TW201319045A - Substituted quinolines and their use as medicaments - Google Patents

Abstract

The invention relates relates to new substituted quinolines of formula 1 wherein R1 is a linear or branched C1-6-alkyl, wherein R1 may optionally be substituted by R3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkl; a five-, six- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; and a five- or six-membered heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; wherein R3 may optionally be substituted further substituted as defined in claim 1 and wherein R2 is selected from the group consisting of halogen, phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; a bicyclic, nine-, ten- or eleven-membered, either aromatic or non-aromatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting of N, S and O; wherein R2 may optionally be further substituted as defined in claim 1, and their use in the preparation of medicaments for the treatment of disease such as asthma, COPD, allergic rhinitis, allergic dermatitis and rheumatoid arthritis.

Description

Substituted quinoline and its use as a medicament

The present invention relates to a novel substituted quinoline of formula 1 , Wherein R ¹ is a linear or branched C _1-6 alkyl group, wherein R ¹ may be optionally substituted by R ³ , and R ^{3 is} selected from the group consisting of: 3, 4, 5, 6 or 7 membered cycloalkyl; , 6 or 7 members comprising 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; and 5 or 6 members comprising 1, 2 or 3 each independently selected from a heteroatom heteroaryl group of the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from the group consisting of: side oxygen Base, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, And wherein R ^{2 is} selected from the group consisting of: halogen; phenyl; 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O; 9, 10 or 11 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-aromatic but not fully saturated heterocyclic rings each independently selected from the group consisting of N, S and O; wherein R ^{2 is} visible Happening 2, 3 or 4 substituents R ⁴ substituents, R ⁴ are independently from each other selected from the group consisting of: linear or branched -OC _1-5 alkyl, -OH, oxo, halogen, -C _1-5 haloalkyl, -SO ₂ CH ₃ , -C _1-3 alkylene-SO ₂ -(C _1-3 alkyl), -SO ₂ -CF ₃ , -CN, C _3-6 naphthenic a C, _1-5 alkyl, 5 or 6 member comprising 1, 2 or 3 saturated heteroatoms each independently selected from the group consisting of N, S, -SO ₂ and O ;-C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -NH-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _1-3 alkyl and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently of one another selected from the group consisting of: straight or branched -C _1-4 alkyl, pendant oxy, -C _{1 -3} haloalkyl, -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 each independently selected from the group consisting of N, S and O a saturated heterocyclic ring of a hetero atom; a 3, 4, 5, 6 or 7 membered cycloalkyl group; 5 or 6 members comprising 1 or 2 heteroatoms each independently selected from the group consisting of N, S and O a heteroaryl group; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a C _1-3 alkyl group, and a -C _1-3 haloalkyl group, and a pharmacologically acceptable salt of the above compound.

1.1 SYK inhibitor

The present invention describes novel substituted quinolines which inhibit the protein kinase Syk (spleen tyrosine kinase); its preparation and formulation and its use in the preparation of medicaments.

Syk is an intracellular tyrosine kinase that has signal transduction in different receptors in B cells, mast cells, monocytes, macrophages, neutrophils, T cells, dendritic cells, and epithelial cells. Important mediator function. Receptors in which Syk performs important functions of signal transduction include, for example, IgE receptors on mast cells and B cells (Fc) RI) and IgG receptors (FcγR1); B cell receptor (BCR) and T cell receptor (TCR) on B cells and T cells; ICAM1 receptor (ICAM1R) on respiratory epithelial cells; DAP12 receptor on cells, dendritic cells and osteoclasts; lectin 1-receptor on T helper cell subset (Th-17 cells) and neutrophils, monocytes and macrophages Integrin receptors of β1-, β2- and β2-integrin (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 and Gut-Landmann et al; Nature Immunology (2007) 8, 630-638; Slack et al, European J. Immunol. (2007) 37, 1600-1612). Best described as Fc The molecular process of signal transduction of RI. In mast cells, IgE and Fc Binding of RI causes cross-linking of the IgE receptor and recruitment and activation of Lyn (from the Src family of tyrosine kinases). Active Lyn phosphate, the so-called ITAM major structure, which is present in many of the receptors listed above and thereby produces a binding site for the SH2 domain of Syk. Due to its binding to the ITAM main structure, Syk is activated and will then release allergic and inflammatory mediators (eg histamine and ß-hexosaminidase (ßHA)) as well as synthetic lipid mediators (eg prostaglandins and leukotrienes) ) The various receptors required for phosphorylation.

In view of its important functions in different signal transduction pathways, Syk has addressed the therapeutic goals of different diseases, such as 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; Expert Opin. Investig. Drugs (2008) Vol. 15 (5); 641-659; Masuda and Schmitz; PPT ( 2008) Vol. 21; 461-467; Riccaboni et al, Drug Discovery Today (2010) vol. 00 (0); 517-530; Efremov and Luarenti, Expert Opin Investig Drugs. (2011) 20(5): 623- 36).

Allergic rhinitis and asthma are diseases that are associated with allergic reactions and inflammatory processes and involve different cell types such as mast cells, eosinophils, T cells, and dendritic cells. IgE (Fc) after exposure to allergens High affinity immunoglobulin receptors of RI) and IgG (FcyRl) are activated and induce the release of pro-inflammatory mediators and bronchoconstrictors. Therefore, inhibitors of Syk kinase activity should be able to inhibit these steps.

Rheumatoid arthritis (RA) is an autoimmune disease in which the bone and ligament structures around the joint are gradually destroyed. B cell in the pathophysiology of RA It plays an important role, for example as evidenced by the therapeutic use of rituximab, a B cell depleting antibody. In addition to the function of Syk in signal transduction of BCR, which also induces the release of pro-inflammatory mediators after stimulation, Syk also plays an important role in the maturation and proliferation of B cells (Cheng et al., Nature (1995). 378, 303-306, Cornall et al., PNAS (2000) 97(4), 1713-1718). Thus, inhibitors of Syk kinase activity may provide a therapeutic regimen for the treatment of autoimmune diseases such as RA and diseases in which B cell proliferation is increased, such as B cell lymphoma.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent deterioration of lung function and chronic inflammation of the trachea, which is caused and produced by all types of toxic substances and causes the disease course to be maintained. At the cellular level, proliferation of T lymphocytes, neutrophils, granulocytes, and macrophages is particularly present in COPD. In particular, there is an increase in the number of CD8-positive lymphocytes, which is directly related to lung function damage. Another feature of COPD is acute degeneration (deterioration) of lung function, which is characterized by viral (eg rhinovirus) or bacterial (eg, Streptococcus pneumoniae, Haemophilus influenzae). Infection with Moraxella catarrhalis.

In view of the pro-inflammatory function 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 In the literature, inhibitors of Syk kinase activity may be novel therapeutic approaches for the treatment of inflammatory processes that cause COPD. It has also been shown that Syk in the epithelial cells of the respiratory tract is involved in ICAM1R-mediated rhinovirus absorption and subsequent replication and blockade of Si-RNA against Syk. (Wang et al; J. Immunol. (2006) 177, 6859-6870; Lau et al; J. Immunol. (2008) 180, 870-880). Therefore, inhibitors of Syk kinase activity can also be therapeutically used for the deterioration caused by rhinovirus.

Various studies have shown 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). The constitutively active ITK-Syk fusion protein was isolated from patients with peripheral T-cell lymphoma (PTCL) by transforming B cells from patients with spinal dysplasia syndrome with a TEL-Syk fusion protein with constitutive Syk activity. In addition, constitutively active Syk is found in B-cell lymphoma cells of patients, particularly B-line acute lymphoblastic leukemia (B-ALL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). ), mantle cell lymphoma and B cell Non-Hodgkin Lymphomas (NHL) and acute myeloid leukemia (AML). Based on this information, Syk appears to be a proto-oncogene in hematopoietic cells and represents a potential target for the treatment of certain leukemias and lymphomas.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG autoantibodies against antigens present on platelets bind to and destroy platelets. IgG-coated circulating platelets in patients with ITP are rapidly cleared by macrophages in the spleen and liver. Given the FcγR-mediated pro-inflammatory function of Syk in macrophages, Syk inhibitors are considered to have therapeutic benefits for FcyR-mediated hematocrit (like ITP). In fact, the Syk inhibitor R788 (R406) improved platelet counts in a single-center open-label study of patients with ITP (Podolanczuk et al; Blood (2009) 113, 3154-3169).

Bullous pemphigoid (Ujiie et al, Journal of Dermatology 2010; 37: 194-204) is a chronic autoimmune subepidermal vesicular skin disease that rarely involves mucosa. Bullous pemphigoid is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the hemidesporous bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2). Pemphigus vulgaris (Venugopal et al., Dermatol. Clin. 2011; 29: 373-80) is a chronic vesicular skin disease with minimally itchy but often painful skin lesions. Pemphigus vulgaris is an autoimmune disease caused by IgG autoantibodies against desmoglein 1 and desmoglein 3, which results in loss of cohesion between keratinocytes in the epidermis. It is characterized by extensive lax blistering and mucosal and cutaneous erosion. In both diseases, IgG autoantibodies bind to Fc receptor gamma (FcRg) and activate FcRg and activate downstream signal transduction via Syk kinase. Thus, inhibitors of Syk kinase activity that block downstream signal transduction of FcRg are therapeutically useful for treating patients with bullous pemphigoid and pemphigus vulgaris.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that essentially affects any organ in the body. It is characterized by inflammation of the microvasculature system and the presence of autoantibodies. FcyR-deficient mice are protected from several aspects of SLE in disease-associated preclinical models, suggesting that Syk inhibitors may have treatment in SLE in view of the inflammatory activity of FcyR-mediated Syk in various cells. benefit.

1.2 prior art

5-Amino-1,6- having antifungal and antibacterial activity is described in U.S. Patent Nos. 3,928,367, 4,017,500, 4,115,395 and 4,260,759. Acridine. WO 9918077 describes 5-piperazinyl-1,6- as a serotonin antagonist Acridine. U.S. Patent No. 7,321,041 describes the use of substituted SYK inhibitors 1,6- Acridine, however, these 1,6- The pyridine has a completely different substitution form from the compounds of the invention. PCT/EP1011050871 discloses 1,6- substituted at 5 and 7 positions Acridine. In contrast, the present invention relates to 5-, 7-disubstituted quinolines, rather than Acridine.

WO 2006038041 discloses substituted quinoline compounds at the 5 and 7 positions, however, the substituted form (especially at the 7 position) is completely different from one of the quinolines of the formula 1 of the present invention.

It has been unexpectedly discovered that quinoline of formula 1 is especially useful for the treatment of respiratory disorders, allergic diseases, osteoporosis, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, and peripheral or central nervous system diseases, especially for the treatment of asthma and allergic rhinitis. , rheumatoid arthritis, atopic dermatitis and COPD.

The present invention is therefore directed to a compound of formula 1 , Wherein R ¹ is a linear or branched C _1-6 alkyl group, wherein R ¹ may be optionally substituted by R ³ , and R ^{3 is} selected from the group consisting of: 3, 4, 5, 6 or 7 membered cycloalkyl; , 6 or 7 members comprising 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; and 5 or 6 members comprising 1, 2 or 3 each independently selected from a heteroatom heteroaryl group of the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from the group consisting of: side oxygen Base, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, And wherein R ^{2 is} selected from the group consisting of: halogen; phenyl; 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O; 9, 10 or 11 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-aromatic but not fully saturated heterocyclic rings each independently selected from the group consisting of N, S and O; wherein R ^{2 is} visible Happening 2, 3 or 4 substituents R ⁴ substituents, R ⁴ are independently from each other selected from the group consisting of: linear or branched -OC _1-5 alkyl, -OH, oxo, halogen, -C _1-5 haloalkyl, -SO ₂ CH ₃ , -C _1-3 alkylene-SO ₂ -(C _1-3 alkyl), -SO ₂ -CF ₃ , -CN, -C _3-6 ring An alkyl, straight or branched chain -C _1-5 alkyl, 4, 5 or 6 member comprising 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, S, -SO ₂ and O Saturated heterocyclic ring; -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -NH-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _1-3 alkyl and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently of one another selected from the group consisting of: straight or branched -C _1-4 alkyl, pendant oxy, -C _{1 -3} haloalkyl, -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 each independently selected from the group consisting of N, S and O a saturated heterocyclic ring of a hetero atom; a 3, 4, 5, 6 or 7 membered cycloalkyl group; 5 or 6 members comprising 1 or 2 heteroatoms each independently selected from the group consisting of N, S and O a heteroaryl group; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a -C _1-3 alkyl group, and a -C _1-3 haloalkyl group, and a pharmacologically acceptable salt of the above compound.

In another embodiment, the invention relates to the compound of Formula 1 above, wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -(CH ₃ ), which may optionally be substituted by R ³ , and R ^{3 is} selected from a group consisting of: 3, 4, 5, 6 or 7 membered cycloalkyl; 5, 6 or 7 members comprising 1, 2 or 3 saturated groups each independently selected from the group consisting of N, S and O a heterocyclic ring; and 5 or 6 members comprising 1, 2 or 3 heteroaryl groups each independently selected from the group consisting of N, S and O; wherein R ³ may optionally be 1, 2, 3 or 4 Substituent substituents, each of which is independently selected from the group consisting of pendant oxy, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N (CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, and pharmacologically acceptable salts of the above compounds.

In another aspect, the present invention relates to a compound of the above formula 1, in which R ¹ substituted by R ^3, R ³ is selected from the group consisting of: 5 or 6 comprising 1 or 2 substituents each independently selected from the group consisting of N, a saturated heterocyclic ring of a hetero atom of the group consisting of S and O, wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of pendant oxy groups, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ ,- C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, and the above A pharmacologically acceptable salt of the compound.

Further, the present invention relates to the compound of the above formula 1 , wherein R ¹ is substituted by R ³ , and R ^{3 is} selected from the group consisting of 5 or 6 members comprising 1 or 2 each independently selected from the group consisting of N, S and O. a heteroatom heteroaryl group, wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from the group consisting of pendant oxy, OH, -CO- NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _1-3 Alkyl-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, and the pharmacological effects of the above compounds Acceptable salt.

In another embodiment, the present invention relates to compounds of the formula 1, in which R ¹ is selected from -CH ₃ or -CH ₂ (CH ₃₎ group consisting of in which R ¹ optionally substituted with R ^3, R ³ is selected from a group consisting of: 3, 4, 5 or 6 membered cycloalkyl; 5 or 6 members comprising 1 or 2 saturated heteroatoms each independently selected from the group consisting of N, S and O; and 5 Or 6 members comprising 1 or 2 heteroaryl groups each independently selected from the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, such substitutions The groups are each independently selected from the group consisting of: a pendant oxy group, -CO-NH ₂ , -CH ₂ -CO-NH ₂ , methyl and -CH ₂ -CN, and a pharmacologically acceptable salt of the above compound .

In a preferred embodiment, the invention relates to a compound of formula 1 , wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -CH ₃ wherein R ¹ is substituted by R ³ and R ³ is 1 A 5-membered saturated heterocyclic ring of a nitrogen atom wherein R ³ is substituted with one pendant oxy group, and a pharmacologically acceptable salt of the above compound.

In another particularly preferred embodiment, the invention relates to a compound of formula 1 above, wherein R ¹ is a group And a pharmacologically acceptable salt of the above compound.

In another preferred embodiment, the invention relates to a compound of formula 1 above, wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -CH ₃ wherein R ¹ is substituted by R ³ and R ³ is included a 6-membered heteroaryl group of a nitrogen atom wherein R ³ is substituted with -CO-NH ₂ and a pharmacologically acceptable salt of the above compound.

In another particularly preferred embodiment, the invention relates to a compound of formula 1 , wherein R ¹ is a group And a pharmacologically acceptable salt of the above compound.

In another embodiment, the invention relates to a compound of formula 1 above, wherein R ^{2 is} selected from the group consisting of: R ^{2 is} selected from the group consisting of: phenyl; 5 or 6 members comprise 1, 2 or 3 a monocyclic heteroaryl group each independently selected from the group consisting of N, S and O; 9 or 10 members comprising 1, 2, 3 or 4 each independently selected from the group consisting of N, S and O bicyclic aromatic or non-aromatic hetero atoms but not fully saturated heterocycle; wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently from each other selected from the group consisting of: linear Chain or branched chain -OC _1-3 alkyl, pendant oxy, -OH, -F, -Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ ,- SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 each independently selected from the group consisting of N, S, SO ₂ and O a saturated heterocyclic ring of a hetero atom; -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkyl-O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted by 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl , isobutyl, tert-butyl, -C _1-3 haloalkyl, pendant oxy, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; 3, 4, 5, 6 or 7 membered cycloalkyl; 5 or 6 members comprising 1 or 2 a heteroaryl group each independently selected from the group consisting of N, S and O; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a methyl group, an ethyl group, a —CF ₃ group, and a compound of the above Pharmacologically acceptable salt.

The present invention is further based on the compound of the above formula 1, wherein R ² is phenyl, wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ independently selected from the group consisting of: Linear or branched -OC _1-3 alkyl, pendant oxy, -OH, -F, -Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 heteroatoms each independently selected from the group consisting of N, S and O Saturated heterocyclic ring; -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _{1- 3-} alkyl-O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, m-isopropyl, n-butyl , isobutyl, tert-butyl, pendant oxy, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; 3, 4, 5, 6 or 7 membered cycloalkyl; 5 or 6 members comprising 1 or 2 a heteroaryl group each independently selected from the group consisting of N, S and O; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group and a methyl group,

And a pharmacologically acceptable salt of the above compound.

In another embodiment, the present invention relates to compounds of the formula 1, wherein R ² is phenyl, and wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ independently of one another Selected from the following group: -OCH ₃ , pendant oxy, -OH, -F, Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-CH ₃ , -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ ,- C _1-3 alkylene-O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, Isobutyl, tert-butyl, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 a saturated heterocyclic ring each independently selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may optionally be formed via a pendant oxy group or a methyl group. The group is substituted, and the pharmacologically acceptable salt of the above compound.

The invention further relates to compounds of formula 1 above, wherein R ² is 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O heteroatoms; R ² optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently from each other selected from the group consisting of: -O- methyl, -O- ethyl, -O- propyl, - O-isopropyl, pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; -NH-CO- CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene) -O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _1-3 alkyl and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Tertiary butyl, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 independently of each other a saturated heterocyclic ring of a hetero atom selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may be optionally constituted by a pendant oxy group, a methyl group and -CF ₃ The group is substituted, and the pharmacologically acceptable salt of the above compound.

In another embodiment, the invention relates to a compound of formula 1 above, wherein R ² is 5 or 6 members comprising 1, 2 or 3 single atoms each independently selected from the group consisting of N, S and O a cycloheteroaryl group; wherein R ² may be optionally substituted with 1, 2, 3 or 4 substituents R ⁴ , and R ^{4 is} independently selected from the group consisting of: -O-CH ₃ , pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl a group, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O heteroatoms; -NH-CO-CH ₃ , -C _1-3 alkylene- N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of Group: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF ₃ , -CH ₂ -CF ₃ , -CHF ₂ , CH ₂ F, -CF ₂ -CF ₃ , -OH, halogen, -extended ethyl-CF ₃ , 5 or 6 members containing 1, 2 Or three saturated heterocycles each independently selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl; wherein R ⁵ may optionally be via a pendant oxy group, A Substituents substituted with a group consisting of -CF ₃ and a pharmacologically acceptable salt of the above compound.

The invention further relates to the compound of formula 1 above, wherein R ² is a 5-membered monocyclic heteroaryl group comprising 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, S and O; The monocyclic heteroaryl group is attached to the quinoline core structure via a carbon atom, and wherein the 5-membered monocyclic heteroaryl group is further substituted as specified in Scheme 14, and the pharmacologically acceptable of the above compounds salt.

The invention also relates to compounds of formula 1 , wherein R ² is a 5-membered monocyclic heteroaryl group containing at least one nitrogen atom and optionally 1 or 2 other heteroatoms each independently selected from the group consisting of N, S and O. Wherein the 5-membered monocyclic heteroaryl group is attached to the quinoline core structure via a nitrogen atom, and wherein the 5-membered monocyclic heteroaryl group can be further substituted as specified in Scheme 14, and the pharmacology of the above compound Acceptable salt.

In another embodiment, the invention relates to a compound of formula 1 above, wherein R ² is 9 or 10 members comprising 1, 2, 3 or 4 heteroatoms each independently selected from the group consisting of N, S and O bicyclic aromatic or non-aromatic, but not completely saturated heterocyclic ring; wherein R ² group optionally substituted by ^4, 2, 3 or 4 substituents R, R ⁴ independently selected from the group consisting of: straight-chain or Branched chain -OC _1-3 alkyl, pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O heteroatoms; NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 Alkyl)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkyl-O -CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, -C _1-3 haloalkyl , -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 each independently selected from the group consisting of N, S and O a saturated heterocyclic ring of an atom; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a methyl group and a -CF ₃ group, and the pharmacologically acceptable compound of the above compound Accept the salt.

The invention further relates to compounds of formula 1 above, wherein R ² is 9 or 10 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-heteroatoms each independently selected from the group consisting of N, S and O Aromatic but not fully saturated heterocyclic ring; wherein R ² may be substituted by 1, 2, 3 or 4 substituents R ⁴ , and R ^{4 is} independently selected from the group consisting of: -O-CH ₃ , -O- , -O- upper propyl, -O- isopropyl, oxo, -OH, -F, -CF _3, methyl, ethyl, propyl and isopropyl, and pharmacology of the compounds described above ethyl Acceptable salt.

