DDR2 INHIBITORS FOR THE TREATMENT OF OSTEOARTHRITIS

Information

  • Patent Application
  • 20150225369
  • Publication Number
    20150225369
  • Date Filed
    July 29, 2013
    10 years ago
  • Date Published
    August 13, 2015
    8 years ago
Abstract
The present invention relates to compounds of the formula I and in particular medicaments comprising at least one compound of the formula I for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states in the triggering of which DDR2 is involved, in particular for use in the treatment and/or prophylaxis of osteoarthritis, hepatocirrhosis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.
Description

The present invention relates to compounds of the formula I and in particular medicaments comprising at least one compound of the formula I for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states in the triggering of which DDR2 is involved, in particular for use in the treatment and/or prophylaxis of osteoarthritis, hepatocirrhosis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.


BACKGROUND OF THE INVENTION

Osteoarthritis (OA) is one of the most disabling diseases in developed countries. The prevalence of OA is estimated to one in ten men and one in five women aged over 60 years worldwide. As such, the disease accounts for considerable health care expenditure and therefore represents a significant socio-economic burden. To date, no disease modifying treatment is available. Current treatment is therefore entirely symptomatic up to the point when total joint replacement may be indicated.


In spite of this significant importance for the health system, the causes of OA remain unclear to date and effective preventative measures furthermore remain a distant aim. A reduction in the joint gap (caused by destruction of the joint cartilage), together with changes in the subchondral bone and osteophyte formation, are the radiological characteristics of the disease. For the patient, however, pain (load-dependent and nocturnal rest pain) with subsequent function impairments are to the fore. It is also these which force the patient into social isolation with corresponding secondary diseases.


The term osteoarthritis according to an unofficial definition denotes “joint wear” which exceeds the usual extent for the age. The causes are regarded as being excessive load (for example increased body weight), connatal or traumatic causes, such as malposition of the joint, or also bone deformations due to bone diseases, such as osteoporosis. Osteoarthritis can likewise arise as a consequence of another disease, for example joint inflammation (arthritis) (secondary osteoarthritis), or accompany overload-induced effusion (secondary inflammation reaction) (activated osteoarthritis). The Anglo-American specialist literature differentiates between osteoarthritis (OA), in which the destruction of the joint surfaces can probably be attributed principally to the effects of load, and arthritis (rheumatoid arthritis, RA), in which joint degeneration due to an inflammatory component is to the fore.


In principle, osteoarthritis is also differentiated according to its cause. Arthrosis alcaptonurica is based on increased deposition of homogentisic acid in joints in the case of previously existing alcaptonuria. In the case of haemophilic arthrosis, regular intra-articular bleeding occurs in the case of haemophilia (haemophilic joint). Arthrosis urica is caused by the mechanical influence of urate crystals (uric acid) on the healthy cartilage (Pschyrembel W. et al.: Klinisches Wörterbuch, Verlag Walter de Gruyter & Co, 253rd Edition, 1977).


The classical cause of osteoarthritis is dysplasia of joints. Using the example of the hip, it becomes clear that the zone with the greatest mechanical stress in the case of a physiological hip position represents a significantly larger area than in the case of a dysplastic hip. However, the stresses caused by the forces acting on the joint are substantially independent of the joint shape. They are essentially distributed over the main stress zone(s). A greater pressure will thus arise in the case of a relatively small zone than in the case of a larger one. The biomechanical pressure on the joint cartilage is thus greater in the case of a dysplastic hip than in the case of a physiological hip position. This rule is generally regarded as the cause of the increased occurrence of arthrotic changes in supporting joints which differ from the ideal anatomical shape.


If the consequences of an injury are responsible for premature wear, the term post-traumatic arthrosis is used. Further causes of secondary arthrosis or osteoarthritis that are being discussed are mechanical, inflammatory, metabolic, chemical (quinolones), trophic, hormonal, neurological and genetic reasons. In most cases, however, the diagnosis given is idiopathic arthrosis, by which the doctor means an apparent absence of a causal disease (H. I. Roach and S. Tilley, Bone and Osteoarthritis, F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).


Medicinal causes of osteoarthritis can be, for example, antibiotics of the gyrase inhibitor type (fluoroquinolones, such as ciprofloxacin, levofloxacin). These medicaments result in complexing of magnesium ions in poorly vascularised tissues (hyaline joint cartilage, tendon tissue), which has the consequence that irreversible damage occurs to connective tissue. This damage is generally more pronounced in the growth phase in children and juveniles. Tendinopathies and arthropathies are known side effects of this class of medicaments. In adults, these antibiotics result in accelerated physiological degradation of the hyaline joint cartilage according to information from independent pharmacologists and rheumatologists (Menschik M. et al., Antimicrob. Agents Chemother. 41, pp. 2562-2565, 1997; Egerbacher M. et al., Arch. Toxicol. 73, pp. 557-563, 2000; Chang H. et al., Scand. J. Infect. Dis. 28, pp. 641-643, 1996; Chaslerie A. et al., Therapie 47, p. 80, 1992). Extended treatment with phenprocoumone can also favour arthrosis by decreasing bone density in the case of stresses of the joint internal structure.


Besides age, known risk factors for osteoarthrosis are mechanical overload, (micro)traumas, joint destabilisation caused by loss of the securing mechanisms, and genetic factors. However, neither the occurrence nor possible interventions have been fully explained (H. I. Roach and S. Tilley, Bone and Osteoarthritis, F. Bronner and M. C. Farach-Carson (Editors), Verlag Springer, Volume 4, 2007).


In a joint affected by osteoarthritis, the content of nitrogen monoxide is increased in some cases. A similar situation has been observed due to high mechanical irritation of cartilage tissue (Das P. et al., Journal of Orthopaedic Research 15, pp. 87-93, 1997; Farrell A. J. et al., Annals of the Rheumatic Diseases 51, pp. 1219-1222, 1992; Fermor B. et al., Journal of Orthopaedic Research 19, pp. 729-737, 2001), whereas moderate mechanical stimulation tends to have a positive effect. The action of mechanical forces is thus causally involved in the progress of osteoarthritis (Liu X. et al., Biorheology 43, pp. 183-190, 2006).


In principle, osteoarthritis therapy follows two aims: firstly freedom from pain under normal load and secondly the prevention of mechanical restrictions or changes in a joint. These aims cannot be achieved in the long term by pain treatment as a purely symptomatic therapy approach, since this cannot halt the progress of the disease. If the latter is to be achieved, the cartilage destruction must be stopped. Since the joint cartilage in adult patients cannot regenerate, the elimination of pathogenetic factors, such as joint dysplasia or malpositions, which result in increased point pressure on the joint cartilage, is in addition enormously important.


Finally, it is attempted to prevent or stop the degeneration processes in the cartilage tissue with the aid of medicaments.


An essential factor for the functioning state and thus the resistance of the joint cartilage to stress is the extracellular matrix, which primarily consists of collagens, proteoglycans and water. The enzymes involved in degradation of the extracellular matrix include, in particular the metalloproteases, aggrecanases and cathepsin enzymes.


The discoidin domain receptors (DDRs) DDR2 (discoidin domain receptor family member 2, also known as CCK-2, tyro-10 or TKT) and DDR1 (discoidin domain receptor family member 1; also known as MCK-10, DDR, NEP, cak, trkE, RTK6 or ptk3) are members of a receptor tyrosine kinase subfamily, which are activated by collagens.


These proteins are characterized by an extracellular discoidin domain, a domain first identified in the slime mold Dictyostelium discoideum that functions in cell aggregation, and a large cytoplasmic juxtamembrane region. Each protein also contains two immunoglobulin domains. Sequence comparisons show that non-mammalian orthologs of DDRs exist: three closely related genes in Caenorhabditis and one in the sponge Geodia cydonium.


Various types of collagen have been identified as ligands of the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. The interaction with collagen both inhibits fibrillogenesis of collagen and regulates expression of matrix-metalloproteases (MMP), enzymes that cleave native fibrillar collagen (Vogel W., FASEB, 13, S77, 1999; Xu et al, J. Biol. Chem. 280:548-55, 2005; Mihai et al., J. Mol. Biol. 361:864-76, 2006). Collagen directly interacts with the extracellular domains and evokes tyrosine phosphorylation of DDRs in a time and concentration dependent manner. DDRs are structurally different from other receptor tyrosine kinases by a discoidin domain and unlike most other receptor tyrosine kinases they are not fully activated within minutes. The binding of collagen to DDRs results in a delayed but sustained tyrosine kinase activation. The maximal activation occurs several hours after collagen stimulation. DDR2 has a much longer juxta-membrane region with supposed autoinhibitory function. DDR2 is only activated by fibrillar collagens (I-III).


Both receptors, DDR1 and DDR2, display several potential tyrosine phosphorylation sites that are able to relay the activation signal by interacting with cytoplasmic effector proteins (Vogel W., FASEB, 13: 577-582, 1999). DDR2 requires srk kinase to be maximally phosphorylated and to activate the matrix metalloproteinase-2 promoter.


The normal function of DDR2 is largely unknown. DDR2 is known to regulate fibroblast and chondrocyte proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2 (Labrador et al., EMBO Reports 2, 5: 446-452, 2001). DDR2 is induced in hepatic stellate cells in response to collagen during liver injury and overexpression of DDR2 enhanced hepatic stellate cell proliferation, activated expression of MMP-2, and enhanced cellular invasion through Matrigel (Olaso et al., J. Clin. Invest., 108: 1369-1378, 2001). DDR2 activation and adhesion in response to collagen may require Wnt and G-protein signaling (Dejmek et al., Int. J. Cancer 103: 344-351, 2003). The lack of DDR2 expression results in dwarfism in mice, probably due to decreased proliferation of cartilage cells during bone growth (Labrador et al., EMBO Reports 2, 5: 446-452, 2001).


It has been reported that DDR1 is over-expressed in numerous human tumors including breast, ovarian, esophageal and brain cancers and in metastatic cancer cells (Barker et al., Oncogene 11: 569-575, 1995; Laval et al., Cell Growth Diff. 5: 1173-1183, 1994; Nemoto et al., Pathobiol. 65: 165-203, 1997; Weiner et al., Pediatr. Neurosurg. 25: 64-72, 1996; Weiner et al., Neurosurgery 47: 1400-1409, 2000; Heinzelmann et al., 10: 4427-4436, 2004). DDR1 and DDR2 have mutually exclusive expression in ovarian and lung tumors, with transcripts for DDR1 in highly invasive tumor cells and transcripts for DDR2 detected in the surrounding stromal cells (Alves et al., Oncogene 10: 609-618, 1995; Barker et al., Oncogene 11: 569-575, 1995). Furthermore, DDR2 expression is associated with invasive mammary carcinomas (Evitmova et al., 2003, Tumor Biol. 24:189-98). Thus the identification of DDR2 as a marker of cancer stem cells suggests that targeting these receptors may prove therapeutically effective in treating human cancers.


An increase in DDR2 expression has been reported to cause an increase in the expression of matrix metailoproteinase-13 (MMP-13) in mice, a protein that remodels the extracellular matrix by degrading major matrix components. These mice exhibited age-related osteoarthritis-like changes in various joints (Li Y et al., J. Biol. Chem. 2005, 280: 548-555). Activation of DDR2 by collagen was also shown to result in the up-regulation of matrix metalloproteinase-1 (MMP-1) expression.


Thus, DDR2 seems to be directly involved in pathophysiological events in osteoarthritis by regulating cell adhesion, proliferation and extracellular matrix remodeling (repress matrix protein production & increased matrix break down).


The scientific rationale for the use of DDR2 inhibitors for the treatment of osteoarthritis follows the line of evidence starting with chondrocytes, osteoarthritis chondrocytes, cartilage animal explants, animal osteoarthritis models and human osteoarthritis cartilage regarding mRNA and protein expression. The protein expression in humans correlates to the cartilage damage and expression of osteoarthritis markers.


Following steps occur during osteoarthritis pathogenesis: The earliest event is a cartilage injury (cartilage impact) or, in senescence, the loss of growth factor sensitivity of articular chondrocytes. This results in an increased expression or activity of HTRA1 by chondrocytes resulting in a break-down of the pericellular collagen VI rich matrix shielding the DDR2 receptor on the chondrocytes surface. If this shield is lost collagen II fibres or fragments become close to the DDR2 receptor and activate this pathway which results in the release of cytokines and degradative proteases (e.g. MMP13, ADAMTS5) and consequently in cartilage degradation. Thus, The DDR2 receptor is regarded as a key receptor in cartilage injury and osteoarthritis.


Besides cancer and osteoarthritis DDR2 seems to be involved in various other human diseases, in particular atherosclerosis, hepatocirrhosis, inflammation, arthritis, and tissue fibrosis.


The WO2005092896 discloses furopyrimidine compounds as DDR inhibitors for hepatocirrhosis, rheumatism and cancer.


Compounds similar to the compounds of the present invention are disclosed in WO2004037789 and WO2006042599 being described as Tie-2 and cRaf inhibitors and in WO2011017142 being described as Aurora and RON kinase inhibitors, all in particular used for the treatment of cancer.


The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.


The object of the present invention was, in particular, to find novel active compounds and particularly preferably novel DDR2 inhibitors which can be employed for the prevention and treatment of osteoarthritis and have, in particular, high selectivity for DDR2. In addition, the aim was to find novel DDR2 inhibitors which are sufficiently stable, at least on local or intra-articular administration.


SUMMARY OF THE INVENTION

Surprisingly, it has been found that the compounds of formula I according to the invention inhibit DDR2 highly effectively, which plays a crucial role in the development of osteoarthritis. The data show that not only cellular potency can be achieved but also inhibition of pro-MMP13 is observed, which is a biomarker for the initiation and progression of osteoarthritis. It was surprising to find that the compounds of the present invention bearing phenyl or hetero-aromatic rings in the R3 position are strong and selective inhibitors of DDR2 and thus few side effects can be expected. Additionally, it was shown that the potentially genotoxic anilinic moiety can be replaced by amino hetero-aromatic rings. In addition, the compounds according to the invention have adequately good stability in synovial fluid, meaning that they are suitable for intra-articular administration and thus for the treatment of osteoarthritis.


The invention relates to compounds of the formula I,




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in which

  • W is O, N, CH2, CH2CH2, CH2CHOH or —(CH2)O—,
  • X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,
  • V is a single bond or —CR4R5—,
  • M is O or —CR4R5—,
  • R1 is mono- or bicyclic heteroaryl, heterocyclyl or aryl containing 3 to 14 carbon atoms and 1 or 4 heteroatoms, independently selected from N, O and S, which is unsubstituted or mono-, di- or trisubstituted by R6,
  • R2 is H, A, CN, OH, OA or Hal,
  • R3 is mono- or bicyclic heteroaryl, heterocyclyl or aryl containing 3 to 14 carbon atoms and 1 or 4 heteroatoms, independently selected from N, O and S, which is unsubstituted or mono-, di- or trisubstituted by R7,
  • R4, R5 are independently from one another selected from the group consisting of H and A,
  • R2, R6 and R7 are independently from one another selected from the group consisting of H, A, Hal, CH2Hal, CH(Hal)2, C(Hal)3, NO2, (CH2)nCN, (CH2)nNR8R9, (CH2)nO(CH2)kNR8R9, (CH2)nNR8(CH2)kNR8R9, (CH2)nO(CH2)kOR18, (CH2)nNR8(CH2)kOR9, (CH2)nCOOR10, (CH2)nCOR10, (CH2)nCONR8R9, C(O)NHA, C(O)NHANH2(CH2)nNR8COR10, (CH2)nNR8CONR8R9, (CH2)nNR8SO2A, (CH2)nSO2NR8R9, (CH2)nS(O)uR10, (CH2)nOC(O)R10, (CH2)nCOR10, (CH2)nSR8, CH═N—OA, CH2CH═N—OA, (CH2)nNHOA, (CH2)nCH═N—R8, (CH2)nOC(O)NR8R9, (CH2)nNR8COOR10, (CH2)nN(R8)CH2CH2OR10, (CH2)nN(R8)CH2CH2OCF3, (CH2)nN(R8)C(R10)HCOOR9, (CH2)nN(R8)C(R10)HCOR9, (CH2)nN(R8)CH2CH2N(R9)CH2COOR8, (CH2)nN(R8)CH2CH2NR8R9, CH═CHCOOR10, CH═CHCH2NR8R9, CH═CHCH2NR8R9, CH═CHCH2OR10, (CH2)nN(COOR10)COOR11, (CH2)nN(CONH2)COOR10, (CH2)nN(CONH2)CONH2, (CH2)nN(CH2COOR10)COOR11, (CH2)nN(CH2CONH2)COOR10, (CH2)nN(CH2CONH2)CONH2, (CH2)nCHR10COR11, (CH2)nCHR10COOR11, (CH2)nCHR10CH2OR11, (CH2)nOCN and (CH2)nNCO,
  • R8, R9 are independently from one another selected from the group consisting of H, A, (CH2)mAr1 and (CH2)mHet, or in NR8R19R8 and R9 form, together with the N-atom they are bound to, a 5-, 6- or 7-membered heterocyclus which optionally contains 1 or 2 additional hetero atoms, selected from N, O and S,
  • R10, R11 are independently from one another selected from the group consisting of H, Hal, A, (CH2)mAr2 and (CH2)mHet,
  • A is selected from the group consisting of alkyl, alkenyl and cycloalkyl,
  • Ar1, Ar2 are independently from one another aromatic hydrocarbon residues comprising 5 to 12 and preferably 5 to 10 carbon atoms which are optionally substituted by one or more substituents, selected from a group consisting of A, Hal, NO2, CN, OR12, NR12R13, COOR12, CONR12R13, NR12COR13, NR12CONR12R13, NR12SO2A, COR12, SO2R12R13, S(O)uA and OOCR12,
  • Het is a saturated, unsaturated or aromatic mono- or bicyclic heterocyclic residue containing 3 to 14 carbon atoms and 1 or 4 heteroatoms, independently selected from N, O and S, which is optionally substituted by one or more substituents, selected from a group consisting of A, Hal, NO2, CN, OR12, NR12R13, COOR12, CONR12R13, NR12COR13, NR12CONR12R13, NR12SO2A, COR12, SO2R12R12, S(O)uA and OOCR12,
  • R12, R13 are independently from one another selected from the group consisting of H, A, and (CH2)mAr3,
  • Ar3 is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from a group consisting of methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH2 and CF3,
  • k, u, n and m are independently from one another 0, 1, 2, 3, 4, or 5,
  • Hal is independently selected from one another from the group consisting of F, Cl, Br and I,


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


The invention preferably relates to all above-mentioned compounds of the formula I in which

  • R1 is




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which is unsubstituted or monosubstituted by R6,

  • R3 is




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which is unsubstituted or mono-, di- or trisubstituted by R7, and


R6 and R7 independently from one another have the meanings as disclosed above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


The invention preferably relates to all above-mentioned compounds of the formula I in which

  • V is —CR4R5—,
  • R1 is




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which is unsubstituted or monosubstituted by R6,

  • R3 is




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which is unsubstituted or mono-, di- or trisubstituted by R7, and


R6 and R7 independently from one another have the meanings as disclosed above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


The invention preferably relates to all above-mentioned compounds of the formula I in which

  • V is a single bond
  • R1 is




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which is unsubstituted or monosubstituted by R6,

  • R3 is




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which is unsubstituted or mono-, di- or trisubstituted by R7, and


R6 and R7 independently from one another have the meanings as disclosed above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,
  • V is a single bond or —CR4R5—,
  • M is O,
  • R1 is




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which is unsubstituted or monosubstituted by R6,

  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl, and
  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


A particularly preferred embodiment of the present invention are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V is —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or monosubstituted by R6,

  • R2 is H, alkyl with 1 to 5 C-atoms, CN, OH, OA or Hal,
  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl,
  • R6 is H, alkyl, C(O)NHA or C(O)NHANH2,
  • R7 is H, alkyl, cycloalkyl, Hal, CF3, ═O, CN, SA, C(O)A, COOH, CONH2, CONHA, CONA2, CONHANHA, (CH2)nOH, (CH2)nOA, OCH2C(O)OA, O(CH2)nNH2, O(CH2)nNHA, O(CH2)nNA2, O(CH2)nNASO2A, AOH, OAOH, OAC(O)NH2, O(CH2)nheterocyclyl, heterocyclyl, SO2CF3 or OANAC(O)OA and
  • n is 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


A particularly preferred embodiment of the present invention are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or monosubstituted by R6,

  • R2 is H, alkyl with 1 to 5 C-atoms, CN, OH, OA or Hal,
  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl,
  • R6 is H, alkyl, C(O)NHA or C(O)NHANH2,
  • R7 is H, alkyl, cycloalkyl, Hal, CF3, ═O, CN, SA, C(O)A, COOH, CONH2, CONHA, CONA2, CONHANHA, (CH2)nOH, (CH2)nOA, OCH2C(O)OA, O(CH2)nNH2, O(CH2)nNHA, O(CH2)nNA2, O(CH2)nNASO2A, AOH, OAOH, OAC(O)NH2, O(CH2)nheterocyclyl, heterocyclyl, SO2CF3 or OANAC(O)OA and
  • n is 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Very particular preference is given to the following compounds of the formula I selected from the group consisting of

  • a) 4-{4-[3-(3,5-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • b) 4-{4-[3-(2,6-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • c) 4-{4-[(3-Pyridin-2-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • d) 4-{4-[3-(2-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • e) 4-{4-[(3-Pyridin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • f) 4-{4-[3-(2-Chloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • g) 4-{4-[3-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • h) 4-{4-[3-(2,5-Dichloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • i) 4-{4-[(3-Isoquinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • j) 4-{4-[(3-Quinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • k) 4-{4-[3-(2-Methoxy-quinolin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • l) 4-{4-[3-(5-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • m) 4-{2-Methyl-4-[3-(5-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • n) 4-{4-[3-(4-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • o) 4-{2-Methyl-4-[3-(4-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • p) 4-{4-[3-(2-Chloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • q) 4-{4-[3-(6-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • r) 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea
  • s) 4-{4-[3-(2-Methoxy-5-methyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • t) 4-{4-[3-(2-Methoxy-5-methyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • u) 4-{4-[3-(5-Chloro-2-methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • v) 4-{4-[3-(2-Chloro-5-methyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • w) 4-{4-[3-(5-Chloro-2-methoxy-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • x) 4-{4-[3-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • y) 4-{4-[3-(2-Chloro-5-methyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • z) 4-{4-[3-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • aa) 1-(5-Chloro-2-methoxy-pyridin-3-yl)-3-[4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • bb) 1-(5-Chloro-2-methoxy-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • cc) 1-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-3-[4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • dd) 1-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • ee) 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • ff) 1-[3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-3-quinolin-3-yl-urea
  • gg) 1-(2-Methoxy-quinolin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • hh) 1-lsoquinolin-3-yl-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Especially preferred are also compounds of the formula I selected from the group consisting of













No.
Compound (chemical name)
















1
1-(3-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


2
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(2,4,5-trichloro-phenyl)-urea


3
4-{4-[3-(3,4-Dichloro-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


4
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(3-trifluoromethyl-phenyl)-



urea


5
1-(2,4-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


6
1-[4-(Pyridin-4-yloxy)-benzyl]-3-m-tolyl-urea


7
1-(3-Acetyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


8
4-{4-[3-(2,4-Dichloro-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


9
1-(4-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


10
1-(2,5-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


11
1-(4-Fluoro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


12
4-{4-[3-(4-Fluoro-phenyl)-ureidomethyl]-phenoxy}-pyridine-



2-carboxylic acid methylamide


13
1-(2,3-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


14
4-{4-[3-(2-Methoxy-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


15
1-(2,5-Dimethoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


16
1-(4-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


17
1-(4-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


18
1-[4-(Pyridin-4-yloxy)-benzyl]-3-p-tolyl-urea


19
4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


20
4-{4-[3-(2,5-Dimethoxy-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


21
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(4-trifluoromethyl-phenyl)-



urea


22
1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


23
4-{4-[3-(2,4,5-Trichloro-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


24
1-(2,3-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


25
1-(2,5-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


26
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(2-trifluoromethyl-phenyl)-



urea


27
1-(3-Chloro-4-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


28
1-(2-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


29
1-[4-(Pyridin-4-yloxy)-benzyl]-3-o-tolyl-urea


30
1-(2,4-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


31
4-{4-[3-(3,5-Dichloro-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


32
1-(5-Chloro-2-methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


33
1-(2-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


34
1-(3-Methylsulfanyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


35
1-(4-Bromo-2-chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


36
1-(2-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


37
1-(2-Chloro-4-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


38
1-(3,4-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


39
4-{4-[3-(3-Chloro-4-methoxy-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


