solvent was distilled off to 1/3. The residue was taken up in DCM and washed with saturated ammonium chloride solution and water. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 44.8 g (88% by HPLC) of (R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one as a solid . Analysis: HPLC-MS: Rt = 0.65 min (J method), M+H = 429

[00389] Alternatively, 6.1 can be synthesized as follows:

[00390] A solution of 20.0 g of 4,6-dichloro-2-methyl-pyrazolo[4,3-c]pyridine 5.1 and 25.4 g of (R)-4-[(R)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.1 in 250 mL of dioxane was added to a suspension of 9.6 g of NaH in mineral oil (60%) in 50 ml of dioxane at 20°C. The resulting mixture was stirred at 40 °C for 5.5 h. The mixture was cooled to room temperature and quenched by the slow addition of 36 mL of 4M HCl in dioxane. The reaction mixture was diluted with 200 mL of isopropyl acetate and water (100 mL). The layers were separated, and the aqueous portion was extracted twice with 100 ml of isopropyl acetate. The organic portions were analyzed to show 40.78 g of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one in a solution mass of 796.3 g for a 99% yield. Purification of 6.1 can be conducted by concentrating a crude isopropyl acetate solution of 50 g of 6.1 in vacuo to 200 mL, whereupon solids crystallize. 500 mL of heptane was slowly charged to the suspension at 20 °C, and the mixture was stirred for 2 h. The solids were collected by filtration, washed with heptane, and dried at 30°C, 46.9 g of 6.1 was isolated as a beige solid at 92% recovery.

[00391] Step 2: Synthesis of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one 7.1

[00392] A mixture of 1.0 g of (R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one 6.1 and 1 mL of anisole in 5 mL of trifluoroacetic acid (TF) A) was stirred at 80 °C for 17 h. The solvent was removed by distillation. The residue was taken up in DCM and washed with saturated aqueous sodium bicarbonate solution. The combined organic phases were concentrated in vacuo and the residue triturated with diethyl ether. The precipitate was filtered and dried to yield 0.37 g of (R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-pyrrolidin-2-one 7.1 as a solid. Analysis: HPLC-MS: Rt = 0.47 min (method J), M+H = 295 Synthesis of (4R)-4-[(1R)-1-(6-Bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one (7.5) for Examples 14 - 16, 18, 22, 26 - 29, 32, 33, 35, 36, 38, 40 - 43, 45, 47 - 49

[00393] Step 1: Synthesis of (4R)-4-[(1R)-1-(6-Bromo-2-methylindazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one

[00394] To a mixture of 1.46 g of 6-bromo-2-methyl-indazol-4-ol 10.2, 1.86 g of (R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 2.2 and 5.06 g of triphenylphosphine in 36.5 mL of THF were added s 4.44 g di-tert-butyl azodicarboxylate (DBAD) over 30 min. The resulting mixture was stirred at room temperature for 18 h. The solvent was evaporated, and the residue triturated with TBME. The precipitate was filtered and washed with TBME. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 2.36 g (54% by HPLC) of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 6.5 like solid. Analysis: HPLC-MS: Rt = 2.00 min (K method), M+H = 472/474

[00395] Step 2: Synthesis of (4R)-4-[(1R)-1-(6-Bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one 7.5

[00396] A mixture of 583 mg (63% by HPLC) of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 6.5 in 10 mL of TFA was stirred at 70 °C for 18 h. The solvent was removed by distillation. The residue was taken up in DCM, poured into saturated aqueous sodium bicarbonate solution and extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 321 mg (84% by HPLC) of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one 7.5. Analysis: HPLC-MS: Rt = 1.63 min (K method), M+H = 338/340 4.1.6. Synthesis of Boronic Acids and Borone Esters 11 of schemes 1 and 2 acid synthesis [2-methyl-4-[(1r) -1-[(3r) -5-oxopirolidin-3- il] pyrazolo [4,3-c] piridin-6-il] Boronic 11.1 For examples 3, 13, 17, 83

[00397] 400 mg of (R)-4-[(R)-1-(6-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-pyrrolidin-2-one 7.1, 620 mg of bis-(pinacolato)-diboron, 122 mg of 1,1'-bis(diphenylphospino)ferrocenedichlorop Ladium(II) and 360 mg of potassium acetate were suspended in 4 mL of dioxane, and the mixture stirred at 100 °C for 1 h. The mixture was diluted with dioxane, filtered through Celite, washed with dioxane, and the solvent was evaporated in vacuo to afford 1.09 g of [2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronic acid (crude) 11.1 as oil, which was used in the next step without further purification. Analysis: HPLC-MS: Rt = 0.26 min (S method), M+H = 305 Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one 11.3 for Examples 15, 16, 41, 42, 43

[00398] 500 mg of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one 7.5, 563 mg of bis-(pinacolato)-diboron, 52 mg of bis(triphenylphosphine)palladium(II) chloride and 435 mg of potassium acetate were suspended in 5 mL of dioxane, and the resulting mixture was stirred at 95 °C for 1 h. The reaction mixture was allowed to reach room temperature, diluted with water and extracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate/methanol) to yield 505 mg (78% by HPLC) of (4R)-4-[(1R)-1-[2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one 11.3. Analysis: HPLC-MS: Rt = 1.76 min (K method), M+H = 387 4.3 Synthesis of patent examples of formula 1 Synthesis of (4R)-4-[(1R)-1-[6-(3,4-Dimethoxyphenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 1)

[00399] A mixture of 150 mg of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one 7.1, 139 mg of (3,4-dimethoxyphenyl)boronic acid 4.22, 17.9 mg of bis(triphenylphosphine)palladium( II) and 764 μL of 2M aqueous sodium carbonate solution in 1.7 mL of DMF was stirred at 90 °C for 20 h. The reaction mixture was allowed to reach room temperature and purified by rpHPLC to yield after lyophilization 42 mg of Example 1. Analysis: HPLC-MS: Rt = 3.72 min (T method), M+H = 397 Synthesis of (4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin- 4-yl]oxyethyl]pyrrolidin-2-one (Example 2)

[00400] Step 1: Synthesis of (4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1-(4-

[00401] To a mixture of 1.0 g of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 6.1, 790 mg of 1-tert-butyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 4.19 and 170 mg of 1,1'-bis(diphenylphospine)ferrocenedichloropalladium(II) (complexed with DCM (1:1)) in 6 mL of dioxane were added to 5.0 mL of 2M aqueous sodium carbonate solution. The resulting mixture was stirred in a sealed tube at 140°C for 1h. The reaction mixture was poured into DCM. The precipitate was filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (DCM/methanol = 1/0 (9/1) to yield 1.0 g (50% by NMR) of (4R)-4-[(1R)-1-[6-(1-tert-butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1- (4-methoxyphenyl)ethyl]pyrrolidin-2-one 8.1 as oil Analysis: HPLC-MS: Rt = 0.63 min (method C), M+H = 517

[00402] Step 2: Synthesis of (4R)-4-[(1R)-1-[6-(1-tert-Butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 2)

[00403] A mixture of 3.90 g (36% by HPLC) of (4R)-4-[(1R)-1-[6-(1-tert-butylpyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one 8.1 in 25 mL of TFA was stirred at 80°C for 3h. The reaction mixture was purified by rpHPLC (SunfireC18, acetonitrile/water, TFA and XbridgeC18, acetonitrile/water, ammonia) and the desired fractions were lyophilized. The residue was triturated with TBME and a small amount of acetone. The solvent was distilled off, and the residue was dried to yield 410 mg of Example 2 as a solid. Analysis: HPLC-MS: Rt = 0.52 min (method C), M+H = 383

[00404] Alternatively, 8.1 can be synthesized as follows: Synthesis of Ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate

[00405] A solution of ethyl 2-cyano-3-ethoxyacrylate (5.0 g, 30 mmol) in anhydrous THF (10 mL) was charged dropwise to a mixture of sodium ethoxide (4.02 g, 59 mmol) and methylhydrazine (1.36 g, 30 mmol) in absolute ethanol (10 mL) at 0°C under nitrogen. After aging the stirred mixture for 90 min, an anhydrous hydrochloric acid solution (3.22 M in CPME, 28 mL, 90 mmol) was charged to the reaction dropwise. The reaction was then concentrated in vacuo to a solid, diluted with isopropyl acetate (20 mL) and concentrated to a solid. The crude slurry was suspended in hot isopropyl acetate (75 mL) and filtered hot. The filtrate was concentrated in vacuo to approximately 15 mL, whereupon a solid crystallized upon cooling to room temperature. The mixture was diluted by the dropwise addition of heptane (30 mL). The mixture was stirred for 1h at room temperature. Ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate was isolated by filtration, washed with heptane and dried under vacuum to afford 3.7 g as a yellowish orange solid in 74% yield. 1H NMR (500 MHz, DMSO-d6) δ = 7.87 (s, 1H), 5.3 (bs, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.60 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). Synthesis of Ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate

[00406] Isoamyl nitrite (420 mg, 3.6 mmol) was charged dropwise to a stirred mixture of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (400 mg, 2.4 mmol) and copper(II) bromide (660 mg, 3.0 mmol) in anhydrous acetonitrile (10 mL) at room temperature. The reaction was stirred for one hour; at which point, the reaction was diluted with isopropyl acetate (100 mL). The mixture was washed with water (100 mL) and concentrated to an oily residue. Purification by silica gel chromatography with methyl t-butyl ether and hexane provided ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (350 mg) as a white solid in 64% yield. 1H NMR (500 MHz, CDCl3) δ = 7.83 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). Synthesis of 3-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid

[00407] An aqueous solution of sodium hydroxide (2M, 10 mL, 20 mmol) was charged to a mixture of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (2.0g, 8.6 mmol) in ethanol (20 mL) at room temperature. The reaction was stirred at 50°C for 1h; at which point, the reaction was cooled to room temperature. An aqueous hydrochloric acid solution (3M, 6.7 mL, 20 mmol) was added dropwise to the reaction to induce crystallization. The 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid solids were collected by filtration, washed with water, followed by heptane and dried to afford 1.4 g as a white solid in 79% yield. 1H NMR (400 MHz, DMSO-d6) δ = 12.59 (s, 1H), 8.27 (s, 1H), 3.85 (s, 3H). Synthesis of 1-(1-(tert-Butyl)-1H-pyrazol-4-yl)ethan-1-one

[00408] Isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF, 28.4 mL, 37 mmol) was charged to a solution of 4-bromo-1-(tert-butyl)-1H-pyrazole (5.0 g, 25 mmol) in anhydrous THF (25 mL) under argon at room temperature. Anhydrous dioxane (3.3 g, 37 mmol) was charged to the reaction, and the reaction was stirred at 45 °C for 4 h. The resulting mixture was cooled to room temperature and charged to an anhydrous solution of acetic anhydride (7.5 g, 73 mmol) in THF (25 mL) at -20 °C. The resulting mixture was warmed to room temperature and concentrated to a residue. The mixture was dissolved in methyl t-butyl ether (50ml) and washed with water (25ml). The organic portion was concentrated to give crude 1-(1-(tert-butyl)-1H-pyrazol-4-yl)ethan-1-one as an oil (7.6 g, 36% by weight) and 67% yield. Crystallization from a mixture of methyl t-butyl ether and heptane provided analytically pure material. 1H NMR (500 MHz, CDCl3) δ = 7.96 (s, 1H), 7.86 (s, 1H), 2.37 (s, 3H), 1.55 (s, 9H). Synthesis of 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-one

[00409] A mixture of lithium tert-butoxide (0.970 g, 12 mmol), palladium(II) acetate (27 mg, 0.12 mmol), and di-tert-butyl(2,4,6-trisopropylbiphenyl-2-yl)phosphine (77 mg, 18 mmol) in anhydrous and degassed 1,4-dioxane (4 mL) under argon was stirred at room temperature for 15 minutes. The mixture was heated to 90°C and stirred at this temperature for 5 minutes. A solution of 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.4 mmol) and 1-(1-(tert-Butyl)-1H-pyrazol-4-yl)ethan-1-one (490 mg, 2.9 mmol) in degassed anhydrous 1,4-dioxane (7 mL) under argon was charged to the catalyst-based suspension at 90 °C drop by drop for 50 minutes. The reaction was stirred at 90°C for 30 minutes. The reaction was cooled to room temperature and quenched by the addition of trifluoroacetic acid (5 mL). The reaction was concentrated to an oily solid. The mixture was suspended in a mixture of acetonitrile (20 mL) and trifluoroacetic acid (20 mL). The mixture was then stirred at 75 °C for 14 h, concentrated to an oily solid. The mixture was suspended in isopropyl acetate (70ml) and washed twice with water (40ml). The organic portion was concentrated to a solid. Purification by silica gel chromatography with ethyl acetate and hexane provided 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-one as an orange solid (650 mg) in 98% yield. 1H NMR (500 MHz, CDCl3) δ = 8.06 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 6.68 (s, 1H), 4.04 (s, 3H), 1.60 (s, 9H). Synthesis of 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

