Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibito

专利摘要:

公开号:AU2005266460A1
申请号:U2005266460
申请日:2005-07-25
公开日:2006-02-02
发明作者:Didier Benard；Herve Bouchard；Youssef El-Ahmad；Stefan Guessregen；Augustin Hittinger；Anne Lebrun；Dominique Lesuisse；Conception Nemecek；Kurt Ritter；Sven Ruf；Hartmut Strobel
申请人:Aventis Pharma SA；
IPC主号:C07D401-06

专利说明:
WO 2006/010641 PCT/EP2005/008720 NOVEL AMINO CYCLIC UREA DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL USE THEREOF AS KINASE INHIBITORS The present invention relates to novel amino cyclic urea derivatives, to a process for preparing them, to their use as medicinal products, to pharmaceutical compositions containing them and to the pharmaceutical use of such derivatives for preventing and treating complaints that may be modulated by inhibiting the activity of protein kinases. The present invention relates to novel amino cyclic urea derivatives that have inhibitory effects on protein kinases. The products of the present invention may thus be used especially for preventing or treating complaints capable of beiig modulated by inhibiting the activity of protein kinases. The inhibition and regulation of protein kinases especially constitute a powerful new mechanism of action for treating a large number of solid tumours. Such complaints that the products of the present patent application can treat are thus most particularly solid tumours. Such protein kinases belong especially to the following group: IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Fltl-3, FAK, Src, Abl, cKit, cdkl-9, Auroral-2, cdc7, Akt, Pdk, S6K, Jnk, IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2, CDK7, CDK2 et EGFR. Such protein kinases belong more especially to the following group:. IGF1, cdc7, Auroral-2, Src, Jnk, FAK, KDR, IR, Tie2, CDK7, CDK2 et EGFR. The protein kinase IGF1-R (Insulin Growth Factor-1 Receptor) is particularly indicated. The protein kinase-FAK is also indicated. The protein kinase AKT is also indicated.
WO 2006/010641 PCT/EP2005/008720 2 The present invention thus relates particularly to novel inhibitors of the IGF-1R receptor that may. be used for oncology treatments. The present invention also relates to novel FAK 5 receptor inhibitors that may be used for oncology treatments. The present invention also relates to novel AKT receptor inhibitors that may be used for oncology treatments. 10 Cancer remains a disease for which the existing treatments are' clearly insufficient. Certain protein kinases, especially including IGF-lR (Insulin Growth Factor 1 Receptor), play an important role in many cancers.. The inhibition of such protein kinases is 15 potentially important in the chemotherapy of cancers, especially for suppressing the growth or survival of tumours. The present invention thus relates to the identification of novel products that inhibit such protein kinases. 20 Protein kinases participate in signalling events that control the activation, growth and differentiation of cells in response either to extracellular mediators or to changes in the environment. In general, these, kinases, belong to two . groups: those that preferentially 25 phosphorylate serine and/or threonine residues and those that preferentially phosphorylate tyrosine residues [S.K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576 596] . The serine/threonine kinases are, for example, the isoforms of the protein kinases C [A.C. Newton, J. Biol. 30 Chem., 1995, 270, pages 28495-284981 and a group of cycline-dependent kinases, for instance cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. Tyrosine kinases comprise growth factor receptors, for instance the epidermal growth factor (EGF) receptor 35 [S. Iwashita and M. Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosol kinases, for instance WO 2006/010641 PCT/EP2005/008720 3 p56tck, p59fYh and - ZAP-70 and the kinases csk [C. Chan et.: al., Ann. Rev. Immunol., 1994, 12, pages 555-592]. Abnormally high levels of kinase protein activity have - been impli.cated in many diseases,- resulting from 5 abnormal 'cellular functions. This- may arise either directly or indirectly from a dysfunction in the mechanisms for controlling the kinase activity, linked, for example, to a - mutation, an overexpression or an inappropriate activation of the enzyme, or an over- or 10 underproduction of cytokines or of growth factors, also involved in the transduction of the signals upstream or downstream 'of athe kinases. In all these cases, a selective inhibition of the action of the kinases offers hope of a beneficial effect. 15 The type 1 receptor for the insulin-like growth factor (IGF-I-R) - is a transmembrane receptor with tyrosine kinase activity which binds firstly to IGFI, but also to IGFII and to insulin with lower affinity. The binding of IGFl to its receptor results in 20 oligomerization of the receptor, the activation of tyrosine kinase, intermolecular autophosphorylation and the phosphorylation of cell substrates (main substrates:. IRS1 and- Shc) . The receptor activated by its ligand induces mitogenic activity in normal cells. However, 25 IGF-I-R- plays an important role in "abnormal" growth. Several clinical reports underline the important role o'f the IGF-I route in the development of - human cancers: IGF-I-R is often found overexpressed in many types 30 of tumour (breast, colon, lung, sarcoma, etc. ) and its presence is often associated with a more aggressive phenotype. High concentrations of circulating IGF1 are strongly correlated With a . risk of prostate cancer, lung cancer 35 and breast cancer. Furthermore, it has been widely documented that WO 2006/010641 PCT/EP2005/008720 4 IGF-I-R is necessary for establishing and maintaining the transformed phenotype in vitro as in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6]. The -kinase activity of IGF-I-R'.is essential for the transformation 5 activity of several oncogenes: EGFR, PDGFR, the large T antigen of the SV40 virus, activated Ras, Raf, and v-Src. The expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which may then result in the formation of a tumor in vivo. The expression of IGF-I-R 10 plays an important role in substrate-independent growth. IGF-I-R has also been shown to be a protector in chemotherapy-induced and radiation-induced apoptosis, and cytokine-induced apoptosis. Furthermore, the inhibition of endogenous IGF-I-R with a negative dominant, the 15 formation of a triple helix or the expression of an antisense sequence brings about suppression of the transforming activity in vitro and reduction of tumour growth in animal models. Among the kinases for which a modulation of the 20 activity is desired, - FAK (Focal Adhesion Kinase) is also a preferred kinase. FAK is a cytoplasmic tyrosine kinase that plays an important role in transducing the signal transmitted by the integrins, a family of heterodimeric receptors of 25 cellular adhesion. FAK~and the integrins are colocalized in perimembrane structures known as adhesion plaques. It has been shown in many cell types that the activation of FAK and its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397 - were 30 dependent on the binding of the integrins to- their extracellular ligands and thus induced during cellular adhesion [Kornberg L, et al. J.. Biol. Chem. 267(33): 23439-442 (1992)] . The autophosphorylation on tyrosine 397 of FAK represents a binding site for another tyrosine 35 kinase, Src, via its SH2 domain [Schaller et al. Mol. Cell. Biol. 14: '1680-1688 1994; Xing et al. Mol. Cell.
WO 2006/010641 PCT/EP2005/008720 5 Biol. 5: 413-421 1994] . Src can then phosphorylate FAK on tyrosine 925, thus recruiting the adapter protein. Grb2 and inducing in certain. cells activation of the ras and MAP kinase pathway involved in controlling cellular 5 proliferation .[Schlaepfer et al. Nature; 372: 786-791 1994; Schlaepfer et~al. Prog. Biophy. Mol. Biol. 71: 435 478 1999; Schlaepfer' and Hunter, J. Biol. Chem. 272: 13189-13195 1997]. The activation of 'FAK can thus induce the jun NH2 10 terminal kinase (JNK) signalling pathway and result in the progression of the cells .to the G1 phase of the cellular cycle [Oktay et. al., J. Cell. Biol. 145: 1461 1469 1999]. Phosphatidylinositol-3-OH kinase (P13-kinase) also binds to FAK on tyrosine.,397 and this interaction 15 might be necessary for the activation of P13-kinase .[Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152 1994; Ling et al. J. Cell. Biochem. 73: 533-544 1999]. The FAK/Src complex phosphorylates various substrates, for instance paxillin and p130CAS in fibroblasts [Vuori 20 et-al. Mol. Cell. Biol. 16: 2606-2613 1996]. The results of numerous studies support the hypothesis. that FAK inhibitors might be useful in' treating cancer. Studies have suggested that FAK might play, an important role- i-n in vitro cell proliferation 25 and/or survival. - For example, in CHO cells, _certain authors have demonstrated that the overexpression of .p125FAK induces an acceleration of the Gl to S transition, suggesting that p125FAK promotes cellular proliferation [Zhao J.-H et al. J. Cell Biol. 143: 1997 30 2008 1998] . Other authors have shown that tumour cells treated with FAK antisense oligonucleotides lose their adhesion and go into apoptosis (Xu et al, Cell Growth Differ. 4: 413-418 1996) . It has also been demonstrated that FAK promotes the migration of cells in vitro. Thus, 35 fibroblasts that are deficient for the expression of FAK ("knockout' mice for FAK) show a rounded morphology and WO 2006/010641 PCT/EP2005/008720 6 deficiencies in cell migration in response to chemotactic signals, and these defects are suppressed by reexpression of FAK - [bJ. Sieg' et al., J. Cell Science. 112: 2677-91 1999] .<The overexpression of the C-terminal domain of FAK 5 -(FRNK) blocks the stretching of adherent cells and reduces cellular* migration in vitro [Richardson A. and Parsons J.T. Nature. 380 538-540 1996]. The overexpression of FAK in CHO or COS cells or in human astrocytoma cells promotes migration of .the cells. The 10 involvement of FAK in promoting the proliferation and migration of cells in numerous cell types in vitro suggests the potential role of FAK, in neoplastic processes. A recent study has effectively demonstrated the increase in the proliferation of tumour cells in vivo 15 after induction of the expression of FAK in .human, astrocytoma cells [Cary L.A. et- al. J. Cell Sci. 109: 1787-94 1996 ; Wang D et al. J. Cell Sci. 113: 4221-4230 2000]. Furthermore, immunohistochemical studies on human biopsies have demonstrated that FAK is overexpressed in 20 prostate cancer, breast cancer, thyroid cancer, cancer of the colon, melanoma, brain cancer and lung cancer, the level of expression of FAK being directly correlated to the tumours, having the most aggressive phenotype [Weiner TM, et al. Lancet. 342 (8878) : 1024-1025 1993; Owens et 25 al. Cancer Research. 55: 2752-2755 1995; Maung K. et al. Oncogene 18: 6824-6828 1999; Wang D et al. J. Cell Sci. 113 : 4221-4230.2000]. Protein kinase AKT (also known as- PKB) - and. phosphoinositide 3-ki.nase (P13K) are involved in a cell 30 signalling pathway that transmits signals from growth factors activating membrane receptors. This transduction pathway is involved in numerous cellular functions: regulation of apoptosis, control of transcription and translation, glucose metabolism, 35 angiogenesis and mitochondrial integrity.. First identified as an important component of insulin-dependent WO 2006/010641 PCT/EP2005/008720 7 signalling pathways regulating metabolic re.sponses, serine/threonine kinase .AKT was then identified as a mediator playing a key role in survival induced by growth factors. It has been shown -that AKT can inhibit death by 5 apoptosis induced by various stimuli, in a certain number of cell types and tumour cells. In accordance with these findings, it has been shown 'that AKT can, . by phosphorylation of giver serine residues, inactivate BAD, GSK3E, caspase-9, and Forkhead transcription factor, and 10 can activate IKKalpha and e-NOS. It is interesting to note that the protein BAD is found hyper-phosphorylated in 11 human tumour cell lines out of 41 studied. Furthermore, it has been shown that hypoxia modulates the induction of VEGF in cells transformed with Ha-ras by 15 activating the P13K/AKT pathway and by involving the, binding sequence of the HIF-1 (hypoxia inducible factor 1) transcription factor known as HRE for "hypoxy responsive element". AKT plays a very- important role- in cancer 20 pathologies. The amplification and/or overexpression of AKT has been reported in many human tumours, for instance gastric carcinoma (amplification of AKT1), ovary carcinomas, breast carcinoma or pancreatic carcinoma (amplification and overexpression of AKT2) and breast 25 carcinomas deficient in oestrogen receptors, and also androgen-independent prostate carcinomas (overexpression of AKT3). Furthermore, AKT is constitutively activated in all the PTEN tumours, the PTEN phosphatase being deleted or inactivated by mutations in many types of tumours, for 30 instance carcinomas of the ovary, of the prostate, of.the endometrium, glioblastomas and melanomas. AKT is also, involved in the oncogenic activation of bcr-abl (references: Khawaja A., Nature 1999, 401, 33-34; Cardone et al. Nature 1998, 282, 1318-1321; Kitada S. et al., Am 35 J Pathol 1998 Jan; 152(1): 51-61; Mazure NM et al. Blood 1997, 90, 3322-3331; Zhong H. et al. Cancer Res. 2000, WO 2006/010641 PCT/EP2005/008720 8 60, 1541-1545) One subject of the present -invention is thus the products of general formula (I): R1 L R2 R3*A 0 N 0
[CR
4
"R
4 ")p NIL R4
R
4 ' yR5 5 in which: p represents the integers 0, 1 and 2, A represents aryl, heteroaryl or a monocyclic or bicyclic. fused carbocyclic or heterocyclic 5- to ll-membered radical, all these radicals optionally being substituted 10 with one or more substituents, which may be identical or different, chosen from the values of R3; X represents a single bond or the following divalent radicals: -N(R6)-; -NH-alk-; alkylene; -0-; -C (O)-; S(O)n-; -N(R6)-C(O)-; -NH-CO-alk-, -N (R6) -C (0) -N (R6')-; 15 -N (R6) -C (S) -N (R6' ) -; -N (R6) -C (0)0-; -N (R6) -SO2-; -N (R6) S02-N (R6' ) -; -C(0) -N (R6) -; -S02-NR6-; and -C (0)0-; Ll represents a single. bond or the following divalent. radicals: alkylene, alkenylene, -alkynylene and cycloalkylene, all optionally substituted with one or 20 more substituents, which may be identical or different, chosen from. the values of R7; phenylene and heteroarylene, these last two radicals optionally, WO 2006/010641 PCT/EP2005/008720 9 substituted with one or more substituents chosen from the values of R8; The radical NRlR2 is such that: either Ri and R2, which may be identical or different, 5 are such that: R1 represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl, all optionally substituted with one or more substituents, which may be identical or, different, chosen from the values of R7; aryl, heteroaryl, arylalkyl 10 and heteroarylalkyl in which each of the aromatic rings may optionally be substituted with one or more substituents, which may be identical or different, chosen from the values of R8; -S02R9; -C'(O)R9; -C(O)OR9; -C(O)NRlOR11, -C(S)NRlORll and -SO2NR1OR11; 15 and R2 represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; or Ri and R2 form, together with" the nitrogen atom to 20 which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, NR1 and S, and optionally substituted with one. or more substituents, .which may be identical or different, chosen 25 from the values of R7; or NRI with Li or NR2 with L, together form a 4- to 10--8 membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, NR12 and S, and optionally substituted 30 with one or more substituents, which may be identical or WO 2006/010641 PCT/EP2005/008720 10 different, chosen from the values of R7; R3 represents a hydrogen atom; a halogen atom; hydroxyl; alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy and alkylenedioxy, all optionally substituted with one or 5 more substituents, which may be identical or different, chosen from the values of R7; -NR13Rl4; -C(O)R13; -S(O),,Rl3; -C(O)OR13; -- C(O)NR15Rl6; -S(O),nNR15R16; SF5; nitro; cyano; 4- to 7-membered heterocycloalkyl optionally substituted with one or more radicals, which 10 may be identical or different, chosen from halogen atoms and alkyl, alkoxy or oxo radicals; aryl and heteroaryl, these last two radicals op-tionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8; 15 being noted that when A represents a mono or bicyclic fused l-membered radical, R3 represents in more oxo, R4, R4', R4'' and R4''', which may be identical or different, are chosen from the values defined below for R4; 20 R4 represents a hydrogen atom; a halogen atom; an. alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; aryl and heteroaryl, these last two radicals optionally 25 substituted with one or more substituents, which may be identical or different, chosen from the values of R8; oxo; it being understood that two substituents from among R4, R4'. and R4'' may form, with the carbon atom(s) to which they are attached, a 3- -to 10-membered ring 30 optionally- containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12; WO 2006/010641 PCT/EP2005/008720 11 L2 is chosen from a single bond; an alkylene; alkenylene; alkynylene; cycloalkylene; -0-; -NR17-; -C(O)- and S02 radical; Y represents a saturated, partially saturated or 5 unsaturated N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, .S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; 10 R5 represents a hydrogen atom; a halogen atom; an alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7;, aryl, arylalkyl, heteroaryl and heteroarylalkyl, in which 15 the aromatic rings are optionally substituted with one or more substituents, which may be identical or different, chosen from -the values of R8; -OR18; -NR19R20; NR19COR20; -NR19CONR19'R20; -NR19-S(O)2-R20; -NR19-S(0)2 NR19'R20; -COR18; COOR21; -CONR22R23; -S(0)nR18; 20 S02NR22R23; cyano; nitro; R6 is such that: either R6 represents a hydrogen atom; an alkyl, alkenyl, alkynyl, acyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be 25 identical- or different, chosen from the values of R7; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which- may be identical or different, chosen from the values of R8; or R6 with NR1R2 together form a 4- to 8-membered 30 heterocycle optionally containing one or more hetero WO 2006/010641 PCT/EP2005/008720 12 atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 5 or R6 with Ll together form a 4- to 8-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, 10 chosen from the values of R7; R6', which may be identical to or different from R6, is chosen from the values of R6; R7 represents a halogen atom; alkyl; cycloalkyle; cycloalkylalkyle; hydroxyl; alkoxy; cycloalkoxy; cyano; 15 CF3; -NR24R25; -NR26COR27; -NR26CONR26'R27; -NR26-S(0)2 R27; -NR26-S(O)2-NR26'R27; -COOR26; -COR26; -CO(NR24R25) ; S(O)nR26; -S(0)2NR24R25; 4- to 7-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from OH and 20 NH2 radicals, halogen atoms, and alkyl, alkoxy or oxo radicals; aryl optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; heteroaryl, optionally substituted with one or more 25 substituents, which may be identical or different, chosen from halogen atoms and NH2, alkyl and alkoxy radicals; phenoxy, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen, atoms and alkyl and alkoxy radicals; WO 2006/010641 PCT/EP2005/008720 13 R8, which may be identical to or different from R7, represents the same values as R7 and in addition represents halogen atoms; nitro; -OCF3; alkylenedioxy; difluoromethylenedioxy; benzyl optionally substituted 5 with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R9, which- may be identical to or different from R6, represents the same values as R6; 10 R10 and Rll, which may be identical to or different from each other and also which may be identical to or different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle 15 optionally containing one or more hetero atoms, which. may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 20 R12 represents a hydrogen atom; an alkyl, alkenyl, alkynyl, cycloalkyl, alkylCO or alkylSO 2 radical, all optionally substituted. with one or more substituents, which may be, identical or different, chosen from halogen atoms, , OH, ilkoxy and dialkylamino radicals; aryl and 25 heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R13, which may be identical to or different from R6, 30 represents the same values as R6; WO 2006/010641 PCT/EP2005/008720 14 R14, which may be identical to or different from R13, represents the same values as R13 and also represents C(O)R28; C(O)N28R29; S02R28 and S02NR28R29; R13 and R14 may optionally form, together with the 5 nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be'identical or different, chosen. from 0, S, N and NR12 and optionally substituted with one, or more substituents, which may be identical or 10 different, chosen from the values of R7; R15 and R16, which may be identical to or different from each- other and also which may be identical to or different from R13, are chosen from the same, values as R13 - and may optionally form, with the nitrogen atom to 15 which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the 20 values of R7; .R17 represents a hydrogen atom, alkyl or cycloalkyl; R18, which may be identical to or different from R6, represents the same values as R6; R19 and R20, which may be identical to or different from 25 each other and also which may be identical to or different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may WO 2006/010641 PCT/EP2005/008720 15 be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 5 R21, which may be identical to or different from R13, represents the same values as R13 and also represents hydrogen; R22 and R23, which may be identical to or different from each other and also which may be identical to or 10 different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which .may be identical or different, chosen from 0, S, N and NR12 15 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R24 and R25, which may be identical or different, represent a hydrogen atom or an alkyl, alkenyl or alkynyl 20 radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals, or alternatively R24 and R25 may optionally form, with the nitrogen atom to which they are attached, a 4- to 7 25 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, N-alkyl and N-C(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH, 30 alkyl, alkoxy and oxo radicals; WO 2006/010641 PCT/EP2005/008720 16 R26 represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical optionally substituted with one or more substituents,- which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; 5 R27, which may be identical to or different from R26, represents the same' values'as R26; R26 and R27 may also optionally form, with the nitrogen atom to which they are ~attached, a 4- to 7-membered heterocycle optionally containing one or more hetero 10 atoms, which may be identical or different, chosen from 0, S, N , N-alkyl and N-C(O)alkyl, and optionally substituted -with one or more substituents, which may be identical or -different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; 15 R28, which may be identical to or different from R26, represents the same values as R26; R29, which may be identical to or different from R26, represents the same values as R26; R30, which may be identical to or different from R26, 20 represents the same values as R26; n represents the integers 0, 1 and 2; the said products of formula (I) being in any possible racemic, enantiomeric and diastereoisomeric isomer form, and also the addition salts with mineral acids and 25 organic acids or with mineral bases and organic bases of the said products of formula (I). One subject of the present invention is thus the products of general formula (I) as above defined in which WO 2006/010641 PCT/EP2005/008720 17 p represents the integers' 0, 1 and 2, A represents aryl, heteroaryl or a monocyclic or bicyclic fused. carbocyclic or heterocyclic 5- to 11-membered radical, all these radicals optionally being substituted 5 with one or -more substituents, which may be identical or different, chosen from the values of. R3; X represents a- single bond or the following divalent radicals: -N(R6)-; -0-; -C(O)-; -S(0)n-; -N(R6)-C(0)-; -N(R6)-C(O)-N(R6')-; -N(R6)-C(S)-N(R6')-~; -N(R6)-C(0)0-; 10 -N(R6)-SO2-; -N(R6)-SO2-N(R6')-; -C(O)-N(R6)-; -S02-NR6-; and -C(O)O-; L1 represents the following divalent radicals: alkylene, alkenylene, alkynylene and cycloalkylene, all optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R7; phenylene and heteroarylene, these last two radicals. optionally substituted with one or more substituents chosen from the values of R8; The radical NRlR2 is such that 20 either R1 and R2, which may be identical or different, are such that R1 represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl, all optionally substituted with one or more substituents, which may be identical or different, 25 chosen from the, values of R7; aryl, heteroaryl, arylalkyl and heteroarylalkyl in which each of the aromatic rings may optionally be substituted with one or more substituents, which may be identical or different, chosen WO 2006/010641 PCT/EP2005/008720 18 from the values of R8; -S02R9; -C(0)R9; -C(0)OR9; -C(O)NRlR11, -C(S)NR1OR11 and -SO2NR1OR11; and. R2 represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl,- all optionally substituted with 5 one or more substituents, which may be identical or different, chosen from the values of R7; or R1 and R2 form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, 10 which may be identical or different, chosen from 0, N, NR12 and S, and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; or NR1 with L1 or NR2 with Li together form a 4- to 8 15 membered heterocycle -optionally containing one or more other 'hetero atoms, which may-be identical or different,. chosen from 0, N, NR12 and S, and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 20 R3 represents a hydrogen atom; a halogen atom; hydroxyl; alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy and alkylenedioxy, all optionally substituted with one or, more substituents,. which may be identical or different, chosen from the values of R7; -NR13R14; -C(0)R13; 25 -S(O),aR13; -C(O)OR13; -C(O)NR15Rl6; -S(O)nNR15Rl6; SF5; nitro; cyano; 4- to 7-membered heterocycloalkyl optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy or oxo radicals'; aryl and heteroaryl, 30 these last two radicals optionally substituted with one.
WO 2006/010641 PCT/EP2005/008720 19 or more substituents, which may be identical or different, chosen from the values of R8; being noted that when A represents a mono or bicyclic fused 11-membered radical, R3 represents in more oxo, 5 R4, R4', R4'' and R4''', which may be identical or different, are chosen from the values defined below for R4; R4 represents a hydrogen atom; a halogen atom; an alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally 10 substituted with one or more substituents, which may be identical or different, chosen from the values of R7; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8; 15 oxo; it being understood that two -substituents from among R4, R4' and R4'' may form, with the carbon atom(s) to which they are attached, a 3- to 10-membered ring optionally containing one. or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12; 20 L2 is chosen from a single bond; an alkylene; alkenylene; alkynylene; cycloalkylene; -0-; -NR17-; -C(0)- and S02 radical; Y represents a saturated, partially saturated or unsaturated N-heterocycle optionally containing one or 25 more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; R5 represents a hydrogen atom; a halogen atom; an alkyl, 30 alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which -may be WO 2006/010641 PCT/EP2005/008720 20 identical or different, chosen from the values of R7; aryl, arylalkyl, heteroaryl and heteroarylalkyl, in which. the aromatic rings are optionally substituted with one or more substituents, which may be identical or different, 5 chosen from the values of R8; -OR18; -NR19R20; NR19COR20; -NR19CONR19'R20; -NR19-S(0)2-R20; -NR19-S(0)2 NR19'R20; -COR18; COOR21; -CONR22R23; -S(O)nR18; S02NR22R23; cyano; nitro; R6 is such that: 10 either R6 represents a hydrogen atom; an alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the' values of R7; aryl and heteroaryl, these last two, radicals optionally 15 substituted with one or more- substituents, which may be identical or different, chosen from the values of.R8; or R6 with NR1R2 together form a 4- to 8-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 20 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; or R6 with L1 together form a 4- to 8-membered heterocycle optionally containing one or more hetero 25 atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R6', which may be identical to or different from R6, is 30 chosen from the values of R6; WO 2006/010641 PCT/EP2005/008720 21 R7 represents a halogen atom; alkyl; cycloalkyle; cycloalkylalkyle; hydroxyl; alkoxy; cycloalkoxy; cyano; CF-3; -N24R25; -NR26COR27; -NR26CONR26'R27; -NR26-S(0)2 R27; -NR26-S(O)2-NR26'R27; -COOR26; -COR26; -CO(NR24R25); 5 S(O)nR26; -S(0)2NR24R25; 4- to 7-membered heterocycle optionally substituted with one or more substituents, whi-ch may be identical or different, chosen from OH and NH2 radicals, halogen atoms, and alkyl, alkoxy or oxo radicals; aryl optionally substituted with one or more 10 substituents, which may be identical or different, .chosen from halogen atoms and alkyl and alkoxy radicals; heteroaryl, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and NH2, alkyl and alkoxy radicals; 15 phenoxy, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R8, which may be identical to or different from. R7, represents the same values as R7 and in addition 20 represents halogen atoms; nitro; -OCF3; alkylenedioxy; difluoromethylenedioxy; benzyl optionally substituted with one or more substituents, which may be identicalor different, chosen from halogen atoms and alkyl and alkoxy radicals; 25 R9, which may be identical to or different from R6, represents the same values as R6; R10 and R11, which may be identical to or different from each other and also which may be identical to or different from R6, are chosen from the same values as R6 30 and may optionally form, with the nitrogen atom to which WO 2006/010641 PCT/EP2005/008720 22 they are attached, a A- to 10-membered heterocycle optionally containing one- or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, 5 which may be identical or different, chosen from the values of R7; R12 represents a hydrogen atom; an alkyl, alkenyl, alkynyl, cycloalkyl, alkylCO or alkylSO 2 radical, all optionally substituted with one or more substituents, 10 which may be identical or different, chosen from halogen atoms, OH, alkoxy and dialkylamino radicals; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and 15 alkyl and alkoxy radicals; R13, which may be identical to or different from R6, represents the same values as R6; R14, which may be identical to or different from R13, represents the same values as R13 and also represents 20 C(0)R28; C(0)N28R29; S02R28 and S02NR28R29; R13 and R14 may optionally form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen 25 from O, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R15 and R16, which may be identical to or different from each other and also which may be identical to or WO 2006/010641 PCT/EP2005/008720 23 different from R13, are chosen from the same values as R13 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one 6r more hetero atoms, which may 5 be identical o-r di-fferent, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R17 represents a hydrogen atom, alkyl or cycloalkyl; 10 R18, which may be identical to or different from R6, represents the same values as R6; R19 and R20, which may be identical to or different from. each other and also which may be identical to or different from R6, are chosen from the same values as R6 15 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, 20 which may be identical or different, chosen from the values of R7; R21, which may be identical to or different from R13, represents the same values as R13 - and also represents hydrogen; 25 R22 and R23, which may be identical to or different from each other and also which may be identical to or different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached, a 4- to, 10-membered heterocycle WO 2006/010641 PCT/EP2005/008720 24 optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the 5 values of R7; R24 and R25, which may be identical or different, represent an alkyl, alkenyl or alkynyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH 10 and alkoxy radicals, or alternatively R24 and R25 may optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may be identical' or different, chosen from 0, S, N, N-alkyl and 15 N-C(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; R26 represents a hydrogen atom or an alkyl, alkenyl or 20 alkynyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; R27, which may be identical to or different from R26, represents the same values as R26; 25 R26 and R27 may also optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N , N-alkyl and N-C (0) alkyl, and optionally 30 substituted with one or more substituents, which may be WO 2006/010641 PCT/EP2005/008720 25 identical or-different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; R28, which may be identical to or different from R26, represents the same values as R26; 5 R29, which may be. identical to or different from R26, represents the same values as R26; R30, which may be identical to or different from R26, represents the same values as R26; n represents the integers 0, 1 and 2; 10 the said products of formula (I) being in any possible racemic, enantiomeric and diastereoisomeric isomer form, and also the addition salts with mineral acids and organic acids or with mineral bases and organic bases of. the said products of formula (I). 15 In the products of formula (I), the value p which represents the integer 0, 1 or 2, and the value R4 which represents one or more substituents of the corresponding ring (R4, R4', R4'', R4''') are thus obtained: it is thus understood that when p represents 0, 1 or 2, then the 20 ring is optionally substituted, respectively, with 2, 4 or 6 substituents R4, which may be identical or different. It is noted that R4 also represents hydrogen. It is also noted that two'substituents R4 may be, borne by the same carbon of the ring or by two different carbons 25 and, in these two cases, may form with the carbon(s) that beat(s) them, a cyclic radical which is itself optionally substituted as defined above.