In a preferred embodiment, the present invention relates to a compound of the above formula 1, wherein R ² is pyridyl, wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently selected from each other Free group consisting of: -O-CH ₃ , pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ - CF ₃ , —CH ₃ , —CH ₂ —CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heteroatoms each independently selected from the group consisting of N, S and O heteroatoms ;-NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _{1 -3} alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , wherein R ⁴ may optionally be 1 or Substituted by two substituents R ⁵ wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF ₃ , -CH ₂ -CF ₃ , -CHF ₂ , CH ₂ F, -CF ₂ -CF ₃ , -OH, halogen, -C _1-2 alkylene-CF ₃ , 5 or 6 members containing 1, 2 or 3 saturated heterocycles each independently selected from the group consisting of N, S and O; 3 5, 6 or 7-membered cycloalkyl group; wherein R ⁵ optionally substituted by the group consisting of oxo, methyl and -CF _3, and pharmacologically acceptable salts of the above compounds.

In another preferred embodiment, the invention relates to a compound of formula 1 above, wherein R ² is pyridine, wherein R ² is substituted with 1 or 2 substituents R ⁴ , and R ^{4 is} independently selected from the group consisting of :-O-CH ₃ , -OH, -F, -CF ₃ , -CHF ₂ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl and -O- R ⁵ , wherein R ^{5 is} selected from a group consisting of methyl, ethyl, propyl, isopropyl, -CF ₃ , -CHF ₂ , CH ₂ F, -CH ₂ -CF ₃ , -CF ₂ -CF ₃ , and the pharmacology of the above compounds Acceptable salt.

In one particularly preferred group of embodiments, the present invention relates to a compound of the above formula 1, wherein R ¹ is selected from the group consisting of: And wherein R ^{2 is} selected from the group consisting of: And a pharmacologically acceptable salt of the above compound.

In another particularly preferred embodiment, the invention relates to a compound of formula 1 above selected from the group consisting of: And a pharmacologically acceptable salt of the above compound.

The invention further relates to the above compound of formula 1 as a medicament.

In another embodiment, the invention relates to the use of a compound of formula 1 above for the treatment of a condition which can be treated by inhibition of the SYK enzyme.

In a preferred embodiment, the invention relates to the use of a compound of formula 1 above for the treatment of a disease selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, B Cellular lymphoma, dermatitis and contact dermatitis, atopic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, antiphospholipid syndrome, Berger's disease, Evans's syndrome, ulcerative colon Inflammation, allergic antibody-based spheroid nephritis, neutropenia, Goodpasture's syndrome, hepatitis, Henoch-Schönlein purpura, allergic vasculitis, immunity Hemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematosus, capsular cell lymphoma, neutropenia, non-familial side Sclerotherapy, Crohn's disease, multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic disease, osteopenia, Psoriasis, Sjögren's syndrome, scleroderma, T-cell lymphoma, urticaria/angioedema, Wegener's granulomatosis, and celiac disease.

In another preferred embodiment, the invention relates to the use of a compound of formula 1 above, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, atopic dermatitis, Contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, and allergic rhinoconjunctivitis.

In a particularly preferred embodiment, the invention relates to the use of a compound of formula 1 above, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, atopic dermatitis and rheumatoid arthritis.

Furthermore, the invention relates to pharmaceutical formulations characterized by the inclusion of one or more compounds of formula 1 .

In another embodiment, the invention relates to a pharmaceutical formulation comprising one or more compounds of formula 1 in combination with an active substance selected from the group consisting of anticholinergic agents, beta mimics Agents, corticosteroids, PDE4 inhibitors, EGFR inhibitors, LTD4 antagonists, CCR3 inhibitors, iNOS inhibitors and HMG-CoA reductase inhibitors.

In another embodiment, the invention relates to a compound selected from the group consisting of Formula 6 Wherein R ¹ and R ^{2 are} as defined above.

3. Terms and definitions used

All substituents are independent of each other unless otherwise specified. For example, if a plurality of C _1-6 alkyl groups are possible substituents of one group, for example, in the case of three substituents, the C _1-6 alkyl groups may independently represent methyl, n-propyl and the Tributyl.

Within the scope of the present application, such substituents may also be represented in structural form in the definition of possible substituents. The asterisk (*) in the structural formula of the substituent is understood to be the point of attachment to the rest of the molecule. In addition, the atom of the substituent after the point of attachment is understood to be the atom in position 1. Thus, for example, the groups N-piperidinyl ( I ), 4-piperidinyl ( II ), 2-tolyl ( III ), 3-tolyl ( IV ) and 4-tolyl ( V ) are represented as follows :

If an asterisk (*) is not present in the structural formula of the substituent, each hydrogen atom at the substituent can be removed and thus the free valence can serve as a binding site to the rest of the molecule. So, for example, VI It may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

Alternatively, in the context of the present application, it is also understood that X ₁ is the point of attachment of the group R ¹ to the structure of formula 1 and X ₂ is the point of attachment of the group R ² to the structure of formula 1 .

The term "C _1-6 alkyl" (as part of another group includes the C _1-6 alkyl) means branched having 1 to 6 carbon atoms and non-branched alkyl group and the term "C _1-3 "Alkyl" means a branched chain having 1 to 3 carbon atoms and an unbranched alkyl group. Thus, "C _1-4 alkyl" means a branched chain having 1 to 4 carbon atoms and an unbranched alkyl group. An alkyl group having 1 to 4 carbon atoms is preferred. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl or hexyl. Abbreviations Me, Et, n -Pr, i -Pr, n -Bu, i -Bu, t -Bu , etc. may also be optionally used in the above groups. Unless otherwise stated, the definitions of propyl, butyl, pentyl and hexyl include all possible isomeric forms of the group. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, t-butyl, t-butyl, and the like.

The term "C _1-6 alkylene" (included as part of another group, a C _1-6 alkylene group) is meant having 1 to 6 carbon atoms branched and non branched alkylene group and the term "C _1-4 alkylene means a branched chain having 1 to 4 carbon atoms and an unbranched alkylene group. The alkylene group having 1 to 4 carbon atoms is preferred. Examples thereof include: methylene, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, 1,2 - dimethyl-ethyl, pentyl, 1,1-dimethyl-propyl, 2,2-dimethyl-propyl, 1,2-dimethyl-propyl, 1,3-di Methyl propyl or hexyl. Unless otherwise indicated, the definitions of propyl, butyl, pentyl and hexyl include all possible isomeric forms of the group having the same number of carbons. Thus, for example, propyl also includes 1-methylethylidene and butyl includes 1-methylpropyl, 1,1-dimethylexylethyl, 1,2-dimethylexene base.

If a carbon chain substituent forms a carbon ring having 3, 5 or 6 carbon atoms with one or two carbon atoms of the alkyl chain, the ring includes, in particular, the following ring examples:

The term "C _2-6 -alkenyl" (including C _2-6 alkenyl as part of another group) means a branched or unbranched alkenyl group having 2 to 6 carbon atoms and the term "C _{2- 4} alkenyl group "means a branched having 2-4 carbon atoms and non-branched alkenyl group with the proviso that it has at least one double bond. The alkenyl group having 2 to 4 carbon atoms is preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise stated, the definitions of propenyl, butenyl, pentenyl, and hexenyl include all possible isomeric forms of the group. Thus, for example, the propylene group includes 1-propenyl and 2-propenyl, and the butenyl group includes 1-butenyl, 2-butenyl and 3-butenyl, 1-methyl-1-propenyl. , 1-methyl-2-propenyl and the like.

The term "C _2-6 alkenylene group" (included as part of other groups of a C _2-6 alkenylene group) means branched having 2 to 6 carbon atoms and non-branched alkenylene group and the term "C _"2-4" extends an alkenyl group to mean a branched chain having 2 to 4 carbon atoms and an unbranched alkylene group. An alkenyl group having 2 to 4 carbon atoms is preferred. Examples thereof include: vinyl group, propylene group, 1-methylvinyl group, butenyl group, 1-methyl propylene group, 1,1-dimethylvinyl group, 1,2-dimethyl group. Base vinyl, pentenyl, 1,1-dimethylpropenyl, 2,2-dimethylpropenyl, 1,2-dimethylpropenyl, 1,3-dimethyl Extend propylene or hexene. Unless otherwise stated, the definitions of propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the group having the same number of carbons. Thus, for example, the propylene group also includes 1-methylvinyl and the butenyl group includes 1-methylpropenyl, 1,1-dimethylvinyl, 1,2-dimethyl Vinyl.

The term "C _2-6 alkynyl" (included as part of another group, a C _2-6 alkynyl group) means branched having 2 to 6 carbon atoms and unbranched alkynyl group and the term "C _2-4 "Alkynyl" means a branched chain having 2 to 4 carbon atoms and an unbranched alkynyl group, with the proviso that it has at least one reference bond. An alkynyl group having 2 to 4 carbon atoms is preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the group. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, and butynyl includes 1-butynyl, 2-butynyl and 3-butynyl, 1-methyl-1 - propynyl, 1-methyl-2-propynyl and the like.

The term "C _2-6 alkynyl extension" (included as part of other groups, a C _2-6 alkynyl group elongation) means branched having 2 to 6 carbon atoms and non-branched alkynyl group and extending term "C _{2-4 an} alkynyl group means a branched chain having 2 to 4 carbon atoms and an unbranched chain alkyl group. Preferred is an alkynyl group having 2 to 4 carbon atoms. Examples include: exoethyl, propenyl, 1-methyl ethynyl, butynyl, 1-methylpropynyl, 1,1-dimethyl-ethynyl, 1,2- Dimethyl ethynyl, pentynyl, 1,1-dimethyl-propenyl, 2,2-dimethyl-propenyl, 1,2-dimethyl-propenyl, 1, 3-Dimethyl-propenyl or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the group having the same number of carbons. Thus, for example, a propynyl group also includes a 1-methyl-exetylene group and a butynyl group includes a 1-methyl-propenyl group, a 1,1-dimethyl-exetylene group, and a 1,2-dimethyl group. Exoacetylene group.

The term "aryl" (including aryl as part of another group) means an aromatic ring system having 6 or 10 carbon atoms. Examples include phenyl or naphthyl, preferably aryl. Unless otherwise stated, an aromatic group may be substituted with one or more groups selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "-C _1-6 alkylene aryl" (including as part of another group, aryl -C _1-6 alkylene) means branched having 1 to 6 carbon atoms and a branched non-stretched An alkyl group substituted with 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, an aromatic group may be substituted with one or more groups selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "heteroaryl -C _1-6 alkylene" (included as part of another group, heteroaryl -C _1-6 alkylene) means (although it has been included in the "aryl group -C _{1- a 6-} alkyl group having a branched chain having 1 to 6 carbon atoms and an unbranched alkyl group substituted by a heteroaryl group.

Such heteroaryl groups include a 5 or 6 membered heterocyclic aromatic group or a 5-10 membered bicyclic heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and Enough to form a conjugated double bond of the aromatic system. The following are examples of 5- or 6-membered heterocyclic aromatic or bicyclic heteroaryl rings:

Unless otherwise stated, such heteroaryl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The following are examples of heteroaryl-C _1-6 alkylene:

The term "C _1-6 haloalkyl" (included as part of another group, a C _1-6 haloalkyl) means with one or more halogen atoms, substituted and non-branched having from 1 to 6 carbon atoms Branched chain alkyl. The term "C _1-4 alkyl" means a branched or unbranched alkyl group having 1 to 4 carbon atoms which is substituted by one or more halogen atoms. An alkyl group having 1 to 4 carbon atoms is preferred. Examples include: CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ .

The term "a C _3-7 cycloalkyl group" (included as part of another group is a C _3-7 cycloalkyl group) means a cyclic alkyl group having 3-7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, a cyclic alkyl group may be substituted with one or more groups selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, hydroxy, fluoro, chloro, bromo and iodo.

The term "C _3-10 cycloalkyl" also means a monocyclic alkyl group having 3 to 7 carbon atoms and a bicycloalkyl group having 7 to 10 carbon atoms, or by at least one C _1-3 carbon bridge. Bridged monocycloalkyl.

Unless otherwise indicated, the term "heterocycle" means a 5, 6 or 7 membered saturated, partially saturated or unsaturated heterocyclic ring which may contain 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The ring can be attached to the molecule via a carbon atom or via a nitrogen atom (if one is present). Although within the scope of the term "heterocycle", the term "saturated heterocycle" refers to a 5, 6 or 7 membered saturated ring. Examples include:

Although within the scope of the terms "heterocyclic" or "heterocyclic group", the term "partially saturated heterocyclic group" means a 5, 6 or 7 membered partially saturated ring containing one or two double bonds and which The double bonds are not sufficient to form an aromatic system. Examples include:

Although within the scope of the term "heterocycle", the terms "heterocyclic aromatic ring", "unsaturated heterocyclic group" or "heteroaryl" mean a 5- or 6-membered heterocyclic aromatic group or a 5-10 membered bicyclic ring. A heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and which contains a conjugated double bond sufficient to form an aromatic system. Examples of 5- or 6-membered heterocyclic aromatic groups include:

Unless otherwise stated, a heterocyclic ring can have a ketone group. Examples include:

Although encompassed by the term "cycloalkyl", the term "bicyclic cycloalkyl" generally means an 8, 9 or 10 membered bicyclic carbon ring. Examples include

Although within the scope of the term "heterocycle", the term "bicyclic heterocycle" generally means a 8, 9 or 10 membered bicyclic ring which may contain one or more, preferably 1-4, more preferably 1-3, or even More preferably 1-2, especially one hetero atom selected from sulfur and nitrogen. The ring may be attached to the molecule via a carbon atom of the ring or via a nitrogen atom of the ring, if one is present. Examples include:

Although within the scope of the term "aryl", the term "bicyclic aryl" means a 5-10 membered bicyclic aryl ring containing a conjugated double bond sufficient to form an aromatic system. An example of a bicyclic aryl group is a naphthyl group.

Although in the category of "heteroaryl", the term "bicyclic heteroaryl" means a 5-10 membered bicyclic heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. It also contains enough conjugated double bonds to form an aromatic system.

Although within the scope of the terms "bicyclic cycloalkyl" or "bicyclic aryl", the term "fused cycloalkyl" or "fused aryl" means a bicyclic ring in which the bridge of the separation ring represents a direct single bond. The following are examples of fused bicyclic cycloalkyl groups:

Although in the category of "bicyclic heterocycle" or "bicyclic heteroaryl", the term "fused bicyclic heterocycle" or "fused bicyclic heteroaryl" means that 1, 2, 3 or 4 are selected from oxygen, A heteroatom of sulfur and nitrogen and wherein the bridge of the separation ring represents a bicyclic 5-10 membered heterocyclic ring of a direct single bond. Further, the "fused bicyclic heteroaryl" contains a conjugated double bond sufficient to form an aromatic system. Examples include pyr , hydrazine, pyridazine, isoindole, oxazole, hydrazine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzisothiazole, Pyridopyrimidine, acridine, pyrimidopyrimidine,

The term "spiro" (spiro) means a 5-10 membered spiro ring which optionally contains 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and the ring may pass through a carbon atom or through a nitrogen atom (if Yes) connected to the molecule. Unless otherwise mentioned, a spiro ring may have a pendant oxy group, a methyl group or an ethyl group. This example includes:

"Halogen" within the scope of the present invention means fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are considered to be preferred halogens.

The compound of formula 1 may have an acidic group (mainly a carboxyl group) and/or a basic group (such as an amine functional group). Thus, the compound of Formula 1 can be present as an internal salt, such as with a pharmaceutically acceptable inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid) or an organic acid (such as maleic acid, fumaric acid, citric acid). a salt formed from tartaric acid or acetic acid, or a pharmaceutically acceptable base such as an alkali metal or alkaline earth metal hydroxide or carbonate, zinc hydroxide or ammonium hydroxide or an organic amine (especially such as diethylamine, triethylamine) , a salt formed by triethanolamine)).

As stated previously, the compound of formula 1 can be converted to its salt, especially to its physiologically and pharmacologically acceptable salts for medical use. In one aspect, the salts can be present as a physiologically and pharmacologically acceptable acid addition salt of a compound of formula 1 with an inorganic or organic acid. On the other hand, when R is hydrogen, the compound of formula 1 can be converted into a physiologically and pharmacologically acceptable salt by reaction with an inorganic base, wherein an alkali metal or alkaline earth metal cation is used as a relative ion. For example, an acid addition salt can be prepared 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 also possible to use a mixture of the above acids. For the preparation of the alkali metal and alkaline earth metal salts of the compound of the formula 1 wherein R represents hydrogen, it is preferred to use alkali metal and alkaline earth metal hydroxides and hydrides, of which alkali metal (especially sodium and potassium) hydroxides and A hydride, and particularly preferably sodium hydroxide and potassium hydroxide.

The compounds of the formula 1 can optionally be converted into their salts, in particular into pharmacologically acceptable acid addition salts with inorganic or organic acids for pharmaceutical use. 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 also possible to use a mixture of the above acids.

The present invention relates to the compounds, which are optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates; in tautomeric form and as free base or pharmaceutically acceptable a corresponding acid addition salt form formed by an acid, such as an acid formed with a hydrohalic acid (such as hydrochloric acid or hydrobromic acid) or an organic acid (such as oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid) Addition salt.

The compounds of the invention may optionally be in the form of racemates, but may also be obtained in the form of the pure enantiomers, i.e., in the (R) or (S) form.

The present invention relates to the compounds which are optionally optical isomers, diastereomers, mixtures of diastereomers, individual enantiomers a mixture or racemic form of the construct; in the form of a tautomer and a corresponding acid addition salt form formed by the free base or a pharmaceutically acceptable acid, for example with a hydrohalic acid (eg hydrochloric acid or hydrobromine) An acid addition salt formed by an acid or an organic acid such as oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid.

The present invention is directed to individual Formula 1 compounds in the form of a pharmaceutically acceptable salt. These pharmacologically acceptable salts of the compound of formula 1 may also exist in the form of their respective hydrate forms (e.g., monohydrate, dihydrate, etc.) and their respective solvates.

For the purposes of the present invention, a hydrate of a compound of formula 1 means a crystalline salt of a compound of formula 1 containing water of crystallization.

For the purposes of the present invention, a solvate of a compound of formula 1 means a crystalline salt of a compound of formula 1 which contains a solvent molecule (e.g., ethanol, methanol, etc.) in the crystal lattice.

Those skilled in the art are well versed in standard methods for obtaining hydrates and solvates (e.g., recrystallization from the corresponding solvent or water).

4. Preparation method

An example of the invention is prepared as shown in Scheme 1, 2 or 3.

Y is -OH, Cl, Br, I, -O triflate, -O tosylate, -O mesylate

PG is a protecting group (eg benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl)

And R ¹ and R ² are as defined above.

Where X is -B(OH) ₂ ,- Acid tetramethyl glycol ester, -trifluoroborate, -SnBu ₃ ; Y is -OH, Cl, Br, I, -O triflate, -O tosylate, -O mesylate Wherein Hal is Cl, Br, I, and PG is a protecting group (eg, benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl)

Where Hal is Cl, Br, I

4.1. Starting materials and intermediates of formulas 2 , 3 and 4 4.1.1. Aryl alkyne 2 in the synthesis scheme 1 Synthesis of 5-ethynyl-1,2,3-trimethoxybenzene ( 2.1 ) for use in Examples 2, 3, 4, 5, 9, 18, 23, 38

Synthesis of 5-ethynyl-1,2,3-trimethoxybenzene according to Rasolofonjatovo, Evelia; Provot, Olivier; Hamze, Abdallah; Brion, Jean-Daniel; Alami, Mouad; Bignon, Jerome; Thoret, Sylviane European Journal of The method of Medicinal Chemistry , 2010, Vol. 45, 3617-3626.

Step 1: 1 g of 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethyldecyl acetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenyl under argon The phosphine palladium (II) chloride and 39 mg of copper (I) iodide were placed in a dry flask. The mixture was stirred at 80 ° C for 1 hour, cooled, diluted with dichloromethane (DCM) and filtered thru EtOAc. The filtrate was extracted with aqueous ammonia and saturated brine and concentrated. The residue was purified by flash chromatography (SiO ₂ : EtOAc EtOAc EtOAc

Yield: 970 mg (oil)

Analysis: HPLC-MS (Method E) Rt = 1.55 min; M+H = 265.

Step 2: Dissolve 230 mg of trimethyl((3,4,5-trimethoxyphenyl)ethynyl)decane, 0.9 mL of tetrabutylammonium fluoride (1 mol/l in THF) in 3 mL It was stirred in THF at 25 ° C for 1 hour. The solution was diluted with DCM and extracted with water. The organic phase solvent was distilled off and the residue was purified via flash chromatography (10 g SiO _2; cyclohexane → cyclohexane / ethyl acetate 7: 3) purification.