[00410] A mixture of 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methylpyrano[4,3-c]pyrazol-4(2H)-one (980 mg, 3.6 mmol) and ammonium acetate (1.11 g, 14 mmol) in anhydrous DMSO (4 mL) was stirred at 110 °C for 4 h; at which point, additional ammonium acetate (1.11 g, 3.6 mmol) was charged to the reaction. After stirring for another 4 h at 110°C, the reaction was cooled to room temperature and diluted with water (20 mL). 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one solids were isolated by filtration, washed with water and dried to give 880 mg for a 90% yield. 1H NMR (500 MHz, DMSO-d6) δ = 10.59 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.73 (s, 1H), 3.99 (s, 3H), 1.53 (s, 9H). Synthesis of 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine

[00411] Phosphorous (V) oxychloride (848 mg, 5.53 mmol) was charged to a mixture of 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (500 mg, 1.84 mmol) in anhydrous acetonitrile (5 mL) under argon. The reaction was stirred at 75-80 °C for 3 h; at which point, the reaction was cooled to room temperature. The reaction poured slowly into a saturated aqueous sodium bicarbonate solution (45 mL). The mixture was stirred for 20 min and concentrated in vacuo to remove the acetonitrile solvent. The resulting aqueous suspension was diluted with isopropyl acetate (50 mL) and washed with water (2 x 20 mL). The organic portion was concentrated to an oil which solidified on standing to afford 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine as a yellow solid (690 mg, 73% by weight) in 92% yield. Analytically pure material was obtained by crystallization from n-propanol and heptane. 1H NMR (500 MHz, CDCl3) δ = 8.08 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 4.20 (s, 3H), 1.62 (s, 9H). Synthesis of (R)-4-((R)-1-((6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (8.1)

[00412] A mixture of (R)-4-((R)-1-hydroxyethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (173 mg, 0.66 mmol), 6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-4-chloro-2-methyl-2H-pyrazolo[4,3-c]pyridine (190 mg, 66 mmol) and sodium hydride (60 wt%, 66 mg, 1.6 mmol) in anhydrous 1,4-dioxane (3 mL) was stirred under argon at 50-70 °C for 18 h. The reaction mixture was cooled to room temperature and quenched by the slow addition of hydrogen chloride solution (4 M in 1,4-dioxane, 0.245 mL, 0.98 mmol). The reaction was diluted with isopropyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous portion was extracted twice with isopropyl acetate (20 ml). The combined organic layers were concentrated to an oil. Purification by chromatography on silica gel with methanol and methyl tert-butyl ether afforded (R)-4-((R)-1-((6-(1-(tert-Butyl)-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[4,3-c]pyridin-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2- one (185 mg) as a white foam in 55% yield. 1H NMR (500 MHz, CDCl3) δ = 7.94 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 5.48 (dddd, J = 4 ? .66 (m, 1H), 2.66-2.57 (m, 2H), 1.64 (s, 9H), 1.48 (d, J = 7.1 Hz, 3H), 1.33 (d, J = 6.2 Hz, 3H). Synthesis of (4R)-4-[(1R)-1-[6-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 3)

[00413] To a mixture of 50 mg of [2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronic acid 11.1, 46.2 mg of 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol 3 .26 and 20 mg of palladium-X-phos were added to 3 mL of dioxane and 65 µL of 5M aqueous sodium carbonate solution. The resulting mixture was heated at 110°C for 14h. The mixture was cooled to room temperature and purified by rpHPLC. The combined organic phases were lyophilized to provide example 3 at 21 mg. Analysis: HPLC-MS: Rt = 0.86 min (Z1 method), M+H = 411

[00414] Example 17 was synthesized analogously to Example 3 using 1-[(4-bromophenyl)methyl]-2-methyl-1H-imidazole 3.27. Analysis: HPLC-MS: Rt = 0.73 min (Z1 method), M+H = 431 Synthesis of (4R)-4-[(1R)-1-[6-(4-Hydroxy-3-methoxy-phenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 8)

[00415] To a mixture of 100 mg of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one 7.1, 110 mg of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 4.24 phenol and 37 mg of 1,1'-bis(diphenylphospine)ferrocene-dichloropalladium(II) (complex with DCM (1:1)) in 1 mL of dioxane and 0.5 mL of methanol were added to 400 µL of 2M aqueous sodium carbonate solution. The reaction mixture was stirred at 140°C for 15 min under microwave irradiation. The reaction mixture was filtered by rpSiO2, washed with methanol and purified by rpHPLC to yield after lyophilization, 80 mg (yield: 68%) of Example 8 as a solid. Analysis: HPLC-MS: Rt = 0.47 min (S method), M+H = 383

[00416] The following Examples were synthesized analogously to Example 8.

[00417] The following examples were synthesized in analogy to Example 8, but using different reaction solvents:

Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 9)

[00418] Step 1: Synthesis of tert-Butyl 4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate

[00419] To a mixture of 100 mg of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one 7.1, 170 mg of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) )pyrazol-1-yl]piperidine-1-carboxylate 4.41 and 37 mg of 1,1'-bis(diphenylphospine)ferrocenedichloropalladium(II) (complexed with DCM (1:1)) in 1 mL of dioxane and 0.5 mL of methanol were added to 400 µL of 2M aqueous sodium carbonate solution. The reaction mixture was stirred at 140 °C for 15 min under microwave irradiation. The reaction mixture was filtered through rpSiO2, washed with methanol and purified by rpHPLC (XbridgeC18, acetonitrile/water, ammonia) to yield after lyophilization 90 mg (80% by NMR) of tert-butyl 4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazole-[ 4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate as a solid.

[00420] Analysis: HPLC-MS: Rt = 0.45 min (method J), M+H = 510

[00421] Step 2: Synthesis of (4R)-4-[(1R)-1-[2-methyl-6—[1-(4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 9)

[00422] A solution of 90 mg (80% by NMR) of tert-butyl 4-[4-[2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate in 2 mL of TFA was stirred at room temperature for 15 min. The reaction mixture was purified by rpHPLC (SunfireC18, acetonitrile/water, TFA) to yield after lyophilization, 83 mg of Example 9 as a solid. Analysis: HPLC-MS: Rt = 0.32 min (method J), M+H = 410 Synthesis of (4R)-4-[(1R)-1-[6-[1-(4,4-Difluorocyclohexyl)pyrazol-4-yl]-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 10)

[00423] A mixture of 100 mg of [2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronic acid 11.1, 87 mg of 4-bromo-1-(4,4-difluoro-cyclohexyl)pyrazole 3.12, 27 mg of 1,1'-bis(diphenylphospine)ferrocenedichloropalladium(II) (complexed with DCM (1:1)) and 493 µL of 2M aqueous sodium carbonate solution in 2 mL of dioxane were stirred at 120°C for 15 min under microwave irradiation. The reaction mixture was filtered and purified by rpHPLC to yield after lyophilization, 23 mg of Example 10 as a solid.

[00424] Analysis: HPLC-MS: Rt = 0.535 min (method C), M+H = 445

[00425] 1H NMR (DMSO, 400 MHz) δ = 1.38 (3H, d), 1.58 (9H, s), 2.00 - 2.20 (10H, m), 2.73 - 2.86 (1H, m), 3.11-3.16 (m, 1H), 3.38(1H, t), 4.09 (3H, s), 4.39-4.49 (1H, m), 5.50-5.61 (1H, m), 7.31 (1H, s), 7.50 (1H, s), 8.00 (1H, s), 8.26 (1H, s), 8.40 (s, 1H).

[00426] Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-[1-(3,3,3-trifluoropropyl)pyrazol-4-yl]indazol-4-yl]oxyethyl]pyrrolidin-2-one (Example 15)

[00427] To a mixture of 100 mg of (4R)-4-[(1R)-1-[2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-4-yl]oxyethyl]pyrrolidin-2-one 11.3, 95 mg of 4-bromo-1-(3,3,3-trifluoro-propyl)pyrazole 3.15 and 9.1 mg of 1,1'-bis(triphenylphosphine)palladium(II) chloride in 1.5 mL of ethanol (80% with toluene) were added to 389 µL of 2M aqueous sodium carbonate solution. The resulting mixture was stirred at 100 °C for 1 h under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were concentrated in vacuo. The crude residue was purified by flash chromatography (heptane/ethyl acetate/methanol) and rpHPLC to afford 27 mg (yield: 25%) of Example 15 as a solid.

[00428] Analysis: HPLC-MS: Rt = 2.33 min (R method), M+H = 422

[00429] The following Examples were synthesized analogously to Example 15. Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-(4-morpholinophenyl)indazol-4-yl]oxyethyl]-pyrrolidin-2-one (Example 22)

[00430] To a mixture of 105 mg of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one 7.4, 96 mg of (4-morpholinophenyl)boronic acid 4.46 and 10.9 mg of 1,1'-bis(triphenylphosphine)palladium(II) chloride in 1 .58 mL of ethanol (80% with toluene) was added to 466 µL of 2M aqueous sodium carbonate solution. The resulting mixture was stirred at 95 °C for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were concentrated in vacuo. The crude residue was purified by flash chromatography (heptane/ethyl acetate/methanol) and rpHPLC to afford 74 mg (yield: 56%) of Example 22 as a solid. Analysis: HPLC-MS: Rt = 2.35 min (R method), M+H = 421

[00431] The following Examples were synthesized similarly to Example 22, but with a modified reaction time. Synthesis of (4R)-4-[(1R)-1-(2-methyl-6-thiazol-4-yl-indazol-4-yl)oxyethyl]pyrrolidin-2-one (Example 29)

[00432] A mixture of 75 mg of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one (9.2), 102 μL of tributyl(thiazol-4-yl)stannane and 7.8 mg of 1,1'-bis(triphenylphosphine)palladium(II) chloride in 1.5 mL of dioxane was stirred at 95 °C for 18 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (heptane/ethyl acetate/methanol) and rpHPLC to give 13 mg (yield: 19%) of Example 29 as a solid. Analysis: HPLC-MS: Rt = 1.98 min (R method), M+H = 343

[00433] The following Example was synthesized similarly to Example 29, but with a modified reaction time. Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-[1-(4-piperidyl)pyrazol-4-yl]indazol 4-yl]oxyethyl]pyrrolidin-2-one (Example 45)

[00434] To a mixture of 125 mg of (4R)-4-[(1R)-1-(6-bromo-2-methyl-indazol-4-yl)oxyethyl]pyrrolidin-2-one 7.5, 167 mg of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pi peridine-1-carboxylate 4.41 and 13 mg of 1,1'-bis(triphenylphosphine)palladium(II) chloride in 1.88 mL of ethanol (80% with toluene) were added to 554 µL of 2M aqueous sodium carbonate solution. The resulting mixture was stirred at 95 °C for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were concentrated in vacuo. The crude residue was purified by flash chromatography (heptane/ethyl acetate/methanol). The residue was dissolved in 2 mL of DCM, 500 µL of TFA was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was purified by flash chromatography (DCM/methanol/ammonia) and elution through an SCX column (Biotage SCX-3) and subsequent rpHPLC to afford 92 mg (yield: 61%) of Example 45 as a solid. Analysis: HPLC-MS: Rt = 1.25 min (R method), M+H = 409 Synthesis of (4R)-4-[(1R)-1-[6-(6-Cyclopropyl-3-pyridyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 50)

[00435] To a mixture of 50 mg of (4R)-4-[(1R)-1-(6-chloro-2-methyl-pyrazolo[4,3-c]pyridin-4-yl)oxyethyl]pyrrolidin-2-one 7.1, 94 mg of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 4 .23 and 20 mg of 1,1'-bis(triphenylphosphine)palladium(II) chloride in 1 mL of DMA were added to 400 μL of 2M aqueous sodium carbonate solution. The reaction mixture was stirred at 130°C for 25 min under microwave irradiation. The reaction mixture was filtered by rpSiO2, washed with methanol and purified by rpHPLC to yield after lyophilization, 22 mg (yield: 37%) of Example 50 as a solid.