WO 2006/010641 PCT/EP2005/008720 26 In the products of formula (I) and subsequently, the terms indicated have the following meanings: - the term "Hal", "Halo" or halogen denotes fluorine, chlorine, bromine or iodine atoms, 5 - the term "alkyl radical", "alk", "Alk" or "ALK" denotes a linear or branched radical containing not more than 12 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, 10 hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl radicals, and also the linear or branched positional isomers thereof. Mention is made more particularly of alkyl radicals containing not more than 6 -carbon atoms, and especially 15 methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, linear or branched pentyl and linear or branched hexyl radicals. - the term "alkenyl radical" denotes a linear or branched radical containing not more than 12 carbon atoms and 20 preferably 4 carbon atoms, chosen, for example, from the following values: ethenyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-butenyl, 3-methyl-2-butenyl, n-pentenyl, hexenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl, and also the linear or branched positional 25 isomers thereof. Among the alkenyl values that may be mentioned more particularly are the values allyl or butenyl. - the term "alkynyl radical" denotes a linear or branched radical containing not more than 12 carbon atoms and WO 2006/010641 PCT/EP2005/008720 27 preferably 4 carbon atoms, chosen, for example, from the following values: ethynyl, propynyl or propargyl, butynyl, n-butynyl, i-butynyl, 3-methyl-2-butynyl, pentynyl or hexynyl, and also the linear or branched 5 positional isomers thereof. Among the alkynyl values that are mentioned more particularly is the propargyl value. - the term "alkoxy radical" denotes a linear or branched radical containing not more than 12 carbon atoms and 10 preferably 6 carbon atoms chosen, for example, from methoxy, ethoxy, -propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy, hexoxy and heptoxy radicals, and also the linear or branched positional isomers thereof, 15 - the term ' "alkoxycatbonyl radical" or alkyl-O-CO denotes a linear or branched radical containing not more than 12 carbon atoms, in which the alkyl radical has the meaning given above: examples that may be mentioned include methoxycarbonyl and ethoxycarbonyl radicals, 20 - the term "alkylenedioxy radical" or -O-alkylene-O denotes a linear or branched radical containing not more than 12 carbon atoms, *in which the alkylene radical has the meaning given above: examples that may be mentioned include methylenedioxy and ethylenedioxy radicals, 25 - the term "alkylsulphinyl" or alkyl-SO- denotes a linear .or branched radical containing not more than 12 carbon atoms, in which the alkyl radical has the meaning given above and preferably contains 4 carbon atoms, - the term "alkylsulphonyl" or alkyl-S02- denotes a 30 linear or branched radical containing not more than 12 carbon atoms, in which the alkyl radical has the meaning given above and preferably contains 4 carbon WO 2006/010641 PCT/EP2005/008720 28 atoms, - the term "alkylsulphonylcarbamoyl" or alkyl S02-NH-C(=O)- denotes a linear or branched radical containing not more- than 12 carbon atoms, in which the 5 alkyl radical has the meaning given above and preferably contains 4 carbon atoms, - the term "alkylthio" or alkyl-S- denotes a linear or branched radical containing not more than 12 carbon atoms and especially represents methylthio, ethylthio, 10 isopropylthio and heptylthio.radicals, - the term "cycloalkyl radical" denotes a 3- to 10 membered monocyclic or bicyclic carbocyclic radical and especially denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, 15 - the term "-O-cycloalkyl radical" denotes ~ a radical in which the cycloalkyl radical has the meaning given above, - the term "cycloalkenyl radical" denotes a 3- to 10 membered monocyclic or bicyclic nonaromatic carbocyclic radical containing at least one double bond, and 20 especially denotes cyclobutenyl, cyclopentenyl and cyclohexenyl radicals, - the term "cycloalkylalkyl radical" denotes a radical in which cycloalkyl and alkyl are chosen from the values indicated above: this radical thus denotes, for example, 25 cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl radicals, - the term "acyl radical" or r-CO- denotes a linear or branched radical containing not more than 12 carbon atoms, in which the radical r represents a hydrogen atom 30 or an alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl or aryl radical, these radicals having the values indicated above and being optionally substituted as indicated: examples that are mentioned include the formyl, acetyl, propionyl, butyryl or benzoyl 35 radicals, or alternatively valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl, WO 2006/010641 PCT/EP2005/008720 29 - the term "acyloxy radical" means acyl-0- radicals in which acyl has the meaning given above: examples that are mentioned include acetoxy or propionyloxy radicals, - the term "acylamino radical" means acyl-NH- radicals in 5 which acyl has the meaning given above, - the term "aryl radical" denotes unsaturated monocyclic radicals or unsaturated radicals consisting of fused carbocyclic rings. Examples of such aryl radicals that may be mentioned include phenyl or naphthyl radicals. 10 Mention is made more particularly of the phenyl radical. - the term "arylalkyl" means radicals resulting from the combination of the optionally substituted alkyl radicals mentioned above and the optionally substituted aryl 15 radicals - also mentioned above: examples that are mentioned include benzyl, phenylethyl, 2-phenethyl, triphenylmethyl or naphthalenemethyl radicals, the term "heterocyclic radical" denotes a saturated (heterocycloalkyl) or partially saturated or unsaturated 20 (heteroaryl) 5- to 10-membered radical containing one or more hetero atoms, which may be identical or different, chosen from oxygen, nitrogen and sulphur atoms: the term "heterocyclic" preferably represents a saturated or partially 'unsaturated 4- to 7-membered heterocyclic 25 radical optionally containing one or more hetero atoms, which may be identical or different, chosen from N, 0 and S. Heterocycloalkyl radicals that may especially be mentioned include dioxolane, dioxane, dithiolane, 30 thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, morpholinyl, or tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidyl, perhydropyranyl, pyrindolinyl, 35 tetrahydroquinolyl, tetrahydroisoquinolyl and thioazolidinyl radicals, all these radicals being WO 2006/010641 PCT/EP2005/008720 30 optionally substituted. Among the heterocycloalkyl radicals that may especially be mentioned are -optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted 5 pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl and thioazolidinyl radicals: -,mention may also be made more particularly of optionally substituted morpholinyl, pyrrolidyl and piperazinyl radicals; the term "heterodycloalkylalkyl radical" means .radicals 10 in which the heterocycloalkyl and alkyl.residues have the above meanings; - among the 5-membered heteroaryl radicals that may be mentioned are furyl radicals such as 2-furyl, thienyl radicals such as 2-thienyl and 3-thienyl, and pyrrolyl, 15 diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl, oxadiazolyl., 3- or 4-isoxazolyl, imidazolyl, pyrazolyl and isoxazolyl radicals. Aniong the 6-membered : 'heteroaryl radicals that may especially be mentioned are pyridyl radicals such as 20 2-pyridyl, - 3-pyridyl -and - 4-pyridyl, and pyrimidyl, pyrimidinyl, pyridazinyl, -pyrazinyl and tetrazolyl radicals; - as fused heteroaryl radicals containing at least one hetero atom chosen from sulphur, nitrogen and oxygen, 25 examples that may 'be mentioned include benzothienyl such as 3-benzothienyl, benzofuryl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, azaindolyl, thionaphthyl; indolyl, purinyl, quinolyl, isoquinolyl and naphthyridinyl. 30 Among the fused heteroaryl radicals that may be mentioned more particularly are benzothienyl, benzofuranyl; indolyl, quinolyl,. benz-imidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolfl, pyrazinyl, pyridazinyl, 35 pyrazolyl, pyridyl, pyrimidinyl,.' pyrrolyl, quinazolinyl, 1, 3, 4-thiadiazolyl, thidzolyl and thienyl radicals and WO 2006/010641 PCT/EP2005/008720 31 triazolyl groups, these radicals optionally being substituted as indicated for the heteroaryl radicals; The term "patient" denotes human beings, but also other mammals. 5 The term "prodrug" denotes a product that may be converted in vivo via metabolic mechanisms (such as hydrolysis) into a product of formula (I). For- example, an 'ester -of a product of formula (I) containing a hydroxyl group may be converted by hydrolysis in vivo 10 into its parent molecule. Alternatively, an ester of a product of formula (I) containing a carboxyl group may be converted by in vivo hydrolysis into its parent molecule. Examples of esters of the products of formula (I) containing a hydroxyl group that may be mentioned include 15 the acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates,, propionates, succinates, fumarates, maleates, methylenebis-3-hydroxynaphthoates, gentisates, isethionates, di-p-tolyltartrates, methanesulphonates, ethanesulphonates, benzene 20 sulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Esters of products of formula (I) that are particularly useful, containing a hydroxyl group, may be prepared from acid residues such as those described by 25 Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503 2507: these esters especially include substituted (aminomethyl) benzoates, dialkylaminomethylbenzoates in which the two alkyl groups may be linked together or may be interrupted with an oxygen atom or with an optionally 30 substituted nitrogen atom, ' i.e. an alkylated nitrogen atom, or alternatively (morpholinomethyl)benzoates, e.g. 3- or 4-(morpholinomethyl)benzoates, and (4-alkyl piperazin-1-yl)benzoates, e.g. '3- or 4-(4-alkylpiperazin 1-yl)benzoates . 35 The carboxyl radical(s) of the products of formula (I) may be salified or esterified with various groups WO 2006/010641 PCT/EP2005/008720 32 known to those skilled in the art, among which nonlimiting examples that may be mentioned include the following compounds: - among the salification compounds, mineral bases such 5 as, for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N dimethylethanolamine, tris (hydroxymethyl) aminomethane, 10 ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine, - among the esterification compounds, alkyl radicals to form alkoxycarbonyl groups such as, for example, 15 methoxycarbonyl, ethoxycarbonyl,- tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals possibly being substituted with radicals chosen, for example, from halogen atoms and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, such as, for example, 20 in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups. The term "esterified carboxyl" means, for example, radicals such as alkyloxycarbonyl radicals, for example 25 methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl. Mention may also be made of radicals formed with readily cleavable ester residues, such as methoxymethyl 30 or ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals., and isopropyloxycarbonyloxy methyl or ethyl radicals., 35 A list of such ester radicals may be found, for example, in European patent EP 0 034 536.
WO 2006/010641 PCT/EP2005/008720 33 The term "amidated carboxyl" means radicals of the type -CONRxRy in which the amino radicals -NRxRy have the meanings given above: especially, Rx and Ry, which may be identical or different, represent a hydrogen atom,. a 5 cyclic radical as defined above or below or an alkyl radical containing from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl or tert-butyl radicals and especially amino, alkylamino and dialkylamino radicals, all these cyclic 10 and alkyl radicals being optionally substituted. The term "alkylamino radical" means, for example, linear or branched methylamino, ethylamino, propylamino or butylamino radicals. Alkyl radicals containing not more than 4 carbon atoms are preferred, the alkyl 15 radicals possibly being chosen from the alkyl radicals mentioned above. The term "dialkylamino radical" means, for example, dimethylamino, diethylamino and methylethylamino radicals. As previously, alkyl radicals containing not 20 more than 4 carbon atoms, chosen from the list indicated above, are preferred. The term "salified carboxyl" means the salts formed, for example, with one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also 25 be made of the salts formed with organic bases such as methylamine, propylamine,- trimethylamine, diethylamine and triethylamine. The sodium salt is preferred. When the products of formula (I) comprise an amino radical that may be salified with an acid, it is clearly 30 understood that these acid salts also form part of the invention. Mention may be made of the salts obtained, for example, with hydrochloric acid or -methanesulphonic acid. The addition salts with mineral or organic acids of the products of formula (I) may be, for. example, the 35 salts -formed with hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulphuric acid, phosphoric WO 2006/010641 PCT/EP2005/008720 34 acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, 5 alkylmonosulphonic acids such as, for example, methanesulphonic acid, ethanesulphonic acid or propanesulphonic acid, alkyldisulphonic acids such as, for example, methanedisulphonic acid or X,fp ethanedisulphonic acid, arylmonosulphonic acids such as 10 benzenesulphonic acid, and aryldisulphonic acids. It may be recalled that stereoisomerism may be defined in its broad sense as the isomerism of compounds having the same structural formulae but whose various groups are arranged differently in space, especially such 15 as in mon6substituted cyclohexanes whose substituent may be in an axial or equatorial position, and the various possible rotational conformations of ethane derivatives. However, there is another type of stereoisomerism, due.to the different spatial arrangements of fixed substituents, 20 either on double bonds or on rings, which is often referred to as geometrical isomerism or cis-trans isomerism. The term "stereoisomer" is used in the present patent application in its broadest -sense and thus relates to all the compounds indicated above. 25 A subject of the present invention is thus the products of general formula (I) as defined above in which A ' represents a phenyl or heteroaryl radical or a monocyclic or bicyclic fused carbocyclic or heterocyclic 5- to 11-membered radical, optionally substituted with 30 one or more substituents, which may be identical or different, chosen from the values of R3, with R3 and the other substituents of the said products of formula (I) being chosen from the values defined for R3 and for the said' substituents, 35- the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, WO 2006/010641 PCT/EP2005/008720 35 and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I).. In the said products of formula (I): 5 A more particularly represents a phenyl, a 5 to 6 membered heteroaryl or a condensed heterocyclic ring system selected from the list: 1,2,3,4-tetrahydro-quinolin, 1,2,3,4-tetrahydro isoquinolin, indolyl, 2,3-dihydro-lH-indolyl, 2,3 10 dihydro-1H-isoindolyl, 2, 3-dihydro-benzothiazole, tetrahydroquinoline or tetrahydroisoquinoline, all these radicals being optionally substituted with one or more radicals chosen from the values of R3; A even more particularly represents a phenyl or 1,2,3,4 15 tetrahydro-quinolin,- 1,2,3,4-tetrahydro-isoquinolin, indolyl, 2, 3-dihydro-lH-indolyl or 2, 3-dihydro-lH isoindolyl, all optionally substituted with one or more substituents, which may be -identical or different, chosen from alkyl, alkoxy, cycloalkyl, alkylamino and 20 dialkylamino radicals, each alkyl radical being optionally substituted with one or more fluorine atom; and -OCF3, SCF3 and SO2CF3 radicals A most particularly represents a phenyl or indolinyl radical optionally substituted with one -or more 25 substituents, which may be' identical or different, chosen from alkyl, alkoxy, SCF3, SO2CF3 and -OCF3 radicals; the other substituents of the said products of formula (I) being chosen'from all the values defined for the said substituents, 30 the said products of formula (I) being in any possible -racemic, enantiomeric and diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I) 35 One subject of the present invention is thus the products of general formula (I) as defined above in which: WO 2006/010641 PCT/EP2005/008720 36 X represents a single bond or -the following divalent radicals: -N(R6)-, -0-, -C(O)-, -S(O)n-, -N(R6)-C(0)-, -N (R6) -C(0) -N(R6' ) -, -N (R6) -SO2-, -C(O)-N (R6) - and -S02 NR6; 5 with R6 and R6', which may be identical or different, and the other substituents of the said products of formula (I) being chosen from all the values defined for R6 and R6' and for the said substituents, the said products of formula (I) being in all. the 10 possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic 'acids or with mineral and organic bases of the said products of formula (I). In the said products of formula (I): 15 X more particularly represents a single bond or the following divalent radicals: -N(R6)-, -0-, -C(O) -S(0)n-, -N(R6)-C(O)- and -N(R6)-SO2-; X most particularly represents a single bond or the following divalent radicals: -N(R6)-, -0-, -C(0)-, and 20 -NH-C(O)-; with R6 and the other substituents of the said products of formula (I) being chosen from all the values defined for R6 and the said substituents, the said products of formula (I) being in all the 25 possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). One subject of the present invention is thus the products 30 of.general formula (I) as defined above in which .Li represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or. several substituents chosen from the values of R7, with R7 and the other substituents of the said products of WO 2006/010641 PCT/EP2005/008720 37 formula (I) being chosen from all the values defined for R7 and for the substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric 5 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). In the said products of formula (I): Ll more particularly represents an alkylene radical 10 containing 1 to 4 carbon atoms and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F), and OH and alkoxy radicals; Ll represents even more-. particularly particularly an 15. alkylene radical containing 1 to 4 carbon atoms optionally substituted with a hydroxyl radical; Ll most particularly represents an alkylene radical containing 1 to 4 carbon atoms; the other substituents of the said products of formula 20 (I) among all the values defined for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral 25 and organic acids or with' mineral and organic bases of the said products of formula (I). One subject of the present invention is thus the products of general formula (I) as defined above in which the radical NRlR2 is such that: 30 either ~R.1 and 'R2, which may be identical or different, are such that: RI represents -a -hydrogen atom, an alkyl or cycloalkyl radical, these last two radicals being optionally WO 2006/010641 PCT/EP2005/008720 38 substituted with one or more substituents, which may be identical or different, chosen from the values of R7; aryl, heteroaryl, arylalkyl, heteroarylalkyl in which each of the aromatic rings may be optionally substituted 5 with one or more substituents, which may be identical or different, chosen from the values of R8; and R2 represents a hydrogen atom, an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, which may be 10 identical or different, chosen from the values of R7; or R1 and R2 form, together with the nitrogen atom to which they are attached, .a 4- to 10-membered heterocycle optionally containing one or more other heteroatoms, which may be identical or different, chosen from 0, N, 15 NR12 and S and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; or NR1 with L1 or NR2 with Li together form a 4- to 8 membered heterocycle optionally substituted with one or 20 more substituents, which may be identical or different, chosen from the values of R7; with R7, R8, R12 and L1 and the other substituents of the said products of formula (I) being chosen from all the values- defined for R7, R8, R12 and L and for the said, 25 substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 30 the said products of formula (I).
WO 2006/010641 PCT/EP2005/008720 39 In the said products of formula (I): the radical NRlR2 is particularly defined as follows: either R1 and R2, which may be identical or different, are such that: 5 R1 represents a hydrogen atom, an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, which may be identical or different,. chosen from the values of R7; aryl and heteroaryl, both optionally substituted with one 10 or more substituents, which may be identical or different, chosen from the values of R8; and R2 represents a hydrogen atom, an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R7; or R1 and R2 form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, 20 N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; or NRl with Ll or NR2, with Li together form a 4- to 8 membered heterocycle optionally substituted with one or 25 more substituents, which may be identical or different, chosen from the values -of R7; the- radical NR1R2 is more particularly defined as follows: WO 2006/010641 PCT/EP2005/008720 40 either R1 and R2, which may be identical or different, are such that: R1 represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, 5 which may be identical or different, chosen from halogen atoms (F) and hydroxyl; alkoxy; cyano, free or esterified carboxyl, phenyl, 3- to 7-membered cycloalkyl, alkylamino, dialkylamino, -NHCO-alkyl, -CO (NH-alkyl), CO(Ndialkyl) radicals and 5-, 6- or 7-membered saturated, 10 partially saturated or unsaturated heterocyclyl radicals containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH or N-alkyl and optionally substituted with one or more substituents, which may be identical or different, chosen 15 from halogen atoms and alkyl, NH2 and alkoxy radicals; or alternatively R1 represents a phenyl radical or a saturated, partially saturated or unsaturated 4- to 7 membered heterocyclic radical, itself containing one or more hetero atoms chosen from 0, S, N, NH and N-alkyl, 20 and optionally substituted with one or more radicals chosen from halogen atoms, alkyl, NH2 and alkoxy radicals; and R2 represents a hydrogen atom, an alkyl or cycloa-lkyl radical optionally substituted with one or more halogen 25 atoms; or R1 and R2 form, together with the nitrogen atom. to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from -0, N, 30 NH, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different-, WO 2006/010641 PCT/EP2005/008720 41 chosen from halogen atoms, alkyl, alkoxy, CF3 and free or esterified carboxyl radicals; or NRlR2 and Li together form a 4- to 7-membered heterocycle optionally substituted with one or more 5 substituents, which may be identical or different, chosen from halogen atoms, alkyl and. alkoxy and free or esterified carboxyl radicals; the radical NRlR2 is even more particularly defined- as follows: 10 either R1 and R2, which may be identical or different, are such that: R1 represents an alkyl radical optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, cyano, free or esterified carboxyl, 15 phenyl and 3- -to 7-membered cycloalkyl radicals, and saturated, partially- saturated or unsaturated 4- to 7 membered heterocyclic radical, itself containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH and N-alkyl and optionally 20 substituted with one or more alkyl radicals, and or alternatively RI represents a 3- to 7-membered cycloalkyl radical, a phenyl radical or a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical, itself containing one or more 25 hetero atoms chosen from 0, S, N, NH and N-alkyl, and optionally substituted with one or more alkyl radicals and R2. represents a hydrogen atom or an alkyl radical optionally substituted with one or more halogen atoms; or R1 and R2 form, with the nitrogen atom to which they 30 are attached, a saturated or unsaturated 4- to 7-membered heterocyclic radical optionally containing one or more.
WO 2006/010641 PCT/EP2005/008720 42 other hetero atoms^ chosen from 0, S, N, NH and N-alkyl, this radical formed by RI and R2 with N being itself optionally substituted with one or more radicals, which may be identical or different, chosen from alkyl, CF3 and 5 free or esterified carboxyl radicals, or NR1 with Li or NR2 and Li together form a saturated or unsaturated 4- to 7-membered heterocycle containing at least one nitrogen atom and optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N 10 alkyl, this radical formed by NRiR2 with Lld itself being optionally substituted with one or more radicals chosen from alkyl and free or esterified carboxyl radicals, with R7, R8 and Li and the other substituents of the said products of the formula (I) being chosen from all the 15 values defined for R7, R8 and Li and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral 20 and organic acids.or with mineral and organic bases of the said products of formula (I). One subject of the present invention is thus the products of general formula (I) as defined below, in which R3 represents a hydrogen atom, a, halogen atom; an alkyl, 25 cycloalkyl, alkoxy or alkylenedioxy radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; -NR13R14; -C(O)R13; -S(O) nRl3; -C(Q)NR15R16; -S(O),NR15Ri6; aryl and heteroaryl, these 30 last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen WO 2006/010641 PCT/EP2005/008720 43 from the values of R8; with R7, R8, R13, R14, R15 and R16 and the other substituents of the said products of formula (I) being chosen from all the values defined for R7, R8, R13, R14, 5 R15 and R16 and for the said substituents, the said products of formula. (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer -forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 10 the said products of formula (I). In the said products of formula (I): R3 more particularly represents a hydrogen atom; alkyl, alkoxy and cycloalkyl radicals optionally substituted with one or more halogen atoms; OCF3 and S(O),-alkyl -15 radicals, the alkyl residue containing 1 to 4 carbon atoms and being optionally substituted with one or more. halogen atoms; alkylamino, optionally substituted with one or more halogen' atoms; dialkylamino, in which the two alkyl residues may optionally form with the nitrogen atom 20 to which -they are attached a 4- to 10-membered heterocyclic radical optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, N-alkyl and S and optionally substituted with one or more 'substituents, which may be 25 identical or different, chosen from halogen atoms (F) and alkyl and alkoxy radicals; R3 particularly represents one or more substituents of the ring A, . which may be identical or different,.. chosen from - alkyl, alkoxy, cycloalkyl, alkylamino and 30 dialkylamino, each optionally substituted with one or more halogen atoms and in which alkyl and alcoxy contain up to 4 carbon atoms; OCF3; SCF3; and SO2CF3; WO 2006/010641 PCT/EP2005/008720 44 R3 especially represents one or more substituents of the ring A, which may be identical or different, chosen from a hydrogen atom and alkyl, OCH3, SCF3 and -OCF3 radicals; the ring A and the other substituents of the said 5 products of formula (I) being chosen from all the values defined for the ring A and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms,- and also the addition salts with mineral 10 and organic acids or with mineral and organic bases of the said products of formula (I). A subject of the present invention is thus the products of general formula (I) as defined above, in which R4 represents a hydrogen atom, a halogen atom (F), an 15 alkyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; it being understood that two substituents R4 may form, with the carbon atom(s) - to which they are attached, a 3- to 7 20 membered ring optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and N-alkyl; with R7 and the other substituents of the said products of formula (I) being chosen from all the values defined 25 for R7 and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric - isomer forms, 'and also the addition salts with mineral and organic acids or with mineral and organic bases of 30 the said products of formula (I). rn the said products of formula (I): - R4 more particularly represents a hydrogen atom, a halogen atom and an alkyl or cycloalkyl radical WO 2006/010641 PCT/EP2005/008720 45 optionally substituted with one or more halogen atoms; it being understood that two substituents R4 may form, with the carbon atom to which they are attached, a 3- to 5 membered carbo or heterocyclic- spirocyclic ring; 5 R4 even more particularly represents hydrogen, alkyl or spiro cycloalkyl; the other substituents of the said products of formula (I) being chosen from all the values defined for the said substituents, 10 the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 15 In the said products of forinula (I), R4 may especially represent hydrogen and alkyl, it being understood that two substituents R4 borne by the same carbon, can form, together with -the carbon atom to which they are attached, a 3- to 6-membered cycloalkyl or heterocycloalkyl radical 20 containing a nitrogen atom; more particularly, R4 represents hydrogen and CH3, it being understood that two substituents R4, borne by the same carbon, can form, together with the carbon atom to which they are attached, a cycloalkyl radical containing 25 from 3 to 6 carbon atoms or an azetidinyl, pyrrolidinyl or piperidyl radical. When two substituents R4 borne by the same carbon form, together with the carbon atom to which they are attached, a cyclic radical, the ring formed is especially a 30 cycloalkyl radical containing from 3 to 6 carbon atoms, and more particularly a cyclopropyl radical; the other substituents of the said products of formula (I) being chosen from all the values defined for the said substituents, WO 2006/010641 PCT/EP2005/008720 46 the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the - addition salts with mineral and organic acids or with mineral and organic bases of 5 the said products of formula (I). One subject of the present invention is thus the products of general formula (I) as defined above in which L2 is chosen from a single bond and an alkylene, cycloalkylene, -0- or -NR17- radical, 10 the other substituents of the said products of formula (I) being chosen from all the values defined for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric 15 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). In the said products of formula (I): L2 especially represents cycloalkylene, -0- and -NR17-; 20 L2 more particularly represents a single bond and methylene; L2 even more particularly represents -CH2, the other substituents of the said products of formula (I) being chosen from all the values defined for the said 25 substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 30 the said products of formula (I). A subject of the present invention is thus the products WO 2006/010641 PCT/EP2005/008720 47 of general formula (I) as defined above in which Y represents an N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S and N and optionally 5 substituted with one or more substituents, which may be identical or different, chosen from the values of R5; with R5 and the other substituents of the said products of formula (I) being chosen from all the values defined for R5 and for the said substituents, 10 the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 15 In the said products of formula (I): Y especially represents a monocyclic or bicyclic heteroaryl radical chosen from pyridyl, pyrimidinyl, pyridazine, pyrazine, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, thiazolyl, imidazolyl, 20 oxazolyl, pyrazolyl, isoxazolyl, 1H-pyrrolo[2,3 bipyridyl, furazanyl, morpholinyl, pyrrolidinyl, indazolyl, 3H-imidazo- (4,5b) -pyridine, 1H-pyrazolo (3, 4b) -pyridine, 1H-pyrazolo- (3,4d) -pyrimidine, piperidyl, thienyl, indolyl, pyrrolyl, purinyl, 25 benzoxazinyl, benzimidazolyl, these radicals being optionally substituted with one or more radicals chosen from the values of R5; Y particularly represents a heteroaryl radical. chosen from pyridyl, pyrimidinyl, azaindolyl, quinolyl, 30 isoquinolyl, cinnolinyl, quinazolinyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl and isoxazolyl, these radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; WO 2006/010641 PCT/EP2005/008720 48 Y more particularly represents a heteroaryl radical chosen from pyridyl, pyrimidinyl, quinolyl, isoquinolyl; azaindolyl, quinazolinyl, thiazolyl, imidazolyl, pyrazolyl, furazanyl and isoxazolyl radicals, 5 these radicals being optionally substituted with one or more radicals chosen from the values of R5; Y even mote particularly represents a heteroaryl radical chosen from pyrid-4-yl, pyrid-3-yl, pyrimidin-4-yl, quinolin-4-yl, quinolin-3-yl, isoquinolin-5-yl, azaindol 10 4-yl and quinazolin-4-yl, these radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; Y most particularly represents a heteroaryl radical chosen, from pyrid-4-yl, pyrimidin-4-yl, quinolin-4-yl, 15 isoquinolin-5-yl, azaindol-4-yl and quinazolin-4-yl, these radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5; Y more specifically represents 4-pyridyl and 4-quinolyl 20 radicals, optionally substituted with one or more radicals chosen from the values of R5 defined in any one of the claims; with R5 and the other substituents of the said products of formula (I) being chosen from all the values defined 25 for R5 and for the said substituents, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 30 the said products of formula (I). A subject of the present invention is thus the .products of general formula (I) as defined above, in which WO 2006/010641 PCT/EP2005/008720 49 R5 more particularly represents a hydrogen atom,. a halogen atom or an alkyl, cycloalkyl, -NHR20, -NHCOR20, -NHCONR19R20 or -NH-S(0)2-R20 .radical; R5 even more particularly represents a hydrogen atom, a 5 halogen atom; an alkyl, cycloalkyl, NH2, -NH-cycloalkyl, -NHCO-alkyl, -NHCO-cycloalkyl, -NHCONH-alkyl or -NHCON(dialkyl) radical, the alkyl. and cycloalkyl residues being optionally substituted with one or more radicals, which may be identical or different, chosen 10 from halogen atoms (F) and alkoxy, morpholinyl, piperidyl, piperazinyl, N-methylpiperazinyl and COOH radicals; NH-aryl, NH-heteroaryl, -NHCO-aryl and -NHCO heteroaryl in which the aromatic residues are optionally substituted with one or more radicals chosen from halogen 15 atoms and alkyl, alkoxy and COOH radicals; with the two alkyl groups of -NHCON(dialkyl) can be linked together to form a ring that optionally can contain oner or more 0, N, S and optionally can be substituted by F or alkyl; 20 with R19, R20 and -the other substituents of the said products of formula (I) being as above defined, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral 25 and organic acids or with mineral and organic bases of the said products of formula (I). A subject of the present invention is thus, particularly, the products of. formula (I) as defined above corresponding to formula (Ia): 30 WO 2006/010641 PCT/EP2005/008720 50 Ra L,a R 2 a Raas .- Xa Aa O N O
[CR
4 a"R 4 a')p N La 1 (1a)
R
4 a R a'Ya-N 4 Rea in which: p represents the integers 0, 1 and 2, Aa represents phenyl, heteroaryl and a monocyclic or 5 bicyclic fused carbocyclic or heterocyclic 5- to 11 membered radical, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R3a; Xa represents a single bond or the following divalent 10 radicals: -N(R6a)-; -0-; -C(O)-; -S(0)n-; -N(R6a)-C(0) -N (R6a) -C(0)-N (R6'a) -; -N (R6a) -SO2-; -C(0)-N (R6a) -; -S02 NR6a-; Lla represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or more 15 substituents chosen from the values of R7a; the radical NRlaR2a is such that: either Rla and R2a, which may be identical or different, are such that: Rla represents a hydrogen atom; alkyl and cycloalkyl, 20 these last two radicals being optionally substituted with WO 2006/010641 PCT/EP2005/008720 51 one or more substituents, which may be identical or different, chosen from the values of R7a; aryl, heteroaryl, arylalkyl and heteroarylalkyl in which each of the aromatic rings may be optionally substituted with 5 one or more substituents, which may be identical or different, chosen from the values of R8a; and R2a represents a hydrogen atom, alkyl and cycloalkyl, these last two radicals being optionally substituted with one or more substituents, which may be identical or 10 different, chosen from the values of R7a ; or Ria and R2a form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or. different, chosen from 0, N, 15 NR12a and S and optionally substituted with one or more substituents,- which may be identical or different, chosen from the values of R7a; or NRla with Lla or NR2a with Lla together form a 4- to 8-membered heterocycle optionally substituted with one or 20 more substituents, which may be identical or different, chosen from the values of R7a; R3a represents a hydrogen atom, a halogen atom; an alkyl, cycloalkyl, alkoxy or alkylenedioxy radical, all optionally substituted with one or more substituents, 25 which may be identical or different, chosen from the values of R7a; -NR13aRl4a; -C(0)Rl3a; -S(O) aRl3a; -C (O) NR15aRl6a; -S (0),NR15aRl6a; aryl and heteroaryl, these last two radicals being optionally substituted with one or more substituents, which may be identical or 30 different, chosen from the values of R8a; WO 2006/010641 PCT/EP2005/008720 52 R4a, R4a', R4a'' and R4a''', which may be identical or different, are chosen from the values defined below for R4 a; R4a represents a hydrogen atom, a halogen atom, an. alkyl 5 or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; it being understood that two substituents from among R4a, R4a' and R4a'' may form,. with the carbon atom(s) to which they are 10 attached, a 3- to 7-membered ring optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and N-alkyl; L2a is chosen from a single bond; alkylene; cycloalkylene; -0- and -NR17a-; 15 Ya represents an N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S and N and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5a; 20 R5a represents a hydrogen atom, a halogen atom, an alkyl or cycloalkyl radical, optionally substituted with one or more substituents, which may be identical or different, chosen from ' the values of R7a; aryl, arylalkyl, heteroaryl and heteroarylalkyl, in which the 25 aromatic rings are optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8a; -OR18a; -NR19aR20a; -NR19aCOR20a; -NR19aCONR19'aR20a; -NR19a-S(O)2-R20a; -NR19a-S(0)2-NR19a'R20a; -COR18a; COOR21a; -CONR22aR23a 30 -S(0)nRl8a ; -SO2NR22aR23a ; cyano; WO 2006/010641 PCT/EP2005/008720 53 R6a is such that: either R6a represents a hydrogen atom or an alkyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or 5 different, chosen from the values of R7a; or R6a with NRlaR2a together form a 5- to 7-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; 10 or R6a with Lla together form a 5- to 7-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R6a', which may be identical to or different from R6a, is 15 chosen from the values of R6a, R7a represents a halogen atom; an alkyl; hydroxyl (OH); alkoxy; cycloalkoxy; cyano radical; -CF3; -N24aR25a; NR26aCOR2-7a; -NR26aCONR26a'R27a; -NR26a-S(O)2-R27a; NR26a-S(O)2-NR26a'R27a; -COOR26a; -COR26a; 20 -CO(NR24aR25a); S(O)nR26a; -S(0)2NR24aR25a; a 4- to 7 membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from OH and NH2 radicals, halogen atoms, and alkyl, alkoxy or oxo radicals; aryl optionally 25 substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; heteroaryl, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and 30 NH2, alkyl and alkoxy radicals; phenoxy, optionally WO 2006/010641 PCT/EP2005/008720 54 substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R8a, which may be identical to or different from R7a, 5 represents the same values as R7a and also represents halogen atoms, -OCF3, alkylenedioxy and difluoromethylenedioxy radicals; R12a represents a hydrogen atom or an alkyl, cycloalkyl, alkylCO or alkylSO 2 radical, all optionally substituted 10 with one or more substituents, which may be identical or different, chosen from halogen atoms and alkoxy radicals; R13a represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from the values of. R7a; a 15 phenyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms, alkyl and alkoxy radicals; a 5- or 6 membered heteroaryl radical optionally substituted with one or more substituents, which may be identical or 20 different, chosen from halogen atoms, alkyl and alkoxy radicals; R14a represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; 25 C(O)R28a; R13a and R14a may optionally form, together with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen WO 2006/010641 PCT/EP2005/008720 55 from 0., S, N and Nalkyl and 'optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R15a and R16a, which may be identical to or different 5 from.each other and also identical to or different from R13a, Are .chosen from the same values as R13a and may optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms which may be 10 identical or different, chosen from 0, S, N and NR12A and optionally substituted with one or more substituents, which may be identical or different, chosen from the values.of R7a; R17a represents a hydrogen atom or an alkyl or cycloalkyl 15 radical; R18a, which may be identical to or different from R6, represents the same values as R6; R19a represents a hydrogen atom or an alkyl or cycloalkyl radical; 20 R20a represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or -more substituents, which may be identical or different, chosen from the values of R7a; aryl and heteroaryl, optionally substituted with one or more substituents, which may be 25 identical or different, chosen from the values of R8a; R19a and R20a, which may be identical to or different from each other, may also form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may WO 2006/010641 PCT/EP2005/008720 56 be identical or different, chosen from 0, S, N and NR12a and optionally substituted with one or more substituents, which may' be identical or different, chosen from the values of R7a; 5 R21a, which may be identical to or different from R13a, is chosen from the values of R13a and also represents a hydrogen atom; R22a and R23a, which may be identical to or different from each other and identical. to or different from R6a, 10 are chosen from the values of R6a and may also form, with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, .chosen from .0, S, N and NR12a and optionally substituted with 15 one or more substituents, which may be identical or different, chosen from the values of R7a; R24a and R25a, which may be identical or different, represent an alkyl radical optionally substituted with one or more substituents, which may be identical or 20 different,, chosen from halogen atoms, and OH and alkoxy radicals, or alternatively R24a and R25a may optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may be identical or 25 different, chosen from 0, S, N , N-alkyl and N-C (O) alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and OH,' alkyl, alkoxy or oxo radicals; R26a represents a hydrogen atom or an alkyl radical 30 optionally substituted. with one or more substituents, WO 2006/010641 PCT/EP2005/008720 57 which may be identical or different, chosen from halogen atoms (F) and OH and alkoxy radicals; R27a, which may be identical to or different from R26a, is chosen from the values of R26a; 5 R26a and R27a, may also optionally form, with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, N-alkyl and N-C(O)alkyl, and optionally 10 substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH, alkyl, alkoxy or oxo radicals; R28a,: which may be identical to or different from R26a, is chosen from the values of R26a; 15 R29a, which may be identical to or different from R26a, is chosen from the values of R26a; R30a, which may be identical to or different from R26a, is chosen from the values of R26a; n represents the integers 0, 1 and 2; 20 p represents the integers 0, 1 and 2; the said products of formula - (Ia) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 25 the said products of formula (Ia). A subject' of the invention is especially the products of formula (I) as defined above such that p represents the WO 2006/010641 PCT/EP2005/008720 58 integer 0, the other substituents of the said products of formula (I) each having any one of the values defined in the present invention. A subject of the invention is especially the products of 5 formula (I) as defined above such that p represents the -integer 1, the other substituents of the said products of formula (I) having any one of the values defined in the present invention. A subject of the invention is especially the products of 10 formula (I) as defined above such that p represents the integer 2, the other substituents of the said products of formula (I) having the values defined in the present invention. A subject of the present invention is, more particularly, 15 the products of formula (I) or (Ia) as defined above corresponding to formula (Ib): Rib NRb R ~ L b 1Rb RabN -Xb Ab O N 0