Yield: 135 mg (90% of theory)

Analysis: HPLC-MS (Method E): Rt: 1.15 min. M+H=193

Synthesis of 5-ethynyl-1,3-difluoro-2-methoxy-benzene ( 2.2 ) for use in Examples 14, 15, 17

2 g of 5-bromo-1,3-difluoro-2-methoxy-benzene, 1.76 g of ethynyl-trimethyl-decane, 629 mg of bis(triphenylphosphine)palladium(II) chloride, 3.1 Ml diisopropyl The mixture of ethylamine and 85 mg of copper iodide in 20 ml of acetonitrile was degassed and then heated at 80 ° C for 2 hours. The mixture was diluted with dichloromethane and filtered through EtOAc (EtOAc)EtOAc. Purification via cerium oxide gave 1.71 g of (3,5-difluoro-4-methoxy-phenylethynyl)-trimethyl-decane.

¹ H NMR (250 MHz, CDCl ₃ ) δ . ppm 0.24 (9H, s), 4.02 (3H, t, J = 1.29 Hz), 6.91-7.09 (2H, m).

Add 1 N tetrabutylammonium fluoride (TBAF) in THF to 1.71 g (3,5-difluoro-4-methoxy-phenylethynyl)-trimethyl-decane at 25 ° C The mixture was stirred overnight. The solvent was removed in vacuo and the residue was purified eluting with EtOAc EtOAc:EtOAc 2-methoxy-benzene.

¹ H NMR (250 MHz, CDCl ₃ ) δ . ppm 3.08 (1H, s), 4.02 (3H, d, J = 1.22 Hz), 6.89-7.15 (2H, m).

4-ethynyl-1-isopropoxy-2-methoxy-benzene ( 2.3 ) (for Examples 10, 11, 13, 16, 19)

4-Ethynyl-1-isopropoxy-2-methoxy-benzene 2.3 was synthesized in two steps analogous to 2.2 from 4-bromo-1-isopropoxy-2-methoxy-benzene.

¹ H NMR (250 MHz, CDCl ₃ ) δ . ppm 1.38 (6 H, d, J = 6.09 Hz), 3.01 (1 H, s), 3.85 (3 H, s), 4.56 (1 H, m), 6.82 (1 H, d, J = 8.22 Hz), 7.00 (1 H, d, J = 1.83 Hz), 7.07 (1 H, dd, J = 8.30, 1.90 Hz).

2-ethynyl-quinoline ( 2.4 ) for use in Example 34

The 2-ethynyl-quinoline 2.4 of Example 34 was synthesized in a 2-step analogous to 2.2 from 2-bromo-quinoline.

Analysis: HPLC-MS: Rt = 1.25 (Method M), M+H = 154.

5-ethynyl-2-methoxypyridine ( 2.5 ) for use in Examples 20, 21

The 5-ethynyl-2-methoxypyridine of Examples 20 and 21 was synthesized in a 2-step analogously to 2.2 from 5-bromo-2-methoxy-pyridine.

¹ H NMR (500 MHz, chloroform-d ) δ ppm 3.11 (1 H, s), 3.92-3.98 (3 H, m), 6.70 (1 H, dd, J = 8.62, 0.53 Hz), 7.64 (1 H ,dd, J =8.54, 2.29 Hz), 8.32 (1 H,d, J =2.14 Hz)

The following aryl alkyne are commercially available: Example 7, 8, 12 4-ethynyl-1,2-dimethoxybenzene 2.6

Example 1 1-ethynyl-benzene 2.7

Example 6 2-ethynylpyridine 2.8

4.1.2. 5-Hydroxy-7-bromo-quinoline in Scheme 2

The title compound is commercially available from Shanghai Haoyuan Chemexpress Co., Ltd. CHINA or via known 3-bromo-5-methoxyaniline (Liedholm, Brita.Acta Chemica Scandinavica, Series B: Organic Chemistry) And Biochemistry (1984), B38 (10), 877-84 or Hodgson, H.H.; Wignall, J. SJournal of the Chemical Society (1926)) are synthesized in two steps.

Step 1: 4.0 g (0.02 mol) 3-bromo-5-methoxy-phenylamine, 4.6 g (0.05 mol) glycerol, 2.46 g (0.02 mol) nitrobenzene and 12 ml 75% sulfuric acid were stirred at 150 ° C. 3 h. After pouring this dark solution into 100 g of crushed ice, 100 ml of ethyl acetate (EtOAc) and 30 ml of 30% NaOH solution were added. After 1 hour, the brown solid was filtered off and the organic layer was separated. After filtration through SiO ₂ and evaporation of the solvent, 7-bromo-5-methoxy-quinoline and 5-bromo-7-methoxy as a mixture of about 60:40 (total 3.5 g, 74%) were isolated. -quinoline. The mixture was separated into individual 7-bromo-5-methoxy-quinoline and 5-bromo-7-methoxy-quine by chromatography on a septum column with benzene-EtOAc (3:1) as solvent. Porphyrin. The yield of pure 7-bromo-5-methoxy-quinoline was 950 mg (27% from the mixture).

Step 2: 1.5 g (0.0064 mol) of 7-bromo-5-methoxy-quinoline was refluxed with 48% HBr (30 ml) for 20 h. After cooling to room temperature, the reaction mixture was poured into 100 ml of water and basified with a saturated ammonia solution. The product was filtered off, washed with water and dried at 50 <0>C under vacuum. The yield of 7-bromo-5-hydroxy-quinoline was 600 mg (41%).

¹ H-NMR (400 MHz, d6-DMSO): δ = 11.1 (1H, s (broad)), 8.88 (1H, s), 8.49 (1H, d), 7.68 (1H, s), 7.48 (1H, m), 7.18 (1H, s) ppm.

4.1.3. Alcohol 3 in Synthetic Processes 1 and 2 Synthesis of (R)-4-((R)-1-hydroxyethyl)-1-(R)-1-phenylethyl)pyrrolidin-2-one ( 3.1 ) and (R)-4-(( S)-1-hydroxyethyl)-1-(R)-1-phenylethyl)pyrrolidin-2-one ( 3.2 ) (for Examples 1, 2, 6, 8, 14)

20 g of (1'R,3R)-1-(1'-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid and N,O-dimethylhydroxylamine hydrochloride at 0 °C Dissolved in 100 mL of dimethylformamide. Add 13.9 g hydroxybenzotriazole, 19.8 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 20 mL N -methylmorpholine at 0 °C The mixture was stirred for 2 h and overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with 10% citric acid solution, 5% sodium hydrogen carbonate and saturated sodium chloride. The organic phase was dried and concentrated.

Yield: 23.8 g (95% of theory)

Analysis (Method E): R _t : 1.12 min, (M+H) ⁺ : 277

The reaction was carried out under a nitrogen atmosphere.

11.95 g of (R)-N-methoxy-5-oxo-l-((R)-1-phenylethyl)pyrrolidine-3-carboxamide at 100 mL at -10 °C In tetrahydrofuran. 30 mL of methylmagnesium bromide (white suspension, temperature +10 ° C) in diethyl ether solution was added over 15 minutes and the mixture was stirred at -10 ° C for 2 h, then warmed to ambient temperature. The mixture was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid, saturated sodium hydrogen carbonate and saturated sodium chloride. The organic phase was dried and concentrated.

Yield: 9.45 g (95% of theory)

The reaction was carried out under an argon atmosphere.

8.5 g (26.8 mmol) of (R)-4-ethenyl-1-((R)-1-phenylethyl)pyrrolidin-2-one in 40 mL of dichloromethane at -50 °C 40.5 mL (40.5 mmol) of lithium hydride 9-BBN in tetrahydrofuran was added dropwise. During the addition, the temperature rose to -30 °C. The mixture was then stirred at -45 ° C for 1 hour. Thereafter, phosphate buffer was added and the mixture was allowed to warm to ambient temperature, diluted with dichloromethane and extracted with water. The organic phase was dried over MgSO4, concentrated and purified EtOAc EtOAc

Yield: 2.60 g 3.1 (30% of theory)

Analysis (Method E): R _t : 1.08 min, (M+H) ⁺ :234

Yield: 2.60 g 3.2 (30% of theory)

Analysis (Method E): R _t : 1.12 min, (M+H) ⁺ :234

5-(Hydroxymethyl)piperidin-2-one ( 3.3 ) (for Example 5)

5-(Hydroxymethyl)piperidin-2-one ( 3.3 ) can be synthesized according to the following literature:

Lerchner, Andreas; Carreira, Erick M. Chemistry A European Journal (2006), 12(32), 8208-8219.

Synthesis of (R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one 3.4 For Examples 21, 27, 29-31, 33, 34, 37, 41-43, 47-49, 51, 53, 55, 56, 61, 63, 65, 66-69, 72, 73, 76, 78 , 81, 83, 85-91, 93-95, 99-102, 104, 105, 107, 109, 111, 112, 114-116, 118-120

Step 1: Synthesis of (1'R,3R/S)-1-(1'-(4-methoxyphenethyl)-5-oxo-3-pyrrolidinecarboxylic acid (diastereomers) mixture)

Heating 100 g of (R)-1-(4-methoxy-phenyl)-ethylamine and 95 g of itaconic acid in 0.5 L of 1-methyl-2-pyrrolidone to 80 ° C and Lasts for 1 hour. The solution was further stirred at 120 ° C for 4 hours. The reaction mixture was cooled to 25 ° C and poured into 1.5 L demineralized water. The precipitate was filtered and washed with demineralized water and Dry at 50 °C.

Yield: 195 g (quantitative yield), solid as a mixture of diastereomers

Analysis (Method G): R _t : 2.6 min and 2.7 min, (M+H) ⁺ :264

Prepared in a similar manner

(1'S,3R/S)-1-(1'-(4-Methoxyphenethyl)-5-oxo-3-pyrrolidinecarboxylic acid as a mixture of diastereomers

Analysis (Method G): R _t : 2.6 min and 2.7 min, (M+H) ⁺ :264

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

260 g of 1,1'-carbonyldiimidazole (CDI) was added to 285 g (1'R,3R/S)-1-(1'-(4-methoxyphenethyl)-5 at 20 °C - a solution of the pendant oxy-3-pyrrolidinecarboxylic acid (mixture of diastereomers) in 1.4 L of 2-methyltetrahydrofuran. The suspension was stirred at 20 ° C for 80 minutes. Add 235 mL of ethyl diiso Propylamine (DIPEA) and 130 g of N,O-dimethylhydroxylamine hydrochloride. The suspension was stirred at 20 ° C for 3 hours. Under cooling, 850 mL of 4 N hydrochloric acid was added. The organic phase was separated and 500 mL of 1 N hydrochloric acid was used. It was washed twice. The aqueous phase was extracted twice with 500 mL of ethyl acetate. The combined organic phases were dried over sodium sulfate.

Yield: 271 g (82% of theory) oily (R/S)-N-methoxy-5- Phenoxy-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-3-carboxamide (mixture of diastereomers)

Analysis (method H): R _t : 11.1 min (41 area%) and 13.8 min (59 area%), (M+H) ⁺ : 307

Step 3: Synthesis of (R/S)-4-ethenyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrole as a mixture of diastereomers Pyridin-2-one

530 mL of 3 M solution of methylmagnesium bromide in diethyl ether was slowly added to 271 g (R/S)-N-methoxy-5-sideoxy-1-[(S)-1-(4- Methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereomers) in a cooled solution of 1.4 L of 2-methyltetrahydrofuran to maintain the temperature at 0 ° C . After the addition was completed, the temperature was maintained at 0 ° C for 75 minutes, followed by warming to 20 ° C. The suspension was stirred at 20 ° C for 16 hours. Add 650 mL of 4 M hydrochloric acid under cooling. 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.

Yield: 188 g (81% of theory) of oily (R/S)-4-ethenyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]- Pyrrolidin-2-one (mixture of diastereomers)

Analysis (Method H): R _t : 7.4 min and 9.6 min, (M+H) ⁺ :262

Step 4: (R)-4-Ethyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrole Pyridin-2-one crystallized under alkali-induced epimerization conditions

103 g of diastereomeric mixture (R/S)-4-ethenyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrole at 25 °C The pyridine-2-one was dissolved in 155 mL of 1-butanol. 18 mL of benzyltrimethylammonium hydroxide (40% in methanol) was added. The solution was stirred at 25 ° C for 30 minutes. The solution was cooled to 0 °C. Start precipitation. The suspension was stirred at 0 ° C for 15 minutes. 100 mL of n-heptane was slowly added and the suspension was stirred at 0 ° C for 30 minutes. 100 mL of n-heptane was added portionwise in 4 portions and then the suspension was stirred at 0 ° C for 30 minutes. The precipitate was separated, washed with n-heptane and dried at 50 °C.

Yield: 77.1 g of a beige solid (75% of theory) with a diastereomer purity of ~95:5 (Method H).

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

Yield: 68.7 g (67% of theory) of colourless solids with &quot;

Analysis (method H): R _t : 6.8 min, (M+H) ⁺ : 262

Step 5: Synthesis of (R)-4-[(S)-1-hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2- ketone

50 g of (R)-4-ethinyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one in acetonitrile at 25 °C 2.4 g of dichloro-(pentamethylcyclopentadienyl)-ruthenium (III)-dimer and 2.8 g of (R,R)-N-(p-toluenesulfonyl)-1,2- were added to the solution. Diphenylethylenediamine [(R,R)-TsDPEN]. Cool the solution to -15 °C. At this temperature, a mixture of 22 mL of formic acid and 135 mL of triethylamine was added. The reaction mixture was stirred at -15 °C for 22 hours and then warmed to 20 °C. 230 mL of 4 molar hydrochloric acid was added under cooling. The aqueous phase was extracted three times with ethyl acetate. The organic phase is washed with diluted and concentrated brine and treated with activated carbon. The organic phase was dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 57.1 g, m.

For further purification, the crude product was crystallized from isopropyl acetate.

Yield: 37.8 g (75% of theory) of beige solid with diastereomer purity >99:1.

Analysis (Method I): R _t : 12.9 min, (M+H) ⁺ :264

The transfer hydrogenation reaction can also be carried out in 2-propanol at 20 °C.

Synthesis of ( R )-4-(hydroxymethyl)-1-(( R )-1-phenylethyl)pyrrolidin-2-one (for Examples 7, 9, 17, 19)

5 g of (1'R,3R)-1-(1'phenethyl)-5-oxo-3-pyrrolidinecarboxylic acid was dissolved in 50 mL of tetrahydrofuran, and then the solution was cooled to 0 °C. 16.5 mL of borane methyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 minutes and the reaction solution was slowly warmed to 25 ° C and stirred at 25 ° C for an additional 2 hours. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate. The aqueous phase was extracted with dichloromethane (×2) and dried over magnesium sulfate and concentrated.

Yield: 5.5 g (80% content, 94% of theory)

Analysis: HPLC-MS (Method D): R _t = 1.20 min (M+H) ⁺ =220

(R )-5-(hydroxymethyl)-3-[( R )-α-methylbenzyl-2-oxazolidinone (3.5) (for Examples 12, 13, 15, 16, 18, 20)

Purchased from Sigma-Aldrich

2-(hydroxymethyl)nicotinium amide, used in Examples 22, 24-26, 32, 35, 36, 39, 40, 44-46, 50, 52, 54, 57-60, 62, 64, 70 , 71, 74-75, 77, 79, 80, 82, 84, 92, 96-98, 103, 106, 108, 110, 113, 117

2-(Hydroxymethyl)nicotinamide can be synthesized according to the following literature:

Goto, Takehiko; Saito, Minoru; Sato, Ryu Bulletin of the Chemical Society of Japan , 1987 , 60, 4178-4180.

Synthesis of 1-chloromethyl-5,5-dimethyl-imidazolidin-2,4-dione for use in Example 23

0.69 ml of sulfinium chloride was added to a solution of 500 mg of 1-hydroxymethyl-5,5-dimethyl-imidazolidin-2,4-dione in 5 ml of DCM at 0 °C for 30 minutes. It was then stirred at 25 ° C for 16 hours. The mixture was evaporated to dryness and used as a crude product in Synthesis Example 23.

4.1.4. Synthesis Process 2 acid, Acid esters and stannanes 4 4.1.4.1. Synthesis R ² -Hal 4-bromo-2-methyl-1-(methylsulfonyl)benzene, used in Example 35

235 mg of sodium sulfite and 470 mg of NaHCO _{3 were} dissolved in 1.75 mL of water and heated to 75 °C. 500 mg of 4-bromo-2-methyl-benzenesulfonium chloride (gas formation) was added portionwise over 10 minutes and the mixture was stirred at 75 ° C for 1 hour. 387 mg of bromoacetic acid and 150 μL of water were added in small portions and the mixture was stirred at 105 ° C overnight. After cooling to 25 °C, the mixture was acidified to pH 1 using 4N HCl. The resulting precipitate was collected and washed with water to give 205 mg.

Analysis: HPLC-MS: Rt=0.73 (method X001_002) M+H=249/251

1-bromo-4-(trifluoromethylsulfonyl)benzene, used in Example 36

1-Bromo-4-(trifluoromethylsulfonyl)benzene is described in: Mongin, Olivier; Porres, Laurent; Charlot, Marina; Katan, Claudine; Blanchard-Desce, Mireille Chemistry-A European Journal , 2007, 13, Pp. 1481-1498.

N-(4-bromobenzyl)-N-ethylacetamide for use in Examples 50, 68

0.568 mL of N-ethylacetamide was dissolved in 20 mL of THF. 0.67 g of potassium t-butoxide was added and the mixture was stirred at 50 ° C for 20 minutes. Then, 1 g of 4-bromobenzyl bromide dissolved in 5 mL of THF was added and the suspension was stirred at 50 ° C for 2 hours. After cooling, ethyl acetate and water were added and the organic phase was extracted with water (1×), dried and evaporated. The product was purified via FCC (cyclohexane / ethyl acetate: &lt;RTI ID=0.0&gt;>&gt;

Analysis: HPLC-MS: Rt = 2.67 min (method C), M+H = 256

N-(4-bromobenzyl)-N-methylacetamide for use in Examples 51, 58

1.316 g of N-methylacetamide was dissolved in 60 mL of THF. 2.02 g of potassium t-butoxide was added and the mixture was stirred at 50 ° C for 20 minutes. Then, 3 g of 4-bromobenzyl bromide dissolved in 10 mL of THF was added and the mixture was stirred at 50 ° C for 2 hours. After cooling, ethyl acetate and water were added, and the organic phase was extracted with water (1×), and the solvent was evaporated to give 2.8 g of N-(4-bromophenylmethyl)-N-methylacetamide as an oil. Analysis: MS: M+H = 242.

4-bromo-1-(trifluoromethyl)-1H-pyrazole, used in example 87

Obtained as described in WO2008/95944.

7-Bromo-3-methylquinazolin-4(3H)-one, used in Examples 91, 92

7-Bromoquinazolin-4(3H)-one can be obtained as described in WO2010/146173.

400 mg of 7-bromoquinazolin-4(3H)-one was dissolved in DMF and 720 mg of CsCO ₃ and 130 μL of methyl iodide were added and the mixture was stirred at 25 ° C for 3 hours. An additional 50 μL of methyl iodide was added and stirred overnight at 25 °C. The mixture was filtered off and the mother liquor was diluted with DCM and extracted with water. The solvent was removed to give 7-bromo-3-methylquinazoline-4(3H)-one as a 490 mg solid.

Analysis: HPLC-MS: Rt = 0.66 min (method X001_004) M+H = 239/241

7-Bromo-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine, used in Example 103

7-Bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine can be obtained as follows: 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.

2.43 g of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine was dissolved in 4.055 g of formic acid and 3.2 mL of formaldehyde solution was added. The mixture was stirred at 70 ° C for 3.5 hours and continuously stirred at 25 ° C overnight. The mixture was concentrated and diluted with water and 10 N NaOH to adjust to basic pH. Followed by tert-butyl methyl ether (3 ×) and the mixture was extracted dried (Na ₂ SO ₄₎ organic phase was filtered and concentrated to an oil to give 2.48 g of 7-bromo-3-methyl-2,3,4,5-tetracarboxylic Hydrogen-1H-benzo[d]azepine.

Analysis: MS: M+H=240/242

6-bromo-2,4-dimethylquinazoline, used in example 107

N-(2-Ethyl-4-bromophenyl)acetamide can be obtained as follows: Woods, Keith W.; Fischer, John P.; Claiborne, Akiyo; Li, Tongmei; Thomas, Sheela A.; Zhu, Gui-Dong; Diebold, Robert B.; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Han, Edward K.; et al, Bioorganic & Medicinal Chemistry , 2006, 14, pp. 6832-6846.

415 mg of N-(2-acetamido-4-bromophenyl)acetamide and 0.624 g of ammonium acetate were dissolved in 5 mL of glacial acetic acid and heated at 100 ° C for 2 days. The solvent was removed and the residue was suspended in water and extracted with DCM. The organic phase was concentrated and purified via FCC _{(25 g SiO 2, DCM:} 30 MeOH 100:: 0 → 70), to give 90 mg as an oil 6-Bromo-2,4-dimethyl-quinazoline. Analysis: HPLC-MS: Rt = 1.26 min (Method V003_003), M+H = 237/239.

5-bromo-2-(difluoromethyl)pyridine, used in example 120

1 g of 5-bromo-pyridine-2-carbaldehyde was dissolved in 50 mL of DCM. The solution was cooled to -70 ° C, then 1.55 mL of diethylaminosulfur trifluoride was added dropwise over 20 minutes. The suspension was stirred at room temperature for 30 minutes, then 10 mL of water was added at 0 ° C, followed by the slow addition of 20 mL of saturated NaHCO ₃ (gas formation). The phases were separated and 4 mL of EtOAc (EtOAc m. HPLC-MS: Rt = 0.72 min (Method X001_004), M+H = 208 / 210.

