NZ619197B2 - Substituted quinolines and their use as medicaments - Google Patents

Substituted quinolines and their use as medicaments Download PDF

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Publication number
NZ619197B2
NZ619197B2 NZ619197A NZ61919712A NZ619197B2 NZ 619197 B2 NZ619197 B2 NZ 619197B2 NZ 619197 A NZ619197 A NZ 619197A NZ 61919712 A NZ61919712 A NZ 61919712A NZ 619197 B2 NZ619197 B2 NZ 619197B2
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New Zealand
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group
chiral
substituted
c1alkylene
optionally
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NZ619197A
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NZ619197A (en
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Daniel Bischoff
Serge Gaston Conversreignier
Georg Dahmann
Stephen Peter East
Matthias Hoffmann
Jasna Klicic
Frederic Jacques Marlin
Clive Mccarthy
Gerhard Schaenzle
John Scott
Reignier Serge Gaston Convers
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Boehringer Ingelheim International Gmbh
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Priority claimed from PCT/EP2012/064172 external-priority patent/WO2013014060A1/en
Publication of NZ619197A publication Critical patent/NZ619197A/en
Publication of NZ619197B2 publication Critical patent/NZ619197B2/en

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Abstract

Disclosed herein are 5-oxygen substituted quinolines of formula (1) wherein R1 is a linear or branched C1-6-alkyl, wherein R1 is substituted by R3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkyl; 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 and the other substituents are as defined herein. Also disclosed is the use of the compounds in the preparation of medicaments for the treatment of diseases such as asthma, COPD, allergic rhinitis, allergic dermatitis and rheumatoid arthritis. erocycle 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 and the other substituents are as defined herein. Also disclosed is the use of the compounds in the preparation of medicaments for the treatment of diseases such as asthma, COPD, allergic rhinitis, allergic dermatitis and rheumatoid arthritis.

Description

Substituted Quinolines and Their Use As Medicaments According to a first aspect of the present invention, there is provided a compound of formula N R2 1, wherein R1 is a linear or branched C1alkyl, wherein R1 is tuted by R3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkyl; a five-, six- or seven-membered, saturated heterocycle comprising one, two or three atoms 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 ndently selected from the group consisting of N, S and O; wherein R3 may optionally be tuted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, 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 omatic, but not fully saturated heterocycle comprising one, two, three or four heteroatoms each independently ed from the group consisting of N, S and O; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of linear or branched –O-C1alkyl, -OH, oxo, halogen, -C1haloalkyl, 3, -C1alkylene-SO2-C1alkyl), -SO2-CF3, -CN, -C3cycloalkyl, linear or branched -C1alkyl, a four, five- or six-membered (10784852_1):JJC ted heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S, -SO2 and O; -C1alkylene-N(C1alkyl)-CO-C1alkyl, -NH-CO-C1alkyl, -CO-NH(CH3), -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1alkylene-O-CO-C1alkyl and * NH wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one r selected from the group consisting of linear or branched -C1alkyl, oxo,-C1haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or sixmembered saturated cycle comprising one, two or three heteroatoms each ndently ed from the group of N, S and O, a three, four-, five-, six- or sevenmembered cycloalkyl, a five- or six-membered heteroaryl comprising one or two atoms each independently selected from the group consisting of N, O and S, wherein R5 may optionally be tuted by a group consisting of oxo,-C1alkyl and haloalkyl, or a pharmacologically acceptable salt of the aforementioned compound.
According to a second aspect of the present invention, there is provided use of a compound according to the first aspect above 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, allergic dermatitis, allergic rhinoconjunctivitis, toid arthritis, anti-phospholipid syndrome, Berger's disease, Evans's me, ulcerative colitis,allergic antibody-based glomerulonephritis, granulocytopenia, Goodpasture's syndrome, hepatitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, immunohaemolytic anaemia, autoimmune haemolytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematodes, capsule cell lymphoma, penia, non-familial lateral sclerosis, Crohn's disease, multiple sclerosis, myasthenia , osteoporosis, ytic diseases, osteopenia, psoriasis, Sjögren's (10784852_1):JJC syndrome, dermy, T-cell lymphoma, ria / angiooedema, r's granulomatosis, artheriosclerosis and coeliac disease.
According to a third aspect of the t invention, there is provided a pharmaceutical formulation characterised in that it contains one or more compounds of formula 1 according to the first aspect above.
According to a fourth aspect of the present invention, there is provided a pharmaceutical formulation characterised in that it contains one or more nds of formula 1 according to the first aspect above in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, 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 antagonists such as methotrexate.
According to a fifth aspect of the t invention, there is provided an intermediate compound selected from formula B N B and from formula C N B OH C, wherein R1 is defined as in the first aspect above. (10784852_1):JJC The invention relates to new substituted quinolines of formula 1 N R2 1, wherein R1 is a linear or branched C1alkyl, wherein R1 may optionally be substituted by R3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered lkyl; 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 mbered aryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; n R3 may optionally be substituted by one, two, three or four substituents each independently from the other selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), lkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, and wherein R2 is selected from the group consisting of halogen, phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three atoms each independently selected from the group consisting of N, S and O; a bicyclic, nine-, ten- or -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; (10784852_1):JJC WO 14060 wherein R2 may optionally be substituted by one, two, three or four substituents R4 which ndently from one another are selected from the group consisting of linear or branched —O-C1_5-alkyl, -OH, oxo, halogen, -C1_5-haloalkyl, -S02CH3, -C1alkylene-S02-(C1alkyl), - g, -CN, C3_6-cycloalkyl,linear or branched -C1_5-alkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group ofN, S, -S02 and O; -C1_3-alkylene-N(C1alkyl)-CO-C1_3-alkyl, -NH-CO-C1_3-alkyl, -CO-NH(CH3), -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1alkylene-O-CO-C1alkyl and wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one another selected from the group consisting of linear or branched -C1_4-alkyl, oxo; -C1_3-haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or six- membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group ofN, S and O; a three, four-, five-, siX- or seven- ed cycloalkyl; a five- or six-membered heteroaryl sing one or two heteroatoms each independently selected from the group ofN, S and 0, wherein R5 may optionally be substituted by a group consisting of oxo, C1_3-alkyl and haloalkyl, and the pharmacologically acceptable salts of the aforementioned compounds.
WO 14060 1. Background to the invention 1.1 SYK-inhibitors The present invention describes new substituted quino lines that inhibit the protein kinase Syk n tyrosine Kinase), the preparation and formulation thereof and their use for preparing a medicament.
Syk is an intracellular tyrosine kinase that has an important mediator flinction in the signal transduction of different receptors in B-cells, mast cells, monocytes, macrophages, neutrophils, T-cells, dendritic cells and epithelial cells. The receptors in which Syk performs an important on in signal uction include for example the ors for IgE (FcéRI) and IgG (Fcle) on mast cells and B cells, the B-cell receptor (BCR) and the T-cell receptor (TCR) on B- and s, the ICAMl receptor (ICAMlR) on epithelial cells of the respiratory tract, the DAP12-recept0r on natural killer cells, dendritic cells and osteoclasts, the dectin 1- receptor on a subpopulation of T-helper cells (Th-17 cells), as well as the integrin receptors for 131-, [32- and B3-integrins on phils, monocytes and macrophages (Wong et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.; Expert Opion. Ther.
Target (2005) 9(5); 901-921; Wang et al.; J. Imrnunol. (2006) 177, 6859-6870; Leib und Gut- Landmann et al.; Nature Immunology (2007) 8, 630-638; Slack et al., European J. Imrnunol. (2007) 37, 1600-1612). The molecular processes are described best for the signal transduction of the FcéRI. In mast cells the binding of IgE to FcéRI causes the cross-linking of IgE-receptors and the recruiting and tion of Lyn (a tyrosine kinase from the Src family). Active Lyn phoshorylates so-called ITAM motifs, which are present in many ofthe receptors listed above, and thereby generates binding sites for the SH2-domain of Syk. As a result of the g to the ITAM motif Syk is activated and then phosphorylates various substrates which are needed for the e of allergic and inflammatory ors such as e. g. histamine and B-hexosamidase (BHA), as well as for the synthesis of lipid ors, such as e. g. prostaglandins and leukotrienes.
In view of its l flinction in different signal transduction pathways Syk has been discussed as a therapeutic target for different diseases such as e. g. allergic rhinitis, asthma, autoimmune diseases, rheumatoid arthritis, osteopenia, osteoporosis, COPD and s leukaemias 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) V0142; 1; Bajpai et al.; Expert Opin.
Investig. Drugs (2008) Vol 15 (5); 641-659; Masuda and Schmitz; PPT (2008) V0121; 461- 467; Riccaboni et al., Drug Discovery Today (2010) V0100 (0); 517-530; Efremov and Luarenti, Expert Opin Investig Drugs. (2011) 20(5):623-36). _ 4 _ Allergic rhinitis and asthma are diseases associated with allergic reactions and inflammatory processes and involving different cell types such as e. g. Mast cells, eosinophils, T-cells and dendritic cells. After re to allergens has occurred, the high aff1nityimmunoglobulin receptors for IgE (FcéRI) and IgG (Fcle) are activated and induce the release of pro- inflammatory mediators and bronchoconstrictors. An inhibitor of the Syk kinase activity should thus be able to inhibit these steps. toid arthritis (RA) is an autoimmune disease in which the bones and ligaments structures surrounding the joints are ssively destroyed. In the pathophysiology of RA, B-cells play a significant role, as has been trated for e by the therapeutic use of rituximab, a B cell-depleting antibody. In addition to the fianction of Syk in the signal transduction of the BCR (which after being stimulated also induces the release ofpro- inflammatory mediators), Syk also plays an important part in the maturation and proliferation ofB cells (Cheng et al. Nature (1995) 378, 303-306, Comall et al., PNAS (2000) 97(4), 1713- 1718). An inhibitor of the Syk kinase activity may thus offer a therapeutic option for the treatment of autoimmune diseases such as RA and diseases with an increased eration of B cells, such as e.g. B-cell lymphomas. c obstructive pulmonary disease (COPD) is characterised by a successive deterioration in lung fianction and chronic inflammation ofthe airways, which is ted and produced by noxious substances of all kinds and butes to the maintenance of the course of the disease. At a ar level, in COPD there is in particular a lication of T-lymphocytes, neutrophils, granulocytes and macrophages. In ular, there is an increase in the number of CD8-positive lymphocytes, that is directly connected with the ment of lung fianction.
Another characteristic of COPD are acute deteriorations in lung fianction (exacerbations), characterised by viral (e.g. Rhinovirus), or bacterial (e.g. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) infections.
In view ofthe pro-inflammatory fianction of Syk in macrophages, T-cells and neutrophils as described above (see: Wong et al.; Expert Opin. Investig. Drugs (2004) 13(7), 743-762; and references cited therein) an inhibitor of the Syk kinase ty could be a new therapeutic approach to the treatment of the inflammatory processes that underlie COPD. It has also been shown that Syk in epithelial cells of the atory tract is involved in the ICAMlR—mediated uptake and subsequent replication of the Rhinovirus and that a si-RNA against Syk blocks these steps (Wang et al.; J. Imrnunol. (2006) 177, 6859-6870; Lau et al.; J. Imrnunol. (2008) 180, 870-880). Thus, an inhibitor of the Syk kinase activity could also be used therapeutically in exacerbations caused by Rhinoviruses. _ 5 _ s studies suggest that Syk is involved in the malignant transformation of lymphocytes (summarised in Sigh and Masuda, Annual Reports in Medicinal Chemistry (2007) V0142; 1). A TEL-Syk filSlOIl n with a constitutive Syk activity transformed B cells of a patient with myelodysplastic syndrome, a constitutively active ITK—Syk filSlOIl protein was isolated from patients with peripheralT-cell lymphomas (PTCL). Moreover, constitutively active Syk was found in B-cell lymphoma cells of ts, especially in B-lineage acute lymphoblastic leukemia (B-ALL), follicular lymphoma (FL), diffilse large B-cell lymphoma ), mantle cell lymphomas and B cell Non-Hodgkin Lymphomas (NHLs) as well as in acute myeloid leukemia (AML). On the basis ofthese data it seems that Syk is a proto- oncogene in haematopoietic cells and represents a potential target for the treatment of certain leukaemias and lymphomas.
Idiophathic thrombocytoenic purpura (ITP) is an autoimmune disease in which IgG autoantibodies against antigens present on ets bind to and destroy platelets. Patients with ITP have an accelerated clearence of circulating ated platelets via macrophages in the spleen and the liver. In view of the pro-inflammatory FcyR—mediated function of Syk in hages an inhibitor of Syk is considered to have a therapeutic benefit in FcyR—mediated cytopenias like ITP. Indeed the Syk tor R788 (R406) improved et counts in a single center, oben label study in patients with ITP (Podolanczuk et al; Blood (2009) 113, 3 154-3 169). s pemphigoid (Ujiie et al. Journal of Dermatology 2010; 37: 194—204) is a chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes.
Bullous pemphigoid is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the smosomal bullous pemphigoid antigens BP230 (BPAgl) and BP180 (BPAg2). Pemphigus vulgaris (Venugopal et al. Dermatol. Clin. 2011;29:373-80) is a chronic blistering skin disease with skin lesions that are rarely pruritic, but which are often painful. Pemphigus vulgaris is an autoimmune disease caused by IgG autoantibodies directed against both desmoglein 1 and desmoglein 3 resulting in the loss of cohesion n nocytes in the epidermis. It is characterized by extensive flaccid blisters and mucocutaneous erosions. In both es IgG autoantibodies bind to PC receptor gamma (FcRg) and activate FcRg and downstream signaling via Syk kinase. Thus, an inhibitor of the Syk kinase activity which blocks downstream signalling of the FcRg could be used therapeutically to treat patients with bullous goid and pemphigus vulgaris. _ 6 _ Systemic lupus erythematosus (SLE) is a c autoimmune disease which can affect lly any organ of the body. It is characterised by a multisystem inflammation of the microvascular and the ce of autoantibodies. FcyR—deficient mice are protected from several aspects of SLE in disease-related preclinical models, suggesting that an inhibitor of Syk can have a therapeutic benefit in SLE in view of the pro-inflammatory FcyR—mediated function of Syk in various cells. 1.2 Prior art US Patents Nos. US 3,928,367, US 4,017,500, US 4,115,395 and US 4,260,759 be 5- amino-1,6-naphthyridines with an antifiangal and antibacterial activity. WO 9918077 describes 5-piperazinyl-1,6-naphthyridines as serotonin antagonists. US Patent US 041 describes substituted 1,6-naphthyridines as SYK-inhibitors, however these 1,6-naphthyridines have a completely different substitution pattern from the compounds according to the invention. PCT/EP1011050871 discloses 1,6-naphthyridines which are tuted in 5- and in 7-position. In st to that the instant invention concerns 5-,7-disubsituted quinolines d of naphthyridines.
WO 2006038041 discloses quinoline-compounds which are substituted in the 5- and 7- position, however the substitution pattern — in particular in the 7-position — is tely different from the one of the quino lines of formula 1 of the instant invention.
Surprisingly it has now been found that quinolines of formula 1 are particularly suitable for the treatment of respiratory complaints, allergic diseases, osteoporosis, gastrointestinal diseases, autoimmune diseases, inflammatory diseases and diseases of the peripheral or central s system, particularly for the treatment of asthma, allergic rhinitis, rheumatoid arthritis, allergic dermatitis and COPD. 2. DESCRIPTION OF THE INVENTION The present ion therefore relates to compounds of formula 1, wherein R1 is a linear or branched lkyl, wherein R1 may optionally be substituted by R3 which is selected from the group consisting of a three-, four-, five-, siX- or seven-membered cycloalkyl; a five-, siX- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each independently ed from the group consisting ofN, S and O; and a five- or six-membered heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and 0; wherein R3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1_5-alkyl, -C1_3-alkylene-CO-NH2, alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, alkylene-CN and -CN, and wherein R2 is selected from the group consisting of halogen, , a five- or six-membered monocyclic heteroaryl sing one, two or three heteroatoms each independently selected from the group consisting ofN, S and O; a bicyclic nine-, ten— or eleven-membered, either aromatic or non-aromatic, but not fially saturated heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting ofN, S and O; wherein R2 may optionally be substituted by one, two, three or four tuents R4 which independently from one another are selected from the group consisting of linear or branched —O-C1_5-alkyl, -OH, oxo, halogen, -C1_5-haloalkyl, -S02CH3, -C1alkylene-SOz-C1alkyl), -SOz-CF3, -CN, -C3_6-cycloalkyl, linear or branched alkyl, a four, five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group ofN, S, -S02 and O; alkylene-N(C1alkyl)-CO-C1_3-alkyl, -NH-CO-C1_3-alkyl, -CO-NH(CH3), -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1_3-alkylene-O-CO-C1alkyl and n R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one r selected from the group consisting of linear or branched -C1_4-alkyl, oxo,-C1_3-haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or six- membered saturated heterocycle comprising one, two or three atoms each independently selected from the group ofN, S and O, a three, four-, five-, siX- or seven- membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently ed from the group consisting ofN, O and S, wherein R5 may optionally be substituted by a group consisting of oxo,-C1_3-alkyl and -C1_3-haloalkyl, and the pharmacologically acceptable salts of the aforementioned compounds.
In another embodiment the invention relates to the above-mentioned compounds of a 1, wherein R1 is ed from the group consisting of —CH3 and -CH2-(CH3) which may optionally be substituted by R3 which is selected from the group consisting of a three-, four-, five-, six- or _ 9 _ membered cycloalkl; a five-, siX- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and O; and a f1ve- or six-membered heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and 0; wherein R3 may ally be substituted by one, two, three or four tuents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), - CO-N(CH3)2, -C1_5-alkyl, -C1_3-alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), -C1_3- alkylene-CO-N(CH3)2, alkylene-CN and -CN, and the pharmacologically acceptable salts of the aforementioned nds.
In a fiarther aspect the instant invention s to the above compounds of formula 1, wherein R1 is substituted by R3 which is selected from the group ting of a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group consisting ofN, S and O, wherein R3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), - CO-N(CH3)2, -C1_5-alkyl, -C1_3-alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), _C1_3- alkylene-CO-N(CH3)2, -C1_3-alkylene-CN and -CN, and the pharmacologically acceptable salts of the aforementioned compounds.
Further, the instant invention refers to the above compounds of formula 1, wherein R1 is substituted by R3 which is ed from the group consisting of a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting ofN, S and O, wherein R3 may ally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1_5-alkyl, -C1_3-alkylene-CO-NH2, alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1_3-alkylene-CN and -CN, _ 10 _ and the pharmacologically acceptable salts of the aforementioned nds.
In another embodiment the instant invention relates to the above-mentioned compounds of formula 1, wherein R1 is a selected from the group consisting of —CH3 or -CH2(CH3), wherein R1 may optionally be substituted by R3 which is selected from the group consisting of a three-, four-, five- or mbered cycloalkl; a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group ting ofN, S and O; and a f1ve- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting ofN, S and 0; wherein R3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, -CO-NH2, O-NH2, methyl and -CH2-CN, and the cologically acceptable salts of the aforementioned nds.
In a preferred embodiment the t invention refers to the compounds of formula 1, wherein R1 is selected from the group consisting of —CH3 and —CH2-CH3, wherein R1 is substituted by R3 which is a f1ve-membered saturated heterocycle comprising one nitrogen-atom, wherein R3 is substituted by one oxo-group and the pharmacologically acceptable salts of the aforementioned compounds.
In a r particularly preferred embodiment the invention relates to the above compound of formula 1, wherein R1 is the group WO 14060 _ 11 _ \\ Z and the pharmacologically acceptable salts of the aforementioned compounds.
In a fiarther preferred embodiment the t invention refers to the above compounds of formula 1, wherein R1 is selected from the group consisting of —CH3 and —CH2-CH3, n R1 is substituted by R3 which is a six-membered heteroaryl comprising one nitrogen- atom, wherein R3 is substituted by 2, and the pharmacologically acceptable salts of the aforementioned compounds.
In a fiarther particularly preferred embodiment the instant invention s to compounds of formula 1, wherein R1 is the group 0 NH2 * \ and the pharmacologically acceptable salts of the aforementioned compounds.
In a fiarther embodiment the invention relates to the above nds of formula 1, wherein R2 is selected from the group consisting of R2 is selected from the group consisting of phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and O; a bicyclic, nine- or ten-membered, either aromatic or non- _ 12 _ aromatic, but not fially saturated cycle comprising one, two, three or four atoms each ndently selected from the group consisting ofN, S and 0; wherein R2 may optionally be tuted by one, two, three or four substituents R4 which independently from one another are selected from the group ting of linear or branched —O-C1_3-alkyl, oxo, -OH, -F, -Cl, -CF3, -CHF2, -S02CH3, -CH2 -SOz-CH3, -SOz-CF3, -CH3, - CHz-CHg, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group ofN, S, S02 and O; -NH-CO- CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1_3-all<ylene-O-CO-C1alkyl and *KNH2 wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one another selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, yl, tert-butyl, -C1_3-haloalkyl, oxo, -OH, halogen, - C1_2-alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group ofN, S and O, a three, four-, five-, siX- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteratoms each independently selected from the group consisting of N, S and 0, wherein R5 may optionally be substituted by a group consisting of oxo, , ethyl, -CF3, and the pharmacologically acceptable salts of the aforementioned compounds.
The instant invention further relates to the above nds of formula 1, wherein R2 is phenyl, _ 13 _ wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one r are selected from the group consisting of linear or branched 3-alkyl, oxo, -OH, -F, -Cl, -CF3, -CHF2, -S02CH3, -CH2 -SOz-CH3, -SOz-CF3, -CH3, - CHz-CHg, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group ofN, S and O; -NH-CO-CH3, -C1_3-alkylene-N(C1alkyl)-CO-C1_3-alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, CH3)2, -O-R5, -CO-R5, -C1_3-alkylene-O-CO-C1alkyl and wherein R4 may optionally be substituted by one or two substituents R5 wherein each R5 is ndently selected from the group consisting of methyl, ethyl, propyl, isopropyl,m isopropyl, l, isobutyl, tert-butyl, oxo, -C1_3-haloalkyl, -OH, halogen, -C1_2-alkylene- C1_3-haloalkyl, a five- or six-membered saturated cycle sing one, two or three atoms each independently selected from the group ofN, S and O, a three, four-, five-, siX- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting ofN, S and 0, wherein R5 may optionally be substituted by a group consisting of oxo, methyl, and the pharmacologically acceptable salts of the aforementioned compounds.
In another embodiment the instant ion refers to the above-mentioned compounds of formula 1, wherein R2 is phenyl, and wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group ting of —OCH3, oxo, -OH, -F, Cl, -CF3, -CHF2, -S02CH3, -SOz-CF3, -CH3, -CH2-CH3, propyl, isopropyl; -NH-CO-CH3, -C1_3-alkylene-N(C1alkyl)-CO-CH3, -CO-NH(CH3), _ 14 _ -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1_3-alkylene-O-CO-C1alkyl and *KNH wherein R4 may optionally be substituted by one or two tuents R5, wherein each R5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, pyl, n-butyl, isobutyl, tert-butyl, -C1_3-haloalkyl, -OH, halogen, -C1_2-alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group ofN, S and O, a three, four-, five-, siX- or seven-membered cycloalkyl, wherein R5 may optionally be substituted by a group ting of oxo, methyl, and the cologically acceptable salts of the aforementioned compounds.
The invention further relates to the above compounds of formula 1, wherein R2 is a five- or six-membered monocyclic heteroaryl sing one, two or three atoms each independently selected from the group consisting ofN, S and 0; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which ndently from one another are selected from the group consisting of—O-methyl, -O- ethyl, -O-propyl, -O-isopropyl, oxo, -OH, -F, -CF3, -CHF2, -S02CH3, -CH2 -SOz-CH3, -SOz-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle sing one or two heteroatoms each independently selected from the group ofN, S and O; -NH-CO-CH3, alkylene-N(C1alkyl)-CO-C1_3-alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1_3-alkylene-O-CO-C1alkyl and *KNH2 _ 15 _ wherein R4 may optionally be substituted by one or two substituents R5 wherein each R5 is independently selected from the group ting of methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, tert-butyl, -C1_3-haloalkyl, -OH, n, -C1alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group ofN, S and O, a three, four-, five-, siX- or seven- membered cycloalkyl, wherein R5 may ally be substituted by a group consisting of oxo, methyl and —CF3, and the pharmacologically acceptable salts of the aforementioned compounds.
The invention ns in another embodiment the above compounds of formula 1, wherein R2 is a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and 0; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of—O-CH3, oxo, -OH, -F, -CF3, -CHF2, -S02CH3, -CH2 -SOz-CH3, -SOz-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered ted cycle comprising one or two heteroatoms each independently from one r selected from the group ofN, S and O; -NH-CO-CH3, -C1_3-alkylene-N(C1alkyl)-CO-C1_3-alkyl, (CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, wherein R4 may optionally be substituted by one or two substituents R5 wherein each R5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -CHF2, CHZF, -CF2-CF3, -OH, n, -ethylen- CF3, a five- or six-membered saturated heterocycle sing one, two or three heteroatoms _ 16 _ each independently from one another ed from the group ofN, S and O, a three, four-, five-, siX- or membered cycloalkyl, wherein R5 may optionally be substituted by a group ting of oxo, methyl and —CF3, and the pharmacologically acceptable salts of the aforementioned compounds.
The instant invention further concerns the above compounds of formula 1, wherein R2 is a five-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group consisting ofN, S and 0; whereby this five-membered monocyclic heteroaryl is linked to the quinoline-core —structure via a carbon atom and wherein this five-membered monocyclic heteroaryl optionally may be fiarther substituted as identified in claim 14, and the pharmacologically acceptable salts of the aforementioned compounds.
The instant invention also relates to compounds of formula 1, wherein R2 is a five-membered monocyclic heteroaryl sing at least one nitrogen atom and optionally one or two r atoms each independently selected from the group consisting ofN, S and 0; whereby this five-membered monocyclic heteroaryl is linked to the quinoline-core —structure via a nitrogen atom, and wherein this mbered monocyclic heteroaryl optionally may be r substituted as identified in claim 14, and the pharmacologically acceptable salts of the aforementioned compounds.
In another embodiment the instant ion relates to the above compounds of formula 1, wherein R2 is a bicyclic, nine- or ten-membered, either aromatic or non-aromatic, but not fully ted heterocycle comprising one, two, three or four heteroatoms each independently selected from the group consisting ofN, S and O; WO 14060 _ 17 _ wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of linear or branched —O-C1_3-alkyl, oxo, -OH, -F, -CF3, -CHF2, -S02CH3, -CH2 -SOz-CH3, F3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently from one another ed from the group ofN, S and O; -NH-CO-CH3, alkylene-N(C1alkyl)-CO-C1_3-alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1_3-alkylene-O-CO-C1alkyl and *KNH2 wherein R4 may optionally be tuted by one or two tuents R5 wherein each R5 is independently selected from the group consisting of methyl, ethyl, propyl, pyl, -C1_3-haloalkyl, -OH, halogen, -C1_2-alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group ofN, S and O, a three, four-, five-, siX- or seven-membered cycloalkyl, wherein R5 may optionally be substituted by a group consisting of oxo, methyl and —CF3, and the pharmacologically acceptable salts of the aforementioned compounds.
The invention further relates to the above compounds of formula 1, wherein R2 is a bicyclic, nine- or ten-membered, either aromatic or non-aromatic, but not fillly saturated heterocycle comprising one, two, three or four atoms each independently selected from the group consisting ofN, S and 0; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of -O-CH3, -O-ethyl, -O-propyl, -O-isopropyl, oxo, -OH, -F, -CF3, methyl, ethyl, propyl and isopropyl, _ 18 _ and the pharmacologically able salts of the entioned compounds.
In a preferred embodiment the invention refers to the above compounds of formula 1, wherein R2 is pyridine, wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of—O-CH3, oxo, -OH, -F, -CF3, -CHF2, -SOZCH3, -CH2 -SOz-CH3, -SOz-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group ofN, S and O; -NH-CO-CH3, -C1_3-alkylene-N(C1alkyl)-CO-C1_3-alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, wherein R4 may optionally be substituted by one or two substituents R5 n each R5 is independently from one another selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, utyl, -CF3, -CH2-CF3, -CHF2, CHZF, -CF2-CF3, -OH, halogen, alkylene-CF3, a five- or six-membered ted heterocycle comprising one, two or three heteroatoms each independently from one another selected from the group ofN, S and O, a three, four-, five-, siX- or seven-membered cycloalkyl, wherein R5 may optionally be substituted by a group consisting of oxo, methyl and —CF3 and the pharmacologically acceptable salts of the aforementioned nds.
In a fiarther preferred ment the invention relates to the above compounds of formula 1, wherein R2 is pyridine, _ 19 _ wherein R2 is substituted by one or two R4 which independently from one another are ed from the group consisting of—O-CH3, -OH, -F, -CF3, -CHF2, -CH3, -CH2-CH3, , isopropyl and -O-R5, wherein R5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CF3, -CHF2, CHZF, -CH2-CF3, -CF2-CF3 and the pharmacologically acceptable salts of the aforementioned compounds.
In a particularly preferred embodiment the instant invention relates to the above compounds according to formula 1, wherein R1 is selected from the group consisting of m J \\< o * * * . . . . o .. o .
O N H2N o 0 NH2 N l l 0% CH3 * \ CH3 N / 2 * * ;; and ; and n R2 is selected from the group consisting of WO 14060 CH3 . CH3 H3C CH3 * ; F * * *CEO \CH / 3 40 9 9 * OH F \Br . CH3. CH3. CH3 * N N * N/\ \I N o N=/ . . * * 9H3 O / N CH3 N N T ,N I I I II N N _ NH2 O.
WO 14060 * * \ N \ N I \‘N / / O / o A ‘13 H3C H3C CH3 F CH3.
* N |\ \> N N\ N F CH3 . o . o .
\N * O\ N | \\ CH3 \> / l/ 00 N \ ? CH3. 04 \CH&. CH3 _ * 0 \CH3 N—CH3 . .
N/ * o \ N F \ /N * CH3 \m / \ U4 N F CH3 _ CH3 \N \[jN\ * N’CH3 * N F \ / * w MF N 3 w and the pharmacologically acceptable salts of the aforementioned compounds.
In another particularly preferred embodiment the invention s to the above compounds according to formula 1 selected from the group consisting of CH3 Chiral WO 14060 _ 23 _ Chiral (_:H3 C“”""' \ CH3 0 | / o CH3 _ O Chiral o Chiral N Chiral o 0% 0 Chiral O Chiral O Chiral N N—< N—< O O Chiral Chiral O/Y\N O Chiral o Chiral N—/( N WO 14060 Chiral Chiral Chiral Chiral Chiral WO 14060 _ 25 _ 9H3 Chiral N | .