R
4 b NLb (Ib)
R
4 'b 1 4 Ybs
R
5 b Ab represents phenyl, heteroaryl or a carbocyclic or heterocyclic 7- to ll-membered cyclic radical, optionally 20 substituted with one or more substituents, which may, be identical or different, chosen from the values of R3b; Xb represents a single bond or the following divalent WO 2006/010641 PCT/EP2005/008720 59 radicals: -N(R6b)-; -0-; -C(O)-; -S(O)n-; -N(R6b)-C(O) and -N(R6b)-SO2-; Llb represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or more 5 substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; the radical NR1bR2b is such that: either Rib and R2b, which may be identical or different, are such that: 10 Rlb represents a hydrogen atom or an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; aryl and heteroaryl, both optionally substituted with one 15 or more substituents, which may be identical or different, chosen from the values of R8b; and R2b represents a hydrogen atom or an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, 20 which may be identical or different, chosen from the values of R7b; or Rlb and R2b form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, 25 which may be identical or different, chosen from 0, N, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; WO 2006/010641 PCT/EP2005/008720 60 or NRlb with Llb or NR2b with Llb together form a 4- to 8-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; 5 R3b represents a hydrogen atom, an alkyl, alkoxy (-OCH3) or cycloalkyl radical, optionally substituted with- one or more fluorine atoms; OCF3 and S(O),-alkyl radicals, the alkyl residue containing 1 to 4 carbon atoms and being optionally substituted with one or more F; alkylamino, 10 optionally substituted with one or more F; dialkylamino, in which the two alkyl residues may optionally form, with the nitrogen atom to which they are attached, a 4- to 10 membered heterocyclic radical optionally containing one or more other hetero atoms, which may be identical. or 15 different, chosen from 0, N, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from F and alkyl and alkoxy radicals; R4b and R4'b, which may be identical or different, 20 represent a hydrogen atom, a halogen atom F and an alkyl or cycloalkyl radical, optionally substituted with one or more F; it being understood that two substituents R4b may form, with the carbon atom to which they are attached, a 3- to 5-membered spirocyclic ring; 25 L2b is chosen from a single bond and methylene; Yb represents a monocyclic or bicyclic heteroaryl radical chosen from pyridyl, pyrimidinyl, pyridazine, pyrazine, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, 30 isoxazolyl, 1H-pyrrolo[2,3-blpyridyl, furazanyl, morpholinyl, pyrrolidinyl, indazolyl, 3H-imidazo- (4,5b) pyridine, 1H-pyrazolo-(3,4b)-pyridine, 1H-pyrazolo- WO 2006/010641 PCT/EP2005/008720 61 (3,4d)-pyrimidine, piperidyl, thienyl, indolyl, pyrrolyl, purinyl, benzoxazinyl, benzimidazolyl, these radicals being optionally- substituted with one or more radicals chosen from the values of R5b; 5 R5b represents a hydrogen atom; a halogen atom; alkyl; cycloalkyl; -NHR20b; -NHCOR20b; -NHCONR19bR20b; -NH-S (0) 2-R2Ob; R6b represents a hydrogen atom or an alkyl radical containing from ,1 to 4 carbon atoms; 10 R6b and NRlbR2b may optionally together form a 5- to 7 membered heterocycle optionally substituted with one or more radicals, which may be identical or different, chosen from the values of R7b; R7b represents a halogen atom ; hydroxyl; cyano; COOH; 15 CF3; alkyl, alkoxy, alkylamino, dialkylamino, -NHCO alkyl, -CO(NH-alkyl) and CO(Ndialkyl) in which the alkyl residues are optionally substituted with one or more substituents, which may be identical or different, .chosen from halogen atoms, OH and methoxy; an aryl radical 20 optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; a 4- to 7-membered heterocycle; heteroaryl, optionally substituted with one or more ' substituents, which may be identical or 25 different, chosen from halogen atoms and NH2, alkyl and alkoxy radicals; R8b, which may be identical to or different from R7b, is chosen from the values of R7b and in addition represents WO 2006/010641 PCT/EP2005/008720 62 halogen atoms and -OCF3, alkylenedioxy and difluoromethylenedioxy radicals; R19b represents a hydrogen atom or an alkyl or cycloalkyl radical; 5 R20b represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; aryl and heteroaryl, optionally substituted with one or more substituents, which may be 10 identical or different, chosen from the values of R8b; R19b and R20b, which may be identical to or different from each other, may also form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may 15 be identical or different, chosen from 0, S, N and Nalkyl and optionally substituted with one or more substituents, which may be identical or. different, chosen from the values of R7b; n represents the integers 0, 1 and 2; 20 the said products of formula (Ib) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ib). 25 A subject of the present invention is, even more particularly, the products of formula (I), (Ia) or (Ib) as defined above, corresponding to formula (Ic): WO 2006/010641 PCT/EP2005/008720 63 Ric LIc R 2 c Rscs .. Xc Ac 0 N 0 R4c N' R~c "L c (Ic)
R
4 1 c 12 in which A represents a phenyl, a 5 to 6-membered heteroaryl or a condensed heterocyclic ring system selected from the 5 list: 1,2,3,4-tetrahydro-quinolin, 1,2,3,4-tetrahydro isoquinolin, indolyl, 2,3-dihydro-1H-indolyl, 2,3 dihydro-lH-isoindolyl, 2,3-dihydro-benzothiazole, tetrahydroquinoline or tetrahydroisoquinoline; all these radicals being optionally substituted with one 10 or more substituents, which may be identical or different, chosen from alkyl, alkoxy, cycloalkyl, alkylamino and dialkylamino radicals, each alkyl radical being optionally substituted with one or more F ; -OCF3, SCF3 and SO2CF3 radicals; 15 Xc represents a single bond or the following divalent radicals: -N(R6c)-; -0-; -C(0)-; and -N(R6c)-C(O)-; Llc represents an alkylene radical containing 1 to 4 carbon atoms, optionally substituted with a hydroxyl radical; 20 either R1c and R2c, which may be identical or different, are such that: RIc represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be WO 2006/010641 PCT/EP2005/008720 64 identical or different, chosen from halogen atoms; hydroxyl; alkoxy; cyano, free or esterified carboxyl, phenyl, 3- to 7-membered cycloalkyl, alkylamino, dialkylamino, -NHCO-alkyl, -CO(NH-alkyl), CO(Ndialkyl) 5 and saturated, partially saturated or unsaturated 5-, 6 or 7-membered heteroaryl radicals containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH and N-alkyl and optionally substituted with one or more substituents, which may be identical or 10 different, chosen from halogen atoms and alkyl, NH2 and alkoxy radicals; or alternatively Rlc represents a phenyl radical or a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical, itself containing one or more hetero atoms chosen from 0, S, N, 15 NH and N-alkyl, and optionally substituted with one or more radicals chosen from halogen atoms and alkyl, NH2 and alkoxy radicals; and R2c represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or 20 more halogen atoms; or Rlc and R2c form, together with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, 25 NH, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, CF3 and free or esterified carboxyl radicals; or NRlc with Llc or NR2c with LlC together form a 4- to 30 7-membered heterocycle optionally substituted with one or WO 2006/010641 PCT/EP2005/008720 65 more substituents, which may be identical or different, chosen from halogen atoms, and alkyl, alkoxy and free or esterified carboxyl radicals; L2c is chosen from a single bond and methylene; 5 R4c and R4'c, which may be identical or different, represent-a hydrogen atom, an alkyl or cycloalkyl radical optionally substituted with one or more halogen atoms; it being understood that two substituents R4c may form, with the carbon atom to which they are attached, a 3-membered 10 to 5-membered spirocyclic ring ; Yc represents a heteroaryl radical chosen from pyrid-4 yl, pyrimidin-4-yl, quinolin-4-yl, isoquinolin-5-yl; azaindol-4-yl and quinazolin-4-yl, these radicals being optionally substituted with one or more substituents, 15 which may be identical or different, chosen from the values of R5c; R5c represents a hydrogen atom, a halogen atom; an alkyl, cycloalkyl, NH2, -NH-cycloalkyl, -NHCO-alkyl, -NHCO cycloalkyl, -NHCONH-alkyl or -NHCON(dialkyl) radical, the 20 alkyl and cycloalkyl residues being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms (F) and alkoxy, morpholinyl, piperidyl, piperazinyl, N-methyl piperazinyl and COOH radicals; NH-aryl, NH-heteroaryl, 25 -NHCO-aryl and -NHCO-heteroaryl in which the aromatic residues are optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and COOH radicals; R6c represents a hydrogen atom or an alkyl radical 30 containing from 1 to 4 carbon atoms; WO 2006/010641 PCT/EP2005/008720 66 R6c and NRlcR2c may optionally together form a 5- to 7 membered heterocycle optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms (F) and alkyl and alkoxy 5 radicals, the said products of formula (Ic) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of 10 the said products of formula (Ic). As illustrations of radicals according to the present invention, without, however, limiting the present invention, examples may be given of NRl forming a ring with Li or NR2 forming a ring with Li, as follows: RI A~ X N X RI X 15 Ri The examples that follow give, without limiting the scope of the present invention, an illustration of radicals that R2 iray form with R6. 0 0 A N A,N A.,N NR1 NR1 NR1 WO 2006/010641 PCT/EP2005/008720 67 The examples that follow give, without limiting the scope of the present invention, an illustration of radicals that R6 can form with L1. 0 R1 0 R1 A N R 1 A , N R2 A ,sN R2 R2N N R2 5 The examples that follow give, without limiting the scope of the present invention, an illustration of radicals that A can represent as a fused heterocyclic radical. R1 R1 RI N-R2 /N-R2 . 0 ,N-R2 N-X Ny RI R1 RI -N =:: N ~ NR2 N-R2 N -R2 N'X N'X/ X The examples that follow give, without limiting the scope 10 of the present invention, an illustration of 3- to 10 membered cyclic radicals . that two substituents R4 can form, together with the carbon atom(s) to which they are attached: WO 2006/010641 PCT/EP2005/008720 68 A A A A II A 0 N 0 N I o WN 00 N,0 0 N YO NL2 N,'L2 & N, L2 A subject of the present invention is, particularly, the products of formula (I) as defined above in which A represents a phenyl, 2,3-dihydro-1H-indolyl, or indolyl 5 radical optionally substituted with one or more radicals chosen from the values of R3, X represents a single bond, -NH-alk-, alkylene, -0-, Nalk-CO-, -NH-CO, -NH-CO-alk-, -NH-CO-NH-, -CO-NH-, -S02,-NR6d or -CO-, 10 Li represents a single bond, an alkylene radical containing 1 to 5 carbon atoms optionally substituted with a hydroxyl radical, an cycloalkylalkyl radical, a phenyl radical, Ri and R2, which may be identical or different, are such 15 that: either R1 represents a hydrogen atom, an alkyl radical optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, NH2, NH(alk), N(alk)2, cyano, free or esterified carboxyl, phenyl and 20 3- to 7-membered cycloalkyl radicals and a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic. radical, itself optionally substituted with WO 2006/010641 PCT/EP2005/008720 69 one or more alkyl radicals and containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH and N-alkyl, or R1 represents a 3- to 7-membered cycloalkyl radical, a 5 phenyl radical or a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with one or more alkyl radicals and containing one or more hetero atoms chosen from 0, S, N, NH and N-alkyl, 10 and R2 represents a hydrogen atom or an alkyl radical, or R1 and R2 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4- to 7-membered heterocyclic radical optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, 15 this radical formed by RI and R2 with N being itself optionally substituted with one or more radicals chosen from alkyl, halogen, NH2, NH(alk), N(alk)2, CF3 and free or esterified carboxyl radicals,, all the above alkyl and alkoxy radicals being linear or 20 branched and containing up to 6 carbon atoms., or NR1R2 forms with Li a saturated or unsaturated 4- to, 10-membered heterocycle containing at least one nitrogen atom and optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, this radical 25 formed by ' NRlR2 with Ll being itself optionally substituted with one or more radicals chosen from alkyl, cycloalkyl and free or esterified carboxyl radicals, R3 represents one or more substituents of the ring A, which may be identical or different, chosen from a 30 hydrogen atom and an alkyl or alkoxy radical containing WO 2006/010641 PCT/EP2005/008720 70 up to 4 carbon atoms, optionally substituted with one or more F; alkyl-S(O)n optionally substituted by F; OCF3;SO2CF2; or SCF3; with n representing 0 or 2; R4 and R4', which may be identical or different, are 5 chosen from a hydrogen atom and an alkyl radical containing up to 4 carbon atoms, R6 represents a hydrogen atom, an acyl radical optionally substituted with one or more F or an alkyl radical containing from 1 to 4 carbon atoms, 10 L2 represents an alkylene radical, Y2 represents a quinolyl, pyridyl or pyrimidinyl radical, optionally substituted by NH2; the said products of, formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric 15 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said 'products of formula (I). A subject of the present invention is, most particularly, the products of formula (I) as defined above 20 corresponding to formula (Id): Rid N L d R 2 d
R
3 ds /Xd o N 0 Rd NL (dd)
R
4 1 d 12 YdsRd (5d WO 2006/010641 PCT/EP2005/008720 71 in which: Ad represents a phenyl or indolyl radical optionally substituted with one or more radicals chosen from the 5 values of R3d, Xd represents -0-, -NH-CO, -NR6 or -CO-, Lid represents an alkylene radical containing 1 to 3 carbon atoms optionally substituted with a hydroxyl radical, 10 Rid and R2d, which may be identical or different, are such that: either Rld represents an alkyl radical optionally substituted with one or.more radicals chosen from halogen atoms and hydroxyl, alkoxy, cyano, free or esterified 15 carboxyl, phenyl and 3- to 7-membered cycloalkyl radicals and a saturated, partially.saturated or unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with one or more alkyl radicals and containing one or more hetero atoms, which may be 20 identical or different, chosen from 0, S, N, NH and N-alkyl, or Rid represents a 3- to. 7-membered cycloalkyl radical, a phenyl radical or a saturated, partially saturated or, unsaturated 4- to 7-membered heterocyclic radical, itself 25 optionally substituted with one or more alkyl radicals and containing one or more hetero atoms chosen from 0, S, N, NH and N-alkyl, and R2d represents a hydrogen atom or an alkyl radical, WO 2006/010641 PCT/EP2005/008720 72 or Rld and R2d form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4- to 7-membered heterocyclic radical optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, 5 this radical formed by Rla and R2d with N being itself optionally substituted with one or more radicals chosen from alkyl, CF3 and free or esterified carboxyl radicals, all the above alkyl and alkoxy radicals being linear or branched and containing up to 6 carbon atoms, 10 or NRldR2d forms with Lld a saturated or unsaturated 4 to 8-membered heterocycle containing at least one nitrogen atom and optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, this radical formed by NRldR2d with Lld being itself 15 optionally substituted with one or more radicals chosen from alkyl and free or esterified carboxyl radicals, R3d represents one or more substituents of the ring Ad, which may be identical or different, chosen from a hydrogen atom and an alkyl or alkoxy radical containing 20 up to 4 carbon atoms, optionally substituted with one or more F; OCF3; SO2CF3; or SCF3; R4d and R4'd, which may be identical or different, are chosen from a hydrogen atom and an alkyl radical containing up to 4 carbon atoms, 25 L2d represents an alkylene radical, Y2d represents a quinolyl, pyridyl or pyrimidinyl radical, the said products of formula (Id) being in all the possible racemic, enantiomeric and diastereoisomeric 30 isomer forms, and also the addition salts with mineral WO 2006/010641 PCT/EP2005/008720 73 and organic acids or with mineral and organic bases of the said products of formula (Id). In the products of formula (Id), Rld and R2d are especially such that: 5 either Rld and R2d, which may be identical or different, are such that: Rld represents an alkyl radical (1 to 6C) optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl; alkoxy; cyano; free and esterified 10 carboxyl; phenyl; cyclopropyl, cyclopentyl, cyclohexyl, isoxazolyl, furyl, pyrazinyl, morpholinyl, pyridyl and isothiazolyl radicals, optionally substituted with one or more alkyl radicals, or R2a represents a cyclopropyl, cyclopentyl, cyclohexyl, 15 phenyl, hexahydropyran, pyrrolidinyl, piperidyl or pyridyl radical optionally substituted with one or more alkyl radicals, and R2d represents a hydrogen atom or an alkyl radical or Rld and R2d form, with the nitrogen atom to which they 20 are attached, a morpholinyl, piperidyl, piperazinyl or pyrrolidinyl radical, optionally substituted with one or more radicals chosen from alkyl, CF3 and free or esterified carboxyl radicals, all the above alkyl and alkoxy radicals being linear or 25 branched and containing up to 6 carbon atoms, or NRldR2d forms with Lid a piperidyl radical optionally substituted with one or more radicals chosen from alkyl and free or esterified carboxyl radicals.
WO 2006/010641 PCT/EP2005/008720 74 A subject of the present invention is especially the products' of formula (I) , (Ia), (Ib) , (Ic) or (Id) as defined above in which, when A represents a phenyl radical, then X represents -0-, -NR6 or -NH-CO, the other 5 substituents of the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being chosen from all the values defined for the said substituents, the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and 10 diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I), (Ia), (Ib), (Ic) or (Id). A subject of the present invention is also especially 15 the products of formula (I), (.Ia) , (Ib) , (Ic) or (Id) as defined above in which, A represents an indolinyl radical, X represents -0-, -NR6, -CO- or -NR6-CO and the other substituents of the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being chosen from all the values 20 defined for the said substituents, the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and 25 organic bases of the said products of formula (I), (Ia), (Ib), (Ic) or (Id). A subject of the present invention is, more specifically, the products of formula (I) as defined above, the names of which are given hereinbelow: 30 - N-[5-(4,4-Dimethyl-2.,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] -2 morpholin-4-yl-acetamide WO 2006/010641 PCT/EP2005/008720 75 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 (dimethyl-morpholin-4-yl)-acetamide trifluoroacetate - 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl)]-2- (2,2,2 trifluoro-ethylamino)-acetamide trifluoroacetate 10 - 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 15 thiomorpholin-4-yl-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 pyrrolidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4 methyl-piperazin-1-yl)-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 piperidin-1-yl-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 76 - N-[5- (4, 4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl inidazolidin-1-yl) -2-trifluoromethoxy- phenyll-2 [(pyridin-3-ylmethyl) -amino] -acetamide trifluoroacetate - N-[5- (4,4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-l-yl) -2-trifluoromethoxy- phenyl] -2 [(pyridin-4-ylmethyl) -amino] -acetamide trifluoroacetate - N-[5- (4,4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl imidazolidin-l-yl) -2-trifluoromethoxy- phenyll-2- (2 hydroxy-ethylanino) -acetamide trifluoroacetate 10 - N-[5- (4,4-Dimethyl-2, 5-dioxo-3--pyridin-4-ylmethyl imidazolidin-l-yl)-2-trifluoromethoxy- phenyll -2- (2-. rethoxy-ethylamino) -acetamide trifluoroacetate - 2-Dimethylamino-N-[5- (4,4-diiethyl-2,5-dioxo-3-pyridin-, 4-ylmethyl-irnidazolidin-1-yl) -2- trifluorornethoxy 15 phenyll-acetamide trifluoroacetate - 2- (Cyanomethyl-amino)-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-l- yl) -2 trifluoromethoxy-phenyl] -acetamide trifluoroacetate - N- [5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazoliclin-1-yl) -2-trifluoromethoxy- phenyll -2- (4 rnethyl-pipericlin-l-yl) -acetarnide - N-[5-('4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylnethyl imidazolidin-l-yl) -2-trifluoromethoxy- phenyl] -2- (4 methyl- [1,4] diazepan-l-yl) -acetamide trifluoroacetate 25 - 2-tert-Butylamino-N-[5-(4, 4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl) -2 trifluoromethoxy-phenyl] -acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 77 - N-[5-( 4
,
4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate ({1[5-( 4 ,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl) methyl}-amino)-acetic acid methyl ester; compound with trifluoro-acetic acid
-
2
-(
2 ,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl- imidazolidin-l-yl)-2 10 trifluoromethoxy-phenyl]-acetamide; compound with trifluoro-acetic acid N-[5-(4;4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4,4 dimethyl-piperidin-1-yl)-acetamide 15 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4 trifluoromethyl-piperidin-1-yl)-acetamide N-[5-( 4 ,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 20 [1,4]oxazepan-4-yl-acetamide - 1-{[5-( 4
,
4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-pyrrolidine-3-carboxylic acid methyl ester - 2-Azetidin-1-yl-N-[5-(4, 4 -dimethyl-2,5-dioxo-3-pyridin 25 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2-(2 fluoro-ethylamino)-acetamide WO 2006/010641 PCT/EP2005/008720 78 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- [(2 methoxy-ethyl)-methyl-amino]-acetamide - ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl methyl}-amino)-acetic acid trifluoroacetate - 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 10 - 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyll-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 15 morpholin-4-yl-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 (dimethyl-morpholin-4-yl)-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(4 methyl-piperazin-1-yl)-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy- phenyl)-3 piperidin-1-yl-propionamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 thiomorpholin-4-yl-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 79 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 pyrrolidin-1-yl-propionamide trifluoroacetate - 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl)-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(2,2,2 trifluoro-ethylamino)-propionamide; compound with 10 trifluoro-acetic acid - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 15 imidazolidin-1-yl)--2-isopropyl-phenyll-2-morpholin-4-yl acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,.5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-isopropyl-phenyl] -2-piperidin-1-yl acetamide trifluoroacetate 20 - N-[-5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-(4-methyl piperazin-1-yl)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] 25 acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 80 - 2-Diethylamino-N-[5- (4,4-direthyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] acetamide trifluoroacetate - 2-tert-Butylamino-N-[5- (4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylnethyi-irnidazoliciin-1-yl) -2-isopropyl phenyl] -acetamide trifluoroacetate - 2-Cyclopentylamino-N- 15- (4, 4-diruethyl-2, 5-dioxo-3 pyridin-4--ylmethyl-imidazolidin-1-yl) - 2-isopropyl phenyll -acetamide trifluoroacetate 10 - 1-Methyl-piperidine-4-carboxylic acid [5-(4,4-dimethyl 2, 5-dioxo-3--pyridin-4-ylnethyl- imidazolidin-1-yl) -2 trifluoromethoxy-phenyll -amide, trifluoro-acetate -3- [3- (2-Cyclopentylarnino-ethoxy) -4-methoxy-phenyl] -5,5 dimethyl-1-quinolin-4-ylmethyl- imidazolidine-2, 4-dione 15 - 3- (3-{2-[ (Furan-2-ylrnethyl)-aminoll-ethoxy}-4-rnethoxy phenyl) -5, 5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2, 4-dione - 3-{3- 12- (2-Hydroxy-1-phenyl-ethylamino) -ethoxy] -4 methoxy-phenyl }-5, 5-dimethyl-1-quinolin- 4-ylmethyl 20 imidazolidine-2, 4-dione - 3-[3,3-Dimethyl-1-(2-morpholin-4-yl-acetyl)-2,3 dihydro-1H-indol-6-yl] -5, 5-dimethyl-1- quinolin-4 ylmethyl-irnidazolidine-2, 4-dione -3-[3,3-Dirnethyl-1- (2-thiomorpholin-4-yl-acetyl) -2,3 25 dihydro-1 H-indol-6-yl] -5, 5-dimethyl- l-quinolin-4 ylmethyl-imidazolidine-2, 4-dione WO 2006/010641 PCT/EP2005/008720 81 - 3-{4-Methoxy-3-[2-(2-morpholin-4-yl-ethylamino) ethoxy]-phenyl}-5,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-[4-Methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,5 5 dimethyl-l-quinolin-4-ylmethyl- imidazolidine-2,4-dione - 3-(4-Methoxy-3-{2-[(pyridin-2-ylmethyl)-amino]-ethoxy} phenyl) -5, 5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-{4-Methoxy-3-[2-(tetrahydro-pyran-4-ylamino)-ethoxy] 10 phenyl}-5,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2, 4-dione - 3-{4-Methoxy-3- [2- (l-methyl-piperidin-4-ylamino) ethoxy] -phenyl} -5, 5-dimethyl-l-quinolin- 4-ylmethyl imidazolidine-2,4-dione 15 - 3-{3-[2-Hydroxy-3-(tetrahydro-pyran-4-ylamino) propoxyl-4-methoxy-phenyl}-5,5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2, 4-dione - 3-{3-[2-Hydroxy-3- (pyridin-4-ylamino) -propoxyl -4 methoxy-phenyl } -5, 5-dimethyl-l-quinolin- 4-ylmethyl 20 imidazolidine-2,4-dione 3-{3-[2-Hydroxy-3-(l-methyl-piperidin-4-ylamino) propoxyl-4-methoxy-phenyl}-5,5-dimethyl- l-quinolin-4 ylmethyl-imidazolidine-2,4-dione the said products of formula (I) being in all the 25 possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with- mineral and organic acids or with mineral and organic 'bases of the said products of formula (I).
WO 2006/010641 PCT/EP2005/008720 82 A subject of the present invention is thus, particularly, the products of formula (I) as defined in any one of the claims, the names of which are given hereinbelow: - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 morpholin-4-yl-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 (dimethyl-morpholin-4-yl)-acetamide.trifluoroacetate 10 - 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl-2-(2,2,2 15 trifluoro-ethylamino)-acetamide trifluoroacetate - 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyll-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 thiomorpholin-4-yl-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 pyrrolidin-1-yl-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-.(4 methyl-piperazin-1-yl)-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 83 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 piperidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2 15 hydroxy-ethylamino)-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 methoxy-ethylamino)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4, 4-dimethyl-2,5-dioxo-3-pyridin 20 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate - 2-(Cyanomethyl-amino)-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-piperidin-1-yl)-acetamide WO 2006/010641 PCT/EP2005/008720 84 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4 methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imidazolidin-l- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate 10 - ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-amino)-acetic acid methyl ester; compound with, trifluoro-acetic acid - 2-(2,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 15 dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-acetamide; compound with trifluoro-acetic acid - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4,4 20 dimethyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (4 trifluoromethyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [1,4]oxazepan-4-yl-acetamide WO 2006/010641 PCT/EP2005/008720 85 - 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-pyrrolidine-3-carboxylic acid methyl ester - 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 5 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2 fluoro-ethylamino)-acetamide 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-[(2 methoxy-ethyl)-methyl-amino]-acetamide - ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] 15 methyl}-amino)-acetic acid trifluoroacetate - 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 20 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 morpholin-4-yl-propionamide trifluoroacetate 25 N-[5-(-4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 (dimethyl-morpholin-4-yl)-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 86 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -3- (4 methyl-piperazin-1-yl) -propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 piperidin-1-yl-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 thiomorpholin-4-yl-propionamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl)-3 pyrrolidin-1-yl-propionamide trifluoroacetate - 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 15 trifluoromethoxy-phenyl]-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -3- (2,2,2 trifluoro-ethylamino)-propionamide; compound with trifluoro-acetic acid 20 - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-morpholin-4-yl 25 acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 87 - 1N-[5- (4,4-Dimethyl-2, 5-dioxo-3-pyridin-4--ylmethyl-. iridazolidin-1-yl) -2-isopropyl-phenyll -2-piperidin-1-yl acetarnide trifluoroacetate - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl.) -2-isopropyl-phenyl] -2- (4-methyl piperazin---yl) -acetamide trifluoroacetate - 2-1Dimethylamino-N~- [5- (4, 4-dimethyl-2, 5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-l-yl) -2-isopropyl-phenyl] acetamide trifluoroacetate 10-- 2-Diethylamino-N- [5- (4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolilin-1-yl) -2-isopropyl-phenyl] acetamide trifluoroacetate - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) -2-isopropyl 15 phenyl] -acetamide trifluoroacetate - 2-Cyclopentylamino-N-[5-(4,4-dimethy1-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2-isopropyl phenylil-acetamile trifluoroacetate - l-Methyl-piperidine-4-carboxylic acid [5- (4,4-dirnethyl 20 2, 5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl) -2 trifluoromethoxy-phenyl] -araide, trifluoro-acetate -3- [3- (2-Cyclopentylamino-ethoxy) -4-methoxy-phenyl] -5,5 dimethyl-1-quinolin-4-ylmethyl- imidazolidine-2, 4-dione - 3- (3-{2- [(Furan-2-yliethyl)-amino]-ethoxy}-4-methoxy 25. phenyl) -5, 5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2, 4-dione WO 2006/010641 PCT/EP2005/008720 88 - 3-{3-[2-(2-Hydroxy-l-phenyl-ethylamino)-ethoxy]-4 methoxy-phenyl}-5,5-dimethyl-l-quinolin- 4-ylmethyl imidazolidine-2,4-dione 3-[3,3-Dimethyl-1-(2-morpholin-4-yl-acetyl) -2,3 5 dihydro-lH-indol-6-yl]-5,5-dimethyl-l- quinolin-4 ylmethyl-imidazolidine-2,4-dione - 3-[3,3-Dimethyl-l-(2-thiomorpholin-4-yl-acetyl)-2,3 dihydro-lH-indol-6-yll-5,5-dimethyl- l-quinolin-4 ylmethyl-imidazolidine-2,4-dione 10 the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said -products of formula (I), 15 The compounds of general formulae Ia, Ib and Ic in which X' denotes NR6, 0 or S are in accordance with the reaction sequences described in Scheme 1. To this end, an intermediate of general formula la, in which the variables have the abovementioned meanings and 20 in which X' denotes NH2, OH or SH, is reacted with a difunctional alkylating agent of general formula Tb, for instance a haloalkanal acetal. The reaction is performed in bulk or in an inert organic solvent, optionally in the presence of a base. A preferred alkylating agent is 25 bromoacetaldehyde diethyl acetal. From the aldehyde obtained by hydrolysis of the acetal, compounds according to the invention of general formula Ib are then obtained by reductive amination. The compounds in which the bonding group Ll is substituted 30 with a hydroxyl (Ia) are prepared by converting the WO 2006/010641 PCT/EP2005/008720 89 aldehyde to the corresponding epoxide and subsequent decyclization with amines. One variant for access to I describes the direct. alkylation of compounds of general formula la with an 5 aminoalkyl halide of general formula Hal-Li-N (RlR2) In. the case where X' represents OH and SH, this reaction is preferably performed in an organic solvent such as ethyl acetate, DMF, NMP or acetone, in the presence of a base such as potassium tert-butoxide, potassium carbonate or 10 caesium carbonate. In the case where X' denotes NH2, the process preferably proceeds first with acylation and the intermediate amide is used for the alkylation. Preferred acyl radicals are acetyl and trifluoroacetyl. Removal of the acyl group once the alkylation, has been performed 15 then gives rise to compounds according to the invention, which may be optionally converted into compounds of general formula Ic via additional steps. 0 OH R3 AX Hl RR3 A. R3 X' R3 N A' "A L'H A 'L'~ AL N 4DMSO N O i 0 N 0 lb 0 N 0 Base N 0 EOH0 N 0 R 1. Base [ 2 N. c 2Ip-NNL [12 ECsp~.L 2, HO la Y a {2 2. H0, H+R5 R5 L, RNR,, Y, Reduction O RI H R R R3, A'HH R3, IX"' N 'R 0 N 0 ,R 0 R4 04 N1O [CH~j N RN , L A L 2 H H1LYR2I Y'R5 ~R5 R1 Base 0 R[R1 H R R3 N, N,, ,R2 L R2 A L, R2 01 1 R4R 0 0R4 O Y IC[CH } N YR R5 YR5 Scheme 1 20 The starting substances of general formula la (X' NH2) required for this sequence may be prepared in accordance with the process summarized in Scheme 2. A suitably WO 2006/010641 PCT/EP2005/008720 90 substituted nitroaniline, which may be obtained, for example, by nitration of the corresponding aniline, is, in the present case, converted into the corresponding isocyanate or into a derivative of similar reactivity, in 5 an inert solvent under the action of phosgene, diphosgene, triphosgene or carbonyldiimidazole, in the presence or absence of an auxiliary base, and reacted with a compound of general formula 2a to give rise to the heterocyclic compounds of general formula 2b. 2a are 10 preferably obtained by reductive amination of the corresponding amino acid derivative with an aldehyde of general formula R5-Y-L 2 '-CHO. As a variant, the intermediates of general formula la (X'= NH2) may also be prepared by direct nitration of 15 compounds of general formula 2c. The subsequent reduction of the nitro compound 2b is performed by catalytic hydrogenation in the presence of a heterogeneous or homogeneous transition metal catalyst, preferably a heterogeneous transition metal catalyst. As 20 a variant, to this end, the reduction may also be performed with a non-precious metal in the presence of an acid. Preferred reagents for this reaction are zinc and dilute 'hydrochloric acid, particularly preferably zinc and glacial acetic acid. O ' N S RSNH V Zn. acid A3_ N 0 R IN tCH 2 I0 .N NH22NH, 20 YsR 25 Scheme 2 WO 2006/010641 PCT/EP2005/008720 91 Similarly, constituent components of general formula la (X' = NH2, OH, SH), are obtained when a correspondingly substituted synthon 3a, -optionally protected on reactive groups, is converted into the corresponding isocyanate or 5 into a derivative of similar reactivity, under the action of phosgene, diphosgene, triphosgene or carbonyldiimidazole, in the presence or absence of an auxiliary base, and condensed with an amino, acid derivative of general formula 2b, in an inert solvent, 10 for instance THF, toluene, dioxane or ethyl acetate, optionally in the presence of an auxiliary base, for instance triethylamine or potassium tert-butoxide. The reaction temperature is preferably between room temperature and the reflux point of the solvent, 15 particularly preferably at the reflux point. As a variant, the cyclization may also be performed in aqueous-acidic solution at elevated temperature. R3 A
NH
2 3a One variant of the process for preparing the compounds of 20 general formulae Ia, Ib and Ic, in which X' denotes NR6, O or S, consists in converting the constituent components of general formulae 3a-d into the corresponding isocyanate or into a derivative of similar reactivity, with phosgene, diphosgene, triphosgene or carbonyl 25 diimidazole, in the presence or absence of an auxiliary base, and in then reacting them with an amino acid derivative of general formula 2a under the conditions mentioned for the preparation of la. The intermediates thus obtained are then converted into compounds of 30 general formulae Ia-c in a manner similar to that for the reactions described in Scheme 1.