4.1.4.2. Synthesis of compound of formula 4 (R ² -X) (Process 2) Synthesis of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)quinoline, used in Examples 33, 75

100 mg of 6-bromoquinacdine, 133 mg of bis-(pinacolyl)-diboron, 16 mg of Pd(II)Cl ₂ (PPh ₃ ) ₂ and 86 mg of potassium acetate were suspended in 1 mL of dioxane. The mixture was heated in a microwave at 100 ° C for 1 hour. After cooling, the mixture was diluted with DCM and extracted with water (2×). The organic phase was concentrated to give 200 mg (94%, 55%) of oily 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxabor. -2-yl)quinoline.

Analysis: HPLC-MS (method X001_002) Rt = 0.48 min, M+H = 188 or less The acid ester is synthesized in a similar manner and used without further purification:

‧4,4,5,5-tetramethyl-2-(3-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaboron For example 35. Reaction conditions: 1 h, 100 ° C. Yield: 74% (content 50%). Analysis: HPLC-MS: Rt = 0.42 min (method X001_003), M+H = 215 ( acid)

‧4,4,5,5-tetramethyl-2-(4-(trifluoromethylsulfonyl)phenyl)-1,3,2-dioxaboron For example 36.

Reaction conditions: 1 h, 100 ° C. Yield: 93% (content 45%). Analysis: HPLC-MS: Rt = 0.72 min (method X001_003)

‧N-ethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)benzyl)acetamide for use in Examples 50 and 68. Reaction conditions: 2 h, 100 ° C. Yield: 93% (content 55%). Analysis: HPLC-MS: Rt = 0.87 min (method X001_002), M+H = 304

‧N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)benzyl)acetamide for use in Examples 51,58. Reaction conditions: 2 h, 100 ° C. Yield: 94% (content 45%). Analysis: HPLC-MS: Rt = 0.83 min (method X001_002), M+H=290

‧6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-3,4-dihydroisoquinolin-1(2H)-one, used in Examples 52, 53. Reaction conditions: 1 h, 100 ° C. Yield: 87% (content 35%). Analysis: HPLC-MS: Rt = 0.81 min (method X001_002), M+H = 274

‧1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)benzyl)piperidin-2-one, used in Examples 54, 55. Reaction conditions: 1 h, 100 ° C. Yield: 92% (content 45%). Analysis: HPLC-MS: Rt = 0.87 min (method X001_003), M+H = 316

‧2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)imidazo[1,2-a]pyridine, used in Examples 60, 61. Reaction conditions: 6 h, 100 ° C. Yield: 98% (content 50%). Analysis: HPLC-MS: Rt = 0.40 min (method X001_004), M+H = 177 ( acid)

‧1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-yl)phenyl)cyclopropylamine, used in Examples 62, 86. Reaction conditions: 1 h, 100 ° C. Yield: 85% (content 40%). Analysis: HPLC-MS: Rt = 0.67 min (method X001_004), M+H=294 and 0.24 min M+H=212 ( acid).

‧6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one, used in Examples 63, 64. Reaction conditions: 1 h, 100 ° C. Yield: 87% (content 50%). Analysis: HPLC-MS: Rt = 0.67 min (method X001_004), M+H = 276

The following examples are similar to the examples but are not synthesized using microwaves:

‧6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine was used in Example 83. Reaction conditions: 1 h, 100 ° C. Yield: 94% (content 45%). Analysis: HPLC-MS: Rt = 0.49 min (method X001_004), M+H = 231 ( acid)

‧4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1-(trifluoromethyl)-1H-pyrazole, used in Example 87. Reaction conditions: 3.5 h, 100 ° C. Yield: 98% (content 55%). Analysis: HPLC-MS: Rt = 1.66 min (method V003_002), M+H = 263

‧2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridine, used in Example 90. Reaction conditions: 1 h, 100 ° C. Yield: 90% (content 40%). Analysis: HPLC-MS: Rt = 0.50 min (method X001_004), M+H = 194 ( acid)

‧3-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)quinazoline-4(3H)-one, used in Examples 91, 92. Reaction conditions: (1 h, 100 ° C). Yield: 98% (content 50%). HPLC-MS: Rt = 0.34 min (Method X001_004).

‧5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole, used in Example 93. Reaction conditions: 11 h, 100 ° C. Yield: 97% (content 60%). Analysis: HPLC-MS: Rt = 0.70 min (method X001_004), M+H = 313

‧1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-benzo[d]imidazole, used in Examples 94, 98. Reaction conditions: 1 h, 100 ° C. Yield: 96% (content 50%). Analysis: HPLC-MS: Rt = 0.58 min (method X001_004), M+H = 259

‧2-(Methylsulfonylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridine, used in Examples 95, 96. Reaction conditions: 1 h, 100 ° C. Yield: 98% (content 45%). Analysis: MS: M+H=298

‧2-(3-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron For example 102. Reaction conditions: 7 h, 100 ° C. Yield: 88% (content 55%). Analysis: HPLC-MS: Rt = 0.90 min (method X001_004), M+H = 303

‧3-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine, used in Example 103. Reaction conditions (1 h, 100 ° C). Yield: 88% (content 50%) HPLC-MS: Rt = 0.61 min (method X001_004), M+H=288

‧2-(Difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine, used in example 104

‧1,2-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-benzo[d]imidazole, used in Examples 105, 106. Reaction conditions (2 h, 100 ° C). Yield: 91% (content 50%). Analysis: HPLC-MS: Rt = 0.57 min (Method X001_004), M+H = 273.

‧2,4-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)quinazoline for use in Example 107. Reaction conditions (7 h, 100 ° C). Yield: 95% (content 40%). Analysis: HPLC-MS: Rt = 0.29 min (method X001_004)

‧2-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)pyridine, used in Example 120.

Reaction conditions (1 h, 100 ° C). Yield: 97% (content 38%). Analysis: HPLC-MS: Rt = 0.27 min (Method X001_004).

the following Acid, trifluoroborate or Acid esters are commercially available:

‧4-(Methanesulfonyl)benzene Acid, used in example 24

‧3,4-dimethoxyphenyl Acid, used in example 25

‧N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-pyridin-2-yl]-acetamide, used in Examples 26, 30

‧Quinoline-6- Acid, used in example 29

‧2-(trifluoromethyl)pyridine-5-yl Acid, used in example 31

‧3-fluoro-4-(methylsulfonyl)phenyl Acid, for example 32

‧1H-benzimidazole-5- Acid tetramethyl glycol ester, used in examples 39, 41

‧4-(4-morpholinylmethyl)phenyl Acid, used in examples 40, 43

‧1-methylcarbazole-6- Acid, used in examples 42, 44

‧4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)pyridin-2-yl]morpholine, used in Examples 45, 48

‧1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl-1H pyrazole, used in Examples 46, 47

‧6-(N-methylnonylcarbonyl)pyridine-3- Acid tetramethyl glycol ester, used in examples 56, 59

‧2-methoxy-5-pyridine Acid, for example 57

‧5-methoxy-3-pyridyl Acid, used in example 65

‧2-Isopropoxy-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine, used in example 66

‧3-Fluoro-2-, ethoxypyridine-5- Acid, used in example 67

‧2-ethoxy-5-pyridine Acid, used in example 69

‧2-(tetrahydropyran-4-yloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine, used in Examples 70, 72

‧2-methoxypyridine-4- Acid, used in examples 71, 73

‧Phenyl Acid, for example 74

‧(4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenyl]-methanone, used in examples 76, 80

‧1-ethyl-1H-pyrazole-4- Acid tetramethyl glycol ester, used in examples 77, 78

‧3-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-3H-imidazo[4,5-B]pyridine, used in example 79

‧1-Methyl-1H-benzimidazole-6- Acid, used in examples 81, 82

‧2-methylphenylpropene [D]thiazole-6-yl Acid tetramethyl glycol ester, used in examples 84, 85

‧5-Methoxypyridine-2-trifluoroborate, used in Examples 88, 97

‧2-T-butoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)pyridine, used in example 89

‧2-Methyl-1-H-benzimidazole-5- Acid tetramethyl glycol ester, used in examples 108, 109

‧6-(2,2,2-Trifluoroethoxy)pyridine-3-boronic acid tetramethyl glycol ester for use in Examples 110, 111

‧1,5-Dimethyl-1H-pyrazole-4- Acid tetramethyl glycol ester, used in example 112

‧1-isopropyl-1H-pyrazole-4- Acid tetramethyl glycol ester, used in examples 113, 115

‧1-propyl-1H-pyrazole-4- Acid tetramethyl glycol ester, used in examples 114, 117

‧1-methyl-3-trifluoromethylpyrazole-4- Acid, for example 116

‧2,3-Dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-pyridine, used in example 99

‧6-(4,4,5,5-tetramethyl-[1,3,2]diboron 2-yl)-3,4-dihydro-2H-piperido[2,3-b]pyridine, used in example 100

‧(4,4,5,5-tetramethyl-[1,3,2]diboron -2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, used in example 101

‧2-[4-(4,4,5,5-tetramethyl-[1,3,2]diboron acetate -2-yl)-pyrazol-1-yl]-ethyl ester, used in Examples 118, 119

4.2. Synthesis of Compounds of Formula 6 : Reactions of Scheme 1, 1, 2, 4, and 5

The first step was carried out according to the following literature: M. Tiano, P. Belmont J. Organic Chem. 2008 , 73 , 4101-4109. The second step was carried out according to N. Nishiwaki, S. Minakata, M. Komatsu, Y. Ohshiro, Synlett 1990 , 5 , 273-275.

Synthesis of 7-phenylquinolin-5-ol ( 6.1 ) for use in Example 1

Step 1 (=Reaction 1): 66 mg 3-ethenyl-2-bromopyridine, 56 μL phenylacetylene, 170 μL DIPEA, 22.5 mg triphenylphosphine palladium(II) chloride, 3 mg Cu (I) I was suspended in 1 mL of DMF under an argon atmosphere and stirred at 25 ° C for 16 hours. Extraction mixture was diluted with DCM and washed with dilute aqueous NH ₃ solution and brine. The organic phase was concentrated and the mixture was separated via flash chromatography (10 g SiO _2, cyclohexane → cyclohexane / ethyl acetate 70:30), to give 40 mg solid 1- (2- (phenylethynyl) pyridine - 3-yl) ethyl ketone. Analysis: HPLC-MS: Rt = 1.21 min (Method E), M+H = 222.

Step 2 (=Reaction 2): 30 mg of 1-(2-(phenylethynyl)pyridin-3-yl)ethanone was suspended in 350 μL of 1 N sulfuric acid and 2.147 mg of mercuric chloride and stirred at 60 ° C. 30 minutes. Then 1 mL of NaOH was added and the mixture was stirred at 25 ° C for an additional 1 hour. Water was added and the neutral pH was adjusted with NaHCO ₃ solution. The precipitate was filtered off and washed with water and dried, to give 30 mg solid 7-phenyl-quinolin-5-ol 6.1. Analysis: HPLC-MS: Rt = 1.18 min (Method D), M+H = 240.

Synthesis of 7-(3,4,5-trimethoxyphenyl)quinolin-5-ol ( 6.2 ) for use in Examples 2, 3, 4, 5, 9, 18, 23

Step 1 (=Reaction 1): 100 mg 3-ethenyl-2-bromopyridine, 140 mg 5-ethynyl-1,2,3-trimethoxybenzene 2.1 , 101 μL triethylamine, 17 mg three Phenylphosphine palladium(II) chloride, 1 mg Cu(I)I was suspended in 4 mL of THF under argon and stirred at 25 ° C for 1 hour. Aqueous NH ₃ solution and extracted with saturated NH ₄ Cl solution mixture was diluted with DCM and washed with dilute. The mixture was separated and the organic phase was concentrated FCC (10 g SiO _2, cyclohexane → cyclohexane / ethyl acetate 70:30) via a solid to give 90 mg 1- (2- (3,4,5-trimethoxyphenyl Phenylethynyl)pyridin-3-yl)ethanone. Analysis: HPLC-MS: Rt = 1.21 min (Method E) M+H = 312.

Step 2 (=Reaction 2): 90 mg of 1-(2-(3,4,5-trimethoxyphenylethynyl)pyridin-3-yl)ethanone was suspended in 750 μL of 1 N sulfuric acid and 4 mg of chlorine. The mercury was stirred and stirred at 60 ° C for 1 hour and 45 minutes. Then 2 mL of NaOH was added and the mixture was stirred at 25 ° C for an additional 1 hour. Water was added and the neutral pH was adjusted with a KHSO ₄ solution. The precipitate was filtered off and washed with water and dried, to give 80 mg solid 7- (3,4,5-trimethoxyphenyl) quinoline-5-ol 6.2. Analysis: HPLC-MS: Rt = 1.18 min (Method D), M+H = 330.

7-(pyridin-2-yl)quinolin-5-ol ( 6.3 ), used in Example 6

The 6-(pyridin-2-yl)quinolin-5-ol ( 6.3 ) of Example 6 was synthesized analogously to 6.2 .

Yield: 4% (in two steps), solid. Analysis: HPLC-MS: Rt = 0.78 min (Method E), M+H = 223.

Alternatively, 6.3 can be synthesized as follows: Godet, Thomas; Belmont, Philippe Synlett, 2008, 16 , 2513-2517

Step 1 (=Reaction 1): 750 mg 3-ethylindenyl-bromopyridine, 550 μL 2-ethynyl-pyridine, 765 μL triethylamine, 255 mg triphenylphosphine palladium(II) chloride, 17 mg Cu(I)I was suspended in 10 mL of DMF under an argon atmosphere and stirred at 25 ° C for 2 hours. Aqueous NH ₃ solution and extracted with saturated NH ₄ Cl solution mixture was diluted with DCM and washed with dilute. The mixture was separated and the organic phase was concentrated FCC (100 g SiO _2, cyclohexane → cyclohexane / ethyl acetate 35:65) via solid to give 455 mg of 1- (2- (pyridin-2-ylethynyl) pyridine 3-yl) ethyl ketone. Analysis: HPLC-MS: Rt = 0.88 min (Method E) M+H = 223.

Step 2 (=Reaction 4): Dissolve 455 mg of 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone in 10 mL of DCM, add 1.069 mL of DIPEA, and cool the solution to 0 °C. And 1.42 mL of tert-butyldimethylmethyltrifluoromethanesulfonate was slowly added. The mixture was stirred at 0 ° C for 30 minutes, warmed to 25 ° C and filtered through a cerium oxide plug (cyclohexane / ethyl acetate 1:1 + a small amount of TEA) to give 1.025 g of oily 3-(1-(3rd) Methyl dimethyl alkoxy) vinyl)-2-(pyridin-2-ylethynyl) pyridine. Analysis: HPLC-MS: Rt = 1.59 min (Method E) M+H = 337.

Step 3 (=Reaction 5): Dissolve 1.025 g of 3-(1-(t-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine in 100 mL of dimethyl 126 mg of silver trifluoromethanesulfonate was added to the oxyethane and stirred at 70 ° C for 7 hours. (3 ×) and the mixture was diluted with DCM and extracted with saturated NaHCO ₃ solution. The organic phase was dried (MgSO ₄₎ and concentrated in vacuo. The residual mixture was dissolved in 10 mL of THF, and 1.2 mL of butyl ammonium fluoride (1 N) in THF was added and the mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with DCM and extracted with water (1 ×) and the organic phase was concentrated via FCC in vacuo and: purification _{(100 g SiO 2, DCM →} DCM 93 7), to give 165 mg solid 7- (pyridin-2-yl) Quinoline-5-ol 6.3 . HPLC-MS: Rt = 0.78 min (Method E).

Synthesis of 7-(3,4-dimethoxyphenyl)quinolin-5-ol ( 6.4 ) for use in Examples 7, 8, 12

7-(3,4-Dimethoxyphenyl)quinolin-5-ol 6.4 of Examples 7, 8, 12 was synthesized analogously to 6.2 . Yield: 76% (two steps), solid. Analysis: HPLC-MS: Rt = 0.96 min (Method E), M+H = 300.

Synthesis of 7-(3,5-difluoro-4-methoxy-phenyl)-quinolin-5-ol ( 6.5 ) for use in Examples 14, 15, 17 and 38

7-(3,5-Difluoro-4-methoxy-phenyl)-quinolin-5-ol 6.5 of Examples 14, 15, 17 and 38 was synthesized analogously to 6.3 . Yield: 19% (in two steps) as a brown solid. Analysis: HPLC-MS: Rt = 1.13 (Method M), M+H = 288.

¹ H NMR (500 MHz, methanol - d 4) δ. ppm 4.03 (3H, s), 7.13 (1 H, d, J = 1.68 Hz), 7.36-7.43 (2 H, m), 7.48 (1 H) , dd, J = 8.39, 4.43 Hz), 7.68 (1 H, s), 8.64 - 8.67 (1 H, m), 8.83 (1 H, dd, J = 4.42, 1.68 Hz)

7-(4-Isopropoxy-3-methoxy-phenyl)-quinolin-5-ol ( 6.6 ) for Examples 10, 11, 13 and 16

7-(4-Isopropoxy-3-methoxy-phenyl)-quinolin-5-ol 6.6 of Examples 10, 11, 13 and 16 was synthesized analogously to 6.3 . Yield: 27% (in two steps) as a brown solid. Analysis: HPLC-MS: Rt = 1.54 min (Method B), M+H = 310.

7-(6-Methoxypyridin-3-yl)quinolin-5-ol ( 6.7 ), used in Examples 20, 21

The 7-(6-methoxypyridin-3-yl)quinolin-5-ol of Examples 20 and 21 was synthesized analogously to 6.2 . Yield: 73% (in two steps) as a solid. Analysis: HPLC-MS: Rt = 0.98 min (Method M), M+H = 253.

[2,7']biquinolinyl-5'-ol ( 6.8 ), used in example 34

The [2,7']biquinolinyl-5'-ol ( 6.8 ) of Example 34 was synthesized in analogy to 6.3 using the method of Godet, Thomas; Belmont, Philippe Synlett, 2008, 16 , 2513-2517.

Yield: 43% (three steps), as a brown solid. Analysis: HPLC-MS: Rt = 1.02 min (Method M), M+H = 272.

4.3. Patent Example of Synthesizing Equation 7 and Formula 1 Synthesis of (R)-4-((R)-1-(7-phenylquinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 1)

30 mg of 7-phenylquinolin-5-ol, 32.5 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidine 2-ketone and 150 mg of triphenylphosphine were dissolved in 3 mL of DCM. 125.5 mg of ditributyl azodicarboxylate (DBAD) was added and the mixture was stirred at room temperature for 21 hours. The mixture was diluted with DCM and extracted with 1 N NaOH and water. The organic phase was concentrated in vacuo and purified via flash column chromatography (FCC) (20 SiO _2; cyclohexane → cyclohexane: ethyl acetate: MeOH 58: 40: 2) purified. The fractions containing the product were concentrated, dissolved in 2 mL of trifluoroacetic acid (TFA) and heated in a microwave at 150 °C for 45 min. The mixture was purified by rpHPLC (XbridgeC18, MeOH / water, TFA), to give Example 1 8 mg of solid after lyophilization.

Analysis: HPLC-MS: Rt = 1.21 min (Method D), M+H = 333.

Synthesis of (R)-4-((R)-1-(7-(3,4,5-trimethoxyphenyl)quinolin-5-yloxy)ethyl)pyrrolidin-2-one (example) 2)

80 mg of 7-(3,4,5-trimethoxyphenyl)quinolin-5-ol, 62 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R) )-1-Phenylethyl)pyrrolidin-2-one and 142 mg of triphenylphosphine were dissolved in 5 mL of DCM. 125.5 mg DBAD was added and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with DCM and extracted with 1 N NaOH and water. The organic phase was concentrated in vacuo and (10 SiO _2, cyclohexane → cyclohexane: ethyl acetate: MeOH 58: 40: 2) via flash chromatography. The product-containing fractions were concentrated, dissolved in 1.5 mL of TFA and heated in a microwave at 150 °C for 75 minutes. The mixture was purified by HPLC (XbridgeC18, MeOH / water, TFA), to give Example 2 21 mg of solid after lyophilization.

Analysis: HPLC-MS: Rt = 1.20 min (Method D), M+H = 423.

¹ H-NMR (400 MHz, DMSO-d6): δ = 9.05 (1H, d), 8.75 (1H, d), 7.78 (1H, s), 7.68 (1H, dd), 7.60 (1H, s), 7.45 (1H, s), 7.10 (2H, s), 5.05 (1H, m), 3.95 (6H, s), 3.77 (3H, s), 3.40 (1H, t), 3.25-3.05 (1H, m) , 2.85 (1H, m), 2.45-2.22 (2H, m), 1.35 (3H, d) ppm.

The following examples were synthesized in a manner similar to Examples 1 and 2.

Synthesis of 5-methoxy-7-(3,4,5-trimethoxyphenyl)quinoline (Example 3)

100 mg of 7-(3,4,5-trimethoxyphenyl)quinolin-5-ol, 42 μL of MeOH and 480 mg of triphenylphosphine were dissolved in 5 mL of DCM. Add 435 mg DBAD and the mixture was stirred at room temperature for 3 days. The mixture was diluted with DCM and extracted with 1 N NaOH and water. The organic phase was concentrated in vacuo and purified with EtOAc EtOAc EtOAc EtOAc

Analysis: HPLC-MS: Rt = 1.11 min (Method E), M+H = 326.