I I I Chiral CH Chiral CH Chiral O Chiral CH Chiral WO 14060 HZN / O (EH3 Chiral CH3 Chiral 9H3 Chiral CH3 Chiral Chiral WO 14060 _ 27 _ Chiral (EH3 Chiral H2N o o l O N \ \ lN I I H N O 2 ¢ CH Chiral H N /O (:DH3 Chiral 2 / F F N / \ /N4 N F I I CH3 Chiral Chiral CH3 Chiral WO 14060 _ 28 _ O Chiral // N CH3 Chiral CH3 Chiral 9H3 Chiral Chiral O Chiral Chiral and the cologically acceptable salts of the aforementioned compounds.
The instant invention r concerns the above-mentioned compounds of formula 1 for use as medicaments.
In a fithher embodiment the invention concerns the use ofthe above compounds according to formula 1 for the manufacture of a medicament for the treatment of a disease which can be treated by inhibition of the SYK enzyme.
In a fiarther embodiment the invention concerns the above compounds according to formula 1 for the treatment of a disease which can be treated by inhibition of the SYK enzyme.
In a preferred embodiment the instant invention relates to the use of the above compounds of formula 1 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of ic rhinitis, , COPD, adult respiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitis and contact dermatitis, allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid tis, anti-phospholipid syndrome, Berger's disease, Evans's syndrome, ulcerative s,allergic antibody-based glomerulonephritis, granulocytopenia, Goodpasture's syndrome, hepatitis, Henoch-Schonlein purpura, hypersensitivity vasculitis, immunohaemolytic anaemia, autoimmune ytic anemia, idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematodes, capsule cell lymphoma, neutropenia, non-familial lateral sclerosis, Crohn's disease, multiple sclerosis, myasthenia gravis, osteoporosis, osteolytic es, osteopenia, psoriasis, Sjogren's syndrome, sclerodermy, T-cell lymphoma, urticaria / angiooedema, Wegener's granulomatosis and coeliac disease.
In a preferred embodiment the instant ion relates to the above compounds of formula 1 for the treatment of a disease selected from the group ting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitis and contact dermatitis, allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, anti- phospholipid me, Berger's disease, Evans's me, ulcerative s,allergic antibody-based glomerulonephritis, granulocytopenia, Arteriosclerosis, pulmonary hypertension, Goodpasture's syndrome, hepatitis, Henoch-Schonlein a, hypersensitivity vasculitis, immunohaemolytic anaemia, autoimmune haemolytic , idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergic conjunctivitis, lupus erythematodes, capsule cell lymphoma, neutropenia, non-familial l sis, Crohn's disease, multiple sclerosis, myasthenia , osteoporosis, osteolytic diseases, osteopenia, psoriasis, n's syndrome, sclerodermy, T-cell lymphoma, urticaria / angiooedema, Wegener's granulomatosis and coeliac disease.
In a r preferred ment the instant invention relates to the use of the above compounds of formula 1_for the manufacture of a medicament for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult espiratory distress syndrome, bronchitis, allergic dermatitis, contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis and ic rhinoconjunctiVitis.
In a r preferred embodiment the instant invention s to above compounds of formula 1 for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, adult espiratory distress syndrome, bronchitis, allergic dermatitis, contact dermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis and allergic rhinoconjunctivitis.
In a ularly preferred embodiment the instant ion s to the use of the above compounds of formula 1 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of asthma, COPD, allergic rhinitis, allergic dermatitis and rheumatoid arthritis.
In a particularly red embodiment the instant invention relates to the above compounds of formula 1 for the treatment of a e selected from the group consisting of asthma, COPD, allergic rhinitis, allergic itis and rheumatoid arthritis. r, the instant invention concerns pharmaceutical formulations characterised in that they contain one or more compounds of formula 1.
In a fiarther embodiment the instant invention relates to a pharmaceutical formulation characterised in that it contains one or more compounds of formula 1 in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR—inhibitors, LTD4-antagonists, CCR3-inhibitors, antagonists, CCRl-antagonists, NSAIDS, COX 2-inhibitors (Coxibe), iNOS- inhibitors and HMG-CoA reductase inhibitors and folic acid antagonists such as methotrexate.
In another embodiment the ion concerns compounds selected from formula g N R2 from formula] N Br from formulaA N | A from formula E _ 33 _ o’R1 N/ 8’0 and from formula 2 o’R1 wherein R1 and R2 are defined as mentioned above. 3. TERMS AND DEFINITIONS USED Unless stated otherwise, all the substituents are independent of one another. If for example a number of C1_6-alkyl groups are possible tuents at a group, in the case of three substituents, for example, C1_6-alkyl could represent, independently of one another, a methyl, an n-propyl and a tert—butyl.
Within the scope of this application, in the definition of possible substituents, these may also be presented in the form of a ural formula. An asterisk (*) in the structural formula of the substituent is to be understood as being the g point to the rest of the molecule.
Mor3eover, the atom ofthe substituent following the linking point is understood as being the atom in position number 1. Thus for example the groups N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl (IV) and 4-tolyl (V) are ented as follows: _ 34 _ I II III IV V If there is no asterisk (*) in the ural formula of the substituent, each hydrogen atom may be removed at the substituent and the valency thus freed may serve as a binding site to the rest of a molecule. Thus, for example, VI may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.
Alternatively to the * within the scope of this application X1 is also understood as being the linking point of the group R1 to the structure of formula 1 and X2 as being the linking point of the group R2 to the structure of a 1.
By the term "C1_6-alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with l to 6 carbon atoms and by the term "C1_3-alkyl" are meant branched and unbranched alkyl groups with l to 3 carbon atoms. kyl" accordingly denotes branched and ched alkyl groups with l to 4 carbon atoms. Alkyl groups with l to 4 carbon atoms are preferred. Examples ofthese include: , ethyl, n-propyl, isopropyl , n-butyl, is0-butyl, sec-butyl, utyl, n-pentyl, is0-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i—Bu, t—Bu, etc., may also ally be used for the above-mentioned groups. Unless stated otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and opyl, butyl includes iso-butyl, sec-butyl and tert—butyl etc.
By the term "C1_6-alkylene" (including those which are part of other groups) are meant branched and unbranched ne groups with l to 6 carbon atoms and by the term "CM-alkylene" are meant branched and unbranched ne groups with l to 4 carbon atoms. Alkylene groups with l to 4 carbon atoms are preferred. Examples ofthese include: methylene, ethylene, propylene, l-methylethylene, butylene, l-methylpropylene, l,ldimethylethylene , l,2-dimethylethylene, pentylene, l,l-dimethylpropylene, 2,2 - dimethylpropylene, l,2-dimethylpropylene, l, 3-dimethylpropylene or hexylene. Unless stated otherwise, the definitions propylene, butylene, pentylene and hexylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for _ 35 _ example, propyl includes also l-methylethylene and butylene includes ylpropylene, l l -dimethylethylene, l ,2-dimethylethylene.
If the carbon chain is substituted by a group which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes, inter alia, the following examples of the rings: * * * * a: a: * * *K* 6 *V* : 2:; 9 9 9 9 9 9 By the term "C2_6-alkenyl" (including those which are part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term "C2_4-alkenyl" are meant ed and ched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethenyl or Vinyl, propenyl, butenyl, pentenyl or hexenyl.
Unless stated otherwise, the definitions yl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes l-propenyl and enyl, butenyl includes 1-, 2- and 3-butenyl, l-methyl-l-propenyl, l- methylpropenyl etc.
By the term "C2_6-alkenylene" (including those which are part of other ) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term alkenylene" are meant branched and unbranched ne groups with 2 to 4 carbon atoms. lene groups with 2 to 4 carbon atoms are preferred. Examples ofthese include: ethenylene, propenylene, l-methylethenylene, butenylene, l-methylpropenylene, l,l- dimethylethenylene, l, 2-dimethylethenylene, pentenylene, l,l-dimethylpropenylene, 2,2-dimethylpropenylene, l, 2-dimethylpropenylene, l, 3-dimethylpropenylene or hexenylene. Unless stated otherwise, the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible ic forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes l-methylethenylene and butenylene includes l-methylpropenylene, l, l-dimethylethenylene, l, 2-dimethylethenylene.
By the term "C2_6-alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term "C2_4-alkynyl" are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Alkynyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and l include all the possible isomeric forms ofthe groups in question. Thus for example propynyl includes ynyl and 2-propynyl, butynyl includes 1, 2- and 3-butynyl, l-methyl-l-propynyl, l-methyl propynyl etc.
By the term "C2_6-alkynylene" (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 6 carbon atoms and by the term "C2_4-alkynylene" are meant branched and unbranched ne groups with 2 to 4 carbon atoms. Preferred are alkynylene groups with 2 to 4 carbon atoms. Examples include: ethynylene, propynylene, l-methylethynylene, butynylene, l-methylpropynylene, l,ldimethylethynylene , l,2-dimethylethynylene, pentynylene, l,l-dimethylpropynylene, 2,2-dimethylpropynylene, methylpropynylene, l,3-dimethylpropynylene or hexynylene.
Unless stated otherwise, the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus for e propynyl also includes l-methylethynylene and butynylene es ylpropynylene, methylethynylene, l, 2-dimethylethynylene.
By the term "aryl" (including those which are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. Examples include: phenyl or naphthyl, the preferred aryl group being phenyl. Unless otherwise , the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert—butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term "aryl-C1_6-alkylene" (including those which are part of other groups) are meant branched and unbranched alkylene groups with l to 6 carbon atoms, which are substituted by an aromatic ring system with 6 or 10 carbon atoms. Examples include: benzyl, l- or ylethyl or 1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among , ethyl, opyl, tert—butyl, hydroxy, fluorine, chlorine, e and iodine. _ 37 _ By the term "heteroaryl-C1alkylene" (including those which are part of other ) are meant - even though they are already included under C1_6-alkylene" - branched and unbranched alkylene groups with l to 6 carbon atoms, which are substituted by a heteroaryl.
A heteroaryl of this kind includes five- or six-membered heterocyclic aromatic groups or -lO-membered, bicyclic heteroaryl rings which may contain one, two, three or four heteroatoms selected from among oxygen, sulphur and en, and contain so many conjugated double bonds that an aromatic system is formed. The ing are examples of five- or six-membered heterocyclic aromatic groups or ic aryl rings: DC No Omf/MFMH‘NQNN <2] «:1? ”0|UQWNNIAZNNC©O©0?‘9 Unless otherwise stated, these heteroaryls may be substituted by one or more groups ed from among methyl, ethyl, iso-propyl, tert—butyl, hydroxy, fluorine, chlorine, bromine and iodine.
The following are examples of heteroaryl-C1alkylenes: CH2)6 2 2 isopropyI—* N C_* C/N/ /<<=H2>4—* / s /| | \ — \N \N N By the term "C1_6-haloalkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with l to 6 carbon atoms, which are substituted by one or more halogen atoms. By the term "C1_4-alkyl" are meant branched and unbranched alkyl groups with l to 4 carbon atoms, which are substituted by one or more halogen atoms. Alkyl _ 33 _ groups with l to 4 carbon atoms are preferred. Examples include: CF3, CHFZ, CHZF, By the term "C3_7-cycloalkyl" ding those which are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms. es include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among , ethyl, iso-propyl, tert—butyl, hydroxy, fluorine, chlorine, e and iodine.
By the term "C3_10-cycloalkyl" are also meant monocyclic alkyl groups with 3 to 7 carbon atoms and also bicyclic alkyl groups with 7 to 10 carbon atoms, or monocyclic alkyl groups which are bridged by at least one C1_3-carbon bridge.
By the term "heterocyclic rings" or "heterocycle" are meant, unless stated otherwise, five-, six- or seven-membered, saturated, partially saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, while the ring may be linked to the molecule through a carbon atom or h a nitrogen atom, if there is one. Although included by the term ocyclic rings" or "heterocycles", the term "saturated heterocyclic ring" refers to five-, six- or seven-membered saturated rings. Examples include: NO Q Q0 S N“ O as SJ “O DO 80 N“ N“w no Nfi HID es N/\>L.
Although included by the term "heterocyclic rings" or "heterocyclic group", the term "partially saturated heterocyclic group" refers to five-, six- or membered partially saturated rings which contain one or two double bonds, without so many double bonds being produced that an aromatic system is formed. Examples include: _ 39 _ Although included by the term "heterocyclic rings" or "heterocycles", the term "heterocyclic aromatic rings" "unsaturated heterocyclic group" or "heteroaryl" refers to five- or six- membered heterocyclic aromatic groups or 5-lO-membered, bicyclic heteroaryl rings which may contain one, two, three or four heteroatoms, selected from among oxygen, r and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed.
Examples of five- or six-membered cyclic aromatic groups include: U m Omflfl P/ <\/3 N/ 3/ N—N NJ LN fl/N oN N’N N/ NokN/ [“3 Nj w Wn N/ N/ NVN kN/ Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may be provided with a keto group. es include: o O Q\//O o 00 N “S" HN N N 9 9 9 9 9 9 Although covered by the term "cycloalkyl", the term "bicyclic cycloalkyls" generally s eight-, nine- or ten-membered bicyclic carbon rings. Examples include <b¢b9§¢hfiffiw&ds Although already included by the term "heterocycle", the term "bicyclic heterocycles" generally denotes eight-, nine- or ten-membered bicyclic rings which may contain one or more heteroatoms, ably 1-4, more preferably 1-3, even more preferably l-2, ularly one heteroatom, selected from among oxygen, sulphur and nitrogen. The ring may be linked to the molecule h a carbon atom ofthe ring or h a nitrogen atom of the ring, if there is one. Examples include: Although already included by the term "aryl", the term "bicyclic aryl" denotes a 5-10 membered, ic aryl ring which contains sufficient conjugated double bonds to form an aromatic system. One example of a bicyclic aryl is naphthyl.
Although already included under "heteroaryl", the term lic heteroaryl" denotes a 5-10 membered, bicyclic heteroaryl ring which may contain one, two, three or four heteroatoms, selected from among oxygen, sulphur and nitrogen, and contains sufficient conjugated double bonds to form an aromatic system.
Although included by the term "bicyclic lkyls" or "bicyclic aryl", the term "fiJsed cycloalkyl" or "fused aryl" denotes bicyclic rings wherein the bridge separating the rings denotes a direct single bond. The following are examples of a fiJsed, bicyclic cycloalkyl: ce,c:>,co,~,oeo,_ Although included by the term "bicyclic heterocycles" or "bicyclic heteroaryls", the term "fiJsed bicyclic heterocycles" of "fiJsed bicyclic heteroaryls" denotes bicyclic 5-10 ed heterorings which contain one, two, three or four atoms, ed from among oxygen, sulphur and nitrogen and wherein the bridge ting the rings denotes a direct single bond.
The "fiJsed bicyclic heteroaryls" moreover contain suff1cient conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyrimidine, ine, dopyrimidine, N N ~ N W \ N N N r \ N i co N H H CrS 0 /> r» N O By the term "spiro group" (spiro) are meant 5-10 membered, spirocyclic rings which may optionally contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, while the ring may be linked to the molecule through a carbon atom or if ble through a nitrogen atom. Unless otherwise mentioned, a spirocyclic ring may be provided with an oxo, methyl or ethyl group. Examples ofthis include: Q33 Cb QC DC— HDCN/, , , "Halogen" within the scope ofthe present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
Compounds of general formula 1 may have acid , mainly carboxyl groups, and/or basic groups such as e. g. Amino fianctions. Compounds of general formula 1 may therefore be present as internal salts, as salts with ceutically usable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, nic acid or organic acids (such as for example maleic acid, filmaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or um hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, inter alia.
As mentioned usly, the compounds of formula 1 may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and co logically acceptable salts thereof. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids. On the other hand, the nd of formula 1 when R is hydrogen may be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion.
The acid addition salts may be ed for e using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, filmaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also le to use mixtures ofthe above-mentioned acids. To e the alkali and alkaline earth metal salts of the compound of formula 1 wherein R denotes hydrogen, it is preferable to use the alkali and alkaline earth metal hydroxides and hydrides, ofwhich the hydroxides and hydrides of the alkali metals, ularly sodium and potassium, are red, while sodium and potassium hydroxide are particularly preferred.
The compounds of general formula 1 may optionally be converted into the salts thereof, particularly for ceutical use into the cologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids for this purpose include succinic acid, hydrobromic acid, acetic acid, fiamaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid.
It is also possible to use es of the above-mentioned acids.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as for example acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids — such as for example , fumaric, diglycolic or methanesulphonic acid.
The compounds according to the invention may optionally be present as racemates, but may also be obtained as pure enantiomers, i.e. In the (R) or (S) form. _ 43 _ The invention s to the compounds in question, optionally in the form of the individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as for example acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids — such as for example oxalic, filmaric, diglycolic or methanesulphonic acid.
The invention s to the respective nds of formula 1 in the form of the pharmacologically acceptable salts thereof. These pharmacologically acceptable salts of the compounds of formula 1 may also be present in the form of their respective hydrates (e.g.
Monohydrates, dihydrates, etc.) as well as in the form of their respective solvates.
By a hydrate of the compound according to the formula 1 is meant, for the purposes of the ion, a crystalline salt of the compound according to formula 1, containing water of crystallisation.
By a solvate of the compound according to formula 1 is meant, for the purposes of the invention, a crystalline salt of the compound according to a 1, which contains solvent molecules (e. g. Ethanol, ol etc) in the crystal lattice.
The skilled man will be familiar with the standard s of ing hydrates and so lvates (e. g. recrystallisation from the corresponding solvent or from water). _ 44 _ 4. METHODS OF PREPARATION The Examples according to the invention were prepared as shown in Schemes 1, 2 or 3.
Schemel ‘ISi\ o 0 0 H \ reac Iont' 4 \ \ ll reaction1 I l I ' + N/ \ / N/ \ R2 \ \ N Br R2 R2 3 § reaction2 reaction 5 PG _ R1—Y R or o R‘_Y OH § \ I I / 2 N R2 N R reaction3 1 E Y is —OH, Cl, Br, I, ate, -OTosy1ate, -OMesy1ate PG is protecting group (e. g. benzyl, 1-pheny1ethy1, 1ethoxypheny1)ethy1) and R1 and R2 are as herein before defined. _ 45 _ Scheme 2 PG — R —Y reaction 6 reaction 8 | + N Br NZ example 22, 27 example 37 2 2 R — Hal —- .
R —X on 7 OH o’R N/ R2 N/ R2 with X being -B(OH)2, -boronic acid pinacolester, -trifluoroborate, -SnBu3; Y being —OH, Cl, Br, I, -OTriflate, -OTosy1ate, y1ate, with Hal being Cl, Br, 1, PG is at protecting group (e. g. benzyl, 1-pheny1ethy1, 1-(4-n1ethoxyphenyl)ethyl) Scheme 3 R1 R1 R1 o’ o’ 0’ reaction 9 R2-Hal \ \ \ I I I / / / N Br N E‘a’o N R2 Z example 27 O with Hal being Cl, Br, I 4.1. ng materials and intermediates of formula 2, 3 and 4 4.1.1. Synthesis of Arylalkines 2 from Scheme 1 Synthesis of 5-ethynyl-1,2,3-trimethoxybenzene (g) for Examples 2, 3, 4, 5, 9, 18, 23, 38 The synthesis of 5-ethynyl—1,2,3-trimethoxybenzene was carried out according to the method of Rasolofonjatovo, Evelia; Provot, Olivier; Hamze, Abdallah; Brion, Jean-Daniel; Alami, Mouad; Bignon, Jerome; Thoret, Sylviane European Journal ofMedicinal Chemistry, 2010, vol. 45, 3617 — 3626. _o _o —O \ SI \ H/ \ —- Br + / o C : Si— —> 0 = H _o _o —O 2 1 m: 1 g 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethylsilylacetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenylphosphinpalladium(ll) de and 39 mg Cu(l)iodide were placed in a dried flask under argon. The mixture was stirred for 1 h at 80°C, afler cooling diluted with dichloromethane (DCM) and filtered through a plug of silica.
The filtrate was extracted with aqueous ammonia, saturated brine and trated. The residue was purified via flash chromatography (SiOz: cyclohexane 9 cyclohexane/ethylacetate 9 : 1) to give trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane.
Yield: 970 mg (oil) Analysis: HPLC-MS (method E) Rt = 1.55 min; M+H = 265.
Step 2: 230 mg Trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane, 0.9 mL tetrabutylammoniumfluoride (1 mol/l in THF) were dissolved in 3 mL of THF and stirred for 1 h at 25°C. The solution was diluted with DCM and extracted with water. The solvent of the organic phase was distilled off and the residue purified via flash chromatography (10 g 8102; cyclohexane 9 exane / cetate 7 : 3).
Yield: 135 mg (90% oftheory) Analysis: S (method E): Rt: 1.15 min. M+H = 193 _ 47 _ sis of 5-Ethynyl-1,3-diflu0r0meth0xy-benzene (Q) for Examples 14, 15, 17 A e of 2 g 5-bromo-l,3-difluoromethoxy-benzene, 1.76 g ethynyl-trimethyl—silane, 629 mg bis(triphenylphosphine)palladium(II) dichloride, 3. lml diisopropylethylamine, and 85 mg copper iodide in 20ml acetonitrile was degassed then heated at 80°C for 2 hours. The mixture was diluted with dichloromethane and filtered through a plug of silica, washed with dilute ammonia and brine then dried over sodium sulphate, filtered and concentrated in vacuo.
Purification over silica ed 1.71 g ifluoromethoxy-phenylethynyl)-trimethyl- silane. 1H NMR (250 MHz, CD013) 5‘ ppm 0.24 (9 H, s), 4.02 (3 H, t, J=1.29 Hz), 6.91 — 7.09 (2 H, lN tetrabutylammonium fluoride (TBAF) in THF was added to 1.71 g (3,5-Difiuoro methoxy-phenylethynyl)-trimethyl-silane and the e strirred at 25°C overnight. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluting with 20:1 heptane:ethyl acetate to give 866mg S-Ethynyl-l,3-difiuoromethoxy- benzene in 72% yield. 1H NMR (250 MHz, CD013) 5 ppm 3.08 (1 H, s), 4.02 (3 H, d, J=1.22 Hz), 6.89 — 7.15 (2 H, In), 4-Ethynylis0pr0p0xymethoxy-benzene (2.3) (for Examples 10, 11, 13, 16, 19) 4-Ethynyl-l-isopropoxymethoxy—benzene 2.3 was synthesized in 2 steps from 4-Bromo-l- isopropoxymethoxy-benzene in analogy to 2.2. _ 43 _ 1H NMR (250 MHz, CD013) 8 ppm 1.38 (6 H, d, J=6.09Hz), 3.01 (1 H, s), 3.85 (3 H, s), 4.56 (1 H, m), 6.82 (1 H, d, J=8.22Hz), 7.00(1 H, d, J=1.83Hz), 7.07 (1 H, dd, J=8.30,1.90Hz). nyl—quinoline (M) for Example 34 2-Ethynyl-quinoline M for Example 34 was synthesized in 2 steps from 2-bromo-quinoline in analogy to 2.2.
Analysis: HPLC-MS: Rt = 1.25 (method M), M+H = 154.
-Ethynyl—2-methoxypyridine (2._5) for Examples 20, 21 nylmethoxypyridine for Example 20, 21 was synthesized in 2 steps from S-Bromo- 2-methoxy-pyridine in analogy to 2.2. 1H NMR (500 MHz, CHLOROFORM-d) 8 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 ing arylalkines were commercially available: 4-Ethynyl-l,2-dimethoxybenzene 2.6 for Example 7, 8, l2 l-Ethynyl-benzene 2.7 for Example 1 2-Ethynylpyridine Q for Example 6 _ 49 _ 4.1.2. sis of 5-hydr0xy-7—br0mo-quinoline from Scheme 2 The title compound can be purchased by Shanghai n Chemexpress Co., Ltd. CHINA or synthesized via known 3-bromomethoxyaniline (Liedholm, Brita. Acta a Scandinavica, Series B: Organic Chemistry and Biochemistry (1984), B38(10), 877-84 or Hodgson, H. H.; Wignall, J. SJournal of the Chemical Society (1926)) in two steps. 0/ O / 0 OH / / N Br Br +061 ~ 2 I/ N Br oi;N Br m: 4.0g (0.02 mol) of 3-Bromomethoxy-aniline, 4.6 g (0.05 mol) of glycerol, 2.46g (0.02 mol) of nitrobenzene and 12 ml of 75% sulfuric acid were stirred for 3 h at 150°C. After this dark solution was poured onto 100 g of crushed ice, 100 ml of ethylacetate (EtOAc) and ml of 30% solution of NaOH. After 1 hour brown solid was filtered off and the organic layer was separated. Afier filtering through SiOz and evaporation of solvent 7-bromo methoxy-quinoline and 5-bromomethoxy-quinoline were separated as mixture approximately 60:40 (total 3.5g, 74%) This mixture was separated to dual 7-bromo methoxy-quinoline and 5-bromomethoxy—quinoline with column chromatography on -gel with benzene-EtOAc (3:1) as . Yield of pure 7-bromomethoxy-quinoline was 950 mg (27% from mixture).
Step 2: 1.5 g (0.0064 mol) of 7-bromomethoxy—quinoline were refluxed with 48% HBr (30 ml) for 20h. After cooling to room ature reaction mixture was poured into 100 ml of water and basified with saturated ammonia solution. Product was filtered off, washed with water and dried at 50°C in vacuo. Yield of 7-bromohydroxy-quinoline was 600 mg (41%). 1H-NMR (400 MHz, d6-DMSO): 8 = 11.1 (lH, s(broad)), 8.88 (1H, s), 8.49 (1H, d), 7.68 (lH,s), 7.48 (lH,m), 7.l8 (lH,s) ppm. 4.1.3. Synthesis of alcohols ; from Scheme 1 and 2 Synthesis of (R)—4-((R)hydroxyethyl)(R)phenylethyl) pyrrolidine—Z-one (Q) and (R)—4-((S)hydroxyethyl)(R)phenylethyl)pyrrolidineone (Q) (for es 1, 2, 6, 8, 14) Step 1: 0 H / N + /N-O # o HO H O \o’N g (1‘R, 3R)(1'-Pheny1ethy1)0xopyrr01idinecarboxylic acid and N,O- dimethylhydroxylamine hydrochloride was dissolved in 100 mL dimethylformamide at 0°C. 13.9 g Hydroxybenzotriazole, 19.8 g 1-ethy1—3-(3-dimethylaminopropyl)carbodiimide (EDC) and 20 mL N—methylmorpholine were added and the mixture stirred at 0°C 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 bicarbonate and saturated sodium chloride solution. The organic phase was dried and concentrated.
Yield: 23.8 g (95% oftheory) Analysis (method E): R: 1.12 min, : 277 Step 2: The reaction was carried out under a en atmosphere. 11.95 g (R)-N-methoxy—5-oxo((R)pheny1ethy1)pyrro1idinecarboxamide (were placed in 100 mL tetrahydrofiJran at -10°C. 30 mL Methylmagnesium bromide in diethyl ether solution was added within 15 min (white sion, temperature at +10°C) and the mixture was stirred at -10°C for 2 h and then warmed to ambient temperature. The mixture was diluted with ethyl acetate and washed with lN hloric acid, saturated sodium bicarbonate and saturated sodium chloride solution solution. The organic phase was dried and concentrated.
Yield: 9.45 g (95% oftheory) Step3: N —. 0 6H OH 31 i Reaction was carried out under argon atmosphere. 8.5 g (26.8 mmol) (R)acetyl-l-((R)-l-phenylethyl)pyrrolidineone were placed in 40 mL dichloromethane at -50°C and 40.5 mL (40.5 mmol) lithium 9-BBN hydride in tetrahydrofuran was added dropwise. During the addition the temperature increased to -30°C.
The mixture was then stirred at -45°C for l h. After this time, phosphate buffer was added and the mixture was warmed to ambient temperature, diluted with dichloromethane and extracted with water. The organic phase was dried over magnesium e, concentrated und purified Via prep HPLC dge C18).
Yield: 2.60 g ofQ (30% oftheory) Analysis (method E): Rt: 108 min, (M+H)+: 234 Yield: 2.60 g ofQ (30% oftheory) is (method E): R: 1.12 min, (M+H)+: 234 2012/064172 -(Hydroxymethyl)piperidine-Z-one (Q) (for Example 5) -(Hydroxymethyl)piperidineone (Q) may be synthesised according to the following ture: Lerchner, Andreas; Carreira, Erick M. Chemistry A European Journal (2006), , 8208- 8219.
Synthesis of (R)[(S)hydroxyethyl][(S)(4-methoxyphenyl)-ethyl]-pyrrolidin one M 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- Step 1: Synthesis of (1'R,3R/S)(1'-(4-Methoxyphenylethyl)oxopyrrolidine carboxylic acid (mixture of diastereoisomers) A suspension of 100 g of (R)(4-methoxy-phenyl)-ethylamine and 95 g itaconic acid in 0.5 L 1-methylpyrrolidinone is heated to 80 CC for 1 hour. The solution is d for additional 4 hours at 120 oC. The reaction mixture is cooled to 25 oC and poured into 1.5 L of demineralized water. The precipitate is filtered, washed with demineralized water and dried at 50 °C.
Yield: 195 g (quantitative yield) solid as a mixture of diastereoisomers Analysis (method G): R: 2.6 min and 2.7 min, (M+H)+: 264 _ 53 _ In analogy is ed (1 'S,31VS)(1 '-(4-Methoxyphenylethyl)oxopyrrolidine carboxylic acid as a mixture of diastereoisomers Analysis (method G): R: 2.6 min and 2.7 min, (M+H)+: 264 Step 2: Synthesis of (R/S)-N-Methoxyoxo[(S)(4-methoxyphenyl)—ethyl]- pyrrolidine—3-carboxamide as a mixture of diastereoisomers 260 g of 1,1 ’-Carbonyldiimidazole (CD1) are added to a solution of 285 g (1 'R,31VS)(1 '- (4-methoxyphenylethyl)oxopyrrolidine carboxylic acid (mixture of diastereoisomers) in 1.4 L yltetrahydrofuran at 20 CC. The suspension is stirred at 20 °C for 80 minutes. 235 mL ethyldiisopropylamine (DIPEA) and 130 g of N,O-dimethylhydroxylamine hydrochloride are added. The suspesion is d for 3 hours at 20 oC. Under cooling 850 mL 4 N hydrochloric acid is added. The c phase is separated and washed two times with 500 mL 1 N hydrochloric acid. The s phase is reextracted two times with 500 mL ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration the solvent is evaporated under reduced pressure.