[00436] Analysis: HPLC-MS: Rt = 0.69 min (U method), M+H = 378

[00437] The following Examples were synthesized analogously to Example 50. Synthesis of (4R)-4-[(1R)-1-[6-(3-Methoxy-4-tetrahydropyran-4-yloxyphenyl)-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 73)

[00438] A mixture of 68 mg of Example 8, 59 mg of tetrahydropyran-4-yl 4-methylbenzenesulfonate and 39 mg of potassium carbonate in 2 mL of DMF was stirred at 80 °C for 3 h and at 100 °C for 10 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were concentrated in vacuo. The resulting residue was purified by rpHPLC to yield after lyophilization, 37 mg of Example 73 as a solid. Analysis: HPLC-MS: Rt = 0.70 min (W method), M+H = 467 Synthesis of (4R)-4-[(1R)-1-[2-methyl-6-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 82)

[00439] To a mixture of 68 mg of Example 9 and 31 mg of sodium acetate in 3 mL of DCM and 0.5 mL of methanol was added 17 µL of formaldehyde (37% aqueous). The resulting mixture was stirred at room temperature for 10 min before 46 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred for 1.75 h before being quenched with water. The organic solvent was distilled off. The resulting residue was purified by rpHPLC to yield after lyophilization, 64 mg of Example 82 as a solid. Analysis: HPLC-MS: Rt = 0.28 min (method X), M+H = 424 Synthesis of (4R)-4-[(1R)-1-[6-[1-(Difluoromethyl)imidazol-4-yl]-2-methyl-pyrazolo[4,3-c]pyridin-4-yl]oxyethyl]pyrrolidin-2-one (Example 83) and 2-methyl-6-[2 -methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]-5H-pyrazolo[4,3-c]pyridin-4-one (Example 13)

[00440] To a mixture of 300 mg of [2-methyl-4-[(1R)-1-[(3R)-5-oxopyrrolidin-3-yl]ethoxy]pyrazolo[4,3-c]pyridin-6-yl]boronic acid (raw) 11.1, 60 mg of 4-bromo-1-(difluoromethyl)imidazole and 41 mg of 1,1'-bis(di phenylphospino)ferrocenedichloro palladium(II) (complex with DCM (1:1)) in 2 mL of dioxane and 0.5 mL of methanol were added to 670 μL of 2M aqueous sodium carbonate solution. The reaction mixture was stirred at 140°C for 15 min under microwave irradiation. The reaction mixture was filtered through Agilent PL-Thiol MP-SPE, washed with methanol and purified by rpHPLC to yield after lyophilization, 9 mg of Example 83 and 4 mg of Example 13 as solids.

[00441] Analysis (Example 83): HPLC-MS: Rt = 0.43 min (method C), M+H = 377

[00442] Analysis (Example 13): HPLC-MS: Rt = 0.38 min (method C), M+H = 408

4.5 Analytical methods

[00443] The Example compounds prepared according to the preceding synthetic schemes were characterized by the following chromatographic methods and/or NMR spectroscopy. 4.5.1 Chromatographic methods (HPLC-MS methods) Method A Method G:

[00444] The stationary phase used was an Inertsil C8-3 (GL Sciences), 5 μm; dimension: 100 x 4.0 mm, (column temperature: constant at 30°C). UV detection 220 nm. Method H:

[00445] The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm; dimension: 150 x 4.6 mm,

[00446] (column temperature: constant at 10°C). DAD 225 nm detection. Method I: Eluent A: Hexane Eluent B: 2-propanol

[00447] The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm; dimension: 150 x 4.6 mm, (column temperature: constant at 10°C). DAD 225 nm detection. Method J: K Method:

[00448] Column: Waters Atlantis dC18 (2.1 x 50 mm column, 3 μm)

[00449] Flow rate: 1 mL/min

[00450] Solvent A: 0.1% formic acid/water

[00451] Solvent B: 0.1% formic acid/acetonitrile

[00452] Injection volume: 3 μL

[00453] Column temperature: 40°C

[00454] UV detection wavelength: 215 nm

[00455] Eluent: 0 to 2.5 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 2.5 to 2.7 minutes, 100% Solvent B; 2.71 to 3.0 minutes, 95% solvent A + 5% solvent B.

[00456] MS detection using Waters LCT Premier, QTof micro, ZQ or Shimadzu LCMS2010EV

[00457] UV detection using Waters 2996 photodiode array, Waters 2998 photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA Method L: Method M:

[00458] Column: Waters SymmetryShield RP8 (2.1 x 50 mm column, 3.5 μm)

[00459] Flow rate: 1 mL/min

[00460] Solvent A: 0.1% formic acid/water

[00461] Solvent B: 0.1% formic acid/acetonitrile

[00462] Injection volume: 3μL

[00463] Column temperature: 40°C

[00464] UV detection wavelength: 215nm

[00465] Eluent: 0 to 2.2 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 2.2 to 2.7 minutes, 100% Solvent B; 2.71 to 3.0 minutes, 95% solvent A + 5% solvent B.

[00466] MS detection using Waters LCT Premier, QTof micro, ZQ or Shimadzu LCMS2010EV

[00467] UV detection using Waters 2996 photodiode array, Waters 2998 photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA Method N: Method O: P method:

[00468] Column: Supelco Ascentis Express (2.1 x 30 mm column, 2.7 μm)

[00469] Flow rate: 1 ml/min

[00470] Solvent A: 0.1% formic acid/water

[00471] Solvent B: 0.1% formic acid/acetonitrile

[00472] Injection volume: 3 μL

[00473] Column temperature: 40°C

[00474] UV detection wavelength: 215nm

[00475] Eluent: 0 to 1.5 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 1.5 to 1.6 minutes, 100% Solvent B; 1.60 to 1.61 minutes, constant gradient from 100% Solvent B to 95% Solvent A + 5% Solvent B; 1.61 to 2.00 minutes, 95% solvent A + 5% solvent B.

[00476] MS detection using Waters LCT Premier, QTof micro, ZQ or Shimadzu LCMS2010EV

[00477] UV detection using Waters 2996 photodiode array, Waters 2998 photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA

Q method

[00478] Column: Atlantis d C18; 50x3mm; 3 μ

[00479] Flow rate: 0.6 ml/min

[00480] Solvent A: 0.1% formic acid in water

[00481] Solvent B: 0.1% formic acid in acetonitrile

[00482] Injection volume: 5 μL

[00483] Column temperature: 35 °C

[00484] UV detection wavelength: Spectra À max (scanning in the 200-400 nm region)

[00485] Eluent: 0 to 3.5 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 3.5 to 3.8 minutes, 100% Solvent B; 3.8 to 3.9 minutes, steady gradient from 100% Solvent B to 95% Solvent A + 5% Solvent B; 3.9 to 4.5 minutes, 95% solvent A + 5% solvent B.

[00486] MS detection using Waters 3100, SQ detector, ES + ve and -ve modes (Cone voltage: 30V, Capillary voltage 3.0 KV)

[00487] UV detection using Waters 2996 photodiode device

R Method:

[00488] Column: Phenomenex Kinetex-XB C18 (2.1 x 100 mm column, 1.7μm)

[00489] Flow rate: 0.6 mL/min

[00490] Solvent A: 0.1% formic acid/water

[00491] Solvent B: 0.1% formic acid/acetonitrile

[00492] Injection volume: 3 μL

[00493] Column temperature: 40°C

[00494] UV detection wavelength: 215 nm

[00495] Eluent: 0 to 5.3 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 5.3 to 5.8 minutes, 100% Solvent B; 5.80 to 5.82 minutes, constant gradient from 100% Solvent B to 95% Solvent A + 5% Solvent B; 5.82 to 7mins, 95% Solvent A + 5% Solvent B

[00496] Detection by MS using Waters SQD

[00497] UV detection using Waters Acquity photodiode array Method S:

T method:

[00498] Column: Phenomenex Gemini C18 (2.0 mm x 100 mm column, 3 μm)

[00499] Flow rate: 0.5 mL/min

[00500] Solvent A: 2 mM ammonium bicarbonate modified at pH 10 with Ammonium Hydroxide/water

[00501] Solvent B: Acetonitrile

[00502] Injection volume: 3 μL

[00503] Column temperature: 40°C

[00504] UV detection wavelength: 215 nm

[00505] Eluent: 0 to 5.5 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 5.5 to 5.9 minutes, 100% Solvent B; 5.90 to 5.92 minutes, constant gradient from 100% Solvent B to 95% Solvent A + 5% Solvent B; 5.92 to 9.00 minutes, 95% solvent A + 5% solvent B. Z Method:

[00506] Column: Waters Atlantis dC18 (2.1 mm x 100.3 μm column)

[00507] Flow rate: 0.6 mL/min

[00508] Solvent A: 0.1% formic acid/water

[00509] Solvent B: 0.1% formic acid/acetonitrile

[00510] Injection volume: 3 μL

[00511] Column temperature: 40 °C

[00512] UV detection wavelength: 215 nm

[00513] Eluent: 0 to 5 minutes, constant gradient from 95% Solvent A + 5% Solvent B to 100% Solvent B; 5 to 5.4 minutes, 100% Solvent B; 5.4 to 5.42 minutes, constant gradient from 100% Solvent B to 95% Solvent A + 5% Solvent B; 5.42 to 7.00 minutes, 95% solvent A + 5% solvent B.

[00514] MS detection using Waters LCT Premier, QTof micro, ZQ or Shimadzu LCMS2010EV

[00515] UV detection using Waters 2996 photodiode array, Waters 2998 photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA Method Z1:

4.5.2 NMR Spectroscopy Bruker DRX 500 MHz NMR Setup

[00516] High-performance digital NMR spectrometer, 2-channel microbay console and Windows XP host Workstation running Topspin version 1.3.

[00517] Equipped with:

[00518] • Oxford instruments 11.74 Tesla magnet (500 MHz proton resonant frequency)

[00519] • B-VT 3000 temperature controller

[00520] • GRASP II gradient spectroscopy accessory for fast acquisition of 2D pulse sequences

[00521] • Deuterium lock switch for gradient shims

[00522] • 5mm Wide Range Inverse Geometry Dual Resonance Probe with Automated Adaptation and Tuning (BBI ATMA). Allows observation of 1H with pulsing/decoupling of cores in the 15N and 31P lock with 2H of frequency range and shielded z gradient coils.

Bruker DPX 400MHz NMR Setup

[00523] High performance Bruker 400 MHz one bay digital two channel NMR spectrometer console and Windows XP host Workstation running XwinNMR version 3.5.

[00524] Equipped with:

[00525] • Oxford instruments 9.39 Tesla magnet (500 MHz proton resonant frequency)

[00526] • B-VT 3300 variable temperature controller unit

[00527] • Switchable four-core probe (QNP) for observation of 1H, 13C, 19F and 31P locks with 2H

Bruker 500 MHz NMR setup

[00528] High performance digital NMR spectrometer, 2 channel one bay console and Linux host workstation running Topspin version 2.1 PL6.

[00529] Equipped with:

[00530] • 11.75 Tesla Bruker-Biospin AVANCE III 500A magnet (500 MHz proton resonant frequency)

[00531] • B-VT 3000 temperature controller

[00532] • Multinuclear Broad Band fluorine observe probe (BBFO) of 5 mm with digital tuning coverage of the decoupling range of 15N and 31P as well as 19F with 1H.

Bruker DPX 400MHz NMR Setup

[00533] High-performance digital NMR spectrometer, 2-channel microbay console and Linux host workstation running Topspin version 2.1 PL6

[00534] Equipped with:

[00535] • 9.40 Tesla Magneto by Bruker-Biospin AVANCE III DPX400C (400 MHz proton resonant frequency)

[00536] • B-VT 3200 variable temperature controller unit

[00537] Multinuclear Broad Band fluorine observe probe (BBFO) of 5 mm with digital tuning coverage of the decoupling range of 15N and 31P as well as 19F with 1H.

5. EXAMPLES

[00538] The following Examples were prepared analogously to the synthetic methods described above. These compounds are suitable as SYK inhibitors and have IC50 values with respect to SYK inhibition of less than or equal to 1 µmol. Additionally, these compounds exhibit very good SYK selectivity which means that - considering that SYK is effectively inhibited - other kinases such as Aurora B (AURB), FLT-3 and GSK 3β are not or almost not inhibited at all. Therefore, unwanted side effects of these effective SYK inhibitors of the invention are minimized.