40
1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


41
1-(4-Ethoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


42
4-{4-[3-(5-Chloro-2-methyl-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


43
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


44
1-(3,5-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


45
1-(3-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


46
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


47
1-(4-Acetyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


48
1-(2-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


49
1-(4-Isopropyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


50
1-(5-Chloro-2-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


51
1-(4-Methylsulfanyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


52
1-(4-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


53
1-(3-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


54
1-(4-Chloro-2-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


55
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(4-trifluoromethoxy-phenyl)-



urea


56
1-(4-tert-Butyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


57
1-(3,5-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


58
1-(4-Bromo-3-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-



urea


59
1-(3,4-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


60
1-(3-Chloro-4-methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


61
1-(3-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea


62
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(pyridin-4-



yloxy)-benzyl]-urea


63
4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


64
1-(4-Bromo-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-



benzyl]-urea


65
1-[4-(Pyridin-4-yloxy)-benzyl]-3-(3-trifluoromethoxy-phenyl)-



urea


66
4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


67
4-{4-[3-(4-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


68
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{1-[4-(pyridin-4-



yloxy)-phenyl]-cyclopropyl}-urea


69
4-(4-{1-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureido]-



ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide


70
4-(4-{1-[3-(2,4,5-Trichloro-phenyl)-ureido]-ethyl}-phenoxy)-



pyridine-2-carboxylic acid methylamide


71
4-(4-{1-[3-(3,4-Dichloro-phenyl)-ureido]-ethyl}-phenoxy)-



pyridine-2-carboxylic acid methylamide


72
4-(4-{1-[3-(5-Chloro-2-methoxy-phenyl)-ureido]-ethyl}-



phenoxy)-pyridine-2-carboxylic acid methylamide


73
4-(4-{1-[3-(3-Chloro-4-methyl-phenyl)-ureido]-ethyl}-



phenoxy)-pyridine-2-carboxylic acid methylamide


74
4-{4-[3-(4-Chloro-3-methyl-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


75
4-{4-[3-(2-Methoxy-5-methyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


76
4-{4-[(3-Benzo[1,2,5]thiadiazol-5-yl-ureido)-methyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


77
4-(4-{3-[2-(2-Dimethylamino-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


78
4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


79
4-{4-[3-(4-Chloro-2-methoxy-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


80
4-{4-[3-(3,4,5-Trimethoxy-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


81
4-{4-[3-(2,5-Dimethoxy-4-nitro-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


82
3-Methoxy-4-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-benzoic acid methyl ester


83
4-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


84
4-{4-[3-(3,5-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


85
4-{4-[(3-Pyridin-2-yl-ureido)-methyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


86
4-(4-{3-[2-(3-Dimethylamino-propoxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


87
4-{4-[3-(2-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


88
4-{4-[(3-Pyridin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


89
4-{4-[3-(2-Chloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


90
4-{4-[(3-Pyridin-4-yl-ureido)-methyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


91
4-{4-[3-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


92
(2-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-



ureido}-4-trifluoromethyl-phenoxy)-acetic acid methyl ester


93
4-{4-[3-(2,5-Dichloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


94
(2-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-



ureido}-4-trifluoromethyl-phenoxy)-acetic acid


95
4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


96
4-{4-[(3-Isoquinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-



2-carboxylic acid methylamide


97
4-{4-[(3-Quinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


98
(5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid


99
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid


100
4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-2-



methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


101
4-{4-[3-(2-Methoxy-quinolin-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


102
4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-



2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


103
4-{4-[3-(2,4-Dichloro-6-methoxy-3-methyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


104
4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-3-



methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


105
4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-



3-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


106
4-(4-{3-[2-(2-Pyrrolidin-1-yl-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


107
(5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid tert-



butyl ester


108
4-(4-{3-[2-(2-Diethylamino-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


109
4-(4-{3-[2-(2-Morpholin-4-yl-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


110
4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


111
4-(4-{3-[2-(2-Methylamino-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


112
4-(4-{3-[2-(2-Piperazin-1-yl-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


113
(5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid



methyl ester


114
(5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid



isopropyl ester


115
4-(4-{3-[2-(Piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


116
4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


117
4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


118
4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


119
4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


120
4-(4-{3-[4-Chloro-5-methyl-2-(2-piperazin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


121
4-(4-{3-[2-(2-Amino-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


122
4-{4-[3-(2-Piperazin-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


123
4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid (2-



amino-ethyl)-amide


124
4-(4-{3-[4-Chloro-5-methyl-2-(piperidin-4-yloxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


125
4-(4-{3-[4-Chloro-5-methyl-2-(2-methylamino-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


126
4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid (6-



amino-hexyl)-amide


127
4-(4-{3-[4-Chloro-2-(2-methylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


128
4-(4-{3-[4-Chloro-2-(2-piperazin-1-yl-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


129
4-(4-{3-[4-Chloro-2-(2-pyrrolidin-1-yl-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


130
4-(4-{3-[4-Chloro-2-(piperidin-4-yloxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


131
4-(4-{3-[4-Chloro-2-(2-morpholin-4-yl-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


132
4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


133
4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-



phenyl]-ureidomethyl}-3-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


134
4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-3-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


135
4-{4-[3-(3-Methanesulfonyl-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


136
4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-methyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


137
4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


138
4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


139
4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


140
4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


141
4-(4-{3-[4-Chloro-5-methyl-2-(2-methylamino-ethoxy)-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


142
4-(4-{3-[4-Chloro-5-methyl-2-(piperidin-4-yloxy)-phenyl]-



ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid



methylamide


143
4-(4-{3-[4-Chloro-5-methyl-2-(2-piperazin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


144
4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-methyl-phenyl]-



ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid



methylamide


145
4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-methyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


146
4-(2-Methyl-4-{3-[2-(2-methylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


147
4-(4-{3-[4-Chloro-2-(2-methylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-



pyridine-2-carboxylic acid methylamide


148
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid (2-amino-ethyl)-amide


149
4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid (2-methylamino-ethyl)-



amide


150
4-(4-{3-[2-(2-Dimethylamino-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


151
4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


152
4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-



pyridine-2-carboxylic acid methylamide


153
4-(4-{3-[4-Chloro-2-(3-dimethylamino-propoxy)-5-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


154
4-{4-[3-(3-Methanesulfonyl-phenyl)-ureidomethyl]-2-methyl-



phenoxy}-pyridine-2-carboxylic acid methylamide


155
4-(4-{3-[2-(2-Amino-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid



methylamide


156
4-(4-{3-[2-(Pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


157
4-{4-[3-(3-Sulfamoyl-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


158
4-{4-[3-(3-Isopropylsulfamoyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


159
4-(4-{3-[5-Methyl-2-(piperidin-4-yloxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


160
4-(4-{3-[2-(2-Amino-2-methyl-propoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


161
4-(4-{3-[4-Chloro-2-(4-dimethylamino-butoxy)-5-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


162
4-[4-(3-{4-Chloro-2-[(2-dimethylamino-ethyl)-methyl-amino]-



5-methyl-phenyl}-ureidomethyl)-phenoxy]-pyridine-2-



carboxylic acid methylamide


163
4-(4-{3-[4-Chloro-2-(3-dimethylamino-propoxy)-5-methyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


164
4-[4-(3-{4-Chloro-2-[(2-dimethylamino-ethyl)-methyl-amino]-



5-methyl-phenyl}-ureidomethyl)-2-methyl-phenoxy]-pyridine-



2-carboxylic acid methylamide


165
4-(4-{3-[4-Chloro-2-(4-dimethylamino-butoxy)-5-methyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-



carboxylic acid methylamide


166
4-(4-{3-[2-(2-Methoxy-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


167
4-{4-[3-(3-Methanesulfonylamino-phenyl)-ureidomethyl]-2-



methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


168
4-(4-{3-[2-(2-Methoxy-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid



methylamide


169
4-(4-{3-[2-(2-Methylamino-ethoxy)-phenyl]-ureidomethyl}-



phenoxy)-pyridine-2-carboxylic acid methylamide


170
4-(4-{3-[5-Methyl-2-(2-methylamino-ethoxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


171
4-(2-Methyl-4-{3-[5-methyl-2-(piperidin-4-yloxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


172
4-(4-{3-[2-(2-Isopropylamino-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


173
4-(4-{3-[5-Chloro-4-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


174
4-(4-{3-[5-Chloro-2-(2-dimethylamino-ethoxy)-4-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


175
4-(4-{3-[2-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


176
4-(4-{3-[2-(2-Amino-ethoxy)-5-chloro-4-methyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


177
4-(4-{3-[5-Chloro-4-methyl-2-(2-methylamino-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


178
4-(4-{3-[5-Chloro-4-methyl-2-(piperidin-4-yloxy)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


179
4-(4-{3-[5-Chloro-4-methyl-2-(2-piperazin-1-yl-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


180
4-(4-{3-[2-(2-Methanesulfonylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


181
4-{4-[(3-Phenyl-ureido)-methyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


182
4-(4-{3-[5-Chloro-4-methyl-2-(pyrrolidin-2-ylmethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


183
4-(4-{3-[5-Chloro-2-(2-isopropylamino-ethoxy)-4-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


184
4-{2-Methyl-4-[3-(2-piperazin-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


185
4-(4-{3-[2-(2-Amino-2-methyl-propoxy)-5-chloro-4-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


186
4-{4-[3-(2-Acetylamino-4-chloro-5-methyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


187
4-[4-(3-{4-Chloro-5-methyl-2-[2-(2,2,2-trifluoro-acetylamino)-



ethoxy]-phenyl}-ureidomethyl)-phenoxy]-pyridine-2-



carboxylic acid methylamide


188
4-(4-{3-[2-(2-Methylamino-ethoxy)-5-



trifluoromethanesulfonyl-phenyl]-ureidomethyl}-phenoxy)-



pyridine-2-carboxylic acid methylamide


189
4-(2-Methyl-4-{3-[2-(2-methylamino-ethoxy)-5-



trifluoromethanesulfonyl-phenyl]-ureidomethyl}-phenoxy)-



pyridine-2-carboxylic acid methylamide


190
4-{4-[3-(2-Carbamoylmethoxy-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


191
4-(4-{3-[2-(3-Amino-propoxy)-4-chloro-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


192
4-{4-[3-(2-Piperazin-1-ylmethyl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


193
4-(4-{3-[4-Chloro-2-(2-methanesulfonylamino-ethoxy)-5-



methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


194
4-(4-{3-[4-Chloro-2-(2-methanesulfonylamino-ethoxy)-5-



trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-



carboxylic acid methylamide


195
4-(4-{3-[2-(2-Hydroxy-ethyl)-phenyl]-ureidomethyl}-2-



methyl-phenoxy)-pyridine-2-carboxylic acid methylamide


196
4-{4-[3-(2-Hydroxymethyl-4-methyl-phenyl)-ureidomethyl]-2-



methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


197
4-(4-{3-[2-(2-Hydroxy-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


198
4-{4-[3-(2-Hydroxymethyl-phenyl)-ureidomethyl]-2-methyl-



phenoxy}-pyridine-2-carboxylic acid methylamide


199
4-(4-{3-[2-(1 -Carbamoyl-1-methyl-ethoxy)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


200
4-{2-Methyl-4-[3-(2-methylcarbamoylmethyl-5-



trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-



carboxylic acid methylamide


201
4-{4-[3-(2-[1,2,4]Triazol-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


202
4-{2-Methyl-4-[3-(2-[1,2,4]triazol-1-yl-5-trifluoromethyl-



phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


203
4-{2-Methyl-4-[3-(2-[1,2,3]triazol-1-yl-5-trifluoromethyl-



phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


204
4-{4-[3-(2-Hydroxy-5-trifluoromethyl-phenyl)-ureidomethyl]-



2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


205
2-Oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid



4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzylamide


206
4-{4-[3-(2-[1,2,3]Triazol-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


207
4-{4-[3-(2-Carbamoylmethyl-5-trifluoromethyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


208
4-(4-{3-[2-(2-Oxo-piperazin-1-ylmethyl)-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


209
4-{4-[3-(2-Carbamoylmethyl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


210
4-{4-[3-(5-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


211
4-{2-Methyl-4-[3-(5-methyl-pyridin-2-yl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


212
4-{4-[3-(4-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


213
4-{2-Methyl-4-[3-(4-methyl-pyridin-2-yl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


214
4-(4-{3-[2-(Acetylamino-methyl)-5-trifluoromethyl-phenyl]-



ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid



methylamide


215
4-(2-Methyl-4-{3-[5-methyl-2-(2-methylamino-ethoxy)-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


216
4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-



ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid



methylamide


217
4-{2-Fluoro-4-[3-(2-methoxy-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


218
4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-



ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid



methylamide


219
4-{4-[3-(4-Chloro-5-methyl-2-pyrrol-1-yl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


220
(2-{3-[3-Methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-



benzyl]-ureido}-4-trifluoromethyl-phenyl)-acetic acid


221
4-{4-[3-(2-Aminomethyl-5-trifluoromethyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


222
4-{4-[3-(5-Trifluoromethyl-[1,3,4]thiadiazol-2-yl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


223
4-{4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


224
4-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


225
4-(4-{3-[3-Chloro-4-(3-oxo-morpholin-4-yl)-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


226
4-{4-[3-(2-Chloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


227
4-{4-[3-(6-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


228
4-{4-[3-(3-Dimethylamino-phenyl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


229
4-{4-[3-(2-Ethoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-2-



methyl-phenoxy}-pyridine-2-carboxylic acid methylamide


230
4-{4-[3-(2-Ethoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


231
4-{4-[3-(4-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-



ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid



methylamide


232
4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-2-fluoro-



phenoxy}-pyridine-2-carboxylic acid methylamide


233
4-{2-Fluoro-4-[3-(3-trifluoromethyl-phenyl)-ureidomethyl]-



phenoxy}-pyridine-2-carboxylic acid methylamide


234
4-{4-[3-(3-Chloro-4-methyl-phenyl)-ureidomethyl]-2-fluoro-



phenoxy}-pyridine-2-carboxylic acid methylamide


235
4-{2-Fluoro-4-[3-(2-[1,2,4]triazol-1-yl-5-trifluoromethyl-



phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


236
4-{4-[3-(5-Methyl-isoxazol-3-yl)-ureidomethyl]-phenoxy}-



pyridine-2-carboxylic acid methylamide


237
4-(4-{3-[2-(2-Acetylamino-ethoxy)-4-chloro-5-methyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


238
4-(4-{3-[2-(2-Acetylamino-ethoxy)-4-chloro-5-trifluoromethyl-



phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


239
4-(4-{3-[2-(2-Acetylamino-ethoxy)-5-trifluoromethyl-phenyl]-



ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid



methylamide


240
4-{4-[3-(2-Imidazol-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid



methylamide


241
4-{4-[3-(4-Acetylamino-3-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


242
4-[4-(3-{4-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-



ethoxy]-5-trifluoromethyl-phenyl}-ureidomethyl)-phenoxy]-



pyridine-2-carboxylic acid methylamide


243
4-{4-[3-(2-Imidazol-1-yl-5-trifluoromethyl-phenyl)-



ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid



methylamide


244
[2-(5-Chloro-4-methyl-2-{3-[4-(2-methylcarbamoyl-pyridin-4-



yloxy)-benzyl]-ureido}-phenoxy)-ethyl]-methyl-carbamic acid



tert-butyl ester


245
1-Phenyl-3-[4-(pyridin-4-yloxy)-benzyl]-urea


246
1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-



[3-methyl-4-(pyridin-4-yloxy)-benzyl]-urea


247
N-[4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-



phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridin-2-yl]-



acetamide


248
1-(4-Chloro-2-methoxy-5-methyl-phenyl)-3-[3-methyl-4-



(pyridin-4-yloxy)-benzyl]-urea


249
1-[4-(2-Methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-3-phenyl-



urea


250
1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-



[3-methyl-4-(pyrimidin-4-yloxy)-benzyl]-urea


251
1-[4-(6-Amino-pyrimidin-4-yloxy)-3-methyl-benzyl]-3-[4-



chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-urea


252
1-(4-Chloro-2-methoxy-5-methyl-phenyl)-3-[3-methyl-4-(2-



methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-urea


253
1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-



[3-methyl-4-(2-methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-



urea


254
1-[4-(2-Amino-pyridin-4-yloxy)-3-methyl-benzyl]-3-[4-chloro-



2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-urea


255
4-[4-[[4-chloro-3-(trifluoromethyl)-phenyl]carbamoylamino]



phenoxy]-N-methyl-pyridine-2-carboxamide










and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,
  • V is a single bond or —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or monosubstituted by R6,

  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7, and

  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


A particularly preferred embodiment of the present invention are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V is a single bond or —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R2 is H, A, CN, OH, OA or Hal,
  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are H,
  • R6 is H, A, ═O, CN, CF3, Hal, COOH, C(O)NH2, C(O)NHA, C(O)NA2, (CH2)nOH, (CH2)nOA, (CH2)naryl, (CH2)n heteroaryl or (CH2)nheterocyclyl,
  • R7 is H, A, ═O, CN, CH2)nOH, (CH2)nOA, CF3, Hal, COOH, (CH2)naryl, (CH2)n heteroaryl or (CH2)nheterocyclyl,
  • A is alkyl, and
  • n is 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


A particularly preferred embodiment of the present invention are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V is a single bond or —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R2 is H, A, CN, OH, OA or Hal,
  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are H,
  • R6 is H, alkyl, cycloalkyl, ═O, CF3, CN, (CH2)nOH, (CH2)nOA, Hal, COOH, C(O)NH2or C(O)NHA,
  • R7 is H, ═O, A, CN, (CH2)nOH, (CH2)nOA, (CH2)naryl, Hal or CF3,
  • A is alkyl, and
  • n is 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Particularly preferred are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V —CR4R5—,
  • M is O,
  • R1 and R6 together are




embedded image


  • R2 is H or alkyl with 1 to 5 C-atoms,

  • R3 and R7 together are





embedded image


  • R4, R5 are H and

  • n 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.



Particularly preferred are compounds of the formula I in which

  • W is N,
  • X, Y, Q, U, T are C,
  • V a single bond,
  • M is O,
  • R1 and R6 together are




embedded image


  • R2 is H or alkyl with 1 to 5 C-atoms,

  • R3 and R7 together are





embedded image


  • R4, R5 are H and

  • n 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.



Very particular preference is given to the following compounds of the formula I selected from the group consisting of

  • a) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzyl]-urea
  • b) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(6-trifluoromethyl-quinolin-4-yloxy)-benzyl]-urea
  • c) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzyl]-urea
  • d) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-([1,8]naphthyridin-4-yloxy)-benzyl]-urea
  • e) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-benzyl]-urea
  • f) 1-[3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-urea
  • g) 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • h) 4-{4-[3-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • i) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(quinolin-4-yloxy)-benzyl]-urea
  • j) 1-[3-Methyl-4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-benzyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-urea
  • k) 4-{4-[3-(1-Ethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • l) 4-{4-[3-(1-Benzyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • m) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(3-trifluoromethyl-pyridin-4-yloxy)-benzyl]-urea
  • n) 4-{4-[3-(1-Hydroxymethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • o) (3-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-2-oxo-5-trifluoro-methyl-2H-pyridin-1-yl)-acetic acid
  • p) 4-{4-[3-(1-Aminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • q) 4-{4-[3-(1-Methylaminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • r) 4-{4-[3-(1-Dimethylaminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is O,
  • X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,
  • V a single bond or —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl, and
  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is O,
  • X, Y, Q, U, T are C,
  • V a single bond or —CR4R5—,
  • M is O,
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl, and
  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Particularly preferred are compounds of the formula I in which

  • W is O,
  • X, Y, Q, U, T are C,
  • V —CR4R5—,
  • M is O,
  • R1 and R6 together are




embedded image


  • R2 is H or alkyl with 1 to 5 C-atoms,

  • R3 is





embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are H,
  • R7 alkyl with 1-5 C-atoms, CN, OH, OA, Hal or CF3

    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Particularly preferred are compounds of the formula I in which

  • W is O,
  • X, Y, Q, U, T are C,
  • V a single bond,
  • M is O,
  • R1 and R6 together are




embedded image


  • R2 is H or alkyl with 1 to 5 C-atoms,

  • R3 is





embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are H,
  • R7 alkyl with 1-5 C-atoms, CN, OH, OA, Hal or CF3

    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Very particular preference is given to the following compounds of the formula I selected from the group consisting of

  • a) (2-Hydroxy-5-trifluoromethyl-pyridin-3-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester
  • b) (2-Hydroxy-5-methyl-pyridin-3-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester
  • c) (4-Trifluoromethyl-pyridin-2-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester
  • d) (4-Trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester
  • e) (2-Hydroxy-5-trifluoromethyl-pyridin-3-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester
  • f) (4-Chloro-3-trifluoromethyl-phenyl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W N,
  • X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,
  • V is a single bond,
  • M is O
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl, and
  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W N,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is —CR4R5—,
  • R1 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R2 is H, A, CN, OH, OA or Hal,


R3 is




embedded image


which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are independently from one another selected from the group consisting of H, alkyl and cycloalkyl, and
  • R6, R7 are independently from one another selected from the group consisting of H, alkyl with 1-5 C-atoms, ═O, CN, Hal, CF3, OH, OA, COOH, C(O)NH2 and C(O)NHA,


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Particularly preferred are compounds of the formula I in which

  • W N,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is —CR4R5—,
  • R1 and R6 together are




embedded image


  • R2 is H,

  • R3 is





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which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R4, R5 are H,
  • R7 is H, alkyl with 1-5 C-atoms, ═O, CF3, OH, OA or Hal,


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Very particular preference is given to the following compounds of the formula I selected from the group consisting of

  • a) 1-[4-(4-Oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea
  • b) 1-[4-(3-Methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-urea
  • c) 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(3-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea
  • d) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea
  • e) 1-(5-Methyl-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is CH2, CH2CH2, CH2CHOH or —(CH2)O—,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is O,
  • R1 is




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which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R3 is




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which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R2, R6 and R7 independently from one another have the meanings as disclosed above


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is CH2, CH2CH2, CH2CHOH or —(CH2)O—,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is O,
  • R1 is




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which is unsubstituted or mono-, di- or trisubstituted by R6,

  • R2 is H or alkyl with 1-5 C-atoms,
  • R3 is




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which is unsubstituted or mono-, di- or trisubstituted by R7,

  • R6 is H, alkyl, cycloalkyl, ═O, CF3, CN, (CH2)nOH, (CH2)nOA, Hal, COOH, C(O)NH2 or C(O)NHA,
  • R7 is H, ═O, A, CN, (CH2)nOH, (CH2)nOA, Hal or CF3,
  • A is alkyl, and
  • n is 0-3


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Another preferred embodiment of the present invention preferably are compounds of the formula I in which

  • W is CH2, CH2CH2, CH2CHOH or —(CH2)O—,
  • X, Y, Q, U, T are C,
  • V is a single bond,
  • M is O,
  • R1 and R6 together are




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  • R2 is H or alkyl with 1-5 C-atoms, and

  • R3 and R7 together are





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and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


Very particular preference is given to the following compounds of the formula I selected from the group consisting of

  • a) 4-{4-[(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • b) 4-{4-[2-(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-1-hydroxy-ethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • c) 4-{4-[2-(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-ethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • d) 4-{4-[(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-ylcarbamoyl)-methoxy]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • e) N-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-2-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenoxy]-acetamide
  • f) N-(2-Fluoro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenoxy]-acetamide
  • g) N-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-2-[4-(quinolin-4-yloxy)-phenoxy]-acetamide
  • h) 2-[4-(3a,7a-Dihydro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenoxy]-N-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-acetamide
  • i) 4-{4-[(2-Hydroxy-5-trifluoromethyl-pyridin-3-ylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide
  • j) 4-{2-Methyl-4-[(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-ylcarbamoyl)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • k) 2-[3-Methyl-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenyl]-N-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-acetamide
  • l) N-(2-Fluoro-5-trifluoromethyl-phenyl)-2-[3-methyl-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenyl]-acetamide


    and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.


If the above-mentioned amino acids can occur in a plurality of enantiomeric forms, all these forms and also mixtures thereof (for example DL forms) are included above and below.