Yield: 271 g (82 % oftheory) of (IVS)-N-Methoxyoxo[(S)-l-(4-methoxyphenyl)-ethyl]- pyrrolidinecarboxamide (mixture of diastereoisomers) as an oil.
Analysis (method H): R: 11.1 min (41 area %) and 13.8 min (59 area %), (M+H)+: 307 WO 14060 _ 54 _ Step 3: Synthesis of (R/S)acetyl[(S)(4-methoxyphenyl)-ethyl]-pyrrolidineone as a mixture of diastereoisomers 530 mL of a 3 M solution of methylmagnesium bromide in diethylether is added slowly to a cooled on of 271 g of (IVS)-N-Methoxyoxo[(S)(4-methoxyphenyl)-ethyl]- pyrrolidinecarboxamide (mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran so that the temperature remains under 0 CC. After complete addition the temperature is kept for 75 minutes at 0 OC and then warmed up to 20 oC. The suspension is d 16 hours at 20 oC. Under cooling 650 mL of a 4 M hydrochloric acid are added. The organic phase is separated and washed with 500 mL saturated sodium carbonate on and with 500 mL saturated brine. The organic phase is dried over sodium sulfate. After filtration the t is evaporated under reduced pressure.
Yield: 188 g (81 % oftheory) of (IVS)acetyl[(S)(4-methoxyphenyl)-ethyl]- pyrrolidineone (mixture of diastereoisomers) as an oil.
Analysis d H): R: 7.4 min and 9.6 min, (M+H)+: 262 Step 4: Crystallization of (R)—4-acetyl[(S)(4-methoxyphenyl)-ethyl]- pyrrolidine-Z- one under base induced epimerization conditions 103 g of a mixture of diastereoisomers (IVS)acetyl[(S)(4-methoxyphenyl)-ethyl]- pyrrolidineone is dissolved in 155 mL 1-butanol at 25 0C. 18 mL benzyltrimethylammonium hydroxide (40 % solution in methanol) is added. The solution is _ 55 _ d for 30 minutes at 25 oC. The solution is cooled to 0 oC. Precipitation starts. The suspension is stirred for 15 minutes at 0 0C. 100 mL n-heptane is added slowly and the suspension is stirred for 30 minutes at 0 OC. The addition of 100 mL portions of n-heptane is repeated 4 times with subsequent stirring of the suspension at 0 0C for 30 minutes. The precipitate is isolated, washed with n-heptane and dried at 50 oC.
Yield: 77.1 g of a beige solid (75 % of theory) with a reoisomeric purity of ~95 : 5 (method H).
For fiarther purification the crude product is dissolved in 3 10 mL 2-methylbutanol at 40 CC (temperature < 50 oC). The on is slowly cooled to 0 oC. Precipitation starts. At 0 0C 385 mL ofn-heptane is added and the sion is stirred for 1 hour. The precipitate is filtrated, washed with n-heptane and dried at 50 oC.
Yield: 68.7 g (67 % oftheory) of a colorless solid with a diastereoisomeric purity of > 99 : 1.
Analysis (method H): R: 6.8 min, (M+H)+: 262 Step 5: Synthesis of (R)—4—[(S)hydr0xyethyl][(S)(4-methoxyphenyl)—ethyl]- pyrrolidin-Z-one 2.4 g of Dichloro-(pentamethylcyclopentadienyl)-rhodium-(III)-dimer and 2.8 g (R,R)-N—(p- toluenesulfonyl)-l,2-diphenylethylendiamine [(R,R)-TsDPEN] is added to a solution of 50 g (R)acetyl-l-[(S)-l-(4-methoxyphenyl)-ethyl]- pyrrolidineone in acetonitril at 25 CC. The solution is cooled to — 15 0C. At this temperature a mixture of 22 mL formic acid and 135 mL triethylamine is added. The reaction mixture is stirred for 22 hours at -l5 CC and then warmed up to 20 0C. 230 mL of a 4 molar hydrochloric acid is added under g. The s phase is extracted 3 times with ethyl acetate. The c phase is washed with diluted and concentrated brine and treated with ted carbon. The organic phase is dried over sodium e. The solvent is evaporated under reduced pressure to obtain 57.1 g of a beige solid with a diastereomeric purity of ~ 97 : 3.
For fiarther purification the crude t is crystallized from isopropyl acetate.
Yield: 37.8 g (75 % oftheory) of a beige solid with a diastereoisomeric purity of > 99 : 1.
Analysis (method I): R: 12.9 min, (M+H)+: 264 The transfer hydrogenation reaction can also be performed in 2-propanol at 20 °C.
Synthesis of (R)(hydr0xymethyl)—1-((R)phenylethyl)pyrrolidin-Z-one (for Example 7, 9, 17, 19) O N of O —> g OH OH g (1 'R,3R)(1'Phenylethyl)oxopyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0°C. 16.5 mL borane dimethyl sulfide (2 M in ydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25°C and stirred for a fiarther 2 h at 25°C. The reaction mixture was trated, diluted in dichloromethane and washed with sodium bicarbonate on. The water phase was extracted with dichloromethane (x2) and the combined organic phases were dried over magnesium sulfate and concentrated.
Yield: 5.5 g (content 80%, 94% oftheory) Analysis: HPLC-MS (method D): R = 1.20 min (M+H)+ = 220 _ 57 _ (R)(Hydr0xymethyl)—3-[(R)-a-methylbenzyl—2-0xazolidin0ne (3.5) (for Example 12, 13, , 16, 18, 20) Commercially available from Sigma -Aldrich 2-(Hydr0xymethyl)nicotinamide for Example 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 may be synthesized ing to the following literature: Goto, Takehiko; Saito, Minoru; Sato, Ryu Bulletin 0fthe Chemical Society ofJapan, 1987, 60, 4178 - 4180 Synthesis of romethyl-5,5-dimethyl—imidazolidine-2,4-di0ne for Example 23 HOJ a) commercially available from Alfa Aesar é WO 14060 _ 53 _ 0.69 ml Thionyl chloride was added to a solution of 500mg 1-Hydroxymethyl-5,5-dimethyl- imidazolidine-2,4-dione in 5ml DCM at 0°C for 30 minutes, then left to stir at 25°C for 16 hours. The mixture was evaporated to dryness and used crude in the synthesis of example 23. 4.1.4. Synthesis of boronic acids, boronic esters and stannanes 4 in Scheme 2 4.1.4.1. Synthesis of Rz-Hal 4-Br0m0methyl—1-(methylsulf0nyl)benzene for Example 35 S\ + §é\ B B 235 mg Sodium sulfite and 470 mg NaHC03 were dissolved in 1.75 mL of water and heated to 75°C. 500 mg of 4-Bromomethyl-benzenesulfonyl chloride were added in portions within 10 min (gas formation) and the mixture stirred for 1 h at 75°C. 387 mg of Bromoacetic acid and 150 uL of water was added in small ns and the mixture stirred at 105°C overnight. After cooling to 25°C the mixture was ied to pH 1 using 4N HCl. The ing precipitate was collected and washed with water to yield 205 mg solid.
Analysis: S: Rt = 0.73 (method X001_002) M+H = 249/251 1-Br0m0(triflu0r0methylsulf0nyl)benzene for e 36 F I?F’Q/Bro 1-Bromo(trifluoromethylsulfonyl)benzene is described in: Mongin, Olivier; Porres, Laurent; Charlot, Marina; Katan, Claudine; Blanchard-Desce, Mireille Chemistry-A European Journal, 2007, 13, p. 1481 — 1498.
N-(4-Br0m0benzyl)-N-ethylacetamide for Examples 50, 68 Br LNkO KCLB. Lu’kofi KOB _ 59 _ 0.568 mL N—ethylacetamide was dissolved in 20 mL THF. 0.67 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50°C. Then 1 g of 4-bromobenzylbromide dissolved in 5 mL THF was added and the suspension stirred for 2 h at 50°C. After cooling, ethylacetate and water were added and the organic phase extracted with water (1x), dried and the solvent distilled off. The product was purified via FCC (cyclohexane/ cetate: 90/10 9 50/50) to yield 830 mg N—(4-bromobenzyl)-N-ethylacetamide as an oil.
Analysis: HPLC-MS: Rt = 2.67 min (method C), M+H = 256 N-(4-Br0m0benzyl)-N-methylacetamide for Examples 51, 58 +T—>/NO 1.316 g N-methylacetamide was dissolved in 60 mL THF. 2.02 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50°C. Then 3 g of 4-bromobenzylbromide dissolved in 10 mL THF was added and the e stirred for 2 h at 50°C. After cooling ethylacetate and water were added and the organic phase extracted with water (1x), dried and the solvent distilled off to yield 2.8 g romobenzyl)-N—methylacetamide as an oil.
Analysis: MS: M+H = 242. 0(triflu0r0methyl)—1H-pyrazole for Example 87 was ed as described in WO2008/95944. 7-Br0m0methquuinazolin-4(3H)-0ne for Examples 91, 92 O O NH+ I/ _, d'fl/ Br N/J Br N/J 7-Bromoquinazolin-4(3H)-one can be obtained as described in WO2010/146173. 400 mg 7-Bromoquinazolin-4(3H)-one was dissolved in DMF and 720 mg of CsC03 and 130 uL of methyliodide were added and the mixture stirred for 3h at 25°C. Additional 50 uL methyliodide were added and stirred overnight at 25°C. The mixture was d off and the mother liquor diluted with DCM and extracted with water. The solvent was removed to yield 490 mg of 7-bromomethquuinazolin-4(3H)-one as solid.
Analysis: HPLC-MS: Rt = 0.66 min (method X001_004) M+H = 239/241 7-Br0m0methyl—2,3,4,5-tetrahydr0-1H-benz0[d]azepine for Example 103 7-Bromo-2,3,4,5-tetrahydro-lH-benzo[d]azepine can be obtained as described in Shah, Unmesh; , Claire M.; Boyle, Craig D.; Chackalamannil, ; ee, William J.; dt, 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, I8, 4204 - 4209.
Br Br 2.43 g 7-Bromo-2,3,4,5-tetrahydro-lH-benzo[d]azepine are 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 h and continued overnight at 25°C. The e was concentrated, diluted with water and 10 N NaOH to adjust to a basic pH. The mixture was then extracted with tertbutylmethylether (3x) and the c phase dried (Na2S04), filtered and concentrated to yield 2.48 g 7-bromo- 3-methyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine as oil.
Analysis: MS: M+H = 240 /242 6-Br0m0-2,4-dimethquuinazoline for Example 107 fi< /j; N—(2-acetylbromophenyl)acetamide can be obtained as bed in: Woods, Keith W.; Fischer, John P.; rne, Akiyo; Li, Tongmei; Thomas, Sheela A.; Zhu, Gui-Dong; d, Robert B.; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Han, Edward K.; et al.
Bioorganz'c &Medicinal Chemistry, 2006 6832 - 6846 , 14, p. 415 mg N—(2-acetylbromophenyl)acetamide and 0.624 g of ammonium acetate was dissolved in 5 mL of glacial acetic acid and heated for 2 days at 100°C. The solvent was removed and the residue suspended in water and extracted with DCM. The organic phase was concentrated and purified via FCC (25 g SiOz, DCM: MeOH 100:0 9 70: 30) to yield 90 mg of 6-bromo-2,4-dimethquuinazoline as oil. is: HPLC-MS: Rt = 1.26 min (method V003_003), M+H =237 / 239.
-Br0m0(diflu0r0methyl)pyridine for Example 120 Br Br / \ I + \ F \—Nk / F H —- N 1 N O F 1 g 5-Bromo-pyridinecarboxaldehyde was dissolved in 50 mL DCM. The solution was cooled to -70°C, then 1.55 mL diethylaminosulfurtrifluoride was added dropwise over 20 minutes. The suspension was stirred for 30 minutes at room temperature, then 10 mL water was added at 0°C followed by slow addition of 20 mL saturated NaHC03 (gas formation).
The phases were separated and 2 mL of 4N HCl in dioxane is added to the organic phase which was trated in vacuo to provide 1.06 g product as yellow solid. HPLC-MS: Rt = 0.72 min (method X001_004), M+H =208 / 210. 4.1.4.2. Synthesis of compounds of formula 4 (Rz-X)(Scheme 2) Synthesis of yl(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)quinoline for Examples 33, 75 \ 7 o\ ,0 7 + /B*B\ % 100 mg 6-Br0moquinaldine, 133 mg bis-(pinacolato)—diboron, 16 mg Pd(II)C12 (PPh3)2 and 86 mg potassium acetate were suspended in 1 mL dioxane and the mixture heated at 100°C in the microwave for 1 h. The mixture was diluted after cooling with DCM and extracted with water (2x). The organic phase was concentrated to yield 200 mg (94%, content 55%) 2-methyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)quinoline as oil.
Analysis: HPLC-MS (method X001_002) Rt = 0.48 min, M+H = 188 The ing boronic esters were synthesized in analogy and were used without fithher purification: ° 4,4,5,5-Tetramethyl(3-methyl(methylsulfonyl)phenyl)-1,3,2-di0xaborolane for Example 35. Reaction conditions: 1h, 100°C. Yield : 74% nt 50%). Analysis: HPLC-MS: Rt = 0.42 min (method X001_003), M+H = 215 (boronic acid) ° 4,4,5 ,5 -Tetramethyl(4-(trifluoromethylsulfonyl)phenyl)- 1 ,3 ,2-dioxab0r0lane for Example 36.
Reaction conditions: 1h, 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-di0xab0rolanyl)benzyl)acetamide for Example 50, 68. Reaction ions: 2 h, 100°C. Yield : 93% (content 55%). is: HPLC-MS: Rt = 0.87 min (method X001_002), M+H = 304 ° N—Methyl-N—(4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-di0xab0r0lanyl)benzyl)acetamide for Example 51, 58. on 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 ramethyl— 1 ,3 ,2-di0xab0rolanyl)-3 ,4-dihydr0is0quinolin-1(2H)-0ne for Example 52, 53. Reaction conditions: 1 h, 100°C. Yield : 87% (content 35%).
Analysis: S: Rt = 0.81 min d X001_002), M+H = 274 1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)benzyl)piperidinon for Example 54, 55. Reaction ions: 1 h, 100°C. Yield : 92% (content 45%). Analysis: HPLC- MS: Rt = 0.87 min (method X001_003), M+H = 316 2-Methyl(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)imidazo[ 1 ,2-a] pyridine for Example 60, 61. Reaction conditions: 6 h, 100°C. Yield : 98% (content 50%). is: S: Rt = 0.40 min (method X001_004), M+H = 177 (boronic acid) 1-(2-Chloro(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)phenyl)cyclopropanamine for Example 62, 86. Reaction conditions: 1 h, 100°C. Yield : 85% (content 40%).
Analysis: HPLC-MS: Rt = 0.67 min (method 04), M+H = 294 and 0.24 min M+H = 212 (boronic acid). 6-(4,4,5 ,5-Tetramethyl-1,3 ,2-dioxaborolanyl)- 1 H-benzo [d] [ 1 ,3]oxazin-2(4H)-one for Example 63, 64. Reaction conditions: 1 h, 100°C. Yield : 87% (content 50%). is: HPLC-MS: Rt = 0.67 min (method X001_004), M+H = 276 The following examples were synthesized in analogy to the described example but without using a ave: 6-(4,4,5 ,5-Tetramethyl- 1 ,3 ,2-dioxaborolanyl)(trifluoromethyl)imidazo [ 1 ,2- a]pyridine for Example 83. on conditions: 1 h, 100°C. Yield : 94% (content 45%). Analysis: HPLC-MS: Rt = 0.49 min (method X001_004), M+H = 231 (boronic acid) 4-(4,4,5 ,5-Tetramethyl- 1 ,3 ,2-dioxaborolanyl)(trifluoromethyl)-1H-pyrazole for Example 87. Reaction conditions: 3.5 h, 100°C. Yield : 98% (content 55%). is: HPLC-MS: Rt = 1.66 min (method V003_002), M+H = 263 2-Cyclobutyloxy—5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine for 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 ic acid) 3-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)quinazolin-4(3H)-o n e f o r example 91, 92 Reaction conditions: (1h, 100°C). Yield 98% (content 50%). HPLC- MS: Rt = 0.34 min (method 04). 5 -(4,4,5 ,5-Tetramethyl- 1 ,3 ,2-dioxaborolanyl)(trifluoromethyl)- 1 H- benzo[d]imidazole for Example 93. Reaction conditions: 11 h, 100°C. Yield : 97% nt 60%). Analysis: HPLC-MS: Rt = 0.70 min (method X001_004), M+H = 313 1-Methyl(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)- 1 H-benzo [d] imidazole for Example 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 xaborolanyl)pyridine for Example 95, 96. Reaction conditions: 1 h, 100°C. Yield : 98% (content 45%).
Analysis: MS: M+H = 298 _ 64 _ ° ethoxy(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 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(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)-2,3 ,4,5-tetrahydro-1H- benzo[d]azepine for Example 103. Reaction conditions (1h, 100°C). Yield: 88% nt 50%) S: Rt = 0.61 min (method X001_004), M+H = 288 ° uoromethoxy)(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)pyridine for Example 104 ° 1 ,2-Dimethyl-5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)- 1 H-benzo dazo le for Example 105, 106. Reaction conditions (2h, 100°C) Yield: 91% (content 50%).
Analysis: HPLC-MS: Rt = 0.57 min (method X001_004), M+H = 273. ° 2,4-Dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)quinazo line for example 107. Reaction conditions (7 h, 100°C). Yield: 95% (content 40%). Analysis: HPLC- MS: Rt = 0.29 min (method X001_004) ° 2-(Difluoromethyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine for Example 120.
Reaction condistions ( 1h, 100°C). Yield: 97% (content 38%). Analysis: S: Rt = 0.27 min ( method X001_004) The following boronic acids, trifluoroborates or boronic esters were commercially available: ° 4-(Methanesulfonyl)benzeneboronic acid for Example 24 ° 3,4-Dimethoxyphenylboronic acid for Example 25 ° N—[5 -(4,4,5 ,5 -Tetramethyl- 1 ,3 ,2-dioxaborolanyl)-pyridinyl] -acetamide for Examples 26, 30 ° Quinolineboronic acid for Example 29 ° fluoromethyl)pyridin—5-ylboronic acid for Example 31 ° 3-Fluoro(methylsulfonyl)phenylboronic acid for Example 32 ° 1H-Benzimidazol—5-boronic acid, pinacol ester for Examples 39, 41 ° 4-(4-Morpholinylmethyl)phenylboronic acid for Examples 40, 43 ° 1-Methylindazolboronic acid for Examples 42, 44 ° 4- [5 -(4,4,5 ,5 -Tetratmethyl-[1 ,3 ,2] dioxaborolanyl)pyridinyl]morpho line for Examples 45, 48 ° 1-Methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-1H le for es 46, 47 ° 6-(N-Methylamidocarbonyl)pyridineboronic acid pinacol ester for Example 56, 59 ° 2-Methoxypyridineboronic acid for Example 57 ° 5-Methyoxypyridinylboronic acid for Example 65 _ 65 _ ° 2-Isopropoxy5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine for e 66 ° 3-Fluoro,ethoxypyridineboronic acid for Example 67 ° 2-Ethoxypyridineboronic acid for e 69 ° 2-(Tetrahydropyran—4-yloxy)-5 -(4,4,5 ,5 -tetrametrhyl- 1 ,3 ,2-dioxaborolanyl)pyridine for Examples 70, 72 ° 2-Methoxypyridineboronic acid for Examples 71, 73 ° Phenylboronic acid for Example 74 ° (4-Methyl—piperazinyl)-[4-(4,4,5 ,5 -tetramethyl-[1 ,3 ,2] dioxaborolanyl)-phenyl] - methanone for Examples 76, 80 ° 1-Ethyl-1H-pyrazoleboronic acid, pinacol ester for Examples 77, 78 ° 3 -Methyl(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)-3H-imidazo [4,5 -B]pyridine for Example 79 ° 1-Methyl-1H-benzoimidazoleboronic acid for Examples 81, 82 ° 2-Methylbenzo[D]thiazol—6-ylboronic acid, pinacol ester for Examples 84, 85 ° Potassium 5-methoxypyridinetrifluoroborate for Examples 88, 97 ° -butoxy(4,4,5,5-tetramethyl-1,3,2-dioxyborolanyl)pyridine for Example ° 2-MethylH-benziomidazoleboronic acid, pinacol ester for Examples 108, 109 ° 6-(2,2,2-Trifluoroethoxy)pyridineboronic acid, pinacol ester for Examples 110, 111 ° 1,5-Dimethyl-1H-pyrazoleboronic acid, pinacol ester for Example 112 ° 1-Isopropyl-1H-pyrazoleboronic acid, pinacol ester for Examples 113, 115 ° 1-Propyl-1H-pyrazoleboronic acid, pinacol ester for Examples 114, 117 ° 1-Methyltrifluoromethylpyrazoleboronic acid for e 116 ° methoxy-5 -(4,4,5 ,5 -tetramethyl-[1 ,3 ,2] dioxaborolanyl)-pyridine for Example 99 ° 6-(4,4,5 ,5-Tetramethyl-[1,3 ,2] orolanyl)-3 ,4-dihydro-2H-pyrano [2,3 - b]pyridine for Example 100 ° (4,4,5 ,5 -Tetramethyl-[1 ,3 ,2] dioxaborolanyl)-3 ydro-1H-isoquinoline carboxylic acid tert-butyl ester for Example 101 ° Acetic acid 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-pyrazolyl]-ethyl ester for Examples 118, 119 4.2. Synthesis of compounds with formula 6: Reaction 1, 2, 4 and 5 of Scheme 1 The first step was made according to the following literature: M. Tiano, P. Belmont J.
Organic Chem. 2008, 73, 4101-4109. The second step was carried out ing to N.
Nishiwaki, S. Minakata, M. u, Y. Ohshiro, Synlett 1990, 5, 273-275.
WO 14060 Synthesis of 7-phenquuinolinol (Q) for Example 1 § reaction 1 \ reaction 2 \ + —— _. / I N \ N Br 2.7 6.1 Step 1 1: reaction 1 1: 66 mg 3-Acetylbromopyridine, 56 uL phenylacetylene, 170 uL DIPEA, 22.5 mg triphenylphosphinpalladium(II) chlorid, 3 mg Cu(I)I were suspended in 1 mL DMF under argon atmosphere and stirred for 16 h at 25°C. The e was diluted with DCM and extracted with diluted aq. NH3 and brine. The organic phase was concentrated and the mixture separated Via flash chromatography (10 g 8102, cyclohexane 9 cyclohexane /ethylacetate 70:30) to yield 40 mg 1-(2-(phenylethynyl)pyridinyl)ethanone as solid.
Analysis: HPLC-MS: Rt = 1.21 min (method E), M+H = 222.
Step 2 1: on 2): 30 mg 1-(2-(Phenylethynyl)pyridinyl)ethanone were suspended in 350 uL 1N sulfuric acid and 2.147 mg ic chloride and stirred for 30 min at 60°C. Then 1 mL ofNaOH was added and the mixture stirred for additional 1 h at 25°C. Water was added and a neutral pH adjusted with NaHC03 solution. The precipitate was filtered off and washed with water and dried to yield 30 mg 7-phenquuinolin—5-ol Q as solid. Analysis: S: Rt = 1.18 min (method D), M+H = 240.
Synthesis of 7-(3,4,5-trimeth0xyphenyl)quinolinol (Q) for Examples 2, 3, 4, 5, 9, 18, 23 § (I) \ \ + —- —' / I N \ / O\ N Br (I) u o I Step 1 1: reaction 1): 100 mg 3-Acetylbromopyridine, 140 mg 5-ethynyl—1,2,3- trimethoxybenzene E, 101 uL ylamine, 17 mg triphenylphosphinpalladium(II) chlorid, _ 67 _ 1 mg Cu(I)I were ded in 4 mL THF under argon atmosphere and stirred for l h at °C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and saturated NH4Cl on. The orgranic phase was concentrated and the the mixture separated Via FCC (10 g SiOz, Cyclohexane 9 cyclohexane /ethylacetate 70:30) to yield 90 mg l-(2-(3,4,5- trimethoxyphenylethynyl)pyridinyl)ethanone as solid. Analysis: HPLC-MS: Rt = 1.21 min (method E) M+H = 312.
Step 2 1: on 2 1: 90 mg l-(2-(3,4,5-trimethoxyphenylethynyl)pyridinyl)ethanone were suspended in 750 uL 1N sulfuric acid and 4 mg mercuric chloride and stirred for 1h 45 minutes at 60°C. Then 2 mL ofNaOH was added and the mixture stirred for additional 1 h at 25°C. Water was added and a neutral pH was adjusted with KHSO4 solution. The itate was filtered off and washed with water and dried to yield 80 mg 7-(3,4,5- trimethoxyphenyl)quinolinolQ as solid. Analysis: HPLC-MS: Rt = 1.18 min (method D), M+H = 330. 7-(pyridin-Z-yl)quinolin01 (Q) for e 6 7-(pyridinyl)quinolinol (Q) for Example 6 was synthesized in analogy to Q.
Yield: 4% (over two steps) as solid. Analysis: HPLC-MS: Rt = 0.78 min (method E), M+H = 223.
Alternatively Q can be synthesized as bed in: Godet, Thomas; Belmont, Philippe Synlett, 2008 ,16, 2513 - 2517 Step 1 Step 2 ril+\o~§ \ '« \ — N/Br N / \ Step 1 1: reaction 1): 750 mg 3-Acetylbromopyridin, 550 uL 2-ethynyl-pyridine, 765 uL triethylamin, 255 mg triphenylphosphinpalladium(II) chlorid, 17 mg Cu(I)I were suspended in mL DMF under argon here and stirred for 2 h at 25°C. The mixture was diluted _ 68 _ with DCM and extracted with diluted aq. NH3 and saturated NH4Cl solution. The organic phase was trated and the mixture ted via FCC (100 g 8102, cyclohexane 9 cyclohexane /ethylacetate 35:65) to yield 455 mg 1-(2-(pyridinylethynyl)pyridin yl)ethanone as solid. Analysis: HPLC-MS: Rt = 0.88 min de E) M+H = 223.
Step 2 1: reaction 4): 455 mg 1-(2-(pyridinylethynyl)pyridinyl)ethanone was dissloved in 10 mL DCM, 1.069 mL of DIPEA was added, the solution was cooled 0°C and 1.42 mL of tert-butyldimethylsilyltrifluormethansulfonate added slowly. The mixture was stirred 30 min at 0°C, warmed to 25°C and filtrated over a plug of silica (cyclohexane / ethylacetate 1:1 + small amount of TEA) to yield 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)(pyridin ylethynyl)pyridine as oil. Analysis: HPLC-MS: Rt = 1.59 min (method E) m+H = 337.
Ste 3 = reaction 5 : 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)(pyridin ylethynyl)pyridine was dissolved in 100 mL dimethoxyethane and 126 mg of trifluormethanesulfonic acid silver salt added and stirred 7 h at 70°C. The mixture is diluted with DCM and extracted with saturated NaHC03 solution (3x). The organic phase was dried (MgSO4) and concentrated in vaccuo. The residual e was dissolved in 10 mL THE, 1.2 mL of tertbutylammoniumfluoride in THF (1N) was added and the mixture stirred for 2 h at °C. The e was diluted with DCM and extracted with water (1x) and the organic phase concentrated in vacuo and purified via FCC (100 g SiOz, DCM 9 DCM 93:7) to yield 165 mg of 7-(pyridinyl)quinolinol Qas solid. HPLC-MS: Rt = 0.78 min d E), M+H = 223.
Synthesis of 7-(3,4-dimeth0xyphenyl)quinolinol (M) for Examples 7, 8, 12 7-(3,4-dimethoxyphenyl)quinolinol M for Example 7, 8, 12 was synthesized in y to Q Yield: 76% (over two steps) as solid. Analysis: HPLC-MS: Rt = 0.96 min (method E), M+H = 300. _ 69 _ sis of 7-(3,5-Diflu0r0meth0xy-phenyl)-quinolin0l (6._5) for Examples 14, 15, 17 and 38 7-(3,5-Difluoromethoxy-phenyl)-quinolinol 6._5 for Example 14, 15, 17 and 38 was synthesized in analogy to Q Yield: 19% (over two steps) as brown solid. Analysis: HPLC- MS: Rt = 1.13 (method M), M+H = 288. 1H NMR (500 MHz, OL-d4) 8 ppm 4.03 (3 H, 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-Is0pr0p0xymeth0xy-phenyl)-quinolinol (M) for Examples 10, 11, 13 and 16 7-(4-Isopropoxymethoxy-phenyl)-quinolin—5-ol M for Examples 10, ll, 13 and 16 was synthesized in analogy to Q .Yield: 27% (over two steps) as brown solid. Analysis: HPLC- MS: Rt = 1.54 min (method B), M+H = 310. 7-(6-meth0xypyridinyl)quinolinol (6._7) for Examples 20, 21 7-(6-methoxypyridinyl)quinolin—5-ol for Example 20, 21 was sized in analogy to 6.2. Yield: 73% (over two steps) as solid. Analysis: HPLC-MS: Rt = 0.98 min (method M), M+H = 253. [2,7']Biquinolinyl-5'-ol (Q) for Example 34 [2,7']Biquinolinyl—5'-ol (Q) for Example 34 was synthesized in analogy to Q using the method of Godet, Thomas; Belmont, Philippe Synlett, 2008 ,16, 2513 — 2517.
Yield: 43% (over three steps) as brown solid. Analysis: HPLC-MS: Rt = 1.02 min (method M), M+H = 272. 4.3. Synthesis of the patent examples of a 1 and formula 1 Synthesis of (R)—4—((R)(7-phenquuin01inyloxy)ethyl)pyrr0lidin0ne (Example 1) 6.1 32 Example 1 30 mg of 7-Phenquuinolinol, 32.5 mg of ((S)hydroxyethyl)((R) ethyl)pyrrolidinone and 150 mg of triphenylphosphine were dissolved in 3 mL of DCM. 125.5 mg of Di—tertbutyl—azodicarboxylate (DBAD) was added and the mixture stirred WO 14060 for 21 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The c phase was concentrated in vacuo and purified via flash column chromatography (FCC) (20 SiOz; cyclohexane 9 cyclohexane: ethylacetate: MeOH 58:40:2).
Product containing fractions were concentrated, dissolved in 2 mL of trifluoroacetic acid (TFA) and heated 45 min at 150°C in the microwave. The mixture was purified with rpHPLC (XbridgeC18, MeOH/water, TFA) to yield after lisation 8 mg ofExample 1 as solid.