[00539] AURB phosphorylates Ser10 and Ser28 on histone H3, a key event in cell mitosis and proliferation. Inhibition of AURB therefore has the potential to block cell proliferation, and could compromise tissues that exhibit high cell regeneration, such as the intestine or bone marrow. It is therefore desired to avoid parallel AURB inhibition of an effective SYK inhibitor to improve the overall clinical safety profile of the compound. Therefore, all example compounds show IC50 values with respect to Aurora B inhibition of more than 1 µM, preferably more than 6 µM, more preferably more than 10 µM, more preferably more than 30 µM, more preferably more than 45 µM, particularly preferably more than 50 µM. The AURB-IC50/SYK-IC50 ratios of all example compounds are preferably greater than 30, more preferably greater than 100.

[00540] FLT-3 is a receptor tyrosine kinase. When an FLT-3 ligand binds to the receptor, the receptor's intrinsic tyrosine kinase activity is activated, which in turn phosphorylates and activates signal transduction molecules (such as SHC) which in turn propagate the signal in the cell. Signaling through FLT-3 plays a role in cell survival, proliferation and differentiation, and is important for lymphocyte (B cell and T cell) development. It is therefore desired to avoid parallel FLT-3 inhibition to improve the overall clinical safety profile of the compound. Therefore, all example compounds of the present invention show IC50 values with respect to FLT-3 inhibition of more than 0.30 µM, preferably more than 1 µM, more preferably more than 10 µM particularly preferably more than 30 µM. The FLT-3-IC50/SYK-IC50 ratios of all example compounds are preferably more than 10, more preferably more than 30.

[00541] Glycogen synthase kinase 3 beta (GSK 3β) is a proline-directed serine-threonine kinase that is prominent in the TGF-β and Wnt intracellular signaling reaction series. GSK 3 β facilitates several series of intracellular signaling reactions, including β-catenin complex activation. In adults, GSK 3β is involved in cell proliferation and energy metabolism, while in neonates it is involved in neuronal cell development and body pattern formation. It is therefore desired to avoid parallel GSK3β inhibition of an effective SYK inhibitor to improve the overall clinical safety profile of the compound. Therefore, all example compounds of the invention show IC50 values with respect to GSK 3β inhibition of more than 1 µM preferably more than 10 µM.

[00542] Furthermore, it is desirable for a SYK inhibitor to have certain human liver microsomal stability (corresponding to Cl < 60% of Qh; % of Qh = percentage of liver blood flow). Otherwise it will be difficult to achieve an adequate plasma level of the SYK inhibitor in the patient to be treated.

[00543] The IC50 values with respect to SYK inhibition, with respect to Aurora inhibition, with respect to FLT3 inhibition and with respect to GSKbeta inhibition as well as human liver microsomal stabilities (Cl [% of Qh]) for each of the individual example substances are shown in the following Table 1 and were experimentally determined as follows:

5.1 Syk Kinase Test

[00544] Recombinant human Syk (amino acids 342-635) was expressed as a fusion protein with an N-terminal GST label, affinity purified and deep frozen to a concentration of approx. 50 - 100 µM in storage buffer (25 mM HEPES pH7.5; 25 mM MgCl2; 5 mM MnCl2; 50 mM KCl; 0.2% BSA; 0.01% CHAPS; 100 µM Na3VO4; 0.5 mM DTT, 10% glycerol) at -80°C until use.

[00545] The catalytic activity of the GST-SYK kinase fusion protein was determined using the Kinase Glo® Luminescence Kinase Test (Promega; V6712). In this homogeneous assay, the amount of ATP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction using luminescence. The luminescence signal obtained further correlates with the amount of ATP still present and thus inversely correlates with kinase activity.

Method

[00546] Test compounds were dissolved in 100% DMSO to a concentration of 10 mM and diluted in DMSO to a concentration of 1 mM. Consecutive dilution is performed in 100% DMSO. All additional dilutions of substances were performed with test buffer (25 mM HEPES pH7.5; 25 mM MgCl2; 5 mM MnCl2; 50 mM KCl; 0.2% HSA; 0.01% CHAPS; 100 μM Na3VO4; 0.5 mM DTT). The dilution steps and concentration range were adapted as needed. 7 µl aliquots of these dilutions were transferred into a 384-well Optiplate plate (Perkin Elmer, #6007290). GST-Syk was diluted to 12 nM in the test buffer and 5 μl of this dilution was used in the kinase test (final Syk concentration = 4 nM in a total volume of 15 μl). After a 15 minute incubation at room temperature, 3 µl of a mixture of 750 nM ATP and 100 µg/ml poly (L-Glutamic Acid L-Tyrosine 4:1, Fluka #81357) in test buffer was added to each well and incubation was continued for an additional 60 minutes at room temperature.

[00547] Positive controls are reaction mixtures that do not contain test substance; Negative controls (ranges) are reaction mixtures that do not contain kinase.

[00548] After 60 minutes, 10 µl of Kinase-Glo® solution (Promega, Cat. #V6712) (warmed to room temperature) was added to each well and the incubation was continued for an additional 15 minutes. Plates were read on an Envision Luminescence Reader (Perkin-Elmer).

Data Evaluation and Calculation:

[00549] The output file from the reader is a csv file that contains the cavity number and measured relative light light units (RLU). For data evaluation and calculation, the negative control measure was set to 100% ctrl and the positive control measure was set to 0% ctrl. Based on these values, the % value for the measurement of each substance concentration was calculated using Assay Explorer software (Accelris). Typically, the % of calculated ctrl values is between 0% and 100% of values, however, it may also occur outside these limits in individual cases based on variability or blending characteristics. IC50 values were calculated from % ctrl values using Assay Explorer software. Calculation: [y=(a-d)/(1+(x/c)Ab)+d] a = low value, δ = high value; x = M conc.; c=IC50 M; b = hill; y = % of ctrl.

5.2 Aurora B Kinase Test

[00550] Recombinant human Aurora B (amino acids 1-344, clone number DU1773, molecular weight 40.2 kDa, University of Dundee) was expressed as a fusion protein as an N-terminal His tag, affinity purified and hard frozen at a concentration of approx. 0.25 - 0.5 mg/ml in storage buffer (50 mM Tris-HCl pH 8; 25 mM Na-β-glycerophosphate; 0.1 mM EGTA; 150 mM NaCl; 0.03% Brij-35; 1mM DTT and 10% glycerol) at -80°C until use.

[00551] Aurora B protein kinase activity was determined using the ADP Glo® Luminescence Kinase Test (Promega; V9103X). In this homogeneous test, the amount of ADP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction using luminescence. The luminescence signal obtained further correlates with the amount of ADP present and thereby correlates with protein kinase activity.

Method

[00552] Test compounds were dissolved in 100% DMSO to a concentration of 10 mM and diluted in DMSO to a concentration of 5 mM. Consecutive dilution is performed in 1:10 steps in 100% DMSO. All further dilutions of substances were performed with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCk, 1 mM EGTA, 60 μM Ultra Pure ATP, 0.01% Brij35, 0.1% BSA, 5 mM β-glycerophosphate) until a concentration was reached that was 2.5 times above the final test concentration (final concentration of compounds: 50 µM to 0.005 nM). 4 µl aliquots of these dilutions were transferred into a 384-well Optiplate (Perkin Elmer, #6007290). His-Aurora B was diluted to 125 nM in the test buffer and 4 μl of this dilution was used in the kinase test (final Aurora B concentration = 50 nM in a total volume of 10 μl). After the 15 minute incubation at room temperature, 2 µl of 250 µM substrate ([LRRLSLGLRRLSLGLRRLSSLGLRRLSLG]; University of Dundee) in test buffer was added to each well, and the incubation was continued for an additional 60 minutes at room temperature.

[00553] Positive controls are reaction mixtures that do not contain test substance; Negative controls (ranges) are reaction mixtures that do not contain kinase.

[00554] After 60 minutes, 10 µl of PAD-Glo® solution (PAD-Glo Reagent #V912B Promega) (warmed to room temperature) was added to each well and incubation was continued for an additional 40 minutes. Then, 20 μl of Kinase detection mix (Detection Buffer #V913B Promega; Kinase Detection Substrate #V914B Promega) was added and incubated for 40 minutes at room temperature. Plates were read on an Envision Luminescence Reader (Perkin-Elmer).

Data evaluation and calculation:

[00555] The output file from the reader is a csv file that contains the measured cavity number and RLU. For data evaluation and calculation, the negative control measure was set to 0% ctrl and the positive control measure was set to 100% ctrl. Based on these values, the % value for the measurement of each substance concentration was calculated using Assay Explorer software (Accelris). Typically, the % of calculated ctrl values is between 0% and 100% of values, however, it may also occur outside these limits in individual cases based on variability or blending characteristics. IC50 values were calculated from % ctrl values using Assay Explorer software. Calculation: [y=(a-d)/(1+(x/c)Ab)+d], a = low value, δ = high value; x = M conc.; c=IC50 M; b = hill; y = % of ctrl.

5.3 FLT3 Kinase Test

[00556] FLT3 is obtained from Invitrogen in 50 mM Tris (pH7.5); 100 mM NaCl; 0.05 mM EDTA, 0.05% NP-40, 2mM DTT; 50% Glycerol #PV3182; Batch 28667I; sequence seen below). The enzyme is diluted to 720 nM (35 µg/ml) in Enzyme Dilution Buffer and 10 µl aliquots are stored at -80°C.

[00557] FLT3 activity is measured using Invitrogen's Z'-LYTETM Assay Technology (#PV3191)

Method

[00558] The assay is performed in Corning 384-well black plates (#3676) in a final volume of 10 μl by adding 5 μl Peptide Kinase Mixture and 2.5 μl compound dilution. The reaction is started by adding 2.5 µl of 4x ATPsolution.

[00559] Final concentration assay: 2 nM FLT3, 4 μM Tyr2 peptide, 470 μM ATP (Km ATP for FLT3)

[00560] Positive controls are reaction mixtures that contain no test compound; Negative controls (ranges) are reaction mixtures that do not contain kinase. As an additional control, the phosphopeptide solution is added to the kinase-free wells (= 100% phosphorylation control). The uninhibited kinase reaction will result in a phosphorylation corresponding to 20%-30% of the phosphorylation control.

[00561] The reaction is carried out for 1 h at room temperature before the 5 μl of development solution is added. After another 1 h incubation at room temperature, 5 μl of the stop reagent is added. Plates are read on a FlexStation II 384 (Molecular Devices).

[00562] To control for any potential protease inhibition present in the developing solution, the phosphopeptide is incubated with the developing solution in the presence of the highest concentration of test compound (usually 100 µM or 10 µM).

Data evaluation and calculation:

[00563] The output text file is evaluated in a "MS-Excel - VB - Makro" and "GrafPadPrism"(Version 5) (GrafPadSoftware Inc.) is used to calculate the results. Data for FLT3 inhibition are reported in M. Data for protease inhibition are reported in % CTL.

5.4 GSK 3β test

[00564] Human GSK3beta (expressed and purified from SF21 cells) is obtained from University Dundee/Scotland (Dr. James Hastie - Dept. of Biochemistry) in 50 mM Tris (pH 7.5); 150 mM NaCl; 0.1 mM EGTA, 270 mM Sucrose, 0.1% β-mercaptoethanol, 1mM benzamidine, 0.2 mM PMSF; sequence seen below). Enzyme is diluted to 3.56 µM (168 µg/ml) in Enzyme Dilution Buffer and 6 µl aliquots are stored at -80°C.

[00565] GSK3β kinase protein activity is measured using Invitrogen's Z'-LYTETM assay technology (#PV3324).

Method:

[00566] The assay is performed in Corning 384-well black plates (#3676) in a final volume of 10 µl by adding 5 µl of Peptide Kinase Mixture and 2.5 µl of compound dilution. The reaction is started by adding 2.5 µl of 4x ATPsolution.

[00567] Final concentration in the assay: GSK3β 5 nM, Ser/Thr9 peptide 2 μM, ATP 7 μM (Km ATP for GSK3β)

[00568] Positive controls are reaction mixtures that contain no test compound; Negative controls (ranges) are reaction mixtures that do not contain ATP. As an additional control, phosphopeptide solution is added to wells without kinase and without ATP (= 100% phosphorylation control). The uninhibited kinase reaction will result in phosphorylation corresponding to 20%-30% of control phosphorylation.

[00569] The reaction is carried out 1 h at room temperature. After 1h, 5 μl of the development solution is added. After another 1 h incubation at room temperature, 5 μl of the stop reagent is added. Finally, the plates are read on a Flex Station II 384 (Molecular Devices).