Furthermore, the abbreviations have the following meanings:


Boc tert-butoxycarbonyl


CBZ benzyloxycarbonyl


DNP 2,4-dinitrophenyl


FMOC 9-fluorenylmethoxycarbonyl


imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring


OMe methyl ester


POA phenoxyacetyl


DCCI dicyclohexylcarbodiimide


HOBt 1-hydroxybenzotriazole


Hal denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.


A is an unbranched (linear), branched or cyclic hydrocarbon chain and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl or decyl.


Cyclic alkyl or cycloalkyl preferably denotes (if A is cyclic it denotes) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.


Additionally, A denotes also alkenyl such as ethenyl, propylenyl, butenyl and the like.


“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. Especially preferred is C1-C5alkyl. A C1-C5alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl.


“Aryl”, Ar” or “aromatic hydrocarbon residue” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Examples of “aryl” groups include, but are not limited to Phenyl, 2-naphthyl, 1-naphthyl, biphenyl, indanyl as well as substituted derivatives thereof. The most preferred aryl is phenyl.


“Heterocycle” and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O. S and N. further including the oxidized forms of sulfur, namely SO and SO2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.


“Heteroaryl” means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O. S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoxazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzdioxinyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, thiophenyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 atoms are included, forming 1-3 rings.


All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.


The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.


Compounds of the formula I according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms. They may therefore be in racemic or optically active form. Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product, but also even the intermediates, may be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or already employed as such in the synthesis.


Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug compounds are taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.


Suitable acid-addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.


Solvates of the compounds of the formula I are taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force. Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol.


The invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. They are particularly preferably mixtures of two stereoisomeric compounds.


Another embodiment of the present invention is a process for the preparation of the compounds of the formula I, characterized in that the compounds are prepared by stepwise reactions of building blocks (see example 2).


It is possible to carry out the reactions stepwise in each case and to modify the sequence of the linking reactions of the building blocks with adaptation of the protecting-group concept.


The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.


If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I.


The compounds of the formula I are preferably obtained by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis, or by hydrogenolysis. Preferred starting materials for the solvolysis or hydrogenolysis are those which contain correspondingly protected amino, carboxyl and/or hydroxyl groups instead of one or more free amino, carboxyl and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom which is connected to an N atom. Preference is furthermore given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group. Preference is also given to starting materials which carry a protected carboxyl group instead of a free carboxyl group. It is also possible for a plurality of identical or different protected amino, carboxyl and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.


The functional derivatives of the compounds of the formula I to be used as starting materials can be prepared by known methods of amino-acid and peptide synthesis, as described, for example, in the said standard works and patent applications.


The compounds of the formula I are liberated from their functional derivatives, depending on the protecting group used, for example, with the aid of strong acids, advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid, or sulfonic acids, such as benzoyl- or p-toluenesulfonic acid. The presence of an additional inert solvent and/or a catalyst is possible, but is not always necessary.


Depending on the respective synthetic route, the starting materials can optionally be reacted in the presence of an inert solvent.


Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether (preferably for substitution on the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; esters, such as ethyl acetate, carboxylic acids or acid anhydrides, such as, for example, acetic acid or acetic anhydride, nitro compounds, such as nitromethane or nitrobenzene, optionally also mixtures of the said solvents with one another or mixtures with water.


The amount of solvent is not crucial; 10 g to 500 g of solvent can preferably be added per g of the compound of the formula I to be reacted.


It may be advantageous to add an acid-binding agent, for example an alkali or alkaline-earth metal hydroxide, carbonate or bicarbonate or other alkali or alkaline-earth metal salts of weak acids, preferably a potassium, sodium or calcium salt, or to add an organic base, such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.


The resultant compounds according to the invention can be separated from the corresponding solution in which they are prepared (for example by centrifugation and washing) and can be stored in another composition after separation, or they can remain directly in the preparation solution. The resultant compounds according to the invention can also be taken up in desired solvents for the particular use.


Suitable reaction temperatures are temperatures from 0 to 40° C., preferably 5 to 25° C.


The reaction duration depends on the reaction conditions selected. In general, the reaction duration is 0.5 hour to 10 days, preferably 1 to 24 hours.


On use of a microwave, the reaction time can be reduced to values of 1 to 60 minutes.


The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by known methods, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se, which are not described here in greater detail.


Conventional work-up steps, such as, for example, addition of water to the reaction mixture and extraction, enable the compounds to be obtained after removal of the solvent. It may be advantageous, for further purification of the product, to follow this with a distillation or crystallisation or to carry out a chromatographic purification.


Another embodiment of the present invention is a process for the preparation of the compounds of the formula I, characterized in that

  • a) the base of a compound of the formula I is converted into one of its salts by treatment with an acid, or
  • b) an acid of a compound of the formula I is converted into one of its salts by treatment with a base.


An acid of the formula I can be converted into the associated addition salt using a base, for example by reaction of equivalent amounts of the acid and base in an inert solvent, such as ethanol, and subsequent evaporation. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts. Thus, the acid of the formula I can be converted into the corresponding metal salt, in particular alkali or alkaline-earth metal salt, using a base (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or into the corresponding ammonium salt. Organic bases which give physiologically acceptable salts, such as, for example, ethanolamine, are also suitable for this reaction.


On the other hand, a base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and acid in an inert solvent, such as ethanol, with subsequent evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.


It has been found that the compounds of the formula I are well tolerated and have valuable pharmacological properties, since they selectively inhibit DDR2.


The invention therefore furthermore relates to the use of compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are caused, promoted and/or propagated by DDR2 and/or by DDR2-promoted signal transduction.


The invention thus also relates, in particular, to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states.


Particular preference is given, in particular, to physiological and/or pathophysiological states which are connected to DDR2.


Physiological and/or pathophysiological states are taken to mean physiological and/or pathophysiological states which are medically relevant, such as, for example, diseases or illnesses and medical disorders, complaints, symptoms or complications and the like, in particular diseases.


The invention furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of osteoarthritis, hepatocirrhosis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.


An especially preferred embodiment of the present invention is a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of osteoarthritis and pain.


The invention furthermore relates to a medicament comprising at least one compound according to the invention and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of Alzheimer's disease, Huntington's disease, mucolipidosis, contact dermatitis, late-onset hypersensitivity reaction, inflammation, endometriosis, scarring, rickets, skin diseases, such as, for example, psoriasis, immunological diseases, autoimmune diseases and immunodeficiency diseases.


Pain is a complex sensory perception which, as an acute event, has the character of a warning and control signal, but as chronic pain has lost this and in this case (as chronic pain syndrome) should be regarded and treated today as an independent syndrome. Hyperalgesia is the term used in medicine for excessive sensitivity to pain and reaction to a stimulus which is usually painful. Stimuli which can trigger pain are, for example, pressure, heat, cold or inflammation. Hyperalgesia is a form of hyperaesthesia, the generic term for excessive sensitivity to a stimulus. Allodynia is the term used in medicine for the sensation of pain which is triggered by stimuli which do not usually cause pain.


It is intended that the medicaments disclosed above include a corresponding use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states.


It is additionally intended that the medicaments disclosed above include a corresponding method for the treatment and/or prophylaxis of the above physiological and/or pathophysiological states in which at least one compound according to the invention is administered to a patient in need of such a treatment.


The compounds according to the invention preferably exhibit an advantageous biological activity which can easily be demonstrated in enzyme assays and animal experiments, as described in the examples. In such enzyme-based assays, the compounds according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.


The compounds according to the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in the combating of the above-mentioned diseases. They can furthermore be used as diagnostic agents or as reagents.


Furthermore, compounds according to the invention can be used for the isolation and investigation of the activity or expression of DDR2. In addition, they are particularly suitable for use in diagnostic methods for diseases in connection with disturbed DDR2 activity. The invention therefore furthermore relates to the use of the compounds according to the invention for the isolation and investigation of the activity or expression of DDR2 or as binders and inhibitors of DDR2.


For diagnostic purposes, the compounds according to the invention can, for example, be radioactively labelled. Examples of radioactive labels are 3H, 14C, 231I and 125I. A preferred labelling method is the iodogen method (Fraker et al., 1978). In addition, the compounds according to the invention can be labelled by enzymes, fluorophores and chemophores. Examples of enzymes are alkaline phosphatase, β-galactosidase and glucose oxidase, an example of a fluorophore is fluorescein, an example of a chemophore is luminol, and automated detection systems, for example for fluorescent colorations, are described, for example, in U.S. Pat. No. 4,125,828 and U.S. Pat. No. 4,207,554.


The compounds of the formula I can be used for the preparation of pharmaceutical compositions, in particular by non-chemical methods. In this case, they are brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and optionally in combination with one or more further active ingredient(s).


The invention therefore furthermore relates to pharmaceutical compositions comprising at least one compound of the formula I and/or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios. In particular, the invention also relates to pharmaceutical compositions which comprise further excipients and/or adjuvants, and also to pharmaceutical compositions which comprise at least one further medicament active ingredient.


In particular, the invention also relates to a process for the preparation of a pharmaceutical composition, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and optionally with a further medicament active ingredient.


The pharmaceutical compositions according to the invention can be used as medicaments in human or veterinary medicine. The patient or host can belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model for the treatment of a human disease.


Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils (such as sunflower oil or cod-liver oil), benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin or Vaseline. Owing to his expert knowledge, the person skilled in the art is familiar with which adjuvants are suitable for the desired medicament formulation. Besides solvents, for example water, physiological saline solution or alcohols, such as, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose or mannitol solutions, or a mixture of the said solvents, gel formers, tablet assistants and other active-ingredient carriers, it is also possible to use, for example, lubricants, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, antioxidants, dispersants, antifoams, buffer substances, flavours and/or aromas or flavour correctants, preservatives, solubilisers or dyes. If desired, compositions or medicaments according to the invention may comprise one or more further active ingredients, for example one or more vitamins.


The terms “pharmaceutical formulation” and “pharmaceutical composition” are used as synonyms for the purposes of the present invention.


As used here, “pharmaceutically tolerated” relates to medicaments, precipitation reagents, excipients, adjuvants, stabilisers, solvents and other agents which facilitate the administration of the pharmaceutical compositions obtained therefrom to a mammal without undesired physiological side effects, such as, for example, nausea, dizziness, digestion problems or the like.


In pharmaceutical compositions for parenteral administration, there is a requirement for isotonicity, euhydration and tolerability and safety of the formulation (low toxicity), of the adjuvants employed and of the primary packaging. Surprisingly, the compounds according to the invention preferably have the advantage that direct use is possible and further purification steps for the removal of toxicologically unacceptable agents, such as, for example, high concentrations of organic solvents or other toxicologically unacceptable adjuvants, are thus unnecessary before use of the compounds according to the invention in pharmaceutical formulations.


The invention particularly preferably also relates to pharmaceutical compositions comprising at least one compound according to the invention in precipitated non-crystalline, precipitated crystalline or in dissolved or suspended form, and optionally excipients and/or adjuvants and/or further pharmaceutical active ingredients.


The solid compounds according to the invention preferably enable the preparation of highly concentrated formulations without unfavourable, undesired aggregation of the compounds according to the invention occurring. Thus, ready-to-use solutions having a high active-ingredient content can be prepared with the aid of compounds according to the invention with aqueous solvents or in aqueous media.


The compounds and/or physiologically acceptable salts and solvates thereof can also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.


Aqueous compositions can be prepared by dissolving or suspending compounds according to the invention in an aqueous solution and optionally adding adjuvants. To this end, defined volumes of stock solutions comprising the said further adjuvants in defined concentration are advantageously added to a solution or suspension having a defined concentration of compounds according to the invention, and the mixture is optionally diluted with water to the pre-calculated concentration. Alternatively, the adjuvants can be added in solid form. The amounts of stock solutions and/or water which are necessary in each case can subsequently be added to the aqueous solution or suspension obtained. Compounds according to the invention can also advantageously be dissolved or suspended directly in a solution comprising all further adjuvants.


The solutions or suspensions comprising compounds according to the invention and having a pH of 4 to 10, preferably having a pH of 5 to 9, and an osmolality of 250 to 350 mOsmol/kg can advantageously be prepared. The pharmaceutical composition can thus be administered directly substantially without pain intravenously, intra-arterially, intra-articularly, subcutaneously or percutaneously. In addition, the preparation may also be added to infusion solutions, such as, for example, glucose solution, isotonic saline solution or Ringer's solution, which may also contain further active ingredients, thus also enabling relatively large amounts of active ingredient to be administered.


Pharmaceutical compositions according to the invention may also comprise mixtures of a plurality of compounds according to the invention.


The compositions according to the invention are physiologically well tolerated, easy to prepare, can be dispensed precisely and are preferably stable with respect to assay, decomposition products and aggregates throughout storage and transport and during multiple freezing and thawing processes. They can preferably be stored in a stable manner over a period of at least three months to two years at refrigerator temperature (2-8° C.) and at room temperature (23-27° C.) and 60% relative atmospheric humidity (R.H.).


For example, the compounds according to the invention can be stored in a stable manner by drying and when necessary converted into a ready-to-use pharmaceutical composition by dissolution or suspension. Possible drying methods are, for example, without being restricted to these examples, nitrogen-gas drying, vacuum-oven drying, lyophilisation, washing with organic solvents and subsequent air drying, liquid-bed drying, fluidised-bed drying, spray drying, roller drying, layer drying, air drying at room temperature and further methods.


The term “effective amount” denotes the amount of a medicament or of a pharmaceutical active ingredient which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician.


In addition, the term “therapeutically effective amount” denotes an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, disease state, complaint, disorder or prevention of side effects or also a reduction in the progress of a disease, complaint or disorder. The term “therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.


On use of compositions or medicaments according to the invention, the compounds according to the invention and/or physiologically acceptable salts and solvates thereof are generally used analogously to known, commercially available compositions or preparations, preferably in dosages of between 0.1 and 500 mg, in particular 5 and 300 mg, per use unit. The daily dose is preferably between 0.001 and 250 mg/kg, in particular 0.01 and 100 mg/kg, of body weight. The composition can be administered one or more times per day, for example two, three or four times per day. However, the individual dose for a patient depends on a large number of individual factors, such as, for example, on the efficacy of the particular compound used, on the age, body weight, general state of health, sex, nutrition, on the time and method of administration, on the excretion rate, on the combination with other medicaments and on the severity and duration of the particular disease.


A measure of the uptake of a medicament active ingredient in an organism is its bioavailability. If the medicament active ingredient is delivered to the organism intravenously in the form of an injection solution, its absolute bioavailability, i.e. the proportion of the pharmaceutical which reaches the systemic blood, i.e. the major circulation, in unchanged form, is 100%. In the case of oral administration of a therapeutic active ingredient, the active ingredient is generally in the form of a solid in the formulation and must therefore first be dissolved in order that it is able to overcome the entry barriers, for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, or can be absorbed by the body. Data on the pharmacokinetics, i.e. on the bioavailability, can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.


Furthermore, medicaments of this type can be prepared by means of one of the processes generally known in the pharmaceutical art.


Medicaments can be adapted for administration via any desired suitable route, for example by the oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and in particular intra-articular) routes. Medicaments of this type can be prepared by means of all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).


Parenteral administration is preferably suitable for administration of the medicaments according to the invention. In the case of parenteral administration, intra-articular administration is particularly preferred.


The invention thus preferably also relates to the use of a pharmaceutical composition according to the invention for intra-articular administration in the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of osteoarthritis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.


Intra-articular administration has the advantage that the compound according to the invention can be administered directly into the synovial fluid in the vicinity of the joint cartilage and is also able to diffuse from there into the cartilage tissue. Pharmaceutical compositions according to the invention can thus also be injected directly into the joint gap and thus develop their action directly at the site of action as intended. The compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally having slow, sustained and/or controlled release of active ingredient. They are thus also suitable for the preparation of delayed-release formulations, which are advantageous for the patient since administration is only necessary at relatively large time intervals.


The medicaments adapted to parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood or synovial fluid of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can comprise suspension media and thickeners. The formulations can be delivered in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in the freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary. Injection solutions and suspensions prepared in accordance with the formulation can be prepared from sterile powders, granules and tablets.


The compounds according to the invention can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.


The compounds according to the invention can also be coupled to soluble polymers as targeted medicament excipients. Such polymers can encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds according to the invention can furthermore be coupled to a class of biodegradable polymers which are suitable for achieving slow release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, polylactic-co-glycolic acid, polymers, such as conjugates between dextran and methacrylates, polyphosphoesters, various polysaccharides and polyamines and poly-ε-caprolactone, albumin, chitosan, collagen or modified gelatine and cross-linked or amphipathic block copolymers of hydrogels.


Suitable for enteral administration (oral or rectal) are, in particular, tablets, dragees, capsules, syrups, juices, drops or suppositories, and suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols, such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof with one another and/or with water) or powders. Also particularly suitable for topical uses are liposomal compositions.


In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active ingredient can be formulated to a cream with an oil-in-water cream base or a water-in-oil base.


Medicaments adapted to transdermal administration can be delivered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be supplied from the plaster by means of iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).


It goes without saying that, besides the constituents particularly mentioned above, the medicaments according to the invention may also comprise other agents usual in the art with respect to the particular type of pharmaceutical formulation.


The invention also relates to a set (kit) consisting of separate packs of

  • a) an effective amount of a compound of the formula I and/or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and
  • b) an effective amount of a further medicament active ingredient.


The set comprises suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules each containing an effective amount of a compound of the formula I and/or pharmaceutically acceptable derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient in dissolved or lyophilised form.


Furthermore, the medicaments according to the invention can be used in order to provide additive or synergistic effects in certain known therapies and/or can be used in order to restore the efficacy of certain existing therapies.


Besides the compounds according to the invention, the pharmaceutical compositions according to the invention may also comprise further medicament active ingredients, for example for use in the treatment of osteoarthritis other DDR2 inhibitors, cathepsin D inhibitors, ADAMTS5 inhibitors, NSAIDS, Cox-2 inhibitors, glucocorticoids, hyaluronic acid, azathioprine, methotrexate, anti-CAM antibodies, such as, for example, anti-ICAM-1 antibody, FGF-18. For the treatment of the other diseases mentioned, the pharmaceutical compositions according to the invention may also, besides the compounds according to the invention, comprise further medicament active ingredients which are known to the person skilled in the art in the treatment thereof.


Even without further comments, it is assumed that a person skilled in the art will be able to use the above description in the broadest scope. The preferred embodiments should therefore merely be regarded as descriptive disclosure which is absolutely not limiting in any way.


The following examples are thus intended to explain the invention without limiting it. Unless indicated otherwise, percent data denote percent by weight. All temperatures are indicated in degrees Celsius. “Conventional work-up”: water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation.


Rf values on silica gel; mass spectrometry: EI (electron impact ionisation): M+, FAB (fast atom bombardment): (M+H)+, THF (tetrahydrofuran), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), EA (ethyl acetate), MeOH (methanol), TLC (thin-layer chromatography).


The following substances have been synthesised and characterised. However, the preparation and characterisation of the substances can also be carried out by other methods by the person skilled in the art.







EXAMPLE 1
Illustrative Compounds of the Formula I
















TABLE 1a









IC50
IC50
stability





Compound
IC50
[p-
[pro-
in
ESI MS



Compound
(chemical
[DDR2]
DDR2]
MMP13]
synovial
Rt/


No.
(structure)
name)
M
M
M
fluid
M + H







 1


embedded image


4-{4-[3-(3,5- Dichloro- pyridin-4-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
8.10E−07









 2


embedded image


4-{4-[3-(2,6- Dichloro- pyridin-4-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.50E−06









 3


embedded image


4-{4-[(3- Pyridin-2-yl- ureido)- methyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
3.80E−06









 4


embedded image


4-{4-[3-(2- Methoxy- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.60E−06









 5


embedded image


4-{4-[(3- Pyridin-3-yl- ureido)- methyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.50E−05









 6


embedded image


4-{4-[3-(2- Chloro- pyridin-4-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.00E−06









 7


embedded image


4-{4-[3-(3- Chloro-5- trifluoromethyl- pyridin-2-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
6.60E−06









 8


embedded image


4-{4-[3-(2,5- Dichloro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.30E−07

2.78E−07

2.246/ 447





 9


embedded image


4-{4-[(3- lsoquinolin-3- yl-ureido)- methyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
3.70E−08

3.67E−07







10


embedded image


4-{4-[(3- Quinolin-3-yl- ureido)- methyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
2.90E−07









11


embedded image


4-{4-[3-(2- Methoxy- quinolin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.90E−07









12


embedded image


4-{4-[3-(5- Methyl- pyridin-2-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
2.00E−06









13


embedded image


4-{2-Methyl-4- [3-(5-methyl- pyridin-2-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
7.80E−07









14


embedded image


4-{4-[3-(4- Methyl- pyridin-2-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
5.70E−07









15


embedded image


4-{2-Methyl-4- [3-(4-methyl- pyridin-2-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
4.00E−07









16


embedded image


4-{4-[3-(2- Chloro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.10E−05









17


embedded image


4-{4-[3-(6- Methoxy- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
5.60E−06









18


embedded image


1-(2-Methoxy- 5-methyl- pyridin-3-yl)-3- [4-(pyridin-4- yloxy)-benzyl]- urea
1.00E−07
3.00E−08
7.33E−07

1.451 min/ 365





19


embedded image


4-{4-[3-(2- Methoxy-5- methyl- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
6.30E−08
2.40E−08
1.55E−07
stable
2.049/ 422





20


embedded image


4-{4-[3-(2- Methoxy-5- methyl- pyridin-3-yl)- ureidomethyl]- 2-methyl- phenoxy}- pyridine-2- carboxylic acid methylamide
1.10E−07
4.10E−08


2.142/ 436





21


embedded image


4-{4-[3-(5- Chloro-2- methoxy- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
4.40E−08
1.40E−08
6.90E−08
stable
2.260/ 442





22


embedded image


4-{4-[3-(2- Chloro-5- methyl- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
7.10E−07



2.033/ 426





23


embedded image


4-{4-[3-(5- Chloro-2- methoxy- pyridin-3-yl)- ureidomethyl]- 2-methyl- phenoxy}- pyridine-2- carboxylic acid methylamide
3.70E−08
6.80E−09
4.54E−08
stable
2.370/ 456





24


embedded image


4-{4-[3-(2- Chloro-5- trifluoromethyl- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
1.30E−07
5.80E−08


2.336/ 480





25


embedded image


4-{4-[3-(2- Chloro-5- methyl- pyridin-3-yl)- ureidomethyl]- 2-methyl- phenoxy}- pyridine-2- carboxylic acid methylamide
4.10E−07
8.70E−08


2.126/ 440





26


embedded image


4-{4-[3-(2- Chloro-5- trifluoromethyl- pyridin-3-yl)- ureidomethyl]- 2-methyl- phenoxy}- pyridine-2- carboxylic acid methylamide
5.20E−08
4.30E−08
4.24E−08

2.421/ 494





27


embedded image


1-(5-Chloro-2- methoxy- pyridin-3-yl)-3- [4-(2-methyl- pyridin-4- yloxy)-benzyl]- urea
1.90E−07
4.20E−08


1.629/ 399





28


embedded image


1-(5-Chloro-2- methoxy- pyridin-3-yl)-3- [3-methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- urea
1.10E−07
1.70E−08
3.48E−07

1.673/ 413





29


embedded image


1-(2-Chloro-5- trifluoromethyl- pyridin-3-yl)- 3-[4-(2- methyl- pyridin-4- yloxy)-benzyl]- urea
3.50E−07
9.40E−08


1.695/ 437





30


embedded image


1-(2-Chloro-5- trifluoromethyl- pyridin-3-yl)- 3-[3-methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- urea
1.00E−07
6.00E−08
9.60E−07

1.756/ 451





31


embedded image


1-(2-Methoxy- 5-methyl- pyridin-3-yl)-3- [3-methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- urea
2.30E−07



1.529/ 393





32


embedded image


1-[3-Methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- 3-quinolin-3- yl-urea
7.10E−06



1.390/ 399





33


embedded image


1-(2-Methoxy- quinolin-3-yl)- 3-[3-methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- urea
1.70E−06



1.758/ 429





34


embedded image


1-Isoquinolin- 3-yl-3-[3- methyl-4-(2- methyl- pyridin-4- yloxy)-benzyl]- urea
1.10E−05



1.644/ 399







text missing or illegible when filed















TABLE 1b







NMR data of the compounds of table 1a








No. of



compound


of table 1a
1HNMR











1
1H NMR (500 MHz, DMSO) ppm = 9.59 (s, 1H), 8.74 (q, J = 4.8, 1H), 8.51 (d,



J = 5.5, 1H), 7.52 (s, 2H), 7.46-7.41 (m, 2H), 7.36 (d, J = 2.6, 1H), 7.27 (t, J = 6.0,



1H), 7.23-7.18 (m, 2H), 7.16 (dd, J = 5.6, 2.6, 1H), 4.36 (d, J = 5.9, 2H), 2.78 (d,



J = 4.8, 3H).