Analysis: S: Rt = 1.21 min (method D), M+H = 333.
Synthesis of (R)—4-((R)(7-(3,4,5-trimethoxyphenyl)quin01inyloxy)ethyl)pyrr0lidin- 2-0ne (Example 2) Example 2 80 mg of 7-(3,4,5-Trimethoxyphenyl)quinolinol, 62 mg of (R)((S)hydroxyethyl) ((R)phenylethyl)pyrrolidinone and 142 mg henylphosphine was dissolved in 5 mL of DCM. 125.5 mg of DBAD was added and the mixture stirred for 6 h at room temperature.
The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash chromatography (10 SiOz; cyclohexane 9 cyclohexane: ethylacetate: MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 1.5 mL of TFA and heated 75 min at 150°C in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 2 as solid. is: HPLC-MS: Rt = 1.20 min (method D), M+H = 423. 1H-NMR (400 MHz, DMSO-d6): 8 = 9.05 (1H,d), 8.75 (1H,d), 7.88 (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 ing Examples were synthesized in analogous manner to Examples 1 and 2.
Example Quino1ine Alcohol for Yield Analysis (corresponding Conversion to formula g) (corresponding to formula 3) Example 7 7-(3 ,4- <R>-4— 58 mg HPLC-MS: (R)((7-(3,4- oxy- (hydroxymethy1) (24%) = 1.22 dimethoxyphenyl) pheny1)quino 1in ((R) min (method quino 1in ol phenylethy1)pyrro 1idin XBM), M+H yloxy)methy1) one = 379 pyrrolidinone e 9 7-(3 ,4,5 - R) 25 mg HPLC-MS: (R)((7-(3,4,5- trimethoxy- (hydroxymethy1) (11%) = 1.24 trimethoxyphenyl) pheny1)quino 1in ((R) min (method quino 1in ol phenylethy1)pyrro 1idin XBM), M+H yloxy)methy1) one = 409 pyrrolidinone Example 14 7-(3 ,5-Difluoro- (R)((S) 15 mg HPLC-MS: (R){(R)[7-(3,5- 4-methoxy- hydroxyethy1)((R)- (11%) = 3.49 Difluoromethoxy- pheny1)pheny1ethy1) min pheny1)-quino 1in quino 1in-5 -o 1 pyrro1idinone (method A), yloxy] -ethy1} - M+H = 399 pyrrolidinone e 17 7-(3 ,5-Difluoro- (R)Hydroxymethy1— HPLC-MS: (R)[7-(3,5- 4-methoxy- pyrro1idinone = 3.40 Difluoromethoxy- )- min (method pheny1)-quino 1in quino 1in-5 -o 1 A), yloxymethy1]- M+H = 385 pyrrolidinone e 20 ethoxy— (R)Hydroxymethy1— 34 mg HPLC-MS: (R)[7-(6-Methoxy— pyridiny1)((R)pheny1- (15%) = 2.78 pyridiny1)- quino 1in-5 -o 1 -oxazo 1idin min quino 1in 0116 (method A), yloxymethy1]- M+H = 352 oxazo1idinone _ 73 _ Synthesis of 5-meth0xy(3,4,5—trimeth0xyphenyl)quinoline le 3) 6 2 Example 3 100 mg of 7-(3,4,5-Trimethoxyphenyl)quinolinol, 42 uL of MeOH and 480 mg of triphenylphosphine was dissolved in 5 mL of DCM. 435 mg of DBADwas added and the mixture stirred for 3 days at room temperature. The mixture was diluted with DCM and ted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 12 mg of Example 3 as solid.
Analysis: HPLC-MS: Rt = 1.11 min (method E), M+H = 326.
The following Examples were synthesized in analogous manner to e 3.
Example Quinoline Alcohol for Yield is (corresponding conversion to formula g) (corresponding to formula 3) Example 4 7-(3,4,5- 15 mg HPLC-MS: Rt = -ethoxy(3,4,5- trimethoxy (15%) 1.20 min hoxyphenyl) phenyl)quinolin- (method E), quinoline 5-ol M+H = 340 Example 5 7-(3,4,5- 5-(Hydroxymethyl) HPLC-MS: Rt = -((7-(3 ,4,5- trimethoxy piperidineone 1 .03 min trimethoxyphenyl) phenyl)quinolin- (method E), quinolin—5-yloxy) 5-ol M+H = 423 )piperidinone Example 12 7-(3,4- (R) HPLC-MS: Rt = ((7-(3,4-di— dimethoxy (hydroxymethyl) 0.94 min methoxyphenyl) phenyl)quinolin- oxazolidinone (method E), quinolin—5-yloxy) 5-ol M+H = 381 methyl) oxazolidinone Examle 18 7—(3,4,5— (R) HPLC-MS: Rt = _ 74 _ (R)((7-(3,4,5- hoxy (hydroxymethyl) trimethoxyphenyl) phenyl)quinolin- oxazolidinone quinolin5yloxy) 5-ol methyl)oxazolidin—2- e 38 7-(3,4,5- (l-Hydroxymethyl- 4 mg HPLC-MS: Rt {l-[7-(3,4,5- Trimethoxy- cyclopropyl)- = 3 .62 Trimethoxy-phenyl)- phenyl)- acetonitrile (method A), quinolin-5yloxy quinolinol M+H = 405 methyl]-cyclopropyl} acetonitrile Synthesis of (R)—4-((R)(7-(pyridinyl)quinolin-S-yloxy)ethyl)pyrrolidin0ne (Example 6) Example 6 mg of 7-(Pyridin—2-yl)quinolinol, 30 mg of ((R)((S)-l-hydroxyethyl)-l-((S)—l-(4- methoxyphenyl)ethyl)pyrrolidinone and 50 mg of triphenylphosphin was dissolved in 2 mL of DCM. 45 mg of DBAD was added and the mixture d for 14 h at room temperature. The mixture was diluted with DCM and extracted with lN NaOH and water. The organic phase was concentrated in vacuo and ved in 0.5 mL of TFA and heated 30 min at 90°C in the microwave. The mixture was purified with HPLC (XbridgeClS, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 6 as solid. is: HPLC-MS: Rt = 0.9 min (method E), M+H = 334.
The following Examples were synthesized in analogous manner to Example 6. _ 75 _ Example Quinoline Alcohol for Yield Analysis (corresponding Conversion to formulag) (corresponding to a 3) Example 8 7-(3 ,4- (R)((S)hydroxy- HPLC-MS: (R)((R)(7-(3,4- dimethoxy ethyl)((S)(4- = 1.26 dimethoxyphenyl)- phenyl)quino lin methoxyphenyl)ethyl)- min (method quino lin-5 )- -5 -ol pyrrolidinone XBM), M+H ethyl)pyrrolidinone = 393 Example 34 [2,7']Bi- (R)((S)hydroxy- HPLC-MS: R)[(R) quinolinyl-5'-ol ethyl)((S)(4- = 3.28 ([2,7']Biquinolinyl-5' methoxyphenyl)ethyl)- min -yloxy)-ethyl]- pyrrolidinone (method A), idinone M+H = 384 Synthesis of (R)—5- [7-(4-Hydr0xymethoxy-phenyl)-quinolin-S-yloxymethyl] - oxazolidin-Z-one (Example 13) e 13 A solution of 0.085 ml of diisopropylazodicarboxylate (DIAD) in THF (2ml) was added to a mixture of 150 mg of 7-(4-Isopropoxymethoxy-phenyl)-quinolinol, 128 mg of (R) Hydroxymethyl((R)phenyl-ethyl)-oxazo lidinone and 1 6 1 mg 0f PS- triphenylphosphine in THF (15 mL) and stirred for 14 h at room temperature. A fiarther 161 mg of PS-triphenylphosphine and 0.085 ml of DIAD were added and stirring continued for a r 4 hr. The mixture was filtered then diluted with EtOAc and extracted with water. The organic phase was concentrated in vacuo and dissolved in 1 mL of TFA and heated 30 min at 150°C in the microwave. The mixture was purified over SiOz g with 1-10% 7N NHg/MeOH:DCM to afford 17 mg ofExample 13 as a solid. is: HPLC-MS: Rt = 2.61 (method A), M+H = 367 The following Examples were synthesized in analogous manner to Example 13.
Example Quinoline Alcohol Analysis (corresponding to (corresponding to formula g) a 3) Example 10 7-(4-Isopropoxy- (lS,4R)[1-(4- 32 mg (64%) HPLC-MS: (R){(R)[7-(4- 3-methoxy- Methoxy-phenyl)- Rt = 3.23 Isopropoxy—3- phenyl)-quino lin- ethyl] {(R) TFA treatment min methoxy-phenyl)- 5-01 [7-(6-methoxy- for 30 mins @ (method A), quino lin-5 ] - pyridin-3 -yl)- 50°C M+H = 421 ethyl} -pyrro lidin- quino lin-5 - 2-one yloxy] -ethyl} - pyrrolidinone Example 1 1 7-(4-Isopropoxy- (lS,4R)[1-(4- 100 mg (36%) HPLC-MS: (R) {(R)[7-(4- oxy- Methoxy-phenyl)- Rt = 2.73 Hydroxy-3 - phenyl)-quino lin- {(R) TFA treatment min methoxy-phenyl)- 5-01 [7-(6-methoxy- for 60 mins @ (method A), quino lin-5 -yloxy] - pyridin-3 -yl)- 110°C M+H = 379 ethyl} -pyrro lidin- quino lin-5 - 2-one yloxy] -ethyl} - pyrrolidinone Example 15 7-(3,5-Difluoro (R)-5 - 28 mg (18%) HPLC-MS: [7-(3,5- methoxy-phenyl)- Hydroxymethyl- Rt = 3.38 Difluoro quino lin-5 -ol 3 -((R)phenyl- min methoxy-phenyl)- ethyl)-oxazo lidin- (method A), quino lin-5 - 2-one M+H = 387 yloxymethyl] - oxazolidinone Example 19 7-(4-Isopropoxy- <R> 23 mg HPLC-MS: [7-(4- 3-methoxy- (hydroxymethyl)- (12%) Rt = 2.65 Hydroxy-3 - phenyl)-quino lin((R) min methoxy-phenyl)- 5-01 ethyl)- (method A), quino lin-5 - pyrrolidineone M+H = 365 yloxymethyl]- pyrrolidinone _ 77 _ Synthesis of (R)—5—((7-(4-is0pr0p0xymeth0xyphenyl)quinolinyloxy)methyl) oxazolidin-Z-one (Example 16) Example 13 Example 16 A mixture of 59 mg (R)[7-(4-hydroxy—3-methoxy-phenyl)-quinolinyloxymethyl]- oxazolidinone (Example 13), 19.3ul 2-iodopropane and 44mg potassium carbonate in DMF (10ml) was stirred at 50°C for 16 hours. The mixture was poured into EtOAc and washed with water then brine and dried over NaZSO4. Purification by FCC over SiOz, eluting with EtOAc - MeOH from 100:0 to 95:5 yielded 56 mg (85%) of (R)[7-(4-Isopropoxy—3- methoxy-phenyl)-quinolinyloxymethyl]-oxazolidinone le 16) as an oily residue.
Analysis S: Rt = 1.09 min (method M), M+H = 409.
Synthesis of (R)—4-{(R)—1-[7-(6-Meth0xy-pyridinyl)—quinolinyloxy]-ethyl}- pyrrolidin-Z-one (Example 21) Example 21 1020 mg of 7-(6-Methoxy—pyridinyl)-quinolinol 6._7, 1171 mg of (R)((S)—l-Hydroxy— ethyl)[(R)(4-methoxy-phenyl)-ethyl]-pyrrolidinone M and 1590 mg of triphenylphosphine were dissolved in 20 mL of THF. 1.19ml of DIAD -was added and the mixture stirred for 24 h at room temperature. The mixture was trated in vacuo and purified over SiOz (l-5% CM) to give 1300mg of (18,4R)—1-[1-(4-Methoxy— _ 73 _ phenyl)-ethyl] {(R)- l - [7-(6-methoxy-pyridin-3 -yl)-quino lin-5 -yloxy] -ethyl} -pyrrolidin one. 727mg of this product was dissolved in acetonitrile (7ml) at 0°C and a solution of 2339 mg ceric ammonium nitrate (CAN) in water (7ml) was added. The mixture was stirred for 6 hours, then poured onto sat NaHC03 (150ml), diluted with water, then extracted with DCM.
Purification over a plug of silica using l-3% 2N MeOH/NH3:DCM d l37mg of required product as a pale brown foam in 26% yield.
Analysis: HPLC-MS: Rt = 2.94 min (method A), M+H = 364 Synthesis of 2-((7-br0m0quinolinyloxy)methyl)nic0tinamide (Example 22) H2N o OH H2N O O \ \ + —> I H0 \ NI / / I \ N Br N / | N Br Example 22 100 mg o-quinolinol, 77.5 mg of 2-(hydroxymethyl)nicotinamide 3._7, 233.5 mg of triphenylphosphine and 205 mg of tbutyl—azodicarboxylate (DBAD) were dissolved in 2.5 mL of DCM and 7.5 mL of THF under Argon at room temperature. After 14 h the precipitate was collected and dried. The mother liquor was concentrated and the formed itate again collected to yield 72 mg Example 22. is: HPLC-MS: Rt = 0.48 min (method X001_002), M+H = 358/360. 1H-NMR (400 MHz, DMSO-d6): 8 = 8.91 (lH,d), 8.65 (lH,d), 8.48 (lH,d), 8.05 (1H, s), 7.95 (1H, d), 7.80 (1H, s), 6.65-7.50 (3H, m), 7.31 (lH,s), 5.58 (2H,s) ppm. _ 79 _ Synthesis of 5,5-Dimethyl[7-(3,4,5-trimethoxy-phenyl)-quinolinyloxymethyl]- imidazolidine-2,4-di0ne (Example 23) 72%HN // O H // \ [ill] O \ O N “Iii \ O;fiL;j§<j —> ‘1'” N ll'i] \ o o \ O\ — Example 23 150mg 7-(3,4,5-Trimethoxy-phenyl)-quinolinol (6.2), 65mg l-chloromethyl-5,5-dimethyl— imidazolidine-2,4-dione (3.7) and 51mg potassium carbonate were dissolved in l.5ml DMF and heated at 70°C for 2 hrs. Water was added and the mixture extracted with EtOAc. The ed organic ts were washed with brine, dried over sodium sulphate, filtered and trated in vacuo.
Purification by HPLC afforded 33mg 5,5-Dimethyl-l-[7-(3,4,5-trimethoxy-phenyl)-quinolin- 5-yloxymethyl]-imidazolidine-2,4-dione in 21% yield.
HPLC-MS: Rt = 3.46 min (method A), M+H = 452.
Synthesis of 2-((7-(4-(methylsulf0nyl)phenyl)quinolinyloxy)methyl)nic0tinamide according to Scheme 2 (Example 24) \ O /N o /N (IDH 6 + o \ /\\ | 0 N Br ExampleZZ Example 24 50 mg Example 22, 33.5 mg 4-methanesulphonyl)benzeneboronic acid, 17.5 mg tetrakis- enylphosphin)-palladium(0), 140 uL 2N aqueous sodium carbonat and 0.5 mL dioxan were heated in the microwave (MW) for 15 min at 140°C. The mixture was purified with HPLC (XbridgeC18, ater, TFA) and the desired fractions lyophilized to yield 60 mg (75%) of Example 24 as yellow solid.
HPLC-MS: Rt = 0.49 min (method X001_002), M+H = 434. 1H-NMR (400 MHz, DMSO-d6): 8 = 9.05 (1H,d), 8.70-8.64 (2H,m), 8.15 (2H,d), .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 analogous manner to Example 24.
Example c acid /ester Analysis (corresponding to formula 4) Example 25 3 ,4-dimethoxyphenyl- 30 mg HPLC-MS: Rt = 0.65 boronic acid (48%) min (method 2-((7-(3 ,4- X001_002), M+H = 416 dimethoxyphenyl) quino lin-5 -yloxy)- methyl)nicotinamide Example 26 N—(5-(4,4,5,5- 14 mg HPLC-MS: Rt = 0.57 tetramethyl-1,3 ,2- (22%) min (method 2-((7-(6-acetamido- dioxaborolan X001_002), M+H = 414 pyridinyl)quinolin- yl)pyridin -yloxy)methyl)- tamide nicotinamide Example 32 o(methyl- 33 mg HPLC-MS: Rt = 0.60 2-((7-(3-fluoro sulfonyl)phenylboroni (41%) min (method (methylsulfonyl) c acid X001_002), M+H = 452 phenyl)quino lin-5 - yloxy)methyl)nicotin amide Example 35 4,4,5,5-tetramethyl 3 5 mg HPLC-MS: Rt = 0.51 2-((7-(3 -methyl (3 l (47%) min (method (methylsulfonyl) (methylsulfonyl) X001_003), M+H = 448 )quino lin-5 - phenyl)-1,3,2- yloxy)methyl)nicotin dioxaborolane Example 36 4,4,5,5-tetramethy1-2_ 5 mg HPLC-MS: Rt = 0.70 2-((7-(4- (4-(trifluoromethy1_ (37%) min (method (trifluoromethyl sulfonyl)pheny1)_ 03), M+H = 488 sulfonyl)phenyl) l ,3 ,2-dioxaborolane quino lin-S - yloxy)methyl)nicotin amide Example 39 5-(4,4,5,5-tetramethyl- 25 mg HPLC-MS: Rt = 0.39 2-((7-( l H- l,3 ,2-dioxaborolan—2- (59%) min (method benzo [d]imidazo 1-5 - yl)- l H-benzo [d] X001_003), M+H = 396 yl)quino lin-S - imidazole 1H—NMR (400 MHz, yloxy)methyl)nicotin DMSO-d6): 8 = 9.45 amide (lH,s), 9.0 , 8.7— 8.55 (2H,m), 8.25 (1H, s), 810—793 (6H, m), 7.65-7.55 (3H, m), 7.52 (1H, dd), 5.75 (2H, 5) Example 40 4—(morpholinomethy1) 34 mg HPLC-MS: Rt = 0.39 2—((7-(4- phenylboronic acid (71%) min (method (morpholinomethyl) 03), M+H = 455 phenyl)quino lin-S - yloxy)methyl)nicotin amide Example 44 1 -methyl- 1 H-indazo l- 25 mg HPLC-MS: Rt = 0.55 2-((7-( 1 -methyl- 1 H- 6-ylboronic acid (57%) min (method indazolyl)quino lin- X001_003), M+H = 410 yloxy)methyl)nicotin amide e 45 4-(5-(4,4,5,5- 38 mg HPLC-MS: Rt = 0.46 2-((7-(6-morpholino- tetramethyl— l ,3,2- (82%) min (method pyridin—3 -yl)quino lin- orolan—Z- X001_002), M+H = 442 _ yl)pyridin yloxy)methy1)nicotin y1)morpho line - amide e 46 1-methy1(4,4,5 ,5- 32 mg HPLC-MS: Rt = 0.46 2-((7-(1-methy1—1H- tetramethyl— 1 ,3 ,2- (81%) min (method pyrazo1y1)quino lin- oro1any1)- X001_002), M+H = 360 _ 1 H-pyrazo 1e yloxy)methy1)nicotin Amide Example 50 N—ethyl—N—(4-(4,4,5,5- 18 mg HPLC-MS: Rt = 0.60 2-((7-(4-((N- tetramethyl— 1 ,3 ,2- (36%) min (method ethylacetamido) dioxaborolan—Z- 02), M+H = 455 methy1)pheny1) y1)benzy1)acetamide quino 1in-5 - yloxy)methy1)nicotin amide e 52 6-(4,4,5,5-tetramethy1— 1 4 mg HPLC-MS: Rt = 0.51 2-((7-(1-oxo-1,2,3,4- 1,3 ,2-dioxaborolan—2- (39%) min (method tetrahydroisoquino lin- 4-dihydroiso- X001_002), M+H = 425 uino 1in-5 - quino 1in- 1 (2H)-one yloxy)methy1)nicotin amide Example 54 6-(4,4,5,5-tetramethy1— 6 mg HPLC-MS: Rt = 0.60 6-(5-((R)((R) 1,3 ,2-dioxaborolan—2- (15%) min (method oxopyrrolidin y1)-3,4-dihydroiso- X001_002), M+H = 467 y1)ethoxy)quinolin quino 1in- 1 (2H)-one y1)-3,4-dihydroisoquino 1in- 1 (2H)-one Example 57 6-methoxypyridin 3 8 mg HPLC-MS: Rt = 0.57 2-((7-(6- ylboronic acid (91%) min (method methoxypyridin X001_002), M+H = 387 y1)quino 1inyloxy) methy1)nicotinamide Example 58 N—methyl-N-(4_ 1 0 mg HPLC-MS: Rt = 0.55 2-((7-(4-((N- (4a4a5a5-tetramethy1_ (27%) min (method methylacetamido) 1,3 ,2-dioxaborolan—2— X001_002), M+H = 441 methy1)pheny1) y1)benzy1)acetarnide WO 14060 _ 33 _ quino 1in-5 - yloxy)methy1)nicotin amide Example 59 N—methy1(4,4,5,5- 37 mg HPLC-MS: Rt = 0.51 -(5 -((3 - tetramethy1-1,3 ,2- (84%) min (method carbamoylpyridin—2- dioxaborolan—Z- 02), M+H = 414 y1)methoxy)quino 1in- y1)picolinamide 7-y1)-N— methy1pico1in-amide Example 60 2-methy1(4,4,5,5- 28 mg HPLC-MS: Rt = 0.50 2-((7-(2-methy1— ethy1- 1 ,3 ,2- (64%) min (method imidazo[1,2- dioxaborolan—Z- X001_002), M+H = 410 a]pyridin y1)imidazo[1 ,2-a] y1)quino 1in pyridine yloxy)methy1)nicotin amide Example 62 1-(2-chloro(4,4,5,5- 5 mg HPLC-MS: Rt = 0.53 2-((7-(4-(1-amino- ethy1-1,3 ,2- (13%) min (method cyclopropy1) dioxaborolan—Z- X001_004), M+H = 445 chloropheny1)quino 1in y1)pheny1)cyclopropan amine yloxy)methy1)nicotin amide e 64 6-(4,4,5,5-tetramethy1- 10 mg HPLC-MS: Rt = 0.42 2-((7-(2-oxo-2,4- 1,3,2-dioxaborolan—2— (28%) min (method dihydro-1H- y1)-1H-benzo[d][1,3] X001_004), M+H = 427 benzo [d] [ 1 ,3]oxazin— oxazin—2(4H)-one 6-y1)quinolin—5- methy1)nicotin amide Example 70 2-(tetrahydro-2H- 26 mg HPLC-MS: = 2-((7-(6-(tetrahydro- pyran—4-yloxy) (54%) 0.6 1min (method an—4- (4,4,5,5-tetramethy1- X001_004), M+H = 457 yloxy)pyridin 1,3,2-dioxaborolan—2— y1)quino 1in y1)pyridine yloxy)methy1)nicotin amide Examle 71 2-methoxypyridin 3 m HPLC-MS: Rt 2-((7-(2-methoxy ylboronic acid 0.56min (method pyridin—4-y1)quinolin- X001_004), M+H = 387 yloxy)methy1)nicotin amide Example 74 phenylboronic acid HPLC-MS: = 2-((7-pheny1quinolin- 0.59min (method - X001_004), M+H = 356 yloxy)methy1)nicotin amide e 75 2-methy1—6-(4,4,5 ,5- 85 mg HPLC-MS: = 2-((2-methyl-6,7'- tetramethyl— l ,3 ,2- (39%) n (method o lin-S '-yloxy) dioxaborolan—Z- X001_004), M+H = 421 methy1)nicotinamide yl)quino line Example 77 1 -ethy1(4,4,5 ,5- HPLC-MS: = (l-ethy1-1H- tetramethyl— l ,3 ,2- 0.50min (method pyrazo1y1)quino lin- dioxaborolan—Z-yl)- X001_004), M+H = 374 - l H-pyrazo 1e methy1)nicotin amide Example 79 3-methy1(4,4,5,5- 18 mg HPLC-MS: = 2—((7-(3-methy1-3H- tetramethyl— l ,3 ,2- (43%) 0.46min d imidazo[4,5- dioxaborolan—Z-yl)- X001_004), M+H = 411 b]pyridin 3H-imidazo [4,5- yl)quino lin-S - b]pyridine yloxy)methyl)nicotin amide Example 80 (4-methy1piperazin- l - HPLC-MS: = 2-((7-(4-(4-methy1 yl)(4-(4,4,5 ,5- 0.44min (method piperazine- l - tetramethyl— l ,3 ,2- X001_004), M+H = 482 yl)phenyl) dioxaborolan—Z- quino lin-S - y1)pheny1)methanone yloxy)methyl)nicotin hydrochloride amide Example 82 1 -methyl- 1H- 17 mg HPLC-MS: = 2-((7-(l-methy1-1H- benzo [d]imidazo 1 (40%) 0.48min (method benzo [d]imidazo 1 ylboronic acid 04), M+H = 410 yl)quino lin-S - yloxy)methyl)nicotin Example 84 2-methy1—6-(4,4,5,5- 28 mg HPLC-MS: Rt = 2-((7-(2-methy1benzo tetramethyl— l ,3 ,2- (62%) 0.55min (method [d]thiazo 1—6- dioxaborolan—2- X001_004), M+H = 427 y1)quinolin - y1)benzo[d]thiazo 1e Syloxy)methy1)nicotin amide Example 92 3-methy1—7-(4,4,5,5- HPLC-MS: = 2-((7-(3 1 tetramethyl— l ,3 ,2- 0.47min (method oxo-3,4- dioxaborolan—2- X001_004), M+H = 438 dihydroquinazolin y1)quinazolin-4(3H)- y1)quinolin 0116 yloxy)methy1)nicotin amide Example 96 2-(methylsu1fony1 HPLC-MS: = 2-((7-(6-(methy1 )(4,4,5,5- 0.39min (method sulfonylmethy1)pyridi tetramethyl— l ,3 ,2- X001_004), M+H = 449 n—3-y1)quinolin dioxaborolan—2- yloxy)methy1)nicotin y1)pyridine amide e 97 potassium trifluoro(5- 45 mg HPLC-MS: = hylsu1fonyl- methoxypyridin (81%) 0.50min (method methy1)(4,4,5,5- y1)borate 04), M+H = 387 tetramethyl— l ,3 ,2- dioxaborolan—2- y1)pyridine Example 98 l-methyl-S-(4,4,5,5- 12 mg HPLC-MS: = 2-((7-(l-methy1-1H- tetramethyl— l ,3 ,2- (26%) 0.39min (method benzo[d]imidazo 1 dioxaborolan—2-y1)- X001_004), M+H = 410 y1)quino lin-S - lH-benzo[d]imidazo 1e yloxy)methy1)nicotin— amide Example 103 3-methy1—7-(4,4,5,5- 7 mg S: Rt = 0.38 (3 -methy1- tetramethyl— l ,3 ,2- (14%) min (method 2,3,4,5-tetrahydro- dioxaborolan—2-y1)- Reaction X001_004), M+H = 439 lH-benzo[d]azepin—7- 2,3 ,4,5-tetrahydro-1H- time: 30 y1)quino lin-S -yloxy) benzo[d]azepine min methy1)nicotinamide Example 106 1,2—dimethyl_5- l 5 mg HPLC-MS: Rt = 0.35 (1,2-dimethy1— (4a4a5a5-tetramethy1_ 3 ) min (method zo [d]imidazo 1- 1,3 ,2-dioxaborolan—2— X001_004), M+H = 424 -y1)quino 1in—5 - y1)- l H- yloxy)methy1)nicotin— d]imidazo 1e amide Example 108 2-methy1—5-(4,4,5,5- 3 0 mg HPLC-MS: Rt = 0.69 2-((7-(2-methy1-1H- tetramethyl— l ,3 ,2- (5 1%) min (method benzo [d]imidazo 1—5 - dioxaborolan—Z-y1)- X001_004), M+H = 410 y1)quino 1in-5 -yloxy) zo[d]imidazo 1e methy1)nicotinamide Example 1 10 5-(4,4,5,5-tetramethy1— 3 9 mg HPLC-MS: Rt = 0.59 2-((7-(6-(2,2,2- 1,3 ,2-dioxaborolan—2- (61%) min (method trifluoroethoxy)pyridi yl)(2,2,2-trifluoro- X001_004), M+H = 455 n—3 -y1)quino 1in-5 - ethoxy)pyridine yloxy)methy1)nicotin— amide e 1 13 l -isopropy1—4-(4,4,5 ,5- 3 6 mg HPLC-MS: Rt = 0.46 2-((7-( l -isopropy1— tetramethyl— l ,3 ,2- (64%) min d lH-pyrazo 1—4- dioxaborolan—Z-y1)- X001_004), M+H = 388 y1)quino 1in-5 - l H-pyrazo 1e yloxy)methy1) nicotinamide Example 1 17 1 -propy1—4-(4,4,5 ,5- 38 mg HPLC-MS: Rt = 0.47 2-((7-(l-propy1-1H- tetramethyl— l ,3 ,2- (67%) min (method pyrazo1—4-y1)quino lin- dioxaborolan—Z-y1)- X001_004), M+H = 388 -yloxy)methy1) l H-pyrazo 1e nicotinamide _ 37 _ Synthesis of (R)—4—((R)(7-br0m0quinolinyloxy)ethyl)pyrrolidin0ne (Example 27) O E O \ N NH I —. g O/RNHH —p N Br |\ 0 O r | N Br fl Example 27 100 mg of 7-Bromo-quinolinol, 234 mg triphenylphosphine and 133 mg of (R)((S) hydroxyethyl)((S)(4-methoxyphenyl)ethyl)pyrrolidinone was dissolved in 2.5 mL of DCM and 7.5 mL of THF. 205 mg DBAD was added (slightly exothermic) and the mixture was stirred overnight at room temperature. Then additional 234 mg triphenylphosphine and 205 mg DBAD was added and the mixture stirred over the weekend. The mixture was diluted with DCM and extracted with 1N NaOH and water and the c phase was concentrated in VdCMO.