The following examples were synthesized in a manner similar to Example 3.

Synthesis of (R)-4-((R)-1-(7-(pyridin-2-yl)quinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 6)

20 mg of 7-(pyridin-2-yl)quinolin-5-ol, 30 mg ((R)-4-((S)-1-hydroxyethyl)-1-((S)-1-( 4-Methoxyphenyl)ethyl)pyrrolidin-2-one and 50 mg of triphenylphosphine were dissolved in 2 mL of DCM. 45 mg of DBAD was added and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM and used 1 N NaOH and water extraction. The organic phase was concentrated in vacuo and dissolved in EtOAc EtOAc EtOAc (EtOAc) Example 6 of a 21 mg solid.

Analysis: HPLC-MS: Rt = 0.9 min (Method E), M+H = 334.

The following examples were synthesized in a manner similar to Example 6.

Synthesis of (R)-5-[7-(4-hydroxy-3-methoxy-phenyl)-quinolin-5-yloxymethyl]-oxazolidin-2-one (Example 13)

Add 0.085 ml of diisopropyl azodicarboxylate (DIAD) in THF (2 ml) to 150 mg of 7-(4-isopropoxy-3-methoxy-phenyl)-quinoline-5 - alcohol, 128 mg of (R)-5-hydroxymethyl-3-((R)-1-phenyl-ethyl)-oxazolidin-2-one and 161 mg of PS-triphenylphosphine in THF (15 The mixture in mL) was stirred at room temperature for 14 hours. An additional 161 mg of PS-triphenylphosphine and 0.085 ml of DIAD were added and stirring was continued for a further 4 hours. The mixture was filtered, then diluted with EtOAc and extracted with water. The organic phase was concentrated in vacuo and taken up in 1 mL TFA and heated in a microwave for 30 min. Via SiO ₂ using _{1-10% 7N NH 3 / MeOH:} DCM eluting mixture was purified to give Example 13 17 mg of solid.

Analysis: HPLC-MS: Rt = 2.61 (method A), M+H = 367

The following examples were synthesized in a manner similar to Example 13.

Synthesis of (R)-5-((7-(4-isopropoxy-3-methoxyphenyl)quinolin-5-yloxy)methyl)oxazolidin-2-one (Example 16)

59 mg (R)-5-[7-(4-hydroxy-3-methoxy-phenyl)-quinolin-5-yloxymethyl]-oxazolidin-2-one (Example 13), A mixture of 19.3 μl of 2-iodopropane and 44 mg of potassium carbonate in DMF (10 ml) was stirred at 50 ° C for 16 hours. The mixture was poured into EtOAc and washed with water, then brine, and dried through Na ₂ SO _4. Purification by SiO ₂ FCC eluting with EtOAc-MeOH 100:0 to 95:5 afforded 56 mg (85%) of (R)-5-[7-(4-isopropoxy- 3-Methoxy-phenyl)-quinolin-5-yloxymethyl]-oxazolidin-2-one (Example 16).

Analytical HPLC-MS: Rt = 1.09 min (Method M), M+H = 409.

Synthesis of (R)-4-{(R)-1-[7-(6-methoxy-pyridin-3-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2- Ketone (Example 21)

1020 mg of 7-(6-methoxy-pyridin-3-yl)-quinolin-5-ol 6.7 , 1171 mg of (R)-4-((S)-1-hydroxy-ethyl)-1- [(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-one 3.4 and 1590 mg of triphenylphosphine were dissolved in 20 mL of THF. 1.19 ml of DIAD was added and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and _{SiO 2 (1-5% MeOH: DCM} ) via purification, to give 1300 mg (1S, 4R) -1- [1- (4- methoxy - phenyl) - ethyl] -4 -{(R)-1-[7-(6-Methoxy-pyridin-3-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one. 727 mg of this product was dissolved in acetonitrile (7 ml) at 0 °C and a solution of 2339 mg of cerium ammonium nitrate (CAN) in water (7 ml) was added. The mixture was stirred for 6 hours and then poured into saturated NaHCO ₃ (150 ml), diluted with water, then extracted with DCM. Silicon dioxide via plug, using _{1-3% 2 N MeOH / NH 3} : DCM eluting with 26% yield to give 137 mg of a pale brown foam desired product.

Analysis: HPLC-MS: Rt = 2.94 min (method A), M+H = 364

Synthesis of 2-((7-bromoquinolin-5-yloxy)methyl)nicotinium amide (Example 22)

100 mg of 7-bromo-quinolin-5-ol, 77.5 mg of 2-(hydroxymethyl)nicotinamide 3.7 , 233.5 mg of triphenylphosphine and 205 mg of azodicarboxylate at room temperature under argon Dibutyl butyl ester (DBAD) was dissolved in 2.5 mL DCM and 7.5 mL THF. After 14 hours, the precipitate was collected and dried. The mother liquor was concentrated again and the precipitate formed was collected to afford 72 mg of Example 22.

Analysis: HPLC-MS: Rt = 0.48 min (method X001_002), M+H = 358/360.

¹ H-NMR (400 MHz, DMSO-d6): δ = 8.91 (1H, d), 8.65 (1H, d), 8.48 (1H, d), 8.05 (1H, s), 7.95 (1H, d), 7.80 (1H, s), 6.65-7.50 (3H, m), 7.31 (1H, s), 5.58 (2H, s) ppm.

Synthesis of 5,5-dimethyl-1-[7-(3,4,5-trimethoxy-phenyl)-quinolin-5-yloxymethyl]-imidazolidin-2,4-dione (Example 23)

150 mg of 7-(3,4,5-trimethoxy-phenyl)-quinolin-4-ol (6.2), 65 mg of 1-chloromethyl-5,5-dimethyl-imidazolidin-2 4-Dione (3.7) and 51 mg of potassium carbonate were dissolved in 1.5 ml of DMF and heated at 70 ° C for 2 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over magnesium sulfates

By HPLC purification, 33 mg of 5,5-dimethyl-1-[7-(3,4,5-trimethoxy-phenyl)-quinolin-5-yloxymethyl was obtained in 21% yield. Base]-imidazolium-2,4-dione.

HPLC-MS: Rt = 3.46 min (Method A) m.

Synthesis of 2-((7-(4-(methylsulfonyl)phenyl)quinolin-5-yloxy)methyl)nicotinium amide according to Scheme 2 (Example 24)

50 mg of Example 22, 33.5 mg of 4-methanesulfonyl)benzene Acid, 17.5 mg of hydrazine-(triphenylphosphine)-palladium (0), 140 μL of 2 N aqueous sodium carbonate solution and 0.5 mL of dioxane were heated in a microwave (MW) at 140 ° C for 15 minutes. The mixture was purified by EtOAc (EtOAc EtOAc EtOAc)

HPLC-MS: Rt = 0.49 min (Method X001_002), M+H=434.

¹ H-NMR (400 MHz, DMSO-d6): δ=9.05 (1H, d), 8.70-8.64 (2H, m), 8.15 (2H, d), 8.10-8.02 (3H, m), 8.0-7.9 (2H, m), 7.65-7.55 (3H, m), 7.52 (1H, dd), 5.7 (2H, s), 3.30 (3H, s) ppm.

The following examples were synthesized in a manner similar to Example 24.

Synthesis of (R)-4-((R)-1-(7-bromoquinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 27)

100 mg of 7-bromo-quinolin-5-ol, 234 mg of triphenylphosphine and 133 mg of (R)-4-((S)-1-hydroxyethyl)-1-((S)-1-( 4-Methoxyphenyl)ethyl)pyrrolidin-2-one was dissolved in 2.5 mL of DCM and 7.5 mL of THF. 205 mg DBAD (slightly exothermic) was added and the mixture was stirred at room temperature overnight. An additional 234 mg of triphenylphosphine and 205 mg of DBAD were then added and the mixture was stirred for a weekend. The mixture was diluted with DCM and extracted with 1N EtOAc & water and EtOAc.

The remaining material was treated with 2 mL of trifluoroacetic acid (TFA) and heated in a microwave at <RTI ID=0.0></RTI><RTIgt; The mixture was concentrated and treated with HPLC (XbridgeC18, MeOH / water, TFA) to give 165 mg as a yellow solid, silicon dioxide by _{FCC (20 g SiO 2; DCM} → DCM: MeOH 90:10) to give 90 mg solid Example 27. Analysis: HPLC-MS: Rt = 0.56 min (Method X001_002), M+H = 335/337.

¹ H-NMR (400 MHz, DMSO-d6): δ = 8.95 (1H, d), 8.50 (1H, d), 7.80 (1H, s), 7.57 (2H, m), 7.30 (1H, s), 4.85 (1H, m), 3.40 (1H, t), 3.15-3.10 (1H, m), 2.82 (1H, m), 2.40-2.22 (2H, m), 1.32 (3H, d) ppm.

Synthesis of 2-(1-((7-(3,4,5-trimethoxyphenyl)quinolin-5-yloxy)methyl)cyclopropyl)acetamide (Example 28)

Add NaOH (1 M, 0.37 mL) to 125 mg {1-[7-(3,4,5-trimethoxy-phenyl)-quinolin-5-yloxymethyl in air at 0 °C A solution of the group of cyclopropyl}-acetonitrile (Example 38) in EtOH (2 ml) was then added with hydrogen peroxide (30% aqueous solution, approximately 50 mg). The mixture was stirred at 0 ° C for 1 hour, then warmed to room temperature and stirred at this temperature for 48 hours. By the addition of saturated Na ₂ S ₂ O ₃ solution and water and then the reaction was quenched with CH ₂ Cl ₂ (3 ×) and extracted with. Washed with brine the combined extracts were dried (MgSO _4), filtered and concentrated.

Purification by HPLC gave 8.2 mg of 2-{1-[7-(3,4,5-trimethoxy-phenyl)-quinolin-5-yloxymethyl]-cyclopropyl} as a colorless solid. - Acetamide.

HPLC-MS: Rt = 3.05 min (Method A).

Synthesis of (R)-4-((R)-1-(6,7'-biquinoline-5'-yloxy)ethyl)pyrrolidin-2-one (Example 29)

40 mg of Example 27, 31 mg of quinoline-6- Acid, 14 mg of hydrazine-(triphenylphosphine)-palladium (0), 120 μL of 2 N aqueous sodium carbonate solution and 0.5 mL of dioxane were heated in a microwave (MW) at 140 ° C for 15 minutes. The mixture was purified by EtOAc (EtOAc EtOAc)

HPLC-MS: Rt = 0.54 min (Method X001_002), M+H=384.

¹ H-NMR (400 MHz, DMSO-d6): δ = 9.05 (2H, d), 8.72 (2H, dd), 7.60 (1H, s), 8.40 (1H, d), 8.25 (1H, d), 8.05 (1H, s), 7.75 (1H, dd), 7.7-7.62 (2H, m), 7.6 (1H, s), 5.08 (1H, m), 3.48 (1H, t), 3.20 (1H, dd) , 2.90 (1H, m), 2.45-2.3 (2H, m), 1.4 (3H, d) ppm.

The following examples were synthesized in a manner similar to Example 29.

Synthesis of (R)-4-((R)-1-(7-iodoquinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 37)

50 mg of Example 27 and 9 mg of copper (I) iodide were suspended in 300 μL of dioxane under argon. 9.6 μL of N,N' dimethylethylenediamine and 45 mg of sodium iodide were added and the mixture was heated to 110 ° C over a weekend. The mixture was diluted with EtOAc EtOAc (EtOAc m.

Analysis: HPLC-MS: Rt = 1.25 min (Method V003_003), M+H = 383.

Synthesis of (R)-4-{(R)-1-[7-(5-trifluoromethyl-pyridin-2-yl)-quinolin-5-yloxy Base]-ethyl}-pyrrolidin-2-one (Example 49)

Step 1 (=Reaction 9): 1 g of (R)-4-[(R)-1-(7-bromo-quinolin-5-yl-oxy)-ethyl]-pyrrolidin-2-one (Example 27), 833 mg of bis(pinacolyl)diboron, 105 mg of bis(triphenylphosphine)palladium(II) chloride and 878 mg of potassium acetate suspended in 10 ml of dioxane and heated at 80 °C 2 hours. The mixture was allowed to cool and then partitioned between DCM and water. The organic layer was separated, dried through Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut 7-(4,4,5,5-tetramethyl-[1,3,2]diboron -2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one.

Analytical HPLC-MS: Rt = 1.05 min (Method B), M+H = 301.

Step 2: 500 mg of (R)-4-{(R)-1-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one, 325 mg 2-bromo-5-trifluoromethyl-pyridine, 46 mg bis(triphenylphosphine) Palladium(II) chloride, 1.96 mL of 2 N aqueous sodium carbonate solution and 10 mL of DMF were heated at 80 ° C for 18 hours. The reaction was partitioned between DCM and NaHCO ₃ (saturated solution), the organic layer was then separated, dried through Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) elute 2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one.

HPLC-MS: Rt = 3.55 min (Method A).

¹ H NMR (500 MHz, methanol - d 4) δ ppm 1.55 (3H, d, J = 6.15 Hz), 2.57 (1 H, dd, J = 17.18, 6.62 Hz), 2.69 (1 H, dd, J =17.18, 9.46 Hz), 3.01-3.13 (1 H, m), 3.40 (1 H, dd, J = 10.17, 5.75 Hz), 3.63-3.74 (1 H, m), 5.17 (1 H, quin, J = 5.95 Hz), 8.07 (1 H, t, J = 6.94 Hz), 8.14 - 8.21 (1 H, m), 8.33 - 8.40 (1 H, m), 8.40 - 8.47 (1 H, m), 8.50 ( 1 H, s), 9.08-9.19 (1 H, m), 9.21-9.28 (1 H, m), 9.33-9.40 (1 H, m).

Synthesis of (R)-4-((R)-1-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)quinolin-5-yloxy)ethyl)pyrrolidine -2-ketone (Example 101)

150 mg of Example 27, 241 mg of 7-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(II) chloride, 671 μL 2 N sodium carbonate aqueous solution and 2 mL DMF was heated at 90 ° C for 2 hours. The mixture was partitioned and the organic layer was separated, dried (Na ₂ SO _4), filtered, and concentrated in vacuo and partitioned between DCM and NaHCO ₃ (saturated solution). The residue was dissolved in 10 mL of 25% EtOAc (EtOAc)EtOAc. Purification by flash chromatography using 0-25% MeOH / EtOAc (EtOAc) 3,4-Tetrahydro-isoquinolin-7-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one.

HPLC-MS: Rt = 2.28 min (Method A) m.

Synthesis of (R)-4-((R)-1-(7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)quinolin-5-yloxy)ethyl)pyrrole Pyridin-2-one (Example 118)

21 mg of pure acetic acid 2-(4-{5-[(R)-1-((R)-5-o-oxy-pyrrolidin-3-yl)-ethoxy]-quinolin-7-yl) The mixture of the 1:1 mixture of the compound of Example 119 and the compound of Example 119 was dissolved in 3 ml of MeCN and 1 ml of 1 N NaOH (aq). The mixture was stirred at 25 deg.] C overnight, then partitioned between DCM and NaHCO ₃ (saturated aqueous solution) and the organic layer was separated, dried (Na ₂ SO _4), filtered and concentrated in vacuo. Purification by reverse phase LC gave 26 mg (71%).

HPLC-MS: Rt = 2.37 min (Method A).

4.5 Chromatography (HPLC-MS method)

The example compounds prepared according to the foregoing synthetic scheme are characterized by the following chromatography, which, if performed, are individually designated in Table 6.

Method A:

Waters ZQ or Waters QTof micro, Agilent G1312A HPLC Pump, Waters 2996 PDA Detector, Waters 2420 Assisted Detector

Dissolve A: water (0.1% formic acid)

Dissolving agent B: acetonitrile (0.1% formic acid)

The stationary phase used was Waters Atlantis dC18 2.1 mm x 100 mm, 3 μm, injection volume 3 μL (column temperature: constant at 40 ° C).

The detector is in the 215 nm wavelength range (nominal).

Method B:

Shimadzu LCMS2010EV, Shimadzu LC-20AB pump, SPD-M20A PDA detector, PL2100 auxiliary detector

Dissolve A: water (0.1% formic acid)

Dissolving agent B: acetonitrile (0.1% formic acid)

The stationary phase used was Waters Atlantis dC18 2.1 mm × 50 mm, 3 Μm, injection volume 3 μL (column temperature: constant at 40 ° C).

The detector is in the 215 nm wavelength range (nominal).

Method C:

Waters ZQ2000; Waters 1515 pump, Waters PDA 996 detector, Waters 2747 injector

Mobile phase: A Wasser + 0.1% formic acid

B acetonitrile + 0.1% formic acid

gradient:

Stationary Phase: Phase: X-terra ^TM MS C18 2,5 μm 4,6 mm×30 mm

Column temperature: about 25 ° C

Diode array detection is performed in the 210-400 nm wavelength range.

Method D

Waters ZMD, Alliance 2690/2695 HPLC, Waters 996/2996 Diode Array Detector

The mobile phase used is:

A: Water containing 0.10% TFA

B: Acetonitrile containing 0.10% TFA

The stationary phase is a Merck Chromolith ^TM Flash RP-18e column, 3 mm × 100 mm (column temperature: constant at 25 ℃).

Diode array detection is performed in the 210-400 nm wavelength range.

Method E

Waters ZMD, Alliance 2690/2695 HPLC, Waters 996/2996 Diode Array Detector

The mobile phase used is:

A: Water containing 0.10% TFA

D: methanol containing 0.10% TFA

The stationary phase is a ^{Waters XBridge TM C18 3.5 μM, 4.6} × 20 mm IS TM ( column temperature: constant at 40 ℃).

Diode array detection is performed in the 210-400 nm wavelength range.

Method G:

Dissolving agent A: water / 0.2% KH ₂ PO ₄ pH=3

Dissolving agent B: acetonitrile

The stationary phase used was Inertsil C8-3 (GL Sciences), 5 μm; size: 100 x 4.0 mm, (column temperature: constant at 30 ° C).

Detection: UV 220 nm

Method H:

Eluent A: Hexane

Dissolving agent B: 2-propanol

The stationary phase used was Chiralpak AD-H (Daicel), 5 μm; size: 150 × 4.6 mm, (column temperature: constant at 10 ° C).

Detection: DAD 225 nm

Method I:

Eluent A: Hexane

Dissolving agent B: 2-propanol

The stationary phase used was Chiralpak AD-H (Daicel), 5 μm; size: 150 × 4.6 mm, (column temperature: constant at 10 ° C).

Detection: DAD 225 nm

Method M:

Shimadzu LCMS2010EV, Shimadzu LC-20AB pump, SPD-M20A PDA detector, PL2100 auxiliary detector

Dissolve A: water (0.1% formic acid)

Dissolving agent B: acetonitrile (0.1% formic acid)

The stationary phase used was Waters Atlantis dC18 2.1 mm x 50 mm, 3 μm, injection volume 3 μL (column temperature: constant at 40 ° C).

The detector is in the 215 nm wavelength range (nominal).

Method XBM:

Waters ZMD, Alliance 2690/2695 HPLC, Waters 996/2996 Diode Array Detector

The mobile phase used is:

C: water containing 0.10% NH ₃

D: methanol

The stationary phase is a ^{Waters XBridge TM C18 3.5 μm, 4.6} × 20 mm IS TM ( column temperature: constant at 40 ℃).

Diode array detection is performed in the 210-400 nm wavelength range.

Method X001_002:

Diode array detection is performed in the 210-400 nm wavelength range.

Method X001_003:

Diode array detection is performed in the 210-400 nm wavelength range.

Method X001_004:

Diode array detection is performed in the 210-400 nm wavelength range.

Method V003_002:

Diode array detection is performed in the 210-400 nm wavelength range.

Method V003_003:

Diode array detection is performed in the 210-400 nm wavelength range.

4.6 NMR method Bruker DRX 500 MHz NMR configuration:

Efficient digital NMR spectrometer, 2-channel micro-rack console and Windows XP host workstation running Topspin version 1.3.

Equipped with:

‧Oxford Instruments magnet 11.74 Tesla (500 MHz proton resonance frequency)

‧B-VT 3000 temperature controller

‧GRASP II gradient spectroscopy accessory for fast acquisition of 2D pulse sequences

‧ 氘 lock switch for gradient shimming

‧ 5 mm wideband inverse geometric double resonance probe (BBI ATMA) with automatic tuning and matching. ¹ H observation is allowed by pulse/decoupling of the nucleus in the frequency range of ¹⁵ N and ³¹ P with a ² H-lock and shielded z-axis gradient coil.

Bruker DPX 250MHz NMR configuration

Efficient single-rack Bruker 250 MHz digital two-channel NMR spectrometer console and Windows XP host workstation running Xwin NMR version 3.5.

Equipped with:

‧Oxford Instruments magnet 5.87 Tesla (250 MHz proton resonance frequency)

‧B-VT 3300 Variable Temperature Controller Unit

‧ Quad core (QNP) switchable probes for ¹ H, ¹³ C, ¹⁹ F and ³¹ P observations with ² H lock

Bruker DPX 400 MHz NMR configuration

Efficient digital NMR spectrometer controlled by Windows XP workstation running Topspin 1.3p18

Equipped with:

‧Bruker UltraShield Plus magnet 9.40 Tesla (400 MHz proton resonance frequency)

‧B-VT 3300 temperature controller

‧GRASP II gradient spectroscopy accessory for fast acquisition of 2D pulse sequences

‧ 氘 lock switch for gradient shimming

‧5 mm selective reverse probe (SEI). ¹ H observation is allowed by ¹³ C pulse/decoupling with a ² H-lock and shielded z-axis gradient coil.