WO 2006/010641 PCT/EP2005/008720 92 0 RI R1 R A -X'A'L' R3 X',LN R2 R 3 N ANH R3 L R2 NH A A II 1 R2 NH2 R NH2 NH 2
NH
2 3b 3c 3d 3e The arylamines 3a are in part described in the literature or may be obtained in accordance with conversions known to those skilled in the art from derivatives known in the 5 literature. The starting substances 3b-e are obtained from 3a via synthetic routes that are in principle similar to the reaction sequences described in Scheme 1. For the conversion, the free amino group is, in the present case, protected with the usual protecting groups 10 or masked in the form of a nitro function, and reduced at a subsequent stage. The compounds according to the invention of general formula Id in which X' denotes -N(R6)-C(O)-, -N(R6)-C(O) N(R6')-, -N(R6)-C(S)-N(R6')-, -N(R6)-C(0)O-, -N(R6)-SO2 15 or -N (R6) -S02-N (R6' ) are obtained by reacting an intermediate of general formula 4a with a difunctional reagent, for instance, activated halocarboxylic acids, haloisocyanates, isothiocyanates or halosulphonyl chlorides (Scheme 3) . Preferred reagents are chloroacetyl 20 chloride, acryloyl chloride, 2-chloropropionyl chloride and chloromethanesulphonyl chloride, and also homologues thereof. The coupling is preferably performed in an inert solvent at low temperature. The use of a base is optional. Among the intermediates formed, the compounds 25 of general formula Id are obtained by reaction with a suitably substituted amine. This reaction may be performed in an inert organic solvent or in bulk, optionally in the presence of an auxiliary base. By using acryloyl chloride in the first step, 30 aminopropionylamides according to the invention are WO 2006/010641 PCT/EP2005/008720 93 obtained after reaction with amines. As a variant, 4a may also be reacted directly with amino substituted difunctional reagents of general formula 4b to give rise to compounds of general formula Id. 0 R1 Id Cl L R2 4b O L Hal R3s ANH 2 0 R3A NH 0 N 0 Cl L a 0 N 0 HNRR 2 Y ~ R4----I -- ~ Id [CH}j NL
[CH
2 ]P NNL 122 4a R5 R5 R2 0 R C1 O" O NsR R3A NH R3*A NH A A R N O HNRR 2 : 0 N 0 R4- R4- I [CH- NIL -[CH], N, (CH21p_,NLIH],N 5
R
5 YR5 Scheme 3 The compounds of general formula I in which X denotes -N(R6)-C(O)- and R2 and'Ll form a nucleus are obtained by reacting compounds of general formula 4a with an 10 activated amino acid derivative of general formula 5. The amino acid may be activated by conversion into the acid chloride or via amide coupling reactions that are sufficiently known to those skilled in the art. The products initially obtained, Ie, may be converted into 15 other compounds Ie according to the invention via other conversions. ORL,R2 R3.A NH 2 a L- R2 R3A NH RI 0 N 0 0a 0 R4- R4 O le CH] N, L2[CH 2 ] N, 4a 5b Scheme 4 Other cyclic derivatives in which X represents the WO 2006/010641 PCT/EP2005/008720 94 abovementioned meanings may be obtained in accordance with similar processes. The compounds of general formula I, in which X' denotes -C(0)-N(R6)-, -S02-NR6- or -C(0)0-, are obtained in 5 accordance with Scheme 5. The intermediates 6b, in which -T denotes -COOH, -COO-Alkyl, -SO2OH, -SO2Cl or -SO2F, are, in the present case, prepared by a reaction sequence as has just been described in Scheme 2. The compounds 6a are commercially -available or may be prepared from 10 commercially available derivatives via conversions known to those skilled in the art. The condensation of 6b with a reagent of formula V-L 1 -N(RlR2) when V represents NH2, NR6, hydrogen or hydroxyl. then gives the desired compounds. In the case where T denotes -COOH or -SO2OH, 15 6b is first activated by the action of agents such as, for example, thionyl chloride, oxalyl chloride or phosphorus pentachloride. As a variant, the activation may also be performed with coupling agents known to those skilled in the art, for instance TOTU or DCC. R R1 R T R3 AT v'YR R 3 -Xs ,NsR2 R3. V I L 1 R R3 'T R 0 N O R2 0 N 0 A ~--N R4-j R4 -j
NH
2
[CH
2 ] N [CH ] N Ii12 O 6b R5 R5 20 e Scheme 5 Scheme 6 illustrates, by way of example, the way in which compounds in which A denotes a system containing a fused homocyclic or heterocyclic nucleus may be prepared. 25 To this end, the system containing nucleus A is first linked to the central heterocycle in accordance with the reaction sequence described for compound 2b. Next, the compounds of general formula I are then obtained by alkylation, acylation, sulphonylation, carbamoylation or 30 thiocarbamoylation and additional reactions, of the derivatives thus obtained.
WO 2006/010641 PCT/EP2005/008720 95 R3 N-L R1, R4 O N O
[CH
2 ] -N Hal-LNR 1
R
2 R5 R1 R3 R3 N) LHal R3 Li-NN N ~R2 0 0 R4 0 N 0 CI Lr~ '- R4O N o
HNR
1
R
2 R4 0 N O R4___ I R4- - -I Y4
[CH
2 1 N [CH]H N] CHp] N R5 YR5 "R5 RI 0 R3 N R3 N N-R2 0 N 0
HNR
1
R
2 0 N 0 R4-~ Y R4_ r
[CH
2 1 N, [CH 2]p NN R5 YR5 Scheme 6 The derivatives of general formula R3-A-NH2 required for the'reaction, may be obtained in accordance or by analogy 5 with processes known in the literature. Thus,' the indolines required for the illustrated example may be prepared as described in document US6114365. The compounds of general formula I may moreover be obtained by reacting an amino acid derivative of general 10 formula 7a with an isocyanate 7b or an analogue of similar reactivity, in which Z denotes a group A-, R3A or R3A(X')- or denotes R,' L,
R
2 ' I R 3 "~XI 15 (Scheme 7). The intermediates 7c formed are then converted into compounds of general formula I by WO 2006/010641 PCT/EP2005/008720 96 alkylation with a halide Hal-L 2 -Y-R5 or another reagent of similar reactivity. The alkylation reactions are preferably performed in an organic solvent, for instance dimethylformamide, N-methylpyrrolidone, ethyl acetate or 5 acetone, in the presence of a base, for instance potassium carbonate, caesium carbonate, sodium hydride or potassium tert-butoxide. The bases dimethylformamide and caesium carbonate are preferably used. 0 Z Hal 0 OR 7b 0 N O vR5 O N O R4- R4R4- T [CH ] NH 2
[CH
2 1] NH [CH 2 1PN 7a 7c YR5 10 Scheme 7 All the, processes for preparing compounds of general formula 1 are distinguished by the fact that the relative sequence of the individual steps is modifiable and may be adapted to the respective needs, determined by the 15 reactivity of the intermediates. The invention also describes all the reactions on compounds of general formula I, which again lead to compounds of general formula I. Thus, compounds of general formula I in which X denotes -N(R6)-C(O)- and R6 20 denotes H may be converted by alkylation into compounds of general formula I, in which R6 denotes an alkyl or a cycloalkyl. The conversion of a radical YR5, which denotes a chloropyridine, into a radical YR5, which denotes aminopyridine, may serve as an additional 25 example. It may be noted that all the reactions for the synthesis of the compounds of formula (I) are well known per se to those skilled in the art and may be performed under standard conditions in accordance with or similar to 30 procedures described in the literature, for .example in Houben-Weyl, Methoden der Organischen Chemie (Methods of WO 2006/010641 PCT/EP2005/008720 97 Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York or in R.C. Larock in: Comprehensive Organic Transformations, VCH publishers, 1989. Depending on the individual 5 circumstances, in order to avoid side reactions during the synthesis of a compound of formula (I) , it may be necessary or advantageous to temporarily block functional groups by introducing protecting groups, and to deprotect them at a subsequent stage in the synthesis, or to 10 introduce functional groups in the form of precursor groups which are converted into the desired functional groups in a subsequent reaction step. Such synthetic strategies and such protecting groups and precursor groups that are suitable in an individual case are known 15 to those -skilled in the art. Standard practices are described, for example, in T.W. Greene and P.G.M. Wuts: "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. If so desired, the compounds of formula (I) may be purified via common purification procedures, for 20 example by recrystallization or chromatography. The starting. materials for the preparation of the compounds of formula (I)' are commercially available or may be prepared in accordance with or analogously to literature procedures. The compounds obtained via the abovementioned 25 synthetic methods constitute an additional subject of the present invention. The products that are the subject of the present invention are endowed with advantageous pharmacological properties: it has been found that they especially have 30 inhibitory properties on protein kinases. Among these protein kinases, mention is especially made of IGFlR. Mention is also made of FAK. Mention is also made of AKT. 35 These properties thus make the products of general WO 2006/010641 PCT/EP2005/008720 98 formula (I) of the present invention usable as medicinal products for treating-malignant tumours. The products of formula (I) may also be used in the veterinary field. 5 One subject of the invention is thus, as medicinal products, the products of formula (I) as defined above, and also prodrugs thereof, the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the 10 pharmaceutically acceptable addition salts with mineral and organic acids or with mineral and organic bases of, the said.products of formula (I). A subject of the invention is thus the use, as medicinal products, of the products of formula (Ia), (Ib), (Ic) or 15 (Id) as 'defined above, and also prodrugs thereof, the said products of formula (Ia), (Ib), (Ic) or (Id) being in all- the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral 20 and organic acids or with mineral and organic bases of the said'products of formula (Ia), (Ib), (Ic) or (Id). A subject of the invention is thus, most particularly, the use, as medicinal products, of the products of formula (I), the names of which are given hereinbelow: 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-, imidazolidin-1-yl) -2-trifluoromethoxy- phenyll -2 morpholin-4-yl-acetamide - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 30 (dimethyl-morpholin-4-yl) -acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 99 - 2-Cyclopentylamino-N-[5-(4-,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2,2,2 trifluoro-ethylamino)-acetamide trifluoroacetate - 2-,Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-27 thiomorpholin-4-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy-- phenyl]-2 15 pyrrolidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)'-2-trifluoromethoxy- phenyl] -2- (4 methyl-piperazin-1-yl)-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 piperidin-1-yl-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate 25 - , N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 100 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2-(2 hydroxy-ethylamino)-acetamide trifluoroacetate - N-[5--(4,4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2 methoxy-ethylamino)-acetamide trifluoroacetate 10 - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate - 2-(Cyanomethyl-amino)-N-[5-(4, 4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 15 trifluoromethoxy-phenyl]-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-piperidin-1-yl)-acetamide - - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-l-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl) -2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 101 - ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-amino) -acetic acid methyl ester; compound with trifluoro-acetic acid 5 - 2-(2,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl] -acetamide; compound with trifluoro-acetic acid - N- [5- (4,4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl 10 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4,4 dimethyl-piperidin-1-yl)-acetamide N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (4 trifluoromethyl-piperidin-1-yl)-acetamide 15 - N-[5-(4,4-Dime-thyl-2, 5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [1,4]oxazepan-4-yl-acetamide - 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] 20 methyl}-pyrrolidine-3-carboxylic acid methyl ester - 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] -2- (2 fluoro-ethylamino)-acetamide WO 2006/010641 PCT/EP2005/008720 102 - N- [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl iridazolidin-1-yl) -2-trifluoromethoxy- phenyl] -2- [(2 methoxy-ethyl) -methyl-amino] -acetamide - ({[5-(4, 4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imiclazolidin-1-yl) -2-trifluoromethoxy- phenylcarbamoyl] methyll-anino) -acetic acid trifluoroacetate - 2-Cyclohexylamino-N- [5- (4, 4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2 trifluoromethoxy-phenyl] -acetarnide trifluoroacetate 10 - 2-Cyclopropylarnino-N-[5- (4, 4-dimethyl-2,5-dioxo-3 pyridin-4-ylntethyl-imidazolidin-1-yl) - 2 trifluorornethoxy-phenyl] -acetamide trifluoroacetate - N-[5- (4, 4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-. imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] -3 15 morpholin-4-yi-propionamide trifluoroacetate N- [5- (4, 4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy- phenyll -3 (dimethyl-morpholin-4-yl) -propionarnide trifluoroacetate N- [5- (4, 4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl) -2-trifluoromethoxy- phenyji-3- (4 rnethyl-piperazin-l-yl) -propionamide trifluoroacetate - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-l-yl) -2-trifluoromethoxy- phenyl] -3 piperidin-1-yl-propionamide trifluoroacetate 25 -N-[5- (4, 4-Dimethyl-2,5-dioxo-3-pyridin-,4-ylmethyl imidazolidin-l-yl) -2-trifluoromethoxy- phenyl] -3 thiomorpholin-4-yl-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 103 - ' N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1lyl)-2-trifluoromethoxy- phenyll-3 pyrrolidin-1-yl-propionamide trifluoroacetate - 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl-propionamide trifluoroacetate - N-[~5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(2,2,2 trifluoro-ethylamino)-propionamide; compound with 10 trifluoro-acetic acid - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl.-imidazolidin-1-yl).-2- trifluoromethoxy phenyl]-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 15 imidazolidin-1-yl)-2-isopropyl-phenyll-2-morpholin-4-yl acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-piperidin-1-yl acetamide trifluoroacetate 20 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenylJ-2-(4-methyl piperazin-1-yl)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] 25 acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 104 - 2-Diethylarnino-N-[5- (4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] acetamide trifluoroacetate - 2-tert-Butylamino-N-[5- (4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imilazolidin-1-yl) -2-isopropyl phenyl] -acetamide trifluoroacetate -2-Cyclopentylaruino-N-[5-(4, 4-dimethyl-2,5-dioxo -3 pyridin-4--ylmethyl-imidazolidin-1-yl) - 2-isopropyl phenyl] -acetamide trifluoroacetate 10 - 1-lMethyl-piperidine-4-carboxylic acid 15-(4,4-dimethyl 2, 5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl) -2 trifluoromethoxy-phenyl] -araice, trifluoro-acetate - 3- [3- (2-Cyclopentylamino-ethoxy) -4-methoxy-phenyll -5,5 dimethyl-1-quinolln-4-yimethyl- irnidazolidine-2, 4-dione 15 - 3- (3-{2-[(Furan-2-ylmethyl) -amino] -ethoxy}-4-methoxy phenyl) -5, 5-dimethyl-1-quinolin-4- ylmethyl irnicazolidine-2, 4-dione - 3-{3-[2-(2-Hydroxy-l-phenyl-ethylamino)-ethoxy]-4 methoxy-phenyl }-5, 5-dimethyl-1-quinolin- 4-ylmethyl 20 imidazolicline-2, 4-dione - 3- [3,3-Dimethyl-1-(2-morpholin-4-yl-acetyl)-2,3 dihydro-1H-indol-6-yl] -5, 5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2, 4-dione - 3-[3,3-Dimethyl-1-(2-thiomorpholin-4-yl-acetyl)-2,3 25 dihydro-lH-indol-6-yl] -5, 5-dirnethyl- I-quinolin-4 ylmethyl-irnidazolidine-2, 4-dione WO 2006/010641 PCT/EP2005/008720 105 - 3-{4-Methoxy-3-[2-(2-morpholin-4-yl-ethylamino) ethoxy]-phenyl}-5,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-[4-Methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyll-5,5 5 dimethyl-l-quinolin-4-ylmethyl- imidazolidine-2,4-dione - 3-(4-Methoxy-3-{2-[(pyridin-2-ylmethyl)-amino]-ethoxy} phenyl)-5,5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-{4-Methoxy-3-[2-(tetrahydro-pyran-4-ylamino)-ethoxy] 10 phenyl}-5,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-{4-Methoxy-3-[2-(l-methyl-piperidin-4-ylamino) ethoxyl-phenyl}-5,5-dimethyl-l-quinolin- 4-ylmethyl imidazolidine-2,4-dione 15 - 3-{3-[2-Hydroxy-3-(tetrahydro-pyran-4-ylamino) propoxyl-4-methoxy-phenyl}-5,5-dimethyl-l- quinolin-4 ylmethyl-imidazolidine-2,4-dione 3-{3-[2-Hydroxy-3-(pyridin-4-ylamino)-propoxy]-4 methoxy-phenyl}-5,5-dimethyl-1-quinolin- 4-ylmethyl 20 imidazolidine-2,4-dione 3-{3-[2-Hydroxy-3-(l-methyl-piperidin-4-ylamino) propoxy]-4-methoxy-phenyl}-5,5-dimethyl- l-quinolin-4 ylmethyl-imidazolidine-2,4-dione and also the prodrugs thereof, the said products of 25 formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the ~pharmaceutically acceptable addition salts with WO 2006/010641 PCT/EP2005/008720 106 mineral and organic acids or with mineral and organic bases of the said products of formula (I). A subject of the invention is thus, most particularly, the use, as medicinal products, of the products of 5 formula (I), the names of which are given hereinbelow: - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy- phenyll -2 morpholin-4-yl-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 10 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 (dimethyl-morpholin-4-yl) -acetamide trifluoroacetate - 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2-. trifluoromethoxy-phenyl]-acetamide trifluoroacetate 15 - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2,2,2 trifluoro-ethylamino) -acetamide trifluoroacetate - 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy 20 phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 thiomorpholin-4-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 pyrrolidin-1-yl-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 107 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-piperazin-1-yl)-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-tri'fluoromethoxy- phenyl]-2 piperidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl)-2 15 [(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 hydroxy-ethylamino)-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (2 methoxy-ethylamino)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate 25 - 2-(Cyanomethyl-amino)-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 108 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-l- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate - ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] 15 methyl}-amino)-acetic acid methyl ester; compound with trifluoro-acetic acid 2-(2,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-acetamide; compound with 20 trifluoro-acetic acid N-'[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4,4 dimethyl-piperidin-1-yl)-acetamide - N-[5-.(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4 trifluoromethyl-piperidin-1-yl)-acetamide WO 2006/010641 PCT/EP2005/008720 109 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [1,4]oxazepan-4-yl-acetamide - 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-pyrrolidine-3-carboxylic acid methyl ester - 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 fluoro-ethylamino)-acetamide - N-[5-(4,4-Dimethyl-2-,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-[(2 15 methoxy-ethyl)-methyl-amino]-acetamide ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyll-amino)-acetic acid trifluoroacetate - 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 20 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - 2-Cycloprdpylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyll-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 morpholin-4-yl-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 110 N-[5-(4,4-Dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 (dimethyl-morpholin-4-yl)-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3- (4 methyl-piperazin-1-yl)-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 piperidin-1-yl-propionamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 thibmorpholin-4-yl-propionamide trifluoroacetate . N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 15 pyrrol.idin-1-yl-propionamide trifluoroacetate - 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl-, 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(2,2,2 trifluoro-ethylamino)-propionamide; compound with trifluoro-acetic acid - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy 25 phenyll-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 - N-[5- (4, 4-Dimethyl-2,5-dcioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2--isopropyl-phenyll -2-morpholin-4-yl acetamide trifluoroacetate - N-[5- (4,4-Dimethyl-2,5-dioxo--3-pyridin-4-ylmethyl 5 imidazoliclin-1-yl) -2-isopropyl-phenyll-2-piperidin-1-yl acetamide trifluoroacetate - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-isopropyl-phenyl]l-2- (4-methyl piperazin-1-yl) -acetamide trifluoroacetate 10 - 2-Dimethylamino-N-[5- (4,4-dimethyl-2,5--dioxo-3-pyridin 4-ylinethyl-imidazoliclin-1-yl) -2-isopropyl-phenyl] acetamile trifluoroacetate - 2-Diethylamino-N- [5- (4, 4-dimethyl-2, 5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-l-yl) -2-isopropyl-phenyl -. 15 acetamicle trifluoroacetate - 2-tert-Butylamino-N-[5-(4, 4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-l-yl) -2-isopropyl phenyl] -acetarnide trifluoroacetate - 2-Cyclopentylamino-N-[5-(4,4.-dimethyl-2,5-clioxo-3 20 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2-isopropyl phenyll -acetamide trifluoroacetate - l-Methyl-piperidine-4-carboxylic acid [5- (4, 4-dimethyl 2, 5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-il-yl) -2 trifluorornethoxy-phenyl] -arnide, trifluoro-acetate 25*- 3- 13- (2-Cyclopentylamino-ethoxy) -4-methoxy-phenyl] -5,5 direthyl-l-quinolin-4-ylmethyl- irnidazolidine-2, 4-dione WO 2006/010641 PCT/EP2005/008720 112 - 3-(3-{2-[(Furan-2-ylmethyl)-amino]-ethoxy}-4-methoxy phenyl)-5,5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-{3-[2-(2-Hydroxy-l-phenyl-ethylamino)-ethoxy]-4 5 methoxy-phenyl}-5,5-dimethyl-l-quinolin- 4-ylmethyl imidazolidine-2,4-dione 3-[3,3-Dimethyl-1-(2-morpholin-4-yl-acetyl)-2,3 dihydro-lH-indol-6-yl]-5,5-dimethyl-l- quinolin-4 ylmethyl-imidazolidine-2,4-dione 10 - 3-[3,3-Dimethyl-l-(2-thiomorpholin-4-yl-acetyl)-2,3 dihydro-1H-indol-6-yl] -5, 5-dimethyl- l-quinolin-4 ylmethyl-imidazolidine-2, 4-dione and also the prodrugs thereof, the said products of formula (I) being in all the possible racemic, 15 enantiomeric.and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral and organic acids or with, mineral and organic bases of the said products of formula (I). The products may be administered via the parenteral, 20 buccal, perlingual, rectal or topical route. A subject of the invention is thus pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicinal products of formula (I) as defined above. 25 These compositions may be in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions. These . pharmaceutical forms are prepared according to the usual methods. The active principle may 30 be incorporated into excipients usually used in these compositions, such as aqueous or nonaqueous vehicles, WO 2006/010641 PCT/EP2005/008720 113 talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preserving agents. 5 The usual dose, which varies according to the individual treated and the complaint 'under consideration, may be, for example, from 10 mg to 500 mg per day orally in man. The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically 10 acceptable salts of the said products of formula (I) for the preparation of medicinal products for inhibiting the activity of protein kinases and especially of a protein kinase. The present invention thus relates to the use of products 15. of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is a protein tyrosine kinase. The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically 20 acceptable salts of the said products of formula (I) in which the protein kinase is chosen from the following group: IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Fltl-3, FAK, Src, Abl, cKit, cdkl-9, Auroral-2, cdc7, Akt, Pdk, S6K, Jnk, 25 IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2, CDK7, CDK2 et EGFR. More particularly such protein kinase is chosen from the following group: IGF1, cdc7, Auroral-2, Src, Jnk, FAK, KDR, IR, Tie2, 30 CDK7, CDK2 et EGFR. The present invention thus relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is IGF1R. 35 The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically WO 2006/010641 PCT/EP2005/008720 114 acceptable salts of the said products of formula (I) in which the protein kinase is FAK. The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically 5 acceptable salts of the said products of formula (I) in which the protein kinase is AKT. The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) in 10 which the protein kinase is in a cell culture, and also to this use in a mammal. The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for 15 the preparation of a medicinal product for preventing or treating a disease characterized by deregulation of the activity of a protein kinase and- especially such a disease in a mammal. The present invention relates to the use of products of 20 formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic 25 disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related macula 30 degeneration, oncology diseases and cancer. The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for treating 35 oncology diseases.
WO 2006/010641 PCT/EP2005/008720 115 The present invention relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product 5 for treating cancers. Among these cancers, the present invention is most .particularly of interest in the treatment of solid tumours and the treatment of cancers that are resistant to cytotoxic agents. 10 Among these cancers, the present invention relates most particularly to the treatment of breast cancer, stomach cancer, cancer of the colon, lung cancer, cancer of the ovaries, cancer of the uterus, brain cancer, cancer of the kidney, cancer of the larynx, cancer of the lymphatic 15 system, cancer of the thyroid, cancer of the urogenital tract, cancer of the tract including the seminal vesicle and prostate, bone cancer, cancer of the pancreas and melanomas. The present invention. is even more particularly of 20 interest in treating breast cancer, cancer of the colon and lung cancer. The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of the said products of formula (I) for 25 the preparation of a medicinal product for cancer chemotherapy. As medicinal products according to the present invention for cancer chemotherapy, the products of formula (I) according to the present invention may be used alone or 30 in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents. The present invention thus relates especially to the pharmaceutical compositions as defined above, 35 characterized in that they are used as medicinal WO 2006/010641 PCT/EP2005/008720 116 products, in particular for cancer chemotherapy. The present invention thus relates especially to the pharmaceutical compositions as defined above containing, in addition to the active principles, other chemotherapy 5 medicinal products for combating cancer. Such therapeutic agents may be commonly used antitumour agents. As examples of known inhibitors of protein kinases, mention may be made especially of butyrolactone, 10 flavopiridol, 2-(2-hydroxyethylamino)-6-benzylamino-9 methylpurine, olomucine, Glivec and Iressa. The products of formula (I) according to the present invention may thus also be advantageously used in combination with antiproliferative agents: as examples of 15 such antiproliferative agents, but without, however, being limited to this list, mention may be made of aromatase inhibitors, antioestrogens, the topoisomerase I inhibitors, the topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase 20 inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that reduce the activity of protein kinases and also anti-angiogenic compounds, gonadorelin agonists, 25 antiandrogens, bengamides, biphosphonates and trastuzumab. Examples that may thus be mentioned include anti microtubule agents, for instance taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, 30 DNA-intercalating agents, for instance cis-platinum, agents that are interactive on topoisomerase,. for instance camptothecin and derivatives, anthracyclines, for instance adriamycin, antimetabolites, for instance 5-fluorouracil and derivatives, and the like.
WO 2006/010641 PCT/EP2005/008720 117 The present invention thus relates to products of formula (I) as protein kinase inhibitors, the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition 5 salts of the said products of formula (I) with. pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases, and also the prodrugs thereof. The present invention relates particularly to products of 10 formula (I) as defined above as IGFlR inhibitors. The present invention also relates to products of formula (I) as defined above as FAK inhibitors. The present invention also relates to products of formula (I) as defined above as AKT inhibitors. 15 The present invention relates more particularly to the products of formula (Ia), (Ib), (Ic) and in particular (Id) as defined above as IGF1R inhibitors. The experimental section hereinbelow more particularly gives an illustration of the above synthetic schemes. 20 The examples whose preparation follows illustrate the present invention without, however, limiting it. Example la : 3-nitro-4-(trifluormethoxy)-aniline 20 g (112.9 mmol) 4-(trifluormethoxy)-aniline were 25 dissolved in to 50ml conc. sulfuric acid and treated at ~50C with a mixture of 24 ml conc. sulfuric acid and 6 ml nitric acid. After stiiring the mixture at 0 0 C for 3h, the reaction mixture was poured on 1L ice water and made alkaline with 200ml conc. aqueous ammonium hydroxide. The 30 resulting solution was extracted with ethyl acetate, the combined organic phases were dried and evaporated to dryness. The residue was purified by flash chromoatography (Silica gel, methylene chloride WO 2006/010641 PCT/EP2005/008720 118 methanol = 98: 2) and subsequent recrystallization from methylenchoride/heptane. Yield: 14.8 g MS(ES+): m/e = 223 LC/MS Retention time [min] = 1.84 5 Example lb : 5,5-Dimethyl-3-(3-nitro-4-trifluormethoxy phenyl) -l-pyridin-4-ylmethyl-imidazolidine-2, 4-dione 29g (146.5mmol) diphosgene in 300 ml 1,2-dichlorethane were treated at -20'C with a solution of 13 g (58.6 mmol) 10 3-nitro-4-(trifluormethoxy)-aniline in 20 ml 1,2 dichlorethane. The mixture was allowed to come to room temperature and then was heated to 50 0C for 3h. After standing over night, the solvent was evaporated and the residual oil was taken up in 250ml THF. 13g (58.6mmol) 2 15 methyl-2-f[(pyridin-4-ylmethyl)-amino]-propionic acid methyl ester in 250 ml THF were added and the mixture was heated to 40 'C for 1h. The solvent was evaporated and the residue purified by flash chromatography (Silica gel, methylene chloride : methanol = 95: 5). Yield: 19.7 g. 20 MS(ES+): m/e = 425 LC/MS Retention time [min] = 1.61 Example 1c : 3-(3-amino-4-trifluormethoxy-phenyl)-5,5 dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2 , 4-dione 25 8.8 g (20.7 mmol ) 5,5-dimethyl-3-(3-nitro-4 trifluormethoxy-phenyl) -l-pyridin-4-ylmethyl imidazolidine-2,4-dione were dissolved in 200ml semi conc. hydrochloric acid. 30g zinc dust -were added in portions and the resulting mixture was refluxed for 1h, 30 cooled to RT, diluted with 100 ml water and extracted with ethyl acetate. The aqueous phase was made alkaline WO 2006/010641 PCT/EP2005/008720 119 with saturated sodium hydroxide solution and extracted with methylene chloride. Separating zinc salts were removed by filtration over cellite. Evaporation of the combined organic phases and flash chromoatography of the 5 residue (Silica gel, methylene chloride : methanol 95: 5)gave 4.7g of the desired product. MS(ES+): m/e = 395 LC/MS Retention time [min] = 1.27 Example Id N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 10 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-chloro-acetamide 500mg (1.27mmol) 3- (3-amino-4-trifluormethoxy-phenyl) 5, 5-dimethyl-l-pyridin-4-ylmethyl-imidazolidine-2, 4-dione and 172 mg (1.33 mmol) Hinig's base were dissolved in 20 15 ml 1,2-dichloroethane. The mixture was cooled to -20 0C and treated with a solution of 143 mg (1.27 mmol) chloroacetylchlorid in 15' ml 1,2-dichloroethane.. After stirring 1h at 00C, 5 ml ethanolic hydrochlric acid were added and the mixture evaporated to dryness. The raw 20 material, containing huening's base hydrochloride was used without further purification. MS(ES+): m/e = 472 LC/MS Retention time [min] = Example le : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 25 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-morpholin-4-yl-acetamide 50mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-chloro acetamide (raw 'Material, as described above) owere 30 dissolved in 2 ml morpholine and heated for lh to 50 0C. Subsequently, the mixture was poured on ice and extracted WO 2006/010641 PCT/EP2005/008720 120 with ethylacetate. The combined organic phases were evaporated to dryness, and the residue was purified by flash chromoatography (Silica gel, methylene chloride methanol = 1. 98: 2 2. 95:5) Yield: 20 mg 5 MS (ES+) : m/e = 522 LC/MS Retention time [min] = 0.97 Example 2 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyll 2- (dimethyl-morpholin-4-yl) -acetamide trifluoroacetate 10 The title compound was prepared as described for example le using 2ml cis-2,6-dimethylmorpholine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 25mg 15 MS(ES+): m/e = 550 LC/MS Retention time [mini = 1.04 Example 3 : 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl) - 2 trifluoromethoxy-phenyl] -acetamide trifluoroacetate 20 The title compound was prepared as described for example 2 using 2ml cyclopentylamine Yield: 18mg MS(ES+): m/e = 520 LC/MS Retention time [min] = 1.11 Example 4 : N- [5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4 25 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2- (2,2,2-trifluoro-ethylamino) -acetamide trifluoroacetate The title compound was prepared as described for example 2 using 2ml 2,2,2-trifluoroethylamine in 1ml N methylpyrrolidone 30 Yield: 10 mg WO 2006/010641 PCT/EP2005/008720 121 MS(ES+): m/e = 534 LC/MS Retention time [min] = 1.57 Example 5 : 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo 3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 5 trifluoromethoxy-phenyl]-acetamide trifluoroacetate The title compound was prepared as described for example 2 using 2ml diethylamine Yield: 12 mg MS(ES+): m/e = 508 LC/MS Retention time [min] = 1.05 10 Example 6 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-thiomorpholin-4-yl-acetamide trifluoroacetate The title compound was prepared as described for example 15 2 using 100mg ( 0.21mmol) N-[5-(4,4-Dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy phenyll-2-chloro-acetamide (raw material, as described above) and 2ml thiomorpholine Yield: 26 mg MS(ES+) m/e .= 538 20 LC/MS Retention time [min] = 0.94 Example 7 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-pyrrolidin-1-yl-acetamide trifluoroacetate The title compound was prepared as described for example 25 6 using 2ml pyrrolidine. Yield: 24 mg MS(ES+): m/e = 506 LC/MS Retention time [min] = 1.05 Example 8 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 30 2-(4-methyl-piperazin-1-yl)-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 122 The title compound was prepared as described for example 2 using 2ml N-methylpiperazine. Yield: 16 mg MS(ES+): m/e = 535 LC/MS Retention time [min] = 1.01 5 Example 9 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 2-piperidin-1-yl-acetamide trifluoroacetate The title compound was prepared -as described for example 2 using 2ml piperidine. Yield: 20 mg 10 MS(ES+): m/e = 520 LC/MS Retention time [min] = 0.92 Example 10 : N- [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-[(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate 15 The title compound was prepared as described for example 6 using 2 ml 2-(aminomethyl)-pyridine. Yield: 35mg MS(ES+): m/e = 543 LC/MS Retention time [min] = 1.18 Example 11 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 20 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy-, phenyl] 2-[(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate The title compound was prepared as described for example 6 using 2 ml 3-(aminomethyl)-pyridine. Yield: 32mg MS(ES+): m/e = 543 25 LC/MS Retention time [min] = 0.87 Example 12 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 2-[(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate The title compound was prepared as described for example 30 6 using 2 ml 4-(aminomethyl)-pyridine. Yield: 35mg WO 2006/010641 PCT/EP2005/008720 123 MS(ES+): m/e =543 LC/MS Retention time [min] = 0.97 Example 13 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyll 5 2-(2-hydroxy-ethylamino)-acetamide trifluoroacetate The title compound was prepared as described for example 6 using 2 ml ethanolamine. Yield: 36mg MS(ES+): m/e = 496 LC/MS Retention time [min] = 0.82 10 Example 14 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-(2-methoxy-ethylamino)-acetamide trifluoroacetate The title compound was prepared as described for example 6 using 2 ml 2-methoxyethylamine. Yield: 33mg 15 MS(ES+): m/e = 510 LC/MS Retention time [min] = 1.14 Example 15 : 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 20 The -title compound was prepared as described for example 6 using 2 ml of 2M solution of dimethylamine DMF. Yield: 12mg MS(ES+): m/e = 480 LC/MS Retention time [min] = 0.85 25 Example 16 : 2-(Cyanomethyl-amino)-N-[5-(4,4-dimethyl 2,5-dioxo-3-pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl] -acetamide trifluoroacetate The title Compound was prepared as described for example 6 using 2 ml aminoacetonitril. Yield: 18mg 30 MS(ES+): m/e = 491 WO 2006/010641 PCT/EP2005/008720 124 LC/MS Retention time [min) = 1.20 Example 17 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2- (4-methyl-piperidin-1-yl) -acetamide 5 The title compound was prepared as described for example 2 using 150mg ( 0.21mmol) N-[5-(4,4-Dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy phenyl]-2-chloro-acetamide (raw material, as described above) and 1ml 4-methylpiperidine. Yield: 30mg 10 MS (ES+): m/e = 534 LC/MS Retention time [min] = 1.07 Example 18 : N-[5- (4,4-Dimethyl-2 ,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-(4-methyl-[1,4]diazepan-1-yl)-acetamide 15 trifluoroacetate The title compound was prepared as described for example 17 using Iml N-methylhomopiperazine. Yield: 60 mg MS(ES+): m/e = 549 LC/MS Retention time [min] = 0.87 20 Example 19 : 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1- yl) -2 trifluoromethoxy-phenyl] -acetamide trifluoroacetate The title compound was prepared as described for example 17 using 1ml tert.-butylamine. Yield: 52 mg 25 MS(ES+): m/e = 508 LC/MS Retention time [min] = 0.92 Example 20 : N- [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2- (1,2, 2-trimethyl-propylamin6) -acetamide 30 trifluoroacetate WO 2006/010641 PCT/EP2005/008720 125 The title compound was prepared as described for example 17 using 1ml 2-amino-3,3-dimethylbutane. Yield: 60 mg MS(ES+): m/e = 536 LC/MS Retention time [min] = 1.13 5 Example 21 : ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy phenylcarbamoyl] -methyl } -amino) -acetic acid methyl ester; compound with trifluoro-acetic acid The title compound was prepared as described for example 10 17 using glycinmethylester hydrochloride and Hinig's base in DMF. MS(ES+): m/e = 524 LC/MS Retention time [min] = 0.92 Example 22 : 2-(2,2-Difluoro-ethylamino)-N-[5-(4,4 15 dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-1 yl) -2-trifluoromethoxy-phenyl] -acetamide; compound with trifluoro-acetic acid The title compound was prepared as described for example 17 using 1ml 2,2-difluorethylamine. Yield: 50 mg 20 MS(ES+): m/e = 516 LC/MS Retention time [min] = 1.03 Example 23 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 2-(4,4-dimethyl-piperidin-1-yl)-acetamide 25 The title compound was prepared as described for example le using 100mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyll 2-chloro-acetamide (raw material, as described above) and 15 mg 4,4-dimethylpiperidine. Yield: 2.5 mg 30 MS(ES+): m/e = 548 WO 2006/010641 PCT/EP2005/008720 126 LC/MS Retention time [min] = 1.09 Example 24 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2-(4-trifluoromethyl-piperidin-1-yl)-acetamide 5 The title compound was prepared as described for example le using 1ml 4-(trifluormethyl)piperidine MS(ES+): m/e = 588 LC/MS Retention time [min] = 1.30 Example 25 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 10 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 2-[1,4]oxazepan-4-yl-acetamide The title compound was prepared as described for example le using lml homomorpholine hydrochlorid and HInig's base. Yield: 10 mg 15 MS(ES+): m/e = 536 LC/MS Retention time [mini = 0.91 Example 26 : 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylic acid 20 methyl ester The title compound was prepared as described for example le using 1 ml methyl-3-pyrrolidinecarboxylate in lml. Yield: 22 mg. MS(ES+): m/e = 564 25 LC/MS Retention time [min] = 1.11 Example 27 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,.5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-acetamide The title compound was prepared as described for example 30 6 using lml azetidine in 1ml DMF. Yield: 85 mg.