The remaining al was treated with 2 mL of racetic acid (TFA) and heated 2 h and min at 90°C in the microwave. The mixture was concentrated and purified with HPLC (XbridgeC18, MeOH / water, TFA) to yield 165 mg yellow solid which was purified by FCC over silica ( 20 g SiOZ; DCM9 DCM: MeOH 90: 10) to yield 90 mg solid as Example 27.Analysis: HPLC-MS: Rt = 0.56 min (method X001_002), M+H = 7. 1H-NMR (400 MHz, DMSO-d6): 8 = 8.95 , 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-trimeth0xyphenyl)quinolinyloxy)methyl)cyclopr0pyl) acetamide (Example 28) H o NH2 Example 38 Example 28 _ 33 _ NaOH (lM, 0.37mL) was added to a on of 125 mg (3,4,5-Trimethoxy-phenyl)- quinolinyloxymethyl]-cyclopropyl} -acetonitrile (Example 38) in EtOH (2ml) under air at 0°C followed by hydrogen peroxide (30%aq, ~50mg). The mixture was stirred at 0°C for 1h then warmed to RT and stirred at that ature for 48 hours. The reaction was quenched by addition of aq sat Na28203 and water then extracted with CH2C12 (3x). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated.
Purification by HPLC gave 2-{l-[7-(3,4,5-Trimethoxy-phenyl)-quinolinyloxymethyl]- cyclopropyl} -acetamide 8.2mg as a colourless solid.
S: Rt = 3.05 min (method A), M+H = 423.
Synthesis of ((R)(6,7'-biquinolin-5'-yloxy)ethyl)pyrrolidin-Z-one (Example 29) O OH NH I \ + B \ HO/ O I I 2\/ —’ O /0 N Br Example 27 Example 29 40 mg Example 27, 31 mg quinolineboronic acidboronic acid, 14 mg tetrakis- (triphenylphosphin)-palladium(0), l20 uL 2N aqueous sodium ate and 0.5 mL dioxan were heated in the microwave (MW) for 15 min at 140°C. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) and the d fractions lyophilized to yield 30 mg (75%) ofExample 29 as yellow solid.
HPLC-MS: Rt = 0.54 min (method X001_002), M+H = 384. lH-NMR (400 MHz, DMSO-d6): 8 = 9.05 (2H,d), 8.72 (2H,dd), 7.60 (lH,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 (lH,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 analogous manner to Example 29. _ 39 _ Example 30 N—(5-(4,4,5,5- 23 mg HPLC-MS: Rt = 0.55 N—(5-(5-((R)((R)- tetramethy1-1,3 ,2- (3 8%) min (method -oxopyrrolidin—3- dioxaborolan—2- X001_002), M+H = 391 y1)ethoxy)quino 1in y1)pyridin y1)pyridin y1)acetamide y1)acetamide Example 31 6-(trifluoromethy1) 38 mg HPLC-MS: Rt = 0.74 (R)((R)(7-(6- pyridin—3 -y1boronic (59%) min (method (trifluoromethyl) acid X001_002), M+H = 402 pyridin—3-y1)quinolin- lH-NMR (400 MHz, -yloxy)ethy1) DMSO-d6): 8 = 9.29 pyrrolidinone (1H,s), 9.02 (1H,d), 8.65 (1H, d), 8.58 (1H, d), 8.1-8.0 (2H, m), 7.65 (1H, dd), 7.61-7.55 (2H, m), 5.05 (1H, m), 3.45 (1H, t), 3.18 (1H, dd), 2.88 (1H, m), 2.45-2.28 (2H, m), 1.38 (3H,d) ppm.
Example 33 2-methy1(4,4,5,5- 8 mg HPLC-MS: Rt = 0.55 ((R)(2- tetramethy1-1 ,3 ,2- (17%) min (method methyl-6,7'- dioxaborolan—2- X001_002), M+H = 398 biquino 1in-5'- y1)quino line yloxy)ethy1) idinone Example 41 5-(4,4,5,5-tetramethy1— 32 mg S: Rt = 0.42 (R)((R)(7-(1H- dioxaborolan—2- (52%) min (method benzo[d]imidazol—5- y1)-1H-benzo[d] X001_003), M+H = 373 y1)quino 1inyloxy) imidazo 1e ethy1)pyrro 2-one Example 42 1-methy1-1H-indazo 1- 30 mg S: Rt = 0.58 (R)((R)(7-(1- 6-y1boronic acid (47%) min (method methyl-1H-indazol—6- X001_003), M+H = 387 y1)quino1m-5 - yloxy)ethy1)pyrrolidin one Example 43 pholinomethy1) 48 mg HPLC-MS: Rt = 0.42 (R)((R)(7-(4- phenylboronic acid (69%) min d (morpholinomethyl) X001_003), M+H = 432 pheny1)quinolin yloxy)ethy1)pyrrolidin one Example 47 l-methy1(4,4,5 ,5- 25 mg HPLC-MS: Rt = 050 (R)((R)(7-(1- tetramethyl— l ,3 ,2- (49%) min (method methyl— 1 H-pyrazo 1—4- dioxaborolan—2-yl)- X001_002), M+H = 337 yl)quinolinyloxy) l H-pyrazo 1e ethyl)pyrrolidin—2-one Example 48 4,4,5,5- 36 mg HPLC-MS: Rt = 048 (R)((R)(7-(6- tetramethyl— l ,3 ,2- (60%) min d morpholinopyridin—3- dioxaborolan—2- X001_002), M+H = 419 yl)quinolin y1)pyridin yloxy)ethy1)pyrrolidin yl)morpho line one Example 51 N—methyl-N-(4_ 16 mg ( HPLC-MS: Rt = 058 N—methyl—N—(4-(5- (4a4a5a5-tetramethy1_ 30%) min (method -((R) 1,3 ,2-dioxaborolan—2— X001_002), M+H = 418 oxopyrrolidin y1)benzyl)acetarnide yl)ethoxy)quinolin yl)benzy1)acetamide Example 53 6-(4,4,5,5-tetramethy1— 10 mg HPLC-MS: Rt = 054 6-(5-((R)((R) 1,3 ,2-dioxaborolan—2- (29%) min (method oxopyrrolidin yl)-3,4-dihydroiso- X001_002), M+H = 402 yl)ethoxy)quinolin quino lin- l (2H)-one yl)-3,4-dihydroiso- quino lin- l (2H)-one Example 55 ,5,5-tetramethy1— 13 mg HPLC-MS: Rt = 0.63 (R)((R)(7-(4- 1,3 ,2-dioxaborolan—2- (17%) min d ((2- yl)-3,4-dihydroiso- X001_002), M+H = 444 methylenepiperidin— l - quino lin- l (2H)-one yl)methyl)pheny1) quino lin-5 - yloxy)ethy1) idinone Example 56 N—methyl—S-(4,4,5,5- 30 mg HPLC-MS: Rt = 0.54 N—methyl—S -(5 -((R)- l - tetramethyl— l ,3 ,2- (52%) min (method ((R)oxopyrrolidin— dioxaborolan—2- x001_002), M+H = 391 3-y1)ethoxy)quinolin— y1)picolinamide 7-y1)picolinamide Example 61 2-methy1—6-(4,4,5,5- 16 mg HPLC-MS: Rt = 0.50 (R)((R)(7-(2- tetramethyl— l ,3 ,2- (32%) min (method methylimidazo [ l ,2- dioxaboro1an—2-y1) X001_004), M+H = 387 a]pyridiny1) imidazo [ l ,2- quinolin—S-yloxy) a]pyridine ethy1)pyrro lidin—2-one Example 63 6-(4,4,5,5-tetramethy1— 10 mg HPLC-MS: Rt = 0.45 (R)((R) 1,3 ,2-dioxaborolan—2- (29%) min (method oxopyrrolidin yl)-lH-benzo[d][1,3] X001_004), M+H = 404 y1)ethoxy)quinolin oxazin—2(4H)-one yl)-lH-benzo[d][l,3] —2(4H)-one Example 65 5-methoxypyridin HPLC-MS: Rt = 0.55 (R)((R)(7-(5- ylboronic acid min d methoxypyridin X001_004), M+H = 364 y1)quinolinyloxy) ethyl)pyrrolidin—2-one Example 66 2-isopropoxy_5- 22 mg S: Rt = 0.70 (R)((R)(7-(6- ,5-tetramethy1- (46%) min (method isopropoxypyridin 1,3 ,2-dioxaborolan-2— X001_004), M+H = 392 y1)quinolinyloxy) y1)pyridine ethyl)pyrrolidin—2-one Example 67 5-fluoromethoxy- HPLC-MS: Rt = 0.64 (R)((R)(7-(5- pyridin—3-ylboronic min (method fluoromethoxy acid X001_004), M+H = 382 pyridin—3-y1)quinolin- -yloxy)ethy1) pyrrolidinone Example 68 N—ethyl—N—(4-(4,4,5,5- 8 mg S: Rt = 0.62 N—ethyl—N—(4-(5-((R)- ethyl— l ,3 ,2- (22%) min d 1 -((R) dioxaborolan—2- X001_004), M+H = 432 oxopyrrolidin y1)benzy1)acetamide y1)ethoxy)quinolin y1)benzy1)acetamide Example 69 6-ethoxypyridin HPLC-MS: Rt = 0.66 (R)((R)(7-(6- ylboronic acid min (method ethoxypyridin—3-y1) X001_004), M+H = 378 quinolin—5- yloxy)ethy1) pyrrolidin-Z-one Example 72 2-(tetrahydro-2H_ HPLC-MS: Rt = 0.63 (R)((R)(7-(6- pyrany10Xy)_5_ min (method (tetrahydro-ZH-pyran- (4a4a5a5-tetramethy1_ X001_004), M+H = 434 4-yloxy)pyridin 1,3 ,2-dioxaborolan—2— no 1inyloxy) y1)pyridine ethyl)pyrrolidin—2-one Example 73 2-methoxypyridin 17 mg HPLC-MS: Rt = 0.58 (R)((R)(7-(2- ylboronic acid (37%) min d methoxypyridin 04), M+H = 364 y1)quino 1inyloxy) ethyl)pyrrolidin—2-one Example 76 (4-methy1piperazin HPLC-MS: = (R)((R)(7-(4-(4- y1)(4-(4,4,5 ,5- 0.46min d methylpiperazine tetramethyl— 1 ,3 ,2- X001_004), M+H = 459 carbonyl)phenyl) dioxaborolan—Z- quino 1in-5 - y1)pheny1)methanone yloxy)ethyl) pyrrolidin-Z-one Example 78 1-ethy1(4,4,5,5- HPLC-MS: = (R)((R)(7-(1- tetramethyl— 1 ,3 ,2- 0.53min (method ethyl- 1 H-pyrazo 1—4- dioxaborolan—Z-y1)- 04), M+H = 351 y1)quino 1in-5 -yloxy) 1 H-pyrazo 1e ethy1)pyrro lidinone Example 81 1 -methyl- 1 H- 23 mg HPLC-MS: = ((R)(7-(1- benzo [d]imidazo 1 (48%) 0.46min (method methyl— 1 H-benzo [d] nic acid X001_004), M+H = 387 imidazo 1 y1)quino 1in-5 - yloxy)ethyl) pyrrolidin-Z-one Example 83 6-(4,4,5,5-tetramethy1— 26 mg HPLC-MS: = ((R)(7-(2- 1,3 ,2-dioxaborolan—2- (42%) 0.59min (method oromethyl) y1)(trifluoromethyl) X001_004), M+H = 441 imidazo[1 ,2- imidazo[1 ,2- a]pyridin a]pyridine y1)quino lin-5 -yloxy) ethy1)pyrro lidin-Z-one Example 85 2-methy1—6-(4,4,5,5- 20 mg S: = (R)((R)(7-(2- tetramethyl— 1 ,3 ,2- (41%) 0.57min (method methylbenzo [d]thiazo dioxaborolan—Z- X001_004), M+H = 404 1y1)quinolin y1)benzo[d]thiazo 1e leXy) ethy1)pyrro lidin-Z-one e 86 tert-butyl 1-(2-chloro- 17 mg HPLC-MS: = (R)((R)(7-(4-(1- 4-(4,4,5,5-tetramethy1- (33%) n (method aminocyclopropy1) 1,3 ,2-dioxaborolan—2- X001_004), M+H = 422 chloropheny1)quino lin ny1)cyclopropy1 -5 -y10xy)ethyl) -1 carbamate pyrrolidin-Z-one Example 87 4-(4,4,5 ,5-tetramethy1— 19 mg HPLC-MS: Rt = 0.55 (R)((R)(7-(1- 1,3 ,2-dioxaborolan—2- (24%) min (method oromethy1)- 1 H- y1) X001_002), M+H = 391 pyrazo1y1)quino lin- (trifluoromethy1)- 1 H- 1H-NMR (400 MHz, -y10xy)ethyl) pyrazo 1e DMSO-d6): 8 = 9.25 pyrrolidin-Z-one (1H,s), 8.90 (1H,s), 8.70 (1H, s), 8.45 (1H, d), 8.00 (1H, d), 7.60 (1H, s), 7.48 (2H, m), 4.95(1H, m), 3.45 (1H, t), 3.18 (1H, dd), 2.85 (1H, m), 2.45-2.25 (2H, m), 1.35 (3H,d) ppm.
Example 88 potassium trifluoro(5- 22 mg HPLC-MS: Rt = 0.53 ((R)(7-(5- methoxypyridin-Z- (48%) min (method methoxypyridin-Z- y1)borate 04), M+H = 364 y1)quino lin-5 -yloxy) ethy1)pyrro lidin-Z-one Example 89 2-tert-but0xy HPLC-MS: Rt = 0.69 (R)((R)(7-(6- (4,4,5,5-tetramethy1— min (method tert-butoxypyridin—3 - 1’3 ,2-dioxaborolan-2— X001_004), M+H = 406 y1)quino lin-5 -yloxy) y1)pyridine ethynpyrrohdin-z-one—- Example 90 2-cyclobutOXy 10 mg HPLC-MS: Rt = 0.65 ((R)(7-(6- (4,4,5,5-tetramethy1— (26%) min d cyclobutoxypyridin—3 - 1,3 ,2-dioxaborolan-2— X001_004), M+H = 404 y1)quino 11n-5 -yloxy) y1)pyridine ethy1)pyrro 11din—2-one Example 91 3-methy1(4,4,5,5- 1 8 mg HPLC-MS: Rt = 0.50 3 -methy1(5 -((R) tetramethyl— 1 ,3 ,2- (32%) min (method ((R)-5 -oxopyrrolidin— dioxaborolan—Z- 04), M+H = 415 3 -y1)ethoxy)quino 11n- y1)quinazo11n-4(3H)- 7-y1)quinazo 11n- 0116 4(3H)-one Example 93 5-(4,4,5,5-tetramethy1— 1 6 mg HPLC-MS: Rt = 0.59 (R)((R)(7-(2- 1,3 ,2-dioxaborolan—2- (3 8%) min d (trifluoromethy1)- 1 H- yl) X001_004), M+H = 441 benzo [d]imidazo 1-5 - (trifluoromethy1)- 1 H- y1)quino 11n-5 -yloxy) benzo[d]1midazole ethy1)pyrro 2-one Example 94 y1(4,4,5,5- 7 mg HPLC-MS: Rt = 0.42 ((R)(7-(1- tetramethyl— 1 ,3 ,2- (19%) min (method methyl- 1 H-benzo [d] dioxaboro1an—2-y1)- X001_004), M+H = 387 imidazo 1-5 - 1H-benzo[d]imidazo 1e y1)quino 11n-5 - yloxy)ethyl) pyrro11dinone Example 95 2-(methylsu1fony1- 23 mg HPLC-MS: Rt = 0.42 (R)((R)(7-(6- methy1)(4,4,5,5- (45%) min (method (methylsulfonylmethy tetramethyl— 1 ,3 ,2- X001_004), M+H = 426 1)pyr1din-3 - orolan—Z- y1)quino 11n-5 - idine yloxy)ethyl) pyrro11dinone Example 99 2,3-Dimethoxy 66 mg HPLC-MS: Rt = 2.91 (R) {(R)[7-(5,6- (4,4,5,5-tetramethy1— (56%) mm Dimethoxy-pyridin-3 - [1,3 ,2]dioxaborolan (method A), yl)-quino 11n-5 -yloxy] - yl)-pyridine M+H = 394 ethyl} -pyrro 11din—2- 0116 Examle 100 6-(4,4,5,5- 9 mg HPLC-MS: Rt = 2.75 (R){(R)[7-(3,4- Tetramethyl- min Dihydro-ZH-pyrano [1,3 ,2]dioxaborolan—2- (method A), [2,3-b]pyridiney1)- y1)-3,4-dihydro-2H- M+H = 390 quino11ny10xy]— pyrano[2,3-b]pyridine ethyl} -pyrro 11din—2- e 102 ethoxy HPLC-MS: Rt = 0.67 (R)((R)(7-(3- (trifluoromethyl) min (method methoxy(trifluoro- pheny1)-4,4,5,5- X001_004), M+H = 431 methy1)pheny1)quinoli tetramethyl— 1 ,3 ,2- n—S-yloxy)ethy1) dioxaborolane pyrrolidin-Z-one Example 104 uoromethoxy)- HPLC-MS: Rt = 0.56 (R)((R)(7-(6- 5-(4,4,5,5-tetramethy1— min (method (difluoromethoxy) 1,3 ,2-dioxaborolan—2- X001_004), M+H = 400 pyridin—3-y1)quinolin- id1ne 1H—NMR (400 MHz, -yloxy)ethy1) DMSO-d6): 8 = 9.95 pyrrolidin-Z-one , 8.80 (1H,s), 8.52 (1H, d), 8.45 (1H, d), 7.90 (1H, s), 7.80 (1H, t), 7.60 (1H, d), 7.52 (1H, dd), 7.45 (1H, s), 7.25 (1H, d), 4.95(1H, m), 3.42 (1H, t), 3.18 (1H, dd), 2.85 (1H, 111), 245—225 (2H, m), 1.35 (3H,d)ppm.
Example 105 1,2—d1methyl_5- 12 mg HPLC-MS: Rt = 0.38 (R)((R)(7-(1,2- (4a4a5a5-tetramethy1_ (31%) min (method dimethyl— 1 H-benzo [d] 1,3 ,2-dioxaborolan—2— 04), M+H = 401 imidazo 1—5- y1)-1H-benzo[d] y1)qu1nolin imidazo 1e yloxy)ethy1) pyrrolidin-Z-one Example 107 2,4-dimethy1-6_ 14 mg HPLC-MS: Rt = 0.47 (R)((R)(7-(2,4- (4,4,5,5-tetramethy1— (36%) min (method dimethquuinazo11n 1,3 ,2-dioxaborolan-2— X001_004), M+H = 413 y1)qu1nolinyloxy) y1)quinazo line yrrohdin-z-one—-— Example 109 2-methy1(4,4,5,5- 37 mg HPLC-MS: Rt = 0.74 (R)((R)(7-(2- tetramethyl— l ,3 ,2- (77%) min (method - 1 H-benzo [d] orolan—2-y1)- X001_004), M+H = 387 imidazo 1-5 - lH-benzo[d]imidazo 1e y1)quino 1in-5 - yloxy)ethyl) pyrrolidinone Example 1 1 1 5-(4,4,5,5-tetramethy1— 1 3 mg HPLC-MS: Rt = 0.62 (R)((R)(7-(6- 1,3 ,2-dioxaborolan—2- (22%) min (method (2,2,2- (2,2,2-trifluoro- X001_004), M+H = 432 trifluoroethoxy) ethoxy)pyridine pyridin—3 -y1)quino linyloxy)ethyl) pyrrolidinone Example 1 12 1,5-dimethy1_4_ 26 mg HPLC-MS: Rt = 0.42 (R)((R)(7-(1,5- a5-tetramethy1_ (59%) min (method dimethyl— l H-pyrazo 1- 1,3 ,2-dioxaborolan—2— X001_004), M+H = 351 4-y1)quino 1in—5 - y1)-1H-pyrazo 1e yloXy) ethy1)pyrro lidin—2-one Example 1 14 l-propy1(4,4,5 ,5- 28 mg S: Rt = 0.49 (R)((R)(7-(1- tetramethyl— l ,3 ,2- (61%) min (method propyl— l H-pyrazo 1—4- dioxaborolan—2-y1)- X001_004), M+H = 365 y1)quino 1in-5 -yloxy) l H-pyrazo 1e ethy1)pyrro lidin—2-one e 1 15 1 -isopropy1—4-(4,4,5 ,5- 20 mg HPLC-MS: Rt = 0.49 (R)((R)(7-(1- tetramethyl— l ,3 ,2- (44%) min (method opy1— 1 H- dioxaborolan—2-y1)- X001_004), M+H = 365 pyrazo1—4-y1)quino lin- l H-pyrazo 1e -yloxy) ethy1)pyrro lidin—2-one Example 1 16 1 -methy1-3 - 3 3 mg S: Rt = 0.51 (R)((R)(7-(1- (trifluoromethy1)- l H- (67%) min (method methyl(trifluoro - pyrazo1—4-y1boronic X001_004), M+H = 405 methyl)- 1 H-pyrazo 1- acid 4-y1)quino 1in—5 - yloXy) ethy1)pyrro lidin—2-one Example 1 19 Acetic acid 2-[4_ 36 mg HPLC-MS: Rt = 2.58 Acetic acid 2-(4- {5- (4a4a5a5-tetramethy1_ (31%) (method A), [(R)((R)oxo- [1,3 ,2]dioxaborolan M+H = 409 pyrrolidinyl)- y1)-pyrazoly1]-ethy1 ethoxy]-quino 1in ester razoly1)- ethyl ester Example 120 2-(difluoromethy1) 19 mg HPLC-MS: Rt 0.47 (R)((R)(7-(6- (4,4,5,5-tetramethy1— (30%) min d (difluoromethyl) 1,3 ,2-dioxaborolan-2— x001_004), M+H = 384 pyridinyl)quinolin- yl)pyridine 1H—NMR (400 MHz, -yloxy)ethyl) DMSO-d6): 8 = 9.20 pyrrolidinone (1H,s), 9.10 (1H,d), 8.69 (1H, d), 8.50 (1H, d), 8.02 (1H, s), 7.90 (1H, d), 7.75 (1H, dd), 7.60 (m, 2H), 7.10 (t, 1H), .05 (1H, m), 3.42 (1H, t), 3.18 (1H, dd), 2.85 (1H, m), 2.45—2.25 (2H, m), 1.35 (3H,d) ppm.
Synthesis of (R)—4—((R)—1-(7-i0doquinolinyl0xy)ethyl)pyrrolidin0ne (Example 37) O O NH NH \ \ l O | o / / N Br N | Example 27 Example 37 50 mg of Example 27 and 9 mg of copper (I) iodide were suspended in 300 uL e under argon. 9.6 uL N,N'dimethylethylendiamine and 45 mg of sodium iodide were added and the mixture heated to 110°C over weekend. The mixture was d with DCM and extracted with aqueous ammonia and water, the organic phase was subsequently concentrated in vacuo WO 14060 _ 93 _ and the al purified with HPLC (XbridgeC18; MeOH/ water, TFA) to yield 15 mg yellow solid as Example 37.
Analysis: HPLC-MS: Rt = 1.25 min (method 03), M+H = 383.
Synthesis of (R)—4-{(R)—1-[7-(5-Triflu0r0methyl-pyridin-Z-yl)—quinolin-S-yloxy]-ethyl}- pyrrolidin-Z-one le 49) Example 27 Example 49 Step 1 1: reaction 9 1: 1 g (R)[(R)(7-Bromo-quinolinyl-oxy)-ethyl]-pyrrolidinone (example 27), 833mg bis (pinacolato) diboron, 105mg Bis(triphenylphosphine)palladium(II) chloride and 878mg potassium acetate were suspended in 10ml dioxan and heated at 80°C for 2 hours. The mixture was allowed to cool, then partitioned between DCM and water. The organic layer was separated, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography using a Hept/EtOAc/MeOH gradient, the product eluting with 20%MeOH/EtOAc to give 976 mg of (R){(R)[7-(4,4,5,5-Tetramethyl- [1,3,2]dioxaborolanyl)-quinolinyloxy]-ethyl}-pyrrolidinone as a tan oil.
Analysis HPLC-MS: Rt = 1.05 min d B), M+H = 301.
Step 2: 500 mg (R){(R)[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolanyl)-quinolin yloxy]-ethyl} -pyrrolidinone (325 mg 2-Bromotrifluoromethyl-pyridine, 46 mg Bis(triphenylphosphine)palladium(II) chloride, 1.96 mL 2N s sodium carbonate and 10 mL DMF were heated at 80°C for 18 hours. The reaction was partitioned between DCM and NaHC03 (sat aq) then the organic layer was separated, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by MPLC using a Hept/EtOAc/MeOH gradient to give 326 mg of (R){(R)[7-(5-Trifiuoromethyl-pyridinyl)-quinolin yloxy]-ethyl} -pyrrolidinone as a yellow solid.
HPLC-MS: Rt = 3.55 min (method A), M+H = 402. 1H NMR (500 MHz, Methanol-d4) 8 ppm 1.55 (3 H, 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 _ 99 _ 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)(7-(1,2,3,4-tetrahydr0is0quinolinyl)quinolinyloxy)ethyl) pyrrolidin-Z-one (Example 101) e 27 Example 101 150 mg e 27, 241 mg 7-(4,4,5,5-Tetramethyl—[l,3,2]dioxaborolan—2-yl)-3,4-dihydro- lH-isoquinolinecarboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(ll) chloride, 671 uL 2N aqueous sodium carbonate and 2 mL DMF were heated for 2 hours at 90°C. The e was partitioned between DCM and NaHC03 (sat aq) and the organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo. The residue was dissolved in 10ml 25% TFA in DCM and stirred at °C overnight then concentrated in vacuo. Purification by flash chromatography using 0- 25% MeOH/DCM gave 75mg (43%) of Example 101 (R){(R)-l-[7-(l,2,3,4-Tetrahydroisoquinolinyl )-quinolinyloxy]—ethyl} -pyrrolidin—2-one as yellow solid.
HPLC-MS: Rt = 2.28 min (method A), M+H = 388. sis of (R)—4—((R)(7-(1-(2-hydr0xyethyl)-1H-pyrazolyl)quinolinyloxy)ethyl) pyrrolidin-Z-one (Example 118) Example 119 Example 118 21 mg of pure acetic acid 2-(4-{5-[(R)—1-((R)oxo-pyrrolidin—3-yl)-ethoxy]-quinolinyl}- pyrazol—l-yl)-ethyl ester (Example 119) and 26 mg of a 1:1 e of Example 119 and Example 118 was dissolved in 3ml MeCN and 1ml 1N NaOH(aq). The mixture was stirred ght at 25°C then ioned between DCM and NaHC03(sat aq) and the organic layer was ted, dried (NaZSO4), filtered and concentrated in vacuo. Purification by reverse phase LC gave 26mg (71%) of a crystalline solid.
HPLC-MS: Rt = 2.37 min (method A), M+H = 367. 4.5 Chromatographic methods (HPLC-MS methods) The Example compounds prepared according to the foregoing synthesis scheme were characterised by the following chromatographic methods, which - if they were carried out - are specified individually in Table 6.
Method A: Waters ZQ or Waters QTof micro, Agilent G1312A HPLC pump, Waters 2996 PDA detector, Waters 2420 ancillary detector Eluent A: Water (0.1 % formic acid) Eluent B: Acetonitrile (0.l % formic acid) Time [min] %A %B Flow rate [mL/min] 0.00 95 5 0.60 .00 0 100 0.60 .40 0 100 0.60 .42 95 5 0.60 7.00 95 5 0.60 The stationary phase used was a Waters Atlantis dC18 2.1 mm x 100 mm, 3 um, injection volume 3 uL n temperature: nt at 40°C).
Detector at a wavelength range 215 nm (nominal).
Method B: Shimadzu LCMS2010EV, Shimadzu LC-20AB pump, SPD-M20A PDA detector, PL2100 ancillary Eluent A: Water (0.1 % formic acid) Eluent B: Acetonitrile (0.l % formic acid) Time [min] %A %B Flow rate [mL/min] 0.00 95 5 1.00 2.50 0 100 1.00 2.70 0 100 1.00 2.71 95 5 1.00 3.50 95 5 1.00 The stationary phase used was a Waters Atlantis dC18 2.1 mm x 50 mm, 3 um, injection volume 3 uL (column temperature: constant at 40°C).
Detector at a wavelength range 215 nm (nominal).
Method C: Waters ZQ2000; Waters 1515 Pump, Waters PDA 996 Detector, Waters 2747 Injecor Mobile Phase: A Wasser + 0,1% formic acid B itril + 0,1% formic acid Gradient: time in min %A %B Flow rate in mL/min 0.00 95.0 5.0 1.00 0.10 95.0 5.0 1.00 3.10 2.00 98.00 1.00 4.50 2.00 98.00 1.00 .00 95.0 5.0 1.00 Stationary phase: Phase: X-terraTM MS C18 2,5 um 4,6 mm x 30 mm Column temperature ca. 25°C Diode array detection took place in the wavelength range 0 nm.
Method D Waters ZMD, Alliance 2690/2695 HPLC, Waters 996/2996 diode array detector The mobile phase used was: A: water with 0.10% TFA B: acetonitrile with 0.10% TFA time in min %A %B flow rate in mL/min 0.00 95 5 2.80 0.30 95 5 2.80 1.60 2 98 2.80 1.90 2 98 2.80 2.00 95 5 2.50 The stationary phase used was a Merck ChromolithTM Flash RP-18e column, 3 mm x 100 mm (column temperature: constant at 25°C).
Diode array detection took place in the wavelength range 210-400 nm.
Method E Waters ZMD, Alliance 695 HPLC, Waters 996/2996 diode array detector The mobile phase used was: A: water with 0.10% TFA D: methanol with 0.10% TFA time in min %A %D flow rate in mL/min 0.00 95 5 4.00 0.20 95 5 4.00 1.60 0 100 4.00 2.10 0 100 4.00 wo 2013/014060 The stationary phase used was a Waters XBridgeTM C18 3.5 uM, 4.6X20 mm ISTM (column temperature: constant at 40°C).
Diode array detection took place in the wavelength range 210-400 nm.
Method G: Eluent A: Water / 0.2 % KH2P04 pH = 3 Eluent B: Acetonitrile Time [min] %A %B Flow rate [mL/min] 0.00 80 20 1.50 .00 20 80 1.50 8.00 20 80 1.50 The stationary phase used was a Inertsil C8-3 (GL Sciences), 5 um; ion: 100 X 4.0 (column ature: constant at 30°C).
Detection UV 220 nm.
Method H: Eluent A: Hexane Eluent B: 2-Propanol Time [min] %A %B Flow rate [mL/min] 00.00 90 10 1.0 .00 90 10 1.0 The stationary phase used was a Chiralpak AD-H (Daicel), 5 um; dimension: 150 x 4.6 mm, (column temperature: constant at 10°C).
Detection DAD 225 nm.