2
1H NMR (500 MHz, DMSO) ppm = 9.58 (s, 1H), 8.78-8.71 (m, 1H), 8.51 (d,



J = 5.5, 1H), 7.52 (s, 2H), 7.44 (d, J = 8.0, 2H), 7.36 (d, J = 2.6, 1H), 7.27 (t, J = 6.0,



1H), 7.23-7.19 (m, 2H), 7.19-7.14 (m, 1H), 4.36 (d, J = 5.9, 2H), 2.78 (d,



J = 4.8, 3H).


3
1H NMR (500 MHz, DMSO) ppm = 9.29 (s, 1H), 8.77-8.71 (m, 1H), 8.66 (t,



J = 6.0, 1H), 8.50 (d, J = 5.6, 1H), 8.21-8.17 (m, 1H), 7.72-7.64 (m, 1H),



7.48-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.23-7.17 (m, 2H), 7.17-7.13 (m, 1H),



6.96-6.90 (m, 1H), 4.46 (d, J = 5.9, 2H), 2.78 (d, J = 4.8, 3H).


4
1H NMR (500 MHz, DMSO) ppm = 8.78-8.71 (m, 1H), 8.53-8.49 (m, 1H),



8.37 (dd, J = 7.7, 1.7, 1H), 8.17 (s, 1H), 7.72-7.67 (m, 1H), 7.48-7.36 (m, 4H),



7.24-7.18 (m, 2H), 7.18-7.13 (m, 1H), 6.93-6.87 (m, 1H), 4.36 (d, J = 5.7,



2H), 3.93 (s, 3H), 2.78 (d, J = 4.9, 3H).


5
1H NMR (500 MHz, DMSO) ppm = 8.81 (s, 1H), 8.74 (dd, J = 9.7, 4.8, 1H), 8.56



(d, J = 2.6, 1H), 8.51 (d, J = 5.5, 1H), 8.14-8.09 (m, 1H), 7.94-7.88 (m, 1H),



7.48-7.41 (m, 2H), 7.37 (d, J = 2.6, 1H), 7.29-7.23 (m, 1H), 7.23-7.18 (m,



2H), 7.18-7.13 (m, 1H), 6.87 (t, 1H), 4.36 (d, J = 5.9, 2H), 2.78 (d, J = 4.8, 3H).


6
1H NMR (500 MHz, DMSO) ppm = 9.37 (s, 1H), 8.77-8.71 (m, 1H), 8.51 (d,



J = 5.6, 1H), 8.12 (d, J = 5.7, 1H), 7.65-7.61 (m, 1H), 7.44 (d, J = 8.0, 2H), 7.36



(d, J = 2.6, 1H), 7.30-7.25 (m, 1H), 7.23-7.18 (m, 2H), 7.18-7.14 (m, 1H),



7.11 (t, J = 6.0, 1H), 4.36 (d, J = 5.9, 2H), 2.78 (d, J = 4.9, 3H).


7
1H NMR (500 MHz, DMSO) ppm = 9.27 (t, 1H), 8.85 (s, 1H), 8.78-8.70 (m,



1H), 8.64-8.59 (m, 1H), 8.51 (d, J = 5.6, 1H), 8.39 (d, J = 2.2, 1H), 7.51-7.45



(m, 2H), 7.37 (d, J = 2.6, 1H), 7.24-7.18 (m, 2H), 7.18-7.14 (m, 1H), 4.52 (d,



J = 6.0, 2H), 2.78 (d, J = 4.8, 3H).


8
1H NMR (400 MHz, DMSO) ppm = 8.78-8.72 (m, 1H), 8.70 (d, J = 2.5, 1H),



8.52 (d, J = 5.6, 1H), 8.45 (s, 1H), 8.06 (d, J = 2.4, 1H), 7.79-7.72 (m, 1H),



7.50-7.44 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.25-7.20 (m, 2H), 7.17 (dd, J = 5.6, 2.6, 1H),



4.39 (d, J = 5.7, 2H), 2.79 (d, J = 4.8, 3H).


9
1H NMR (500 MHz, DMSO) ppm = 9.17 (s, 1H), 9.05 (s, 1H), 8.78-8.70 (m,



1H), 8.51 (d, J = 5.6, 1H), 8.06 (s, 1H), 7.98 (d, J = 8.2, 1H), 7.79 (d, J = 8.4, 1H),



7.68-7.59 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.40 (m, 1H), 7.38 (d, J = 2.6,



1H), 7.24-7.19 (m, 2H), 7.17-7.14 (m, 1H), 4.44 (d, J = 5.8, 2H), 2.78 (d,



J = 4.9, 3H).


10
1H NMR (500 MHz, DMSO) ppm = 9.11 (s, 1H), 8.80 (d, J = 2.6, 1H), 8.77-8.71



(m, 1H), 8.51 (d, J = 5.6, 1H), 8.48 (d, J = 2.5, 1H), 7.93-7.81 (m, 2H),



7.60-7.51 (m, 2H), 7.51-7.45 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.25-7.19 (m, 2H), 7.17



(dd, J = 5.5, 2.6, 1H), 7.01-6.94 (m, 1H), 4.41 (d, J = 5.9, 2H), 2.78 (d, J = 4.9,



3H).


11
1H NMR (500 MHz, DMSO) ppm = 8.77 (s, 1H), 8.76-8.70 (m, 1H), 8.51 (d,



J = 5.6, 1H), 8.47 (s, 1H), 7.78-7.72 (m, 1H), 7.69 (d, J = 8.2, 1H), 7.56 (t, 1H),



7.52-7.44 (m, 3H), 7.41-7.33 (m, 2H), 7.26-7.19 (m, 2H), 7.19-7.13 (m,



1H), 4.40 (d, J = 5.7, 2H), 4.10 (s, 3H), 2.78 (d, J = 4.8, 3H).


12
not present


13
not present


14
not present


15
not present


16
1H NMR (500 MHz, DMSO) ppm = 8.75 (d, J = 4.9, 1H), 8.59-8.48 (m, 2H),



8.27 (s, 1H), 7.98 (dd, J = 4.6, 1.8, 1H), 7.63 (t, 1H), 7.49-7.43 (m, 2H),



7.39-7.32 (m, 2H), 7.25-7.20 (m, 2H), 7.19-7.13 (m, 1H), 4.38 (d, J = 5.7, 2H), 2.78



(d, J = 4.8, 3H).


17
1H NMR (500 MHz, DMSO) ppm = 8.77-8.72 (m, 1H), 8.53-8.49 (m, 2H),



8.15 (d, J = 2.7, 1H), 7.81-7.76 (m, 1H), 7.46-7.41 (m, 2H), 7.37 (d, J = 2.6,



1H), 7.23-7.18 (m, 2H), 7.16 (dd, J = 5.6, 2.6, 1H), 6.75-6.70 (m, 2H), 4.34 (d,



J = 5.9, 2H), 3.79 (s, 3H), 2.78 (d, J = 4.8, 3H).


18
1H NMR (400 MHz, DMSO) ppm = 8.79-8.72 (m, 2H), 8.24 (d, J = 2.1, 1H),



8.13 (s, 1H), 7.53-7.43 (m, 4H), 7.42-7.36 (m, 2H), 7.32-7.27 (m, 2H), 4.37



(d, J = 5.7, 2H), 3.90 (s, 3H), 2.18 (s, 3H).


19
1H NMR (500 MHz, DMSO) ppm = 8.78-8.71 (m, 1H), 8.51 (d, J = 5.6, 1H),



8.25 (d, J = 2.1, 1H), 8.10 (s, 1H), 7.53-7.49 (m, 1H), 7.46-7.39 (m, 3H), 7.38



(d, J = 2.6, 1H), 7.23-7.18 (m, 2H), 7.16 (dd, J = 5.6, 2.6, 1H), 4.35 (d, J = 5.5,



2H), 3.90 (s, 3H), 2.78 (d, J = 4.8, 3H), 2.18 (s, 3H).


20
1H NMR (500 MHz, DMSO) ppm = 8.79-8.72 (m, 1H), 8.50 (d, J = 5.6, 1H),



8.25 (d, J = 2.1, 1H), 8.09 (s, 1H), 7.52-7.49 (m, 1H), 7.39 (t, 1H), 7.34-7.32



(m, 1H), 7.30 (d, J = 2.6, 1H), 7.28-7.24 (m, 1H), 7.15-7.09 (m, 2H), 4.32 (d,



J = 5.3, 2H), 3.90 (s, 3H), 2.78 (d, J = 4.8, 3H), 2.18 (s, 3H), 2.10 (s, 3H).


21
1H NMR (400 MHz, DMSO) ppm = 8.79-8.70 (m, 1H), 8.51 (d, J = 5.6, 1H),



8.47 (d, J = 2.5, 1H), 8.39 (s, 1H), 7.73 (d, J = 2.4, 1H), 7.51 (t, J = 5.8, 1H),



7.47-7.41 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.24-7.18 (m, 2H), 7.16 (dd, J = 5.6, 2.6, 1H),



4.37 (d, J = 5.7, 2H), 3.94 (s, 3H), 2.79 (d, J = 4.8, 3H).


22
1H NMR (500 MHz, DMSO) ppm = 8.79-8.70 (m, 1H), 8.51 (d, J = 5.6, 1H),



8.41 (d, J = 2.1, 1H), 8.19 (s, 1H), 7.85-7.80 (m, 1H), 7.62 (t, J = 5.8, 1H),



7.49-7.43 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.25-7.19 (m, 2H), 7.19-7.14 (m, 1H), 4.38



(d, J = 5.7, 2H), 2.78 (d, J = 4.8, 3H), 2.26 (s, 3H).


23
1H NMR (500 MHz, DMSO) ppm = 8.80-8.71 (m, 1H), 8.50 (d, J = 5.6, 1H),



8.47 (d, J = 2.4, 1H), 8.39 (s, 1H), 7.73 (d, J = 2.4, 1H), 7.50 (t, J = 5.8, 1H), 7.34



(d, J = 2.1, 1H), 7.29 (d, J = 2.6, 1H), 7.26 (dd, J = 8.3, 2.2, 1H), 7.17-7.08 (m,



2H), 4.34 (d, J = 5.6, 2H), 3.94 (s, 3H), 2.78 (d, J = 4.8, 3H), 2.10 (s, 3H).


24
1H NMR (500 MHz, DMSO) ppm = 8.96 (d, J = 2.2, 1H), 8.77-8.72 (m, 1H),



8.63 (s, 1H), 8.51 (d, J = 5.6, 1H), 8.39 (d, J = 2.2, 1H), 7.80 (t, J = 5.8, 1H),



7.49-7.45 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.24-7.20 (m, 2H), 7.17 (dd, J = 5.6, 2.6, 1H),



4.40 (d, J = 5.7, 2H), 2.78 (d, J = 4.8. 3H).


25
1H NMR (500 MHz, DMSO) ppm = 8.78-8.72 (m, 1H), 8.51 (d, J = 5.6, 1H),



8.41 (d, J = 2.1, 1H), 8.18 (s, 1H), 7.84-7.80 (m, 1H), 7.61 (t, J = 5.7, 1H), 7.35



(d, J = 2.1, 1H), 7.31-7.26 (m, 2H), 7.17-7.10 (m, 2H), 4.35 (d, J = 5.6, 2H),



2.78 (d, J = 4.8, 3H), 2.27 (s, 3H), 2.10 (s, 3H).


26
1H NMR (400 MHz, DMSO) ppm = 8.98 (d, J = 2.3, 1H), 8.78-8.71 (m, 1H),



8.63 (s, 1H), 8.52 (d, J = 5.6, 1H), 8.40 (dd, J = 2.3, 1.0, 1H), 7.79 (t, J = 5.7, 1H),



7.38 (d, J = 2.1, 1H), 7.33-7.27 (m, 2H), 7.18-7.10 (m, 2H), 4.39 (d, J = 5.6,



2H), 2.79 (d, J = 4.8, 3H), 2.12 (s, 3H).


27
1H NMR (500 MHz, DMSO) ppm = 8.63 (d, J = 6.8, 1H), 8.46 (d, J = 2.5, 1H),



8.43 (s, 1H), 7.73 (d, J = 2.5, 1H), 7.58 (t, 1H), 7.50-7.45 (m, 2H), 7.30-7.25



(m, 3H), 7.25-7.22 (m, 1H), 4.38 (d, J = 5.8, 2H), 3.94 (s, 3H), 2.61 (s, 3H).


28
1H NMR (500 MHz, DMSO) ppm = 8.64 (d, J = 6.8, 1H), 8.46 (d, J = 2.5, 1H),



8.42 (s, 1H), 7.73 (d, J = 2.5, 1H), 7.59-7.52 (m, 1H), 7.37 (d, J = 2.1, 1H),



7.33-7.28 (m, 1H), 7.28-7.15 (m, 3H), 4.35 (d, J = 5.8, 2H , 3.94 (s, 3H), 2.62 (s,



3H), 2.12 (s, 3H).


29
1H NMR (500 MHz, DMSO) ppm = 8.97 (d, J = 2.2, 1H), 8.63 (s, 1H), 8.43-8.36



(m, 1H), 8.31 (d, J = 5.7, 1H), 7.78 (t, 1H), 7.47-7.39 (m, 2H), 7.19-7.10 (m, 2H),



6.76 (d, J = 2.4, 1H), 6.73-6.67 (m, 1H), 4.38 (d, J = 5.7, 2H), 2.40 (s, 3H)



1.91 (s, 0H), 1.23 (s, 0H).


30
1H NMR (500 MHz, DMSO) ppm = 8.97 (d, J = 2.2, 1H), 8.62 (s, 1H), 8.42-8.37



(m, 1H), 8.29 (d, J = 5.7, 1H), 7.76 (t, 1H), 7.35-7.30 (m, 1H), 7.28-7.23 (m,



1H), 7.07 (d, J = 8.2, 1H), 6.67 (d, J = 2.4, 1H), 6.63-6.58 (m, 1H), 4.36 (d,



J = 5.6, 2H), 2.39 (s, 3H), 2.11 (s, 3H).


31
1H NMR (500 MHz, DMSO) ppm = 8.65 (d, J = 6.8, 1H), 8.24 (d, J = 2.1, 1H),



8.13 (s, 1H), 7.54-7.49 (m, 1H), 7.44 (t, 1H), 7.36 (d, J = 2.1, 1H), 7.33-7.27



(m, 1H), 7.26 (d, J = 2.7, 1H), 7.24-7.17 (m, 2H), 4.34 (d, J = 5.7, 2H), 3.90 (s,



3H), 2.62 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H).


32
1H NMR (500 MHz, DMSO) ppm = 9.32 (s, 1H), 8.91 (d, J = 2.5, 1H), 8.62-8.59



(m, 1H), 8.55-8.52 (m, 1H), 7.97-7.87 (m, 2H), 7.65-7.61 (m, 1H),



7.61-7.55 (m, 1H), 7.41-7.38 (m, 1H), 7.36-7.31 (m, 1H), 7.25 (d, J = 2.6, 1H),



7.22-7.16 (m, 2H), 7.14 (t, J = 6.1, 1H), 4.39 (d, J = 5.8, 2H), 2.61 (s, 3H), 2.11 (s,



3H).


33
1H NMR (500 MHz, DMSO) ppm = 8.77 (s, 1H), 8.61 (d, J = 6.7, 1H), 8.48 (s,



1H), 7.75-7.67 (m, 2H), 7.57 (t, 1H), 7.51-7.46 (m, 1H), 7.41-7.31 (m, 3H),



7.23-7.16 (m, 3H), 4.39 (d, J = 5.8, 2H), 4.10 (s, 3H), 2.60 (s, 3H), 2.12 (s, 3H).


34
1H NMR (500 MHz, DMSO) ppm = 9.25 (s, 1H), 9.05 (s, 1H), 8.64 (d, J = 6.8,



1H), 8.04 (s, 1H), 8.02-7.96 (m, 1H), 7.78 (d, J = 8.3, 1H), 7.71-7.60 (m, 2H),



7.49-7.38 (m, 2H), 7.38-7.30 (m, 1H), 7.30-7.16 (m, 3H), 4.43 (d, J = 5.8,



2H), 2.62 (s, 3H), 2.12 (s, 3H).





















TABLE 2









IC50






IC50
[p-




Compound
Compound
[DDR2]
DDR2]



No.
(structure)
(chemical name)
nM
nM
Mass




















 1


embedded image


1-(3-Chloro-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
110

353.81





 2


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(2,4,5-trichloro- phenyl)-urea
1400

422.70





 3


embedded image


4-{4-[3-(3,4-Dichloro- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

195
445.31





 4


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(3- trifluoromethyl-phenyl)- urea
36

387.36





 5


embedded image


1-(2,4-Dichloro-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
1400

388.25





 6


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-m-tolyl-urea
1000

333.39





 7


embedded image


1-(3-Acetyl-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
10000

361.40





 8


embedded image


4-{4-[3-(2,4-Dichloro- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

255
445.31





 9


embedded image


1-(4-Bromo-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
3800

398.26





 10


embedded image


1-(2,5-Dichloro-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
270

388.25





 11


embedded image


1-(4-Fluoro-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
3400

337.35





 12


embedded image


4-{4-[3-(4-Fluoro-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

775
394.41





 13


embedded image


1-(2,3-Dichloro-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
100000

388.25





 14


embedded image


4-{4-[3-(2-Methoxy- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
1900

406.44





 15


embedded image


1-(2,5-Dimethoxy-phenyl)- 3-[4-(pyridin-4-yloxy)- benzyl]-urea
440

379.42





 16


embedded image


1-(4-Chloro-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
5900

353.81





 17


embedded image


1-(4-Methoxy-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
13000

349.39





 18


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-p-tolyl-urea
4100

333.39





 19


embedded image


4-{4-[3-(5-Chloro-2- methoxy-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
30
14
440.89





 20


embedded image


4-{4-[3-(2,5-Dimethoxy- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
98

436.47





 21


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(4- trifluoromethyl-phenyl)- urea
2000

387.36





 22


embedded image


1-(3,5-Bis-trifluoromethyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
560

455.36





 23


embedded image


4-{4-[3-(2,4,5-Trichloro- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

100
479.75





 24


embedded image


1-(2,3-Dimethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
100000

347.42





 25


embedded image


1-(2,5-Dimethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
13000

347.42





 26


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(2- trifluoromethyl-phenyl)- urea
20000

387.36





 27


embedded image


1-(3-Chloro-4-methyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
740

367.84





 28


embedded image


1-(2-Ethyl-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
100000

347.42





 29


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-o-tolyl-urea
100000

333.39





 30


embedded image


1-(2,4-Dimethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
28000

347.42





 31


embedded image


4-{4-[3-(3,5-Dichloro- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

175
445.31





 32


embedded image


1-(5-Chloro-2-methoxy- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
87

383.83





 33


embedded image


1-(2-Chloro-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
100000

353.81





 34


embedded image


1-(3-Methylsulfanyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
5500

365.45





 35


embedded image


1-(4-Bromo-2-chloro- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
9500

432.71





 36


embedded image


1-(2-Methoxy-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
1700

349.39





 37


embedded image


1-(2-Chloro-4- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
2800

421.81





 38


embedded image


1-(3,4-Dichloro-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
2100

388.25





 39


embedded image


4-{4-[3-(3-Chloro-4- methoxy-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

64
440.89





 40


embedded image


1-(4-Chloro-2- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
9900

421.81





 41


embedded image


1-(4-Ethoxy-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
100000

363.42





 42


embedded image


4-{4-[3-(5-Chloro-2- methyl-phenyl)- ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

230
424.89





 43


embedded image


1-(2-Chloro-5- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
42

421.81





 44


embedded image


1-(3,5-Dimethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
1800

347.42





 45


embedded image


1-(3-Methoxy-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
4000

349.39





 46


embedded image


1-(4-Fluoro-3- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
100

405.35





 47


embedded image


1-(4-Acetyl-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
8800

361.40





 48


embedded image


1-(2-Bromo-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
100000

398.26





 49


embedded image


1-(4-lsopropyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
9600

361.44





 50


embedded image


1-(5-Chloro-2-methyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
1700

367.84





 51


embedded image


1-(4-Methylsulfanyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
10000

365.45





 52


embedded image


1-(4-Ethyl-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
9900

347.42





 53


embedded image


1-(3-Bromo-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
56

398.26





 54


embedded image


1-(4-Chloro-2-methyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
100000

367.84





 55


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(4- trifluoromethoxy-phenyl)- urea
7500

403.36





 56


embedded image


1-(4-tert-Butyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
16000

375.47





 57


embedded image


1-(3,5-Dichloro-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
1200

388.25





 58


embedded image


1-(4-Bromo-3-methyl- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
4700

412.29





 59


embedded image


1-(3,4-Dimethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
2100

347.42





 60


embedded image


1-(3-Chloro-4-methoxy- phenyl)-3-[4-(pyridin-4- yloxy)-benzyl]-urea
2800

383.83





 61


embedded image


1-(3-Ethyl-phenyl)-3-[4- (pyridin-4-yloxy)-benzyl]- urea
490

347.42





 62


embedded image


1-(2-Methoxy-5- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
2

417.39





 63


embedded image


4-{4-[3-(2-Methoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
61

474.44





 64


embedded image


1-(4-Bromo-3- trifluoromethyl-phenyl)-3- [4-(pyridin-4-yloxy)- benzyl]-urea
1700

466.26





 65


embedded image


1-[4-(Pyridin-4-yloxy)- benzyl]-3-(3- trifluoromethoxy-phenyl)- urea
35

403.36





 66


embedded image


4-{4-[3-(5-Chloro-2- methoxy-4-methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
55
9
454.91





 67


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-trifluoromethyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
175

508.88





 68


embedded image


1-(4-Chloro-3- trifluoromethyl-phenyl)-3- {1-[4-(pyridin-4-yloxy)- phenyl]-cyclopropyl}-urea
4600

447.84





 69


embedded image


4-(4-{1-[3-(2-Methoxy-5- trifluoromethyl-phenyl)- ureido]-ethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
150

488.47





 70


embedded image


4-(4-{1-[3-(2,4,5-Trichloro- phenyl)-ureido]-ethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide

735
493.78





 71


embedded image


4-(4-{1-[3-(3,4-Dichloro- phenyl)-ureido]-ethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide

1800
459.33





 72


embedded image


4-(4-{1-[3-(5-Chloro-2- methoxy-phenyl)-ureido]- ethyl}-phenoxy)-pyridine-2- carboxylic acid methylamide
340
74
454.91





 73


embedded image


4-(4-{1-[3-(3-Chloro-4- methyl-phenyl)-ureido]- ethyl}-phenoxy)-pyridine-2- carboxylic acid methylamide

1750
438.91





 74


embedded image


4-{4-[3-(4-Chloro-3- methyl-phenyl)- ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

175
424.89





 75


embedded image


4-{4-[3-(2-Methoxy-5- methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
69

420.47





 76


embedded image


4-{4-[(3- Benzo[1,2,5]thiadiazol-5- yl-ureido)-methyl]- phenoxy]-pyridine-2- carboxylic acid methylamide

670
434.48





 77


embedded image


4-(4-{3-[2-(2- Dimethylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
78

531.53





 78


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
100
24
454.91





 79


embedded image


4-{4-[3-(4-Chloro-2- methoxy-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
410

440.89





 80


embedded image


4-{4-[3-(3,4,5-Trimethoxy- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

750
466.49





 81


embedded image


4-{4-[3-(2,5-Dimethoxy-4- nitro-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
230

482.47





 82


embedded image


3-Methoxy-4-{3-[4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}- benzoic acid methyl ester
2900

464.48





 83


embedded image


4-{4-[3-(4-Chloro-2,5- dimethoxy-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
760
140
470.91





 84


embedded image


4-{4-[3-(3,5-Dichloro- pyridin-4-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
810
745
446.29





 85


embedded image


4-{4-[(3-Pyridin-2-yl- ureido)-methyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
3800