WO 2006/010641 PCT/EP2005/008720 127 MS(ES+): m/e = 492 LC/MS Retention time [min] = 0.88 Example 28 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 5 2- (2-fluoro-ethylamino) -acetamide The title compound was prepared as described for example le using 2-fluoroethylamine hydrochlorid and Hinig's base. Yield: 10 mg MS(ES+): m/e = 498 10 LC/MS Retention time [min] = 0.93 Example 29 N- [5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 2- [ (2-methoxy-ethyl) -methyl-amino] -acetamide The title compound was prepared as described for example 15 le using 1 ml N-(2-methoxyethyl)-methylamine. Yield: 10 mg MS(ES+): m/e = 524 LC/MS Retention time [min] = 0.91 Example 30 : ({ [5- (4, 4-Diinethyl-2, 5-dioxo-3-pyridin-4 20 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy phenylcarbamoyl] -methyll-amino) -acetic acid trifluoroacetate 100 mg (0.16 mmol) ({[5-(4,4-Dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy 25 phenylcarbamoyl]-methyl}-amino)-acetic, acid methyl ester trifluoro acetate were dissolved in 5ml dioxane/water (9/1) and treated with 9.3 mg (0.39 mmol) lithium hydroxide. After stirring for 1H at 50 'C, the solvent was evaporated and the residue, was purified by 30 preparative HPLC. (C18 reversed 'phase column, elution WO 2006/010641 PCT/EP2005/008720 128 with a water (0.1% trifluoracetic acid) acetonitrilee gradient) Yield: 10 mg. MS(ES+): m/e = 510 LC/MS Retention time [min] 0.93 5 Example 31 : 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate The title compound was prepared as described for example 2 using 200mg ( 0.43 mmol) N-[5-(4,4-Dimethyl-2,5-dioxo 10 3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 trifluoromethoxy- phenyli-2-chloro-acetamide and 1ml cyclohexylamine. Yield: 90 mg. MS (ES+) : m/e 534 LC/MS Retention time [min] = 1.09 15 Example 32 : 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate The title compound was prepared as described for example 2 using 250mg ( 0.53 mmol) N-[5-(4,4-Dimethyl-2,5-dioxo 20 3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 trifluoromethoxy- phenyl]-2-chloro-acetamide, lml cyclopropylamin and 1 ml DMF. Yield: 85mg MS(ES+): m/e = 492 LC/MS Retention time [min] = 0.89 25 Example. 33a : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] acrylamide 1000mg (2.5.4 mmol) 3- (3-amino-4 -trifluormethoxy-phenyl) 5,5-dimethyl-l-pyridin-4-ylmethyl-imidazolidine-2,4-dione 30 were dissolved in 25 ml 1,2-dichloroethane. The mixture WO 2006/010641 PCT/EP2005/008720 129 was cooled to -2.0 0 C and treated with a solution of 272 mg (3.00 mmol) acrylic acid chloride in 5 ml 1,2 dichloroethane. The mixture was allowed to reach RT, and then evapoarted to dryness. The raw material was used 5 without further purification. MS(ES+): m/e = Example 33b N- [5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 3-morpholin-4-yl-propionamide trifluoroacetate 10 50mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-acrylamide (raw material, as described above) were dissolved in 1 ml morpholine stirred at RT for lh. Subsequently, the mixture was poured on ice and extracted with 15 ethylacetate. The combined organic phases were evaporated to dryness and the residue was purified by by preparative HPLC. (Ci8 reversedd phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 13.5mg 20 MS (ES+) : m/e = 536 LC/MS Retention time [min] = 0.93 Example 34 N-[5,(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 3- (dimethyl-morpholin-4-yl) -propionamide trifluoroacetate 25 The title compound was prepared as described for example 33b using 1ml 2,6-dimethylmorpholine. Yield: 57mg MS(ES+): m/e 564 LC/MS Retention time [min] = 1.05 WO 2006/010641 PCT/EP2005/008720 130 Example 35 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 3-(4-methyl-piperazin-1-yl)-propionamide trifluoroacetate The title compound was prepared as described for example 5 33b using 200mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl) acrylamide (raw material, as described above) and 1ml N methylpiperazine. Yield: 85mg MS(ES+): m/e = 549 10 LC/MS Retention time [min] = 0.82 Example 36 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 3-piperidin-1-yl-propionamide trifluoroacetate 15 The title compound was prepared as described for example 35 using 1ml piperidine. Yield: 118mg MS(ES+): m/e = 534 LC/MS Retention time [min] 0.99 Example 37 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 20 ylmethyl-imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] 3-thiomorpholin-4-yl-propionamide trifluoroacetate The title compound was prepared as described for example 35 using 1ml thiomorpholine. Yield: 105mg MS(ES+): m/e = 552 25 LC/MS Retention time [min] 1.02 Example 38 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 3-pyrrolidin-1-yl-propionamide trifluoroacetate The title compound was prepared as described for example 30 35 using 1ml pyrrolidine. Yield: 100mg WO 2006/010641 PCT/EP2005/008720 131 MS(ES+): m/e = 520 LC/MS Retention time [min]' = 0.98 Example 39 : 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 5 trifluoromethoxy-phenyl] -propionamide trifluoroacetate The title compound was prepared as described for example 35 using lml cyclopentylamine. Yield: 65mg MS (ES+) : m/e = 534 LC/MS Retention time [min] = 1.08 10 Example 40 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-trifluoromethoxy- phenyl] 3- (2,2, 2-trifluoro-ethylamino) -propionamide; compound with trifluoro-acetic acid The title compound was prepared as described for example 15 35 using lml trifluorethylamine. Yield: 49mg MS(ES+): m/e = 548 LC/MS Retention time [min] = 1.02 Example 41 : 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo 3-pyridin-4-ylmethyl-imidazolidin-1-yl)-2 20 trifluoromethoxy-phenyl]-propionamide trifluoroacetate The title compound was prepared as described for example 35 using lml diethylamine. Yield: 75mg MS(ES+): m/e = 522 LC/MS Retention time [min] = 1.00 25 Example 42a : 4-isopropyl-3-nitroaniline 25 g (185 mmol) 4-isopropyl-aniline were dissolved in to 260 ml conc. sulfuric acid and treated at -5 'C with 17.9 g nitric acid (65%). After stirring the mixture at 0 0C for 0.5h, the reaction mixture was poured on ice water 30 and the precipitating product collected via filtration WO 2006/010641 PCT/EP2005/008720 132 and dried. The resulting 23.8 g product were essentially pure and were used for the subsequent step without further purification. MS(ES+): m/e = 181 5 LC/MS Retention time [min] = 1.96 Example 42b : 5,5-Dimethyl-3- (3-nitro-4-isopropylphenyl) 1-pyridin-4-ylmethyl-imidazolidine-2, 4-dione 6.04 g (30 mmol) diphosgene in 50 ml 1,2-dichlorethane were treated at -20"C with a solution of 2 g (11.1 mmol) 10 3-nitro-4-isopropyl-aniline in 20 ml 1,2-dichlorethane. The mixture was allowed to come to room temperature and then was heated to 50 'C for 5h. After standing over night, the solvent was evaporated and the residual oil was taken up in 40ml THF. 3.93 g (18.7 mmol) 2-methyl-2 15 [(pyridin-4-ylmethyl)-amino] -propionic acid methyl ester in 30 ml THF were added and the mixture was refluxed for 6h. The solvent was evaporated and the residue taken up in ethylacetate and washed with water. THe organic phase was dried, the solvent evaporated and the residue was 20 purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 2.7 g. MS(ES+): m/e = 441 LC/MS Retention time [min] = 1.67 25 Example 42c 3-(3-amino-4-isopropyl-phenyl)-5,5 dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2, 4-dione 2.64 g (6.90 mmol ) 5,5-dimethyl-3-(3-nitro-4-isopropyl phenyl) -1-pyridin-4-ylmethyl-imidazolidine-2, 4-dione were dissolved in 50 ml acetic acid. 7.22 g zinc dust were 30 added in portions while temperature was kept below 45 0C. The mixture was stirred for lh at RT, then diluted with WO 2006/010641 PCT/EP2005/008720 133 100 ml water, made alkaline with 6N sodium hydroxide solution and extracted with methylene chloride. Separating zinc salts were removed by filtration over cellite. Evaporation of the combined organic phases 5 yielded 1.53 g product that were used without further purification. MS (ES+) : m/e = 353 LC/MS Retention time [min] = 0.91 Example 42d : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 10 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloro acetamide 1.37 mg (3.89 mmol) 3-(3-amino-4-isopropyl-phenyl)-5,5 dimethyl-l-pyridin-4-ylmethyl-imidazolidine-2,4-dione and 528 mg (4.08 mmol) Hinig's base were dissolved in 50 ml 15 1,2-dichloroethane. The mixture was cooled to -20 'C and treated with a solution of 439 mg (3.89 mmol) chloroacetylchlorid in 20 ml 1,2-dichloroethane. After stirring 1h at 0 0 C, 25 ml ethanolic hydrochloric acid were added:and the mixture evaporated to dryness. The raw 20 material, containing huening's base hydrochloride was used without further purification. Example 42e N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] -2 morpholin-4-yl-acetamide trifluoroacetate 25 The title compound was prepared as described for example., 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloro acetamide (raw material as described above) and 1ml of the appropriate amine. The raw material was purified by 30 preparative HPLC. (C18 reversed phase column, elution WO 2006/010641 PCT/EP2005/008720 134 with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 70mg MS(ES+): m/e = 480 LC/MS Retention time -[min] = 0.95 5 Example 43 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] -2 piperidin-1-yl-acetamide trifluoroacetate The title compound was prepared as described for example 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 10 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl)-2-chloro acetamide (raw material as described above) (raw amterial as described above) and lml of the appropriate amine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% 15 trifluoracetic acid) /acetonitrile gradient) Yield: 80mg MS(ES+): m/e = 478 LC/MS Retention time [min] = 0.96 Example 44 : N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] -2- (4 20 methyl-piperazin-1-yl) -acetamide trifluoroacetate The title compound was prepared as described for example 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloro acetamide (raw material as described above) and lml of 25 the appropriate amine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 30mg MS(ES+): m/e = 491 30 LC/MS Retention time [min] = 0.94 WO 2006/010641 PCT/EP2005/008720 135 Example 45 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl) -2 isopropyl-phenyl] -acetamide trifluoroacetate The title compound was prepared as described for example 5 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] -2-chloro acetamide (raw material as described above) and lml of a 2m solution of dimethylamine in DMF. The raw material was purified by preparative HPLC. (C18 reversed phase column, 10 elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 25mg MS(ES+): m/e = 438 LC/MS Retention time [min] = 0.98 Example 46 : 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo 15 3-pyridin-4-ylmethyl-imidazolidin-1-yl) -2-isopropyl phenyll -acetamide trifluoroacetate The title compound was prepared as described for example 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl) -2-isopropyl-phenyl] -2-chloro 20 acetamide- (raw material as described above) and lml of the appropriate amine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 65mg 25 MS(ES+): m/e = 466 LC/MS Retention time [min] = 1.00 Example 47 : 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl) -2 isopropyl-phenyl] -acetamide trifluoroacetate 30 The title compound was prepared as described for example 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4- WO 2006/010641 PCT/EP2005/008720 136 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloro acetamide (raw material as described above) and Iml of the appropriate amine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution 5 with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 50 mg MS (ES+) : m/e = 466 LC/MS Retention time [min] = 0.91 Example 48 : 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5 10 dioxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl) - 2 isopropyl-phenyll -acetamide trifluoroacetate The title compound was prepared as described for example 2 using 150 mg N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl]-2-chloro 15 acetamide (raw material as described above) and 1ml of the appropriate amine. The raw material was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 50mg 20 MS(ES+): m/e = 478 LC/MS Retention time [min] = 1.08 Example 49 : 1-Methyl-piperidine-4-carboxylic acid [5 (4,4-dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy-phenyl] -amide, 25 trifluoro-acetate 48 mg (0.26 mmol) 1-methyl-piperidine-4-carboxylic acid hydrochloride were dissolved in 5 ml thionyl chloride and heated to reflux for 30 min. The excess thionyl choride was removed by evaporation and the resulting acid 30 chloride dissolved in 5 ml methylene chloride. This solution was added to a solution of 100 mg (0.25 mmol) 3- WO 2006/010641 PCT/EP2005/008720 137 (3-amino-4-trifluormethoxy-phenyl)-5,5-dimethyl-l pyridin-4-ylmethyl-imidazolidine-2,4-dione and 111 mg (0. 68mmol) huenig's base and the mixture was stirred overnight at RT and heated to reflux for 1h. The mixture 5 was poured on saturated sodium bicarbonate solution, extracted with ethylacetate, then dried and evaporated. The residue was was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 10 mg 10 MS(ES+): m/e = 520 LC/MS Retention time [min] = 0.86 Example 50 : 1-Methyl-piperidine-3-carboxylic acid [5 (4,4-dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy-phenyll -amide; 15 compound with trifluoro-acetic acid 270 mg (1.50 mmol) 1-methyl-piperidine-3-carboxylic acid hydrochloride were suspended in 20ml methylene chloride, 216 mg (1.70 mmol) oxalyl chloride follwoed by 11 mg DMF were added and the mixture stirred at RT for 15 h.. The 20 solvent was removed by evaporation. To 30 mg (0.15 mmol) of the resulting acid chloride hydrochloride were given a solution of 39 mg (0.10 mmol) 3-(3-amino-4 trifluormethoxy-phenyl)-5,5-dimethyl-1-pyridin-4 ylmethyl-imidazolidine-2,4-dione and 12 mg (0.10 mmol) 25 DMAP in 3 ml methylene chloride. After stiring for 2 h at RT, the mixture was poured on diluted sodium bicarbonate solution, extracted with methylene chloride, then dried and evaporated. The residue was was purified by preparative HPLC. (C18 reversed phase column, elution 30 with a water (0.1% trifluoracetic acid) /acetonitrile gradient) Yield: 8 mg WO 2006/010641 PCT/EP2005/008720 138 MS(ES+): m/e = 520 LC/MS Retention time [min] = 0.92 Example 51a 2- (2, 2-Diethoxy-ethoxy) -1-methoxy-4-nitro benzene 5 A suspension of 7.50 g 2-methoxy-5-nitro-phenol, 9.61 g 2-bromo-1,1-diethoxy- ethane and 15.89 g cesium carbonate in 75 ml N,N-dimethylformamide was stirred at 100 0 C for 4 hours. After cooling to room temperature the reaction mixture was treated with an aqueous 1% solution of sodium 10 hydroxide and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration of the solvent under reduced pressure the residue was dissolved in a mixture of ethyl a-cetate and n-heptane. After removal of the 15 ethyl acetate under reduced pressure the resulting residue was filtered off and the clear solution concentrated under reduced pressure. The residue was directly subjected to the subsequent reaction without. further purification. Yield: 9,45 g 20 MS(ES+): m/e = 1H-NMR ( 250 MHz, DMSO/TMS): d = 7.92 (d, 1H);7.82 (s, 1H); 7.19 (d, 1H); 4.83 (t, 1H); 4.08 (d, 2H); 3.90 (s, 3H);- 3.62 (m, 4H); 1.13 (t, 6H) Example 51a : 3-(2,2-Diethoxy-ethoxy)-4-methoxy 25 phenylamine A mixture of 10,70 g 2-(2,2-diethoxy-ethoxy)-1-methoxy-4 nitro-benzene and 1,20 g of 10% palladium on carbon in 150 ml methanol was stirred for 2 hours under hydrogen atmosphere. The reaction mixture was filtered through a 30 chem elut cartridge and the compound eluted with additional methanol. After contration under reduced WO 2006/010641 PCT/EP2005/008720 139 pressure the residue was directly subjected to the subsequent reaction without further purification. Yield: 7,90 g 1H-NMR (400 MHz,DMSO/TMS): d = 6.65 (d, 1H); 6.28 (d, 5 1H); 6.09 (dd, 1H); 4.77 (t, 1H); 4.66 (s, 2H); 3.83 (d, 2H); 3.62 (m, 7H); 1.14 (t ,6H) Example 51c : 3-[3-(2,2-Diethoxy-ethoxy)-4-methoxy phenyl] -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2, 4-dione 10 To a solution of 317 mg di-imidazol-1-yl-methanone and 20 mg imidazole in 4 ml tetrahydrofuran a solution of 500 mg 3- (2, 2-diethoxy-ethoxy) -4-methoxy-phenylamine in 2 ml tetrahydrofuran was slowly added at 0 C. After .stirring at 0 0 C for' 1 hour 505 mg 2-methyl-2-[(quinolin-4 15 ylmethyl)-amino]-propionic acid methyl ester were added and the reaction mixture was allowed to warm up to room temperature. After 2 hours stirring at room temperature the solution was heated for 2 hours at 70'C. After cooling to room temperature the solvent of the mixture 20 was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid. Yield: 300 mg 25 MS(ES+): m/e = 508 1H-NMR (400 MHz,DMSO/TMS): d = 8.88 (d ,1H); 8.27 (d ,1H); 8.08. (d ,1H); 7.83 (t, 1H); 7.70 (t, 1H); 7.59 (d, 1H); 7.16 (s, 1H); 7.09 (d, 1H); 7.03 (d, 1H); 5.13 (s, 2H); 4.84 (t, 1H); 3.95 (d, 2H); 3.82 (s, 3H); 3.69 (m, 30 2H); 3.56 (m, 2H); 1.43 (s ,6H); 1.15 (t, 6H).
WO 2006/010641 PCT/EP2005/008720 140 Example 51d [5-(4,4-Dimethyl-2,5-dioxo-3-quinolin-4 ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy] acetaldehyde 410 mg 3-[3-(2,2-Diethoxy-ethoxy)-4-methoxy-phenyl]-5,5 5 dimethyl-1-quinolin-4-ylmethyl- imidazolidine-2,4-dione were dissolved in 8 ml 1,4-dioxane and 2,05 ml of an aqueous 1 N solution of hydrochloric acid were added. The mixture was stirred for 2 hours at 800C. Removal of the solvent under reduced pressure yielded a white solid, 10 which was coevaporated twice with toluene. Yield: 340 mg MS(ES+): m/e = 434 1H-NMR(400MHz, DMSO/TMS): d 9.70(s,1H);9.15(d,1H); 8.50(d,1H);8.35(d,1H);8.10(t,H);8.02(d,1H);7.95(t,1H);7. 10(m,3H);5.33(s,2H);4.82(s,2H);3.84(s,3H);1.48 (s,6H) 15 Example 51e : 3- [4-Methoxy-3- (2-morpholin-4-yl-ethoxy) phenyl]-5,5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione A solution of 20 mg [5-(4,4-dimethyl-2,5-dioxo-3 quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy 20 phenoxy]- acetaldehyde in 1 ml 1,2-dichloroethane was treated with 8,02 mg morpholine and 14,62 mg sodium triacetoxyborohydride. After stirring of the reaction mixture for 16 hours the solvent was removed under reduced pressure. The residue was purified by preparative 25 HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid. The product was obtained as its trifluoroacetate salt. Yield: 8,6 mg 30 MS (ES+) : m/e = 505 WO 2006/010641 PCT/EP2005/008720 141 1H-NMR (500 MHz, DMSO/TMS): d = 9.98 (s, 1H); 8.89 (d, 1H); 8.37 (d, 1H); 8.09 (d, 1H); 7.84 (t, 1H); 7.72 (t, 1H); 7.63 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.35 (t, 2H); 4.03 (m, 2H); 3.85 (s, 3H); 3.73 (m, 2H); 1.44 (s 5 ,6H) Example 52 3- [4-Methoxy-3- (2-morpholin-4-yl-ethoxy) phenyl] -5 ,5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione The following compounds were prepared in analogy to 10 example 51e by using 70 mg [5-(4,4-dimethyl-2,5-dioxo-3 quinolin-4-ylmethyl-imidazolidin-1-yl) -2-methoxy phenoxy]- acetaldehyde as starting material and the corresponding amine.s instead of morpholine. The product was obtained as its trifluoroacetate salt. 15 Yield: 44 mg MS(ES+): m/e ='503 1H-NMR (500 MHz, DMSO/TMS): d = 9.31 (s, 1H); 8.94. (d, 1H); 8.32 (d, 1H); 8.12 (d, 1H); 7.88 (t, 1H); 7.75 (t, 1H); 7.68 (d, 1H);-'7.15 (m, 3H); 5.18 (s, 2H.); 4.32 (t, 20 2H); 3.85 (s, 3H); 3.06 (m, 2H); 1.85 (m, 2H),; 1.69 (m, 4H); 1.45 (s, 6H) Example 53 : 3-{4-Methoxy-3-[2-(4-methyl-piperazin-1-yl) ethoxy] -phenyl}-5, 5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione 25 Yield: 50 mg MS(ES+): m/e = 518 1H-NMR (500 MHz, DMSO/TMS): d = 8.93 (d, 1H); 8.32 (d, 1H); 8.12 (d, 1H); 7.88 (t, 1H); 7.75 (t, 1H); -7.68 (d, 1H); 7.10 (m, -3H); 5.16 (s, 2H); 4.15- (m, 2H); 3.82 (s, 30 3H); 3.05 (m, 2H); 2.78 (s, 3H); 1.44 (s, 6H) WO 2006/010641 PCT/EP2005/008720 142 Example 54 3-{4-Methoxy-3-[2-(2-methoxy-ethylamino) ethoxy] -phenyl} -5 ,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2,4-dione The product was obtained as its trifluoroacetate salt. 5 Yield: 23,4 mg MS(ES+): m/e = 493 1H-NMR (500 MHz, DMSO/TMS): d = 8.92 (d, 1H); 8.73 (m, 2H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.64 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.25 (t, 10 2H); 3.84 (s, 3H); 3.40 (m, 2H); 3.33 (s, 3H); 3.28 (m, 2H); 1.44 (s, 6H) Example 55 : 3- [3- (2-Cyclopentylamino-ethoxy) -4-methoxy phenyl] -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione 15 The product was obtained as its trifluoroacetate salt. Yield: 53,2 mg MS(ES+): m/e = 503 1H-NMR (500 MHz, DMSO/TMS): d = 8.92 (d, 1H); 8.70 (m, 2H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 20 1H)-; 7.64 (d, IH); 7.15 (m, 3H); 5.16 (s, 2H); 4.23 (t, 2H); 3.85 (s, 3H); 3.37 (m, 2H); 2.02 (m, 2H); 1.72 (m, 2H); 1.58 (m, 4H); 1.44 (s, 6H) Example 56 : 3-(4-Methoxy-3-{2-[(5-methyl-isoxazol-3 ylmethyl) -amino] -ethoxy} -phenyl) -5, 5-dimethyl-1 25 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione The product was obtained as its trifluoroacetate salt. Yield: 60,1 mg MS (ES+) : m/e = 530 1H-NMR (500 MHz, DMSO/TMS): d = 9.43 (m, 2H); 8.90. (d, 30 1H).; 8.30 (d, 1H); 8.10 (d, 1H); 8.85 (t, 1H); 7.73 (t, 1H); 7.64 (d, .lH); 7.15 (m, 3H); 6.42 (s, 1H); 5.16 (s, WO 2006/010641 PCT/EP2005/008720 143 2H); 4.44 (s, 2H); 4.28 (t, 2H); 3.85 (s, 3H); 2.45 (s, 3H); 1.44 (s, 6H) Example 57 : 3- (3-{2- [ (Furan-2-ylmethyl) -amino] -ethoxy} 4-methoxy-phenyl)-5,5-dimethyl-1-quinolin-4- ylmethyl 5 imidazolidine-2,4-dione The product was obtained as its trifluoroacetate salt. Yield: 17,6 mg MS(ES+): m/e = 515 1H-NMR (500 MHz, DMSO/TMS): d = 9.23 (m, 2H); 8.91 (d, 10 1H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.83 (dd, 1H); 7.73 (t, 1H); 7.64 (d, 1H); 7.15 (m, 3H); 6.68 (d, 1H); 6.55 (dd, 1H); 5.16 (s, 2H); 4.39 (m, 2H); 4.24 (t, 2H); 3.85 (s, 3H); 1.44 (s, 6H) Example 58 : 3-(4-Methoxy-3-{2-[(5-methyl-pyrazin-2 15 ylmethyl) -amino] -ethoxy}-phenyl) -5, 5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione The product was obtained as its trifluoroacetate salt. Yield: 27,5 mg MS(ES+): m/e = 541 20 1H-NMR (500 MHz, DMSO/TMS): d = 9.33 (m, 2H); 8.93 (d, 1H); 8.67 (s, 1H); 8.63 (s, 1H); 8.29 (d, 1H); 8.11 (d, 1H); 7.87 (t, 1H); 7.75 (t, 1H); 7.66 (d, 1H); 7.15 (m, 3H); 5.16 (s, 2H); 4.52 (m, 2H); 4.30 (t, 2H); 3.85 (s, 3H);'2.55 (s, 3H); 1.44 (s, 6H) 25 Example 59 - 3-{4-Methoxy-3-[2-(2-morpholin-4-yl ethylamino) -ethoxy] -phenyl }-5, 5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2 , 4-dione The following compounds were prepared in analogy to example 51e by using 80 mg [5-(4,4-dimethyl-2,5-dioxo-3 30 quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy WO 2006/010641 PCT/EP2005/008720 144 phenoxy]- acetaldehyde as starting material and the corresponding amines instead of morpholine. Yield: 14,4 mg MS(ES+): m/e = 548 5 1H-NMR (500 MHz, DMSO/TMS): d = 8.91 (d, 1H); 8.29 (d, 1H); 8.11 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.63 (d, 1H); 7.15 (m, 3H); 5.16 (s, 2H); 4.26 (t, 2H); 3.85 (s, 3H); 1.44 (s, 6H) Example 60 3-{4-Methoxy-3-[2-(2-pyridin-4-yl 10 ethylamino) -ethoxy] -phenyl}-5, 5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2, 4-dione The product was obtained as its trifluoroacetate salt. Yield: 26,2 mg MS(ES+): m/e = 540 15 1H-NMR (500 MHz, DMSO/TMS): d = 8.93 (d, 1H); 8.86 (m, 2H); 8.68 (d, 2H); 8.30 (d, 1H); 8.11 (d, 1H); 7.85 (t, 1H); 7.74 (t, 1H); 7.65 (d, iH); 7.55 (d, 2H); 7.15 (m, 3H); 5.16 (s, 2H); 4.26 (t, 2H); 3.80 (s, 3H); 3.10 (t, 2H); 1.44 (s, 6H) 20 Example 61 : 3
-[
4 -Methoxy-3-(2-pyrrolidin-1-yl-ethoxy) phenyl] -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2, 4-dione The product was obtained as its trifluoroacetate salt. Yield: 42,5 mg 25 MS(ES+): m/e = 489 1H-NMR (500 MHz, DMSO/TMS): c = 10.05 (s, 1H); 8.91 (d, iH); 8.70 (s, 1H); 8.28 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.72 (t, 1H); 7.64 (d, 1H); 7.15 (ru, 3H); 5.15 (s, 2H); 4.29 (t, 2H); 3.85 (s, 3H); 3.20 - 3.05 (m, 6H); 30 2.10 1.80 (m, 4H); 1.44 (s, 6H) WO 2006/010641 PCT/EP2005/008720 145 Example 62 3-{3-[2-(2-Hydroxy-ethylamino)-ethoxy]-4 methoxy-phenyl}-5,5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione Yield: 10,3 mg 5 MS(ES+): m/e = 479 1H-NMR (500 MHz, DMSO/TMS) : d = 8. 90 (d, 1H) ; 8. 65 (m, 2H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.63 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.25 (t, 2H); 3.83 (s, 3H); 3.70 (t, 2H); 3.41 (m, 2H); 3.15 (m, 10 2H); 1.44 (s, 6H) Example 63 3- [3- (2-Ethylamino-ethoxy) -4-methoxy phenyl] -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2, 4-dione Yield: 18,1 mg 15 MS(ES+): m/e = 463 1H-NMR (500 MHz, DMSO/TMS): d = 8.90 (d, 1H); 8.58 (m, 2H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.63 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.21 (t, 2H); 3.85 (s, 3H); 3.38 (t, 2H); 3.08 (q, 2H); 1.45 (s, 20 6H); 1.23 (t, 3H) Example 64 : 3- (4-Methoxy-3-{2- [ (pyridin-2-ylmethyl) amino] -ethoxy} -phenyl) -5, 5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2, 4-dione Yield: 46,7 mg 25 MS(ES+): m/e = 526 1H-NMR (500 MHz, DMSO/TMS): d = 9.30 (s, 1H); 8.92 (d, 1H); 8.66 (m, 1H); 8.29 (d, 1H); 8.11 (d, 1H); 7.93 (t, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.52 (d, 1H); 7.45 (m, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.51 (m, 30 2H); 4.30 (t, 2H); 3.85 (s, 3H);3.46 (m, 2H); 1.44 (s,. 6H) WO 2006/010641 PCT/EP2005/008720 146 Example 65 3-(4-Methoxy-3-{2-[(thiazol-2-ylmethyl) amino]-ethoxy}-phenyl)-5,5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2, 4-dione Yield: 37,8 mg 5 MS(ES+): m/e = 532 1H-NMR (500 MHz, DMSO/TMS): d = 9.55 (s, 1H); 8.90 (d, 1H); 8.27 (d, 1H); 8.11 (d, 1H); 7.97 (d, 1H); 7.90 (d, iH); 7.85 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.77 (m, 2H); 4.29 (t, 2H); 3.85 (s, 10 3H); 1.44 (s, 6H) Example 66 - 3-{4-Methoxy-3-[2-(2-pyridin-3-yl ethylamino) -ethoxy] -phenyl }-5,5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2,4-dione Yield: 41,2 mg 15 MS(ES+): m/e = 540 1H-NMR (500 MHz, DMSO/TMS): d = 8.92 (d, 1H); 8.82 (s, 2H); 8.59 (m, 2H); 8.29 (d, 1H); 8.11 (d, 1H); 7.88 (in, 2H); 7.75 (t, IH); 7.65 (d, IH); 7.55 (n, 1H); 7.15 (in, 3H); 5.17 (s, 2H); 4.26 (t, 2H); 3.81 (s, 3H); 3.42 (m, 20 4H); 3.05 (n, 2H); 1.44 (s, 6H) Example 67 : 3-(4-Methoxy-3- {2-[(pyridin-4-ylmethyl)-. amino] -ethoxy }-phenyl) -5, 5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2,4-dione Yield: 39,8 mg 25 MS(ES+): m/e = 526 1H-NMR (500 MHz, DMSO/TMS): d = 9.28 (s, 2H); 8.93 (d, 1H); 8.71 (d, 2H); 8.31 (d, 1H); 8.12 (d, 1H); 7.87 (t, 1H);.7.75 (t, 1H); 7.68 (d, 1H); 7.59 (d, 2H); 7.15: (n, 3H); 5.18 (s, 2H); 4.40 (i, 2H); 4.27 (t, 2H); 3.85 (s, 30 3H); 3.43 (m, 2H)); 1.44 (s, 6H) WO 2006/010641 PCT/EP2005/008720 147 Example 68 3-{4-Methoxy-3-[2-(tetrahydro-pyran-4 ylamino)-ethoxy]-phenyl}-5,5-dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2,4-dione Yield: 42,6 mg 5 MS(ES+): m/e = 519 1H-NMR (500 MHz, DMSO/TMS): d = 8.90 (d, 1H); 8.75 (s, 2H); 8.29 (d, 1H); 8.11 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.64 (d, 1H); 7.15 (m, 3H); 5.15 (s, 2H); 4.25 (t, 2H); 3.93 (m, 2H); 3.85 (s, 3H); 3.43 (m,2H); 3.32 (t, 10 2H); 2.00 (m, 2H); 1.56 (m, 2H); 1.44 (s, 6H) Example 69 : 3-{3-[2-(2-Hydroxy-1-phenyl-ethylamino) ethoxy] -4-methoxy-phenyl}-5,5-dimethyl-1-quinolin- 4 ylmethyl-imidazolidine-2,4-dione Yield: 15,2 mg 15 MS(ES+): m/e = 555 1H-NMR (500 MHz, DMSO/TMS): d = 9.19 (s, 2H); 8.90 (d, 1H); 8.28 (d, 1H); 8.11 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.58 (d, 2H); 7.46 (m, 3H); 7.15 (m, 3H); 5.70 (s, 1H); 5.15 (s, 2H); 4.54 (m, 1H); 4.25 (t, 20 2H); 3.85 (s, 3H); 3.28 (m, 2H); 3.17 (m, 2H); 1.43 (s, 6H) Example 70 : 3-{4-Methoxy-3-[2-(1-methyl-piperidin-4 ylamino)-ethoxy]-phenyl}-5,5-dimethyl-1-quinolin- 4 ylmethyl-imidazolidine-2,4-dione 25 The title compound was prepared in analogy to example 51e by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4 ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxyl acetaldehyde as starting material and 4-amino-1 methylpiperidine instead of, morpholine. 30 Yield: 25,0 mg MS(ES+): m/e = 532 WO 2006/010641 PCT/EP2005/008720 148 1H-NMR (500 MHz, DMSO/TMS) : d = 8.87 (d, 1H); 8.25 (d, 1H); 8.08 (d, 1H); 7.82 (t, 1H); 7.69 (t, 1H); 7.59 (d, 1H); 7.12 (s, 1H); 7.07 (d, 1H); 7.02 (dd, 1H); 5.13 (s, 2H); 4.00 (t, 2H); 3.81 (s, 3H); 2.91 (t, 2H); 2.70 (m, 5 2H); 2.45 (m, IH); 2.14 (s, 3H); 1.92 (m, 2H); 1.78 (m, 2H) ; 1.43 (s, 6H); 1. 25 (m, 3H) Example 71b - 3-{2- [5- ( 4 ,4-Dimethyl-2,5-dioxo-3-quinolin 4-ylmethyl-imidazolidin-1-yl) -2-methoxy- phenoxy] ethylamino } -pyrrolidine-1-carboxylic acid tert-butyl 10 ester The title compound was prepared in analogy to example 51e by using 70 mg [5-(4,4-dimrethyl-2,5-dioxo-3-quinolin-4 ylmethyl-imidazolidin-1-yl) -2-methoxy-phenoxy] acetaldehyde as starting material and 3-amino 15 pyrrolidine-1-carboxylic acid tert-butyl ester instead of morpholine. The product was obtained as its trifluoroacetate salt. Yield: 44 mg MS(ES+): m/e = 604 1H-NMR (500 MHz, DMSO/TMS) : d = 8. 97 (m, 2H) ; 8. 90 (d, 20 1H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.64 (d, 1H)); 7.15 (m, 3H); 5.15 (s, 2H); 4.24 (t, 2H); 3.95 (m, 2H); 3.85 (s, 3H); 3.70 - 3.40 (m, 3H); 3.29 (m, 2H); 2.25 (m, 1 H); 2.09 (m, 1H); 1.44 (s, 6H); 1.41 (s, 9H) 25 Example '71a : 3-{4-Methoxy-3-[2-(pyrrolidin-3-ylamino) ethoxy]-phenyl}-5,5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione A solution of 40 mg 3
-{