Method 1: Eluent A: Hexane Eluent B: 2-Propanol Time [min] %A %B Flow rate [mL/min] 00.00 90 10 1.0 .00 90 10 1.0 The stationary phase used was a pak AD-H (Daicel), 5 um; dimension: 150 x 4.6 mm, (column temperature: nt at 10°C).
Detection DAD 225 nm.
Method M: Shimadzu LCMS2010EV, Shimadzu LC-20AB pump, SPD-M20A PDA detector, PL2100 ancillary Eluent A: Water (0.1 % formic acid) Eluent B: Acetonitrile (0.1 % formic acid) Time [min] %A %B Flow rate [mL/min] 0.00 95 5 1.00 1.50 0 100 1.00 1.6 0 100 1.00 2012/064172 1.61 95 5 1.00 2.00 95 5 1.00 The stationary phase used was a Waters Atlantis dC18 2.1 mm x 50 mm, 3 um, injection volume 3 uL (column temperature: constant at 40°C).
Detector at a wavelength range 215 nm (nominal).
Method XBM: Waters ZMD, ce 2690/2695 HPLC, Waters 996/2996 diode array detector The mobile phase used was: C: water with 0.10% NH3 D: methanol time in min %C %D flow rate in mL/min 0.00 95 5 4.00 0.20 95 5 4.00 1.60 2 100 4.00 1.90 2 100 4.00 The stationary phase used was a Waters XBridgeTM C18 3.5um, 4.6X20mm ISTM (column temperature: constant at 40°C).
Diode array detection took place in the wavelength range 210-400 nm.
Method X001 002: Diode array detection took place in the wavelength range 210-400 nm.
Method X001 003: ime [min] % Sol % Sol [Methanol] | low n] Temp [0C] [H20,0.10%TFA] __——_ ———__ ———__ ———__ Diode array detection took place in the wavelength range 210-400 nm.
Method X001 004: b 001_004 D Bridge C18, 2.1 x 20 mm, 2.5 pm % Sol [Methanol] | low [nil/min] Temp [CC] Diode array detection took place in the wavelength range 210-400 nm.
Method V003 002: inie [min] % Sol [H20, % ol [Methanol, | low [nil/min] Temp [CC] 0.1% NH3] 0.l%NH3] _—__ Diode array detection took place in the ngth range 210-400 nm.
Method V003 003: 003_003 Bridge C18, 4.6 X 30 mm, 3.5 um | low [ml/min] Temp [0C] ———__ Diode array detection took place in the wavelength range 210-400 nm. 4.6 NMR methods Configuration ofthe Bruker DRX 500 MHz NMR: High performance digital NMR spectrometer, 2-channel microbay console and Windows XP host ation running n version 1.3.
Equipped with: 0 Oxford instruments magnet 11.74 Tesla (500 MHz proton resonance frequency) 0 B-VT 3000 temperature controller 0 GRASP II gradient spectroscopy accessory for fast acquisition of2D pulse sequences 0 ium lock switch for gradient shimming 0 5mm Broad Band Inverse geometry double resonance probe with automated tuning and matching (BB1 ATMA). Allows 1H observation with pulsing/decoupling of nuclei in the ncy range 15N and 31P with 2H lock and shielded z-gradient coils.
Configuration ofthe Bruker DPX 250MHz NMR High performance one bay Bruker 250 MHz l two channel NMR spectrometer console and Windows XP host workstation running XwinNMR version 3.5.
Equipped with: 0 Oxford instruments magnet 5.87 Tesla (250 MHz proton resonance frequency) 0 B-VT 3300 le temperature controller unit 0 Four nucleus (QNP) switchable probe for observation of 1H, C, 19F and 31P with 2H lock Configuration of the Bruker DPX 400 MHz NMR High mance digital NMR spectrometer controlled by a Windows XP workstation running Topspin l.3p18 ed with: o Bruker UltraShield Plus magnet 9.40 Tesla (400 MHz proton nce frequency) 0 B-VT 3300 temperature controller 0 GRASP II gradient spectroscopy accessory for fast acquisition of2D pulse sequences 0 Deuterium lock switch for gradient shimming 0 5mm Selective Inverse Probe (SEI). Allows 1H observation with pulsing/decoupling of 13C with 2H lock and shielded z-gradient coils.
. EXAMPLES The following Examples were prepared ously to the methods of synthesis described above. These compounds are suitable as SYK inhibitors and have IC50-values of less than or equal to 1 umol. The ICso-values of the individual example substances are shown in the following Table 1 and were experimentally ined as follows: Syk Kinase Test Recombinant human Syk (amino acids 342-635) was expressed as a fusion protein with an N- terminal GST tag, affinity-purified and rozen at a concentration of approx. 50 - 100 uM in test buffer (25 mM HEPES pH7.5; 25 mM 5 mM MnClzg 50 mM KCl; either 0.2% BSA or 0.2% HSA; 0.01% CHAPS; 100 uM Na3V04; 0.5 mM DTT) and 10% glycerol at - 80°C until use.
The catalytic activity of the GST-Syk kinase fusion protein was determined using the Kinase Glo® Luminescence Kinase test (Promega; V6712). In this homogeneous test the amount of ATP remaining after the kinase reaction is quantified by a luciferin-luciferase reaction using luminescence. The luminescence signal obtained correlates with the amount of ATP still present and thus correlates inversely with the activity of the protein kinase.
Method The test nds were dissolved in 100 % DMSO at a concentration of 10 mM and diluted in DMSO to a concentration of 1 mM. All fiarther dilutions of the substances were carried out with 7.5 % DMSO in test buffer until a concentration was reached which was 7.5 times above the final test concentration (final concentration of the nds: 30 uM to 1 nM). 2 ul ts of these dilutions were transferred into a 384-well Optiplate (Perkin Elmer, # 6007290). k was diluted to 6.0 nM in the test buffer and 10 ul of this dilution were used in the kinase test (final concentration of Syk = 4 nM in a total volume of 15 ul). After minutes incubation at room ature 3 ul of a mixture of 750 nM ATP and 100 ug/ml poly (L-Glutamic acid L-Tyrosine 4:1), Fluka # 81357) in test buffer were added to each well and the incubation was continued for a fiarther 60 s at room temperature.
Positive controls are the reaction mixtures that contain no test substance; negative controls (blanks) are reaction mixtures that contain no kinase.
WO 14060 After 60 minutes, 10 ul Kinase-Glo® solution (Promega, Cat. # V6712) d to room temperature) were added to each well and incubation was continued for a fithher 15 minutes.
The plates were read in a Microplate Scintillation and Luminescence r (Canberra Packard GmbH).
Data evaluation and Calculation: The output file of the "Counter" is a text file that contains the well number and measured counts in two columns. For data evaluation and calculation, the measurement of the negative control was set as 100 % inhibition and the measurement of the positive control was set as 0% inhibition. Based on this values the % inherent value for the measurement of each nce concentration was ated using an "MS-Excel — VB macro". Normally, the % inhibition values calculated are between 100% and 0 % inhibition values but may also occur outside these limits in individual cases. The IC50 values were calculated from the % inhibition values using "GraphPadPrism“ software (Version 5) (GraphPad Software Inc.).
The following Examples of formula 1 N R1 having the following properties were prepared according to the methods of synthesis bed above, wherein * denotes the position where the each of the groups R1 and R2 are linked to the rest of the molecule of formula 1: 2012/064172 Table 1: Structure Chiral Chiral wo 14060 Chiral Chiral Chiral WO 14060 Chiral Chiral WO 14060 Chiral Chiral Chiral WO 14060 Chiral Chiral WO 14060 WO 14060 Chiral WO 14060 WO 14060 WO 14060 Chiral Chiral WO 14060 WO 14060 WO 14060 Chiral WO 14060 WO 14060 WO 14060 WO 14060 Chiral Chiral WO 14060 Chiral WO 14060 Chiral Chiral WO 14060 WO 14060 wo 14060 Chiral Chiral 6. INDICATIONS As has been found, the nds of formula 1 are terised by their range of applications in the therapeutic field. ular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used on the basis of their ceutical activity as SYK-inhibitors. Examples include respiratory complaints, allergic diseases, osteoporosis, gastrointestinal diseases or complaints, immune or autoimmune diseases, ic es, inflammatory diseases, e.g. inflammatory diseases of the joints, skin and eyes and diseases of the peripheral or central nervous system.
Particular mention should be made of the prevention and treatment of respiratory tract and pulmonary diseases which are accompanied by increased mucus production, inflammation and/or obstructive diseases of the airways. Examples of these include asthma, paediatric asthma, ARDS (Adult Respiratory Distress Syndrome), acute, ic or chronic bronchitis, autoimmune haemolytic , chronic obstructive bronchitis (COPD) (including the treatment of Rhinovirus-induced exacerbations), coughs, allergic rhinitis or sinusitis, allergic rhinoconjunctivitis, chronic rhinitis or sinusitis, alveolitis, farmers' lung, hyperreactive airways, infectious itis or pneumonitis, bronchiectasis, ary fibrosis, bronchial oedema, pulmonary oedema, pneumonia or interstitial pneumonia triggered by various causes such as aspiration, inhalation of toxic gases or bronchitis, pneumonia or interstitial pneumonia triggered by cardiac insufficiency, radiation, chemotherapy, cystic fibrosis or mucoviscidosis, alphal-antitrypsin deficiency, artheriosclerosis and ary hypertension.
The compounds according to the invention are preferably also suitable for the treatment of ic diseases such as for example allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, and contact dermatitis, ria / angiooedema and allergic dermatitis.
Mention should also preferably be made of the treatment of inflammatory diseases of the gastrointestinal tract. es ofthese are Crohn's disease and ulcerative colitis.
The nds according to the invention are preferably also suitable for the treatment of inflammatory diseases of the joints or inflammatory diseases of the skin and eyes. Examples of these are rheumatoid arthritis, antibody-based glomerulonephritis, psoriasis, Kawasaki syndrome, coeliac e (sprue), artheriosclerosis (see Hilgendorf et al, Arterioscler Thromb Vasc Biol. 2011, vol. 31; pp.l99l-l999) and r's granulomatosis.
The compounds according to the invention are preferably also suitable for the treatment of autoimmune diseases. Examples of these are hepatitis (autoimmune-based), lupus erythematodes, anti-phospholipid me, Berger's disease, Evans's syndrome, haemolytic anaemia, ITP (idiopathic thrombocytopenic purpura; adult, neonatal and paediatric), myasthenia gravis, Sjogren's syndrome, sclerodermy, Bullous pemphigoid and Pemphigus vulgaris.
The compounds according to the invention are preferably also suitable for the ent of B- cell lymphomas, like c lymphocytic leukaemia and non Hodgkin's lymphomas or T cell lymphomas. n may preferably also be made of the prevention and treatment of diseases of the peripheral or central nervous system. Examples of these are acute and chronic multiple sclerosis or non-familial lateral sclerosis.
Mention may preferably also be made of the prevention and treatment of orotic diseases such as for example disease-associated osteopenia, osteoporosis and osteolytic diseases.
The present ion relates particularly preferably to the use of compounds of formula 1 for preparing a pharmaceutical composition for the treatment of diseases selected from among , COPD, allergic rhinitis, Adult Respiratory Distress Syndrome, bronchitis, allergic itis, contact dermatitis, ITP, rheumatoid arthritis and allergic rhinoconjunctivitis.
Most preferably, the compounds of formula 1 may be used for the treatment of a disease selected from among asthma, allergic rhinitis, rheumatoid arthritis, allergic dermatitis, ary hypertension and COPD. 7. ATIONS The compounds of formula 1 may be used on their own or in conjunction with other active substances of formula 1 according to the invention. The compounds of formula 1 may optionally also be used in conjunction with other pharmacologically active substances.
Preferably the active substances used here may be selected for example from among the betamimetics, anticholinergics, osteroids, NSAIDS, COX2-inhibitors (Coxibe), folic acid antagonists (or dihydrofolate reductase inhibitors), PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine ts, Hl-antihistamines, PAF-antagonists, nhibitors, HMG-CoA reductase inhibitors (statins), PI3-kinase-inhibitors, CCR3- antagonists, CCR2-antagonists, CCRl-antagonists, IKKZ-inhibitors, A2a agonists, alpha integrin-inhibitors, CRTH2-antagonists, histamine 1, combined Hl/H3-antagonists, p38 kinase inhibitors, methylxanthines, ENaC-inhibitors, CXCRl-antagonists, CXCRZ- antagonists, Bruton’s tyrosine kinase inhibitors (BTK—inhibitors), Janus kinase -inhibitors (JAK—inhibitor), IA phosphoinositidekinase inhibitors (P13K—delta—-inhibitors), dihydroorotate dehydrogenase inhibitors, ICE-inhibitors, LTB4-antagonists, S-LO antagonists, FLAP-antagonists. LTB4-antagonists; cromoglycine, dissociated glucocorticoid cs, anti-TNF-antibodies, TNF-receptor Fc, pegylated anti-TNF-Fab, Anti-1L6 receptor antibodies, Anti-CD20 antibodies, anti-GM-CSF antibodies, anti-CD46- antibodies, anti-IL-l- antibodies, anti-IL antibodies, anti-IL antibodies, anti-IL-S- antibodies, L-l3- antibodies, anti-IL-4/IL-l3- antibodies, or double or triple combinations thereof, such as for example combinations of one, two or three compounds selected from among the o SYK—inhibitors of formula 1, corticosteroids, CCRl-antagonists, nhibitors (Coxibe) and folic acid nists such as methotrexate o hibitors of formula 1, corticosteroids, betamimetics, CCR3-antagonists and CRTH2-antagonists o SYK—inhibitors of formula 1, metics, corticosteroids, EGFR— inhibitors and PDE4- antagonists, o SYK—inhibitors of formula 1, anticholinergics, betamimetics, corticosteroids, EGFR- inhibitors and PDE4-antagonists, o hibitors of formula 1, PDE4-inhibitors, corticosteroids and EGFR— inhibitors o SYK—inhibitors of formula 1, EGFR— inhibitors and PDE4- inhibitors, 0 SYK—inhibitors of formula 1 and EGFR- inhibitors, 0 SYK—inhibitors of formula 1, betamimetics and anticholinergics o SYK—inhibitors of formula 1, anticholinergics, betamimetics, corticosteroids and PDE4- inhibitors, . o hibitors of formula 1, anticholinergics, betamimetics, corticosteroids, iNOS tors, HMG-CoA reductase inhibitors.
Combinations of three active nces each taken from one of the above-mentioned categories of compounds are also an object of the invention.
Suitable betamimetics used are preferably compounds ed from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterole, bambuterol, bitolterol, erol, carbuterol, clenbuterol, rol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol, terbutalin, ide, tolubutero l, zinterol,6-Hydroxy—8- { l -hydroxy [2-(4-methoxy—phenyl)- l , l - dimethyl-ethylamino]-ethyl} -4H-benzo [ l ,4]oxazine-3 -one; 8- {2- [2-(2,4-Difluor-phenyl)- l , l - dimethyl-ethylamino]- l -hydroxy-ethyl} roxy-4H-benzo [ l ,4]oxazine-3 -one; 8- {2- [2- (3 ,5 -Difluor-phenyl)- l , l -dimethyl-ethylamino]- l -hydroxy-ethyl} hydroxy-4H- benzo [ l ,4]oxazine-3 -one ; 8- {2- [2-(4-Ethoxy—phenyl)- l , l -dimethyl-ethylamino]hydroxy- ethyl} roxy-4H-benzo [l,4]oxazine-3 -one; 8- {2- [2-(4-Fluor-phenyl)- l , l -dimethyl-ethylamino]- l -hydroxy-ethyl} hydroxy-4H-benzo [ l ,4]oxazine-3 -one; N—(S - {2- [3-(4,4-Diethyloxo-4H- benzo [d] [ l ,3]oxazine- l -yl)- l l -dimethyl-propylamino]- l xy-ethyl} hydroxy-phenyl)- sulfonamide; N—(S - {2- 4-Diethylfluorooxo-4H-benzo [d] [ l ,3 ]oxazine- l -yl)- l l -dimethyl-propylamino]- l -hydroxy-ethyl} hydroxy-phenyl)-methansulfonamide; N—(S - {2- [3 -(4,4-Diethylmethoxyoxo-4H-benzo [d] [ l ,3 ]oxazine- l -yl)- l , l -dimethylpropylamino ]- l -hydroxy-ethyl} hydroxy-phenyl)-methansulfonamide; N—(S - {2-[ l , l- Dimethyl(2-oxo-4,4-dipropyl-4H-benzo [d] [ l ,3]oxazine- l -yl)-propylamino]hydroxyethyl } roxy-phenyl)-methansulfonamide; 8- {2-[1 , l-Dimethyl(2-oxo-2,3-dihydro- benzoimidazo l- l -yl)-propylamino]hydroxy-ethyl} hydroxy-4H-benzo [ l ,4]oxazine-3 - one; 8- {2-[1 , l -Dimethyl-3 -(6-methyloxo-2,3 -dihydro-benzoimidazo leyl)-propylamino]- l-hydroxy-ethyl} hydroxy-4H-benzo [ l zine-3 -one; 8- {2-[ l , l -Dimethyl-3 -(2-oxo-5 - trifluormethyl-2,3-dihydro-benzoimidazo l- l -yl)-propylamino]- l -hydroxy-ethyl} hydroxy- 4H-benzo [ l ,4]oxazine-3 -one; 8- {2-[1 , l-Dimethyl-3 -(3 -methyloxo-2,3 -dihydro- benzoimidazo l- l -yl)-propylamino]hydroxy-ethyl} hydroxy-4H-benzo [ l ,4]oxazine-3 - one; N—[2-Hydr0xy—5 -(( l R)- l -hydroxy—2- {2- [4-(2-hydr0xyphenyl-ethylarnino)-phenyl] - ethylarnino } )-phenyl] -f0rrnarnide; 8-Hydr0xy-5 -(( l R)- l -hydroxy—2- {2- [4-(6-rneth0xy- biphenylylarnin0)-phenyl] -ethylarnin0 } -ethyl)- lH-quino line0ne; 8-Hydr0xy—5 - [( l R)- l - hydroxy—Z-(6-phenethylarnin0-hexylarnin0)-ethyl] - l H-quino line0ne; 5 - [( l R)(2- {4- [4- (2-Arnin0rnethyl-pr0p0xy)-phenylarnino]-phenyl} -ethylarnin0)- l -hydr0xy-ethyl] y— l H-quino -0ne; [3 -(4- {6- [(2R)Hydr0xy(4-hydroxyhydr0xyrnethyl— phenyl)-ethylarnin0]-hexyloxy} -butyl)-5 -rnethyl-phenyl] -urea; 4-(( l R) {6-[2-(2,6-Dichlorbenzyloxy )-ethoxy]-hexylarnino } - l -hydr0xy—ethyl)hydr0xymethyl-phen0 l; 3 -(4- {6- [(2R)- 2-Hydr0xy—2-(4-hydroxy—3-hydroxymethyl-phenyl)-ethylarnin0]-hexyloxy} -butyl)- benzenesulfonarnide; 3 -(3 - {7-[(2R)Hydroxy(4-hydroxy—3-hydroxymethyl—phenyl)- ethylarnino]—heptyloxy} -propyl)-benzenesulfonarnide; 4-(( l R) {6- [4-(3 - Cyclopentanesulfonyl-phenyl)-but0xy]-hexylarnino } - l -hydr0xy-ethyl)hydr0xyrnethylphenol , 4-(2- {6-[2-(2,6-dichlor0-benzyloxy)-ethoxy] -hexylarnin0 } - l -hydroxy—ethyl) hydroxyrnethyl-pheno l; erol; N— l -Adarnantanyl {3 - [(2R)( {(2R)hydr0xy—2- [4- hydroxy—3-(hydr0xymethyl)phenyl] ethyl} amino)pr0pyl]phenyl} acetamide; 2-(3 - {2-[2- hydroxy—3-rnethanesulfonylamino-phenyl)-ethylarnin0]-pr0pyl} l)-N—[4-(4-hydr0xy— phenyl)Vinyl-penta-2,4-dienyl] -acetarnide; (lR)-5 - {2- [6-(2,2-Difluorphenyl—ethoxy)- hexylarnino]— l -hydr0xy—ethyl} hydroxy- l o line0ne; (R, S)(2- {[6-(2,2-Difluor- 4-phenylbutoxy)hexyl]amino } - l -hydr0xy—ethyl)(hydr0xyrnethyl)phen0l; (R, S)(2- {[6- (2,2-Diflu0rphenylethoxy)hexyl]amino } - l -hydr0xy—ethyl)(hydroxyrnethyl)phenol; (R, S)(2- {[4,4-Difluor(4-phenylbut0xy)hexyl]amino } - l -hydr0xy—ethyl) (hydroxymethyl)phen0 l; (R, S)(2- {[6-(4,4-Diflu0rphenylbut0xy)hexyl]amino } - l - hydroxy-ethyl)(hydr0xymethyl)phen0l; 5-(2- {[6-(2,2-Difluor phenylethoxy)hexyl] amino } - l -hydroxy—ethyl) hydroxyquino line-2( l H)-one; (R, S)- [2-( {6- [2,2-Diflu0r(3-rnethylphenyl)eth0xy]hexyl} yethyl] (hydroxymethyl)phen0 l; 4-( l R) {[6-(2,2-Difluorphenylethoxy)hexyl]amino } - l - hydroxyethyl)(hydr0xyrnethyl)phen0 l; (R,S)(Hydr0xymethyl)( l -hydroxy {[4,4,515 fluor(3-phenylpr0p0xy)hexyl]amino } pheno l; (R, S)-[5 -(2- {[6-(2,2- Difluor-Z-phenylethoxy)hexyl]amino } - l -hydr0xy—ethyl) hydroxyphenyl] formarnide; (R, S)- 4- [2-( {6- [2-(3 -Br0rn0phenyl)-2,2-diflu0r0ethoxy] hexyl} amino)- 1 xyethyl] - 2- (hydroxymethyl)phenol; (R, S)—N—[3-( l ,l -Difluor {[6-( {2-hydr0xy—2-[4-hydr0xy (hydroxymethyl)phenyl] ethyl} amino)hexyl]0xy} ethyl)phenyl] -urea; 3 - [3 -( l , l -Difluor {[6- ( {2—hydr0xy[4-hydroxy(hydroxyrnethyl) phenyl] ethyl} - amin0)hexyl]oxy} ethyl)phenyl]imidazo lidine-2,4-di0ne; (R, 2-( {6- [2,2-Diflu0r(3 - methoxyphenyl)eth0xy]hexyl} amino)hydr0xyethyl](hydr0xyrnethyl)phen0 l; 5 -(( l R) {[6-(2,2-Difluorphenylethoxy)hexyl]amino } - l -hydr0xyethyl) hydroxyquinoline-2(1H)- one; 4-(( l R) {[4,4-Diflu0r(4-phenylbut0xy)hexyl]amino } - l -hydr0xy—ethyl) (hydroxymethyl)phen0 l; (R, S)(2- {[6-(3 ,3-Diflu0rphenylprop0xy)hexyl]amino } - l - hydroxy-ethyl)(hydr0xymethyl)phen0l; (R,S)-(2- {[6-(2,2-Difluorphenylethoxy)-4,4- wo 2013/014060 - 14o - difluorohexyl]amino } - l -hydroxyethyI)(hydroxymethyl)pheno l; (R, S)(2- {[6-(2,2- Difluorphenylpropoxy)hexyl]amino } hydroxy ethyl) (hydroxymethyl)pheno l; 3 - [2-(3- Chlor-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N- {2-[2-(4-hydroxy—2-oxo-2,3-dihydrobenzothiazolyl )-ethylamino]-ethyl} -propionamide; N—(2-Diethylamino-ethyl)-N- {2-[2-(4- hydroxy—2-oxo-2,3-dihydro-benzothiazolyl)-ethylamino]-ethyl} (2-naphthalen- l -ylethoxy )-propionamide; 7-[2-(2- {3-[2—(2-Chlor-phenyl)-ethylamino]-propylsulfanyl} - mino)- l -hydroxy-ethyl]hydroxy-3H-benzothiazolone, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or es thereof.
According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, cetate, hydrocitrate, hydrofilmarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate , ably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, lmarate and hydromethanesulphonate. Ofthe above-mentioned acid addition salts the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred ing to the invention.
The anticholinergics used are preferably compounds ed from among tiotropium salts, particularly the bromide salt, oxitropium salts, particularly the bromide salt, flutropium salts, particularly the e salt, opium salts, particularly the bromide salt, Aclidinium salts, particularly the bromide salt, glycopyrronium salts, particularly the bromide salt, trospium salts, particularly the chloride salt, tolterodin, (3R)-l-Phenethyl(9H- xanthenecarbonyloxy)- l -azoniabicyclo[2.2.2]octan-salts ; 2,2-Diphenyl nic acid tropenole ester-methobromide; 2,2-Diphenyl propionic acid scopine ester-methobromide; 2- Fluor-2,2—Diphenyl acetic acid scopine ester-methobromide; 2-Fluor-2,2-Diphenyl acetic acid tropenole ester-methobromide; 3,3',4,4'-Tetrafluor benzilic acid tropenole ester- methobromide; 3,3',4,4'-Tetrafluor benzilic acid scopine ester-methobromide; 4,4'-Difluor benzilic acid ole ester-methobromide ; 4,4'-Difluor ic acid scopine ester- methobromide; 3,3'-Difluor benzilic acid tropenole ester-methobromide; 3,3'-Difluor benzilic acid scopine ester-methobromide; 9-Hydroxy—fluorenecarboxylic acid tropenole ester- romide; 9-Fluor-fluorenecarboxylic acid ole methobromide; 9- Hydroxy—fluorenecarboxylic acid scopine ester-methobromide; 9-Fluor-fluorene carboxylic acid scopine ester-methobromide; 9-Methyl—fluorenecarboxylic acid tropenole ester-methobromide; 9-Methyl-fluorenecarboxylic acid scopine ester-methobromide; Benzilic acid cyclopropyl tropine ester-methobromide; 2,2-Diphenyl propionic acid cyclopropyltropine methobromide; 9-Hydroxy-xanthenecarboxylic acid wo 2013/014060 cyclopropyltropine ester-methobromide; yl-fluorenecarboxylic acid cyclopropyltropine ester-methobromide; 9-Methyl-xanthenecarboxylic acid ropyltropine ester-methobromide; oxy-fluorenecarboxilic acid cyclopropyltropine ester-methobromide; 4,4'-Difluor benzilic acid methyl ester cyclopropyltropine ester-methobromide; 9-Hydroxy-xanthenecarboxylic acid tropenole ester-methobromide; 9-Hydroxy-xanthenecarboxylic acid scopine ester-methobromide; 9- Methyl-xanthenecarboxylic acid tropenole methobromide; 9-Methyl—xanthene ylic acid scopine ester-methobromide; 9-Ethyl-xanthenecarboxylic acid tropenole ester-methobromide; 9-Difluormethyl-xanthenecarboxylic acid tropenole ester- methobromide; 9-Hydroxymethyl—xanthenecarboxylic acid scopine ester-methobromide; 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N- {2-[2-(4-hydroxy—2-oxo-2,3- dihydro-benzothiazolyl)-ethylamino]-ethyl} -propionamide; N—(2-Diethylamino-ethyl)-N- {2-[2-(4-hydroxy—2-oxo-2,3-dihydro-benzothiazo lyl)- ethylamino]-ethyl} -3 -(2-naphthalen- l -yl-ethoxy)-propionamide; 7- [2-(2- {3 - [2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl} -ethylamino)- l -hydroxy-ethyl] - 4-hydroxy-3H-benzothiazolone and Darotropium; optionally in the form of the solvates or hydrates thereof.
In the above-mentioned salts the cations pium, oxitropium, flutropium, ipratropium, glycopyrronium, aclidinium and trospium are the pharmacologically active ingredients. As anions, the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, e, maleate, acetate, citrate, filmarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, e, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts, the chlorides, bromides, iodides and methanesulphonate are particularly preferred.