377.40





 86


embedded image


4-(4-{3-[2-(3- Dimethylamino-propoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
1200

477.56





 87


embedded image


4-{4-[3-(2-Methoxy-pyridin- 3-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
1600

407.43





 88


embedded image


4-{4-[(3-Pyridin-3-yl- ureido)-methyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
15000

377.40





 89


embedded image


4-{4-[3-(2-Chloro-pyridin-4- yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
1000
1450
411.85





 90


embedded image


4-{4-[(3-Pyridin-4-yl- ureido)-methyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
100000

377.40





 91


embedded image


4-{4-[3-(3-Chloro-5- trifluoromethyl-pyridin-2- yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
6600

479.85





 92


embedded image


(2-{3-[4-(2- Methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid methyl ester
38

532.47





 93


embedded image


4-{4-[3-(2,5-Dichloro- pyridin-3-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
42

446.29





 94


embedded image


(2-{3-[4-(2- Methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid
1600

518.45





 95


embedded image


4-(4-{3-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
81

565.98





 96


embedded image


4-{4-[(3-Isoquinolin-3-yl- ureido)-methyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
170

427.46





 97


embedded image


4-{4-[(3-Quinolin-3-yl- ureido)-methyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
290

427.46





 98


embedded image


(5-Chloro-2-{3-[4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid
3300

552.89





 99


embedded image


4-{4-[3-(4-Chloro-3- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid

2850
465.81





100


embedded image


4-{4-[3-(5-Chloro-2- methoxy-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
120
25
454.91





101


embedded image


4-{4-[3-(2-Methoxy- quinolin-3-yl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
190

457.49





102


embedded image


4-{4-[3-(2-Methoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
50

488.47





103


embedded image


4-{4-[3-(2,4-Dichloro-6- methoxy-3-methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
14000
4600
489.36





104


embedded image


4-{4-[3-(5-Chloro-2- methoxy-phenyl)- ureidomethyl]-3-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
270

454.91





105


embedded image


4-{4-[3-(2-Methoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-3-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
180

488.47





106


embedded image


4-(4-{3-[2-(2-Pyrrolidin-1- yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
140

557.57





107


embedded image


(5-Chloro-2-{3-[4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid tert-butyl ester
22

609.00





108


embedded image


4-(4-{3-[2-(2-Diethylamino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
30

559.59





109


embedded image


4-(4-{3-[2-(2-Morpholin-4- yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
72

573.57





110


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-morpholin-4-yl- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
290
130
554.05





111


embedded image


4-(4-{3-[2-(2-Methylamino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
64
24
517.51





112


embedded image


4-(4-{3-[2-(2-Piperazin-1- yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
130
47
572.59





113


embedded image


(5-Chloro-2-{3-[4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid methyl ester
57

566.92





114


embedded image


(5-Chloro-2-{3-[4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenoxy)- acetic acid isopropyl ester
24

594.97





115


embedded image


4-(4-{3-[2-(Piperidin-4- yloxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
20

543.55





116


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
410

538.05





117


embedded image


4-(4-{3-[4-Chloro-2-(2- diethylamino-ethoxy)-5- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
425

540.06





118


embedded image


4-(4-{3-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
200
55
512.01





119


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-methyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
210

468.94





120


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-piperazin-1-yl- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
176

553.06





121


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
34

503.48





122


embedded image


4-{4-[3-(2-Piperazin-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

135
528.53





123


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid (2-amino-ethyl)-amide
3100

483.96





124


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(piperidin-4-yloxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
66
40
524.02





125


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-methylamino-ethoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
187
52
497.98





126


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-methyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid (6-amino-hexyl)-amide
150

540.06





127


embedded image


4-(4-{3-[4-Chlorc~2-(2- methylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
47
34
551.95





128


embedded image


4-(4-{3-[4-Chloro-2-(2- piperazin-1-yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
91
63
607.03





129


embedded image


4-(4-{3-[4-Chloro-2-(2- pyrrolidin-1-yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
250

592.02





130


embedded image


4-(4-{3-[4-Chloro-2- (piperidin-4-yloxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
34
24
577.99





131


embedded image


4-(4-{3-[4-Chloro-2-(2- morpholin-4-yl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
96

608.02





132


embedded image


4-(4-{3-[4-Chloro-2-(2- diethylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
125

594.03





133


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-morpholin-4-yl- ethoxy)-phenyl]- ureidomethyl}-3-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
2000

568.07





134


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]- ureidomethyl}-3-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
1200

552.07





135


embedded image


4-{4-[3-(3- Methanesulfonyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

390
454.50





136


embedded image


4-(4-{3-[4-Chloro-2-(2- diethylamino-ethoxy)-5- methyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
390

554.09





137


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
140

552.07





138


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-morpholin-4-yl- ethoxy)-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
310

568.07





139


embedded image


4-(4-{3-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
26
18
526.04





140


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-4-chloro-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
121

537.93





141


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-methylamino-ethoxy)- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide
43
25
512.01





142


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(piperidin-4-yloxy)- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide
36
33
538.05





143


embedded image


4-(4-{3-[4-Chloro-5-methyl- 2-(2-piperazin-1-yl- ethoxy)-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
77
66
567.09





144


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-4-chloro-5-methyl- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide
49
53
497.98





145


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-4-chloro-5-methyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
91
65
483.96





146


embedded image


4-(2-Methyl-4-{3-[2-(2- methylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
33
15
531.53





147


embedded image


4-(4-{3-[4-Chloro-2-(2- methylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
41

565.98





148


embedded image


4-{4-[3-(4-Chloro-3- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid (2-amino-ethyl)-amide

785
507.90





149


embedded image


4-{4-[3-(4-Chloro-3- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid (2-methylamino-ethyl)- amide

925
521.93





150


embedded image


4-(4-{3-[2-(2- Dimethylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
42
10
545.56





151


embedded image


4-{4-[3-(5-Chloro-2- methoxy-4-methyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
100

468.94





152


embedded image


4-(4-{3-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
25

580.01





153


embedded image


4-(4-{3-[4-Chloro-2-(3- dimethylamino-propoxy)-5- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
140
55
526.04





154


embedded image


4-{4-[3-(3- Methanesulfonyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

1250
468.53





155


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide
40
18
517.51





156


embedded image


4-(4-{3-[2-(Pyrrolidin-2- ylmethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
43
16
543.55





157


embedded image


4-{4-[3-(3-Sulfamoyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

500
455.49





158


embedded image


4-{4-[3-(3- Isopropylsulfamoyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

100000
497.57





159


embedded image


4-(4-{3-[5-Methyl-2- (piperidin-4-yloxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
83

489.58





160


embedded image


4-(4-{3-[2-(2-Amino-2- methyl-propoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
360
95
531.53





161


embedded image


4-(4-{3-[4-Chloro-2-(4- dimethylamino-butoxy)-5- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
160

540.06





162


embedded image


4-[4-(3-{4-Chloro-2-[(2- dimethylamino-ethyl)- methyl-amino]-5-methyl- phenyl}-ureidomethyl)- phenoxy]-pyridine-2- carboxylic acid methylamide

1600
525.05





163


embedded image


4-(4-{3-[4-Chloro-2-(3- dimethylamino-propoxy)-5- methyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
40
16
540.06





164


embedded image


4-[4-(3-{4-Chloro-2-[(2- dimethylamino-ethyl)- methyl-amino]-5-methyl- phenyl}-ureidomethyl)-2- methyl-phenoxy]-pyridine- 2-carboxylic acid methylamide

300
539.08





165


embedded image


4-(4-{3-[4-Chloro-2-(4- dimethylamino-butoxy)-5- methyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide
210

554.09





166


embedded image


4-(4-{3-[2-(2-Methoxy- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
140

518.49





167


embedded image


4-{4-[3-(3- Methanesulfonylamino- phenyl)-ureidomethyl]-2- methyl-phenoxy}-pyridine- 2-carboxylic acid methylamide

1500
483.55





168


embedded image


4-(4-{3-[2-(2-Methoxy- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide
130

532.52





169


embedded image


4-(4-{3-[2-(2-Methylamino- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
2800
1900
449.51





170


embedded image


4-(4-{3-[5-Methyl-2-(2- methylamino-ethoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
310
195
463.54





171


embedded image


4-(2-Methyl-4-{3-[5-methyl- 2-(piperidin-4-yloxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
47

503.60





172


embedded image


4-(4-{3-[2-(2- lsopropylamino-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
140
31
545.56





173


embedded image


4-(4-{3-[5-Chloro-4-methyl- 2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
260

538.05





174


embedded image


4-(4-{3-[5-Chloro-2-(2- dimethylamino-ethoxy)-4- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
140
28
512.01





175


embedded image


4-(4-{3-[2-(2-Amino-ethyl)- 5-trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide

1300
487.48





176


embedded image


4-(4-{3-[2-(2-Amino- ethoxy)-5-chloro-4-methyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
27

483.96





177


embedded image


4-(4-{3-[5-Chloro-4-methyl- 2-(2-methylamino-ethoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
74
27
497.98





178


embedded image


4-(4-{3-[5-Chloro-4-methyl- 2-(piperidin-4-yloxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
35
25
524.02





179


embedded image


4-(4-{3-[5-Chloro-4-methyl- 2-(2-piperazin-1-yl- ethoxy)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
160
38
553.06





180


embedded image


4-(4-{3-[2-(2- Methanesulfonylamino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
32

581.57





181


embedded image


4-{4-[(3-Phenyl-ureido)- methyl]-phenoxy}-pyridine- 2-carboxylic acid methylamide
4900

376.42





182


embedded image


4-(4-{3-[5-Chloro-4-methyl- 2-(pyrrolidin-2-ylmethoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
59
30
524.02





183


embedded image


4-(4-{3-[5-Chloro-2-(2- isopropylamino-ethoxy)-4- methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
89
35
526.04





184


embedded image


4-{2-Methyl-4-[3-(2- piperazin-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

76
542.56





185


embedded image


4-(4-{3-[2-(2-Amino-2- methyl-propoxy)-5-chloro- 4-methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
460
175
512.01





186


embedded image


4-{4-[3-(2-Acetylamino-4- chloro-5-methyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

330
495.97





187


embedded image


4-[4-(3-{4-Chloro-5-methyl- 2-[2-(2,2,2-trifluoro- acetylamino)-ethoxy]- phenyl}-ureidomethyl)- phenoxy]-pyridine-2- carboxylic acid methylamide
660

579.96





188


embedded image


4-(4-{3-[2-(2-Methylamino- ethoxy)-5- trifluoromethanesulfonyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
710
320
581.57





189


embedded image


4-(2-Methyl-4-{3-[2-(2- methylamino-ethoxy)-5- trifluoromethanesulfonyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
270
115
595.60





190


embedded image


4-{4-[3-(2- Carbamoylmethoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
120
40
517.46





191


embedded image


4-(4-{3-[2-(3-Amino- propoxy)-4-chloro-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
590
106
551.95





192


embedded image


4-{4-[3-(2-Piperazin-1- ylmethyl-5-trifluoromethyl- phenyl]-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

1150
542.56





193


embedded image


4-(4-{3-[4-Chloro-2-(2- methanesulfonylamino- ethoxy)-5-methyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
180

562.04





194


embedded image


4-(4-{3-[4-Chloro-2-(2- methanesulfonylamino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
64

616.01





195


embedded image


4-(4-{3-[2-(2-Hydroxy- ethyl)-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridine-2- carboxylic acid methylamide

15000
434.50





196


embedded image


4-{4-[3-(2-Hydroxymethyl- 4-methyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

17650
434.50





197


embedded image


4-(4-{3-[2-(2-Hydroxy- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
96

504.46





198


embedded image


4-{4-[3-(2-Hydroxymethyl- phenyl)-ureidomethyl]-2- methyl-phenoxy]-pyridine- 2-carboxylic acid methylamide

7500
420.47





199


embedded image


4-(4-{3-[2-(1-Carbamoyl-1- methyl-ethoxy)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
100000

545.52





200


embedded image


4-{2-Methyl-4-[3-(2- methylcarbamoylmethyl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

455
529.52





201


embedded image


4-{4-[3-(2-[1,2,4]Triazol-1- yl-5-trifluoromethyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

41
511.46





202


embedded image


4-{2-Methyl-4-[3-(2- [1,2,4]triazol-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

14
525.49





203


embedded image


4-{2-Methyl-4-[3-(2- [1,2,3]triazol-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

19
525.49





204


embedded image


4-{4-[3-(2-Hydroxy-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

38
474.44





205


embedded image


2-Oxo-6-trifluoromethyl- 2,3-dihydro-indole-1- carboxylic acid 4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzylamide

1100
484.43





206


embedded image


4-{4-[3-(2-[1,2,3]Triazol-1- yl-5-trifluoromethyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

31
511.46





207


embedded image


4-{4-[3-(2- Carbamoylmethyl-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

285
515.49





208


embedded image


4-(4-{3-[2-(2-Oxo- piperazin-1-ylmethyl)-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide

855
556.54





209


embedded image


4-{4-[3-(2- Carbamoylmethyl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

985
501.46





210


embedded image


4-{4-[3-(5-Methyl-pyridin-2- yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
2000
1500
391.43





211


embedded image


4-{2-Methyl-4-[3-(5-methyl- pyridin-2-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
780
630
405.46





212


embedded image


4-{4-[3-(4-Methyl-pyridin-2- yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
570
380
391.43





213


embedded image


4-{2-Methyl-4-[3-(4-methyl- pyridin-2-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
400
205
405.46





214


embedded image


4-(4-{3-[2-(Acetylamino- methyl)-5-trifluoromethyl- phenyl]-ureidomethyl}-2- methyl-phenoxy)-pyridine- 2-carboxylic acid methylamide

45
529.52





215


embedded image


4-(2-Methyl-4-{3-[5-methyl- 2-(2-methylamino-ethoxy)- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
69
40
477.56





216


embedded image


4-{4-[3-(5-Chloro-2- methoxy-4-methyl-phenyl)- ureidomethyl]-2-fluoro- phenoxy}-pyridine-2- carboxylic acid methylamide
43

472.90





217


embedded image


4-{2-Fluoro-4-[3-(2- methoxy-5-trifluoromethyl- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
21

492.43





218


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-methyl-phenyl)- ureidomethyl]-2-fluoro- phenoxy}-pyridine-2- carboxylic acid methylamide
150

472.90





219


embedded image


4-{4-[3-(4-Chloro-5-methyl- 2-pyrrol-1-yl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

114
489.96





220


embedded image


(2-{3-[3-Methyl-4-(2- methylcarbamoyl-pyridin- 4-yloxy)-benzyl]-ureido}-4- trifluoromethyl-phenyl)- acetic acid

23500
516.48





221


embedded image


4-{4-[3-(2-Aminomethyl-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

180
487.48





222


embedded image


4-{4-[3-(5-Trifluoromethyl- [1,3,4]thiadiazol-2-yl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

575
452.41





223


embedded image


4-{4-[3-(5-tert-Butyl-2H- pyrazol-3-yl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

7950
422.49





224


embedded image


4-{4-[3-(5-tert-Butyl- isoxazol-3-yl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

53
423.47





225


embedded image


4-(4-{3-[3-Chloro-4-(3-oxo- morpholin-4-yl)-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide

8800
509.95





226


embedded image


4-{4-[3-(2-Chloro-pyridin-3- yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
19000
11000
411.85





227


embedded image


4-{4-[3-(6-Methoxy-pyridin- 3-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide
5500
6300
407.43





228


embedded image


4-{4-[3-(3-Dimethylamino- phenyl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

1500
419.48





229


embedded image


4-{4-[3-(2-Ethoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
84

502.49





230


embedded image


4-{4-[3-(2-Ethoxy-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide
89

488.47





231


embedded image


4-{4-[3-(4-Chloro-2- methoxy-5-trifluoromethyl- phenyl)-ureidomethyl]-2- fluoro-phenoxy}-pyridine-2- carboxylic acid methylamide
100

526.87





232


embedded image


4-{4-[3-(5-Chloro-2- methoxy-phenyl)- ureidomethyl]-2-fluoro- phenoxy}-pyridine-2- carboxylic acid methylamide
52
19
458.88





233


embedded image


4-{2-Fluoro-4-[3-(3- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

27
462.40





234


embedded image


4-{4-[3-(3-Chloro-4-methyl- phenyl)-ureidomethyl]-2- fluoro-phenoxy}-pyridine-2- carboxylic acid methylamide

72
442.88





235


embedded image


4-{2-Fluoro-4-[3-(2- [1,2,4]triazol-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

27
529.45





236


embedded image


4-{4-[3-(5-Methyl-isoxazol- 3-yl)-ureidomethyl]- phenoxy}-pyridine-2- carboxylic acid methylamide

2050
381.39





237


embedded image


4-(4-{3-[2-(2-Acetylamino- ethoxy)-4-chloro-5-methyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
300

525.99





238


embedded image


4-(4-{3-[2-(2-Acetylamino- ethoxy)-4-chloro-5- trifluoromethyl-phenyl]- ureidomethyl}-phenoxy)- pyridine-2-carboxylic acid methylamide
61

579.96





239


embedded image


4-(4-{3-[2-(2-Acetylamino- ethoxy)-5-trifluoromethyl- phenyl]-ureidomethyl}- phenoxy)-pyridine-2- carboxylic acid methylamide
140

545.52





240


embedded image


4-{4-[3-(2-Imidazol-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide

2900
524.50





241


embedded image


4-{4-[3-(4-Acetylamino-3- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

710
501.46





242


embedded image


4-[4-(3-{4-Chloro-2-[2-(1,3- dioxo-1,3-dihydro-isoindol- 2-yl)-ethoxy]-5- trifluoromethyl-phenyl}- ureidomethyl)-phenoxy]- pyridine-2-carboxylic acid methylamide
440

668.03





243


embedded image


4-{4-[3-(2-Imidazol-1-yl-5- trifluoromethyl-phenyl)- ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methylamide

9400
510.48





244


embedded image


[2-(5-Chloro-4-methyl-2-{3- [4-(2-methylcarbamoyl- pyridin-4-yloxy)-benzyl]- ureido}-phenoxy)-ethyl]- methyl-carbamic acid tert- butyl ester
620

598.10





245


embedded image


1-Phenyl-3-[4-(pyridin-4- yloxy)-benzyl]-urea
9200

319.36





246


embedded image


1-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]-3-[3- methyl-4-(pyridin-4-yloxy)- benzyl]-urea
230

468.98





247


embedded image


N-[4-(4-{3-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]- ureidomethyl}-2-methyl- phenoxy)-pyridin-2-yl]- acetamide
6

526.04





248


embedded image


1-(4-Chloro-2-methoxy-5- methyl-phenyl)-3-[3- methyl-4-(pyridin-4-yloxy)- benzyl]-urea
770

411.89





249


embedded image


1-[4-(2-Methyl-furo[3,2- b]pyridin-7-yloxy)-benzyl]- 3-phenyl-urea
650

373.41





250


embedded image


1-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]-3-[3- methyl-4-(pyrimidin-4- yloxy)-benzyl]-urea
1200

469.97





251


embedded image


1-[4-(6-Amino-pyrimidin-4- yloxy)-3-methyl-benzyl]-3- [4-chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]-urea
440

484.99





252


embedded image


1-(4-Chloro-2-methoxy-5- methyl-phenyl)-3-[3- methyl-4-(2-methyl- furo[3,2-b]pyridin-7-yloxy)- benzyl]-urea
750

465.94





253


embedded image


1-[4-Chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]-3-[3- methyl-4-(2-methyl- furo[3,2-b]pyridin-7-yloxy)- benzyl]-urea
70

523.03





254


embedded image


1-[4-(2-Amino-pyridin-4- yloxy)-3-methyl-benzyl]-3- [4-chloro-2-(2- dimethylamino-ethoxy)-5- methyl-phenyl]-urea
31

484.00





255


embedded image


4-[4-[[4-chloro-3- (trifluoromethyl)- phenyl]carbamoylamino] phenoxy]-N-methyl- pyridine-2-carboxamide
110







text missing or illegible when filed






















TABLE 3a









IC50
IC50
stability
ESI




Compound
IC50
[p-
[pro-
in
MS




(chemical
[DDR2]
DDR2]
MMP13]
synovial
Rt/


No.
Compound (structure)
name)
M
M
M
fluid
M + H






















1


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(1H- pyrrolo[2,3- b]pyridin-4- yloxy)-benzyl]- urea
4.40E- 07



 2.115/ 472.2





2


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(6- trifluoromethyl- quinolin-4- yloxy)-benzyl]- urea
4.00E- 07
5.60E- 06


 2.442/ 537.2





3


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(1H- pyrrolo[2,3- b]pyridin-4- yloxy)-benzyl]- urea
6.60E- 08
2.00E- 08


 1.836/ 458.2





4


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4- ([1,8]naphthyri- din-4-yloxy)- benzyl]-urea
4.80E- 06



 1.849/ 470.2





5


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(2-oxo- 1,2,3,4- tetrahydro- pyrido[2,3- d]pyrimidin-5- yloxy)-benzyl]- urea
1.50E- 08
5.90E- 09


 2.208/ 489.2





6


embedded image


1-[3-Methyl-4- (2-methyl- pyridin-4- yloxy)-benzyl]- 3-(1-methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- urea
1.10E- 07
3.00E- 08
2.58E-07

 1.609/ 447.2





7


embedded image


4-{2-Methyl-4- [3-(1-methyl- 2-oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
3.70E- 08
1.20E- 08
3.29E-08
stable
 2.814/ 490.2





8


embedded image


4-{4-[3-(1- Methyl-2-oxo- 5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
9.70E- 08
2.80E- 08
1.48E-08

 2.113/ 476.2





9


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(quinolin-4- yloxy)-benzyl]- urea
5.10E- 08



 1.802/ 469.1





10


embedded image


1-[3-Methyl-4- (2-oxo- 1,2,3,4- tetrahydro- pyrido[2,3- d]pyrimidin-5- yloxy)-benzyl]- 3-(1-methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- urea




 1.934/ 503.2





11


embedded image


4-{4-[3-(1- Ethyl-2-oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
9.10E- 08









12


embedded image


4-{4-[3-(1- Benzyl-2-oxo- 5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide
2.60E- 07









13


embedded image


1-(1-Methyl-2- oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)-3- [4-(3- trifluoromethyl- pyridin-4- yloxy)-benzyl]- urea
1.60E- 06









14


embedded image


4-{4-[3-(1 Hydroxymethl- 2-oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide










15


embedded image


(3-{3-[4-(2- Methylcarbaoyl- pyridin- 4-yloxy)- benzyl]- ureido}-2-oxo- 5-trifluoro- methyl-2H- pyridin-1-yl)- acetic acid










16


embedded image


4-{4-[3-(1- Aminomethyl- 2-oxo-5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine- 2-carboxylic acid methylamide










17


embedded image


4-{4-[3-(1- Methylamino methyl-2-oxo- 5- trifluoromethyl- 1,2-dihydro- pyridin- 3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide










18


embedded image


4-{4-[3-(1- Dimethylamio methyl-2-oxo- 5- trifluoromethyl- 1,2-dihydro- pyridin-3-yl)- ureidomethyl]- phenoxy}- pyridine-2- carboxylic acid methylamide







text missing or illegible when filed















TABLE 3b







NMR data of the compounds of table 3a








No. of



compound


of table 3a
1HNMR





1
1H NMR (400 MHz, DMSO-d6) ppm = 8.66 (s, 1H), 8.22 (d, J = 2.5, 1H), 8.17 (d,



J = 5.6, 1H), 7.97-7.91 (m, 1H), 7.74 (t, J = 5.8, 1H), 7.43 (d, J = 3.5, 1H),



7.41-7.35 (m, 2H), 7.22-7.13 (m, 2H), 6.49 (d, J = 5.6, 1H), 6.24 (d, J = 3.5, 1H), 4.34



(d, J = 5.7, 2H), 3.83 (s, 3H), 3.57 (s, 3H).


2
1H NMR (500 MHz, DMSO-d6) ppm = 8.84 (d, J = 5.2, 1H), 8.69 (s, 1H),



8.66-8.64 (m, 1H), 8.25 (d, J = 8.8, 1H), 8.23 (d, J = 2.5, 1H), 8.10 (dd, J = 8.9, 2.2, 1H),



7.96-7.93 (m, 1H), 7.79 (t, J = 5.9, 1H), 7.49-7.46 (m, 2H), 7.36-7.32 (m, 2H),



6.72 (d, J = 5.2, 1H), 4.38 (d, J = 5.9, 2H), 3.57 (s, 3H).