5. Examples

The following examples were prepared analogously to the above synthetic methods. Such compounds are useful as inhibitors of SYK and IC ₅₀ values of less than or equal to 1 μmol. Examples of materials of the individual IC ₅₀ values shown in Table 1 below and measured experimentally as follows:

Syk kinase test

Recombinant human Syk (amino acid 342-635) was expressed as a fusion protein with an N-terminal GST tag, purified by affinity and tested at -80 ° C in assay buffer (25 mM HEPES pH 7.5; 25 mM MgCl ₂ ;5 mM MnCl ₂ ; 50 mM KCl; 0.2% BSA or 0.2% HSA; 0.01% CHAPS; 100 μM Na ₃ VO ₄ ; 0.5 mM DTT) and 10% glycerol were deep frozen at a concentration of about 50-100 μM until use.

Determination of the catalytic activity of GST-Syk kinase fusion proteins; Kinase Glo ^® using fluorescent kinase assay (V6712 Promega). In this homogeneity test, the amount of ATP remaining after the kinase reaction was quantified by fluorescence using a luciferin-luciferase reaction. The resulting fluorescent signal correlates with the amount of ATP still present and is therefore inversely related to the activity of the protein kinase.

method

Test compounds were dissolved in 100% DMSO at a concentration of 10 mM and diluted to a concentration of 1 mM in DMSO. All other dilutions of the material were performed in test buffer containing 7.5% DMSO until a concentration 7.5 times higher than the final test concentration (final concentration of compound: 30 μM to 1 nM) was reached. A 2 μl aliquot of these dilutions was transferred into a 384-well Optiplate (Perkin Elmer, #6007290). GST-Syk was diluted to 6.0 nM and 10 μl of this dilution in assay buffer for kinase assay (Syk final concentration = 4 nM, total volume 15 μl). After incubation for 15 minutes at room temperature, add 750 nM ATP and 100 μg/ml poly(L-glutamic acid L-tyrosine 4:1) (Fluka # 81357) to each well for 3 μl in assay buffer. The mixture was incubated for an additional 60 minutes at room temperature.

The positive control is the reaction mixture that does not contain the test substance; the negative control (blank) is the reaction mixture that does not contain the kinase.

After 60 minutes, each well was added 10 μl kinase solution -Glo ^® (Promega, Catalog No .: # V6712) (warmed to room temperature) and the incubation was continued for another 15 minutes. The plates were read using a microplate scintillation and fluorescence counter (Canberra Packard GmbH).

Data evaluation and calculation:

The output file of the "Counter" is a text file containing the hole number and the measured count in both columns. For data evaluation and calculation, the measurement of the negative control was set to 100% inhibition and the measurement of the positive control was set to 0% inhibition. Based on this value, the "MS-Excel-VB Macro" is used to calculate the eigenvalue percentage for measuring the concentration of each substance. Typically, the calculated percent inhibition value is between 100% and 0% inhibition, but may also be outside of these limits in individual cases. Use "GraphPadPrism" software (Version 5) (GraphPad Software Inc.) is calculated from the percent inhibition values of IC ₅₀ values.

The following examples of Formula 1 having the following properties

Prepared according to the above synthetic method, wherein * represents the position at which each of the groups R ¹ and R ² is attached to the rest of the molecule of Formula 1 :

6. Indications

As has been found, the compounds of formula 1 are characterized by a series of applications in the therapeutic field. These applications, which are specifically mentioned, are the use of the compounds of the formula 1 according to the invention, preferably as SYK inhibitors, based on their pharmaceutically active activity. Examples include respiratory conditions, allergic diseases, osteoporosis, gastrointestinal diseases or conditions, immune or autoimmune diseases, allergic diseases, inflammatory diseases (such as joints, skin and eye inflammatory diseases) and peripheral or central nervous system diseases .

Particular mention should be made of the prevention and treatment of respiratory and pulmonary diseases associated with increased mucus production, inflammation and/or obstructive disease. Examples of such diseases include asthma; childhood asthma; ARDS (Adult Respiratory Syndrome); acute, allergic or chronic bronchitis; autoimmune hemolytic anemia; chronic obstructive bronchitis (COPD) (including treatment of rhinovirus induction) Cough; allergic rhinitis or sinusitis; allergic rhinoconjunctivitis; chronic rhinitis or sinusitis; alveolitis; farmer's lung; respiratory tract sensitivity; infectious bronchitis or pneumonia; bronchiectasis; Bronchial edema; pulmonary edema; pneumonia or interstitial pneumonia caused by various causes (such as inhalation, inhalation of toxic gases or bronchitis); caused by cardiac insufficiency, radiation, chemotherapy, cystic fibrosis or mucoidosis Pneumonia or interstitial pneumonia; α1-antitrypsin deficiency, atherosclerosis and pulmonary hypertension.

The compounds of the invention are also preferably suitable for the treatment of allergic diseases such as allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, and contact dermatitis, urticaria/angioedema and atopic dermatitis.

Preferably, reference should also be made to the treatment of gastrointestinal inflammatory diseases. Examples of such diseases are Crohn's disease and ulcerative colitis.

The compounds of the invention are also preferably suitable for the treatment of joint inflammatory diseases or inflammatory diseases of the skin and eyes. Examples of such diseases are rheumatoid arthritis, antibody-based spheroid nephritis, psoriasis, Kawasaki syndrome, celiac disease (oral diarrhea), atherosclerosis (see Hilgendorf et al., Arterioscler Thromb Vasc Biol. 2011, Vol. 31; pp. 1991-1999) and Wegener's granulomatosis.

The compounds of the invention are also preferably suitable for the treatment of autoimmune diseases. Examples of such diseases are hepatitis (based on autoimmunity), lupus erythematosus, antiphospholipid syndrome, Berg's disease, Evans syndrome, immune hemolytic anemia, ITP (esthetic thrombocytopenic purpura; adulthood) Humans, newborns and children), myasthenia gravis, Hugh's syndrome, scleroderma, bullous pemphigoid and pemphigus vulgaris.

The compounds of the invention are also preferably suitable for the treatment of B cell lymphomas, such as chronic lymphocytic leukemia and non-Hodgkin's lymphoma or T cell lymphoma.

It is also preferred to mention the prevention and treatment of peripheral or central nervous system diseases. Examples of such diseases are acute and chronic multiple sclerosis or non-familial lateral sclerosis.

It is also preferred to mention the prevention and treatment of osteoporosis diseases such as diseases associated with osteopenia, osteoporosis and osteolytic diseases.

Particularly preferred according to the invention is the use of a compound of formula 1 for the preparation of a pharmaceutical composition for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, bronchitis, atopic dermatitis Contact dermatitis, ITP, rheumatoid arthritis and allergic rhinoconjunctivitis.

The compound of formula 1 is preferably used to treat a disease selected from the group consisting of asthma, allergic rhinitis, rheumatoid arthritis, atopic dermatitis, pulmonary hypertension, and COPD.

7. Combination

The compound of formula 1 can be used alone or in combination with other active substances of formula 1 of the present invention. The compound of formula 1 may also be used in combination with other pharmacologically active substances, as appropriate. The active substance used herein may preferably be selected, for example, from a beta mimetic, an anticholinergic agent, a corticosteroid, an NSAIDS, a COX2-inhibitor (Coxibe), a folic acid antagonist (or a dihydrofolate reductase inhibitor), PDE4 inhibitor, LTD4 antagonist, EGFR inhibitor, MRP4 inhibitor, dopamine agonist, H1 antihistamine, PAF-antagonist, iNos inhibitor, HMG-CoA reductase inhibitor (statins), PI3 kinase inhibitor, CCR3 antagonist, CCR2 antagonist, CCR1 antagonist, IKK2 inhibitor, A2a agonist, α-4 integrin inhibitor, CRTH2 antagonist, histamine 1, combined H1/H3-antagonist , p38 kinase inhibitor, methylxanthine, ENaC inhibitor, CXCR1 antagonist, CXCR2 antagonist, Bruton's tyrosine kinase inhibitors (BTK inhibitor), Janus kinase Inhibitor (JAK inhibitor), IA phosphoinositide-3-kinase δ inhibitor (PI3K-δ inhibitor), dihydroorotate dehydrogenase inhibitor, ICE inhibitor, LTB4 antagonist, 5-LO antagonism Agent, FLAP antagonist. LTB4 antagonist, cromoglycine, dissociated glucocorticoid mimetic, anti-TNF antibody, TNF receptor Fc, pegylated anti-TNF-Fab, anti-IL6 receptor antibody, anti-CD20 antibody, anti-GM-CSF Antibody, anti-CD46 antibody, anti-IL-1 antibody, anti-IL-2 antibody, anti-IL-4 antibody, anti-IL-5 antibody, anti-IL-13 antibody, anti-IL-4/IL-13 antibody or double or triple Combination, such as a combination of one, two or three compounds selected from the group consisting of:

‧ or 1 SYK inhibitor, corticosteroid, CCR1 antagonist, COX2 inhibitor (Coxibe) and folic acid antagonist, such as methotrexate

‧ SYK inhibitors of formula 1 , corticosteroids, beta mimics, CCR3 antagonists, and CRTH2 antagonists

‧ SYK inhibitors of formula 1 , beta mimics, corticosteroids, EGFR inhibitors, and PDE4 antagonists,

‧ SYK inhibitors of formula 1 , anticholinergic agents, beta mimics, corticosteroids, EGFR inhibitors, and PDE4 antagonists,

‧ SYK inhibitors of formula 1 , PDE4 inhibitors, corticosteroids and EGFR inhibitors,

‧ of Formula 1 SYK inhibitors, EGFR inhibitors and PDE4 inhibitors,

‧Form 1 SYK inhibitor and EGFR inhibitor,

‧ SYK inhibitors of formula 1 , beta mimics and anticholinergic agents,

‧ SYK inhibitors of formula 1 , anticholinergic agents, beta mimics, corticosteroids and PDE4 inhibitors,

‧ SYK inhibitors of formula 1 , anticholinergic agents, beta mimics, corticosteroids, iNOS inhibitors, HMG-CoA reductase inhibitors.

Combinations of three active substances each selected from one of the above compound classes are also an object of the present invention.

Suitable beta mimics for use are preferably selected from the group consisting of: arformoterol, carmoterol, formoterol, indacaterol, salmeterol. (salmeterol), albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, Fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, horse Mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procate Procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol ), terbutalin, tiaramide, tolubuterol, net (zinterol), 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H -Benzo[1,4]oxazin-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]oxazine- 1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulfonamide, N-(5-{2-[3 -(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propyl Amino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulfonamide, N-(5-{2-[3-(4,4-diethyl-6-methoxy) -2-Sideoxy-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2 -hydroxy- Phenyl)-methanesulfonamide, 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)-methanesulfonamide, 8-{2-[1,1- Dimethyl-3-(2-o-oxy-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzene And [1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzo) Imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1 -Dimethyl-3-(2-o-oxy-5-trifluoromethyl-2,3-dihydro-benzimidazol-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-benzimidazol-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]-carbenamide, 8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamine) -Phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one, 8-hydroxy-5-[(1R)-1-hydroxyl Benzyl-2-(6-phenethylamino-hexylamino)-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-quinoline-2- Ketone, [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-hydroxyl) -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-adamantyl-2- {3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl)ethyl)amino)propyl]phenyl}phenyl} Indoleamine, 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)-hexylamine 1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one, (R,S)-4-(2-{[6-(2,2-difluoro-4-benzene) Butyloxy)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-di Fluoro-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-(hydroxyl) Methyl)phenol, 4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxyl) Methyl)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]carbenamide, (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]-B) Amino]hexyl]oxy}ethyl)phenyl]-urea, 3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxyl] -3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-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-hydroxyquinoline-2 (1H )-keto, 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-phenyl) (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-benzothiazole-7- -ethylamino]-ethyl}-propanamide, N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-yloxy) -2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propanamide, 7-[ 2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylthio}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy- 3H-benzothiazol-2-one, optionally in the form of a racemate, enantiomer or diastereomer, and optionally as a pharmacologically acceptable acid addition salt or solvate thereof Or hydrated form.

According to the present invention, the acid addition salt of the β-mimetic agent is preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, hydrogen methanesulfonate, hydrogen nitrate, and cis. Dialkyl methoxide, hydrogen acetate, hydrogen citrate Salt, hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate and hydrogen p-toluenesulfonate, preferably selected from the group consisting of hydrochloride, hydrobromide, sulfuric acid Hydrogen salt, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate. Among the above acid addition salts, hydrochlorides, methanesulfonates, benzoates and acetates are especially preferred in accordance with the present invention.

The anticholinergic agent used is preferably a compound selected from the group consisting of tiotropium salts, especially bromide salts; oxitropium salts, especially bromide salts; and flutropium. a salt, especially a bromide salt; an ipratropium salt, especially a bromide salt; an aclidinium salt, especially a bromide salt; a glycopyrronium salt, especially a bromide Salt; trospium salt, especially chloride salt; tolterodin; (3R)-1-phenethyl-3-(9H-dibenzopyran-9-carbonyloxy --1-nitrogenbicyclo[2.2.2]octane salt; tropinol 2,2-diphenylpropionate; bromide 2,2-diphenylpropionate ; 2-fluoro-2,2-diphenylacetate phthalic acid ester methyl bromide; 2-fluoro-2,2-diphenylacetic acid tropin ester methyl bromide; 3,3',4,4 '-Tetrafluorodiphenyl glycolic acid tropin ester methyl bromide; 3,3',4,4'-tetrafluorodiphenyl glycolate terpine base ester methyl bromide; 4,4'-difluoro Tetrolol ester of diphenyl glycolic acid; bromide of 4,4'-difluorodiphenyl glycolate; 3,3'-difluoro Tertinoyl ester of phenylglycolate; bromide of 3,3'-difluorodiphenyl glycolate; thiol ester of 9-hydroxy-hydrazine-9-formate; 9-fluoro-hydrazine-9-carboxylic acid tropine ester methyl bromide; 9-hydroxy-hydrazine-9-carboxylic acid decyl base ester methyl bromide; 9-fluoro-hydrazine-9-carboxylic acid strontium base acetate Bromide; 9-methyl-茀-9-A Tropicol ester methyl bromide; 9-methyl-hydrazine-9-formic acid base alkyl bromide; diphenyl glycolic acid cyclopropyl tropine ester methyl bromide; 2,2-diphenyl Cyclopropyltropine base methyl bromide; 9-hydroxy-dibenzopyran-9-carboxylic acid cyclopropyl tropine ester methyl bromide; 9-methyl-fluorene-9-formic acid propylene Base acid ester methyl bromide; 9-methyl-dibenzopyran-9-carboxylic acid cyclopropyl tropine ester methyl bromide; 9-hydroxy-hydrazine-9-formic acid cyclopropyl tropine ester Methyl bromide; 4,4'-difluorodiphenyl glycolic acid methyl propyl propyl tropyl ester methyl bromide; 9-hydroxy-dibenzopyran-9-carboxylic acid tropin ester methyl bromide; 9-hydroxy-dibenzopyran-9-carboxylic acid decanoate methyl bromide; 9-methyl-dibenzopyran-9-carboxylic acid tropin ester methyl bromide; 9-methyl-di Benzopyran-9-carboxylate base methyl bromide; 9-ethyl-dibenzopyran-9-carboxylic acid tropin ester methyl bromide; 9-difluoromethyl-dibenzocyto 9-hydroxymethyl-dibenzopyran-9-carboxylic acid decyl base methyl bromide; 3-[2-(3-chloro-phenyl) -ethoxy]-N-(2-diethyl -ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl} -propionamide; N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole- 7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propanamine; 7-[2-(2-{3-[2-( 2-Chloro-phenyl)-ethylamino]-propylthio}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one and Dato Darotropium; as the case may be in the form of a solvate or hydrate.

Among the above salts, the cationic tiotropium, oxitropium, filotropium, ipratropium, glycopyrronium, adiponium and trosium are pharmacologically active ingredients. As the anion, the above salt may preferably contain chloride ion, bromide ion, iodide ion, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartaric acid. Root, oxalate, succinate, benzoate or p-toluenesulfonate, and chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate are preferred as relative ions. Among all the salts, chlorides, bromides, iodides and methanesulfonates are especially preferred.

Tiotropium bromide is especially important. In the case of tiotropium bromide, the pharmaceutical combination of the invention preferably comprises tiotropium bromide in the form of crystalline tiotropium bromide monohydrate known from WO 02/30928. If tiotropium bromide is used in anhydrous form in the pharmaceutical combination of the invention, anhydrous crystalline tiotropium bromide known from WO 03/000265 is preferably used.

The corticosteroid used herein is preferably a compound selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide. , deflazacort, dexamethasone, etiprednole, flunisolide, fluticasone, loteprednole, mometasone, Prednisolone, prednisone, rofleponide, triamcinolone, tipredane; pregnancy-1,4-diene-3, 20-diketone; 6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]] Benzyl hydrazino]oxy]-, (6-α, 11-β, 16-α)-(9CI); 16,17-butylene dioxy-6,9-difluoro-11-hydroxy-17 -(methylthio)androst-4-en-3-one, 6,9-difluoro-17-[(2-furylcarbonyl)oxy]-11-hydroxy-16-methyl-3- Side oxy-androgen-1,4-diene-17-thiocarboxylic acid (S)-fluoromethyl ester, 6,9-difluoro-17-[(2-furylcarbonyl)oxy]-11- Hydroxy-16-methyl-3-oxo-androstidine-1,4-diene-17-thioformic acid (S)-fluoromethyl ester, 6-α,9-α-difluoro-11-β -hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androgen-1,4-diene-17β-carboxylic acid cyanide The methyl esters, each optionally in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their salts and derivatives, solvates and/or hydrates.

The steroid is particularly preferably selected from the group consisting of budesonide, fluticasone, mometasone, ciclesonide and 6,9-difluoro-17-[(2-furylcarbonyl)oxy]-11-hydroxy-16- (3-)-oxy-androgen-1,4-diene-17-thiocarboxylic acid (S)-fluoromethyl ester, optionally in the form of its racemate, enantiomer or diastereomeric Isomer form and optionally in the form of its salts and derivatives, solvates and/or hydrates.

Any reference to a steroid includes reference to any salt or derivative, hydrate or solvate thereof that may be present. Examples of possible salts and derivatives of steroids may be: alkali metal salts such as sodium or potassium salts; sulfobenzoates, phosphates, isonicotinic acid salts, acetate salts, propionates, dihydrogen phosphate salts , palmitate, pivalate or citrate.

The PDE4 inhibitor which can be used is preferably a compound selected from the group consisting of enprofyllin, theophyllin, roflumilast, ariflo (cilomilast). ), tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, Oglemilast, tetomilast; 5-[(N-(2,5-dichloro-3-pyridyl)-carbenamide]-8-methoxy-quinoline ( D-4418), 5-[N-(3,5-Dichloro-1-oxoyl-4-pyridyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)- Quinoline (D-4396 (Sch-351591)), N-(3,5-dichloropyridin-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3- Glycolate (AWD-12-281 (GW-842470)), 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-嘌呤-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-yloxy-1-phenylpyrrolo[3,2,1-jk][1 , 4] benzodiazepine-3-yl]-4-pyridinecarboxamide (PD-168787), 4-[6,7-diethoxy -2,3-bis(hydroxymethyl)-1-naphthyl]-1-(2-methoxyethyl)-2(1H)-pyridone (T-440), 2-[4-[6 ,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthyl]-2-pyridyl]-4-(3-pyridyl)-1(2H)-pyridazinone (T -2585), (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-indole (V-11294A), β-[ 3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-di-oxo-2H-isoindole-2-propanamide (CDC-801) , 9-ethyl-2-methoxy-7-methyl-5-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine-6(5H)-one ( D-22888), 5-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-(3S,5S)-2-piperidyl Pyridone (HT-0712), 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxoyl-4-pyridyl)B Base]-α,α-bis(trifluoromethyl)-benzyl alcohol (L-826141), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoro Methoxy-3-cyclopropylmethoxybenzamide, (-)p-[(4 a R*,10 b S*)-9-ethoxy-1,2,3,4,4a ,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6] Pyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy) 4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S -methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1- Formic acid], 2-methoxycarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-[4-(3-cyclopentyloxy-4) -Methoxyphenyl)pyrrolidine-2-ylideneacetate, (S)-(-)-[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2 -subunit]ethyl acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9 H -pyrazolo[3,4-c]-1 , 2,4-triazolo[4,3-a]pyridine, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(t-butyl)-9 H -pyrazole [3,4-c]-1,2,4-triazolo[4,3-a]pyridine,

It is optionally in the form of a racemate, enantiomer or diastereomer and is optionally in the form of a pharmaceutically acceptable acid addition salt, solvate and/or hydrate.

The acid addition salt of the above PDE4 inhibitor with a pharmacologically acceptable acid means, for example, a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, Hydrogen methanesulfonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen benzoate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, dibutyl The acid hydrogen salt, hydrogen benzoate and hydrogen p-toluenesulfonate are preferably hydrochloride, hydrobromide, hydrogen sulfate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate.