Ofparticular importance is tiotropium bromide. In the case oftiotropium e the pharmaceutical combinations according to the invention preferably n it in the form of the crystalline tiotropium e monohydrate, which is known from W0 02/30928. If the pium bromide is used in anhydrous form in the ceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265. wo 2013/014060 Corticosteroids used here are preferably compounds selected from among ethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etipredno le, fluniso lide, fluticasone, loteprednole, mometasone, predniso lone, prednisone, rofleponide, triamcino lone, tipredane; Pregna- l ,4-diene-3,20-dione, 6-fluoro-l l-hydroxy- l 6, l 7- [( l -methylethylidene) bis(oxy)][[4- [(nitrooxy)methyl]benzoyl]oxy] -, (6-alpha,l l-beta, l 6-alpha)- (9C1); 16, l 7-butylidenedioxy- fluoro-l oxy- l 7-(methylthio)androsten—3 -one; 6,9-Difluor- l 7- [(2- filranylcarbonyl)oxy] - l 1 -hydroxy- l 6-methyloxo-androsta- l ,4-dien- l 7-carbothione acid (S)-fluoromethylester; (S)-fluoromethyl 6,9-difluoro- l 7-[(2-fiJranylcarbonyl)oxy] -l 1- hydroxy- l 6-methyloxo-androsta- l ,4-diene- l othionate;6-alpha,9-alpha-difluoro-l lbeta-hydroxy- l 6alpha-methyloxo- l 7alpha-(2,2,3 ,3 -tetramethylcyclopropylcarbonyl)oxy- androsta- l ,4-diene- l 7beta-carboxylic acid cyanomethyl ester, each optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Particularly preferably the steroid is selected from among budesonide, fluticasone, mometasone, ciclesonide and (S)-fluoromethyl 6,9-difluoro- l fi4ranylcarbonyl)oxy]—l 1- hydroxy- l 6-methyloxo-androsta- l ,4-diene- l 7-carbothionate, optionally in the form of the racemates, omers or diastereomers thereof and ally in the form of the salts and derivatives, so lvates and/or es thereof Any reference to steroids includes a reference to any salts or derivatives, es or es thereofwhich may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, enzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, ates, pivalates or furoates thereof PDE4 tors which may be used are preferably nds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tof1milast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, oglemilast, tetomilast; 5-[(N-(2,5-dichloropyridinyl)- carboxamide]methoxy-Quino line (D-44 l 8); 5-[N—(3 ,5-dichloro- l -oxidopyridinyl)- carboxamide]methoxy(trifluoromethyl)-Quinoline (D-4396 (Sch-35 1591)); N—(3,5- dichloropyridyl)-[l-(4-fluorobenzyl)hydroxy-indolyl]glyoxylic acid amide (AWD- 12-281 (GW-842470)); 9-[(2-fluorophenyl)methyl]-N-methyl(trifluoromethyl)-9H-Purin- 6-amine (NCS-6 l 3); 4- [(2R)—2- [3-(cyclopentyloxy)methoxyphenyl] phenylethyl] - wo 2013/014060 ne 40); N—[(3R)-3 ,4,6,7-tetrahydromethyloxo- l -phenylpyrrolo [3 ,2, l - jk] [ l ,4]benzodiazepin-3 -yl] idinecarboxamide (PD-168787); 4-[6,7-diethoxy-2,3 - bis(hydroxymethyl)- l -naphthalenyl] - l -(2-methoxyethyl)-2( l idinone (T-440); 2-[4- [6,7-diethoxy—2,3-bis(hydroxymethyl)- l halenyl] pyridinyl] (3 -pyridinyl)- 1 (2H)- Phthalazinone (T-25 85); (3 -(3 -cyclopenyloxymethoxybenzyl)ethylaminoisopropyl- 3H-purine (V-l 1294A); beta- [3 -(cyclopentyloxy)methoxyphenyl] - l ,3 -dihydro- l ,3-dioxo- 2H-Isoindolepropanamide (CDC-801); o [ l ,5-a]pyrido [3 ,2-e]pyrazine-6(5H)—one, 9- ethylmethoxymethylpropyl- (D-228 8 8); 5 - [3 -(cyclopentyloxy)methoxyphenyl] -3 - [(3 -methylphenyl)methyl] -, (3 S ,5 S)Piperidinon (HT-0712); 4-[ l - [3 ,4- fluoromethoxy)phenyl](3-methyloxidopyridinyl)ethyl] -alpha,alphabis (trifluoromethyl)-Benzenemethanol (L-826 l 4 l ); N—(3 ,5 -Dichloro0X0-pyridinyl) difluormethoxycyclopropylmethoxybenzamide; (-)p-[(4aR* , l ObS *)—9-Ethoxy— 1,2,3 ,4,4a, l Ob-hexahydromethoxymethylbenzo [s] [ l ,6]naphthyridinyl]-N,N- diisopropylbenzamide; (R)-(+)- l -(4-Brombenzyl) [(3-cyclopentyloxy)methoxyphenyl] - 2-pyrrolidon; 3-(Cyclopentyloxymethoxyphenyl)- l -(4-N'-[N—2-cyano-S-methylisothioureido ]benzyl)—2-pyrro lidon; cis[4-Cyano(3-cyclopentyloxy methoxyphenyl)cyclohexan— l -carboxylic acid] ; 2-carbomethoxycyano(3- cyclopropylmethoxydifluoromethoxyphenyl)cyclohexanone; cis[4-Cyano(3- cyclopropylmethoxydifluormethoxyphenyl)cyclohexan— l -o l]; (R)-(+)-Ethyl[4-(3 - cyclopentyloxymethoxyphenyl)pyrrolidinyliden] acetat; )-Ethyl[4-(3 - cyclopentyloxymethoxyphenyl)pyrrolidinyliden] acetat; 9-Cyclopentyl—5 ,6-dihydro ethyl-3 -(2-thienyl)-9H—pyrazo lo [3 ,4-c] - l ,2,4-triazolo [4,3 -a]pyridin ; opentyl—5 ,6- dihydroethyl—3 -(tert—butyl)-9H-pyrazolo [3 ,4-c] -l ,2,4-triazo lo [4,3 -a]pyridin, optionally in the form of the racemates, omers or diastereomers and optionally in the form ofthe pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
By acid addition salts with pharmaco logically acceptable acids which the mentioned PDE4-inhibitors might be in a position to form are meant, for example, salts selected from among the hydrochloride, hydrobromide, odide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofilmarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofilmarate and hydromethanesulphonate.
CRTH2 antagonists which may be used are preferably compounds selected from among Ramatroban, Setipiprant, Laropiprant and wo 2013/014060 ODC-9 l 01 (2-( l -ethyl-5 -fluoromethyl- l H-indole-3 -yl-methyl)-quino line; see WWW.chemietek.com/products.aspx?pid=l32), optionally in the form ofthe racemates, enantiomers or diastereomers and optionally in the form of the pharmaco logically acceptable acid addition salts, solvates and/or hydrates f.
CCR3 antagonists which may be used are preferably nds selected from among l-(4- acetyl-benzyl)[4-(3,4-dichloro-benzyl)-morpholinylmethyl]-urea (GW766994) N iN (BMS 639623), AZD 1744, AZD 3778 and YM-34403l as disclosed in anic & Medicinal Chemistry Letters (2008), 18(2), 576-5 85.
NSAIDS which may be used are preferably compounds selected from among Aceclofenac, Acemetacin, Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin, Azapropazon, Benorilat, Bermoprofen, Bindarit, Bromfenac, Bucloxinsaure, m, Bufexamac, Bumadizon, Butibufen, Butixirat, Carbasalatcalcium, Carprofen, Cholin Magnesium Trisalicylat, Celecoxib, Cinmetacin, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac, Enfenaminsaure, Etersalat, Etodolac, Etofenamat, Etoricoxib, Feclobuzon, ac, en, Fenclofenac, Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin, Flufenaminsaure, Flufenisal, Flunoxaprofen, Flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac, Ibuprofen, fen, Indometacin, Indometacinfamesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac, Lomoxicam, Loxoprofen, coxib, Meclofenaminsaure, Meclofen, Mefenaminsaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton, Naproxen, Nifluminsaure, zin, Oxaprozin, Oxipinac, Oxyphenbutazon, Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, Pirprofen, Pranoprofen, wo 2013/014060 Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsaure, Rofecoxib, Romazarit, Salicylamid, lsaure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensaure, Taramid, Tilnoprofenarbamel, Timegadin, Tinoridin, Tiopinac, Tolfenaminsaure, Tolmetin, Ufenamat, Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.
COX2-inhibitors (Coxibe) which may be used are preferably nds selected from among Celecoxib,Meloxicam, Etoricoxib, Lumiracoxib, Parecoxib, xib and Valdecoxib.
Folic acid antagonists (or dihydrofo late reductase inhibitors) which may be used are preferably compounds selected from among methotrexate, trimethoprim, oprim, exed and iclaprim.
A CCR1 antagonist which may be used for combination with the SYK inhibitors of formula 1 is preferably selected from among CCX354 (GSK) and EMS-817399 (BMS).
A Bruton’s tyrosine kinase inhibitor (BTK—inhibitors) which may be combined with the SYK- inhibitors of formula I is preferably selected from among PC1-32765 (Pharmacyclic, see Honigberg et al, PNAS, , vol. 107, No. 29, pp. 13075-13080), AVL-292 (Avila) and 6- cyclopropylfluoro(2-hydroxymethyl-3 - { 1 -methyl-5 - [5 -(4-methyl-piperazinyl)- pyridinylamino]oxo- 1 ,6-dihydro-pyridinyl}-phenyl)-2H-isoquinolin—1-one (=RN486) (Roche) see Hu Daigen et al.JPET 341: 90-103, 2012).
A Janus kinase -inhibitors (JAK—inhibitor) which may be combined with the SYK-inhibitors of formula I is preferably selected from among GLPG-0634 (Abbott/Galapagos), tinib (Lilly), VX-509 (Vertex) and Tofacitinib (Pfizer).
A IA phosphoinositidekinase- delta inhibitors (PI3K—delta-inhibitors) which may be ed with the hibitors of a I is ably selected from among Cal-101 (Calistoga) and GS-1101. wo 2013/014060 A oorotate dehydrogenase inhibitor which may be combined with the SYK—inhibitors of formula I is ably Leflunomid (Aventis).
Furthermore the hibitors of formula 1 may be combined with either Hydroxychloroquine, Sulfasalizine or Abatacept (CTLA-4 Ig).
An anti-TNF-antibody which may be combined with the SYK—inhibitors of formula 1 is preferably selected from amgong Adalimumab and golimumab.
A ceptor PC which may be combined with the SYK—inhibitors of formula 1 is preferably Etanercept.
A pegylated anti-TNF-Fab which may be combined with the SYK—inhibitors of formula 1 is preferably certolizumab pegol.
An anti-1L6 receptor antibody which may be combined with the SYK—inhibitors of formula 1 is preferably selected from among Actemra and Roactemra.
An anti-CD20 dy which may be combined with the hibitors of formula 1 is preferably Rituximab.
LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zaf1rlukast; (E)—8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]- 2-( l H-tetrazol-S-yl)-4H- l -benzopyranone (MEN-91507); 4-[6-Acetyl[3-(4-acetyl hydroxypropylphenylthio)propoxy]propylphenoxy]—butyric acid 1); l-(((R)—(3- (2-(6,7-Difluorquinolinyl)ethenyl)phenyl)(2-(2-hydroxy propyl)phenyl)thio)methylcyclopropane-acetic acid; l-(((l(R)—3(3 -(2-(2,3-Dichlorthieno[3,2- b]pyridin-5 -yI)-(E)-ethenyl)phenyl)-3 -(2-( 1 xy- l -methylethyl)phenyl) )thio)methyl)cyclopropane acetic acid; [2—[[2-(4-tert-Butylthiazolyl) benzofiaranyl]oxymethyl]phenyl] acetic acid, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form ofthe pharmacologically acceptable acid addition salts and optionally in the form of the salts and tives, solvates and/or hydrates f By acid addition salts with pharmacologically acceptable acids which the LTD4-antagonists may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, ulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofilmarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and wo 2013/014060 hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofilmarate and hydromethanesulphonate. By salts or derivatives which the LTD4-antagonists may be capable of forming are meant, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, es, propionates, dihydrogen phosphates, palmitates, pivalates or fiJroates.
The EGFR—inhibitors used are preferably nds selected from among 4- [(3-chloro henyl)amino]—6- {[4-(morpholineyl)- l -oxobutene- l -yl] amino } cyclopropylmethoxy-quinazo line, 4-[(3-chlorofluorophenyl)amino] {[4-(N,N— diethylamino)- l -oxobutene- l -yl] amino } cyclopropylmethoxy-quinazo line, 4- [(3 -chloro- 4-fluorophenyl)amino]—6- {[4-(N,N—dimethylamino)- l -oxobutene- l ino } cyclopropylmethoxy-quinazo line, 4- [(R)-( l -phenyl-ethyl)amino] orpholineyl)- l-oxobutene- l -yl] amino } cyclopentyloxy-quinazo line, 4- [(3 -chlorofluoro- phenyl)amino] {[4-((R)methyloxo-morpholineyl)- l -oxobutene- l -yl] amino } cyclopropylmethoxy-quinazo line, 4-[(3-chlorofluoro-phenyl)amino] {[4-((R)methyl— 2-oxo-morpholineyl)- l -oxobutene- l -yl]amino } [(S)-(tetrahydrofi1ran—3 y] - quinazo line, 4- [(3 -chlorofluoro-phenyl)amino] {[4-((R)methoxymethyloxomorpholineyl )- l -oxobutene- l -yl]amino } cyclopropylmethoxy-quinazo line, 4- [(3 - chlorofluoro-phenyl)amino][2-((S)methyloxo-morpholineyl)-ethoxy] methoxy-quinazo line, chlorofluorophenyl)amino]( {4-[N—(2-methoxy—ethyl)-N— methyl-amino]oxobutene- l -yl} amino)cyclopropylmethoxy-quinazo line, 4- [(3 - chlorofluorophenyl)amino] {[4-(N,N—dimethylamino)- l -oxobutene- l -yl]amino } cyclopentyloxy-quinazo line, 4- [(R)-( l -phenyl-ethyl)amino] ,N—bis-(2-methoxy- ethyl)-amino)- l -oxobutene- l -yl]amino } cyclopropylmethoxy-quinazo line, 4- [(R)-( l - -ethyl)amino]( {4-[N—(2-methoxy-ethyl)-N-ethyl-amino]oxobutene- l - yl} amino)cyclopropylmethoxy-quinazo line, 4- [(R)-( l l-ethyl)amino]( {4- [N—(2- methoxy-ethyl)-N-methyl-amino]- l -oxobutene- l -yl} amino)cyclopropylmethoxyquinazo line, 4- [(R)-( l -phenyl-ethyl)amino]( {4- [N-(tetrahydropyranyl)-N-methyl- amino]oxobutene- l -yl} amino)cyclopropylmethoxy-quinazo line, 4- [(R)-( l -Phenyl- ethyl)amino]( {4-[N—(2-methoxy—ethyl)-N-methyl-amino]- l -oxobutene- l -yl} amino) cyclopropylmethoxy-quinazo line, 4- [(R)-( l -Phenyl-ethyl)amino]( {4- [N—(tetrahydropyran- 4-yl)-N-methyl-amino]- l -oxobutene- l -yl} amino)cyclopropylmethoxy-quinazoline, 4- [(3 ofluorophenyl)amino] {[4-(N,N—dimethylamino)- l -oxobutene- l -yl]amino } - 7-((R)-tetrahydro filran-3 -yloxy)-quinazo line, 4- [(3-chlorofluorophenyl)amino] {[4- (N,N—dimethylamino)- l -oxobutene- l -yl]amino } ((S)-tetrahydro filran-3 -yloxy)- quinazo line chlorofluorophenyl)amino]( {4-[N-(2-methoxy-ethyl)-N-methyl- amino]oxobutene- l -yl} amino)cyclopentyloxy-quinazo line, 4- [(3-chloro wo 2013/014060 fluorophenyl)arnino]—6- {[4-(N-cyclopropyl-N-rnethyl-amino)0X0buteney1]amino } cyclopentyloxy-quinazo line, 4- [(3-chlorofluoropheny1)amino] {[4-(N,N— dimethylarnino)0X0buteney1]amino } [(R)-(tetrahydr0fiJran-Z-yl)methoxy] - quinazo line, 4- [(3 -chlorofluoropheny1)amino] {[4-(N,N—dirnethylarnino)0X0 buteney1]amino } [(S)-(tetrahydr0fiJran-Z-yl)methoxy] -quinazo line, 4- [(3 y1— phenyl)arnino]—6 . 7-bis—(2-meth0xy-ethoxy)-quinaz0line, 4- [(3-ch10r0flu0r0pheny1)amino]- 7- [3 -(rn0rph01iney1)-propyloxy] [(Vinylcarbonyl)arnino]-quinaz0 line, 4-[(R)-(1 -pheny1— ethyl)arnin0](4-hydroxy-pheny1)-7H-pyrro10 [2,3 -d]pyrirnidine, 3-cyan0 [(3 -ch10r0 fluorophenyl)arnino]—6- {[4-(N,N—dimethylamino)0X0buteney1]amino } eth0xy- quino line, 4- { [3 -ch10r0(3 -flu0r0-benzy10xy)-phenyl]amino } (5 - {[(Z-methanesulphonylethyl )arnino]rnethy1} —2-yl)quinazo line, 4-[(R)-(1 -pheny1—ethyl)arnino]—6- {[4-((R) methyl-Z-oxo-rn0rph01ineyl)buteney1]amino } th0xy-quinazo line, 4- [(3- chlorofluor0pheny1)amino] {[4-(rn0rph01ineyl)0X0buteney1] amino } [(tetrahydrofiJran-Z-yl)methoxy]-quinazoline, 4- [(3-ch10r0flu0r0pheny1)amino]( {4- [N,N—bis—(2-meth0xy-ethy1)-arnino]0X0buteneyl} amin0) [(tetrahydro fiJran-Z- y1)rnethoxy]-quinazo line, 4- [(3 -ethyny1—phenyl)arnino]—6- { [4-(5 .5 -dimethy1—2—oxomorpholiney1 )0X0buteney1]amino } -quinazo line, 4- [(3 -ch10r0fluoropheny1 )arnin0][2-(2.2-dirnethyloxo-morpho1ineyl)-ethoxy]rnethoxy-quinazoline, 4- [(3 0fluor0-pheny1)arnino][2-(2.2-dirnethy1—6-oxo-rn0rph01ineyl)-ethoxy] tetrahydrofiJran-Z-y1)methoxy]-quinazo line, 4- [(3 -ch10r0flu0r0-phenyl)arnino] [2- (2.2-dimethy1—6-oxo-rnorpho 1iney1)-ethoxy] [(S)-(tetrahydrofixan—Z-ylflnethoxy] - quinazo line, 4- [(3 -ch10r0fluor0-pheny1)arnino]{2-[4-(2-0X0-rn0rph01iney1)- piperidiney1] -eth0xy} rneth0xy-quinazo line, 4- [(3 -ch10rofluoro-phenyl)amino][ 1 - (tert.-buty10xycarbony1)-piperidiney10xy]rneth0xy-quinazo line, 4- [(3-ch10r0fluoro- pheny1)arnino](trans—4-arnino-cyc10hexan— 1 -y10xy)rnethoxy-quinazo line, 4-[(3-ch10r0- 4-flu0ro-pheny1)arnino](trans—4-methanesu1phonylamino-cyclohexan— 1 -y10xy)methoxyquinazo line, 4- [(3 0fluoro-pheny1)amino](tetrahydr0pyran—3 -y10xy)rneth0xy- quinazo line, 4- [(3 -ch10r0flu0r0-pheny1)amin0](1-methy1—piperidineyloxy) methoxy-quinazo line, 4-[(3-chlor0fluor0-pheny1)arnino] { 1-[(rn0rph01ine y1)carb0ny1] idineyloxy} rneth0xy-quinazoline, 4- [(3 -ch10r0fluorophenyl )amino]—6- { 1-[(rnethoxymethyl)carbonyl]-piperidineyloxy}rnethoxy-quinazoline, 4- [(3 -ch10rofluor0-phenyl)arnino](piperidine-3 -y10xy)rnethoxy-quinazo line, 4- [(3- chlorofluoro-pheny1)amino]—6-[ 1 etylarnino-ethy1)-piperidineyloxy] rneth0xy— quinazo line, 4- [(3 0fluoro-pheny1)amino](tetrahydropyran—4-yloxy)eth0xy- quinazo line, 4- [(3 -chlorofluoro-pheny1)arnino]((S)-tetrahydrofi1ran—3 )hydroxyquinazo line, 4- [(3 -ch10r0fluor0-pheny1)arnino](tetrahydropyran—4-yloxy)(2-rnethoxyethoxy )-quinazoline, 4- [(3 -ch10r0fluor0-pheny1)arnino] {trans [(dimethylarnino)sulphonylarnino]-cyclohexan— 1 -y10xy} rneth0xy-quinazo line, 4- [(3 - ch10r0fluor0-pheny1)arnino]—6- {trans [(rnorpho1ineyl)carbony1arnino]-cyc10hexan— 1 - wo 2013/014060 yloxy} rneth0xy-quinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] {trans [(rn0rph0 liney1)su1phonylarnino]-cyclohexan— 1 } rneth0xy-quinazo line, 4- [(3 - ch10r0fluor0-pheny1)arnino](tetrahydr0pyranyloxy)(2-acetylarnino-eth0xy)- quinazo line, 4- [(3 -chlor0fluoro-pheny1)amino](tetrahydropyran—4-yloxy)(2- methanesulphonylarnino-eth0xy)-quinaz0 line, 4- [(3-ch10r0fluor0-phenyl)arnino] { 1 - [(piperidiney1)carb0ny1] -piperidineyloxy} rneth0xy-quinazo line, 4- [(3-ch10r0 fluoro-pheny1)amin0]—6-( 1 -arnin0carbonylrnethyl-piperidiney10xy)rneth0xy- quinazo line, 4- [(3 -chlor0fluoro-pheny1)amino]—6-(cis—4- {N— [(tetrahydropyran—4- y1)carb0ny1] -N-rnethyl-arnin0 } -cyclohexan— 1 -y10xy)rnethoxy-quinazo line, 4- [(3-ch10r0 fluoro-pheny1)arnino]—6-(cis—4- {N—[(rnorpho1iney1)carbonyl]-N-rnethyl-arnino } - cyclohexan—1-y10xy)rnethoxy-quinazolin ; 4- {2- [4-(3-chlorofluoro-pheny1arnino) y-quinazo1in—6-y10xy]—ethy1}rnethy1—rn0rpholine-Z-one, 4- {4-[4-(3-ch10r0 fluoro-phenylarnino)rneth0xy-quinazo1in—6-y10xy]-cyc10hexy1} rnethy1—piperazine one, 4-[(3 -chlor0fluoro-pheny1)arnino]—6-(cis—4- {N-[(rnorpho1iney1)su1phony1]-N- methyl—amino } hexan— 1 -y10xy)rneth0xy- quinazo line, 4- [(3 -ch10r0fluoropheny1 )arnino](transethansu1ph0nylarnino-cyclohexan- 1 )methoxy—quinazoline, 4- [(3 -ch10r0fluor0-phenyl)amino]( 1 -rnethanesulph0ny1—piperidineyloxy)eth0xy- quinazo line, 4- [(3 -ch10rofluor0-pheny1)arnino]( 1 anesu1phonyl-piperidine yloxy)(2-rneth0xy-ethoxy)-quinazo line, 4- [(3-ch10r0fluoro-pheny1)amino]—6-[ 1 -(2- methoxy-acety1)-piperidiney10xy](2-methoxy-ethoxy)-quinazo line, 4- [(3 -ch10r0 fluoro-phenyl)arnino](cis—4-acety1arnino-cyclohexany10xy)rnethoxy-quinazo line, 4- [(3 -ethyny1—pheny1)amino]—6-[ 1 -(tert. -buty10xycarbony1)-piperidineyloxy] rnethoxyquinazo line, 4- [(3 -ethyny1—phenyl)arnino](tetrahydropyran—4-y10xy] rneth0xy— quinazo line, 4- [(3 -chlor0fluoro-pheny1)amino]—6-(cis—4- {N—[(piperidiney1)carb0ny1]—N— methyl—amino } -cyclohexan— 1 -y10xy)methoxy-quinazo line, 4- [(3 0fluoropheny1 o](cis {N— [(4-rnethy1—piperaziney1)carb0ny1]-N-rnethy1—amino } - cyclohexan— 1 -y10xy)rnethoxy-quinazoline, 4- [(3 -ch10r0fluor0-phenyl)arnino] {cis—4- [(rnorpho 1ineyl)carbony1arnino]-cyc10hexan— 1 -y10xy} rneth0xy-quinazo line, 4- [(3 - ch10r0fluor0-pheny1)arnino]—6- { 1-[2-(2-0x0pyrr01idin—1-y1)ethy1]-piperidineyloxy} methoxy-quinazo line, 4-[(3-chlor0fluor0-pheny1)arnino] { 1-[(rn0rph01ine b0ny1] -piperidineyloxy} (2-methoxy-ethoxy)-quinazoline, 4- [(3 -ethyny1— )arnino](1 -acetyl-piperidineyloxy)rnethoxy-quinazo line, 4-[(3-ethyny1— phenyl)amino ] ( 1 -rnethy1—piperidineyloxy)rneth0xy-quinazo line, 4- [(3-ethyny1— pheny1)arnino](1 -rnethanesu1phonyl-piperidineyloxy)rnethoxy-quinazo line, 4- [(3 - ch10r0fluor0-phenyl)arnin0]( 1 -rnethy1—piperidineyloxy)-7(2-rnethoxy-ethoxy)- quinazo line, 4- [(3 ofluor0-pheny1)arnino]( 1 -isopr0py10xycarbonyl—piperidine yloxy)rnethoxy-quinazo line, 4- [(3-ch10rofluoro-pheny1)arnino](cis—4-rnethylarninocyclohexan — 1 -y10xy)rnethoxy-quinazoline, 4- [(3 -ch10r0fluor0-phenyl)arnino] {cis—4- [N—(2-rnethoxy-acetyl)-N—methy1—amino]-cyclohexan— 1 -y10xy} rneth0xy-quinazo line, 4- [(3 - ethynyl-pheny1)arnino](piperidiney10xy)methoxy-quinazo line, 4-[(3-ethyny1— phenyl)amino]—6-[ 1 -(2-methoxy-acetyl)-piperidineyloxy]rneth0xy-quinazo line, 4- [(3- ethynyl-phenyl)amino]—6- { 1 - [(rnorpho 1iney1)carbony1] idineyloxy} rnethoxyquinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] { 1-[(cis—2,6-dirnethy1—rnorpholine y1)carb0ny1] -piperidineyloxy} rneth0xy-quinazoline, 4- [(3 -ch10r0fluorophenyl )amino]—6- { 1-[(2-rnethyl-rnorpho1iney1)carbony1]-piperidineyloxy}rneth0xyquinazo line, 4- [(3 -ch10r0fluor0-pheny1)arnin0]{1-[(S , S)-(2-oxa-5 -azabicyclo [2,2, 1]hept-5 -y1)carb0ny1] -piperidineyloxy} rneth0xy-quinazo line, 4- [(3 0- 4-flu0r0-pheny1)arnino]—6- { 1-[(N—rnethyl—N—2-meth0xyethyl-arnino)carbonyl]-piperidine yloxy} rneth0xy-quinazo line, 4- [(3 -ch10r0fluor0-pheny1)amino]( 1 -ethy1—piperidine yloxy)rnethoxy-quinazo line, 4- [(3-chlor0fluor0-pheny1)arnino] { 1-[(2- methoxyethyl)carbonyl]-piperidineyloxy} rneth0xy-quinazo line, 4-[(3-ch10r0fluor0- phenyl)amino]—6- { 1 neth0xypropy1—arnino)-carbonyl]-piperidiney10xy} rnethoxyquinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] -(N—rnethanesulphonyl-N-rnethylcyclohexan— 1 -y10xy]rneth0xy-quinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] [cis—4-(N-acetyl-N—methyl-amino)-cyc10hexan— 1 -y10xy]rneth0xy-quinazo line, 4-[(3-ch10r0- 4-fluor0-pheny1)arnino](trans—4-rnethylamino-cyclohexan— 1 -y10xy)rneth0xyquinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] [trans(N—rnethanesulphonyl—N—rnethylamin0 )-cyclohexan— 1 -y10xy]rneth0xy-quinazo line, 4- [(3 0flu0r0-pheny1)arnino] (transdirnethylarnino-cyclohexan— 1 -y10xy)rnethoxy-quinazo line, 4- [(3 -ch10rofluoropheny1 o](trans—4- {N— [(rnorpho1iney1)carbony1] -N-rnethyl-arnin0 } -cyclohexan— 1 - yloxy)rnethoxy-quinazo line, 4- [(3-chlor0fluor0-pheny1)arnino] [2-(2.2-dirnethy1—6- OX0-rn0rph01iney1)-ethoxy] [(S)-(tetrahydr0 fiJran-Z-yl)methoxy]-quinazo line, 4- [(3 - ch10r0fluor0-phenyl)arnin0]( 1 anesu1phonyl-piperidiney10xy)rnethoxy- quinazo line, 4- [(3 -ch10rofluor0-pheny1)arnino]( 1 -cyan0-piperidiney10xy)rnethoxyquinazo line, 3-Cyan0 [(3 -ch10rfluorphenyl)arnino] {[4-(N,N—dirnethylarnino)0X0 butene- 1 ino } eth0xy—quino line, [4- [(3 -ch10r0fluoro-pheny1)amino]—6- {[4- (hornornorpho liney1)0X0buteney1] amino } [(S)-(tetrahydrofi1ran—3 -y1)0xy] - quinazo line, 4- [(3 -ch10r0flu0r0-pheny1)arnino](2- {4-[(S)-(2-0X0-tetrahydr0fi1ran—5 -y1)- carbonyl] -piperaziney1} -ethoxy) [(Vinylcarbonyl)arnino]-quinaz0 line, 4- [(3 -ch10ro fluoro-pheny1)arnino]—7-[2-((S)rnethy1—2-0X0-rn0rph01iney1)-eth0xy] [(Vinylcarbonyl)arnino]-quinaz0 line, 4- [(3 -ch10r0flu0r0-pheny1)arnino] [4-((R) methyloxo-rnorpho1iney1)-butyloxy] inylcarbony1)amino]-quinaz0 line, 4- [(3- chloroflu0ro-pheny1)arnino][4-((S)methy1—2-oxo-rn0rph01iney1)-butyloxy] [(Vinylcarbonyl)arnino]-quinaz0 line, 4- [(3-ch10r0fluor0-pheny1)amino](2- {4- [(S)—(2- OX0-tetrahydro fiJran-S -y1)carb0ny1] -piperazineyl} -ethoxy) [(Vinylcarbonyl)amino]- quinazo line, 4- [(3 0flu0r0-pheny1)arnino] [2-((S)—6-rnethy1—2-0X0-rn0rph01ine y1)-ethoxy] [(Vinylcarbonyl)arnino]-quinaz0 line, 4- [(3 -ch10r0fluor0-pheny1)arnino] [4- ((R)rnethy1—2-oxo-rn0rph0 1iney1)-buty10xy] [(Vinylcarbonyl)arnino]-quinaz0 line, 4- [(3-chlorofluoro-phenyl)amino][4-((S)methyloxo-morpholineyl)-butyloxy] [(Vinylcarbonyl)amino]-quinazo line, cetuximab, trastuzumab, panitumumab (=ABX-EGF), Mab ICR—62, nib, pelitinib, canertinib and erlotinib, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof.
By acid addition salts with pharmacologically acceptable acids which the EGFR-inhibitors may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, itrate, hydromaleate, cetate, enzoate, hydrocitrate, hydrofilmarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofilmarate and hydromethanesulphonate.
Examples of dopamine agonists which may be used preferably include compounds selected from among bromocriptine, cabergoline, dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and Viozan. Any reference to the above- mentioned dopamine agonists within the scope of the present invention includes a reference to any cologically acceptable acid addition salts and optionally hydrates f which may exist. By the logically acceptable acid addition salts which may be formed by the above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, filmaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Examples of Hl-antihistamines ably include compounds selected from among epinastine, zine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, hazine, ebastine, olopatadine, desloratidine and meclozine. Any reference to the mentioned Hl- antihistamines within the scope of the t invention includes a reference to any pharmacologically acceptable acid addition salts which may exist.
Examples of PAF-antagonists preferably include compounds selected from among fant, 4-(2-chlorophenyl)methyl [3(4-morpholinyl)propanon- l -yl]-6H-thieno- [3 ,2-f] - [1,2,4]triazolo ] [ l ,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro- l -methyl[(4-morpho- linyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3 ,2-f] [ l ,2,4]triazo lo [4,3-a] [ l ,4]diazepines.
Any reference to the above-mentioned above-mentioned PAF-antagonists includes within the scope of the present invention a reference to any pharmacologically acceptable acid addition salts thereofwhich may exist.