3
1H NMR (500 MHz, DMSO-d6) ppm = 12.02 (s, 1H), 8.67 (s, 1H), 8.22 (d,



J = 2.5, 1H), 8.16 (d, J = 5.8, 1H), 7.97-7.93 (m, 1H), 7.75 (t, J = 5.9, 1H),



7.45-7.38 (m, 3H), 7.23-7.19 (m, 2H), 6.51 (d, J = 5.8, 1H), 6.30-6.27 (m, 1H), 4.35



(d, J = 5.8, 2H), 3.57 (s, 3H).


4
1H NMR (500 MHz, DMSO-d6) ppm = 9.22 (dd, J = 4.3, 1.9, 1H), 8.96 (d, J = 5.7,



1H), 8.91 (dd, J = 8.4, 1.9, 1H), 8.69 (s, 1H), 8.22 (d, J = 2.5, 1H), 7.98-7.93 (m,



1H), 7.83 (dd, J = 8.3, 4.3, 1H), 7.80 (t, J = 5.9, 1H), 7.54-7.32 (m, 4H), 6.82 (d,



J = 5.7, 1H), 4.39 (d, J = 5.9, 2H), 3.57 (s, 3H).


5
1H NMR (500 MHz, DMSO-d6) ppm = 9.52 (s, 1H), 8.65 (s, 1H), 8.21 (d, J = 2.5,



1H), 7.96-7.93 (m, 1H), 7.92 (d, J = 5.9, 1H), 7.73 (t, J = 5.9, 1H), 7.40-7.34



(m, 2H), 7.16-7.11 (m, 2H), 7.00 (s, 1H), 6.18 (d, J = 5.9, 1H), 4.38 (s, 2H),



4.32 (d, J = 5.8, 2H), 3.56 (s, 3H).


6
1H NMR (400 MHz, DMSO) ppm = 8.68 (s, 1H), 8.63 (d, J = 6.7, 1H), 8.21 (d,



J = 2.5, 1H), 8.01-7.92 (m, 1H), 7.81-7.73 (m, 1H), 7.35 (d, J = 2.1, 1H),



7.32-7.13 (m, 4H), 4.34 (d, J = 5.8, 2H), 3.57 (s, 3H), 2.61 (s, 3H), 2.11 (s, 3H).


7
1H NMR (500 MHz, DMSO-d6) ppm = 8.74 (q, J = 4.6, 1H), 8.65 (s, 1H), 8.50 (d,



J = 5.6, 1H), 8.22 (d, J = 2.5, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J = 5.9, 1H),



7.34-7.31 (m, 1H), 7.29 (d, J = 2.6, 1H), 7.25 (dd, J = 8.2, 2.2, 1H), 7.15-7.11 (m, 1H),



7.10 (dd, J = 5.6, 2.6, 1H), 4.33 (d, J = 5.8, 2H), 3.57 (s, 3H), 2.79 (d, J = 4.9, 3H),



2.10 (s, 3H).


8
1H NMR (400 MHz, DMSO) ppm = 8.77-8.69 (m, 1H), 8.65 (s, 1H), 8.51 (d,



J = 5.6, 1H), 8.22 (d, J = 2.5, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J = 5.9, 1H),



7.45-7.40 (m, 2H), 7.38 (d, J = 2.6, 1H), 7.23-7.17 (m, 2H), 7.17-7.13 (m, 1H), 4.35



(d, J = 5.7, 2H), 3.57 (s, 3H), 2.78 (d, J = 4.8, 3H).





















TABLE 4









IC50






IC50
[p-





Compound
[DDR2]
DDR2]
ESI MS Rt/


No.
Compound (structure)
(chemical name)
M
M
M + H







1


embedded image


(2-Hydroxy-5- trifluoromethyl-pyridin- 3-yl)-carbamic acid 3- methyl-4-(2- methylcarbamoyl- pyridin-4-yloxy)-benzyl ester
2.90E- 07

1.877/477.2





2


embedded image


(2-Hydroxy-5-methyl- pyridin-3-yl)-carbamic acid 4-(2- methylcarbamoyl- pyridin-4-yloxy)-benzyl ester


1.915/409.2





3


embedded image


(4-Trifluoromethyl- pyridin-2-yl)-carbamic acid 4-(2- methylcarbamoyl- pyridin-4-yloxy)-benzyl ester
3.30E- 08

1.983/447.1





4


embedded image


(4-Trifluoromethyl- pyridin-2-yl)-carbamic acid 3-methyl-4-(2- methylcarbamoyl- pyridin-4-yloxy)-benzyl ester
4.10E- 08

2.470/461.2





5


embedded image


(2-Hydroxy-5- trifluoromethyl-pyridin- 3-yl)-carbamic acid 4- (2-methylcarbamoyl- pyridin-4-yloxy)-benzyl ester
6.10E- 07

2.150/463.1





6


embedded image


(4-Chloro-3- trifluoromethyl-phenyl)- carbamic acid 4-(2- methylcarbamoyl- pyridin-4-yloxy)-benzyl ester
4.20E- 07
2.70E- 07
2.176/480.1







text missing or illegible when filed















TABLE 4b







NMR data of the compounds of table 4a








No. of



compound


of table 4a
1HNMR





1
1H NMRT500 MHz, DMSO-d6) ppm = 12.52 (s, 1H), 8.81 (s, 1H), 8.76 (q,



J = 4.5, 1H), 8.51 (d, J = 5.6, 1H), 8.02 (d, J = 2.5, 1H), 7.68-7.64 (m, 1H), 7.53-7.49



(m, 1H), 7.41 (dd, J = 8.2, 2.1, 1H), 7.32 (d, J = 2.6, 1H), 7.17 (d, J = 8.2, 1H),



7.11 (dd, J = 5.6, 2.6, 1H), 5.21 (s, 2H), 2.79 (d, J = 4.8, 3H), 2.12 (s, 3H).


2
1H NMR (500 MHz, Chloroform-d) ppm = 8.41 (d, J = 5.7, 1H), 8.35-8.30 (m,



1H), 8.17-8.10 (m, 1H), 7.72 (d, J = 2.5, 1H), 7.61 (s, 1H), 7.51-7.47 (m, 2H),



7.14-7.09 (m, 2H), 7.01 (dd, J = 5.6, 2.5, 1H), 6.97-6.94 (m, 1H), 5.24 (s, 2H),



3.01 (d, J = 5.0, 3H), 2.22 (s, 3H).


3
1H NMR (500 MHz, Chloroform-d) ppm = 8.70 (s, 1H), 8.42-8.37 (m, 2H), 8.34



(s, 1H), 8.08-7.99 (m, 1H), 7.71 (d, J = 2.5, 1H), 7.52-7.46 (m, 2H), 7.23-7.19



(m, 1H), 7.14-7.09 (m, 2H), 6.99 (dd, J = 5.6, 2.6, 1H), 5.27 (s, 2H), 3.00



(d, J = 5.1, 3H).


4
1H NMR (500 MHz, DMSO-d6) ppm = 10.80 (s, 1H), 8.75 (q, J = 4.8, 1H), 8.55



(d, J = 5.2, 1H), 8.51 (d, J = 5.6, 1H), 8.16 (s, 1H), 7.52-7.49 (m, 1H), 7.44-7.39



(m, 2H), 7.28 (d, J = 2.6, 1H), 7.21-7.15 (m, 1H), 7.12 (dd, J = 5.6, 2.6, 1H), 5.23



(s, 2H), 2.78 (d, J = 4.9, 3H), 2.12 (s, 3H).


5
1H NMR (400 MHz, DMSO-d6) ppm = 12.50 (s, 1H), 8.82 (s, 1H), 8.78-8.71



(m, 1H), 8.52 (d, J = 5.6, 1H), 8.01 (d, J = 2.5, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4,



2H), 7.40 (d, J = 2.6, 1H), 7.25 (d, J = 8.4, 2H), 7.17 (dd, J = 5.6, 2.7, 1H), 5.24 (s,



2H), 2.79 (d, J = 4.8, 3H).


6
1H NMR (300 MHz DMSO-d6) ppm = 10.34 (s, 1H) 8.81 (q, J = 4.8, 1H), 8.54



(d, J = 5.6, 1H), 8.05 (d, J = 2.5, 1H), 7.73 (dd, J = 8.9, 2.6, 1H), 7.68-7.63 (m,



1H), 7.63-7.56 (m, 2H), 7.36 (d, J = 2.5, 1H), 7.32-7.24 (m, 2H), 7.21 (dd,



J = 5.6, 2.6, 1H), 5.23 (s, 2H), 2.79 (d, J = 4.8, 3H).





















TABLE 5a









IC50






IC50
[p-





Compound
[DDR2]
DDR2]
ESI MS


No.
Compound (structure)
(chemical name)
M
M
Rt/M + H







1


embedded image


1-(2-Fluoro-5- trifluoromethyl- phenyl)-3-[4-(4-oxo- 4,5-dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea
1.10E- 07
1.80E- 08






2


embedded image


1-(4-Chloro-3- trifluoromethyl- phenyl)-3-[4-(4-oxo- 4,5-dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea
2.30E 06







3


embedded image


1-(2-Methoxy-5- trifluoromethyl- phenyl)-3-[4-(4-oxo- 4,5-dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea
6.20E- 08
1.10E- 07






4


embedded image


1-[4-(4-Oxo-4,5- dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]-3- (3-trifluoromethyl- phenyl)-urea
2.50E- 08
3.20E- 07






5


embedded image


1-[4-(3-Methyl-4-oxo- 4,5-dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]-3- (1-methyl-2-oxo-5- trifluoromethyl-1,2- dihydro-pyridin-3-yl)- urea


 1.717/ 473.2





6


embedded image


1-(2-Methoxy-5- trifluoromethyl- phenyl)-3-[4-(3- methyl-4-oxo-4,5- dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea


 1.985/ 472.2





7


embedded image


1-(1-Methyl-2-oxo-5- trifluoromethyl-1,2- dihydro-pyridin-3-yl)- 3-[4-(4-oxo-4,5- dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea


 1.665/ 459.1





8


embedded image


1-(5-Methyl-pyridin-3- yl)-3-[4-(4-oxo-4,5- dihydro-3H- imidazo[4,5-c]pyridin- 2-ylmethyl)-phenyl]- urea


 1.108/ 375.1







text missing or illegible when filed















TABLE 5b







NMR data of compounds of table 5a








No. of



compound


of table 5a
1HNMR





6
1H NMR (500 MHz, DMSO-d6) ppm = 11.16 (s, 1H), 9.41 (s, 1H), 8.66-8.35



(m, 2H), 7.58-6.82 (m, 7H), 6.49 (s, 1H), 4.15 (s, 2H), 3.98-3.90 (m, 6H).


7
1H NMR (400 MHz, DMSO-d6) ppm = 11.16 (s, 1H), 9.61 (s, 1H), 8.79 (s, 1H),



8.23 (d, J = 2.5, 1H), 7.99 (s, 1H), 7.39 (d, J = 8.3, 2H), 7.23 (d, J = 8.2, 2H), 7.08



(t, J = 6.1, 1H), 6.46 (d, J = 7.0, 1H), 4.06 (s, 2H), 3.58 (s, 3H).


8
1H NMR (400 MHz, DMSO-d6) ppm = 12.78 (s, 1H), 11.08 (s, 1H), 8.93 (s, 1H),



8.91 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.43-7.35 (m, 2H), 7.26-7.17



(m, 2H), 7.04 (t, J = 5.8, 1H), 6.44 (d, J = 7.0, 1H), 4.03 (s, 2H), 2.27 (s, 3H).




















TABLE 6







Compound
IC50
IC50


No.
Compound (structure)
(chemical name)
[DDR2]
[p-DDR2]




















1


embedded image


4-{4-[(4-Chloro-3- trifluoromethyl- phenylcarbamoyl)- methyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
110
nM
44 nM





2


embedded image


4-{4-[2-(4-Chloro-3- trifluoromethyl- phenylcarbamoyl)-1- hydroxy-ethyl]-2- methyl-phenoxy}- pyridine-2-carboxylic acid methylamide
21
μM






3


embedded image


4-{4-[2-(4-Chloro-3- trifluoromethyl- phenylcarbamoyl)- ethyl]-2-methyl- phenoxy}-pyridine-2- carboxylic acid methylamide
1.6
μM






4


embedded image


4-{4-[(1-Methyl-2-oxo- 5-trifluoromethyl-1,2- dihydro-pyridin-3- ylcarbamoyl)- methoxy]-phenoxy}- pyridine-2-carboxylic acid methylamide
570
nM






5


embedded image


N-(1-Methyl-2-oxo-5- trifluoromethyl- 1,2-dihydro-pyridin-3- yl)-2-[4-(2- oxo-1,2,3,4- tetrahydro-pyrido[2,3- d]pyrimidin-5-yloxy)- phenoxy]-acetamide








6


embedded image


N-(2-Fluoro-5- trifluoromethyl- phenyl)-2-[4-(2-oxo- 1,2,3,4-tetrahydro- pyrido[2,3-d]pyrimidin- 5-yloxy)-phenoxy]- acetamide








7


embedded image


N-(1-Methyl-2-oxo-5- trifluoromethyl- 1,2-dihydro-pyridin-3- yl)-2-[4-(quinolin-4- yloxy)-phenoxy]- acetamide








8


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2-[4-(3a,7a-Dihydro- 1H-pyrrolo[2,3- b]pyridin-4-yloxy)- phenoxy]-N-(1- methyl-2-oxo-5- trifluoromethyl-1,2- dihydro-pyridin-3-yl)- acetamide








9


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4-{4-[(2-Hydroxy-5- trifluoromethyl- pyridin-3- ylcarbamoyl)-methyl]- 2-methyl-phenoxy}- pyridine-2-carboxylic acid methylamide








10


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4-{2-Methyl-4-[(1- methyl-2-oxo-5- trifluoromethyl-1,2- dihydro-pyridin-3- ylcarbamoyl)-methyl]- phenoxy}-pyridine-2- carboxylic acid methylamide








11


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2-[3-Methyl-4-(3- methyl-2-oxo-1,2,3,4- tetrahydro-pyrido[2,3- d]pyrimidin-5-yloxy)- phenyl]-N-(1-methyl- 2-oxo-5- trifluoromethyl-1,2- dihydro-pyridin-3-yl)- acetamide








12


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N-(2-Fluoro-5- trifluoromethyl- phenyl)-2-[3-methyl-4- (3-methyl-2-oxo- 1,2,3,4-tetrahydro- pyrido[2,3-d]pyrimidin- 5-yloxy)-phenyl]- acetamide









In order to avoid any doubt, in all cases where the chemical name of a compound according to the invention and the depiction of the chemical structure of the compound mistakenly do not agree, the compound according to the invention is defined unambiguously by the depiction of the chemical structure.


EXAMPLE 2
Preparation of the Compounds According to the Invention

The compounds according to the invention can be prepared, for example, by methods known to the person skilled in the art by the following synthesis sequences. The examples indicated describe the synthesis, but do not restrict the latter to the examples.


EXAMPLE 2.1
Synthesis of 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea



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1. Synthesis of 3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzonitrile

4-Chloro-2-methyl-pyridine (1.00 g, 7.84 mmol, 1 eq.) and 4-Hydroxy-3-methyl-benzonitrile (1.57 g, 11.76 mmol, 1.5 eq.) are mixed together and heated for about 16 h to 160° C. Reaction mixture was cooled down to room temperature, EtOAc and 2N NaOH were added, organic phase was separated and washed twice with 2N NaOH and water. The organic phase was separated, washed once with saturated NaCl-solution and dried over Na2SO4. After filtration the organic phase was reduced in vacuo. The brown residue (HPLC/MS: Rt=1.227 min, M+H 243.1) became crystalline upon standing on air.


2) Synthesis of 3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzylamine

3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzonitrile (1.20 g, 5.35 mmol, 1 eq.) was dissolved in MeOH/NH3 (20%, 5 ml), sponge nickel (0.60 g) as catalyst were added and the mixture was stirred under an atmosphere of H2 (5 bar) at 50° C. for about 16 h. The reaction mixture was reduced in vacuo. The residue (HPLC/MS: Rt=0.435 min, M+H 229.1) was used directly in the next reaction without further purification.


3) Synthesis of 2-Methoxy-5-methyl-pyridin-3-ylamine

2-Methoxy-5-methyl-3-nitro-pyridine (1.00 g, 5.95 mmol, 1 eq.) was dissolved in THF (10 ml), wet Pd/C (0.50 g) was added. The reaction mixture was stirred at room temperature for about 16 h under an atmosphere of H2 (400 ml, 17.84 mmol, 3 eq.). The reaction mixture was filtrated and the solvend removed in vacuo. The product (HPLC/MS: Rt=1.058 min, M+H 129.3) was obtained as brown crystals, which were used in the next reaction without further purification.


4) Synthesis of 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea

Synthesis of 2-Methoxy-5-methyl-pyridin-3-ylamine (48.00 mg, 0.35 mmol, 1 eq.) was dissolved in DCM (10 ml), 4-nitro-phenyl-chloro-formiate (78.00 mg, 0.39 mmol, 1.1 eq.) and pyridine (31 ml) were added. The mixture was stirred for 2 h at room temperature. Then were added 3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzylamine (80.00 mg, 0.35 mmol, 1 eq.) and N-ethyl-diisopropyl-amine (0.06 ml, 0.35 mmol, 1 eq.). The mixture was stirred for about 16 h at room temperature. To the mixture was added DCM. The organic layer was washed once with 1N NaOH and twice with water, it was dried over Na2SO4, filtrated and the solvent removed in vacuo. The residue was purified by preparative HPLC.


HPLC (RP-18): Chromolith-prep RP-18e 100-25, Shimadzu LC 8A


Eluent A: H2O+0.1% TFA


Eluent B: Acetonitrile+0.1% TFA


Gradient: 99:1->1:99 in 15 min.


30 ml/min, Detektion: UV 220 nm


The product (HPLC/MS: Rt=1.503 min, M+H 393.2) was obtained as yellow oil.


1H-NMR (DMSO, 500 mHz) σ in ppm=8.66 (d, J=5 Hz, 1H), 8.25 (d, J=5 Hz, 1H), 8.13 (s, 1H), 7.52 (m, 1H), 7.45 (m, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.27 (m, 1H), 7.27-7.19 (m, 2H), 4.35 (d, J=5 Hz, 2H), 3.90 (s, 3H), 2.63 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H)


Abbreviations:

DCM=dichloromethane


DMA=dimethylacetamide


DMF=dimethylformamide


EA=ethyl acetate


MTBE=methyl tert-butyl ether


PE=petroleum ether


RT=room temperature


TFA=trifluoroacetic acid


EXAMPLE 2.2
Synthesis of 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methyl amide



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1) Synthesis of 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide

A solution of 4-Hydroxy-3-methyl-benzonitrile (0.100 g; 0.717 mmol) in dry DMF (3 mL) was treated with potassium-tert-butyl at (0.088 g; 0.788 mmol). The reaction mixture was stirred at RT for 2 h and 4-Chloro-pyridine-2-carboxylic acid methylamide (0.130 g; 0.717 mmol) and potassium carbonate (0.020 ml; 0.358 mmol) were added. The resulting suspension was then heated to 130° C. for 4 days. For purification the reaction mixture was allowed to cool down to RT and it was washed with 1 N NaOH-solution (5 mL) and water (5 mL). The solid, that precipitated while washing, was filtrated and added into the organic layer. The aqueous phase was extracted with DCM (2×15 mL) and the combined organic layers were evaporated to dryness. The resulting solid was dissolved in DCM (20 mL), dried with Na2SO4 and concentrated to afford the crude product. The product was purified with flash column chromatography (Combi Flash RF, Si-60, 24 g-column, gradient PE/EE 95:5 to 50:50 in 12 min then for 7 min isocratic 50:50, flow 35 ml/min, UV 254 nM) resulting in 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (136,000 mg; 0.443 mmol) as yellow solid.


2) Synthesis of 4-(4-Aminomethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide

A solution of 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (0.690 g; 0.836 mmol) in methanol (5 mL) and NH3 in methanol (20%, 5 mL) was treated with nickel sponge (0.5 g Johnson Matthey, A-7000) and purged with H2. The reaction mixture was stirred at RT for 17.5 h with a pressure of five bar. The catalyst was filtrated off and the solvent was evaporated. The crude product was then purified by flash column chromatography (Flashmaster, UV 240 nM, 70 g silica gel column, flow 20 ml/min, DCM/MeOH 9:1) yielding 4-(4-Aminomethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (0.182 g; 0.584 mmol) as yellow resin.


3) Synthesis of 1-Methyl-3-nitro-5-trifluoromethyl-1H-pyridin-2-one

To a solution of 3-Nitro-5-(trifluoromethyl)pyridin-2-ol (60.0 g; 288.33 mmol) in DMF (500 ml) was added potassium carbonat (120.0 g; 864.99 mmol) and iodomethan (19.7 ml; 317.16 mmol). The resulting suspension was stirred for about 16 h at 80° C. The reaction mixture was diluted with EtOAc and extracted 3× with water, dried over Na2SO4, filtrated and the solution evaporated to dryness.


The residue was treated with THF/petroleum ether (PE). The precipitated product was filtered off, rinsed with PE and dried in vacuo to yield a brown solid.


4) Synthesis of 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one

To a solution of 1-Methyl-3-nitro-5-trifluoromethyl-1H-pyridin-2-one (9.40 g, 42.32 mmol) in THF (100 ml) and MeOH (10 ml) was added 5% Pd/C (54% H2O, 2 g). The reaction was stirred under an atmosphere of hydrogen at room temperature. After 16 h additional Pd/C (4 g) were added and stirring was continued under hydrogen (1 atm) for 23 hours. The solids were removed via filtration and the filtrate reduced in vacuo to yield 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one (7.9 g, 41.1 mmol).


5) Synthesis of 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methyl amide

3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one (1.64 g, 8.55 mmol) was dissolved in DCM (50 ml), 4-nitro-phenyl-chloro-formiate (1.90 g, 9.437 mmol) and pyridine (0.76 ml) were added. The mixture was stirred for 2 h at room temperature. Then were added 4-(4-Aminomethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (2.32 mg, 8.55 mmol) and N-ethyl-diisopropyl-amine (2.91 ml, 17.10 mmol). The mixture was stirred for about 16 h at room temperature. To the mixture was added DCM. The organic layer was washed once with 1N NaOH and twice with water, it was dried over Na2SO4, filtrated and the solvent removed in vacuo. The residual mixture was taken up with MTBE, the resulting white precipitate was filtered off and dried in vacuo.


4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide was obtained as white solid (HPLC/MS: Rt=2.184 min, M+H 490.2).


1H NMR (500 MHz, DMSO-d6) ppm=8.74 (q, J=4.6, 1H), 8.65 (s, 1H), 8.50 (d, J=5.6, 1H), 8.22 (d, J=2.5, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J=5.9, 1H), 7.34-7.31 (m, 1H), 7.29 (d, J=2.6, 1H), 7.25 (dd, J=8.2, 2.2, 1H), 7.15-7.11 (m, 1H), 7.10 (dd, J=5.6, 2.6, 1H), 4.33 (d, J=5.8, 2H), 3.57 (s, 3H), 2.79 (d, J=4.9, 3H), 2.10 (s, 3H).


Method Info: HPLC/MS


A: H2O+0.05% HCOOH|B: MeCN+0.04% HCOOH


T: 30° C.|Flow: 2 ml/min|Column: Chromolith RP-18e 50-4.6 mm|MS: 85-800 amu


1%->100% B: 0->2.8 min|100% B: 2.8->3.3 min


EXAMPLE 2.3
Synthesis of (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester



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1) Synthesis of 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide

A solution of 4-hydroxy-3-methylbenzaldehyde (503.7 mg; 3.7 mmol) in dry DMF (7 mL) was treated with potassium-tert-butoxide (456.7 mg; 4.1 mmol). The reaction mixture was stirred at RT for 2 h and then 4-chloro-pyridine-2-carboxylic acid methylamide (672.6 mg; 3.7 mmol) and potassium carbonate (255.7 mg; 1.9 mmol) were added. The resulting suspension was heated to 130° C. for 5 days. For purification the reaction mixture was allowed to cool down to RT and water (50 mL) and DCM (50 mL) were added. The phases were separated and the organic layer was washed with 1 M NaOH-solution (50 mL) brine (20 mL), dried over Na2SO4 and the solvent was evaporated. The crude product was purified with flash column chromatography (Combi Flash RF, Si-60, 120 g-column, gradient CH/EE 100:0 to 45:55 in 28 min, flow 85 ml/min, UV 254 nM and 280 nM) obtaining 4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (598 mg; 2.21 mmol) as white solid.