[00570] To control for any potential protease inhibition present in the developing solution, the phosphopeptide is incubated with the developing solution in the presence of the highest concentration of test compound (usually 100 µM).

Data evaluation and calculation:

[00571] The output text file is evaluated in a "MS-Excel - VB - Makro" and "GrafPadPrism"(Version 5) (GrafPadSoftware Inc.) is used to calculate the results. Data for GSK3beta inhibition are reported in M. Data for protease inhibition are reported in % CTL.

5.5 Human Liver Microsomal Stability Test

[00572] It is also desirable for a SYK inhibitor that is sufficiently specific for SYK as described above to have some human liver microsomal stability (corresponding to Cl < 60% of Qh; % of Qh = percentage of liver blood flow). Otherwise, it will be difficult to achieve an adequate plasma level of the SYK inhibitor in the patient to be treated.

Method:

[00573] Metabolic degradation for a specific SYK inhibitor is performed at 37°C with pooled human liver microsomes (human liver microsomes are commercially available as "BD UltraPoolTM" by Corning Life Sciences, Fogostraat 12, 1060 LJ Amsterdam, The Netherlands). The final incubation volume of 100 µl per time point contains TRIS buffer pH 7.6 in RT (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/ml), and the test compound at a final concentration of 1 µM.

[00574] Following a short pre-incubation period at 37°C, the reaction is initiated by addition of beta-nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH, 1 mM) and terminated by transferring an aliquot in solvent after different time points. Additionally, NADPH-independent degradation is monitored in NADPH-free incubations terminated at the last time point.

[00575] The quenched (terminated) incubations are then pelleted by centrifugation (10000 g, 5 min).

[00576] An aliquot of the supernatant is analyzed by LC-MS/MS for the remaining amount of the parent compound. The half-life (t1/2 INVITRO) is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

Data evaluation and calculation:

[00577] The intrinsic release (CL_INTRINSIC) is calculated considering the amount of protein in the incubation:

[00578] CL_INTRINSIC [μl/min/mg protein] = (Ln 2/(t1/2 INVITRO [min] * protein content [mg/ml])) * 1000

[00579] Protein content [mg/ml] was determined with Sigma Aldrich's "Bicinchoninic Acid Kit" (commercially available).

[00580] The high-scale intrinsic clearance (CL_UP_INT) is calculated considering the liver weight [g of liver/kg of body weight], and the microsomal recovery [mg of protein/g of liver]:

[00581] CL_UP_INT [ml/min/kg] = 0.001 *CL_INTRINSIC*liver weight*microsomal recovery

[00582] with microsomal recovery = 45 mg of protein/g of liver

[00583] with liver weight = 25.7 g liver/kg body weight

[00584] The percentage of blood flow in the liver (% of Qh) is finally calculated considering the blood flow in the human liver Q [ml/min/kg]: % of Qh [%] = ((Q * CL_UP_INT)/(Q+ CL_UP_INT)/Q)*100

[00585] with liver blood flow (Q) = 20.7 ml/min/kg. Table 1:

6. Comparison of SYK inhibitory capacity and SYK selectivity of compounds of the invention compared to selected compounds of WO 2013/014060 and WO 2011/092128

[00586] Having an efficient SYK inhibitory ability is not the only important aspect that a SYK inhibitor to be used as a medicine to treat SYK related diseases has to show. Equally important as the low IC50 value with respect to SYK inhibition (IC50 (SYK) < 1 µM) is that the candidate compound does not show unwanted inhibitory effects on other kinases that could lead to unwanted or even dangerous side effects. Examples of such other kinases that should not be inhibited by the candidate SYK inhibitor are AURB, FLT3 and GSKbeta.

[00587] Therefore, IC50 values with respect to SYK, AURB, FLT3 and GSKbeta for structurally intimate compounds described in WO 2013/014060 and WO 2011/092128 were experimentally determined according to the same assays as described in chapter 5. IC50 values measured with respect to SYK, AURB, FLT3 and GSKbeta of these prior art compounds structurally closer are in the following tables 2a to 6c in comparison to the respective previously determined IC50 values of a representative selection of compounds of the invention (same test conditions).

[00588] Furthermore, it is desirable for a SYK inhibitor that is sufficiently specific for SYK as described above to have certain human liver microsomal stability (corresponding to Cl < 60% of Qh; Qh = liver blood flow). Otherwise, it will be difficult to achieve an adequate plasma level of the SYK inhibitor in the patient to be treated. Consequently, likewise the Cl values for structurally intimate compounds described in WO 2013/014060 and in WO 2011/092128 were experimentally determined according to the same human liver microsomal test as described in chapter 5. An experimentally determined Cl value greater than 60% of Qh is considered to be unacceptable for achieving an adequate plasma level of the respective SYK inhibitor in the patient to be treated.

6.1 Comparisons for compounds with alkyl substituted pyrazole structures

[00589] Whereas all compounds of the invention (see Table 2a) and of WO 2013/014060 (see Table 2b) with alkyl-substituted pyrazole structures have suitable IC50-(SYK) values less than 1 μM, only the compounds of the invention (see Table 2a) have IC50 values with respect to AURB greater than 50 μM (compared to IC50 values (AURB) significantly below 5 µM for the compounds of WO 2013/014060 in Table 2b). Likewise, the IC50 values with respect to FLT3 are higher for the compounds of the invention (Table 2a) compared to the compounds of WO 2013/014060 (see Table 2b). Therefore, compounds of the invention with alkyl-substituted pyrazole structures are not only efficient SYK inhibitors (like the compounds of WO 2013/014060 (see Table 2b)), but also, do not have unwanted inhibitory effects on other kinases such as, AURB, FLT3 and GSK3beta (unlike the compounds of WO 2013/014060 (see Table 2b)). Compounds of the invention with alkyl-substituted pyrazole structures therefore show significantly improved SYK selectivity compared to the more structurally intimate compounds described in WO2013/014060. Table 2a: compounds of the invention with alkyl-substituted pyrazole structures nd = not detected Table 2b: WO 2013/014060 compounds with alkyl substituted pyrazole

6.2 Comparisons for compounds with optionally substituted bicyclic heteroaryl structures

[00590] Whereas all compounds of the invention (see Table 3a) and of WO 2013/014060 (see Table 3b) with optionally substituted bicyclic heteroaryl structures have (SYK)-suitable IC50 values less than 1 μM, only the compounds of the invention (see Table 3a) have IC50 values with respect to AURB greater than 30 μM, most of them even greater than 50 μM M (compared to IC50 values (AURB) mainly below 1μM for the compounds of WO 2013/014060 in Table 3b). Therefore, the compounds of the invention with optionally substituted bicyclic heteroaryl structures are not only efficient SYK inhibitors (like the compounds of WO 2013/014060 (see Table 3b)), but also, they do not have undesired inhibitory effects on other kinases such as AURB (different from the compounds of WO 2013/014060 (see Table 3b)).

[00591] Compounds of the invention with optionally substituted bicyclic heteroaryl structures therefore show significantly improved SYK selectivity compared to the more structurally intimate compounds described in WO2013/014060. Table 3a: Compounds of the invention with optionally substituted bicyclic heteroaryl structures nd = not detected Table 3b: Compounds of WO 2013/014060 with optionally substituted bicyclic heteroaryl structures

6.3 Comparisons for compounds with alkoxy-substituted phenyl structures

[00592] All compounds of the invention (see Table 4a), WO 2011/092128 (see Table 4b) and WO 2013/014060 (see Table 4c) with alkoxy-substituted phenyl structures have suitable (SYK)-IC50 values less than 1 µM. However, whereas the compounds of the invention (see Table 4a) have IC50 values with respect to AURB greater than 45μM, often even greater than 50μM, the IC50 (AURB) values of WO 2011/092128 (see Table 4b) and WO 2013/014060 (see Table 4c) are mostly < 5μM, often even below 1μM and therefore, compounds of the invention with alkoxy-substituted phenyl structures have less undesired inhibitory effects on other kinases such as AURB compared to most compounds of WO 2011/092128 (Table 4b) and of WO 2013/014060 (see Table 4c).

[00593] Only example 8 of WO 2011/092128 (see Table 4b) similarly shows an IC50 value (with respect to AURB) greater than 50 μM that seems comparable to the compounds of the present invention, however, example 8 of WO 2011/092128 (see Table 4b) shows with Cl =77% of Qh, a microsomal stability of human liver significantly lower than 60% Qh that would lead to an inappropriately low plasma level of the SYK inhibitor in a patient being treated. Similarly, example 2 of WO2013/014060 (see Table 4c) shows with IC50 (AURB) = 16.9 μMa, a slightly higher IC50 value with respect to AURB than the other prior art compounds, however, likewise here the microsomal stability of human liver is with Cl = 81% Qh inadequate. In comparison to these, compounds of the invention with alkoxy-substituted phenyl structures (see Table 4a) show acceptable Cl values less than 60% Qh (all Cl = < 23)% Qh).

[00594] The compounds of the invention with alkoxy-substituted phenyl structures therefore show a significantly improved SYK selectivity and additionally an acceptable human liver microsomal stability comparable to all structurally closer compounds described in WO2013/014060 and in WO2011/092128. Table 4a: Compounds of the invention with alkoxy-substituted phenyl structures nd= not determined Table 4b: Compounds from WO 2011/092128 with alkoxy-substituted phenyl structures Table 4c: Compounds of 2013/014060 with alkoxy-substituted phenyl structures

6.4 Comparisons for compounds with heterocycle-substituted or heterocycle-ringed phenyl structures

[00595] Whereas all compounds of the invention (see Table 5a), from WO 2013/014060 (see Table 5b) with heterocycle-substituted or heterocycle-ringed phenyl structures have (SYK)-suitable IC50 values less than 1 μM, only the compounds of the invention (see Table 5a) have IC50 values with respect to AURB mainly greater than 45μM, mainly greater than 50 μM (compared to IC50 values (AURB) below 1 µM for the compounds of WO 2013/014060 in Table 5b). Therefore, compounds of the invention with heterocycle-ringed or heterocycle-substituted phenyl structures are not only efficient SYK inhibitors (like the compounds of WO 2013/014060 (see Table 5b)), but also, do not have undesired inhibitory effects on other kinases such as AURB (different from the compounds of WO 2013/014060 (see Table 5b)).

[00596] Compounds of the invention with heterocycle-ringed or heterocycle-substituted phenyl structures therefore show significantly improved SYK selectivity compared to the more structurally intimate compounds described in WO2013/014060. Table 5a: Compounds of the invention with heterocycle-ringed or heterocycle-substituted phenyl structures Table 5b: Compounds of WO 2013/014060 with heterocycle ringed or heterocycle substituted phenyl structures

6.5 Comparisons for compounds with optionally substituted pyridine structures

[00597] Whereas all compounds of the invention (see Table 6a), WO 2011/092128 (see Table 6b) and WO 2013/014060 (see Table 6c) with optionally substituted pyridine structures have (SYK)-suitable IC50 values less than 1 µM, only the compounds of the invention (see Table 6a) have IC50 values with respect to AURB greater than 49μM, mostly even greater than 50μM (compared to IC50 values (AURB) around 1μM for the compounds of WO 2011/092128 in Table 6b and WO 2013/014060 in Table 6c). Consequently, compounds of the invention with optionally substituted pyridine structures are not only efficient inhibitors of SYK (like the compounds of WO 2011/092128 (Table 6b) and of WO 2013/014060 (see Table 6c)), but also do not have undesired inhibitory effects on other kinases such as AURB (unlike the compounds of WO 2011/092128 (Table 6b) and WO 2013/014060 (see Table 6c)).

[00598] Compounds of the invention with optionally substituted pyridine structures therefore show significantly improved SYK selectivity compared to the more structurally intimate compounds described in WO 2011/092128 or in WO2013/014060. Table 6a: Compounds of the invention with optionally substituted pyridine structures nd= not determined Table 6b: Compound from WO 2011/092128 with optionally substituted pyridine structure Table 6c: Compound of WO 2013/014060 with optionally substituted pyridine structure

6. INDICATIONS

[00599] As noted, the compounds of formula 1 are characterized by their range of applications in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used on the basis of their pharmaceutical activity as Syk inhibitors. Examples include respiratory diseases, allergic diseases, osteoporosis, gastrointestinal diseases or illnesses, immune or autoimmune diseases, allergic diseases, inflammatory diseases, for example, inflammatory diseases of the joints, skin and eyes, and diseases of the peripheral or central nervous system.