MRP4-inhibitors used are preferably compounds selected from among N—acetyl— dinitrophenyl-cysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol l7-beta- glucuronide, iol 3,17-disulphate, estradiol 3-glucuronide, estradiol 3-sulphate, e 3-sulphate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, glycolithocholic acid sulphate, ibuprofen, thacin, ofen, ketoprofen, lithocholic acid sulphate, methotrexate,((E)[[[3-[2-(7-chloroquinolinyl)ethenyl]phenyl]-[[3-dimethylamino) oxopropyl]thio]methyl]thio]-propanoic acid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid , sildenafil, sulf1npyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsin and ast, dipyridamole, optionally in the form of the racemates, omers, diastereomers and the pharmaco lly acceptable acid addition salts and hydrates thereof The invention s more preferably to the use of MRP4-inhibitors for preparing a pharmaceutical composition for treating respiratory complaints, containing the SYK— inhibitors of formula 1 and MRP4-inhibitors according to the invention, the MRP4-inhibitors preferably being selected from among dehydroepiandrosterone 3-sulphate, estradiol 3,17- disulphate, flurbiprofen, thacin, indoprofen, taurocholate, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid on salts and hydrates thereof. The separation of enantiomers from the racemates can be carried out using methods known from the art (e. g. chromatography on chiral phases, etc.) .
By acid addition salts with pharmacologically acceptable acids are meant, for example, salts selected from among the hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulphonates, preferably the hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and hydromethanesulphonates.
The invention further relates to pharmaceutical preparations which contain a triple combination of the SYK—inhibitors of formula 1, MRP4-inhibitors and another active substance according to the invention, such as, for example, an anticholinergic, a PDE4 inhibitor, a steroid, an ntagonist or a betamimetic, and the ation thereof and the use thereof for ng respiratory complaints.
Compounds which may be used as iNOS tors are compounds selected from among: S- (2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, 5,6-dihydromethyl- 4H-l,3-Thiazineamine (=AMT), L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrullin, S-ethylthiocitrulline, L-NA (N‘D-nitro-L-arginine), L-NAME (N‘D-nitro-L-argininemethylester), L-NMMA (NG- thyl-L-arginine), L-NIO (N‘D-iminoethyl-L-omithine), L-NIL (N‘D-iminoethyl-lysine), (S)acetimidoylaminoamino-hexanoic acid (lH—tetrazol—S-yl)-amide (SC-51) (J. Med.
Chem. 2002, 45, 689), N—[[3-(aminomethyl)phenyl]methyl]-Ethanimidamide (=l400W), (S)—4-(2-acetimidoylamino-ethylsulphanyl)amino-butyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600), 2-[2-(4-methoxy-pyridinyl)-ethyl]-3H— o[4,5-b]pyridine (BYKl91023) (M01. Pharmacol. 2006, 69, 328-337), 2-((R) amino-l-phenyl-propoxy)chlorofluorobenzonitrile (WO 01/62704), 2-((lR,3S) aminohydroxy- l -thiazo l-5 -yl-butylsulphanyl)trifluoromethyl-nicotinonitrile (WO 41794), 2-(( l R. 3 S)—3-aminohydroxy- l -thiazo l-5 -yl-butylsulphanyl)chloro- benzonitrile (), 2-((lR.3S)aminohydroxy-l-thiazol-S-yl- butylsulphanyl)chloro-benzonitrile (), (2S.4R)amino(2-chloro trifluoromethyl-phenylsulphanyl)thiazo1-5 -yl—butan— 1 -ol (), 2-(( l R. 3 S)- 3-aminohydroxy- l -thiazo l-5 -yl-butylsulphanyl)-5 -chloro-nicotinonitrile (WO 2004/041794), aminohydroxy- l -phenyl-butylsulphanyl)methoxy— nicotinonitrile (WO 02/090332), substituted 3-phenyl-3,4-dihydro-l-isoquinolinamine such as e.g. (lS.5S.6R)—7-chloromethylaza-bicyclo[4.1.0]heptenylamine (ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R,5R)—5-ethylmethylthiazolidinylideneamine (Bioorg. Med. Chem. 2004, I2, 4101), (4R,5R)ethylmethyl- selenazolidinylideneamine (Bioorg. Med. Chem. Lett. 2005, I5, 1361), 4- aminotetrahydrobiopterine (Curr. Drug Metabol. 2002, 3, 119-121), (4-chloro-phenyl)- N—( l - {2-oxo [4-(6-trifluoromethyl-pyrimidinyloxy)-piperidine- l -yl] -ethylcarbamoyl} nyl—ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, , 3-(2,4- difluoro-phenyl)[2-(4-imidazo l- l -ylmethyl-phenoxy)-ethoxy]phenyl-pyridine (PPA25 0) wo 14060 (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), 3-{[(benzo[l,3]dioxolylmethyl)- carbamoyl]-methyl} (2-imidazo l- l -yl-pyrimidinyl)-piperazine- l -carboxylate (BBS- 1) (Drugs Future 2004, 29, 45-52), (2-imidazol-l-ylmethyl-pyrimidinyl)- pyrrolidinecarboxylic acid (2-benzo[l,3]dioxolyl-ethyl)-amide (BBS-2) (Drugs Future 2004, 29, 45-52) and the ceutical salts, gs or solvates thereof Examples of iNOS-inhibitors within the scope of the present invention may also include antisense oligonucleotides, particularly those antisense oligonucleotides which bind iNOS- coding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense oligonucleotides, which bind iNOS coding nucleic acids, for modulating the expression of iNOS. iNOS-antisense ucleotides as described particularly in WO 01/52902 may therefore also be combined with the PDE4-inhibitors of the t ion on account of their similar effect to the iNOS-inhibitors.
Suitable HMG-CoA reductase inhibitors (also called statins) which may be preferably used in double or triple combinations with the compounds of formula 1 are selected from among Atorvastatin, Cerivastatin, Flurvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, optionally in form of their pharmaceutically available acid addition salts, prodrugs, solvates or es thereof 8. FORMULATIONS Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% ofthe total ition, i.e. in amounts which are ient to achieve the dosage range specified hereinafter.
The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e. g. a hard gelatine capsule), as a solution or sion. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or s-ethanolic solution or using a propellant gas formulation.
Preferably, therefore, pharmaceutical formulations are characterised by the content of one or more compounds of formula 1 according to the preferred embodiments above.
It is particularly preferable if the nds of formula 1 are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be ed, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as ium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate ate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or t incompatibilities the core may also consist of a number of layers. rly the tablet g may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e. g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Capsules containing one or more active substances or combinations of active substances may for e be ed by mixing the active substances with inert carriers such as lactose or ol and packing them into gelatine capsules. Suitable suppositories may be made for e by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the tives thereof Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraff1ns (e.g. petroleum fractions), vegetable oils (e. g. groundnut or sesame oil), mono- or polyfianctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e. g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. , spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, c acid and sodium lauryl sulphate).
For oral administration the tablets may, of course, contain, apart from the entioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various ves such as starch, preferably potato starch, gelatine and the like.
Moreover, lubricants such as ium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients ned above.
It is also preferred if the compounds of a 1 are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula 1 have to be made ble in forms le for inhalation. ble preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional logically acceptable excipients.
Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.
Inhalable powders If the active substances of formula 1 are present in admixture with physiologically acceptable ents, the ing logically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. n), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these ents with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the ion, lactose is the particularly preferred excipient, while lactose monohydrate is most ularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ents together are known from the prior art.
Propellant-containing inhalable aerosols The propellant-containing inhalable aerosols which may be used according to the invention may contain the compounds of a 1 dissolved in the propellant gas or in dispersed form.
The propellant gases which may be used to e the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, ne or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof ularly preferred propellant gases are ated alkane derivatives selected from TGl34a (l,l,l,2-tetrafluoroethane), TG227 (l,l,l,2,3,3,3-heptafluoropropane) and mixtures thereof The propellant-driven inhalation aerosols used within the scope of the use ing to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, idants, lubricants and pH adjusters. All these ingredients are known in the art.
Propellant-free inhalable solutions The nds of formula 1 according to the invention are preferably used to prepare propellant-free inhalable solutions and ble suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The t may be water on its own or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, ric acid and/or phosphoric acid.
Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, filmaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also le to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e. g. as ings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e. g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, hyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms ents and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the ative ties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable cological effect. The excipients and additives include, for example, surfactants such as soya in, oleic acid, an esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, Vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic . The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, Vitamin A, Vitamin E, tocopherols and similar Vitamins or provitamins occurring in the human body. Preservatives may be used to t the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the tration known from the prior art.
For the treatment forms described above, ready-to-use packs of a medicament for the treatment of atory complaints are provided, containing an enclosed description including for e the words respiratory disease, COPD or asthma, together with a yridine according to formula 1 and one or more combination partners selected from those described above.
WE

Claims (28)

CLAIM :
1. A compound of formula 1 N R2 1, wherein R1 is a linear or branched C1alkyl, wherein R1 is substituted by R3 which is selected from the group consisting of a three-, four-, five-, six- or seven-membered cycloalkyl; a five-, six- or seven-membered, saturated heterocycle sing one, two or three atoms 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 by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, and wherein R2 is selected from the group consisting of n, phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each ndently 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 atoms each independently selected from the group consisting of N, S and O; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group ting of linear or branched –O-C1alkyl, -OH, oxo, n, -C1haloalkyl, -SO2CH3, -C1alkylene-SO2-C1alkyl), -SO2-CF3, -CN, -C3cycloalkyl, linear or branched alkyl, a four, five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one (10784852_1):JJC another ed from the group of N, S, -SO2 and O; -C1alkylene-N(C1alkyl)-CO-C1alkyl, -NH-CO-C1alkyl, -CO-NH(CH3), -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, alkylene-O-CO-C1alkyl and * NH wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one another selected from the group consisting of linear or branched -C1alkyl, oxo,-C1haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or sixmembered saturated heterocycle comprising one, two or three atoms each independently selected from the group of N, S and O, a three, four-, five-, six- or sevenmembered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteroatoms each independently selected from the group consisting of N, O and S, wherein R5 may optionally be substituted by a group consisting of oxo,-C1alkyl and -C1haloalkyl, or a pharmacologically able salt of the aforementioned compound.
2. The compound of formula 1 according to claim 1, wherein R1 is selected from the group consisting of –CH3 and -CH2-(CH3) which is substituted by R3 which is selected from the group ting of a three-, four-, five-, six- or seven- membered cycloalkyl; a five-, six- or seven-membered, saturated heterocycle comprising one, two or three heteroatoms each ndently 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 by one, two, three or four substituents each ndently selected from the group consisting of oxo, OH, 2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, or a pharmacologically acceptable salt of the aforementioned compound. (10784852_1):JJC
3. The compound of formula 1 according to claim 1 or claim 2, wherein R1 is substituted by R3 which is selected from the group consisting of a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group consisting of N, S and O, n R3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, or a pharmacologically acceptable salt of the entioned compound.
4. The compound of formula 1 according to claim 1 or claim 2, wherein R1 is substituted by R3 which is selected from the group consisting of a five- or six-membered heteroaryl comprising one or two heteroatoms each independently ed from the group consisting of N, S and O, wherein R3 may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of oxo, OH, -CO-NH2, -CO-NH(CH3), -CO-N(CH3)2, -C1alkyl, -C1alkylene-CO-NH2, -C1alkylene-CO-NH(CH3), -C1alkylene-CO-N(CH3)2, -C1alkylene-CN and -CN, or a pharmacologically acceptable salt of the entioned compound.
5. The compound of formula 1 according to any one of claims 1 to 4, wherein R1 is a selected from the group ting of –CH3 or -CH2(CH3), wherein R1 is substituted by R3 which is selected from the group ting of a three-, four-, five- or six-membered cycloalkyl; a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group consisting of N, S and O; and a five- or six-membered heteroaryl comprising one or two heteroatoms each ndently selected from the group consisting of N, S and O; wherein R3 may optionally be substituted by one, two, three or four substituents each ndently ed from the group consisting of oxo, 2, -CH2-CO-NH2, methyl and -CH2-CN, (10784852_1):JJC or a pharmacologically acceptable salt of the aforementioned compound.
6. The compound of formula 1 according to any one of claims 1 to 5, n R1 is selected from the group consisting of –CH3 and –CH2-CH3, wherein R1 is substituted by R3 which is a five-membered saturated heterocycle comprising one nitrogen-atom, wherein R3 is substituted by one oxo-group or a pharmacologically acceptable salt of the aforementioned compound.
7. The compound of formula 1 ing to any one of claims 1 to 5, wherein R1 is the group 3 N * O or a pharmacologically acceptable salt of the aforementioned compound.
8. The nd of formula 1 according to any one of claims 1 to 5, wherein R1 is selected from the group ting of –CH3 and –CH2-CH3, n R1 is substituted by R3 which is a six-membered heteroaryl comprising one nitrogen-atom, wherein R3 is substituted by –CO-NH2, or a cologically acceptable salt of the aforementioned compound.
9. The compound of formula 1 according to any one of claims 1 to 5, wherein R1 is the group O NH or a pharmacologically acceptable salt of the aforementioned compound. (10784852_1):JJC
10. The compound of formula 1 according to any one of claims 1 to 9, n R2 is selected from the group consisting of phenyl, a five- or six-membered monocyclic heteroaryl comprising one, two or three heteroatoms each independently selected from the group ting of N, S and O; a bicyclic, nine- or ten-membered, either aromatic or matic , 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 substituted by one, two, three or four substituents R4 which ndently from one another are selected from the group ting of linear or branched –O-C1alkyl, oxo, -OH, -F, -Cl, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S, SO2 and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, , -C1alkylene-O-CO-C1alkyl and * NH wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently from one another selected from the group consisting of , ethyl, propyl, isopropyl, isopropyl, n-butyl, isobutyl, tert-butyl, -C1haloalkyl, oxo, -OH, halogen, alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle sing one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, a five- or six-membered heteroaryl comprising one or two heteratoms each independently ed from the group consisting of N, S and O, wherein R5 may optionally be substituted by a group consisting of oxo, methyl, ethyl, -CF3, or a pharmacologically acceptable salt of the aforementioned compound. (10784852_1):JJC
11. The compound of a 1 according to any one of claims 1 to 10, wherein R2 is phenyl, wherein R2 may optionally be substituted by one, two, three or four substituents R4 which ndently from one another are selected from the group consisting of linear or branched –O-C1alkyl, oxo, -OH, -F, -Cl, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or mbered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, , -C1alkylene-O-CO-C1alkyl and * NH wherein R4 may optionally be substituted by one or two substituents R5 , wherein each R5 is independently ed from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, oxo, -C1haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each ndently selected from the group of N, S and O, a three, four-, five-, six- or sevenmembered cycloalkyl, a five- or six-membered aryl comprising one or two heteroatoms each independently selected from the group consisting of N, S and O, wherein R5 may optionally be substituted by a group consisting of oxo, methyl, or a pharmacologically acceptable salt of the aforementioned compound.
12. The compound of formula 1 according to claim 11, wherein R2 is phenyl, and n R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of –OCH3, oxo, -OH, -F, Cl, -CF3, -CHF2, -SO2CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl; -NH-CO-CH3, alkylene-N(C1alkyl)-CO-CH3, -CO-NH(CH3), -alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1alkylene-O-CO-C1alkyl and (10784852_1):JJC * NH wherein R4 may optionally be substituted by one or two substituents R5, wherein each R5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopropyl, n-butyl, isobutyl, tert-butyl, -C1haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or mbered saturated heterocycle comprising one, two or three heteroatoms each independently from one another ed from the group of N, S and O, a three, four-, five-, six- or membered cycloalkyl, wherein R5 may optionally be substituted by a group consisting of oxo, methyl, or a pharmacologically acceptable salt of the aforementioned compound.
13. The compound of formula 1 according to any one of claims 1 to 10, wherein R2 is a five- or mbered monocyclic aryl comprising one, two or three heteroatoms each independently selected from the group consisting of N, S and O; wherein R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are ed from the group consisting of–O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, oxo, -OH, -F, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered ted heterocycle comprising one or two heteroatoms each independently ed from the group of N, S and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1alkylene-O-CO-C1alkyl and * NH wherein R4 may optionally be substituted by one or two substituents R5 , wherein each R5 is ndently selected from the group ting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -C1haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a (10784852_1):JJC five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently selected from the group of N, S and O, a three, four-, five-, six- or embered cycloalkyl, wherein R5 may optionally be substituted by a group consisting of oxo, methyl and –CF3, or a pharmacologically acceptable salt of the aforementioned compound.
14. The compound of a 1 according to claim 13, wherein R2 is a five- or six-membered monocyclic heteroaryl sing one, two or three heteroatoms each independently selected from the group consisting of N, S and O; n R2 may optionally be substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of –O-CH3, oxo, -OH, -F, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, F3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently from one another selected from the group of N, S and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, wherein R4 may optionally be substituted by one or two substituents R5 , wherein each R5 is independently ed from the group consisting of methyl, ethyl, propyl, pyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -CHF2, CH2F, -CF2-CF3, -OH, halogen, -ethylen-CF3, a five- or six-membered saturated heterocycle comprising one, two or three atoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or membered cycloalkyl, wherein R5 may optionally be substituted by a group consisting of oxo, methyl and –CF3, or a pharmacologically acceptable salt of the aforementioned compound.
15. The compound of formula 1 according to claim 14, n (10784852_1):JJC R2 is a five-membered monocyclic heteroaryl comprising one, two or three atoms each independently selected from the group ting of N, S and O; whereby this embered monocyclic heteroaryl is linked to the quinoline core structure via a carbon atom and wherein this embered monocyclic heteroaryl optionally may be r substituted as identified in claim 14, or a pharmacologically acceptable salt of the aforementioned compound.
16. The compound of formula 1 according to claim 14, wherein R2 is a five-membered monocyclic heteroaryl comprising at least one nitrogen atom and optionally one or two further heteroatoms each independently selected from the group consisting of N, S and O; y this five-membered monocyclic heteroaryl is linked to the quinoline core structure via a nitrogen atom, and wherein this five-membered monocyclic heteroaryl optionally may be further substituted as identified in claim 14, or a pharmacologically acceptable salt of the aforementioned compound.
17. The compound of formula 1 according to any one of claims 1 to 10, wherein R2 is a bicyclic, nine- or ten-membered, either ic 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 substituted by one, two, three or four tuents R4 which independently from one another are selected from the group consisting of linear or branched –O-C1alkyl, oxo, -OH, -F, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle sing one or two heteroatoms each independently from one another selected from the group of N, S and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, -C1alkylene-O-CO-C1alkyl and * NH (10784852_1):JJC wherein R4 may optionally be substituted by one or two substituents R5 , n each R5 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, haloalkyl, -OH, halogen, -C1alkylene-C1haloalkyl, a five- or six-membered saturated cycle comprising one, two or three heteroatoms each independently from one another selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, wherein R5 may optionally be substituted by a group ting of oxo, methyl and –CF3, or a pharmacologically able salt of the aforementioned compound.
18. The compound of formula 1 according to claim 17, wherein R2 is a bicyclic, nine- or mbered, 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 substituted by one, two, three or four substituents R4 which independently from one another are selected from the group consisting of -O-CH3, -O-ethyl, -O-propyl, -O-isopropyl, oxo, -OH, -F, -CF3, methyl, ethyl, propyl and pyl, or a pharmacologically acceptable salt of the aforementioned compound.
19. The compound of formula 1 according to claim 13 or claim 14, wherein R2 is pyridine, wherein R2 may optionally be substituted by one, two, three or four substituents R4 which ndently from one r are ed from the group consisting of –O-CH3, oxo, -OH, -F, -CF3, -CHF2, -SO2CH3, -CH2 -SO2-CH3, -SO2-CF3, -CH3, -CH2-CH3, propyl, isopropyl, a five- or six-membered saturated heterocycle comprising one or two heteroatoms each independently selected from the group of N, S and O; -NH-CO-CH3, -C1alkylene-N(C1alkyl)-CO-C1alkyl, -CO-NH(CH3), -(C1alkylene)-O-CO-CH3, -CO-NH2, -CO-N(CH3)2, -O-R5, -CO-R5, (10784852_1):JJC wherein R4 may optionally be substituted by one or two tuents R5 , wherein each R5 is independently from one another selected from the group consisting of , ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CF3, -CH2-CF3, -CHF2, CH2F, -CF2-CF3, -OH, halogen, -C1alkylene-CF3, a five- or six-membered saturated heterocycle comprising one, two or three heteroatoms each independently from one r selected from the group of N, S and O, a three, four-, five-, six- or seven-membered cycloalkyl, wherein R5 may optionally be substituted by a group ting of oxo, methyl and –CF3 or a pharmacologically acceptable salt of the aforementioned compound.
20. The compound of formula 1 according to claim 19, wherein R2 is pyridine, n R2 is substituted by one or two R4 which independently from one another are selected from the group consisting of , -OH, -F, -CF3, -CHF2, -CH3, -CH2-CH3, propyl, isopropyl and -O-R5, wherein R5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, -CF3, -CHF2, CH2F, -CH2-CF3, -CF2-CF3 or a pharmacologically acceptable salt of the aforementioned compound.
21. The compound according to formula 1 according to claim 1, wherein R1 is ed from the group consisting of (10784852_1):JJC 3 H N O N 2 * N * N * N O * O ;;; * ; O ;; O ; ; O N O NH N 2 O 3 N CH * ;; * and * ; and wherein R2 is selected from the group ting of 3 CH * O * O * O CH * O * N O O CH CH 3 CH H CH ; 3 ; ; 3 C ; 3 3 ; * F * * * O CH O 3 O O S F CH CH * O OH CH ; 3 ; 3 ; Br ; 3 ; * * O * F O N S N N CH F 3 ; N ; F F CH ; 3 ; * * * O * N O S 3 S F N CH CH O 3 ; ; 3 ; O ; * CH * N N * N N N I N ; O ; N ; ; (10784852_1):JJC * N * * CH N N F N CH N 3 O CH F ; 3 ; F ; O ; * * N O O N CH N 3 N O ; O H C ; ; 3 ;; * Cl * * N O N NH ; 2 ; N O ; * * * N N * O O O H C CH F CH 3 H C ; 3 3 ; 3 H C ; O ; 3 ; * N CH CH 3 3 * N N * N N N 3 CH ; N ; 3 ; N * F * N * S F F 3 N N F F Cl NH ; N ; 2 ; N F ; * N * N N O N N O H C CH 3 3 3 ; H C CH 3 3 ; O ; O ; 852_1):JJC N * O * N CH * N F N N O N F F CH CH CH ; 3 ; O 3 ;; 3 ; * O * * * N F N CH N O F ; ; F ; ; N * CH N 3 CH * O 3 N F F CH ; 3 N CH ; 3 ; N O * * N N CH F * 3 CH N 3 H C N N F 3 ; F CH ; 3 ; N CH N CH * N F * F N N CH N CH 3 N 3 ; H C 3 ; F OH ; N ; * * N F CH N O and F , or a pharmacologically acceptable salt of the aforementioned nd.
22. The compound according to formula 1 according to claim 1 selected from the group consisting of (10784852_1):JJC 3 Chiral CH 3 Chiral 3 Chiral O O CH N 3 CH O O O O N O N N O O CH O CH ; CH 3 3 ¸ CH 3 ;; Chiral O CH 3 Chiral N CH O CH 3 N 3 O O N N O N O O CH CH 3 CH 3 ; ; 3 ; O Chiral 3 Chiral Chiral CH O 3 O N N O CH 3 3 O O O O N O N N CH O O O CH CH 3 3 ; H C 3 ; H C CH 3 3 ; O Chiral O Chiral N N Chiral O CH O 3 CH O 3 O O O N CH 3 O N CH OH ; CH 3 ; OH ; O Chiral O Chiral O Chiral N N N O CH 3 O F F N CH N N 3 O O F CH H C CH 3 ; F CH 3 ; 3 3 ; 852_1):JJC O Chiral O Chiral Chiral O N 3 O F N O N CH O 3 O CH F CH H C 3 3 ; 3 ; OH ; O Chiral O Chiral N N O O CH H N O N N N N N O O 3 ; CH 3 ; N Br ; O 3 N CH H N O 3 O N 2 2 O H C N 3 N O O O CH O 3C O O CH H 3 3 ; CH 3 ; H C 3 ; O NH H N O CH Chiral O N O N O N CH N O O O O CH N N CH 3 3 ; N Br ; H C 3 ; CH CH 3 Chiral 3 Chiral H C 3 Chiral O O O N N O O O N N O N ; N N CH 3 ; F F ; 852_1):JJC O Chiral H N O 2 N CH Chiral O 3 N O N O CH N O O N N S N F CH 3 ; N CH 3 ; ; 2 O H N O N CH 3 Chiral N N O N F CH O S 3 S F O CH O 3 ; O ; N I ; H N O CH Chiral O 3 H N O 2 N O O O N O N CH 3 N N N O N O CH H C 3 ; N 3 ; O ; N ; CH Chiral O H N O N 2 CH Chiral O O N N N CH CH O 3 3 N N N N N N N ; O ; ; H N O H N O 2 2 CH Chiral O O O N N N N N N N N N N O ; CH 3 ; CH 3 ; O Chiral CH Chiral 3 H N O N O CH 3 O N N CH N 3 N N F N CH ; F F ; O ; 852_1):JJC 3 Chiral CH Chiral 3 H N O O N N O O O N CH N 3 N N CH 3 N N O ; O ; O ; CH Chiral 3 CH Chiral H N O 2 O N O N O N O N N N O N N O ; ; H C 3 ; H N O H N O H N O 2 O N N N CH 3 O N N CH N CH N N O 3 ; O ; H C 3 ; H N O H N O 2 CH Chiral O O N N O N N N N N CH CH 3 3 N ; N ; NH 2 ; 3 Chiral H N O O CH 2 N 3 Chiral O O N O N N N N O N O N O ; N O ; H C 3 ; 3 Chiral CH 3 Chiral CH 3 Chiral N O N O O O N N CH N N 3 O N CH O 3 H C CH 3 ; F CH 3 3 ; O ; 852_1):JJC H N O 2 CH Chiral H N O 3 3 Chiral O O N O N O N O N N N O N N N N O O 3 ; O ; H C 3 ; O CH Chiral 3 H N O H N O O 2 O N ; H C 3 ; ; N CH CH Chiral N CH Chiral O H N O O 2 N O O O N N 3 N N N N CH ; N ; H C 3 3 ; H N O H N O N CH Chiral O N N O N N CH N O 3 N N N CH CH 3 ; 3 ; N ; H N O H N O CH Chiral 2 3 O O O N 3 O N F S N N N N N ; N F F ; N ; CH Chiral CH 3 3 H C 3 Chiral N O O O N S F N F 3 N N ; Cl NH 2 ; N F ; 852_1):JJC 3 Chiral CH Chiral N CH 3 Chiral O N N N N O N O N N O H C 3 ; H C CH 3 3 ; O ; O NH 2 CH CH 3 Chiral Chiral O O N N N N N O N N F N N CH CH 3 3 O ; O ; N F F ; O NH CH Chiral 2 3 Chiral N O N N O N N N N O O S S 3 ; O CH ; O CH 3 3 ; O Chiral O NH O NH 2 2 O O O CH N N N O N N N CH N 3 O N N O CH CH CH 3 ; 3 ; 3 ; O Chiral O Chiral N CH 3 Chiral O CH O CH 3 3 N CH N N N F N O ; ; F F ; 3 Chiral 3 Chiral O NH 2 O N O N N N O 3 N CH N ; F F ; CH 3 ; 852_1):JJC O NH 3 Chiral O NH O 2 N O CH N N 3 N O 3 N N N N N 3 ; N CH 3 ; N ; O NH CH Chiral 2 3 O N 3 Chiral N N N N O O O N N F N F N ; F F F ; F ; CH Chiral O NH N CH Chiral O N N CH O N N N N H C N 3 CH ; N CH 3 3 ; N 3 ; CH Chiral CH Chiral O O NH O N N N N CH N 3 F N N CH N H C CH 3 ; F ; N 3 ; O Chiral O Chiral H C Chiral 3 N O CH O 3 O O CH N N N F N CH N N ; O and F , and the pharmacologically able salts of the aforementioned compounds. (10784852_1):JJC
23. Use of a compound according to any one of claims 1 to 22 for the manufacture of a ment for the treatment of a e selected from the group consisting of allergic rhinitis, asthma, COPD, adult respiratory distress syndrome, bronchitis, pulmonary hypertension, B-cell lymphoma, itis and contact dermatitis, allergic dermatitis, allergic rhinoconjunctivitis, rheumatoid arthritis, anti-phospholipid syndrome, Berger's disease, Evans's syndrome, ulcerative colitis,allergic antibody-based glomerulonephritis, granulocytopenia, Goodpasture's syndrome, hepatitis, Henoch-Schönlein purpura, hypersensitivity vasculitis, immunohaemolytic anaemia, autoimmune haemolytic , idiopathic thrombocytopenic purpura, Kawasaki me, allergic conjunctivitis, lupus erythematodes, capsule cell lymphoma, neutropenia, non-familial lateral sclerosis, Crohn's disease, multiple sis, myasthenia gravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis, Sjögren's syndrome, sclerodermy, T-cell ma, urticaria / angiooedema, r's granulomatosis, artheriosclerosis and coeliac disease.
24. The use of a compound according to claim 23, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, adult respiratory distress syndrome, itis, allergic dermatitis, contact dermatitis, idiopathic thrombocytopenic a, rheumatoid arthritis, artheriosclerosis and allergic rhinoconjunctivitis.
25. The use of a compound according to claim 23 or claim 24, wherein the disease is selected from the group consisting of asthma, COPD, allergic rhinitis, allergic itis and rheumatoid arthritis.
26. A pharmaceutical formulation characterised in that it contains one or more compounds of a 1 ing to at least one of claims 1 to 22.
27. A pharmaceutical formulation characterised in that it contains one or more compounds of formula 1 according to at least one of claims 1 to 22 in combination with an active substance selected from the group consisting of anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, CRTH2-antagonists, CCR1-antagonists, NSAIDS, COX bitors (Coxibe), iNOS- (10784852_1):JJC inhibitors, HMG-CoA reductase inhibitors and folic acid antagonists such as methotrexate.
28. An intermediate compound selected from a B N B and from formula C N B OH C, wherein R1 is d as in any one of claims 1 to 20. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (10784852_1):JJC
NZ619197A 2011-07-26 2012-07-19 Substituted quinolines and their use as medicaments NZ619197B2 (en)

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Application Number Priority Date Filing Date Title
EP11175444 2011-07-26
EP11175444.6 2011-07-26
PCT/EP2012/064172 WO2013014060A1 (en) 2011-07-26 2012-07-19 Substituted quinolines and their use as medicaments

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NZ619197B2 true NZ619197B2 (en) 2016-05-03

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