2) Synthesis of 4-(4-hydroxymethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide

4-(4-formyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (400 mg; 1.5 mmol) was dissolved in dry THF (6 mL). The mixture was treated with sodium borohydride (61 mg; 1.6 mmol) and stirred for 3 h at 50° C. For purification methanol (15 mL) was added and the mixture was stirred for further 30 min. Then the mixture was evaporated to dryness and water (10 mL) and ethylacetate (30 mL) were added. The phases were separated, the organic layer was washed with brine (10 mL) and dried over Na2SO4. Finally the solvent was evaporated yielding in 4-(4-hydroxymethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (370 mg; 1.4 mmol) as white solid.


3) Synthesis of (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester

4-Trifluoromethyl-pyridin-2-ylamine (53.6 mg; 0.33 mmol) was dissolved in DCM (1.1 ml). Additionally, 4-nitrophenylchlorformiate (73.6 mg; 0.37 mmol) and pyridine (0.029 ml; 0.37 mmol) were added and the reaction mixture was stirred for 2 h. Then 4-(4-hydroxymethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (90 mg; 0.33 mmol) dissolved in DMF (1 mL) and N-ethyldiisopropylamina (0.112 mL; 0.66 mmol) were added and the reaction mixture was stirred for further 2 d at RT. For purification the solvent was evaporated and the crude product was directly purified with prep. HPLC (Agilent 1100 Series, SunFire™ Prep C18 OBM™ 5 μm (150-30 mm) column, gradient ACN/H2O 99:1 to 30:70 in 3 min, then 30:70 to 60:40 in 18 min, flow 50 ml/min, UV 220 nM) yielding in (4-trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl ester (22.8 mg; 0.05 mmol) as white TFA-salt.


HPLC/MS: (T: 30° C.|Flow: 2 ml/min|Column: Chromolith, RP-18e 50-4.6 mm, 4%->100% B: 0->2.8 min|100% B: 2.8->3.3 min, A: H2O+0.05% HCOOH, B: MeCN+0.04% HCOOH):


Rt=2.470 min, [M+H] 461.2


1H NMR (500 MHz, DMSO-d6) ppm=10.80 (s, 1H), 8.75 (q, J=4.8, 1H), 8.55 (d, J=5.2, 1H), 8.51 (d, J=5.6, 1H), 8.16 (s, 1H), 7.52-7.49 (m, 1H), 7.44-7.39 (m, 2H), 7.28 (d, J=2.6, 1H), 7.21-7.15 (m, 1H), 7.12 (dd, J=5.6, 2.6, 1H), 5.23 (s, 2H), 2.78 (d, J=4.9, 3H), 2.12 (s, 3H).


EXAMPLE 2.4
Synthesis of 1-[4-(4-Oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea and 1-(5-Methyl-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea



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1) Synthesis of 1-[4-(4-Oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea was prepared as described in WO2006/042599 A1 in four steps.


2) Synthesis of 1-(5-Methyl-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea



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To a solution of 5-Methyl-pyridin-3-ylamine (100.00 mg; 0.925 mmol) in THF was added Triphosgen (109.76 mg; 0.370 mmol) and triethylamine (0.26 ml; 1.849 mmol) at 10° C. The mixture was stirred at r.t. for 2 hours. A solution of 2-(4-Amino-benzyl)-3,5-dihydro-imidazo[4,5-c]pyridin-4-one (177.74 mg; 0.740 mmol) in (5.00 ml) was added and the mixture was stirred at r.t. for about 16 h. Water was added and the mixture was extracted with DCM. The crude product precipitates as a yellow solid. The solid was collected by filtration, washed with water and dried in vacuo. The crude product was purified by flash chromatography on silica gel (Teledyne-Isco Combi Flash RF, Si-60, 4 g, gradient: DCM/MeOH 100:0 to 80:20 in 13 min and 5 min isocratic 80:20, flow-rate: 18 ml/min, UV 254 nm) to afford 1-(5-Methyl-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea (33.00 mg; 0.085 mmol).


1H NMR (400 MHz, DMSO-d6) ppm=12.78 (s, 1H), 11.08 (s, 1H), 8.93 (s, 1H), 8.91 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.43-7.35 (m, 2H), 7.26-7.17 (m, 2H), 7.04 (t, J=5.8, 1H), 6.44 (d, J=7.0, 1H), 4.03 (s, 2H), 2.27 (s, 3H).


HPLC/MS: Rt=1.108 min, [M+H]=375.1


Method Info: HPLC/MS


A: H2O+0.05% HCOOH|B: MeCN+0.04% HCOOH


T: 30° C.|Flow: 2 ml/min|Column: Chromolith RP-18e 50-4.6 mm|MS: 85-800 amu; gradient 4%->100% B: 0->2.8 min|100% B: 2.8->3.3 min


EXAMPLE 2.5
Synthesis of 4-{4-[(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide



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1) Synthesis of (4-hydroxy-3-methyl-phenyl)-acetic acid methyl ester

A solution of (4-methoxy-3-methyl-phenyl)-acetonitrile (3.3 g; 20.4 mmol) in DCM (20 mL) was cooled to −78° C. and treated drop wise with boron tribromide (5.8 ml; 61.2 mmol) in DCM (30 mL) over 30 min. The reaction mixture was allowed to warm to RT and was then stirred for 20 h. For purification methanol (50 mL) was added drop wise at 0° C. and the solution was washed with water (2×50 mL). The aqueous phase was back extracted with DCM (5×50 mL) and the combined organic layers were dried over Na2SO4. Finally the solvent was evaporated and the crude product was purified with flash column chromatography (Combi Flash RF, Si-60, 120 g-column, gradient CH/EE 100:0 to 75:25 in 29 min then isocratic 75:25 for 13 min, flow 85 ml/min, UV 254 nM and 280 nM) obtaining (4-hydroxy-3-methyl-phenyl)-acetic acid methyl ester (1.8 g; 8 mmol) as colourless oil.


2) Synthesis of (4-hydroxy-3-methyl-phenyl)-acetic acid

(4-Hydroxy-3-methyl-phenyl)-acetic acid methyl ester (1.8 g; 8 mmol) was dissolved in a 2 M NaOH-solution (20 mL) and stirred for 1.5 h at RT. The reaction mixture was then adjusted to pH 4 with a 6 M HCl-solution and extracted with DCM (4×70 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated obtaining (4-hydroxy-3-methyl-phenyl)-acetic acid (1.3 g; 7.9 mmol) as white solid.


3) Synthesis of N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-hydroxy-3-methyl-phenyl)-acetamide

5-amino-2-chlorobenzotrifluoride (455.2 mg; 2.3 mmol) and (4-hydroxy-3-methyl-phenyl)-acetic acid (429.7 mg; 2.3 mmol) were dissolved in dry DMF (9 mL). Additionally HOBT (463.3 mg; 3 mmol), EDCI (490.783 mg; 2.6 mmol) and 4-methylmorpholine (0.27 mL; 2.6 mmol) were added to start the reaction. The reaction mixture was stirred for 24 h at 60° C. Then water (30 mL) and DCM (30 mL) were added and the phases were separated. The organic layer was washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and the solvent was evaporated. The crude product was purified with flash column chromatography (Combi Flash RF, Si-60, 40 g-column, gradient CH/EE 100:0 to 50:50 in 16 min then isocratic 50:50 for 8 min, flow 40 ml/min, UV 254 nM and 280 nM) obtaining N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-hydroxy-3-methyl-phenyl)-acetamide (243 mg; 0.5 mmol) as yellow oil.


4) Synthesis of 4-{4-[(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide

A solution of N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-hydroxy-3-methyl-phenyl)-acetamide (243 mg; 0.5 mmol) in dry DMF (1.1 mL) was treated with potassium-tert-butoxide (64 mg; 0.6 mmol). The reaction mixture was stirred at RT for 2 h and 4-chloro-pyridine-2-carboxylic acid methylamide (104 mg; 0.6 mmol) and potassium carbonate (35.9 mg; 0.3 mmol) were added. The resulting suspension was heated to 130° C. for 1 day. For purification the reaction mixture was allowed to cool to RT and water (15 mL) and DCM (15 mL) were added. The phases were separated and the organic layer was washed with water (15 mL), brine (15 mL), dried over Na2SO4 and finally the solvent was evaporated. The crude product was purified with flash column chromatography (Combi Flash RF, Si-60, 24 g-column, gradient CH/EE 100:0 to 35:65 in 21 min then isocratic 35:65 for 6 min, flow 35 mL/min, UV 254 nM and 280 nM) obtaining 4-{4-[(4-chloro-3-trifluoromethyl-phenylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide (82.5 mg, 0.2 mmol) as yellow solid.


HPLC/MS (Method Info: A: H2O+0.05% HCOOH|B: MeCN+0.04% HCOOH, T: 30° C.|Flow: 2 ml/min|Column: Chromolith RP-18e 50-4.6 mm|MS: 85-800 amu, 4%->100% B: 0->2.8 min|100% B: 2.8->3.3 min)


Rt=2.526 min [M+H] 478.1


1H NMR (300 MHz, DMSO-d6) ppm=10.63 (s, 1H), 8.82-8.66 (m, 1H), 8.49 (d, J=5.7, 1H), 8.28-8.15 (m, 1H), 7.92-7.81 (m, 1H), 7.65 (d, J=8.8, 1H), 7.41-7.32 (m, 1H), 7.33-7.23 (m, 2H), 7.17-7.04 (m, 2H), 3.72 (s, 2H), 2.78 (d, J=4.8, 3H), 2.09 (s, 3H).


EXAMPLE 3
Autophosphorylation Assay for Biochemical Activity Testing of DDR2

The autophosphorylation assay was run in two steps: the enzymatic reaction in which His-tagged DDR2 with ATP as co-substrate phosphorylates itself and the detection reaction where a time resolved FRET between XL665® labelled anti-6His antibody bound to the His-tag of the enzyme and cryptate labelled anti-phospho-Tyrosine-antibody (PT66) bound the phosphorylated Tyrosine residue of DDR2 was analysed. The autophosphorylation activity was detectable directly via the increase in HTRF signal.


The autophosphorylation assay was performed as 1536 well or 384 well HTRF® (Cisbio, Codolet, France) assay format in Greiner low volume medium binding 384-well microtiter plates and was used for high throughput screen. 4 nM His-tagged human recombinant DDR-2 kinase domain (His-TEV-DDR2 467-855 aa) and 150 μM ATP as co-substrate were incubated in a total volume of 6 μl (50 mM HEPES, 10 mM Mg-chloride, 0.01% Brij®-35, 2 mM DTT, 1% DMSO, 1 mM EGTA, 0.1% BSA, pH 7.5) in the absence or presence of the test compound (10 dilution concentrations) for 150 min at 22° C. The reaction was stopped by the addition of 4 μl detection solution (16.5 nM anti-6His antibody-XL665® (Cisbio, Codolet, France) and 2.75 nM Anti-phospho-tyrosine (PT66) labelled with Eu-Cryptate® (PT66-K, Cisbio, Codolet, France) in 50 mM HEPES, 400 mM KF, 0.1% BSA, 20 mM EDTA, pH 7.0). After 1 h incubation at room temperature the HTRF was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at excitation wavelength 340 nm (laser mode) and emission wavelengths 615 nm and 665 nm. The ratio of the emission signals was determined. The full value used was the inhibitor-free reaction. The pharmacological zero value used was Nilotinib (LC Laboratories, USA) in a final concentration of 4 The inhibitory values (IC50) were determined using either the program Symyx Assay Explorer® or Condosseo® from GeneData (see tables in Example 1).


EXAMPLE 4
Phospho-DDR2 Cellular Assay

Assays were performed in a 384 well plate format, using cell line HEK293 transfected with human DDR2 (PLT460F_(DDR2)-P7-1)


Materials and Methods:

Cells were seeded at a density of 10'000 cells/well in 384well poly-D-lysine coated Black/clear plate (Cellcoat Greiner) and incubated in DMEM medium in the presence of 10% fetal bovine serum at 37° C., 5% CO2 for 48 h. Medium was replaced by serum-free medium and cells were incubated at 37° C., 5% CO2 for 8 h. Compound to be tested in 5% DMSO or 5% DMSO and 50 μg/ml of chicken collagen II were added and cells were incubated at 37° C., 5% CO2 for 16 h


Cells were rinsed with ice-cold PBS, lysed with lysis buffer (M-PER Thermo #78501) for 30 min at room temperature and centrifuged for 1 min at 1000 RPM. In parallel, White High binding 384 well plates (Corning) were coated with mouse anti-human DDR2 capture antibody (R&D Systems kit DuoSet IC Human phospho-DDR2 ELISA), overnight at RT.


An aliquot of cell lysate was transferred to the coated plates and incubated for 2 h at RT. Plates were washed and mouse anti-phospho-tyrosine detection antibody (R&D Systems kit DuoSet IC Human phospho-DDR2 ELISA) conjugated to horse radish peroxidase (HRP) was added for 2 h at RT. Plates were washed and chemiluminescent substrate for HRP (Thermo) was added for 15 min at RT. Luminescence was measured on a luminometer.


Percentage inhibition of Collagen II induced DDR2 phosphorylation was calculated using Inhibitor controls (50 μg/ml collagen II+0.3 μM Dasatinib) and Neutral control (50 μg/ml collagen II+1% DMSO) using Genedata software (see tables in Example 1).


EXAMPLE 5
Investigation of the Anti-Hyperalgesic Effect in Animals

In order to induce an inflammation reaction, a carrageenan solution (CAR, 1%, 50 μl) was injected intra-articularly on one side into a rat knee joint. The uninjected side was used for control purposes. Six animals per group were used. The threshold was determined by means of a micrometer screw (medial-lateral on the knee joint), and the thermal hyperalgesia was determined by means of a directed infrared light source by the Hargreaves method (Hargreaves et al., 1988) on the sole of the foot. Since the site of inflammation (knee joint) is different from the site of measurement (paw sole), use is made here of the term secondary thermal hyperalgesia, the mechanism of which is of importance for the discovery of effective analgesics.


Experimental description of thermal hyperalgesia (Hargreaves test): the experimental animal is placed in a plastic chamber on a quartz sheet. Before testing, the experimental animal is firstly given about 5-15 minutes time to familiarise itself with the environment. As soon as the experimental animal no longer moves so frequently after the familiarisation phase (end of the exploration phase), the infrared light source, whose focus is in the plane of the glass bottom, is positioned directly beneath the rear paw to be stimulated. An experiment run is then started by pressing the button: infrared light results in an increase in the skin temperature of the rear paw. The experiment is terminated either by the experimental animal raising the rear paw (as an expression of the pain threshold being reached) or by automatic switching-off of the infrared light source when a prespecified maximum temperature has been reached. Light reflected by the paw is recorded as long as the experimental animal sits still. Withdrawal of the paw interrupts this reflection, after which the infrared light source is switched off and the time from switching on to switching off is recorded. The instrument is calibrated in such a way that the infrared light source increases the skin temperature to about 45 degrees Celsius in 10 s (Hargreaves et al. 1988). An instrument produced by Ugo Basile for this purpose is used for the testing.


CAR was purchased from Sigma-Aldrich. Administration of the specific cathepsin D inhibitor, compound no. 23 (from Example 1, Table 1, (S)-2-[(2S,3S)-2-((3S,4S)-3-amino-4-{(S)-3-methyl-2-[(S)-4-methyl-2-(3-methyl-butyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyric acid), was carried out intra-articularly 30 minutes before the CAR. Triamcinolone (TAC) in an amount of 10 μg/joint was used as positive control, and the solvent (vehicle) was used as negative control. The hyperalgesia is quoted as the difference in the withdrawal times between the inflamed and non-inflamed paw.


Result: TAC was capable of reducing the CAR-induced swelling, but the specific DDR2 inhibitor was not. In contrast, the specific DDR2 inhibitor was able to reduce the extent of thermal hyperalgesia as a function of the dose. Assessment: it has been shown that the compounds of the present invention exert an anti-hyperalgesic action. This can be postulated, since the compounds of the present invention exhibited no influence on inflammatory swelling and thus on the hyperalgesia trigger. It can thus be assumed that the compounds of the present invention develop a pain-reducing action in humans.


EXAMPLE 6
Stability of the Compounds According to the Invention in Bovine Synovial Fluid
Extraction of Bovine Synovial Fluid:

In the preparation of bovine explants (for the diffusion chamber or other assays), either cow hoof (metacarpal joints) or cow knee is used. The synovial fluid can be obtained from both joints. To this end, the synovial fluid is carefully removed from the open joint using a 10 ml syringe and a cannula and transferred into prepared 2 ml Eppendorf vessels. The Eppendorf vessels are labelled depending on the animal (cow passport is available). It must be ensured here that blood does not enter the joint gap during preparation of the joints. If this is the case, the synovial fluid will become a reddish colour and must consequently be discarded. The synovial fluid is basically highly viscous and clear to yellowish in colour. The removal together with a macroscopic analysis of the synovial fluid is documented.


Batch for Stability Testing of Substances in SF:

In order to check the stability of individual compounds, a pool of four different bovine synovial fluids is mixed. To this end, about 1 ml per SF is used. The mixture is prepared directly in a 5 ml glass vessel. The SFs are mixed thoroughly, but carefully. No air bubbles or foam should form. To this end, a vortex unit is used at the lowest speed. The compounds to be tested are tested in an initial concentration (unless required otherwise) of 1 μM. After addition of the substance, the batch is again mixed thoroughly and carefully. For visual monitoring, all SF batches are photographed, and the pictures are filed in the eLabBio file for the corresponding experiment. FIG. 1 shows photodocumentation of this type by way of example. The batches are incubated in the incubator for 48 h at 37° C. and 7.5% CO2.


Sampling:

The sampling is carried out after the pre-agreed times (unless required otherwise, see below). 200 μl of the SF are removed from the mixture per time and transferred directly into a 0.5 ml “low-binding” Eppendorf vessel. “Low-binding” Eppendorf vessels are used in order to minimise interaction of the substances with the plastic of the vessels. 200 μl of acetonitrile have already been introduced into the Eppendorf vessel, so that a 1+1 mixture of the SF forms thereafter. This simplifies the subsequent analysis, but precipitation of protein may occur immediately after addition of the SF. This should be noted on the protocol. The 0 h sample is taken immediately after addition of the substance. This corresponds to the 100% value in the stability calculation. Ideally, the concentration employed should be retrieved here. The samples can be frozen at −20° C.

    • 0 h
    • 6 h
    • 24 h
    • 48 h


The negative control used is SF without substance. The positive control used is SF with 1 μM of substance. This corresponds to the 0 h value and thus 100% stability.


The samples are stored in “low-binding” Eppendorf vessels at −20° C. The samples are subsequently measured quantitatively.


Data Processing:

The concentrations measured (ng/ml) are plotted against the time in a graph (Graph Pad Prism®). The percentage stability of the substance is determined here. The 100% value used is the initial value in the SF at time 0 h. The data are stored in eLabBio under the respective experiment number and reported in the MSR database (as percent stability after the corresponding incubation times).


Results:

All compounds measured remained stable (see tables in Example 1). Compound stability is defined as >80% compound recovery after 48 h.


EXAMPLE 7
Evaluation of the DDR2 Inhibitors on the Production of MMP13 by SW1353 Cells Upon Stimulation with Collagen Type II
Principle:

The binding of Collagen type II to the DDR2 receptor of the SW1353 cells initiate a signalling cascade resulting in the increase of MMP13 expression. MMP13 is released in the culture medium in its pro-form, the proMMP13 which can be measured with an ELISA.


DDR2 inhibitors are evaluated for their ability to block this signalling cascade and therefore proMMP13 production upon collagen stimulation.


Material and Methods:

















Name
Supplier
Cat. number









RPMI 1640
Gibco
21765



FCS
Promocell
C37350



L-Glutamin
Gibco
25030



Natrium
Gibco
11360



Pyruvate



HEPES
Gibco
15630



Eisessig
MERCK
8.18755.1000



Trypsin/EDTA
Invitrogen
25300



Collagen Typ II
SIGMA
C9301-5MG



DMSO
MERCK
1.02931.0500



Dasatinib
TRC
D193600



Human Pro-
R&D Systems
DM1300



MMP-13



Quantikine



ELISA Kit










Cell Culture:

SW1353 cells (ATCC, HTB-94), conserved in liquid nitrogen, are thawed and cultivated at 1.6.106 cells in a T75 in RPMI1640 supplemented with 2 mM Glutamin, 1 mM Na-Pyruvate, 10% FCS, at 37° C., 5% CO2 for three days. SW1353 cells are then harvested with trypsin/EDTA and resuspended in RPMI1640 supplemented with 2 mM Glutamin, 1 mM Na-Pyruvate, 25 mM HEPES and 0.5% FCS (assay medium) and inoculated in a 96 well plate at 30 000 cells/well in 100 μL of the assay medium and further incubated 24 hours at 37°, 5% CO2 to enable cell adhesion. For stimulation of the DDR2 receptor, 50 μL of a collagen type II solution 160 μg/mL (final concentration in the well is 40 μg/mL) will be added in each well as well as 50 μL of the different dilutions of the inhibitors (MSCs) from 0.003 μM to 10 μM (final concentration in the plate). Each condition is performed in four-plicates. After three additional days of culture, the supernatant will be harvested for proMMP13 measurement.


The Different Controls Present on Each Plate are Composed of Assay Medium with:


Positive control (with the reference compound): 40 μg/mL Collagen type II, 0.03 μM Dasatinib (reference compound) in 0.1% DMSO


Negative control (no inhibition): 40 μg/mL Collagen type II and 0.1% DMSO


Medium control (no stimulation): 0.005% Acetic acid and 0.1% DMSO


All wells contains 0.1% DMSO and 0.005% acetic acid.


MSCs concentrations used are 10, 3, 1, 0.3, 0.1, 0.03, 0.01 and 0.003 μM


The solutions needed are:

    • Collagen type II is diluted at 2 mg/mL in 0.25% acetic acid. This stock solution can be stored at 4° C. for a week and is diluted 1/12.5 in the assay medium (to obtain 160 μg/mL in 0.02% acetic acid) before being used in the assay.
    • MSCs from 0.012 to 40 μM in assay medium with 0.4% DMSO (they are then further diluted ¼ in the assay plate)
    • Dasatinib 0.12 μM in assay medium with 0.4% DMSO (it is then further diluted ¼ in the assay plate)
    • Acetic acid 0.02% in assay medium (control).


ProMMP13 Measurement:

The harvested supernatants are either directly used or stored at −20° C. until use. ProMMP13 is measured with a commercial ELISA kit, according the recommendation of the manufacturer (see Annex). Briefly, 50 μL of each samples are used undiluted and the standard curve is realised in the assay medium. At the end of the assay the ELISA plate is read on a Paradigm MTP-Reader (Beckman Coulter) at 540 (reference wavelength) and 450 nm. All the absorbance values obtained at 450 nm are corrected with the absorbance at 540 nm and a ‘Four Parameter Fit’ is used to establish the standard curve. From the standard curve the concentrations of proMMP13 in all the samples are calculated. All the calculations are realised by the Paradigm software.


Calculations:

The data reported in the database are the % effect of the compounds at the two highest concentrations (10 and 3 μM) as well as the IC50.


% effect at the two highest concentrations is calculated according to the formula:







%


_effect
@
10






μM

=



MMP






13
@
10






μM

-

MMP





13





negative_control




MMP





13





positive_control

-

MMP





13





negative_control







The IC50s are calculated with the software Graph Pad Prism (see tables in Example 1).


EXAMPLE 8
Injection Vials

A solution of 100 g of a compound of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, filtered under sterile conditions, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of a compound of the formula I.


EXAMPLE 9
Solution

A solution is prepared from 1 g of a compound of the formula I, 9.38 g of NaH2PO42H2O, 28.48 g of Na2HPO4.12H2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.


EXAMPLE 10
Ointment

500 mg of a compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.


EXAMPLE 11
Ampoules

A solution of 1 kg of a compound of the formula I in 60 l of bidistilled water is filtered under sterile conditions, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of a compound of the formula I.