[00600] Particular mention should be made of the prevention and treatment of respiratory tract and lung diseases that are accompanied by increased mucus production, inflammation and/or obstructive airway diseases. Examples of these include asthma, pediatric asthma, ARDS (Adult Respiratory Distress Syndrome), acute, allergic, or chronic bronchitis, autoimmune hemolytic anemia, chronic obstructive bronchitis (COPD) (including treatment of Rhinovirus-induced exacerbations), coughs, allergic rhinitis or sinusitis, allergic rhinoconjunctivitis, chronic rhinitis or sinusitis, alveolitis, farmer's lung, hyperreactive airways, infectious bronchitis or pneumonitis, bronchitis estasis, pulmonary arterial hypertension, pulmonary fibrosis, bronchial edema, pulmonary edema, pneumonia or interstitial pneumonia activated by various causes such as aspiration, inhalation of toxic gases or bronchitis, pneumonia or interstitial pneumonia activated by heart failure, radiation, chemotherapy, cystic fibrosis or mucoviscidosis, alpha1-antitrypsin deficiency.

[00601] The compounds according to the invention are preferably likewise suitable for the treatment of allergic diseases such as, for example, allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, and contact dermatitis, urticaria/angioedema and allergic dermatitis.

[00602] Mention should likewise preferably be made of the treatment of inflammatory diseases of the gastrointestinal tract. Examples of these are Crohn's disease and ulcerative colitis.

[00603] The compounds according to the invention are preferably likewise suitable for the treatment of inflammatory diseases of the joints, blood vessels and kidneys or inflammatory diseases of the skin and eyes. Examples of these are rheumatoid arthritis, antibody-based glomerulonephritis, psoriasis, Kawasaki syndrome, celiac disease (sprue), arteriosclerosis and Wegener's granulomatosis, osteoarthritis, systemic scleroderma, ankylosing spondylitis.

[00604] The compounds according to the invention are preferably likewise suitable for the treatment of autoimmune diseases. Examples of these are hepatitis (autoimmune based), lupus erythematosus, lupus nephritis, systemic lupus, systemic lupus erythematosus, discoid lupus, cutaneous lupus erythematosus (acute, subacute, chronic), antiphospholipid syndrome, Berger's disease, Evans syndrome, immunoemolytic anemia, ITP (idiopathic thrombocytopenic purpura; adult, neonatal and pediatric), myasthenia gravis, Sjogren's syndrome, scleroderma, bullous pemphigoid and pemphigus vulgaris.

[00605] The compounds according to the invention are preferably likewise suitable for the treatment of B-cell lymphomas such as chronic lymphocytic leukemia and non-Hodgkin's lymphomas or T-cell lymphomas.

[00606] The compounds according to the invention are preferably likewise suitable for the treatment of Graft versus Host Disease.

[00607] Mention may preferably likewise be made of the prevention and treatment of diseases of the peripheral or central nervous system. Examples of these are acute and chronic multiple sclerosis or unfamiliar lateral sclerosis.

[00608] Mention may preferably likewise be made of the prevention and treatment of osteoporotic diseases such as, for example, disease-associated osteopenia, osteoporosis and osteolytic diseases.

[00609] The present invention particularly preferably relates to the use of the compounds of formula 1 to prepare a pharmaceutical composition for the treatment of diseases selected from asthma, COPD, allergic rhinitis, Adult Respiratory Distress Syndrome, bronchitis, allergic dermatitis, contact dermatitis, ITP, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and allergic rhinoconjunctivitis.

[00610] Even more preferably, the compounds of formula 1 can be used for the treatment of disease selected from asthma, allergic rhinitis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, allergic dermatitis and COPD.

7. COMBINATIONS

[00611] The compounds of formula 1 can be used alone or together with other active substances of formula 1 according to the invention. The compounds of formula 1 can optionally likewise be used together with other pharmacologically active substances. Preferably, the active substances used herein may be selected from, for example, betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, MRP4 inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists, iNos inhibitors, HMG-CoA reductase inhibitors (statins), PI3 kinase inhibitors, C CR3, CCR2 antagonists, CCR1 antagonists, IKK2 inhibitors, A2a agonists, alpha-4-integrin inhibitors, CRTH2 antagonists, histamine 1, combined H1/H3 antagonists, p38 kinase inhibitors, methylxanthines, ENaC inhibitors, CXCR1 antagonists, CXCR2 antagonists, ICE inhibitors, LTB4 antagonists, 5-LO, FLAP antagonists. LTB4 antagonists; chromoglycine, dissociated glucocorticoid mimetics, immunosuppressive agents, cytostatics, non-steroidal anti-inflammatory drugs (NSAIDs), chloroquine, hydroxychloroquine, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL6 antibodies, anti-IL6 receptor antibodies, anti-IL- antibodies 13 antibodies, anti-IL_18 antibodies, anti-CD30 L antibodies, anti-Ox40L antibodies, anti-IL-4/IL-13 antibodies, anti-IL-23 antibodies (p19), anti-IL-12/IL-23 antibodies (p40), anti-CD3 antibodies, anti-CD4 antibodies, anti-CD154 antibodies, CD89 antibodies, anti-IL-2/CD25 receptor antibodies, anti-CD22 antibodies, anti-interferon antibodies, anti -ICOS, anti-ICOS antibodies, anti-CD20 antibodies, anti-CD40 antibodies, anti-BAFF/BLyS antibodies, anti-CD18 antibodies, anti-CD62L antibodies, anti-CD147 antibodies, anti-integrin antibodies, LFA-1 interfering agents, IL-36 downstream modulators, M-CSF/c-fms antagonists, CTLA-4 fusions, mTor modulators, Dobre-like receptor inhibitors Bell-Fold 7 (TLR7 inhibitor), Bell-Fold 9-like receptor inhibitors (TLR9 inhibitors), T-cell costimulatory modulators such as CTLA-4 fusions, JAK inhibitors, IRF modulators, CX3 chemokine receptor antagonists (CX3CR1 antagonists), IRAK inhibitors (in particular IRAK1 and IRAK4 inhibitors), Sphingosine-1-phosphate modulators ( S1P reaction series modulators),

[00612] or double or triple combinations thereof, such as, for example, combinations of one, two or three compounds selected from among

[00613] • Formula 1 Syk inhibitors, betamimetics, corticosteroids, EGFR inhibitors and PDE4 antagonists,

[00614] • Formula 1 Syk inhibitors, anticholinergics, betamimetics, corticosteroids, EGFR inhibitors and PDE4 antagonists,

[00615] • Formula 1 Syk inhibitors, PDE4 inhibitors, corticosteroids and EGFR inhibitors,

[00616] • Formula 1 Syk inhibitors, EGFR inhibitors and PDE4 inhibitors,

[00617] • Formula 1 Syk inhibitors and EGFR inhibitors,

[00618] • Formula 1 Syk inhibitors, betamimetics and anticholinergics

[00619] • Formula 1 Syk inhibitors, anticholinergics, betamimetics, corticosteroids and PDE4 inhibitors,

[00620] • Formula 1 Syk inhibitors, anticholinergics, betamimetics, corticosteroids, iNOS inhibitors, HMG-CoA reductase inhibitors.

[00621] Combinations of the three active substances each taken from one of the above-mentioned categories of compounds are likewise an object of the invention.

[00622] Suitable betamimetics used are preferably compounds selected from arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, milveterol , orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, thiaramid, tolubuterol, zinterol, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazine- 3-one; 8-{2-[2-(2,4-Difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[2-(3,5-Difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; N-(5-{2-[3-(4,4-Diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide; N-(5-{2-[3-(4,4-Diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide; N-(5-{2-[3-(4,4-Diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide; N-(5-{2-[1,1-Dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide; 8-{2-[1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[1,1-Dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[1,1-Dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 8-{2-[1,1-Dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide; 8-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one; 8-Hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylaminohexylamino)-ethyl]-1H-quinolin-2-one; 5-[(1R)-2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one; [3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea; 4-((1R)-2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol; 3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide; 3-(3-{7-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulfonamide; 4-((1R)-2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol, 4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol; Vilanterol; N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; 2-(3-{2-[2-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-propyl}-phenyl)-N-[4-(4-hydroxy-phenyl)-2-vinyl-penta-2,4-dienyl]-acetamide; (1R)-5-{2-[6-(2,2-Difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one; (R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinoline-2(1H)-one; (R,S)-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; 4-(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol; (R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide; (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; (R,S)-N-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]urea; 3-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione; (R,S)-4-[2-({6-[2,2-Difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol; 5-((1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one; 4-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol; (R,S)-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; (R,S)-4-(2-{[6-(2,2-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol; 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide; N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide; 7-[2-(2-{3-[2-(2-Chlor-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.

[00623] According to the invention, the acid addition salts of betamimetics are preferably selected from hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably the hydrochloride , hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. Of the above-mentioned acid addition salts, salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

[00624] The anticholinergics used are preferably compounds selected from among

[00625] Tiotropium salts, particularly the bromide salt, oxitropium salts, particularly the bromide salt, flutropium salts, particularly the bromide salt, ipratropium salts, particularly the bromide salt, aclidinium salts, particularly the bromide salt, glycopyrronium salts, particularly the bromide salt, trospium salts, particularly the chloride salt, tol therodine, (3R)-1-Phenethyl-3-(9H-xanthene-9-carbonoyloxy)-1-azoniabicyclo[2.2.2]octane salts; tropenol methobromide 2,2-Diphenyl propionic acid ester; 2,2-Diphenyl propionic acid ester scopine methobromide; 2-Fluoro-2,2-Diphenylacetic acid ester scopine methobromide; tropenol methobromide 2-Fluoro-2,2-Diphenylacetic acid ester; tropenol methobromide 3,3',4,4'-Tetrafluoro benzyl acid ester; Scopine Methobromide 3,3',4,4'-Tetrafluoro Benzyl Acid Ester; tropenol methobromide 4,4'-Difluorobenzyl acid ester; scopine methbromide 4,4'-Difluorobenzyl acid ester; tropenol methobromide 3,3'-Difluorobenzyl acid ester; scopine methbromide 3,3'-Difluorobenzyl acid ester; tropenol methobromide 9-Hydroxy-fluorene-9-carboxylic acid ester; tropenol methobromide 9-Fluoro-fluorene-9-carboxylic acid ester; Scopine Methobromide 9-Hydroxy-fluorene-9-carboxylic acid ester; 9-Fluoro-fluorene-9-carboxylic acid ester scopine methobromide; tropenol methobromide 9-Methyl-fluorene-9-carboxylic acid ester; 9-Methyl-fluorene-9-carboxylic acid ester scopine methbromide; cyclopropyl tropine methbromide benzylic acid ester; cyclopropyltropine methobromide 2,2-Diphenyl propionic acid ester; cyclopropyltropine methobromide 9-Hydroxy-xanthene-9-carboxylic acid ester; cyclopropyltropine methobromide 9-Methyl-fluorene-9-carboxylic acid ester; 9-Methyl-xanthene-9-carboxylic acid ester cyclopropyltropine methobromide; cyclopropyltropine methobromide 9-Hydroxyfluorene-9-carboxylic acid ester; cyclopropyltropine methyl ester methobromide 4,4'-Difluorobenzyl acid ester; tropenol methobromide 9-Hydroxy-xanthene-9-carboxylic acid ester; 9-Hydroxy-xanthene-9-carboxylic acid ester scopine methobromide; tropenol methobromide 9-Methyl-xanthene-9-carboxylic acid ester; 9-Methyl-xanthene-9-carboxylic acid ester scopine methbromide; tropenol methobromide 9-Ethyl-xanthene-9-carboxylic acid ester; tropenol methobromide 9-Difluoromethyl-xanthene-9-carboxylic acid ester; 9-Hydroxymethyl-xanthene-9-carboxylic acid ester scopine methobromide;

[00626] 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;

[00627] N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;

[00628] 7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one and Darotropium;

[00629] optionally in the form of solvates or hydrates thereof.

[00630] In the aforementioned salts, the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium, aclidinium and trospium are the pharmacologically active ingredients. As anions, the above-mentioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, while chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as counterions. Of all salts, chlorides, bromides, iodides and methanesulfonate are particularly preferred.

[00631] Of particular importance is tiotropium bromide. In the case of tiotropium bromide, the pharmaceutical combinations according to the invention preferably contain in the form of crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.