The CRTH2 antagonist which can be used is preferably a compound selected from the group consisting of Ramatroban, Setipiprant, Laropiprant and ODC-9101 (2-(1-ethyl) -5-fluoro-2-methyl-1H-indol-3-yl-methyl)-quinoline; see www.chemietek.com/products.aspx?pid=132 ), which is optionally a racemate An enantiomeric or diastereomeric form and optionally in the form of a pharmaceutically acceptable acid addition salt, solvate and/or hydrate thereof.

The CCR3 antagonist which can be used is preferably a compound selected from the group consisting of 1-(4-ethylindenyl-benzyl)-3-[4-(3,4-dichloro-benzyl)-morpholine- 2-ylmethyl]-urea (GW766994) (BMS 639623), AZD 1744, AZD 3778, and YM-344031, as disclosed in Bioorganic & Medicinal Chemistry Letters (2008), 18(2), 576-585.

The NSAID which can be used is preferably a compound selected from the group consisting of Aceclofenac, Acemetacin, Acetylsalicylsäure, Alclofenac, Aminprofen. (Alminoprofen), Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin, Azapropazon , Benorilat, Bermoprofen, Bindarit, Bromfenac, Bucloxinsäure, Bucolom, Bufexamac , Bumadizon, Butibufen, Buticirat, Carbasalatcalcium, Carprofen, Choline Magnesium Trisalicylat), Celecoxib, Cinmetacin, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, right Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac, Enphenacic Acid (Enfenaminsäure), Etersalat, Etodolac, Etofenamat, Etoxoxib (Et Oricoxib), Feclobuzon, Felbinac, Fenbufen, Fenclofenac, Fenoprofen, Fentiazac, ubiquitin Fepradinol, Feprazon, Flobufen, Floctafenin, Flufenaminsäure, Flufenisal, Flunoxaprofen , flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glucametacin, ibufenac, ibuprofen (Ibuprofen), Ibuprofen (Indobufen), Indometacin, Indometacinfarnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen (Ketoprofen), Ketorolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofen, Lumiracoxib , meclofenaminsäure, meclofen, mefenaminsäure, Meloxicam, Mesalazin, Miroprofen, Moxazole Acid (Mofezolac), nabumeton, Naproxen, Nifluminsäure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon ), Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac, Piroxicam, Pyridine Pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetac In), Proquazon, Protizininsäure, Rofecoxib, Romazarit, Salicylamid, Salicylsäure, Shamis Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensäure, Taramid, Tirolin ester (Tilnoprofenarbamel), Timegadin, Tinoridin, Tiopinac, Tolfenaminsäure, Tolmetin, Ufenamat, Wade Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.

The COX2 inhibitor (Coxibe) which can be used is preferably a compound selected from the group consisting of Celecoxib, Meloxicam, Etoricoxib, Lumiracoxib, Pa Parecoxib, Rofecoxib, and Valdecoxib.

The folic acid antagonist (or dihydrofolate reductase inhibitor) which can be used is preferably a compound selected from the group consisting of methotrexate, trimethoprim, brodimoprim, and culture. Pemetrexed and iclaprim.

The CCR1 antagonist which can be used in combination with the SYK inhibitor of Formula 1 is preferably selected from the group consisting of CCX354 (GSK) and BMS-817399 (BMS).

A Bruton tyrosine kinase inhibitor (BTK inhibitor) which can be combined with a SYK inhibitor of formula I is preferably selected from PCI-32765 (Pharmacyclic, see Honigberg et al, PNAS, (2010), Vol. 107, p. Phase 29, pages 13075-13080), AVL-292 (Avila) and 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-( 4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquine Polin-1-one (= RN486) (Roche), see Hu Daigen et al JPET 341: 90-103, 2012).

A two-faced kinase inhibitor (JAK) that can be combined with a SYK inhibitor of formula I The formulation) is preferably selected from the group consisting of GLPG-0634 (Abbott/Galapagos), Baricitinib (Lilly), VX-509 (Vertex), and Tofacitinib (Pfizer).

The IA phosphoinositide-3-kinase-delta inhibitor (PI3K-delta inhibitor) which can be combined with the SYK inhibitor of formula I is preferably selected from the group consisting of Cal-101 (Calistoga) and GS-1101.

The dihydroorotate dehydrogenase inhibitor which can be combined with the SYK inhibitor of formula I is preferably Leflunomid (Aventis).

Furthermore, the SYK inhibitor of formula I can be combined with hydroxychloroquine, sulfasalazine or Abatacept (CTLA-4 Ig).

The anti-TNF antibody which can be combined with the SYK inhibitor of formula I is preferably selected from the group consisting of Adalimumab and golimumab.

The TNF receptor Fc which can be combined with the SYK inhibitor of formula I is preferably etanercept.

The PEGylated anti-TNF-Fab which can be combined with the SYK inhibitor of formula I is preferably certolizumab pegol.

The anti-IL6 receptor which can be combined with the SYK inhibitor of formula I is preferably selected from the group consisting of Actemra and Roactemra.

The anti-CD20 antibody which can be combined with the SYK inhibitor of formula I is preferably rituximab (Rituximab).

The LTD4 antagonist which can be used is preferably a compound selected from the group consisting of: montelukast, pranlukast, zafirlukast, (E)-8-[2-[4 -[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopipene-4-one (MEN- 91507), 4-[6-Ethyl-3-[3-(4-ethinyl-3-hydroxy-2-propylphenylthio)propoxy 2-ylphenoxy]-butyric acid (MN-001), 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl))vinyl) 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)-vinyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl) Phenyl)propyl)thio)methyl)cyclopropaneacetic acid, [2-[[2-(4-t-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl] Phenyl]acetic acid,

Where appropriate, in the form of a racemate, enantiomer or diastereomer, as the case may be in the form of a pharmaceutically acceptable acid addition salt and, where appropriate, its salts and derivatives, solvates and / or hydrate form.

An acid addition salt of a LTD4 antagonist capable of forming a pharmacologically acceptable acid means, for example, a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, methane. Hydrogen sulfonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen benzoate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, succinic acid The hydrogen salt, hydrogen benzoate and hydrogen p-toluenesulfonate are preferably hydrochloride, hydrobromide, hydrogen sulfate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate. A salt or derivative which a LTD4 antagonist can form means, for example, an alkali metal salt (such as a sodium salt or a potassium salt), an alkaline earth metal salt, a sulfobenzoate, a phosphate, an isonicotinic acid salt, an acetate salt, a propionic acid. Salt, dihydrogen phosphate, palmitate, pivalate or citrate.

The EGFR inhibitor used is preferably a compound selected from the group consisting of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-side oxygen 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-cyclo Propyl methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-side oxygen 2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6- {[4-(morpholin-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-yloxy-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-methoxy A) Keto-6-o-oxy-morpholin-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- fluorine Amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy- Quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino group -l-oxy-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-buten-1-yl}amino group - 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-yloxy -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 Porphyrin, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino] -1-Sideoxy-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino] -6-{[4-(N,N-Dimethylamino)-1-yloxy-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yl Oxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-yloxy- 2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-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-sided oxy-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- Methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1- side Oxy-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-( Physo-4-yl)-propoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)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-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4 -(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methylsulfonyl-ethyl)amino]methyl}-furan-2- 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)amine -6-{[4-(morpholin-4-yl)-1-yloxy-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)-amine -1-yloxy-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-buten-1-yl]amine }-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-) Oxyoxy-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- side Methyl-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino -6-[1-(Tertibutoxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) Amino]-6-(trans-4-amino-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) Amino]-6-(trans-4-methylsulfonylamino-cyclohex-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)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-benzene) Amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy}-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-acetamidoamino-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]-cyclohex-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro- 4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohex-1-yloxy}-7-methoxy-quinazoline Porphyrin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yl Oxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7- (2-Ethylamino-ethoxy)-quinazoline, 4-[(3- 4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline, 4- [(3-Chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy- Quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy- Quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N- -Amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis- 4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-{2 -[4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-ethyl}-6-methyl-morpholin-2- Ketone, 4- {4-[4-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-1-methyl-piperazine- 2-keto, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-A -Amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(anti- 4-ethanesulfonylamino-cyclohex-1-yloxy)-7-methoxy-quinazoline, 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-chloro-4-fluoro-phenyl) Amino]-6-[1-(2-methoxy-ethenyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-ethenylamino-cyclohex-1-yloxy)-7-methoxy-quinazoline 4-[(3-ethynyl-phenyl)amino]-6-[1-(t-butoxycarbonyl)-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-[(piperidin-1-yl)) Carbonyl]-N-methyl-amino}-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohex-1-yloxy)-7- Oxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexane- 1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-sideoxy) Pyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]- 6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3 -ethynyl-phenyl)amino]-6-(1-ethenyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-acetylene) -phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amine 4-(1-methylsulfonyl-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-isopropoxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro- Phenyl)amino]-6-(cis-4-methylamino-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro) -phenyl)amino]-6-{cis-4-[N-(2-methoxy-ethinyl)-N-methyl-amino]-cyclohex-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-ethinyl)-piperidin-4-yloxy]-7-methoxy-quinazoline 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy- Quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]- Piperidin-4-yloxy}-7-methoxy-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-Methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-nitrogen) Hetero-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro) -phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy - quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quin Oxazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}- 7-Methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl] -piperidin-4-yloxy}-7- Methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methylsulfonyl-N-methyl-amino) -cyclohex-1-yloxy]7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-B Mercapto-N-methyl-amino)-cyclohex-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino] -6-(trans-4-methylamino-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino group ]-6-[trans-4-(N-methylsulfonyl-N-methyl-amino)-cyclohex-1-yloxy]-7-methoxy-quinazoline, 4-[( 3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohex-1-yloxy)-7-methoxy-quinazoline, 4- [(3-Chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexyl -1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6) -Sideoxy-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4) -fluoro-phenyl)amino]-6-(1-methylsulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4- Fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy- Oxazoline, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-yloxy- 2-buten-1-yl]amino}-7-ethoxy-quinoline, [4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(high Morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4 -[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-o-oxy-tetrahydrofuran-5-yl)-carbonyl]-piperazine -1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2 -((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[( 3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butoxy]-6 -[(vinyl carbonyl Amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo- Morpholin-4-yl)-butoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7- (2-{4-[(S)-(2-Sideoxy-tetrahydrofuran-5-yl)-carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amine ]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine- 4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4- ((R)-6-Methyl-2-oxo-morpholin-4-yl)-butoxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3 -chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butoxy]-6- [(Vinylcarbonyl)amino]-quinazoline, cetuximab, trastuzumab, panitumumab (=ABX-EGF), Mab ICR- 62. Gefitinib, pelitinib, canertinib and erlotinib, optionally as racemates, enantiomers or non-pairs Isomerized form, as the case may be pharmacologically Acceptable acid addition salts, solvates and/or hydrate forms.

An acid addition salt which an EGFR inhibitor can form with a pharmacologically acceptable acid means, for example, a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, methane. Hydrogen sulfonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen benzoate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, succinic acid The hydrogen salt, hydrogen benzoate and hydrogen p-toluenesulfonate are preferably hydrochloride, hydrobromide, hydrogen sulfate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate.

Examples of dopamine agonists that can be used preferably include a combination selected from the group consisting of : bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, prak Pramipexol, roxindol, ropinirol, talipexol, terguride, and viozan. Any reference to the above dopamine agonist within the scope of the present invention includes reference to any pharmacologically acceptable acid addition salt and optionally hydrates which may be present. The physiologically acceptable acid addition salt which may be formed from the above dopamine agonist means, for example, a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate. Acid salts, acetates, fumarates, succinates, lactates, citrates, tartrates and maleates.

Examples of H1-antihistamine preferably include a compound selected from the group consisting of: epinastine, cetirizine, azelastine, fexofenadine, left Levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine ), bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, Diphenhydramine, promethazine, ebastine, olopatadine, desloratidine, and meclozine. The above H1-antibody is within the scope of the present invention Any reference to histamine includes references to any pharmacologically acceptable acid addition salt that may be present.

Examples of PAF antagonists preferably include a compound selected from the group consisting of lexipafant, 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3 -Acetone-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine, 6-( 2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thieno-[3, 2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. Within the scope of the present invention, any reference to the above PAF antagonists includes references to any pharmacologically acceptable acid addition salts which may be present.

The MRP4 inhibitor used is preferably a compound selected from the group consisting of N-acetamido-dinitrophenyl-cysteine, cGMP, cholate, diclofenac, 3-glucuronide dehydroepiandrosterone, 3-hydrodesulfonic acid dehydroepiandrosterone, dilazep, dinitrophenyl-s-glutathione, 17-beta-glucuronide estradiol, 3,17-hydrogen estradiol , 3-glucuronide estradiol, 3-estradiol estradiol, 3-sulfate estrone, flupirtine, folic acid, N5-formyl-tetrahydrofolate, glycocholate, glucosinolate Sulfate, ibuprofen, indomethacin, ibuprofen, ketoprofen, lithochalate sulfate, methotrexate, (( E )-3-[[[3-[2-(7- Chloro-2-quinolyl)vinyl]phenyl]-[[(3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propionic acid), α -naphthyl-β-D-glucuronide, nitrobenzylhydrazinium riboside, probenecid, sildenafil, sulfinpyrazone, taurode deoxycholate Acid esters, taurocholate, taurodeoxycholate, taurolithic acid cholate, taurolithic acid sulfate, topotecan, trequinis n) and zaprinast, dipyridamole, optionally as a racemate, enantiomer, diastereomer and its pharmacologically acceptable acid addition Salt and hydrate forms.

More preferably, the present invention relates to the use of an MRP4 inhibitor for the preparation of a pharmaceutical composition for treating a respiratory condition comprising a SYK inhibitor of the formula 1 of the present invention and an MRP4 inhibitor, preferably selected from the group consisting of 3 - dehydroepiandrosterone sulfate, 3,17-estradiol estradiol, flupirtine, indomethacin, ibuprofen, bovine cholate, as the racemate, as opposed to Isomers, diastereomers, and pharmacologically acceptable acid addition salts and hydrate forms. The enantiomers can be separated from the racemate using methods known in the art (e.g., for palm phase chromatography, etc.).

The acid addition salt formed with a pharmacologically acceptable acid means, for example, a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, hydrogen methanesulfonate. , hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen benzoate, hydrogen citrate, hydrogen fumarate, hydrogen hydrogen tartrate, hydrogen oxalate, hydrogen succinate, benzene The hydrogen formate and the hydrogen p-toluenesulfonate are preferably hydrochloride, hydrobromide, hydrogen sulfate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate.

Further, the present invention relates to a pharmaceutical preparation comprising the SYK inhibitor of the formula 1 of the present invention, an MRP4 inhibitor, and another active substance (for example, an anticholinergic agent, a PDE4 inhibitor, a steroid, a LTD4 antagonist or β Triple combination of mimetic agents, as well as methods for their preparation and their use for treating respiratory conditions.

The compound which can be used as an iNOS inhibitor is a compound selected from the group consisting of S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, 5,6-dihydro-6- Methyl-4H-1,3-thiazin-2-amine (=AMT), L-cutosin, 2-iminopiperidine, S-isopropylisothiourea, S-methylisosulfide Urea, S-ethylisothiourea, S-methylthio citrulline, S-ethylthio citrulline, L-NA (N ^ω -nitro-L-arginine), L-NAME (N ^ω -nitro-L-methyl arginine), L-NMMA (N ^G -monomethyl-L-arginine), L-NIO (N ^ω -iminoethyl-L-ornithine) ), L-NIL (N ^ω -iminoethyl-isoamino acid), (S)-6-acetamimidin-decylamino-2-amino-hexanoic acid (1 H -tetrazole-5 -yl)-decylamine (SC-51) ( J. Med. Chem. 2002, 45 , 1686-1689), N-[[3-(aminomethyl)phenyl]methyl]-acetamidine (= 1400W), (S)-4-(2-acetamidomidino-ethylthio)-2-amino-butyric acid (GW274150) (Bioorg.Med.Chem.Lett . 2000, 10 , 597-600), 2- [2- (4-methoxy - pyridin-2-yl) - ethyl] -3 H - 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-( (1 R,3S)-3-Amino-4-hydroxy-1-thiazol-5-yl-butylthio)-6-trifluoromethyl-nicotinonitrile (WO 2004/041794), 2-((1R .3S)-3-Amino-4-hydroxy-1-thiazol-5-yl-butylthio)-4-chloro-benzonitrile (WO 2004/041794), 2-((1R.3S)- 3-Amino-4-hydroxy-1-thiazol-5-yl-butylthio)-5-chloro-benzonitrile (WO 2004/041794), (2S.4R)-2-Amino-4- (2-Chloro-5-trifluoromethyl-phenylthio)-4-thiazol-5-yl-butan-1-ol (WO 2004/041794), 2-((1R.3S)-3-amine 4-hydroxy-1-thiazol-5-yl-butylthio)-5-chloro-nicotinic nitrile (WO 2004/041794), 4-((S)-3-amino-4-hydroxy- 1-phenyl-butylthio)-6-methoxy-nicotinonitrile (WO 02/090332); substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine, such as (1S.5S.6R)-7-Chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine (ONO-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-arazolidine-2-ylideneamine ( Bioorg. Med. Chem. Lett. 2005, 15 , 1361), 4-aminotetrahydrobiopterin ( . Curr.Drug Metabol 2002, 3, 119-121 ), (E) -3- (4- chloro - phenyl) - N -(1-{2-Sideoxy-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylaminecarbamyl}- 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. Pharmacol. Exp. Ther. 2002, 303 , 52-57) , 3-{[(Benzo[1,3]dioxol-5-ylmethyl)-aminecarboxylidene]-methyl}-4-(2-imidazol-1-yl-pyrimidine) 4-yl)-piperazine-1-carboxylate (BBS-1) ( Drugs Future 2004, 29 , 45-52), (R)-1-(2-imidazol-1-yl-6-methyl -pyrimidin-4-yl)-pyrrolidine-2-carboxylic acid (2-benzo[1,3]dioxol-5-yl-ethyl)-decylamine (BBS-2) ( Drugs Future 2004, 29 , 45-52) and its pharmaceutical salts, prodrugs or solvates.

Examples of iNOS inhibitors within the scope of the invention may also include antisense oligonucleotides, particularly those antisense oligonucleotides that bind to iNOS encoding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense oligonucleotides for modulating iNOS expression, binding to iNOS encoding nucleic acids. Thus, iNOS antisense oligonucleotides, particularly as described in WO 01/52902, can also be combined with the PDE4 inhibitors of the invention due to their similar effects to iNOS inhibitors.

A suitable HMG-CoA reductase inhibitor (also known as a statin) which is preferably used in combination with a compound of formula 1 in a double or triple combination is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin. (Flurvastatin), lovastatin (Lovastatin), pitavastatin, Pravastatin, rosuvastatin, simvastatin, pharmaceutically acceptable acid addition salts, as appropriate , prodrug, solvate or hydrate form.

8. Formulations

Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The amount of the pharmaceutically effective compound should be in the range of from 0.1% by weight to 90% by weight, preferably from 0.5% by weight to 50% by weight of the total composition, i.e., an amount sufficient to achieve the dosage range specified below.

The preparation may be administered orally in the form of a powder, solution or suspension in a lozenge, a powder, a capsule such as a hard gelatin capsule. When administered by inhalation, the active substance combination can be administered in the form of a powder, an aqueous solution or an aqueous ethanol solution or using a propellant gas formulation.

Accordingly, preferably, the pharmaceutical formulation is characterized by the amount of one or more of the compounds of formula 1 of the above preferred embodiments.

Oral administration of the compound of formula 1 is especially preferred, and one or two administrations per day are also particularly preferred. Suitable lozenges can be obtained, for example, by mixing the active substances with known excipients such as inert diluents such as calcium carbonate, calcium phosphate or lactose; disintegrating agents such as corn starch or Alginic acid; a binder such as starch or gelatin; a lubricant such as magnesium stearate or talc; and/or a delayed release agent such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain several layers.

The coated tablet can thus be prepared by coating a core similar to a tablet prepared by coating a commonly used substance, such as collidone or shellac. , gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or to prevent incompatibility, the core may also consist of multiple layers. Similarly, the drag coating layer can be composed of multiple layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

The syrup containing the active substance of the present invention or a combination thereof may additionally contain a sweetener such as saccharin, cyclamate, glycerin or sugar; and a flavor enhancer such as a fragrance such as vanillin or orange extract. It may also contain a suspending adjuvant or thickening agent (such as sodium carboxymethylcellulose), a wetting agent (such as a condensation product of a fatty alcohol with ethylene oxide) or a preservative (such as a paraben).

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and packaging it in a gelatin capsule. Suitable suppositories can be prepared, for example, by mixing with a carrier provided for this purpose, such as a neutral lipid or polyethylene glycol or a derivative thereof.

Excipients which may be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fraction), vegetable oils (e.g., peanut or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); Such as natural mineral powders (such as kaolin, clay, talc, chalk), synthetic mineral powders (such as highly dispersed tannins and citrates), sugars (such as sucrose, lactose) And glucose), emulsifiers (such as lignin, waste sulfite liquid, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate) .

For oral administration, in addition to the carriers mentioned above, the tablets may of course contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, and such as starch (preferably potato starch), gelatin and the like. Various additives. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used in the ingot making process at the same time. In the case of an aqueous suspension, the active substance may be combined with various flavor enhancers or colorants other than the excipients mentioned above.