Claims
  • 1. Compounds of the formula I,
  • 2. Compounds according to claim 1 in which W is N,X, Y, Q, U, T are C,V is a single bond or —CR4R5—,M is O,R1 is
  • 3. Compounds according to claim 1 in which W is N,X, Y, Q, U, T are C,V is a single bond or —CR4R5—,M is O,R1 is
  • 4. Compounds according to claim 1 in which W is N,X, Y, Q, U, T are C,V is a single bond or —CR4R5—,M is O,R1 and R6 together are
  • 5. Compounds according to claim 1 in which W is O,X, Y, Q, U, T are independently from one another C or N, with the proviso that one or more of X, Y, Q, U and T are carbon atoms and that M is bonded to a carbon atom,V is a single bond or —CR4R5—,M is O,R1 is
  • 6. Compounds according to claim 1 in which W is O,X, Y, Q, U, T are C,V is a single bond or —CR4R5—,M is O,R1 and R6 together are
  • 7. Compounds according to claim 1 in which W N,X, Y, Q, U, T are C,V is a single bond,M is —CR4R5—,R1 is
  • 8. Compounds according to claim 1 in which W N,X, Y, Q, U, T are C,V is a single bond,M is —CR4R5—,R1 and R6 together are
  • 9. Compounds according to claim 1 in which W is CH2, CH2CH2, CH2CHOH or —(CH2)O—,X, Y, Q, U, T are C,V is a single bond,M is O,R1 is
  • 10. Compounds according to claim 1 in which W is CH2, CH2CH2, CH2CHOH or —(CH2)O—,X, Y, Q, U, T are C,V is a single bond,M is O,R1 is
  • 11. Compounds according to claim 1a) 4-{4-[3-(3,5-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideb) 4-{4-[3-(2,6-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidec) 4-{4-[(3-Pyridin-2-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamided) 4-{4-[3-(2-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidee) 4-{4-[(3-Pyridin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamidef) 4-{4-[3-(2-Chloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideg) 4-{4-[3-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideh) 4-{4-[3-(2,5-Dichloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidei) 4-{4-[(3-Isoquinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamidej) 4-{4-[(3-Quinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamidek) 4-{4-[3-(2-Methoxy-quinolin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidel) 4-{4-[3-(5-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidem) 4-{2-Methyl-4-[3-(5-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamiden) 4-{4-[3-(4-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideo) 4-{2-Methyl-4-[3-(4-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidep) 4-{4-[3-(2-Chloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideq) 4-{4-[3-(6-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamider) 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[4-(pyridin-4-yloxy)-benzyl]-ureas) 4-{4-[3-(2-Methoxy-5-methyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidet) 4-{4-[3-(2-Methoxy-5-methyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamideu) 4-{4-[3-(5-Chloro-2-methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidev) 4-{4-[3-(2-Chloro-5-methyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidew) 4-{4-[3-(5-Chloro-2-methoxy-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamidex) 4-{4-[3-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidey) 4-{4-[3-(2-Chloro-5-methyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamidez) 4-{4-[3-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamideaa) 1-(5-Chloro-2-methoxy-pyridin-3-yl)-3-[4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureabb) 1-(5-Chloro-2-methoxy-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureacc) 1-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-3-[4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureadd) 1-(2-Chloro-5-trifluoromethyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureaee) 1-(2-Methoxy-5-methyl-pyridin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureaff) 1-[3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-3-quinolin-3-yl-ureagg) 1-(2-Methoxy-quinolin-3-yl)-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-ureahh) 1-Isoquinolin-3-yl-3-[3-methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-urea
  • 12. Compounds according to claim 11 1-(3-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea2 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(2,4,5-trichloro-phenyl)-urea3 4-{4-[3-(3,4-Dichloro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide4 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(3-trifluoromethyl-phenyl)-urea5 1-(2,4-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea6 1-[4-(Pyridin-4-yloxy)-benzyl]-3-m-tolyl-urea7 1-(3-Acetyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea8 4-{4-[3-(2,4-Dichloro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide9 1-(4-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea10 1-(2,5-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea11 1-(4-Fluoro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea12 4-{4-[3-(4-Fluoro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide13 1-(2,3-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea14 4-{4-[3-(2-Methoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide15 1-(2,5-Dimethoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea16 1-(4-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea17 1-(4-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea18 1-[4-(Pyridin-4-yloxy)-benzyl]-3-p-tolyl-urea19 4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide20 4-{4-[3-(2,5-Dimethoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide21 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(4-trifluoromethyl-phenyl)-urea22 1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea23 4-{4-[3-(2,4,5-Trichloro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide24 1-(2,3-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea25 1-(2,5-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea26 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(2-trifluoromethyl-phenyl)-urea27 1-(3-Chloro-4-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea28 1-(2-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea29 1-[4-(Pyridin-4-yloxy)-benzyl]-3-o-tolyl-urea30 1-(2,4-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea31 4-{4-[3-(3,5-Dichloro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide32 1-(5-Chloro-2-methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea33 1-(2-Chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea34 1-(3-Methylsulfanyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea35 1-(4-Bromo-2-chloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea36 1-(2-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea37 1-(2-Chloro-4-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea38 1-(3,4-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea39 4-{4-[3-(3-Chloro-4-methoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide40 1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea41 1-(4-Ethoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea42 4-{4-[3-(5-Chloro-2-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide43 1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea44 1-(3,5-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea45 1-(3-Methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea46 1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea47 1-(4-Acetyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea48 1-(2-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea49 1-(4-Isopropyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea50 1-(5-Chloro-2-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea51 1-(4-Methylsulfanyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea52 1-(4-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea53 1-(3-Bromo-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea54 1-(4-Chloro-2-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea55 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(4-trifluoromethoxy-phenyl)-urea56 1-(4-tert-Butyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea57 1-(3,5-Dichloro-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea58 1-(4-Bromo-3-methyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea59 1-(3,4-Dimethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea60 1-(3-Chloro-4-methoxy-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea61 1-(3-Ethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea62 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea63 4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide64 1-(4-Bromo-3-trifluoromethyl-phenyl)-3-[4-(pyridin-4-yloxy)-benzyl]-urea65 1-[4-(Pyridin-4-yloxy)-benzyl]-3-(3-trifluoromethoxy-phenyl)-urea66 4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide67 4-{4-[3-(4-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide68 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{1-[4-(pyridin-4-yloxy)-phenyl]-cyclopropyl}-urea69 4-(4-{1-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureido]-ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide70 4-(4-{1-[3-(2,4,5-Trichloro-phenyl)-ureido]-ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide71 4-(4-{1-[3-(3,4-Dichloro-phenyl)-ureido]-ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide72 4-(4-{1-[3-(5-Chloro-2-methoxy-phenyl)-ureido]-ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide73 4-(4-{1-[3-(3-Chloro-4-methyl-phenyl)-ureido]-ethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide74 4-{4-[3-(4-Chloro-3-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide75 4-{4-[3-(2-Methoxy-5-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide76 4-{4[(3-Benzo[1,2,5]thiadiazol-5-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide77 4-(4-{3-[2-(2-Dimethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide78 4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide79 4-{4-[3-(4-Chloro-2-methoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide80 4-{4-[3-(3,4,5-Trimethoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide81 4-{4-[3-(2,5-Dimethoxy-4-nitro-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide82 3-Methoxy-4-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-benzoic acid methyl ester83 4-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide84 4-{4-[3-(3,5-Dichloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide85 4-{4[(3-Pyridin-2-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide86 4-(4-{3-[2-(3-Dimethylamino-propoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide87 4-{4-[3-(2-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide88 4-{4[(3-Pyridin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide89 4-{4-[3-(2-Chloro-pyridin-4-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide90 4-{4[(3-Pyridin-4-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide91 4-{4-[3-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide92 (2-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid methyl ester93 4-{4-[3-(2,5-Dichloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide94 (2-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid95 4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide96 4-{4 [(3-Isoquinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide97 4-{4 [(3-Quinolin-3-yl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide98 (5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid99 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid100 4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide101 4-{4-[3-(2-Methoxy-quinolin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide102 4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide103 4-{4-[3-(2,4-Dichloro-6-methoxy-3-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide104 4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-3-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide105 4-{4-[3-(2-Methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-3-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide106 4-(4-{3-[2-(2-Pyrrolidin-1-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide107 (5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid tert-butyl ester108 4-(4-{3-[2-(2-Diethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide109 4-(4-{3-[2-(2-Morpholin-4-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide110 4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide111 4-(4-{3-[2-(2-Methylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide112 4-(4-{3-[2-(2-Piperazin-1-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide113 (5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid methyl ester114 (5-Chloro-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenoxy)-acetic acid isopropyl ester115 4-(4-{3-[2-(Piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide116 4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide117 4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide118 4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide119 4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide120 4-(4-{3-[4-Chloro-5-methyl-2-(2-piperazin-1-yl-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide121 4-(4-{3-[2-(2-Amino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide122 4-{4-[3-(2-Piperazin-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide123 4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carb oxylic acid (2-amino-ethyl)-amide124 4-(4-{3-[4-Chloro-5-methyl-2-(piperidin-4-yloxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide125 4-(4-{3-[4-Chloro-5-methyl-2-(2-methylamino-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide126 4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carb oxylic acid (6-amino-hexyl)-amide127 4-(4-{3-[4-Chloro-2-(2-methylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide128 4-(4-{3-[4-Chloro-2-(2-piperazin-1-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide129 4-(4-{3-[4-Chloro-2-(2-pyrrolidin-1-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide130 4-(4-{3-[4-Chloro-2-(piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide131 4-(4-{3-[4-Chloro-2-(2-morpholin-4-yl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide132 4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide133 4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-phenyl]-ureidomethyl}-3-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide134 4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ureidomethyl}-3-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide135 4-{4-[3-(3-Methanesulfonyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide136 4-(4-{3-[4-Chloro-2-(2-diethylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide137 4-(4-{3-[4-Chloro-5-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide138 4-(4-{3-[4-Chloro-5-methyl-2-(2-morpholin-4-yl-ethoxy)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide139 4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide140 4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide141 4-(4-{3-[4-Chloro-5-methyl-2-(2-methylamino-ethoxy)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide142 4-(4-{3-[4-Chloro-5-methyl-2-(piperidin-4-yloxy)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide143 4-(4-{3-[4-Chloro-5-methyl-2-(2-piperazin-1-yl-ethoxy)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide144 4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide145 4-(4-{3-[2-(2-Amino-ethoxy)-4-chloro-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide146 4-(2-Methyl-4-{3-[2-(2-methylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide147 4-(4-{3-[4-Chloro-2-(2-methylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide148 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid (2-amino-ethyl)-amide149 4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid (2-methylamino-ethyl)-amide150 4-(4-{3-[2-(2-Dimethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide151 4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide152 4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide153 4-(4-{3-[4-Chloro-2-(3-dimethylamino-propoxy)-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide154 4-{4-[3-(3-Methanesulfonyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide155 4-(4-{3-[2-(2-Amino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide156 4-(4-{3-[2-(Pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide157 4-{4-[3-(3-Sulfamoyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide158 4-{4-[3-(3-Isopropylsulfamoyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide159 4-(4-{3-[5-Methyl-2-(piperidin-4-yloxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide160 4-(4-{3-[2-(2-Amino-2-methyl-propoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide161 4-(4-{3-[4-Chloro-2-(4-dimethylamino-butoxy)-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide162 4-[4-(3-{4-Chloro-2-[(2-dimethylamino-ethyl)-methyl-amino]-5-methyl-phenyl}-ureidomethyl)-phenoxy]-pyridine-2-carboxylic acid methylamide163 4-(4-{3-[4-Chloro-2-(3-dimethylamino-propoxy)-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide164 4-[4-(3-{4-Chloro-2-[(2-dimethylamino-ethyl)-methyl-amino]-5-methyl-phenyl}-ureidomethyl)-2-methyl-phenoxy]-pyridine-2-carboxylic acid methylamide165 4-(4-{3-[4-Chloro-2-(4-dimethylamino-butoxy)-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide166 4-(4-{3-[2-(2-Methoxy-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide167 4-{4-[3-(3-Methanesulfonylamino-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide168 4-(4-{3-[2-(2-Methoxy-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide169 4-(4-{3-[2-(2-Methylamino-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide170 4-(4-{3-[5-Methyl-2-(2-methylamino-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide171 4-(2-Methyl-4-{3-[5-methyl-2-(piperidin-4-yloxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide172 4-(4-{3-[2-(2-Isopropylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide173 4-(4-{3-[5-Chloro-4-methyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide174 4-(4-{3-[5-Chloro-2-(2-dimethylamino-ethoxy)-4-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide175 4-(4-{3-[2-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide176 4-(4-{3-[2-(2-Amino-ethoxy)-5-chloro-4-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide177 4-(4-{3-[5-Chloro-4-methyl-2-(2-methylamino-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide178 4-(4-{3-[5-Chloro-4-methyl-2-(piperidin-4-yloxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide179 4-(4-{3-[5-Chloro-4-methyl-2-(2-piperazin-1-yl-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide180 4-(4-{3-[2-(2-Methanesulfonylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide181 4-{4[(3-Phenyl-ureido)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamide182 4-(4-{3-[5-Chloro-4-methyl-2-(pyrrolidin-2-ylmethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide183 4-(4-{3-[5-Chloro-2-(2-isopropylamino-ethoxy)-4-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide184 4-{2-Methyl-4-[3-(2-piperazin-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide185 4-(4-{3-[2-(2-Amino-2-methyl-propoxy)-5-chloro-4-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide186 4-{4-[3-(2-Acetylamino-4-chloro-5-methyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide187 4-[4-(3-{4-Chloro-5-methyl-2-[2-(2,2,2-trifluoro-acetylamino)-ethoxy]-phenyl}-ureidomethyl)-phenoxy]-pyridine-2-carboxylic acid methylamide188 4-(4-{3-[2-(2-Methylamino-ethoxy)-5-trifluoromethanesulfonyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide189 4-(2-Methyl-4-{3-[2-(2-methylamino-ethoxy)-5-trifluoromethanesulfonyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide190 4-{4-[3-(2-Carbamoylmethoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide191 4-(4-{3-[2-(3-Amino-propoxy)-4-chloro-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide192 4-{4-[3-(2-Piperazin-1-ylmethyl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide193 4-(4-{3-[4-Chloro-2-(2-methanesulfonylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide194 4-(4-{3-[4-Chloro-2-(2-methanesulfonylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide195 4-(4-{3-[2-(2-Hydroxy-ethyl)-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide196 4-{4-[3-(2-Hydroxymethyl-4-methyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide197 4-(4-{3-[2-(2-Hydroxy-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide198 4-{4-[3-(2-Hydroxymethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide199 4-(4-{3-[2-(1-Carbamoyl-1-methyl-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide200 4-{2-Methyl-4-[3-(2-methylcarbamoylmethyl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide201 4-{4-[3-(2-[1,2,4]Triazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide202 4-{2-Methyl-4-[3-(2-[1,2,4]triazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide203 4-{2-Methyl-4-[3-(2-[1,2,3]triazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide204 4-{4-[3-(2-Hydroxy-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide205 2-Oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzylamide206 4-{4-[3-(2-[1,2,3]Triazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide207 4-{4-[3-(2-Carbamoylmethyl-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide208 4-(4-{3-[2-(2-Oxo-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide209 4-{4-[3-(2-Carbamoylmethyl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide210 4-{4-[3-(5-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide211 4-{2-Methyl-4-[3-(5-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide212 4-{4-[3-(4-Methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide213 4-{2-Methyl-4-[3-(4-methyl-pyridin-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide214 4-(4-{3-[2-(Acetylamino-methyl)-5-trifluoromethyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide215 4-(2-Methyl-4-{3-[5-methyl-2-(2-methylamino-ethoxy)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide216 4-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide217 4-{2-Fluoro-4-[3-(2-methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide218 4-{4-[3-(4-Chloro-2-methoxy-5-methyl-phenyl)-ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide219 4-{4-[3-(4-Chloro-5-methyl-2-pyrrol-1-yl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide220 (2-{3-[3-Methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-4-trifluoromethyl-phenyl)-acetic acid221 4-{4-[3-(2-Aminomethyl-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide222 4-{4-[3-(5-Trifluoromethyl-[1,3,4]thiadiazol-2-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide223 4-{4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide224 4-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide225 4-(4-{3-[3-Chloro-4-(3-oxo-morpholin-4-yl)-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide226 4-{4-[3-(2-Chloro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide227 4-{4-[3-(6-Methoxy-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide228 4-{4-[3-(3-Dimethylamino-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide229 4-{4-[3-(2-Ethoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide230 4-{4-[3-(2-Ethoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide231 4-{4-[3-(4-Chloro-2-methoxy-5-trifluoromethyl-phenyl)-ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide232 4-{4-[3-(5-Chloro-2-methoxy-phenyl)-ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide233 4-{2-Fluoro-4-[3-(3-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide234 4-{4-[3-(3-Chloro-4-methyl-phenyl)-ureidomethyl]-2-fluoro-phenoxy}-pyridine-2-carboxylic acid methylamide235 4-{2-Fluoro-4-[3-(2-[1,2,4]triazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide236 4-{4-[3-(5-Methyl-isoxazol-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide237 4-(4-{3-[2-(2-Acetylamino-ethoxy)-4-chloro-5-methyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide238 4-(4-{3-[2-(2-Acetylamino-ethoxy)-4-chloro-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide239 4-(4-{3-[2-(2-Acetylamino-ethoxy)-5-trifluoromethyl-phenyl]-ureidomethyl}-phenoxy)-pyridine-2-carboxylic acid methylamide240 4-{4-[3-(2-Imidazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamide241 4-{4-[3-(4-Acetylamino-3-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide242 4-[4-(3-{4-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-5-trifluoromethyl-phenyl}-ureidomethyl)-phenoxy]-pyridine-2-carboxylic acid methylamide243 4-{4-[3-(2-Imidazol-1-yl-5-trifluoromethyl-phenyl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide244 [2-(5-Chloro-4-methyl-2-{3-[4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester245 1-Phenyl-3-[4-(pyridin-4-yloxy)-benzyl]-urea246 1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-[3-methyl-4-(pyridin-4-yloxy)-benzyl]-urea247 N-[4-(4-{3-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-ureidomethyl}-2-methyl-phenoxy)-pyridin-2-yl]-acetamide248 1-(4-Chloro-2-methoxy-5-methyl-phenyl)-3-[3-methyl-4-(pyridin-4-yloxy)-benzyl]-urea249 1-[4-(2-Methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-3-phenyl-urea250 1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-[3-methyl-4-(pyrimidin-4-yloxy)-benzyl]-urea251 1-[4-(6-Amino-pyrimidin-4-yloxy)-3-methyl-benzyl]-3-[4-chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-urea252 1-(4-Chloro-2-methoxy-5-methyl-phenyl)-3-[3-methyl-4-(2-methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-urea253 1-[4-Chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-3-[3-methyl-4-(2-methyl-furo[3,2-b]pyridin-7-yloxy)-benzyl]-urea254 1-[4-(2-Amino-pyridin-4-yloxy)-3-methyl-benzyl]-3-[4-chloro-2-(2-dimethylamino-ethoxy)-5-methyl-phenyl]-urea255 4-[4-[[4-chloro-3-(trifluoromethyl)-phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide
  • 13. Compounds according to claim 1a) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzyl]-ureab) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(6-trifluoromethyl-quinolin-4-yloxy)-benzyl]-ureac) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzyl]-uread) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-([1,8]naphthyridin-4-yloxy)-benzyl]-ureae) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-benzyl]-ureaf) 1-[3-Methyl-4-(2-methyl-pyridin-4-yloxy)-benzyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureag) 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideh) 4-{4-[3-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidei) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(quinolin-4-yloxy)-benzyl]-ureaj) 1-[3-Methyl-4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-benzyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureak) 4-{4-[3-(1-Ethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidel) 4-{4-[3-(1-Benzyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamidem) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(3-trifluoromethyl-pyridin-4-yloxy)-benzyl]-urean) 4-{4-[3-(1-Hydroxymethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideo) (3-{3-[4-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzyl]-ureido}-2-oxo-5-trifluoro-methyl-2H-pyridin-1-yl)-acetic acidp) 4-{4-[3-(1-Aminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamideq) 4-{4-[3-(1-Methylaminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamider) 4-{4-[3-(1-Dimethylaminomethyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide
  • 14. Compounds according to claim 1a) (2-Hydroxy-5-trifluoromethyl-pyridin-3-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl esterb) (2-Hydroxy-5-methyl-pyridin-3-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl esterc) (4-Trifluoromethyl-pyridin-2-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl esterd) (4-Trifluoromethyl-pyridin-2-yl)-carbamic acid 3-methyl-4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl estere) (2-Hydroxy-5-trifluoromethyl-pyridin-3-yl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4-yloxy)-benzyl esterf) (4-Chloro-3-trifluoromethyl-phenyl)-carbamic acid 4-(2-methylcarbamoyl-pyridin-4
  • 15. Compounds according to claim 1a) 1-[4-(4-Oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(3-trifluoromethyl-phenyl)-ureab) 1-[4-(3-Methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-3-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureac) 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(3-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-uread) 1-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-ureae) 1-(5-Methyl-pyridin-3-yl)-3-[4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-ylmethyl)-phenyl]-urea
  • 16. Compounds according to claim 1a) 4-{4-[(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamideb) 4-{4-[2-(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-1-hydroxy-ethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamidec) 4-{4-[2-(4-Chloro-3-trifluoromethyl-phenylcarbamoyl)-ethyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamided) 4-{4-[(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-ylcarbamoyl)-methoxy]-phenoxy}-pyridine-2-carboxylic acid methylamidee) N-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-2-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenoxy]-acetamidef) N-(2-Fluoro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenoxy]-acetamideg) N-(1-Methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-2-[4-(quinolin-4-yloxy)-phenoxy]-acetamideh) 2-[4-(3a,7a-Dihydro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenoxy]-N-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-acetamidei) 4-{4-[(2-Hydroxy-5-trifluoromethyl-pyridin-3-ylcarbamoyl)-methyl]-2-methyl-phenoxy}-pyridine-2-carboxylic acid methylamidej) 4-{2-Methyl-4-[(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-ylcarbamoyl)-methyl]-phenoxy}-pyridine-2-carboxylic acid methylamidek) 2-[3-Methyl-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenyl]-N-(1-methyl-2-oxo-5-trifluoromethyl-1,2-dihydro-pyridin-3-yl)-acetamidel) N-(2-Fluoro-5-trifluoromethyl-phenyl)-2-[3-methyl-4-(3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy)-phenyl]-acetamide
  • 17. Compounds according to claim 1 and physiologically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, as DDR2 inhibitors.
  • 18. Pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
  • 19. Pharmaceutical composition according to claim 18 comprising further excipients and/or adjuvants.
  • 20. Pharmaceutical composition comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.
  • 21. Process for the preparation of a pharmaceutical composition, characterised in that a compound according to claim 1 and/or one of its physiologically acceptable salts, solvates and stereoisomers, including mixtures thereof in all ratios, is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.
  • 22. Medicament comprising at least one compound according to claim 1 and/or one of its physiologically acceptable salts, solvates and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states.
  • 23. Medicament comprising at least one compound according to claim 1 and/or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states, selected from the group consisting of osteoarthritis, hepatocirrhosis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.
  • 24. A method comprising administering a pharmaceutical composition according to claim 18 by intra-articular administration for the treatment and/or prophylaxis of physiological and/or pathophysiological states selected from the group consisting of osteoarthritis, traumatic cartilage injuries, pain, allodynia or hyperalgesia.
  • 25. Set (kit) consisting of separate packs of a) an effective amount of a compound according to claim 1 and/or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, andb) an effective amount of a further medicament active ingredient.
Priority Claims (1)
Number Date Country Kind
12006134.6 Aug 2012 EP regional
PCT Information
Filing Document Filing Date Country Kind
PCT/EP2013/002236 7/29/2013 WO 00