[00632] Corticosteroids used herein are preferably compounds selected from

[00633] beclomethasone, betamethasone, budesonide, butixocort, cyclosonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, tipredane; Pregna-1,4-diene-3,20-dione, 6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-, (6-alpha,11-beta,16-alpha)-(9CI); 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one; 6,9-Difluoro-17-[(2-furanylcarbonoyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothione (S)-fluoromethyl ester; (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonoyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate; 6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonoyl)oxy-androsta-1,4-diene-17beta-carboxylic acid cyanomethyl ester, each optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of salts and derivatives, solvates and/or hydrates thereof.

[00634] Particularly preferably, the steroid is selected from budesonide, fluticasone, mometasone, cyclosonide and (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonoyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or days stereomers thereof and optionally in the form of salts and derivatives, solvates and/or hydrates thereof.

[00635] Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

[00636] PDE4 inhibitors that can be used are preferably compounds selected from emprofilin, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafenthrine, lirimilast, apremilast, arophylline, atizoram, oglemilast, tectomilast; 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline (D-4418); 5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline (D-4396 (Sch-351591)); N-(3, 5-Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]glyoxyl (AWD-12-281 (GW-842470)); 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-Purin-6-amine (NCS-613); 4-[(2R)-2-[3 -(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine (CDP-840); N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide(PD-168787); 4-[6,7- Dietoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone (T-440); ); (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V-11294A); beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-Isoindol-2-propanamide (CDC-801); Imidazo[1,5-a]pyrido[3,2-e ]pyrazine-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl- (D22888); 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-, (3S,5S)-2-piperidinone (HT-0712); 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol (L-826141); N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide; (-)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide; (R)-(+)-1-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon; 3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone; cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one; cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; (R)-(+)-Ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate; (S)-(-)-Ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate; 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine; 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,

[00637] optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.

[00638] By acid addition salts with pharmacologically acceptable acids in which the aforementioned PDE4 inhibitors may be in a position to form, it is understood, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

[00639] LTD4 antagonists that can be used are preferably compounds selected from montelukast, pranlukast, zafirlukast; (E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507); 4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric acid (MN-001); 1-(((R)-(3-(2-(6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid; 1-(((1(R)-3(3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl) )-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid; [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid,

[00640] optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.

[00641] By acid addition salts with pharmacologically acceptable acids in which LTD4 antagonists may be able to form, it is understood, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydro benzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. By salts or derivatives in which LTD4 antagonists may be able to form is meant, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

[00642] The EGFR inhibitors used are preferably compounds selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo -2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholine-4- yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro- phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4- yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2) - methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-e ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-butene-1-yl}amino )-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6- ({4-[N-(tetrahydroxy ropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene- 1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-clo ro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7 -cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N, N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl) -propyloxy]-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl] amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulfonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl) -1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6 - ({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-butene-1-yl ]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R )-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonoyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]- 6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonoyl]-piperidine-4-yloxy}-7-methoxy-quinazoline lyn, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran- 3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy }-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonoylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohe xan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonyl) amino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonoylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline lyn, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonoyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonoyl ]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazolin; 4-{2-[4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-ethyl}-6-methyl-morpholin-2-one, 4-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-1-methyl-piperazine-2-one, 4-[(3 -chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quin Zoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-clo ro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl) )amino]-6-[1-(tert-butyloxycarbonoyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidine-1- yl)carbonoyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-yl)carbonoyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[ (3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonoylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy -quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonoyl]-piperidine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline, 4-[(3- ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy) -7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonoyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline lyn, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl) -phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonoyl]-piperidine-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro -phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonoyl]-piperidine-4 -yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonoyl]-piperidine-4-yloxy}-7-methoxy-quin Zoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonoyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline lyn, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonoyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy ]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7- methoxy-quinazoline, 3-Cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, [4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-butene-1- yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)-carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[ (3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinyl) carbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydro) furan-5-yl)carbonoyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(3-chloro- 4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonoyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonoyl)amino] -quinazoline, cetuximab, trastuzumab, panitumumab (=ABX-EGF), Mab ICR-62, gefitinib, pelitinib, canertinib and erlotinib, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof.

[00643] By acid addition salts with pharmacologically acceptable acids in which EGFR inhibitors may be able to form, it is meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydro benzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

[00644] Examples of dopamine agonists that can be used preferably include compounds selected from bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane. Any reference to the aforementioned dopamine agonists within the scope of the present invention includes reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which may exist. By the physiologically acceptable acid addition salts that can be formed by the aforementioned dopamine agonists is meant, for example, pharmaceutically acceptable salts that are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

[00645] Examples of H1 antihistamines preferably include compounds selected from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimethindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, and bastine, olopatadine, desloratidine and meclozine. Any reference to the aforementioned H1 antihistamines within the scope of the present invention includes reference to any pharmacologically acceptable acid addition salts which may exist.

[00646] Examples of PAF antagonists preferably include compounds selected from lexipphant, 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines, 6-(2-chlorophenyl)-8,9-di- hydro-1-methyl-8-[(4-morpholinyl)carbonoyl]-4H,7H-cyclopenta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines. Any reference to the aforementioned PAF antagonists includes within the scope of the present invention reference to any pharmacologically acceptable acid addition salts thereof which may exist.

[00647] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) preferably include compounds selected from Aceclofenac, Acemetacin, Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Anthraphenin, Azapropazone, Benorilate, Bermoprofen, Bindarite, Bromfenac, Bucloxinsaure, Bucolom, Bufe Xamaco, Bumadizone, Butibufen, Butixirate, Carbasalatcalcium, Carprofen, Magnesium Choline Trisalicylate, Celecoxib, Cinmetacin, Cinoxicam, Clidanaco, Clobuzarite, Deboxamethe, Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenaco, Enphenaminsaure, Etersalate, Etodolac, Etofenamate, E toricoxib, Feclobuzone, Felbinaco, Fembufen, Fenclofenac, Fenoprofen, Fentiazac, Fepradinol, Feprazone, Phlobufen, Floctafenin, Flufenaminsaure, Flufenisal, Flunoxaprofen, Flurbiprofen, Flurbiprofenaxethyl, Furofenac, Furprofen, Glucametacin, Ibufenac, Ibuprofen, Indobufen, Indomethacin, Indo Metacinfarnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarite, Lonazolac, Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsaure, Meclofene, Mefenaminsaure, Meloxicam, Mesalazine, Miroprofen, Mofezolac, Nabumetone, Naproxen, Nifluminsaure, Olsalazine, Oxaprozin , Oxypinac, Oxyfenbutazone, Parecoxib, Phenylbutazone, Pelubiprofen, Pimeprofen, Pyrazolac, Priroxicam, Pirprofen, Pranoprofen, Prifelone, Prinomode, Proglumetacin, Proquazone, Protizininsaure, Rofecoxib, Romazarite, Salicylamide, Salicylsaure, Salmistein, Salnacedin, Salsalate, Sulindac, Sudoxy cam, Suprofen, Talniflumate, Tenidape, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensaure, Taramide, Tilnoprofenarbamel, Timegadine, Tinoridine, Tiopinac, Tolfenaminsaure, Tolmetin, Ufenamate, Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.

[00648] MRP4 inhibitors used are preferably compounds selected from N-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulfate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide, estradiol 3,17-disulfate, est radiol 3-glucuronide, estradiol 3-sulfate, estrone 3-sulfate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, glycolithocholic acid sulfate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulfate, methotrexate, ((E)-3-[[[3-[2-(7-chloro-2-quinoline) acid) yl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, sildenafil, sulfinpyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulfate, topotecan, trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.

[00649] Examples of JAK inhibitors preferably include compounds selected from Tofacitinib and Ruxolitinib.

[00650] Examples of immunosuppressive agents preferably include compounds selected from mycophenolate mofetil, mycophenolic acid, azathioprine, cyclosporine, tacrolimus, pimecrolimus, abetimus, gusperimus and leflunomide.

[00651] An example of a cytostatic substance is cyclophosphamide.

[00652] The invention more preferably relates to the use of MRP4 inhibitors to prepare a pharmaceutical composition for treating respiratory diseases, containing the Syk inhibitors of formula 1 and MRP4 inhibitors according to the invention, the MRP4 inhibitors preferably being selected from dehydroepiandrosterone 3-sulfate, estradiol 3,17-disulfate, flurbiprofen, indomethacin, indoprofen, taurocholate, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof. Separation of the enantiomers from the racemates can be carried out using methods known in the art (for example, chromatography on chiral phases, etc.).

[00653] Acid addition salts with pharmacologically acceptable acids means, for example, salts selected from among hydrochlorides, hydrobromides, hydroiodides, hydrosulfates, hydrophosphates, hydromethanesulfonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluene sulphonates, preferably the hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and hydromethanesulphonates.

[00654] The invention also relates to pharmaceutical preparations that contain a triple combination of Syk inhibitors of formula 1, MRP4 inhibitors and another active substance according to the invention, such as, for example, an anticholinergic, a PDE4 inhibitor, a steroid, an LTD4 antagonist or a betamimetic, and their preparation and their use to treat respiratory diseases.

[00655] Compounds that can be used as iNOS inhibitors are the compounds selected from: S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1,3-Thiazine-2-amine (=AMT), L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S -ethylisothiourea, S-methylthiocitrulline, S-ethylthiocitrulline, L-NA (Nw-nitro-L-arginine), L-NAME (Nw-nitro-L-arginine methylester), L-NMMA (NG-monomethyl-L-arginine), L-NIO (Nw-iminoethyl-L-ornithine), L-NIL (Nw-iminoethyl-lysine), (1H-tetrazol-5 (S)-6-acetimidoylamino-2-aminohexanoic acid -yl)-amide (SC-51) (J. Med. Chem. 2002, 45, 1686-1689), N-[[3-(aminomethyl)phenyl]methyl]-Ethanimid-amide (=1400W), (S)-4-(2-acetimidoylamino-ethylsulfanyl)-2-amino-butyric acid ( GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600), 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) (Mol. Pharmacol. 2006, 69, 328-337), 2-( (R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO 01/62704), 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile (WO 2004/041794), 2-((1R.3S)-3-amino -4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-4-chloro-benzonitrile (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-5-chloro-benzonitrile (WO 2004/041794), (2S.4R)-2-amino -4-(2-chloro-5-trifluoromethyl-phenylsulfanyl)-4-thiazol-5-yl-butan-1-ol (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulfanyl)-5-chloro-nicotinonitrile (WO 2004/041794), 4-(( S)-3-amino-4-hydroxy-1-phenyl-butylsulfanyl)-6-methoxy-nicotinonitrile (WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine such as for example (1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine (ON O-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem. 2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg. Med. Chem. Lett. 2005, 1 5, 1361), 4-aminotetrahydrobiopterin (Curr. Drug Metabol. 2002, 3, 119-121), (E)-3-(4-chlorophenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl -ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine (PPA250) (J. Pharmaco Exp. Ther. 2002, 303, 52 -57), 3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), acid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (R) -1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylic acid (BBS-2) ( Drugs Future 2004, 29, 45-52 ) and the pharmaceutical salts, prodrugs or solvates thereof.

[00656] Examples of iNOS inhibitors within the scope of the present invention may likewise include antisense oligonucleotides, particularly those antisense oligonucleotides that bind iNOS-encoding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense oligonucleotides that bind iNOS-encoding nucleic acids to modulate iNOS expression. iNOS antisense oligonucleotides as particularly described in WO 01/52902 can therefore likewise be combined with the PDE4 inhibitors of the present invention because of their similar effect to the iNOS inhibitors.

[00657] Suitable HMG-CoA reductase inhibitors (also called statins) which can preferably be used in double or triple combinations with the compounds of formula 1 are selected from Atorvastatin, Cerivastatin, Flurvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, optionally in the form of their pharmaceutically available acid addition salts, prodrugs, solvates or their hydrates.

8. FORMULATIONS

[00658] Forms suitable for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the total composition, i.e. in amounts that are sufficient to reach the dosage range specified below.

[00659] The preparations can be administered orally in the form of a tablet, as a powder, as a powder in a capsule (eg, a hard gelatin capsule), as a solution or suspension. When administered by inhalation, the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution, or using a propellant gas formulation.

[00660] Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula 1 according to the above preferred embodiments.

[00661] It is particularly preferable if the compounds of formula 1 are administered orally, and it is likewise particularly preferable if they are administered once or twice a day. For example, suitable tablets can be obtained by mixing the active substance(s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or release delay binders such as carboxymethyl cellulose, acetate phthalate cellulose, or polyvinyl acetate. Tablets may likewise comprise several layers.