2 -[5-(4,4-dimethyl-2,5-dioxo-3 quinolin-4-ylmethyl-imidazolidin-1-yl) -2-methoxy 30 phenoxyl-ethylamino}-pyrrolidine-1-carboxylic acid. tert butyl ester in 2 ml of a 8 N solution of hydrochloric WO 2006/010641 PCT/EP2005/008720 149 acid in methanol was stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was dissolved in a mixture of 2 ml water and 1 ml acetonitrile. Lyophilization of the 5 resulting mixture yielded a white foam. The product was obtained as its hydrochloric salt. Yield: 25,1 mg MS(ES+): m/e = 504 1IH-NMR (500 MHz, DMSO/TMS): d = 9.35 (m, 1H); 9.26 (m, 1H); 8.97 (d, 1H); 8.34 (d, 1H); 8.16 (d, 1H); 7.93 (t, 10 1H); 7.78 (m, 2H); 7.15 (m, 3H); 5.20 (s, 2H); 4.29 (t, 2H); 4.06 (m, 1H); 3.85 (s, 3H); 3.25 (m, 1H); 2.36 (m, 1H); 2.20 (m, 1H); 1.45 (s, 6H) Example 72 : 3-{3-[2-Hydroxy-3- (tetrahydro-pyran-4 ylamino) -propoxy] -4-methoxy-phenyl} -5, 5-dimethyl-1 15 quinolin-4-ylmethyl-imidazolidine-2,4-dione To a solution of 60,92 mg trimethylsulfoxonium iodide in 1 ml dimethyl sulfoxide 6,64 mg sodium hydride were added at room temperature. After stirring for 10 minutes 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl 20 imidazolidin-1-yl) -2-methoxy-phenoxyl- acetaldehyde were added and the mixture stirred for additional 1 hour at room temperature. After concentration under reduced pressure the residue was partitioned between 2 ml- ethyl acetate and 2 ml of a saturated aqueous solution of 25 ammonium chloride. The organic layer was dried over sodium sulfate. After filtration the solvent was removed under reduced pressure. The residue was dissolved in 1 ml ethanol and 23,37 mg tetrahydro-pyran-4-ylamine were added. 'The resulting solution was stirred for 1 hour at 30 70C. After cooling to room temperature the solvent of the mixture was removed under reduced, pressure and the WO 2006/010641 PCT/EP2005/008720 150 residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid) . Lyophilization of the solution yielded a white solid. Yield: 12,8 mg 5 MS(ES+): m/e = 549 1H-NMR (500 MHz, DMSO/TMS): d = 8.90 (d, 1H); 8.55 (m, 2H); 8.29 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.64 (d, 1H); 7.08 (m, 3H); 5.93 (m, 1H); 5.15 (s, 2H); 4.18 (m, 1H); 3.95 (m, 4H); 3.83 (s, 3H); 3.20 (m, 10 1H); 3.06 (m, 1H); 1.95 (m, 2H); 1.59 (m, 2H); 1.43 (s,6 H) Example 73 - 3-{3-[2-Hydroxy-3-(4-methyl-piperazin-1-yl) propoxy]-4-methoxy-phenyl}-5,5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2,4-dione 15 The following compound was prepared in analogy to example 72 by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin 4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxyl acetaldehyde as starting-material and 1-methyl-piperazine instead of tetrahydro-pyran-4-ylamine. Yield: 7,9 mg 20 MS(ES+): m/e = 548 1H-NMR (500 MHz, DMSO/TMS): d = 8.92 (d, 1H); 8.29 (d, 1H); 8.11 (d, 1H); 7.85 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.10 (m, 3H); 5.15 (s, 2H); 4.15 (s, 1H); 3.95 (d, 2H); 3.82 (s, 3H); 2.75 (m, 2H); 1.43 (s, 6H) 25 Example 74 : 3-(3-{2-Hydroxy-3-[(pyridin-4-ylmethyl) amino]-propoxyl-4-methoxy-phenyl)-5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine-2 , 4-dione The following compound was prepared in analogy to example 72 by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin 30 4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy] acetaldehyde as starting material and pyridin-4-yl- WO 2006/010641 PCT/EP2005/008720 151 methylamine instead of tetrahydro-pyran-4-ylamine. The product was obtained as its trifluoroacetate salt. Yield: 10,2 mg MS(ES+): m/e = 556 5 1H-NMR (500 MHz, DMSO/TMS): d = 9.13 (s, 2H); 8.92 (d, 1H); 8.69 (d, 2H); 8.30 (d, 1H); 8.10 (d, 1H); 7.86 (t, 1H); 7.73 (t, 1H); 7.66 (d, 1H); 7.57 (d, 2H); 7.08 (m, 3H)); 5.15 (s, 2H); 4.30 (m, 2H); 4.22 (m, 1H); 4.00 (m, 1H); 3.95 (m, 1H); 3.78 (s, 3H); 3.23 (m, 1H); 3.07 (m, 10 1Hf); 1.44 (s, 6H) Example 75 - 3- (3- ( 2 -Hydroxy-3-morpholin-4-yl-propoxy) -4 methoxy-phenyl]-5,5-dimethyl-1-quinolin-4- ylmethyl imidazolidine-2,4-dione The following compounds were prepared in analogy to 15 example 72 by using the corresponding amines instead of tetrahydro-pyran-4-ylamine. Yield: 23,4 mg MS(ES+): m/e = 535 1H-NMR (500 MHz, DMSO/TMS): d = 8.92 (d, 1H); 8.30 (d, 20 1H); 8.10 (d, 1H); 7.86 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.10 (m, 3H); 6.03 (m, 1H); 5.15 (s, 2H); 4.34 (m, 1H); 3.98 (m, 4H); 3.83 (s, 3H); 3.55 - 3.12 (m, 8H); 1.44 (s, 6H) Example 76 : 3-{3- [2-Hydroxy-3- (pyridin-4-ylamino) 25 propoxyl -4-methoxy-phenyl} -5, 5-dimethyl-1-quinolin- 4 ylmethyl-imidazolidine-2,4-dione Yield: 20,3 mg MS(ES+): m/e = 542 1H-NMR (500 MHz, DMSO/TMS) : d = 8. 90 (d, 1H) ; 8. 30 (d, 30 1H); 8.10 (m, 4H); 7.85 (t, 1H); 7.73 (t, IH); 7.64 (d, 1H); 7.16 (s, 1H); 7.13 (d, 1H); 7.08 (dd, 1H); 6.82 (d, WO 2006/010641 PCT/EP2005/008720 152 2H); 5.70 (m, 1H); 5.15 (s, 2H); 4.39 (m, 1H); 4.15 (m, 2H); 4.00 (m, 1H); 3.92 (m, 1H); 3.74 (s, 3H); 1.44 (s, 6H) Example 77 - 3-{3-[2-Hydroxy-3-(1-methyl-piperidin-4 5 ylamino) -propoxy] -4-methoxy-phenyl} -5, 5-dimethyl- 1 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione The following compound was prepared in analogy to example 72 by using 4-amino-1-methyl-piperidine instead of tetrahydro-pyran-4-ylamine. In this case the crude 10 product was purified in addition by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid) . Lyophilization of the solution yielded a white solid. Yield: 3,0 mg MS (ES+) : m/e = 562 15 1H-NMR (500 MHz, DMSO/TMS): d = 8.90 (d, 1H); 8.77 (m, 1H); 8.28 (d, 1H); 8.10 (d, 1H); 7.97 (m, 1H); 7.84 (t, 1H); 7.73 (t, 1H); 7.62 (d, 1H); 7.12 (m, 3H); 5.95 (m, 1H); 5.15 (s, 2H); 4.50 (m, 1H); 4.18 (m, 1H); 4.00 2.70 (m, 8H); 3.83 (s, 3H); 3.18 (s, 3H); 2.25 (m, 1H); 20 2.06 (m, 2H); 1.75 (m, 1H); 1.44 (s, 6H) Example 78 - 3-{3- [2-Hydroxy-3- (pyrrolidin-3-ylamino) propoxy]-4-methoxy-phenyl}-5,5-dimethyl-l- quinolin-4 ylmethyl-imidazolidine-2, 4-dione The following compound was prepared in analogy to example 25 72 by using 3-amino-pyrrolidine-l-carboxylic acid tert butyl ester instead of tetrahydro-pyran-4-ylamine. In this case the crude product was dissolved in 2 ml of a 8 N solution of hydrochloric acid in methanol and the resulting solution. was stirred for 1 hour at room 30 temperature. After removal of the solvent under reduced pressure the residue was dissolved in a mixture of 2 ml WO 2006/010641 PCT/EP2005/008720 153 water and 1 ml acetonitrile. After lyophilisation of the solution the residue was purified in addition - by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic 5 acid) . Lyophilization of the solution yielded a white solid. Yield: 8,5 mg MS(ES+): m/e = 534 1H-NMR (500 MHz, DMSO/TMS): d = 9.00 (m, 2H); 8.90 (d, 10 1H); 8.28 (d, 1H); 8.10 (d, 1H); 7.84 (t, 1H); 7.73 (t, 1H); 7.63 (d, 1H); 7.12 (m, 3H); 5.95 (m, 1H); 5.15 (s, 2H); 4.17 (m, 1H); 3.99 (m, 3H); 3.84 (s, 3H); 3.25 (m, 2H); 3.12 (m, 1H); 2.34 (m, 1H); 2.06 (m, 1H); 1..44 (s, 6H) 15 Example 79a - 3-(1-Acetyl-3,3-dimethyl-2,3-dihydro-lH indol-6-yl) -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione 1- (6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone was prepared according to a procedure published by Daniel 20 Elbaum et al. Patent Application US 6114365. The title compound was prepared in analogy to example 51c by using 100 mg 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl) ethanone instead of 2-amino-thiazole-5-carboxylic acid methyl ester. Yield: 28 mg 25 MS (ES+) : m/e = 457 1H-NMR (500 MHz, DMSO/TMS) : d = 8. 97 (d, 1H); 8. 34 (d, 1H), 8.14 (d, 1H); 8.08 (s, 1H); 7.93 (t, 1H); 7.77 (m, 2H); 7.49 (d, 1H); 7.12 (d, 1H); 5.23 (s, 2H); 3.93 (s, 2H); 2.19 (s, 3H); 1.45 (s, 6 H); 1.35 (s, 6H) WO 2006/010641 PCT/EP2005/008720 154 Example 79b - 3- (3,3-Dimethyl-2 ,3-dihydro-1H-indol-6-yl) 5, 5-dimethyl-1-quinolin-4-ylmethyl- imidazolidine-2 , 4 dione 230 mg 3-(l-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6 5 yl)-5,5-dimethyl-l-quinolin-4-ylmethyl-imidazolidine-2,4 dione were dissolved in 5 ml water and 5 ml of an aqueous 2 N solution of hydrochloric acid in a process vial. After sealing with a teflon septum the vial was placed in the microwave cavity and the reaction mixture was stirred 10 for 15 minutes at 120 0 C by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% 15 trifluoroacetic acid). Lyophilization of the solution yielded a white solid. MS(ES+): m/e = 414 1H NMR(500MHz,DMSO/TMS):d=8.97(d,lH);8.34(d,lH);8.15(d,lH);7 20 .93(t,1H);7.69(t,lH);7.73(d,1H);7.18 (d,lH);6.78(m,2H);5.2 0 (s,2H) ;3.32(s,2H) ;1.44(s,6H) ;1.28(s,6H) Example 79c 3- [3,3-Dimethyl-1- (2-morpholin-4-yl acetyl) -2, 3-dihydro-1H-indol-6-yl -5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine-2, 4-dione 25 To a solution of 50 mg 3-(3,3-dimethyl-2,3-dihydro-1H indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione in 1 ml 1,2-dichloroethane 0,04 ml ethyl-diisopropyl-amine and 13,67 mg chloroacetylchloride were added at 0 0 C. After stirring 30 for 1 hour at 0 0 C 10,5 mg morpholine were added and the reaction mixture was stirred for 1 hour at room WO 2006/010641 PCT/EP2005/008720 155 temperature. Then 10,5 mg morpholine were added and the mixture was stirred for further 16 hours at room temperature. After removing of the solvent under reduced pressure the residue was purified by preparative HPLC 5 (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid. Yield: 26,0mg MS(ES+): m/e = 542 10 1H-NMR (500 MHz, DMSO/TMS): d = 10.28 (m, 1H); 8.92 (d, 1H); 8.28 (d, 1H); 8.15 (s, 1H); 8.11 (d, 1H); 7.86 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.48 (d, 1H); 7.25 (d, 1H); 5.17 (s, 2H); 4.45 (m, 2H);*3.90 (m, 6H); 3.48 (M, 2H); 3.23 (m, 2H); 1.45 (s, 6H); 1.38 (s, 6H) 15 Example 80 - 3-[3,3-Dimethyl-1-(2-thiomorpholin-4-yl acetyl) -2,3-dihydro-1H-indol-6-yl] -5,5-dimethyl- 1 quinolin-4-ylmethyl-imidazolidine-2, 4-dione The following compound was prepared in analogy to example 79c by using thiomorpholine instead of morpholine. Yield: 20 12,5 mg MS(ES+): m/e = 558 1H-NMR (500 MHz, DMSO/TMS): d = 9.95 (m, 1H); 8.90 (d, 1H); 8.28 (d, 1H); 8.15 (s, 1H); 8.10 (d, 1H); 7.86 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.48 (d, 1H); 7.25 (d, 25 1H); 5.17 (s, 2H); 4.45 (m, 2H); 3.90 (s, 2H); 3.33 (m, 2H); 3.10 (m, 2H); 2.95 (m, 2H); 1.45 (s, 6H); 1.38 (s, 6H) LC/UV/MS experiments have been conducted with a Waters 1-525 pump, a Waters 2488 UV detector, and a multiplexed 30 ESI-TOF mass spectrometer (Micromass MUX-LCT) using YMC J'sphere H80 (30*2.1 mm, 4u, 80A) columns. UV data have WO 2006/010641 PCT/EP2005/008720 156 been recorded at 220 nm and at 254 nm. For gradient separation, H20+0.05% TFA and ACN+ 0.05% TFA are mixed in 95:5 (0 min) to 5:95 (3.4 min) to 5:95 (4.4 min) ratios at a flow rate of 1 ml min-1. 5 Example 81 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-isopropylphenyl] -2- (4 methylpiperidin-1-yl) acetamide; compound with trifluoroacetic acid 10 The title compound was prepared as described for example 42e. M+H+ measured = 492 LC/MS retention time [min] = 1.36 15 Example 82 N-[5- (4, 4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-isopropylphenyl] -2- (2,2,2 trifluoroethylamino) acetamide; compound with trifluoroacetic acid 20 The title compound was prepared as described for example 42e. M+H+ measured = 492 LC/MS retention time [min] = 1.17 25 Example 83 N- [5- (4,4-Dimethyl-2, 5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2 trifluoromethoxyphenyl]nicotinamide; compound with trifluoroacetic acid 30 51 mg (0.51 mmol) of triethylamine and 45 mg (0.25 mmol) of 3-nicotinyl chloride are added to 100 mg (0.25 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione in 5 ml of THF and stirred at RT for 6 h. For workup, the mixture was 35 added to water, extracted with ethyl acetate, dried and concentrated. The remaining residue was purified by means WO 2006/010641 PCT/EP2005/008720 157 of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 50 mg. M+H+ measured = 500 LC/MS retention time [min] = 1.04 5 Example 84 2-(2,2-Difluoroethylamino)-N-[5-(4,4-dimethyl-2,5-dioxo 3-pyridin-4-ylmethylimadazolidin-1-yl)-2 isopropylphenyl]acetamide; compound with trifluoroacetic 10 acid The title compound was prepared as described for example 42e using 1 ml of difluoroethylamine. Yield: 80 mg M+H+ measured = 474 15 LC/MS retention time [min] = 0.95 Example 85 2-({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidine-1-yl)-2 20 trifluoromethoxyphenylcarbamoyl]methyl} amino) acetamide; compound with trifluoroacetic acid The title compound was prepared as described for example 2 using 69 mg (0.63 mmol) of glycinamide hydrochloride in 5 ml of DMF and 162 mg (1.26 mmol) of Hiinig's base. 25 M+H+ measured = 509 LC/MS retention time [min] = 0.53 Example 86 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 30 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3 pyridin-3-ylpropionamide 1.0 g (6.6 mmol) of 2-pyridylpropionic acid are dissolved in 20 ml of methylene chloride, 1.92 g (15.1 mmol) of oxalyl chloride and 3 drops of DMF are added, and the 35 mixture is stirred at RT for 3.5 h and finally concentrated. 78 mg (0.38 mmol) of the remaining acid WO 2006/010641 PCT/EP2005/008720 158 chloride hydrochloride are dissolved in 5 ml of methylene chloride and added to a solution of 100 mg (0.25 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)-5,5-dimethyl-l pyridin-4-ylmethylimidazolidine-2,4-dione and 38.5 mg 5 (0.38 mmol) of triethylamine in 7.5 ml of methylene chloride. After stirring for 2.5 hours at RT, the mixture is concentrated and the remaining residue is purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). The free bases are obtained from the fractions of 10 value by treatment with sodium hydrogencarbonate solution. Yield: 40 mg M+H+ measured = 528 LC/MS retention time [min] = 0.97 15 Example 87 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3 thiazol-2-ylpropionamide 20 was prepared as described for example 86. M+H+ measured = 534 LC/MS retention time [min] = 1.15 Example 88 25 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-2 pyridin-2-ylacetamide 1.0 g (5.8 mmol) of 2-pyridyl acetic acid hydrochloride were dissolved in 7.5 ml of acetyl chloride, 2.40 g (11.5 30 mmol) of phosphorous pentachloride were added and the mixture was stirred overnight. Subsequently, the mixture was admixed with 670 mg of acetone, and the precipitate as a solid was filtered off with suction, washed with acetyl chloride and diethyl ether and dried under reduced 35 pressure. 73.1 mg (0.38 mmol) of the crude acid chloride dissolved WO 2006/010641 PCT/EP2005/008720 159 in 5 ml of dichloromethane were added to a solution of 100 mg (0.25 mmol) of 3-(3-amino-4 trifluoromethoxyphenyl)-5,5-dimethyl-l-pyridin-4 ylmethylimadazolidine-2,4-dione and 39 mg (0.38 mmol) of 5 triethylamine in 7.5 ml of dichloromethane. After 2 h at RT, the mixture is concentrated and the remaining residue is purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). The free bases are obtained from the fractions 'of value by treating with 10 sodium hydrogencarbonate solution. Yield: 40 mg M+H+ measured = 514 LC/MS retention time [min] = 1.02 15 Example 89 N- [5- (4, 4-Dimethyl-2 , 5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 (2-methylbenzimidazol-1-yl) acetamide was prepared as described for example 88. 20 M+H+ measured = 567 LC/MS retention time [min] = 1.06 Example 90 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 25 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 pyridin-3-ylacetamide was prepared as described for example 88. M+H+ measured = 514 LC/MS retention time [min.] = 0.92 30 Example 91 3- [4-Isopropylamino-.3- (4-methylpiperazine-1-carbonyl) phenyl] -5, 5-dimethyl-1-pyridin-4-ylmethylimidazolidine 2, 4-dione 35 a) N-(4-methylpiperazin-1-yl)-2-isopropylamino-5 nitrobenzamide WO 2006/010641 PCT/EP2005/008720 160 20 g (77 mmol) of methyl 3-bromo-5-nitrobenzoate were dissolved in 200 ml of THF, 11.4 g (192 mmol) of isopropylamine were added dropwise and the mixture was stirred at 60'C for 16 h. Subsequently, the precipitate 5 was filtered off with suction and the filtrate was concentrated. 20 g of crude material remained. 64 ml (160 mmol) of n-butyllithium (2.5 m in hexane) were added dropwise at 0 0 C to 76 ml of N-methylpiperazine and, after stirring at RT for 1 hour, a solution of 19 g of 10 the crude intermediate (approx. 79 mmol) in 100 ml of THF was added dropwise. After stirring at RT for 1 hour, 200 ml of water are added and the mixture is extracted with ethyl acetate. The residue remaining after concentration and drying of the organic phases is purified by flash 15 chromatography (silica gel, 9:1 methylene chloride/methanol). Yield: 20 g b) N-(4-methylpiperazin-1-yl)-5-amino-2-isopropylamino benzamide 2.0 g (6.5 mmol) of N-(4-methylpiperazin-1-yl)-2 20 isopropylamino-5-nitrobenzamide were dissolved in 40 ml of glacier acetic acid and 6.8 g of zinc powder were added gradually at 45-50 0 C. For workup, 40 ml of water were added, the mixture was extracted once with ethyl acetate, the water phase was alkalized with NaOH, and the 25 mixture was extracted repeatedly with methylene chloride. The residue remaining after drying and concentration (1.9 g) could be used for the next reaction without further purification. c) the title compound was prepared analogously to the 30 process described for ex. 136a) by use of N-(4 methylpiperazin-1--yl)-5-amino-2-isopropylaminobenzamide. M+H+ measured = 479 LC/MS retention time [min] = 0.85 35 Example 92 5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4- WO 2006/010641 PCT/EP2005/008720 161 ylmethylimidazolidin-1-yl)-2-isopropoxy-N-piperidin- 4 ylmethylbenzamide hydrochloride 941 mg (4.67 mmol) of 2-chloro-5-nitrobenzoate acid was heated with 10 ml of thionyl chloride to reflux until gas 5 evolution had ended. Subsequently, the mixture was concentrated and coevaporated twice with toluene. The residue is taken up in 10 ml of methylene chloride and added dropwise to a solution of 1000 mg (4.67 mmol) of 4 (aminomethyl)-l-Boc-piperidine and 567 mg (5.6 mmol) of 10 triethylamine. After 1 hour at RT, the mixture is poured onto sat. sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated. 1350 mg of the crude product were added slowly at 0 0 C to a sodium isopropoxide solution (obtained by addition of 15 500 mg of NaH (96%) to 50 ml of isopropanol), and the mixture was stirred at RT for 2 h. After 1 h at RT, the mixture was poured onto ice, extracted with ethyl acetate, dried and concentrated. 1200 mg of the crude product were hydrogenated in 50 ml 20 of ethanol with 20 mg of Pd on carbon. For workup, the mixture was filtered off with suction, concentrated and purified by flash chromatography (silica gel, methylene chloride:methanol = 98:2). Yield: 920 mg of N-(piperidin 4-ylmethyl)-5-amino-2-isopropoxybenzamide 25 The title compound was obtained analogously to example lb by reaction of 50 mg of N-(piperidin-4-ylmethyl)-5-amino 2-isopropoxybenzamide with diphosgene and subsequent reaction with methyl 2-methyl-2-[(pyridin-4 ylmethyl)amino]propionate. The BOC group was detached by 30 heating the crude product with aqueous TFA and the crude product was purified by means of preparative HPLC. (RP18, acetonitrile/water, 0.1% TFA). Yield: 64 mg M+H+ measured = 494 35 LC/MS retention time [min] = 0.93 WO 2006/010641 PCT/EP2005/008720 162 Example 93 N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3H imidazole-4-carboxamide; compound with trifluoroacetic 5 acid 168 mg (1.5 mmol) of imidazole-4-carboxylic acid were dissolved in 5 ml of dichloromethane, 216 mg (1.7 mmol) of oxalyl chloride and 11 mg (0.15 mmol) of DMF were added, and the mixture was stirred at RT overnight and 10 finally concentrated. A solution of 39 mg (0.1 mmol) of 3-(3-amino-4 trifluoromethoxyphenyl)-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione in 3 ml of dichloromethane and 12 mg (0.1 mmol) of DMAP were added 15 to 28 mg of the remaining solid and the mixture was heated under reflux for 2 h. For workup, the mixture was added to water, alkalized, extracted with CH2Cl2, dried and concentrated. The remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% 20 TFA). Yield: 30 mg M+H+ measured 489 LC/MS retention time [min] = 1.02. 25 Example 94: N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-1 methyl-3-piperidinecarboxamide; compound with trifluoroacetic acid 30 was prepared as described for example 93. M+H+ measured = 520 LC/MS retention time [min] = 0.92 Example 95 35 3-[3-(Azetidin-3-ylamino)-4-trifluoromethoxyphenyl]-5,5 dimethyl-1-pyridin-4-ylmethylimidazolidine-2, 4-dione; WO 2006/010641 PCT/EP2005/008720 163 compound with trifluoroacetic acid 394 mg (1 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl) 5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione were dissolved in 1 ml of DMF, 166 mg (1.2 mmol) of 5 potassium carbonate and 413 mg (1.3 mmol) of 1 (diphenylmethyl)-3-azetidine methanesulphonate were added, and the mixture was stirred at 80'C for 5 h. For workup, the mixture was added to ice-water, extracted with CH2Cl2, dried and concentrated. 10 The remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). The intermediate obtained in this way was dissolved in 3 ml of methanol, admixed with 10 mg of 5% Pd/C and 50 mg (0.8 mmol) 'of ammonium formate, and heated under reflux 15 -for 2 h. The residue remaining after filtration and evaporation was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). M+H+ measured = 450 LC/MS retention time [min] = 0.86 20 Example 96 3-[3-(2-Dimethylaminoethylamino)-4 tri-fluoromethoxyphenyl]-5,5-dimethyl-1-pyridin-4-yl methylimidazolidine-2,4-dione; compound with 25 trifluoroacetic acid a) N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl] 2,2,2-trifluoroacetamide; compound with trifluoroacetic acid 30 394 mg (1.0 mmol) of 3-(3-amino-4 trifluoromethoxyphenyl)-5,5-dimethyl-l-pyridin-4-yl methylimidazolidine-2,4-dione were dissolved in 5 ml of 4:1 dichloromethane/pyridine and cooled to 00C, and 252 mg (1.2 mmol) of trifluoroacetic anhydride dissolved 35 in 5 ml of 4:1 dichloromethane/pyridine were added dropwise at 0 0 C. After stirring at RT, the mixture was WO 2006/010641 PCT/EP2005/008720 164 added to ice-water, extracted with CH2C12, concentrated and dried. The remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 550 mg 5 b) 60 mg (0.1 mmol) of N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl]-2,2,2-trifluoroacetamide, TFA salt were dissolved in 3 ml of ethyl acetate, 18 mg (0.13 mmol) o-f 2-dimethyl(amino)ethylamine . HCl, 69 mg 10 (0.5 mmol) -of potassium carbonate and 1 drop of water were added, and. the mixture was. heated under reflux for 12 h. For workup, the mixture was added to water, alkalized, extracted with ethyl acetate, dried and concentrated. The remaining residue is purified by means 15 of preparative HPLC (RP18; acetonitrile/water, 0.1% TFA). Yield: 30 mg. M+H+ measured = 466 LC/MS retention time [min] 0.98 20 Example 97 5,5-Dimethyl-1-pyridin-4-ylmethyl-3-[3-(2-pyrrolidin-1 ylethylamino)-4-trifluormethoxyphenyl]imidazolidine-2,4 dione; compound with trifluoroacetic acid prepared as described for example 96 25 M+H+ measured = 492 LC/MS -retention time [min] = 1.03 'Example 98 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 30 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyll 2-,2,2-trifluoro-N-(2-piperidin-1-ylethyl)acetamide; compound with trifluoroacetic acid prepared as described for'example 96. Preparative HPLC of the product mixture (RP18., acetonitrile/water, 0.1% TFA) 35 gives, in: addition-to the main product of example 97, the title compound as a further reaction product.
WO 2006/010641 PCT/EP2005/008720 165 M+H+ measured = 602 LC/MS retention time [fmin] 1.26 Example- 99 5 5,5-Dime'thyl-3-[3-(2-piperidin-1-ylethylamino)-4 trifluoromethoxyphenyl]-1-pyridin-4-ylmethyl imidazolidine-2, 4-dione prepared as described for example. 96 M+H+ measured = 506 10 LC/MS retention time [min] = 1.05 Example 100 3-[3-(2-Diisopropylaminoethylamino)-4 trifluoromethoxyphenyl]-5,5-dimethyl-1-pyridin-4 15 ylmethylimidazolidine-2,4-dione prepared as described for example 96 M+H+ measured = 522 LC/MS retention time [min] = 1.14 20 Example 101 3-[3-(2-Diethylaminoethylamino)-4 trifluoromethoxyphenyl] -5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example.96 25 M+H+ measured = 494 LC/MS retention time [min] = 0.99 .Example 102 30 5,5-Dimethyl-3-{3-[(2-methylthiazol-4-ylmethyl)amino]-4 trifluoromethoxyphenyl}-1-pyridin-4-ylmethyl imidazolidine-2,4-dione prepared as described for example 96 M+H+ measured = 506 35 LC/MS retention time [min] = 1.25 WO 2006/010641 PCT/EP2005/008720 166 Example 103 3-[3-(1-Cyclohexylazetidin-3-ylamino)-4 trifluormethoxyphenyl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione 5 300 mg (0.76 mmol) of '3-(3-amino-4 trifluoromethoxyphenyl)5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione were dissolved in 15 ml of ethyl acetate, admixed with 492 mg (1.52 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 10 631 mg (4.56 mmol) of K2CO3, and heated under reflux for 4 h. To complete the reaction, a further 49 mg (0.15 mmol) of 1-cyclohexylazetidin-3-yl methanesulphonate oxalate and 63 mg (0.46 mmol) of K2CO3 were added, and the mixture was stirred under reflux once 15 again for 2 h. Subsequently, the mixture was concentrated and the residue purified by flash chromatography (150 g of silica gel/95:5 CH2Cl2:CH30H). Yield: 13 mg M+H+ measured = 532 20 LC/MS retention time [min] = 1.12 Example 104 3-{5-tert-Butyl-1-[2-(4-methylpiperazin-1-yl)-2 oxoethyl]-1H-pyrazol-3-yl}-5,5-dimethyl-1-pyridin-4 25 ylmethylimidazolidine-2,4-dione; compound with trifluoroacetic acid a) 2-(3-amino-5-tert-butylpyrazol-1-yl)-1-(4 methylpiperazin-1-yl)ethanone 1.90 g (13.7 mmol) of 3-amino-tert-butylpyrazole were 30 dissolved under argon in 60 ml of abs. DMF, 1.89 g (13.7 mmol) of potassium carbonate and 1.96 g (11.1 mmol) of 2-chloro-l-(4-methylpiperazin-1-yl)ethanone were added, and the mixture was stirred at 80'C for 2 h. To complete the reaction, a further 0.49 g (2.6 mmol) of 2-, 35 chloro-l-(4-methylpiperazin-1-yl)ethanone was added and the mixture was stirred at 800C for a further 3.5 h. For WO 2006/010641 PCT/EP2005/008720 167 workup, the mixture was admixed with 10% sodium chloride solution, extracted with ethyl acetate, dried and concentrated by rotary evaporation. The remaining residue is purified by means of flash chromatography (silica gel, 5 methylene chloride:methanol = 85:15) Yield: 1.85 g 229 mg (1.1 mmol) of methyl 2-methyl-2-[(pyridin-4 ylmethyl)aminolpropionate were initially charged at 0 0 C 10 in 5 ml of THF under argon, 196 mg (1.2 mmol) of 1,1-carbonyldiimidazole were added, and the mixture was stirred at 0 0 C for 15 min and at RT for 1 h. Subsequently, 285 mg (1.0 mmol) of 2-(3-amino-5-tert butylpyrazol-1-yl)-1-(4-methylpiperazin-1-yl)ethanone 15 dissolved in 2.5 ml of DMF were added and the mixture was stirred at 50'C for 3 h and at 75'C for 1 h. For workup, the mixture was concentrated, taken up in water, extracted with ethyl acetate, dried and concentrated. The remaining residue was purified by means of preparative 20 HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 35 mg (TFA salt) M+H+ measured = 482 LC/MS retention time [min] = 0.96 25 Example 105 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethyl sulphanylphenyl]-2-morpholin-4-ylacetamide; compound with trifluoroacetic acid 30 a) 5,5-Dimethyl-3-(3-nitro-4-trifluoromethyl sulphanylphenyl)-1-pyridin-4-ylmethylimidazolidine-2,4 dione; trifluoroacetic acid salt 4.0 g (7.9 mmol) of 5,5-dimethyl-1-pyridin-4-ylmethyl-3 (4-trifluoromethylsulphanylphenyl)imidazolidine-2,4-dione 35 were dissolved in 150 ml of acetonitrile, and a total 2.4 g (18.1 mmol) of nitronium tetrafluoroborate were added WO 2006/010641 PCT/EP2005/008720 168 at 0 0 C over several hours. After the mixture had been heated slowly to RT, the solvent was removed, and the residue. was taken up in 100 ml of water, basified with 10 ml of conc. ammonia and extracted with methylene 5 chloride. The residue remaining after drying, filtration and evaporation was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 420 mg of title compound (and also 620 mg of isomeric 5,5-dimethyl-3-(2-nitro-4-trifluoromethyl 10 sulphanylphenyl)-l-pyridin-4-ylmethylimidazolidine-2,4 dione) b) 370 mg (0.67 mmol) of 3-(3-nitro-4-trifluoromethyl sulphanylphenyl)-5,5-dimethyl-l-pyridin-4-ylmethyl imidazolidine-2,4-dione are dissolved in 5 ml of glacial 15 acetic acid, 655 mg (10.0 mmol) of zinc powder are added with gentle cooling up to a temperature of 40 0 C, and the mixture-is stirred at RT for 1.5 h. Subsequently, the mixture is diluted with water and the acidic solution is extracted with a little ethyl acetate. 20 The remaining water phase is alkalized with 6 M NaOH, and extracted with ethyl acetate, dried and concentrated. Yield: 270 mg c) N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethyl 25 sulphanylphenyll-2-morpholin-4-ylacetamide; compound with trifluoroacetic acid The compound was prepared according to the process described under example 1d and e starting from 100 mg (0.24 mmol) of 3-(3-amino-4-trifluoromethylsulphanyl 30 phenyl)-5,5-dimethyl-l-pyridin-4-ylmethylimidazolidin 2,4-dione. Yield: 40 mg M+H+ measured = 538 LC/MS retention time [min] = 1.1 35 Example 106 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4- WO 2006/010641 PCT/EP2005/008720 169 ylmethylimidazolidin-1-yl) -2-trifluoromethyl sulphanylphenyl] -2-piperidin-1--ylacetamide; compound with trifluoroacetic acid The compound was prepared according to the process 5 described under example Id and e starting from 47 mg (0.11 mmol) of 3- (3-amino-4-tri-fluoromethylsulphanyl phenyl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidin 2,4-dione using 1 ml of piperidine. Yield: 7 mg 10 M+H+ measured = 536 LC/MS retention time [min] = 1.05 Example 107 2-tert-Butylamino-N-[5- (4,4-dimethyl-2,5-dioxo-3-pyridin 15 4-ylmethylimidazolidin-1-yl)-2-trifluoromethyl sulphanylphenyl]acetamide; compound with trifluoroacetic acid The compound was prepared according to the process described under example 1d and e starting from 47 mg 20 (0.11 mmol) of 3-(3-amino-4-trifluoromethylsulphanyl phenyl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine 2,4-dione using 1 ml of tert-butylamine. Yield: 5 mg M+H+ measured = 524 25 LC/MS retention time [min] = 1.04 Example 108 N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl]-2 30 morpholin-4 -yJpropionamide 125 mg (0.32 mmol) of 3-(3-amino-4-trifluoromethoxy phenyl)-5,5-dimethyl-l-pyridin-4-ylmethylimidazolidine 2,4-dione were initially charged in 5 ml of CH2Cl2, cooled to -20 C, and admixed with 43 mg (0.34 mmol) of 35 Htnig's base, and 48 mg of 2-chloropropionyl chloride were added dropwise. After stirring at 400C for 2 h and.