It is also preferred to administer a compound of formula 1 by inhalation, and it is especially preferred to administer one or two times a day. For this purpose, the compound of formula 1 must be formulated for use in a form suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing dosages of aerosols or propellant-containing inhalable solutions, optionally in admixture with conventionally acceptable excipients.

Within the scope of the present invention, the term propellant-free inhalable solution also includes concentrates or sterile ready-to-use inhalable solutions. Formulations that can be used in accordance with the present invention are described in more detail in the remainder of this specification.

Respirable powder

If the active substance of the formula 1 is present in admixture with a physiologically acceptable excipient, the following excipients which are physiologically acceptable can be used to prepare the inhalable powder according to the invention: a monosaccharide (for example glucose or arabinose) ), disaccharides (such as lactose, sucrose, maltose), oligosaccharides and polysaccharides (such as dextran), polyols (such as sorbitol, mannitol, xylitol), salts (such as sodium chloride, calcium carbonate) Or a mixture of such excipients. Preferably, a monosaccharide or a disaccharide is used, and lactose or glucose is preferred, especially, but not exclusively, in its hydrated form. For the purposes of the present invention, lactose is a particularly preferred excipient, with lactose monohydrate being especially preferred. A method of preparing an inhalable powder by grinding and micronizing and finally mixing the components together is known from the prior art.

Inhalable aerosol containing propellant

The inhalable aerosol containing the propellant which can be used in the present invention may contain a compound of formula 1 dissolved in a propellant gas or in a dispersed form. Propellant gases useful in the preparation of the inhaled aerosols of the present invention are known from the prior art. Suitable propellant gas systems are selected from the group consisting of hydrocarbons (such as n-propane, n-butane or isobutane) and halogenated hydrocarbons (such as fluorinated derivatives such as preferably methane, ethane, propane, butane, cyclopropane or cyclobutane). ()). The propellant gases mentioned above may be used independently or in a mixture thereof. Particularly preferred propellant gas is fluorine selected from the group consisting of TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-hexafluoropropane) and mixtures thereof Alkane derivatives. The propellant-driven inhalation aerosol used in the context of the use according to the invention may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusting agents. All such ingredients are known in the art.

Inhalable solution without propellant

The compound of formula 1 of the present invention is preferably used in the preparation of a propellant-free inhalable solution and a respirable suspension. The solvent used for this purpose includes an aqueous solution or an alcohol solution, preferably an ethanol solution. The solvent may be only water or a mixture of water and ethanol. The solution or suspension can be adjusted to a pH of from 2 to 7, preferably from 2 to 5, using a suitable acid. The pH can be adjusted using an acid 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 acid and sulfuric acid. It is also possible to use an acid which has formed an acid addition salt with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. Mixtures of the above acids may also be used, if desired, especially where the acid (such as citric acid or ascorbic acid) has properties other than its acidifying properties (for example as a flavoring agent, antioxidant or complexing agent). According to the invention, it is especially preferred to adjust the pH using hydrochloric acid.

Cosolvents and/or other excipients can be added to the propellant-free inhalable solution for the purposes of the present invention. Preferred cosolvents are cosolvents containing hydroxyl groups or other polar groups, such as alcohols, especially isopropanol; glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerin, polyoxypropylene Ethyl alcohol and polyoxyethyl ester fatty acid ester. The term excipients and additives in this context denotes any pharmacologically acceptable substance which is not an active substance, but which may be formulated in a pharmacologically suitable solvent with the or the active substance to modify the active substance formulation. Qualitative nature. Preferably, the materials do not have a pharmacological effect or, in the case of the desired therapy, have no appreciable pharmacological effects or at least no undesirable pharmacological effects. Excipients and additives include, for example, surfactants (such as soybean phospholipids), oleic acid, sorbitan esters (such as polysorbates), polyvinylpyrrolidone, It is a stabilizer, a binder, an antioxidant, and/or a preservative (which ensures or extends the shelf life of the finished pharmaceutical formulation), flavoring agents, vitamins, and/or other additives known in the art. The additive also includes a pharmacologically acceptable salt, such as sodium chloride as an isotonic agent. For example, preferred excipients include antioxidants such as ascorbic acid (with the proviso that they have not been used to adjust the pH), vitamin A, vitamin E, tocopherol and similar vitamins or provitamins produced in the human body. Preservatives can be used to protect the formulation from pathogen contamination. Suitable preservatives are the preservatives known in the art, especially cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates (such as sodium benzoate known from the prior art).

For the above treatment forms, a ready-to-use kit for treating respiratory conditions, containing a closed instruction including words such as respiratory diseases, COPD or asthma, and formula 1 And a combination of one or more of the above compounds.

Claims (30)

a compound of formula 1 , Wherein R ¹ is a linear or branched C _1-6 alkyl group, wherein R ¹ may be optionally substituted by R ³ , and R ^{3 is} selected from the group consisting of: 3, 4, 5, 6 or 7 membered cycloalkyl; , 6 or 7 members comprising 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; and 5 or 6 members comprising 1, 2 or 3 each independently selected from a heteroatom heteroaryl group of the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from the group consisting of: side oxygen Base, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkylene-CN and -CN, And wherein R ^{2 is} selected from the group consisting of: halogen; phenyl; 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O; 9, 10 or 11 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-aromatic but not fully saturated heterocyclic rings each independently selected from the group consisting of N, S and O; wherein R ^{2 is} visible Happening 2, 3 or 4 substituents R ⁴ substituents, R ⁴ are independently from each other selected from the group consisting of: linear or branched -OC _1-5 alkyl, -OH, oxo, halogen, -C _1-5 haloalkyl, -SO ₂ CH ₃ , -C _1-3 alkylene-SO ₂ -(C _1-3 alkyl), -SO ₂ -CF ₃ , -CN, -C _3-6 ring An alkyl group, a straight chain or a branched chain -C _1-5 alkyl group; 4, 5 or 6 members comprising 1, 2 or 3 heteroatoms independently selected from the group consisting of N, S, -SO ₂ and O Saturated heterocyclic ring; -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -NH-CO-C _1-3 alkyl, -CO-NH ( CH ₃ ), -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _1-3 alkane Base and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently of one another selected from the group consisting of: straight or branched -C _1-4 alkyl, pendant oxy, -C _{1 -3} haloalkyl, -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 each independently selected from the group consisting of N, S and O a saturated heterocyclic ring of a hetero atom; a 3, 4, 5, 6 or 7 membered cycloalkyl group; 5 or 6 members comprising 1 or 2 heteroatoms each independently selected from the group consisting of N, S and O a heteroaryl group; wherein R ⁵ may be optionally substituted with a group of a group consisting of a pendant oxy group, a -C _1-3 alkyl group, and a -C _1-3 haloalkyl group, and a pharmacologically acceptable salt of the above compound . A compound of formula 1 according to claim 1, wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -(CH ₃ ), which may optionally be substituted by R ³ , and R ^{3 is} selected from the group consisting of: 3, 4 a 5, 6 or 7 membered cycloalkyl group; 5, 6 or 7 members comprising 1, 2 or 3 saturated heteroatoms each independently selected from the group consisting of N, S and O; and 5 or 6 members a heteroaryl group comprising 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, such substituents Each is independently selected from the group consisting of: pendant oxy, OH, -CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, - C _1-3 alkylene-CO-NH ₂ , -C _1-3 alkylene-CO-NH(CH ₃ ), -C _1-3 alkylene-CO-N(CH ₃ ) ₂ , -C _1-3 alkyl-CN and -CN, and pharmacologically acceptable salts of the above compounds. A compound of formula 1 according to any one of claims 1 or 2 wherein R ¹ is substituted by R ³ and R ^{3 is} selected from the group consisting of 5 or 6 members comprising 1 or 2 each independently selected from N, S and O a saturated heterocyclic ring of a hetero atom consisting of a group, wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of pendant oxy, OH, - CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _{1- 3-} alkyl-CO-NH(CH ₃ ), -C _1-3 alkyl-CO-N(CH ₃ ) ₂ , -C _1-3 alkyl-CN and -CN, and the pharmacology of the above compounds A salt that is acceptable for learning. A compound of formula 1 according to any one of claims 1 or 2 wherein R ¹ is substituted by R ³ and R ^{3 is} selected from the group consisting of 5 or 6 members comprising 1 or 2 each independently selected from N, S and O a heteroaryl group of a hetero atom consisting of a group wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from the group consisting of pendant oxy, OH, - CO-NH ₂ , -CO-NH(CH ₃ ), -CO-N(CH ₃ ) ₂ , -C _1-5 alkyl, -C _1-3 alkylene-CO-NH ₂ , -C _{1- 3-} alkyl-CO-NH(CH ₃ ), -C _1-3 alkyl-CO-N(CH ₃ ) ₂ , -C _1-3 alkyl-CN and -CN, and the pharmacology of the above compounds A salt that is acceptable for learning. The compound of formula 1 or 2 of the request item is selected from the group consisting of in which R ¹ consisting of -CH ₃ or -CH ₂ (CH _3), in which R ¹ optionally substituted with R ^3, R ³ is selected from the group consisting of: a 3, 4, 5 or 6 membered cycloalkyl group; 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; and 5 or 6 members comprising 1 or And a heteroaryl group each independently selected from the group consisting of N, S and O; wherein R ³ may be optionally substituted with 1, 2, 3 or 4 substituents, each independently selected from A group consisting of a pendant oxy group, -CO-NH ₂ , -CH ₂ -CO-NH ₂ , methyl and -CH ₂ -CN, and a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -CH ₃ wherein R ¹ is substituted by R ³ and R ³ is saturated with 5 members comprising 1 nitrogen atom A heterocyclic ring wherein R ³ is substituted with one pendant oxy group, and a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ¹ is as follows And a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ^{1 is} selected from the group consisting of -CH ₃ and -CH ₂ -CH ₃ wherein R ¹ is substituted by R ³ and R ³ is a 6-membered heterocyclic ring containing 1 nitrogen atom An aryl group wherein R ³ is substituted with -CO-NH ₂ and a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ¹ is as follows And a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ^{2 is} selected from the group consisting of: R ^{2 is} selected from the group consisting of: phenyl; 5 or 6 members comprising 1, 2 or 3 each independently selected from N a heterocyclic monocyclic heteroaryl group of the group consisting of S and O; 9 or 10 members comprising 1, 2, 3 or 4 bicyclic aromatic groups each independently selected from the group consisting of N, S and O heteroatoms but not non-aromatic fully saturated heterocycle; wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently from each other selected from the group consisting of: linear or branched -OC _1-3 alkyl, pendant oxy, -OH, -F, -Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heteroatoms each independently selected from the group consisting of N, S, SO ₂ and O ;-NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _{1 -3} alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene -O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl , isobutyl, tert-butyl, -C _1-3 haloalkyl, pendant oxy, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members 1, 2 or 3 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; 3, 4, 5, 6 or 7 membered cycloalkyl; 5 or 6 members comprising 1 or 2 a heteroaryl group each independently selected from the group consisting of N, S and O; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a methyl group, an ethyl group, a —CF ₃ group, and a compound of the above Pharmacologically acceptable salt. The requested item 1 or 2 of Formula 1 compounds, wherein R ² is phenyl, optionally substituted with wherein R ^2, 3 or 4 substituents R ⁴ substituents, R ⁴ independently selected from the group consisting of: Linear or branched -OC _1-3 alkyl, pendant oxy, -OH, -F, -Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 heteroatoms each independently selected from the group consisting of N, S and O Saturated heterocyclic ring; -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _{1- 3-} alkyl-O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Tertiary butyl, pendant oxy, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 a saturated heterocyclic ring each independently selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; 5 or 6 members comprising 1 or 2 each independently selected from A hetero atom heteroaryl group of the group consisting of N, S and O; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a methyl group, and a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 11, wherein R ² is phenyl, and wherein R ^{2 is} optionally substituted with 1, 2, 3 or 4 substituents R ⁴ , and R ⁴ are independently of each other selected from the group consisting of: - OCH ₃ , pendant oxy group, -OH, -F, Cl, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, Isopropyl, -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-CH ₃ , -CO-NH(CH ₃ ), -(C _{1- 3} alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene- O-CO-C _1-3 alkyl group and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, Isobutyl, tert-butyl, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 a saturated heterocyclic ring each independently selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may optionally be via a pendant oxy group or a methyl group Substituting a group, and a pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 1 or 2, wherein R ² is 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O heteroatoms; R ² optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently from each other selected from the group consisting of: -O- methyl, -O- ethyl, -O- propyl, - O-isopropyl, pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; -NH-CO- CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene) -O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _1-3 alkyl and Wherein R ⁴ optionally substituted with 1 or 2 substituents R ⁵ substituents, wherein each R ⁵ is independently selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, Tertiary butyl, -C _1-3 haloalkyl, -OH, halogen, -C _1-2 alkylene-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 independently of each other a saturated heterocyclic ring of a hetero atom selected from the group consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may be optionally constituted by a pendant oxy group, a methyl group and -CF ₃ The group is substituted, and the pharmacologically acceptable salt of the above compound. A compound of formula 1 according to claim 13 wherein R ² is 5 or 6 members comprising 1, 2 or 3 monocyclic heteroaryl groups each independently selected from the group consisting of N, S and O heteroatoms; wherein R ² Optionally, 1, 2, 3 or 4 substituents R ^{4 are} substituted, and R ^{4 is} independently selected from the group consisting of: -O-CH ₃ , pendant oxy, -OH, -F, -CF ₃ , - CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl, 5 or 6 members include 1 Or two saturated heterocycles each independently selected from the group consisting of N, S and O; -NH-CO-CH ₃ , -C _1-3 alkyl-N (C _1-3 alkyl) )-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl. , propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF ₃ , -CH ₂ -CF ₃ , -CHF ₂ , CH ₂ F, -CF ₂ -CF ₃ , -OH, Halogen, -extended ethyl-CF ₃ , 5 or 6 members comprising 1, 2 or 3 each independently selected from each other a saturated heterocyclic ring of a hetero atom consisting of N, S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may optionally be via a pendant oxy group, a methyl group and a group consisting of -CF ₃ The group is substituted, and the pharmacologically acceptable salt of the above compound. The compound of formula 1 of claim 14, wherein R ² is a 5-membered monocyclic heteroaryl group comprising 1, 2 or 3 heteroatoms each independently selected from the group consisting of N, S and O; wherein the 5 member is a cycloheteroaryl group is attached to the quinoline core structure via a carbon atom, and wherein the 5-membered monocyclic heteroaryl group is further substituted as described in claim 14 and the pharmacologically acceptable of the above compounds salt. A compound of formula 1 according to claim 14 wherein R ² is a 5-membered monocyclic heteroaryl containing at least one nitrogen atom and optionally 1 or 2 other heteroatoms each independently selected from the group consisting of N, S and O Wherein the 5-membered monocyclic heteroaryl group is attached to the quinoline core structure via a nitrogen atom, and wherein the 5-membered monocyclic heteroaryl group is further substituted, as specified in claim 14, and the above compound Pharmacologically acceptable salt. A compound of formula 1 according to claim 1 or 2, wherein R ² is 9 or 10 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-heteroatoms each independently selected from the group consisting of N, S and O but not completely saturated aromatic heterocyclic ring; wherein R ² is optionally substituted by 1, 2, ⁴ or 4 substituents R, R ⁴ are independently from each other selected from the group consisting of: linear or branched -OC _{1- 3} alkyl, pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ ,- CH ₂ —CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; -NH-CO-CH ₃ , -C _1-3 alkyl-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)- O-CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , -C _1-3 alkylene-O-CO-C _{1 -3} alkyl and Wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, -C _1-3 haloalkyl , -OH, halogen, -C _1-2 alkyl-C _1-3 haloalkyl, 5 or 6 members comprising 1, 2 or 3 each independently selected from the group consisting of N, S and O a saturated heterocyclic ring of an atom; a 3, 4, 5, 6 or 7 membered cycloalkyl group; wherein R ⁵ may be optionally substituted with a group consisting of a pendant oxy group, a methyl group and a -CF ₃ group, and the pharmacologically acceptable compound of the above compound Accept the salt. A compound of formula 1 according to claim 17, wherein R ² is 9 or 10 members comprising 1, 2, 3 or 4 bicyclic aromatic or non-aromatic groups each independently selected from the group consisting of N, S and O heteroatoms However, the heterocyclic ring is not completely saturated; wherein R ² may be optionally substituted by 1, 2, 3 or 4 substituents R ⁴ , and R ^{4 is} independently selected from the group consisting of: -O-CH ₃ , -O-ethyl acceptable, -O- propyl, -O- isopropyl, oxo, -OH, -F, -CF _3, methyl, ethyl, propyl and isopropyl, and pharmacology of the compounds described above Salt. A compound of formula 1 according to claim 14, wherein R ² is pyridine, wherein R ^{2 is} optionally substituted with 1, 2, 3 or 4 substituents R ⁴ , and R ^{4 is} independently selected from the group consisting of: -O- CH ₃ , pendant oxy, -OH, -F, -CF ₃ , -CHF ₂ , -SO ₂ CH ₃ , -CH ₂ -SO ₂ -CH ₃ , -SO ₂ -CF ₃ , -CH ₃ , -CH _2- CH ₃ , propyl, isopropyl, 5 or 6 members comprising 1 or 2 saturated heterocyclic rings each independently selected from the group consisting of N, S and O; -NH-CO-CH ₃ , -C _1-3 alkylene-N(C _1-3 alkyl)-CO-C _1-3 alkyl, -CO-NH(CH ₃ ), -(C _1-3 alkylene)-O- CO-CH ₃ , -CO-NH ₂ , -CO-N(CH ₃ ) ₂ , -O- R ⁵ , -CO- R ⁵ , wherein R ⁴ may be optionally substituted with 1 or 2 substituents R ⁵ , wherein Each R ^{5 is} independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF ₃ , -CH ₂ -CF ₃ , -CHF ₂ , CH ₂ F, -CF ₂ -CF ₃ , -OH, halogen, -C _1-2 alkylene-CF ₃ , 5 or 6 members comprising 1, 2 or 3 each independently selected from N a saturated heterocyclic ring of a hetero atom of a group consisting of S and O; a 3, 4, 5, 6 or 7 membered cycloalkyl group; R ⁵ optionally substituted by oxo group, consisting of -CF ₃ and methyl, and pharmaceutically acceptable salts of the above compounds. A compound of formula 1 according to claim 19, wherein R ² is pyridine, wherein R ² is substituted by 1 or 2 R ⁴ , and R ^{4 is} independently of each other selected from the group consisting of: -O-CH ₃ , -OH, -F , -CF ₃ , -CHF ₂ , -CH ₃ , -CH ₂ -CH ₃ , propyl, isopropyl and -O- R ⁵ , wherein R ^{5 is} selected from the group consisting of methyl, ethyl, and propyl Base, isopropyl, -CF ₃ , -CHF ₂ , CH ₂ F, -CH ₂ -CF ₃ , -CF ₂ -CF ₃ , and a pharmacologically acceptable salt of the above compound. The compound of formula 1 of claim 1, wherein R ^{1 is} selected from the group consisting of: And wherein R ^{2 is} selected from the group consisting of: And a pharmacologically acceptable salt of the above compound. A compound of formula 1 of claim 1 which is selected from the group consisting of And a pharmacologically acceptable salt of the above compound. A compound of claim 1 or 2 for use as a medicament. Use of a compound according to any one of claims 1 to 22 for the manufacture of a medicament for the treatment of a condition which can be treated by inhibition of the SYK enzyme. Use of a compound according to any one of claims 1 to 22 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis , pulmonary hypertension, B-cell lymphoma, dermatitis and contact dermatitis, atopic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, antiphospholipid syndrome, Berger's disease, Evans's disease Syndrome), ulcerative colitis, allergic antibody-based spheroid nephritis, neutropenia, Goodpasture's syndrome, hepatitis, Henoch-Schönlein purpura, allergies Vasculitis, immune hemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematosus, capsular cell lymphoma, neutrophil reduction , non-familial lateral sclerosis, Crohn's disease, multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic disease Osteopenia, psoriasis, Sjogren's syndrome (Sjögren's syndrome), scleroderma, T-cell lymphoma, urticaria / angioedema, Wegener's granulomatosis (Wegener's granulomatosis), atherosclerosis and celiac disease. The use of the compound of claim 25, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, and adult respiratory distress syndrome Group, bronchitis, atopic dermatitis, contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, atherosclerosis and allergic rhinoconjunctivitis. The use of a compound according to any one of claims 25 and 26, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, atopic dermatitis and rheumatoid arthritis. A pharmaceutical formulation comprising one or more compounds of formula 1 according to any one of claims 1 to 22. A pharmaceutical formulation characterized by comprising one or more compounds of formula 1 according to any one of claims 1 to 22 in combination with an active substance selected from the group consisting of anticholinergic agents, beta mimics, Corticosteroids, PDE4 inhibitors, EGFR inhibitors, LTD4 antagonists, CCR3 inhibitors, CRTH2 antagonists, CCR1 antagonists, NSAIDS, COX 2 inhibitors (Coxibe), iNOS inhibitors, HMG-CoA reductase inhibitors, and folic acid An antagonist, such as methotrexate. a compound selected from the group consisting of formula 6 Wherein R ¹ and R ^{2 are} as defined in any one of claims 1 to 20.