[00662] Coated tablets can be suitably prepared by coating the cores produced similarly to tablets with substances normally used for tablet coatings, for example, collidone or varnish, arabic starch, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core can likewise consist of several layers. Similarly, the tablet coating may consist of several layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[00663] Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, for example a flavoring agent such as vanillin or orange extract. They may likewise contain suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[00664] Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivatives thereof.

[00665] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono or polyfunctional alcohols (for example, ethanol or glycerol), carriers such as, for example, natural mineral powders (for example, kaolins, clays, talc, chalk), synthetic mineral powders (for example, highly dispersed silicic acid and silicates ), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[00666] For oral administration, the tablets may, of course, contain, in addition to the aforementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin, and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used at the same time for the tableting process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or coloring agents in addition to the excipients mentioned above.

[00667] It is likewise preferred if the compounds of formula 1 are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula 1 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing dosimeter aerosols or propellant-free inhalable solutions which are optionally present in admixture with conventional physiologically acceptable excipients.

[00668] Within the scope of the present invention, the term propellant-free inhalable solutions likewise includes sterile ready-to-use inhalable solutions or concentrates. Preparations that can be used according to the invention are described in more detail in the next part of the specification.

inhalable powders

[00669] If the active substances of formula 1 are present in mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention: monosaccharides (for example, glucose or arabinose), disaccharides (for example, lactose, sucrose, maltose), oligo- and polysaccharides (for example, dextran), polyalcohols (for example, sorbitol, mannitol , xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purpose of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is particularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and finally mixing the components together are known from the prior art.

Inhalable aerosols containing propellant

[00670] The propellant-containing inhalable aerosols that can be used according to the invention may contain the compounds of formula 1 dissolved in the propellant gas or in dispersed form. Propellant gases which can be used to prepare inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as, preferably, fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-directed inhalation aerosols used within the scope of use according to the invention may likewise contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.

Propellant-free inhalable solutions

[00671] The compounds of formula 1 according to the invention are preferably used to prepare propellant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent can be water alone or a mixture of water and ethanol. Solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH can be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and the like. Preferred inorganic acids are hydrochloric and sulfuric acids. It is likewise possible to use acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can likewise be used, particularly in the case of acids which have properties other than their acidifying qualities, for example as flavorings, antioxidants or complexing binders, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

[00672] Cosolvents and/or other excipients can be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred cosolvents are those containing hydroxyl groups or other polar groups, for example alcohols - particularly isopropyl alcohol, glycols - particularly propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in suitable pharmacological solvents to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, with regard to the desired therapy, no appreciable or at least undesirable pharmacological effect. For example, excipients and additives include surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing binders, antioxidants and/or preservatives that ensure or extend the shelf life of the finished pharmaceutical formulation, flavorings, vitamins and/or other additives known in the art. Additives likewise include pharmacologically acceptable salts such as sodium chloride as isotonic binders. Preferred excipients include antioxidants such as ascorbic acid, for example, as long as it has not already been used to adjust pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins that occur in the human body. Preservatives can be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates, sodium benzoate in concentration known from the prior art.

[00673] For the forms of treatment described above, ready-to-use packs of a drug for the treatment of airway diseases are provided, containing an accompanying description that includes, for example, the words airway disease, COPD or asthma, together with an imidazolyl-pyrimidine according to formula 1 and one or more combination pairs selected from those described above.

Claims (34)

1. Compound, characterized by the fact that it has formula 1 wherein A is selected from the group consisting of N and CH and wherein M is selected from the group consisting of -CH 2 -, -O, -NH- and -N(C 1-4 alkyl)-; R3 is selected from the group consisting of methyl and ethyl; and wherein R1 is selected from the group consisting of C6-10-aryl, Het and Hetaryl; which is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1- 3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, -OH, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2 ,-NH(CH3), -N(CH3)2, whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, -OH, halogen and C1-3-alkyl, and wherein Het is selected from the group consisting of a five- to six-membered monocyclic heterocycle with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O, and a bi-heterocycle nine- to eleven-membered cyclic with 1, 2, 3 or 4 heteroatoms each independently selected from N, S and O; Hetaryl is selected from the group consisting of a five- to six-membered monocyclic heteroaromate having 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O; and a nine- to eleven-membered bicyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently of one another selected from N, S and O; and the pharmaceutically acceptable salts of the aforementioned compounds. 2. Compound, characterized by the fact that it has the formula 1' wherein A, M, Het, Hetaryl, R1 and R3 are defined according to claim 1, and the pharmaceutically acceptable salts of the aforementioned compounds. 3. Compound of formula 1 according to claim 1 or formula 1' of claim 2, characterized in that M is -CH2- and in which R3 is methyl, and in which R1 is selected from the group consisting of phenyl, Het and Hetaryl; which is optionally also substituted with one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1- 3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 4. Compound of formula 1a according to claim 1 or of formula 1a' according to claim 2, characterized in that R1 is selected from the group consisting of phenyl, Het and Hetaryl; which is optionally also substituted with one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1- 3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 5. Compound of formula 1a or formula 1a' according to claim 4, characterized in that R1 is a) selected from the group consisting of Het and Hetaryl; which is optionally also substituted with one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1 -3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, at which substituent X is optionally further substituted by one, two or three substituents from a group selected from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, or wherein R1 is b) phenyl, which is optionally further substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of, -CN, halogen, -C1-6-alkyl, -( C1-3-alkylene)-Hetaryl, -(C1-3-alkylene)-Het, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo and -C1-4-alkyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 6. Compound of formula 1a or of formula 1a' according to claim 4 or 5, characterized in that R1 is a five- to six-membered monocyclic heteroaromate with 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, O and S, or a 9- to 11-membered bicyclic heteroaromate with 1, 2, 3 or 4 heteroatoms each independently each other selected from the group consisting of N, O and S, wherein this R1 residue is bonded to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-C1 -6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O- Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, - C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, whereby substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 7. Compound of formula 1a or formula 1a' according to claim 4, characterized in that R1 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl, in which this residue R1 is linked to the rest of the molecule by a C atom or a N atom and is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-methyl, -O-ethyl, O-propyl, O-butyl, -C1-3-haloalkyl, cyclo three-, four-, five- or six-membered alkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1- 4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het,Hetaryl, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 8. Compound of formula 1a or formula 1a' according to claim 4, characterized in that R1 is phenyl, which is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, three- to seven-membered cycloalkyl , Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4- haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 9. Compound of formula 1a or formula 1a' according to claim 4, characterized in that it is selected from the group consisting of and the pharmaceutically acceptable salts of the aforementioned compounds. 10. Compound of formula 1a or formula 1a' according to claim 4, characterized in that it is 11. Compound of formula 1a or formula 1a' according to claim 4, characterized in that it is 12. Compound of formula 1a or formula claim 4, characterized by the fact that it is 13. Compound of formula 1a or formula claim 4, characterized by the fact that it is 14. Compound of formula claim 4, characterized by the fact that it is 15. Compound of formula 1a or formula 1a' according to claim 4, characterized in that it is 16. Compound, characterized in that it is a pharmaceutically acceptable salt of a compound as defined in any one of claims 10 to 15. 17. Compound of formula 1c according to claim 1 left of formula 1c' according to claim 2 characterized in that R1 is selected from the group consisting of phenyl, Het and Hetaryl; which is optionally also substituted with one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1- 3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 18. Compound of formula 1c or formula 1c' according to claim 17, characterized in that R1 is a) selected from the group consisting of Het and Hetaryl; which is optionally also substituted with one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1 -3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, Hetaryl, -NH2, whereby substituent X is optionally further substituted by one, two or three substituents from a group selected from the group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, or wherein R1 is b) phenyl, which is optionally further substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of, -CN, halogen, -C1-6-alkyl, - (C1-3-alkylene)-Hetaryl, -(C1-3-alkylene)-Het, -C1-6-haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo and -C1-4-alkyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 19. Compound of formula 1c or formula 1c' according to claim 17 or 18, characterized in that R1 is a five- to six-membered monocyclic heteroaromate with 1, 2 or 3 heteroatoms each independently of one another selected from the group consisting of N, O and S, or a 9- to 11-membered bicyclic heteroaromato with 1, 2, 3 or 4 heteroatoms each which independently of one another is selected from the group consisting of N, O and S, wherein this residue R1 is bonded to the remainder of the molecule by a C atom or by an N atom and is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O -C1-6-alkyl, -C1-6- haloalkyl, three- to seven-membered cycloalkyl, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O- Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, the xo, -C1-4-alkyl, -O-C1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 20. Compound of formula 1c or formula 1c' according to claim 17, characterized in that R1 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, furanyl, pyrazolopyridinyl, indazolyl, thiazolyl, imidazo-pyridinyl and indolyl, in which this residue R1 is linked to the remainder of molecule by a C atom or a N atom and is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -methyl, -ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -O-methyl, -O-ethyl, O-propyl, O-butyl, -C1-3-haloalkyl , three-, four-, five- or six-membered cycloalkyl, Het, Hetaryl, -CO-N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C 1-4-alkyl, -C1-4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 21. Compound of formula 1c or formula 1c' according to claim 17, characterized in that R1 is phenyl, which is optionally also substituted by one, two or three substituents Z, whereby each Z is a substituent selected from the group consisting of -OH, oxo, -CN, halogen, -C1-6-alkyl, -O-C1-6-alkyl, -C1-6-haloalkyl, cycloalkyl from three to seven-membered, Het, Hetaryl, -CO- N(CH3)2, -CO-NHCH3, -CO-NH2, -(C1-3-alkylene)-O-(C1-3-alkyl), -O-Het, which is optionally also substituted by one, two or three substituents X, whereby each X is selected from the group consisting of halogen, oxo, -C1-4-alkyl, -O-C1-4-alkyl, -C1- 4-haloalkyl, -O-(C1-4-alkylene)-Het, Het, -NH2, whereby the substituent X is optionally also substituted by one, two or three substituents from a group selected from oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and the pharmaceutically acceptable salts of the aforementioned compounds. 22. Compound of formula 1c or formula 1c' according to claim 17, characterized in that it is selected from the group consisting of and the pharmaceutically acceptable salts of the aforementioned compounds. 23. Compound of formula 1c or formula 1c' according to claim 17, characterized in that it is 24. Compound of formula 1c or formula 1c' according to claim 17, characterized in that it is 25. Compound of formula 1c or formula 1c' according to claim 17, characterized in that it is 26. Compound of formula 1c or formula 1c' according to claim 17, characterized in that it is 27. Compound, characterized in that it is a pharmaceutically acceptable salt of a compound as defined in any one of claims 23 to 26. 28. Intermediate compound, characterized in that it is selected from the group consisting of formula 6 wherein R1 is as defined in claim 1 and wherein Hal is Cl or Br and wherein X is -B(OH)2, boronic acid pinacolester, -trifluoroborate or -SnBu3 and wherein PG is a protecting group selected from the group consisting of benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl. 29. Intermediate compound, characterized by the fact that it has formula 10.2 30. Compound according to any of claims 1 to 27, characterized in that it is for the treatment of a disease selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitis and contact dermatitis, allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, antiphospholipid syndrome, Berger's disease, Evans syndrome, ulcerative colitis, glomerulonephritis Allergic antibody-based disease, granulocytopenia, Goodpasture syndrome, hepatitis, Henoch-Schonleina purpura, hypersensitivity vasculitis, immunoemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematosus, lupus nephritis, capsule cell lymphoma, neutropenia, non-familial lateral sclerosis, arteriosclerosis, Crohn's disease , multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis, Sjogren's syndrome, scleroderma, T-cell lymphoma, urticaria/angioedema, Wegener's granulomatosis, and celiac disease. 31. Compound according to any of claims 1 to 27, characterized in that it is for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, allergic dermatitis, contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, lupus erythematosus, lupus nephritis and allergic rhinoconjunctivitis. 32. Compound according to any of claims 1 to 27, characterized in that it is for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematosus, lupus nephritis and rheumatoid arthritis. 33. Pharmaceutical formulations, characterized in that they contain one or more compounds as defined in one of claims 1 to 27 and a pharmaceutically acceptable excipient. 34. Pharmaceutical formulations, characterized in that they contain one or more compounds as defined in one of claims 1 to 27 in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors, LTD4 antagonists, CCR3 inhibitors, iNOS inhibitors, CRTH2 antagonists, HMG-CoA reductase inhibitors and NSAIDs.