WO 2006/010641 PCT/EP2005/008720 170 standing overnight, 1 ml of ethaolic HCl was added and the mixture was concentrated to dryness. The residue was dissolved in 1 ml of morpholine and stirred at 100 0 C for 2 h. For workup, the mixture was 5 added to water, extracted with ethyl acetate, dried and concentrated. The remaining residue is purified by means of flash chromatography (silica gel, methylene chloride:methanol 95:5). The 140 mg of racemate obtained in this way was separated 10 by chiral prep. Chromatography. M+H+ measured = 536 LC/MS retention time [min] = 0.9 Example 109 15 N- [5- (4 ,4-Dimethyl-2, 5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyll -2 morpholin-4-ylpropionamide preparation as described for example 108 M+H+ measured = 536 20 LC/MS retention time [min] = 0.92 Example 110 N-[5- (4, 4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 25 piperidine-1-ylpropionamide; compound with trifluoroacetic acid preparation as described for example 108 M+H+ measured = 534 LC/MS retention time [min] = 1 30 Example 111 2-Cyclohexylamino-N- [5- (4, 4-dimethyl-2, 5-dioxo-3-pyridin 4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl]propionamide; compound with 35 trifluoroacetic acid preparation as described for example 108 WO 2006/010641 PCT/EP2005/008720 171 M+H+ measured 548 LC/MS retention time [min] = 1.11 Example 112 5 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenylJpropionamide; compound with trifluoroacetic acid preparation as described for example 108 10 M+H+ measured = 506 LC/MS retention time [min] = 0.97 Example 113 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 15 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl propionamide; compound with trifluoroacetic acid preparation as described for example 108 M+H+ measured = 534 20 LC/MS retention time [min] = 1.13 Example 114 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-2 25 (pyrrolidine-3-ylamino)propionamide hydrochloride preparation as described for example 108 M+H+ measured = 535 LC/MS retention time [min] = 0.89 30 Example 115 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl] propionamide; compound with trifluoroacetic acid preparation as described for example 108 35 M+H+ measured = 522 WO 2006/010641 PCT/EP2005/008720 172 LC/MS retention time [min] = 1.01 Example 116 N- [5- (4, 4-Dimethyl-2, 5-dioxo-3-pyridin-4 5 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 (2,2, 2-trifluoroethylamino) propionamide; compound with trifluoroacetic acid preparation as described for example 108 M+H+ measured = 548 10 LC/MS retention time [min] = 1.36 Example 117 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 15 [1,4] oxazepan-4-ylpropionamide; compound with trifluoroacetic acid preparation as described for example 108 M+H+ measured = 550 LC/MS retention time [min] 1.02 20 Example 118 N- [5- (4, 4-Dimethyl-2, 5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 [methyl- (1-methylpyrrolidin-3-yl) amino] propionamide 25 preparation as described for example 108 M+H+ measured = 563 LC/MS retention time [min] = 0.97 Example 119 30 N- [5- (4, 4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -3 dimethylamino-4-methylpentamide a) N- [5- (4,4-dinethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl]-4 35 methylpent-2-enamide; compound with trifluoroacetic acid 240 mg (2.1 mmol) of 4-methyl-2-pentenecarboxylic acid WO 2006/010641 PCT/EP2005/008720 173 were initially charged in 3 ml of methylene chloride and 794 mg (6.3 mmol) of oxalyl chloride were added at 00C. After stirring at RT for 3 h, the mixture was concentrated and coevaporated twice with toluene. 278 mg 5 of the acid chloride obtained in this way, dissolved in 5 ml of 1,2-dichloroethane, were added at -20 0 C to a solution of 500 mg (1.27 mmol) of 3-(3-amino-4 trifluoromethoxyphenyl)-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione in 10 ml of 1,2 10 dichloroethane, and stirred at RT for 1 h. For workup, the mixture was concentrated by rotary evaporation and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 250 mg -15 b) 100 mg (0.16 mmol) of N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl]-4-methylpent-2-enamide (TFA salt) were dissolved in 0.5 ml of DMF, 1 ml of dimethylamine solution (40% in H20) were added and the mixture was 20 stirred at 500C for 8 h. For workup, the mixture was concentrated by rotary evaporation and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 17 mg 25 M+H+ measured = 536 LC/MS retention time [min] = 1.03 Example 120 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 30 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl] 1,2,3,4-tetrahydroisoquinoline-1-carboxamide; compound with trifluoroacetic acid 152 mg (0.38 mmol) of FMOC-L-1,2,3,4 tetrahydroisoquinoline-1-carboxylic acid-are initially 35 -charged in 10 ml of CH2C12, 55 mg (0.43 mmol) of oxalyl chloride and 3 mg of DMF are added under argon, and the WO 2006/010641 PCT/EP2005/008720 174 mixture is stirred at RT overnight. Subsequently, the mixture was concentrated by rotary evaporation and 100 mg (0.25 mmol) of 3-(3-amino-4-trifluoromethoxyphenyl)-5,5 dimethyl-1-pyridin-4-ylmethylimidazolidine-2, 4-dione 5 dissolved in 7.5 ml of methylene chloride were added. After addition of 31 mg (0.25 mmol) of DMAP, the mixture was stirred at RT for 7 h. For workup, the mixture was concentrated and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 10 0.01% TFA). The 90 mg of FMOC derivative (TFA salt) remaining after freeze-drying of the fraction of value were deprotected by stirring in a 20% solution of piperidine in DMF for 1 hour. The end product was obtained by concentration by rotary evaporation and again 15 by preparative HPLC (RP18, acetonitrile/water, 0.01% T FA) . Yield: 38 mg of white solid (TFA salt) M+H+ measured = 554 LC/MS retention time [min] = 1.13 20 Example 121 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] - (.S) piperidine-2-carboxamide 25 prepared as described for example 120 M+H+ measured = 506 LC/MS retention time [min] = 0.97 Example 122 30 3-[3,3-Dimethyl-1-( (R)-1,2,3,4-tetrahydroisoquinoline-1 carbonyl) -2, 3-dihydro-1H-indol-6-yl] -5, 5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2 4-dione prepared as described for example 120 M+H+ measured= 524 35 LC/MS retention time [min] = 1.1 WO 2006/010641 PCT/EP2005/008720 175 Example 123 3-[3,3-Dimethyl-1-((S)-piperidine-2-carbonyl)-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione 5 prepared as described for example 120 M+H+ measured = 476 LC/MS retention time [min] = 0.96 Example 124 10 3-[3,3-Dimethyl-1-((R)-piperidine-2-carbonyl)-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 120 M+H+ measured = 476 15 LC/MS retention time [min] = 0.96 Example 125 3-[1-(1-tert-Butylazetidine-2-carbonyl)-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 20 ylmethylimidazolidine-2,4-dione prepared as described for example 120 M+H+ measured = 504 LC/MS retention time [min] = 1.08 25 Example 126 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidine-1-yl)-2-trifluoromethoxyphenyl] (R)-piperidine-2-carboxamide prepared as described for example 120 30 M+H+ measured = 506 LC/MS retention time [min] = 0.97 Example 127 (R)-2-Amino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 35 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-2 phenylacetamide WO 2006/010641 PCT/EP2005/008720 176 prepared as described for example 120 M+H+ measured = 528 LC/MS retention time [min] = 1.09 5 Example 128 (S)-2-Amino-3-cyclohexyl-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl]propionamide prepared as described for example 120 10 M+H+ measured = 548 LC/MS retention time [min] = 1.25 Example 129 (R)-2-Amino-3-cyclohexyl-N-[5-(4,4-dimethyl-2,5-dioxo-3 15 pyridin-4-ylmethylimidazolidin-1-yl)-2 trifluoromethoxyphenyl]propionamide prepared aa described for example 120 M+H+ measured = 548 LC/MS retention time [min] = 1.23 20 Example 130 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyll-3 methylamino-3-phenylpropionamide 25 prepared as described for example 120 M+H+ measured = 556 LC/MS retention time [min] = 1.09 Example 131 30 (R)-2-Amino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 .ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3 phenylpropionamide prepared as described for example 120 M+H+ measured,= 542 35 LC/MS retention time [min] =i1.-09 WO 2006/010641 PCT/EP2005/008720 177 Example 132 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -1 tert-butylazetidine-2-carboxamide 5 prepared as described for example 120 M+H+ measured = 534 LC/MS retention'time [min] = 1.04 Example -133 10 3-[3,3-Dimethyl-1-( (S)-1,2,3,4-tetrahydroisoquinoline-1 carbonyl) -2, 3-dihydro-1H-indol-6-yl] -5, 5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 120 M+H+ measured = 524 15 LC/MS retention time [min] = 1.1 Example 134 N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] 20 1,2,3, 4 -tetrahydroisoquinoline-1-carboxamide; compound with trifluoroacetic acid prepared as described for example 120 M+H+ measured = 554 LC/MS retention time [min] = 1.1 25 Example 135 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl) -2-trifluoromethoxyphenyl] -2 amino-4-methylpentamide; compound with trifluoroacetic 30 acid prepared as described for example 120 M+H+ measured = 508 LC/MS retention time [min] = 1.09 35 Example 136 3- [3, 3-Dimethyl-1- ( 2 -morpholin-4-ylacetyl) -2 ,3-dihydro- WO 2006/010641 PCT/EP2005/008720 178 1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4-ylmethyl imidazolidine-2,4-dione a) 3-(l-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) 5,5-dimethyl-l-pyridin-4-ylmethylimidazolidine-2,4-dione 5 7.26 g .(36.7 mmol) of diphosgene were initially charged at -20'C in 80 ml of 1,2-dichloroethane, and 3.0 g (14.5 mmol) of 1-(6-amino-3,3-dimethyl-2,3-dihydroindol-1 yl)ethanone, dissolved in 80 ml of 1,2-dichloroethane, were added dropwise. After stirring at RT for 2 h and 10 reflux for 1 h, the mixture was concentrated fully. The remaining residue was dissolved in 80 ml of THF, added to a solution of 3.06 g (14.7 mmol) of methyl 2-methyl-2 [(pyridin-4-ylmethyl)amino]propionate in 80 ml of THF, and heated under reflux for 8 h. The residue remaining 15 after evaporation was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 4.69 g. b) 3-(3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-5,5 dimethyl-l-pyridin-4-ylmethylimidazolidine-2,4-dione 1.9 g (3.65 mmol) of the above compound were dissolved in 20 8 ml of dioxane and 8 ml of 2N HCl, and the mixture was heated in a microwave at 120 0 C for 15 min. Subsequently, the mixture was concentrated, taken up with sodium carbonate solution, extracted with ethyl acetate, dried and concentrated by rotary evaporation. Yield: 1.3 g. 25 c) 440 mg (1.2 mmol) of 3-(3,3-dimethyl-2,3-dihydro-lH indol-6-yl)-5,5-dimethyl-l-pyridin-4-ylmethyl imidazolidine-2,4-dione were dissolved in 5 ml of 1,2-dichloroethane and cooled to -20'C, and a solution of 163 mg (1.44 mmol) of chloroacetyl chloride dissolved in 30 5 ml of 1,2-dichloroethane was added dropwise. The crude product remaining after concentration was used for the subsequent reactions without further purification. d) 3-[3,3-dimethyl-1-(2-morpholin-4-ylacetyl)-2,3' 35 dihydro-lH-indol-6-yl]-5,5-dimethyl-l-pyridin-4 ylmethylimidazolidine-2,4-dione WO 2006/010641 PCT/EP2005/008720 179 120 mg (approx. 0.3 mmol) of the above crude product were dissolved in 2.5 ml of 1,2-dichloroethane, added to a solution of 0.9 mmol of morpholine in 1,2-dichloroethane and stirred at 60 0 C for 2 h. Subsequently, the mixture 5 was poured onto ice-water, extracted with methylene chloride, dried and concentrated. The remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). Yield: 15 mg 10 M+H+ measured = 492 LC/MS retention time [min] = 0.95 Example 137 3- [3, 3-Dimethyl-1- (2-thiomorpholin-4-ylacetyl) -2,3 15 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2, 4-dione prepared as described for example 136 by use of thiomorpholine instead of morpholine. M+H+ measured = 508 20 LC/MS retention time [min] 0.99 Example 138 3- [3 ,3-Dimethyl-1- (2-piperidin-1-ylacetyl) -2, 3-dihydro 1H-indol-6-yl] -5 ,5-dimethyl-1-pyridin-4 25 ylmethylimidazolidine-2, 4-dione prepared as described for example 136 by use of piperidine instead of'morpholine. M+H+ measured = 490 LC/MS retention time [min] = 1 30 Example 139 3-{3,3-Dimethyl-1-[2- (4-methylpiperazin-1-yl)acetyll-2,3 dihydro-1H-indol-6-yl) -5, 5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2, 4-dione 35 prepared as described for example 136 by use of 1- WO 2006/010641 PCT/EP2005/008720 180 methylpiperazine instead of morpholine. M+H+ measured = 505 LC/MS retention time [min] = 0.92 5 Example 140 3-{1-[2-(3,5-Dimethylpiperazin-1-yl)acetyl]-3,3-dimethyl 2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of 10 2,6-dimethylpiperazine instead of morpholine. M+H+ measured = 519 LC/MS retention time [min] = 0.89 Example 141 15 3-{3,3-Dimethyl-1-[2-(4-methylperhydro-1,4-diazepin-1 yl)acetyl]-2,3-dihydro-1H-indol-6-yll-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of N-methylhomopiperazine instead of morpholine. 20 M+H+ measured = 519 LC/MS retention time [min] = 0.81 Example 142 3-[3,3-Dimethyl-1-[2-pyrrolidin-1-ylacetyl)-2,3-dihydro 25 1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of pyrrolidine instead of morpholine. M+H+ measured = 476 30 LC/MS retention time [min] = 0.81 Example 143 3-[1-(2-Diethylaminoacetyl)-3,3-dimethyl-2,3-dihydro-1H indol-6-yl]-5,5-dimethyl-1-pyridin-4 35 y1methylimidazolidine-2, 4-dione prepared as described for example 136 by use of WO 2006/010641 PCT/EP2005/008720 181 diethylamine instead of morpholine. M+H+ measured = 478 LC/MS retention time [min] = 0.97 5 Example 144 3-(1-{2-[((S)-1-Ethylpyrrolidin-2-ylmethyl)amino]acetyl} 3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of (S)-(-) 10 2-aminomethyl-l-ethylpyrrolidine instead of morpholine. M+H+ measured = 533 LC/MS retention time [min] = 0.88 Example 145 15 3-(1-{2-[((R)-1-Ethylpyrrolidin-2-ylmethyl)-amino]acetyl} 3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-l pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of (R)-(+) 1-ethyl-2-aminomethylpyrrolidine instead of morpholine. 20 M+H+ measured = 533 LC/MS retention time [min] = 0.89 Example 146 3-[1-(2-Cyclopropylaminoacetyl)-3,3-dimethyl-2,3, 25 dihydro-1H-indol-6-yl]-5,5-dimethyl-l-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of cyclopropylamine instead of morpholine. M+H+ measured = 462 30 LC/MS retention time [min] = 0.95 Example 147 3-[1-(2-Cyclopentylaminoacetyl)-3,3-dimethyl-2,3-dihydro 1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 35 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of WO 2006/010641 PCT/EP2005/008720 182 cyclopentylamine instead of morpholine. M+H+ measured = 490 LC/MS retention time [min) = 1.06 5 Example 148 3-[1-(2-Cyclohexylaminoacetyl)-3,3-dimethyl-2,3-dihydro 1H-indol-6-yl]-5,5-dimethyl-1-pyridin- 4 ylmethylimidazolidine- 2 ,4-dione prepared as described for example 136 by use of 10 cyclohexylamine instead of morpholine. M+H+ measured = 504 LC/MS retention time [min] = 1.19 Example 149 15 3-[1-(2-Hexahydropyrrolo[1,2-a]pyrazin-2-ylacetyl)-3,3 dimethyl-2, 3-dihydo-1H-indol-6-yl] -5 ,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of octahydro-pyrrolo[1,2-A]pyrazine instead of morpholine. 20 M+H+ measured = 531 LC/MS retention time [min] = 0.99 Example 150 3-{1-[2-(3-Dimethylamino-2,2-dimethylpropylamino)acetyl] 25 3,3-dimethyl-2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-l pyridin-4-ylmethylimidazolidine- 2 ,4-dione prepared as described for example 136 by use of N,N dimethylneopentanamide instead of morpholine. M+H+ measured = 535 30 LC/MS retention time [min] = 0.85 Example 151 3-{1-[2-(4-Isopropylpiperazin-1-yl)acetyl]-3,3-dimethyl 2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-1-pyridin-4 35 ylmethylimidazolidine- 2 ,4-dione prepared as described for example 136 by use of WO 2006/010641 PCT/EP2005/008720 183 isopropylpiperazine instead of morpholine. M+H+ measured = 533 LC/MS retention time [min] = 1 5 Example 152 3-[3,3-Dimethyl-1-(2-perhydro-1,4-oxazepin-1-ylacetyl) 2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of 10 homomorpholine hydrochloride and Hunig's base instead of morpholine. M+H+ measured = 506 LC/MS retention time [min] = 0.94 15 Example 153 3-{1-[2-((S)-3-Dimethylainopyrrolidin-1-yl)acetyl]-3,3 dimethyl-2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of (3S)-(-) 20 3-(dimethylamino)pyrrolidine instead of morpholine. M+H+ measured = 519 LC/MS retention time [min] = 0.85 Example 154 25 3-[1-(2-tert-Butylaminoacetyl)-3,3-dimethyl-2,3-dihydro 1H-indol-6-yl}-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of tert-, butylamine instead of morpholine. 30 M+H+ measured = 478 LC/MS retention time [min] = 1.02 Example 155 3-{3,3-Dimethyl-1-[2-(2,2,2-trifluoroethylamino)acetyl] 35 2,3-dihydro-1H-indol-6-yll-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione WO 2006/010641 PCT/EP2005/008720 184 prepared as described for example 136 by use of trifluoroethylamine instead of morpholine. M+H+ measured = 504 LC/MS retention time [min] = 1.11 5 Example 156 3-[1-(2-Dimethylaminoacetyl)-3,3-dimethyl-2,3-dihydro-1H indol-6-yll-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione 10 prepared as described for example 136 by use of dimethylamine (2M in THF) instead of morpholine. M+H+ measured = 450 LC/MS retention time [min] = 0.98 15 Example 157 3-[1-(2-Isopropylaminoacetyl)-3,3-dimethyl-2,3-dihydro 1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of 20 isopropylamine instead-of morpholine. M+H+ measured = 464 LC/MS retention time [min] =0.97 Example 158 25 3-[1-(2-Cyclobutylaminoacetyl)-3,3-dimethyl-2,3-dihydro 1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of cyclobutylamine instead of morpholine. 30 M+H+ measured = 476 LC/MS retention time [min] = 0.99 Example 159 3-{1-[2-(2-Amino-2-methylpropylamino)acetyl]-3,3 35 dimethyl-2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2,4-dione WO 2006/010641 PCT/EP2005/008720 185 prepared as described for example 136 by use of 1,2-diamino-2-methylpropane instead of morpholine. M+H+ measured = 493 LC/MS retention time [min] = 0.87 5 Example 160 3-{1- [2- ( (R) -3-Dimethylaminopyrrolidine-1-yl) acetyl] -3,3 dimethyl-2,3-dihydro-1H-indol-6-yl}-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2 , 4-dione 10 prepared as described for example 136 by use of (3R)-(+) 3-(dimethylamino)pyrrolidine instead of morpholine. M+H+ measured = 519 LC/MS retention time [min] = 0.89 15 Example 161 3- (3, 3-Dimethyl-1-{2- [methyl (1-methylpyrrolidin-3 yl) amino] acetyl}-2 ,3-dihydro-1H-indol-6-yl) -5 ,5-dimethyl 1-pyridin-4-ylmethylimidazolidine-2, 4-dione prepared as described for example 136 by use of 20 N,N-dimethyl-3-aminopyrrolidine instead of morpholine. M+H+ measured = 519 LC/MS retention time [min] = 0.85 Example 162 25 3- (1-{2- El-Hydroxycyclopropylmethyl) amino] acetyl}-3, 3 dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1 pyridin-4-ylmethylimidazolidine-2 , 4-dione prepared as described for example 136 by use of 1 (aminomethylycyclopropanol instead of morpholine. 30 M+H+ measured = 492 LC/MS retention time [min] = 0.97 Example 163 2-{2-[6-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 35 ylmethylimidazolidin-1-yl) -3, 3-dimethyl-2, 3-dihydro-iH indol-1-yl] -2-oxoethylamino}acetamide WO 2006/010641 PCT/EP2005/008720 186 prepared as described for example 136 by use of glycinamide hydrochloride and Hunig's base instead of morpholine. M+H+ measured = 479 5 LC/MS retention time [min] = 0.95 Example 164 3-[1-(2-Azetidin-1-ylacetyl)-3,3-dimethyl-2,3-dihydro-1H indol-6-yl]-5,5-dimethyl-1-pyridin-4 10 ylmethylimidazolidine-2,4-dione prepared as described for example 136 by use of azetidine instead of morpholine. M+H+ measured = 462 LC/MS retention time [min] = 0.94 15 Example 165 3-{3,3-Dimethyl-1-[2-(pyrrolidin-3-ylamino)acetyl]-2,3 dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione; compound 20 prepared as described for example 136 by use of 3-amino 1-N-BOC-pyrrolidine instead of morpholine. and subsequent detachment of the BOC group with 2N HCl. M+H+ measured = 491 LC/MS retention time [min] = 0.87 25 Example 166 N-(Piperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3 dihydroindole-1-carboxamide 30 1.00 g (2.74 mmol) of 3-(3,3-dimethyl-2,3-dihydro-1H indol-6-yl)-5,5-dimethyl-l-pyridin-4-ylmethyl imidazolidine-2,4-dione were dissolved in 10 ml of THF, and a solution of 609 mg (2.74 mmol) of 4-isocyanato trifluoroacetylpiperidine in 10 ml of THF was added 35 dropwise, partly reacted. After heating under reflux for 5 h, the mixture was concentrated, the remaining residue WO 2006/010641 PCT/EP2005/008720 187 was taken up in 2 ml of dioxane/2N HCl (1:1), and heated in a microwave at 120'C for 15 min. For workup, the mixture was concentrated and the remaining residue was purified by means of preparative HPLC (RP18, 5 acetonitrile/water, 0.1% TFA). After release of the base by treating with sodium hydrogencarbonate solution, 240 mg of the title compound remain. From unhydrolysed intermediate compound obtained analogously to the above preparation method, pure 10 N-(piperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3 dihydroindole-1-carboxamide were obtained by preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). M+H+ measured = 491 15 LC/MS retention time [min] = 0.96 Example 167 3-[3,3-Dimethyl-1-(pyridine-2-carbonyl)-2,3-dihydro-1H indol-6-yl]-5,5-dimethyl-1-pyridin-4-ylmethyl 20 imidazolidine-2,4-dione 100 mg (0.27 mmol) of 3-[3,3-dimethyl-2,3-dihydro-1H indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethyl imidazolidine-2,4-dione were dissolved in 5 ml of dichloromethane, 107 mg (0.82 mmol) of Hunig's base and 25 73 mg (0.41 mmol) of picolinyl chloride hydrochloride were added, and the mixture was stirred at RT for 15 h. For workup, the mixture was concentrated and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). After release 30 of the base by treating with sodium hydrogencarbonate solution, 22 mg of the title compound remain. M+H+ measured = 470 LC/MS retention time [min] = 1.2 35 Example 168 3-[3,3-Dimethyl-1-(pyridine-3-carbonyl)-2,3-dihydro-1H- WO 2006/010641 PCT/EP2005/008720 188 indol-6-yl]-5,5-dimethyl-1-pyridin-4-ylmethyl imidazolidine-2,4-dione prepared as described for example 167 M+H+ measured = 470 5 LC/MS retention time [min] = 1.02 Example 169 5,5-Dimethyl-1-pyridin-4-ylmethyl-3-{3-[(pyridin-2 ylmethyl) amino] -4-trifluoromethoxyphenyl }imidazolidine 10 2,4-dione prepared as described for example 96 M+H+ measured = 486 LC/MS retention time [min] = 0.95 15 Example 170 1-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3 [1-(2,2,2-trifluoroacetyl)piperdin-4-yl]urea; compound with trifluoroacetic acid 20 prepared as described for example 166 M+H+ measured = 617 LC/MS retention time [min] = 1.33 Example 171 25 1-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4 ylmethylimidazolidin-1-yl)-2-trifluoromethoxyphenyl]-3 piperidin-4-ylurea prepared -as described for example 166 M+H+ measured = 521 30 LC/MS retention time [min] = -0.94 Example 172 3-[1-(2-Dimethylamino-2-phenylacetyl)-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 35 ylmethylimidazolidine-2,4-dione prepared as described for example 136c) by use of WO 2006/010641 PCT/EP2005/008720 189 chlorophenylacetyl chloride, dimethylamine in 1,2 dichloroethane as a solvent M+H+ measured = 526 LC/MS retention time [min] = 1.06 Example 173 3- [1- (2-Azetidin-1-yl-2-phenylacetyl) -3, 3-dimethyl-2, 3 dihydro-1H-indol-6-yl] -5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2 , 4-dione 10 prepared as described for example 136c) by use of chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent M+H+ measured = 538 LC/MS retention time [min] = 1.11 15 Example 174 3- [1- (2-Isopropylamino-2-phenylacetyl) -3,3-dimethyl-2, 3 dihydro-1H-indol-6-yl] -5, 5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione 20 prepared as described for example 136c) by use of chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent M+H+ measured = 540 LC/MS retention time [min] = 1.13 25 Example 175 3- [1- (2-Cyclopropylamino-2-phenylacetyl) -3, 3-dimethyl 2, 3-dihydro-1H-indol-6-yl] -5 ,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2, 4-dione 30 prepared as described for example 136c) by use of chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent M+H+ measured = 538 LC/MS retention time [min] = 1.12 35 Example 176 WO 2006/010641 PCT/EP2005/008720 190 3-[1-(2-Cyclobutylamino-2-phenylacetyl)-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136c) by use of 5 chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent M+H+ measured = 552 LC/MS retention time [min] = 1.16 10 Example 177 3-[1-(2-Cyclopentylamino-2-phenylacetyl)-3,3-dimethyl 2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 136c) by use of 15 chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent M+H+ measured = 566 LC/MS retention time [min] =-1.19 20 Example 178 3-[3,3-Dimethyl-1-(pyridine-2-sulphonyl)-2,3-dihydro-1H indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione 100 mg (0.27 mmol) of 3-(3,3-dimethyl-2,3-dihydro-lH 25 indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethyl imidazolidine-2,4-dione were initially charged in 1 ml of pyridine, and 88 mg (0,41 mmol) of 2-pyridylsulphonyl chloride hydrochloride were added. For workup, the mixture was concentrated fully and the residue purified 30 by flash chromatography (100 g of silica gel/95:5 CH2Cll:CH30H). Yield: 80 mg M+H+ measured = 506 LC/MS retention time [min] = 1.28 35 Example 179 WO 2006/010641 PCT/EP2005/008720 191 3-[3,3-Dimethyl-1-(pyridine-3-sulphonyl)-2,3-dihydro-1H indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 178 5 M+H+ measured = 506 LC/MS retention time [min] = 1.27 Example 180 3-[3,3-Dimethyl-1-pyridin-2-ylmethyl-2,3-dihydro-1H 10 indol-6-yl)-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl 1-pyridin-4-ylmethylimidazolidine-2,4-dione with 2 15 bromomethylpyridine M+H+ measured = 456 LC/MS retention time [min] = 1.05 Example 181 20 3-[1-(1-Cyclohexylazetidin-3-yl)-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl]-5,5-dimethyl-1-pyridin-4 ylmethylimidazolidine-2,4-dione prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-5,5-dimethyl 25 1-pyridin-4-ylmethylimidazolidine-2,4-dione with 1 cyclohexylazetidin-3-yl methanesulphonate oxalate M+H+ measured = 502 LC/MS retention time [min] = 1.16 30 Example 182 N-(1-Cyclopropylpiperidin-4-yl)-6-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethylimidazolidin-1-yl)-3,3 dimethyl-2,3-dihydroindole-1-carboxamide 50 mg (0.1 mmol) of 1-[5-(4,4-dimethyl-2,5-dioxo-3 35 pyridin-4-ylmethylimidazolidin-1-yl)-2-trifluoromethoxy- WO 2006/010641 PCT/EP2005/008720 192 phenyl}-3-piperidin-4-ylurea were dissolved in 2 ml of methanol, 1 g of molecular sieve (4A), 53 mg of glacial acetic acid, 77 mg (0.44 mmol) of [(1 ethoxycyclopropyl)oxy]trimethylsilane and 17 mg (0.26 5 mmol) of sodium cyanatoborohydride were added, and the mixture was heated under reflux for 1 h. Subsequently, the mixture was filtered and concentrated, and the remaining residue was purified by flash chromatography (silica gel, 95:5 methylene chloride/methanol). 10 Yield: 22 mg M+H+ measured = 531 LC/MS retention time [min] = 1.08 Example 183 15 N-(1-Methylpiperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3 dihydroind-ole-1-carboxamide prepared as described for example 182 by use of formaldehyde (37% in water) instead of [(1-ethoxycyclo 20 propyl)oxy]trimethylsilane M+H+ measured = 505 LC/MS retention time [min] = 1.07 Example 184 25 N-(1-Ethylpiperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3 dihydroindole-1-carboxamide prepared as described for example 182 by use of acetaldehyde instead of [(1-ethoxycyclo 30 propyl)oxyltrimethylsilane M+H+ measured = 519 LC/MS retention time [min] = 0.99 Example 185 35 N-(1-Isobutylpiperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3- WO 2006/010641 PCT/EP2005/008720 193 dihydroindole-1-carboxamide prepared as described for example 182 by use of isobutyraldehyde instead of [(1-ethoxycyclo propyl)oxy]trimethylsilane 5 M+H+ measured = 547 Example 186 N-(1-Isopropylpiperidin-4-yl)-6-(4,4-dimethyl-2,5-dioxo 3-pyridin-4-ylmethylimidazolidin-1-yl)-3,3-dimethyl-2,3 10 dihydroindole-1-carboxamide prepared as described for example 182 by use of acetone instead of [(1-ethoxycyclopropyl)oxy]trimethylsilane M+H+ measured = 533 LC/MS retention time [min] = 1.01 15 Example 187 N-(Piperidin-4-ylamide)-6-[3-(2-aminopyrimidin-4 ylmethyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-3,3 dimethyl-2,3-dihydroindole-1-carboxamide 20 a) 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-H-indol-6-yl) 5,5-dimethyl-1-(2-methylsulphanylpyrimidin-4 ylmethyl)imidazolidine-2,4-dione 2.40 g (7.6 mmol) of 1-(6-amino-3,3-dimethyl-2,3 dihydroindol-1-yl)ethanone were initially charged in. 25 10 ml of DMF, 2.72 g (8.36 mmol) of caesium carbonate were added, and the mixture was stirred at RT for 30 min. Subsequently, 6.66 g (9.12 mol) of 4-bromomethyl-2 methylthiopyrimidine (30% in THF) were added and the mixture.was stirred at RT for 15 h. For workup, the 30 mixture was filtered with suction from the precipitate and concentrated, and the remaining residue was purified by flash chromatography (silica gel, 95:5 methylene chloride/methanol). Yield 3.5 g 35 b) 3 -(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-1
(
2 -methanesulphonylpyrimidin-4-ylmethyl)-5,5- WO 2006/010641 PCT/EP2005/008720 194 dimethylimidazolidine-2,4-dione 3.5 g (7.72 mmol) of 3-(1-acetyl-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl)-5,5-dimethyl-1-(2 methylsulphanylpyrimidin-4-ylmethyl)imidazolidine-2,4 5 dione were dissolved in 50 ml of methylene chloride, and a solution of 4.65 g (23.1 mmol) of m-chloroperbenzoic acid (85%) in 10 ml of methylene chloride was added gradually. After a total of 15 h at RT, the mixture was concentrated and the remaining residue was purified by 10 flash chromatography (silica gel, 95:5 methylene chloride/methanol). Yield 3.7 g c) 1-(2-aminopyrimidin-4-ylmethyl)-3-(3,3-dimethyl-2,3 dihydro-lH-indol-6-yl)-5,5-dimethylimidazolidine-2,4 15 dione 3.7 g (7.62 mmol) of 3-(l-acetyl-3,3-dimethyl-2,3 dihydro-1H-indol-6-yl)-1-(2-methanesulphonylpyrimidin-4 ylmethyl)-5,5-dimethylimidazolidine-2,4-dione were dissolved in 10 ml of dioxane, 10 ml of aqueous ammonia 20 solution (33%) were added, and the mixture was heated in a microwave at 120'C for 20 minutes. Subsequently, the mixture was concentrated and the remaining crude 3-(1 acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-1-(2 methanesulphonylpyrimidin-4-ylmethyl)-5,5 25 dimethylimidazolidine-2,4-dione (3.7 g) was heated in a microwave with 5 ml of dioxane and 5 ml of 2 N HCl at 120'C for 20 min. For workup, the mixture was concentrated, taken up in sodium carbonate solution, extracted with ethyl acetate, dried and concentrated. The 30. remaining residue was purified by flash chromatography (silica gel, 95:5 methylene chloride/methanol). Yield 1.7 g d) N-piperidin-4-yl-6-[3-(2-aminopyrimidin-4-ylmethyl) 4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-3,3-dimethyl 35 2,3-dihydroindole-l-carboxamide 200 mg (0.-53 mmol) of 1-(2-aminopyrimidin-4-ylmethyl)-3- WO 2006/010641 PCT/EP2005/008720 195 (3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-5,5 dimethylimidazolidine-2,4-dione were dissolved in 3 ml of THF, and a solution of 118 mg (0.53 mmol) of 4-isocyanatotrifluoroacetylpiperidine in 3 ml of THF was 5 added. Aft-er stirring at RT for 1 h, the mixture is concentrated and taken up in 3 ml of dioxane and 3 ml of 2 N HCl, and the mixture is heated in a microwave at 120 0 C for 15 min. For workup, the mixture was concentrated and the remaining residue was purified by 10 means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). After release of the base by treating with sodium hydrogencarbonate solution, 60 mg of the title compound were obtained. M+H+ measured = 507 15 LC/MS retention time [min] = 0.98 Example 188 1-(2-Aminopyrimidin-4-ylmethyl)-3-[1-(2-tert butylaminoacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6 20 yl]-5,5-dimethylimidazolidine-2,4-dione prepared as described for example 136 M+H+ measured = 494 LC/MS retention time [min] = 1-.01 25 Example 189 1-(2-Aminopyrimidin-4-ylmethyl)-3-[1-(2-azetidin-1 ylacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5 dimethylimidazolidine-2,4-dione prepared as described for example 136 30 M+H+ measured = 478 LC/MS retention time [min] = 1.01 Example 190 1-(2-Aminopyrimidin-4-ylmethyl)-3-[1-(2 35 cyclopropylaminoacetyl)-3,3-dimethyl-2,3-dihydro-1H indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione WO 2006/010641 PCT/EP2005/008720 196 prepared as described for example 136 M+H+ measured = 478 LC/MS retention time [min] = 0.96 5 Example 191 1- (2-Aminopyrimidin-4-ylmethyl) -3- [1- (2 cyclopentylaminoacetyl) -3,3-dimethyl-2 , 3-dihydro-1H indol-6-yl] -5 ,5-dimethylimidazolidine-2, 4-dione prepared as described for example 136 10 M+H+ measured = 506 LC/MS retention time [min] = 1.05 Example 192 1- (2-Aminopyrimidin-4-ylmethyl) -3- [3, 3-dimethyl-1 15 (pyridine-2-carbonyl) -2, 3-dihydro-1H-indol-6-yl] -5,5 dimethylimidazolidine-2, 4-dione prepared as described for example 167 M+H+ measured = 486 LC/MS retention time [min] = 1.23 20 Example 193 1- (2-Aminopyrimidin-4-ylmethyl) -3- [1- (2-azetidin-1-yl-2 phenylacetyl) -3, 3-dimethyl-2, 3-dihydro-1H-indol-6-yl] 5, 5-dimethylimidazolidine-2 , 4-dione prepared as described for example 136 c) by use of 25 chlorophenylacetyl chloride in 1,2-dichloroethane as a solvent. M+H+ measured = 554 LC/MS retention time [min] = 1.15 30 Example 194 1- (2-Aminopyrimidin-4-ylmethyl) -3- [3, 3-dimethyl-1 (pyridine-3-carbonyl) -2 ,3-dihydro-1H-indol-6-yl] -5,5 dimethylimidazolidine-2, 4-dione prepared as described for example 167 35 M+H+ measured = 486 LC/MS retention time [min] = 1.07 WO 2006/010641 PCT/EP2005/008720 197 Example 195 1-(2-Aminopyrimidin-4-ylmethyl)-3-[3,3-dimethyl-1-((S) piperidine-2-carbonyl)-2,3-dihydro-1H-indol-6-yl]-5,5 5 dimethylimidazolidine-2,4-dione prepared as described for example 120 M+H+ measured = 492 LC/MS retention time [min] = 1.05 10 Example 196 1-(2-Aminopyrimidin-4-ylmethyl)-3-[3,3-dimethyl-1-((R) piperidine-2-carbonyl)-2,3-dihydro-1H-indol-6-yl]-5,5 dimethylimidazolidine-2,4-dione prepared as described for example 120 15 M+H+ measured = 492 LC/MS retention time [min] = 1.01 Example 197 1-(2-Aminopyrimidin-4-ylmethyl)'-3-[3,3-dimethyl-1-((R) 20 1,2,3,4-tetrahydroisoquinoline-1-carbonyl)-2,3-dihydro 1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione prepared as described for example 120 M+H+ measured = 540 LC/MS retention time [min] = 1.16 25 Example 198 1-(2-Aminopyrimidin-4-ylmethyl)-3-[3,3-dimethyl-1-((S) 1,2,3,4-tetrahydroisoquinoline-1-carbonyl)-2,3-dihydro 1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione 30 prepared as described for example 120 M+H+ measured = 540 LC/MS retention time [min] = 1.23 Example 199 WO 2006/010641 PCT/EP2005/008720 198 3- [1- ( 2 -Dimethylamino-acetyl) -3, 3-dimethyl-2, 3-dihydro 1H-indol-6-yl] -5 ,5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2,4-dione To a solution of 50 mq 3-(3,3-dimethyl-2,3-dihydro-1H 5 indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione in 1 ml 1,2-dichloroethane 0.04 ml ethyl-diisopropyl-amine and 13.7 mg chloroacetylchloride were added at 0 0 C. After stirring for 1 hour at 0 0 C 5.5 mg dimethyl-amine were added and 10 the reaction mixture was stirred for 2 days at room temperature. After removing of the solvent under reduced pressure the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). 15 After lyophilization of the solution the resulting crude product was purified in addition by flash chromatography on silica gel with a dichloro-methane/methanol gradient. The fractions containing the product were evaporated to yield a white solid. 20 Yield: 3 mg M+H+ measured = 500 1H-NMR (500 MHz, DMSO/TMS): d = 8.98 (d, 1H); 8.25 (d, 1H); 8.12 (s, 1H); 8.08 (d, 1H); 7.83 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.43 (d, 1H); 7.19 (d, 1H); 5.15 (s, 25 2H); 3.93' (s, 2H); 2.65 (m, 2H); 2.60-2.40 (s, 6H); 1.44 (s, 6H); 1.35 (s, 6H) Example 200 3 -{3, 3-Dimethyl-1- [2- ( 2 , 2 , 2 -trifluoro-ethylamino) 30 acetyl]-2,3-dihydro-1H-indol-6-yl}- 5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine-2 , 4-dione To a solution of 100 mg 3
-(
3
,
3 -dimethyl-2,3-dihydro-1H indol-6-yl) -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione in 2 ml 1,2-dichloroethane in a 35 process vial 0.08 ml ethyl-diisopropyl-amine and 27.2 mg chloroacetylchloride were added at 0 0 C. After stirring WO 2006/010641 PCT/EP2005/008720 199 for 1 hour at 0 0 C 119.4 mg 2,2,2-trifluoro-ethylamine were added. The resulting mixture was stirred for 1 hour at room temperature and then further 119.4 mg 2,2,2 trifluoro-ethylamine were added. The vial was sealed with 5 a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 1000 C by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After further 15 minutes stirring at 150'C the solution was heated for 1 hour at 1500C. The solvent 10 was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoracetic acid). Lyophilization of the solution yielded a white solid. 15 Yield : 39 mg M+H+ measured = 554 1H-NMR (500 MHz, DMSO/TMS): d 8.96 (d, 1H); 8.33 (d, 1H); 8.14 (m, 2H); 7.90 (t, 1H); 7.75 (m, 2H); 7.42 (d, 1H); 7.16 (d, 1H); 5.21 (s, 2H); 3.88 (s, 2H); 3.80 20 (s,2H); 3.55 (m, 2H); 1.46 (s, 6H); 1.35 (s, 6H) Example 201 3-{ 3, 3-Dimethyl-1- [2- (4-methyl-piperazin-1-yl) -acetyl] 2,3-dihydro-1H-indol-6-yl}-5,5- dimethyl-1-quinolin-4 25 ylmethyl-imidazolidine-2, 4-dione To a solution of 70 mg 3-(3,3-dimethyl-2,3-dihydro-1H indol-6-yl)-5,5-dimethyl-l-quinolin-4-ylmethyl imidazolidine-2,4-dione in 2 ml 1,2-dichloroethane in a process vial 0.06 ml ethyl-diisopropyl-amine and 13.5 mg 30 chloroacetylchloride were added at 00C. After stirring for 1 hour at 00C 33.9 mg 1-methyl-piperazine were added. The resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue purified by preparative HPLC 35 (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoracetic WO 2006/010641 PCT/EP2005/008720 200 acid). Lyophilization of the solution yielded a white solid. Yield : 65 mg M+H+ measured = 555 5 1H-NMR (500 MHz, DMSO/TMS): d 8.90 (d, 1H); 8.28 (d, 1H); 8.11 (m, 2H); 7.85 (t, 1H); 7.73 (t, 1H); 7.65 (d, 1H); 7.41 (d, 1H); 7.16 (dd, 1H); 5.17 (s, 2H); 3.94 (s, 2H); 3.90-3.30 (m, 4H); 3.10 (m, 4H); 2.79 (s, 3H); 2.68 (m, 2H); 1.44 (s, 6H); 1.35 (s, 6H) 10 Example 202 3- [1- (2-Cyclopentylamino-acetyl) -3, 3-dimethyl-2 , 3 dihydro-1H-indol-6-yl] -5 ,5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2, 4-dione 15 The following compounds were prepared in analogy to example 201 by using the corresponding amines instead of 1-methyl-piperazine. Further 0.1 ml of the corresponding amines were added and' the reaction mixtures were stirred for 15 minutes at 1000C by microwave-assisted heating 20 (Emrys Optimizer, Personal Chemistry). The product was obtained as its trifluoroacetic salt. Yield: 45 mg -M+H+ measured = 540 1H-NMR (500 MHz, DMSO/TMS) : d = 8.95 (m, 2H); 8. 90 (d, 25 1H); 8.28 (d, 1H); 8.13 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.72 (t, 1H); 7.63 (d, 1H); 7.48 (d, 1H); 7.25 (dd, 1H); 5.17 (s, 2H); 4.20 (t, 2H); 3.97 (s, 2H); 2.00 (m, 2H)'; 1. 70 (m, 4H) ; 1. 55 (m, 2H); 1.44 (s, 6H); 1.38 (s, 6H) 30 Example 203 3- [1- (2-Isopropylamino-acetyl) -3, 3-dimethyl-2 , 3-dihydro 1H-indol-6-yl] -5,5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2,4-dione 35 The product was obtained as its trifluoroacetic salt. Yield: 43 mg WO 2006/010641 PCT/EP2005/008720 201 M+H+ measured = 1H-NMR (500 MHz, DMSO/TMS): d = 8.90 (d, 1H); 8.79 (m, 2H); 8.28 (d, 1H); 8.13 (d, 1H); 8.10 (d, 1H); 7.85 (t, 1H); 7.72 (t, 1H); 7.63 (d, 1H).; 7.48 (d, 1H); 7.25 (dd, 5 1H); 5.17 (s, 2H); 4.19 (t, 2H)); 4.00 (s, 2H); 3.37 (m, 1H); 1.45 (s, 6H); 1.38 (s, 6H); 1.28 (d, 6H) Example 204 3-{3,3-Dimethyl-1-[2-(pyrrolidin-3-ylamino) -acetyl];-2, 3 10 dihydro-1H-indol-6-yl} -5,5- dimethyl-1-quinolin-4 ylmethyl-imidazolidine-2,4-dione In addition the reaction mixture was stirred for further 15 minutes at 100 0 C by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). 15 After lyophilization the residue was dissolved in 2 ml of a 8 N solution of hydrochloric acid in methanol and stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was dissolved in a mixture of 2 ml water and 1 ml 20 acetonitrile. Lyophilization of the resulting mixture yielded a white foam. The product was obtained as its hydrochloric salt. Yield: 19 mg M+H+ measured = 541 25 1H-NMR (500 MHz, DMSO/TMS): d= 9.90-9.25(m, 4H); 8.98 (d, 1H); 8.3.5 (d, 1H); 8.19 (d, 1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.80 (m, 21H); 7.48 (d, 1H); 7.25 (d, 1H); 5.13 (s, 2H); 4.29 (m, 2H); 3.96 (m, 3H); 3.70-3.30 (m, 2H); 3.25 (m, 2H); 2.35 (m, 1H); 2.25 (m, 1H); 1.46 (s, 6H); 30 1.39 (s, 6H) Example 205 3- {1- [2- (2-Dimethylamino -ethylamino) -acetyl] -3 ,3 dimethyl-2,3-dihydro-1H-indol-6-yl}- 5,5-dimethyl-1 35 quinolin-4-ylmethyl-imidazolidine-2 , 4-dione WO 2006/010641 PCT/EP2005/008720 202 After lyophilization the crude product was partitioned between 5 ml ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over sodium sulphate. After 5 removing of the solvent under reduced pressure the residue was purified in addition by flash chromatography on silica gel with a dichloro methane/methanol/water/triethylamine gradient. The fractions -containing the product were evaporated to yield 10 a white solid. Yield: 9.5 mg M+H+ measured = 543 1H-NMR (500 MHz, DMSO/TMS): d = 8.89 (d, 1H); 8.25 (d, 1H); 8.12 (s, 1H); 8.08 (d,' 1H); 7.82 (t, 1H); 7.70 (t, 15 1H); 7.60 (d, 1H); 7.40 (d, 1H); 7.13 (d, 1H), 5.13 (s, 2H); 3.89 (s, 2H); 3.52 (d, 2H); 2.65 (t, 2H); 2.36 (t, 2H); 2.17 (s, 6H); 1.43 (s, 6H); 1.33 (s, 6H) Example 206 20 3-{3 , 3-Dimethyl-1- [2- (1-methyl-piperidin-4-ylamino) acetyl] -2 ,3-dihydro-1H-indol-6-yl 1- 5, 5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine-2, 4-dione After lyophilization the crude product was purified in addition by flash chromatography on silica gel with a 25 dichloro-methane/methanol/water/triethylamine gradient. The fractions containing the product were evaporated to yield a white solid. Yield: 2 mg M+H+ measured = 569 30 1H-NMR (500 MHz, DMSO/TMS): d = 8.89 (d, 1H); 8.25 (d, 1H); 8.12 (s, IH); 8.08 (d, 1H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.40 (d, 1H); 7.15 (d, 1H), 5.14 (s, 2H); 3.93 (s, 2H); 3.60 (m, 2H); 3.52 (s, 1H); 3.32 (s, 3H); 2.85 (m, 2H); 2.28 (m, 2H); 1.84 (m, 2H); 1.43 (s, 35 6H); 1.34' (s,' 6H) WO 2006/010641 PCT/EP2005/008720 203 Example 207a 3, 3-Dimethyl-6-nitro-2 , 3-dihydro-1H-indole 2 g 1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl) ethanone were dissolved in a mixture of 6 ml dioxane and 5 6 ml of an aqueous 2 N solution of hydrochloric acid in a process vial. The vial was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 1200C by microwave-assisted heating' (Emrys Optimizer, Personal Chemistry). After 10 removal of the solvent under reduced pressure the residue was treated with an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried, over anhydrous sodium sulfate. Filtration and concentration of the solvent under reduced pressure 15 yielded a white solid. Yield: 1.7 g M+H+ measured = 193 1H-NMR (400 MHz, DMSO/TMS): d = 7.43 (dd, 1H); 7.19 (m, 2H); 6.15 (s, 1H); 3.35-3.25 (s, 2H); 1.25 (s, 6H) 20 Example 207b 4- (3, 3-Dimethyl-6-nitro-2 , 3-dihydro-indol-1-ylmethyl) piperidine-1-carboxylic acid tert- butyl ester A process vial with a suspension of 1 g 3,3-dimethyl-6 25 nitro-2,3-dihydro-1H-indole, 1.59 g 4-bromomethyl piperidine-l-carboxylic acid tert-butyl ester and 1.17 g potassium tert-butoxide in 10 ml N,N-dimethylformamide was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was, stirred for 15 30 minutes * at 1000C by microwave-assisted heating,, (Emrys Optimizer, Personal Chemistry). After removal .of the solvent under reduced pressure the residue was purified by flash chromatography on silica gel with a n-heptane/ ethylacetate gradient. The fractions containing the. 35 product were combined and evaporated to yield a white WO 2006/010641 PCT/EP2005/008720 204 solid. Yield: 0.24 g M+H+ measured = 388 1H-NMR (400 MHz, DMSO/TMS): d = 7.44 (m, 1H); 7.19 (m, 5 2H); 3.95 (m, 2H); 3.27 (s, 2H),; 3.05 (d, 2H); 2.70 (m, 2H); 1.83 (m, 1H); 1.65 (m, 2H); 1.40 (s, 9H); 1.28 (s, 6H); 1.10 (m, 2H) Example 20'7c 10 4- (6-Amino-3, 3-dimethyl-2, 3-dihydro-indol-1-ylmethyl) piperidine-1-carboxylic acid tert- butyl ester A mixture of 240 mg 4-(3,3-dimethyl-6-nitro-2,3-dihydro indol-1-ylmethyl)-piperidine-1-carboxylic acid tert butyl ester, 20 mg of 10% palladium on carbon 'and 5 ml 15 ethanol was stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through a chem elut cartridge and the compound was eluted with ethanol. After concentration under reduced pressure the residue was directly subjected to the subsequent reaction without 20 further purification. Yield: 216 mg M+H+ measured = 360 1H-NMR (400 MHz, DMSO/TMS): d 6.59 (d, 1H); 5.80 (d, 1H); 5.73 (s, 1H); 4.61 (s, 2H); 3.95 (m, 2H); 3.00 (s, 25 2H); 2.79 (d, 2H)); 2.70 (m, 2H); 1.72 (m, 3H); 1.39 (s, 9H); 1.15 (s, 6H); 1.05 (m, 2H) Example 207d 4-[6- (4,4-Dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl 30 imidazolidin-1-yl) -3, 3-dimethyl-2, 3- dihydro-indol-1 ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester To a solution *of 50 mg 4-(6-amino-3,3-dimethyl-2,3 dihydro-indol-1-ylmethyl)-piperidine-1-carboxylic acid tert- butyl ester in 5 ml tetrahydrofuran 0.05 ml ethyl-. 35 diisopropyl-amine and 28 mg 4-nitrophenyl chloroformate were added and the mixture was stirred for 2 hours at WO 2006/010641 PCT/EP2005/008720 205 room temperature. Afterwards 36 mg 2-methyl-2-[(quinolin 4-ylmethyl)-aminol-propionic acid methyl ester were added to the reaction mixture. After 16 hours stirring at room temperature the solvent was removed under reduced 5 pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid. Yield: 25 mg 10 M+H+ measured = 612 1H-NMR (250 MHz, DMSO/TMS): d = 8.97 (d, 1H); 8.35 (d, 1H); 8.13 (d, 1H); 7.91 (t, 1H); 7.79 (t, 1H); 7.70 (d, 1H); 7.08 (d, 1H); 6.60 (d, 1H); 6.51 (s, 1H); 5.19 (s, 2H); 4.20-3.80 (m, 2H); 3.17 (s, 2H); 2.93 (d, 2H); 2.75 15 (m, 2H); 1.73 (m, 3H); 1.43 (s, 6H); 1.38 (s, 9H); 1.26 (s, 6H) ; 1. 07 (m, 2H) Example 208 3- (3,3-Dimethyl-1-piperidin-4-ylmethyl-2, 3-dihydro-1H 20 indol-6-yl) -5 ,5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2,4-dione A solution of 25 mg 4-[6-(4,4-dimethyl-2,5-dioxo-3 quinolin-4-ylmethyl-imidazolidin-1-yl)-3,3-dimethyl-2,3 dihydro-indol-1-ylmethyl]-piperidine-1-carboxylic acid 25 tert-butyl ester in 2 ml of a 8 N solution of hydrochloric acid in methanol was stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/ 30 acetonitrile gradient with 0.1% trifluoroacetic acid) Lyophilization of the combined fractions containing the product yielded a white solid, that was partitioned between 2 ml of a satured aqueous solution of sodium hydrogen carbonate and 2 ml ethyl acetate. The organic 35 layer was dried over sodium sulfate. After filtration the solvent was removed under reduced pressure. The residue WO 2006/010641 PCT/EP2005/008720 206 was dissolved in a mixture of 1 ml acetonitrile and 2 ml water. After addition of 0.01 ml of a 1 N solution of hydrochloric acid the resulting solution was lyophilized to yield a white foam. The product was obtained as its 5 hydrochloric salt. Yield: 15 mg M+H+ measured = 512 1H-NMR (500 MHz, DMSO/TMS) : d = 8.95 (d, 1H) ; 8.73 (m, 1H); 8.50 (m, 1H); 8.33 (d, 1H);. 8.15 (d, 1H); 7.90 (t, 10 1H); 7.76 (t, 1H); 7.68 (m, 1H); 7.10 (d, 1H); 6.63 (dd, 1H); 6.55 (d, 1H); 5.19 (s, 2H); 3.30 (m, 2H); 3.17 (s, 2H); 2.95 (d, 2H); 2.88 (m, 2H); 1.90 (m, 3H); 1.50-1.35 (m, 8H); 1.27 (s, 6H) 15 General procedure for the preparation of the following compounds (Example 209 to 221) The following compounds were prepared in analogy to example 201 by using 100 mg-3-(3,3-dimethyl-2,3-dihydro 20 1H-indol-6-yl) -5, 5-dimethyl-1-quinolin-4-ylmethyl imidazolidine-2,4-dione as starting material and 3 equivalents of the corresponding amines instead of 1 methyl-piperazine. The reaction mixture was stirred for 1 hour at 100'C by 25 microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After purification the residue was partitioned between 5 ml of a saturated aqueous solution of sodium hydrogen carbonate and 5 ml ethyl acetate. The organic layer was dried over sodium sulfate. After 30 filtration the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 1 ml acetonitrile and 2 ml water and lyophilized. Example 209 WO 2006/010641 PCT/EP2005/008720 207 cis /trans-3-{1- [2- (3,5-Dimethyl-piperazin-1-yl) -acetyl] 3,3-dimethyl-2 ,3-dihydro-1H-indol-6-yl}- 5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione This title compound was purified in addition by flash 5 chromatography on silica gel with a dichloro methane/methanol/water/triethylamine gradient. The fractions containing the product were combined and evaporated to yield a white solid. Yield: 35.5 mg 10 M+H+ measured = 569 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.69 (t, 1H); 7.60 (d, iH); 7.39 (d, 1H); 7.13 (dd, 1H); 5.15 (s, 2H); 4.05 (s, 2H); 3. 23 (s, 2H); 2. 73 (m, 4H) ; 1. 67 (t, 2H) ; 1.44 (s, 15 6H); 1.33 (s, 6H); 0.91 (d, 6H) Example 210 3- [1- (2-Diethylamino-acetyl) -3 ,3-dimethyl-2, 3-dihydro-1H indol-6-yl] -5, 5-dimethyl-1- quinolin-4-ylmethyl 20 imidazolidine-2,4-dione Yield: 50 mg M+H+ measured = 528 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.69 (t, 1H); 7.60 (d, 25 1H); 7.39 (d, 1H); 7.12 (dd, 1H); 5.15 (s, 2H); 4.05 (s, 2H); 3.36 .(s, 2H); 2.60 (q, 4H); 1.44 (s, 6H); 1.33 (s, 6H); 1.01 (t, 6H) Example 211 30 3- [3, 3-Dimethyl-1- (2-pyrrolidin-1-yl-acetyl) -2, 3-dihydro 1H-indol-6-yl]-5,5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2,4-dione Yield: 19.5 mg M+H+ measured = 526 .35 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.69 (t, 1H); 7.60 (d, WO 2006/010641 PCT/EP2005/008720 208 1H); 7.39 (d, 1H); 7.12 (dd, 1H); 5.15 (s, 2H); 3.98 (s, 2H) ; 3. 43 (s, 2H); 2. 60 (m, 4H); 1.72 (m, 4H); 1. 44 (s, 6H); 1.34 (S, 6H) 5 Example 212 (S) -3- (1-{2- [ (1-Ethyl-pyrrolidin-2-ylmethyl) -amino] acetyl}-3,3-dimethyl-2,3-dihydro-1H- indol-6-yl) -5,5 dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2, 4-dione The title compound was purified in addition by flash 10 chromatography on silica gel with a dichloro methane/methanol/water/triethylamine gradient. - The fractions containing the product were evaporated to yield a white solid. Yield: 30.5 mg 15 M+H+ measured = 583 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.13 (s, 1H); 8.08 (d, 1H); 7.82 (t, 1H); 7.69 (t, 1H).; 7.60 (d, 1H); 7.39 (d, 'lH); 7.13 (dd, 1H); 5.15 (s, 2H); 3.90 (s, 2H); 3.50 (q, 2H); 3.05 (m, 1H); 2.83 (m, 20 1H); 2.40 (m, 1H); 2.14 (m, 1H); 2.05 (m, 1H); 1.82 (m, 1H); 1.64 (m, 3H); 1.46 (s, 6H); 1.35 (s, 6H); 1.24 (m, 2H); 1.04 (t, 3H); 0.86 (m, 1H) Example 213 25 3-[l- (2-Cyclopropylamino-acetyl) -3,3-dimethyl-2,3 dihydro-lH-indol-6-yl] -5,5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2, 4-dione Yield: 46 mg M+H+ measured = 512 30 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, .lH); 8.25 (d, 1H); 8.13 (s, 1H); 8.09 (d, 1H); 7.82 (t, .1H); 7.69 (t, 1H); 7.60 (d, 1H); 7.39 (d, 1H); 7.13 (dd, 1H); 5.15 (s, 2H); 3.91 (s, 2H); 3.53 (s, 2H); 2.25 (m, 1H); 1.45 (s, 6H); 1.35 (s, 6H); 0.37 (m, 2H); 0.26 (m, 2H) 35 Example 214 WO 2006/010641 PCT/EP2005/008720 209 3- [1- (2-Cyclobutylamino-acetyl) -3, 3-dimethyl-2, 3-dihydro 1H-indol-6-yl] -5, 5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2, 4-dione Yield: 18.8 mg 5 M+H+ measured = 526 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m-, 2H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (s, 1H); 7.38 (d, 1H); 7.14. (d, 1H); 5.15 (s, 2H); 3.92 (s,, 2H); 3.44 (s, 2H); 3.25 (m, 1H); 2.08 (m, 2H); .1.72 (m, 10 2H); 1.64 (m, 1H); 1.55 (m, 1H); 1.43 (s, 6H); 1.34 (s, 6H) Example 215 3- [1- (2-Cyclohexylamino-acetyl) -3, 3-dimethyl-2, 3-dihydro 15 1H-indol-6-yl] -5,5-dimethyl-1- quinolin-4-ylmethyl imidazolidine-2 , 4-dione Yield: 50.8 mg M+H+ measured = 554 1H-NMR (500 MHz, DMSO/TMS)': d = -8.88 (d, 1H); 8.25 (d, 20 1H); 8.12 (s, 1H); 8.08 (d, 1H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (s, 1H); 7.38 (d, 1H); 7.12 (d, 1H); 5.14 (s, 2H); 3.92 (s, 2H); 3.50 (s, 2H); 2.37 (m, 1H); 1.83 (m, 2H); 1.68 (m, 2H); 1.55 (m, 1H); 1.43 (s, 6H); 1.34 (s, 6H); 1.19 (m, 4H); 1.05 (m, 2H) 25 Example 216 (R) -3-{1- [2- ( 3 -Dimethylamino-pyrrolidin-1-yl) -acetyl] 3, 3-dimethyl-2, 3-dihydro-1H-indol-6- yl} -5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine-2, 4-dione 30 The title compound was purified in addition by flash chromatography on silica- gel with a dichloro methane/methanol/water/triethylamine gradient. The fractions containing the product were combined and evaporated to yield a white solid. 35 Yield: 33.7 mg M+H+ measured = 569 WO 2006/010641 PCT/EP2005/008720 210 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.39 (d, 1H); 7.12 (dd, 1H); 5.14 (s, 2H); 3.97 (s, 2H); 3.35-3.30 (s, 2H); 2.73 (m, 3H); 2.60 (m, 1H); 2.10 5 (s, 6H); 1.84 (m, 1H); 1.60 (m, 1H); 1.43 (s, 6H); 1.32 (s, 6H); 0.85 (m, 1H) Example 217 3-{1-[2- (4-Isopropyl-piperazin-1-yl) -acetyl] -3,3 10 dimethyl-2, 3-dihydro-1H-indol-6-yl}- 5 ,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione Yield: 40.4 mg M+H+ measured = 583 1H-NMR (500 MHz, DMSO/TMS) : d = 8.88 (d, 1H); 8.25 (d, 15 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.39 (d, 1H); 7.12 (dd, 1H); 5.14 (s, 2H); 4.03 (s, 2H); 3.25 (s, 2H); 2.60-2.40 (m, 9H); 1.43 (s, 6H); 1.32 (s, 6H); 0.95 (d, 6H) 20 Example 218 3-{3,3-Dimethyl-1- [2- (4-methyl- [1,4]diazepan-1-yl) acetyl] -2,3-dihydro-1H-indol-6-yl}- 5,5-dimethyl-1 quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione The title compound was purified in addition by flash 25 chromatography on silica gel with a dichloro methane/methanol/water/triethylamine gradient. The fractions containing the product were combined and evaporated to yield a white solid. Yield: 16.5 mg 30 M+H+ measured = 569 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.39 (di, 1H); 7.12 (d, 1H); 5.14 (s, 2H); 4.02 (s, 2H); 3.45 (s, 2H); 2.78 (m, 4H); 2.24 (s, 3H); 1.75 (m, 35 2H); 1.45 (s, 6H); 1.30 (m, 10H) WO 2006/010641 PCT/EP2005/008720 211I Example 219 3-{1- [2- (3-Dimethylamino-2, 2-dimethyl-propylamino) acetyl] -3,3-dimethyl-2,3-dihydro-1H- indol-6-yl}-5,5 dimethyl-1-quinolin-4-ylmethyl-imidazolidine- 2 , 4-dione 5 The title compound was purified in addition by flash chromatography on silica gel with a dichloro methane/methanol/water/triethylamine gradient.. The fractions containing the product were combined and evaporated to yield a white solid. 10 Yield: 30.8 mg M+H+ measured = 585 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 1H); 8.12 (s, 1H); 8.08 (d, 1H); 7.80 (t, 1H); 7.70 (t, 1H); 7.60 (d, 1H); 7.4.0 (d, 1H); 7.12 (d, 1H); 5.14 (s, 15 2H); 3.92 (~s,' 2H); 3.48 (s, 2H); 2.39 (d, 2H); 2.21 (s, 6H); 2.12 (s, 2H); 1.89 (m, 1H); 1.43 (s, 6H); 1.33 (s, 6H); 0.85 (s, 6H) Example 220 20 (R) -3- (1-{2- [ (1-Ethyl-pyrrolidin-2-ylmethyl) -amino] acetyl}-3,3-dimethyl-2,3-dihydro-1H- indol-6-yl) -5,5 dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2, 4-dione The title compound was purified in addition by flash chromatography on silica gel with a dichloro 25 methane/methanol/water/triethylamine gradient.. The fractions containing the product were combined and evaporated to yield a white solid. Yield: 9 mg M+H+ measured = 583 30 1H-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, IH); 8.25 (d, 1H); 8.13 (s, 1H); 8.08 (d, 1H); 7.82 (t, 1H); 7.69 (t, 1H); 7.60 (d, 1H); 7.39 (d, IH); 7.13 (dd, 1H); 5.15 (s, 2H); 3.90 (s, 2H); 3.50 (q, 2H); 3.05 (m, 1H); 2.83 (m, 1H); 2.40 (m ,1H); 2.14 (m, iH); 2.05 (m, 1H); 1.82 (m, 35 1H) ; 1.64 (m, 3H); 1.46 (s, 6H); 1.35 (s, 6H); 1.24 (m, 2H); 1.04 (t, 3H); 0.86 (m, 1H) WO 2006/010641 PCT/EP2005/008720 212 Example 221 3-{1- [2- (4 ,4-Difluoro-piperidin-1-yl) -acetyl].-3,3 dimethyl-2,3-dihydro-lH-indol-6-yl}- 5,5-dimethyl-1 5 quinolin-4-ylmethyl-imidazolidine-2, 4-dione The following compound was prepared in analogy to example A003440050 by using 4,4-difluoro-piperidine instead of 2,6 dimethylpiperazine. The reaction mixture was stirred for 15 minutes at 100-C 10 by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). Yield: 55 mg M+H+ measured = 576 1He-NMR (500 MHz, DMSO/TMS): d = 8.88 (d, 1H); 8.25 (d, 15 1H); 8.08 (m, 2H); 7.82 (t, 1H); 7.69 (t, 1H); 7.60 (d, 1H); 7.39 (d, 1H); 7.13 (dd, 1H); 5.15 (s, 2H); 3.98 (s, 2H); 3.44 (s, 2H); 2.72 (m, 4H); 1.97 (m, 4H); 1.45 (s, 6H); 1.35 (s, 6H) Example 222: PHARMACEUTICAL COMPOSITION 20 Tablets corresponding to the following formula were prepared: Product of Example 9 ...... .................... 0.2 g Excipient for a finished tablet weighing...... 1 g (details of the excipient: lactose, talc, starch, 25 magnesium stearate). Example 223: PHARMACEUTICAL COMPOSITION Tablets corresponding to the following formula were prepared: Product of Example 32.......................... 0.2 g 30 Excipient for a finished tablet weighing ..... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate). . The examples of pharmaceutical compositions 222 and 223 above illustrate the present invention, it being WO 2006/010641 PCT/EP2005/008720 213 understood that the same preparations may be made with other preferred products of the present invention and form part of the present invention.

权利要求:
Claims (1)
[1] 10-membered heterocycle optionally containing one or more. hetero atoms, which may be identical or different, chosen from 0,- S, N and NR12 and optionally substituted with one or more substituents, which may be identical or 10 different, chosen from the values of R7; R15 and R16, which may be identical to or different from each other and also which may be identical to or different from R13, are chosen from the same values as R13 and may optionally form, with the nitrogen atom to 15 which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the 20 values of R7; R17 represents a hydrogen atom, alkyl or cycloalkyl; R18, which may be identical to or different from R6, represents the same values as R6; R19 and R20, which may be identical to or different from 25 each other and also which may be identical to or different from R6, are chosen from the same values as R6. and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may WO 2006/010641 PCT/EP2005/008720 221 be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 5 R21, which may be identical to or different from _R13, represents the same values as R13 and also represents hydrogen; R22 and R23, which may be identical to or different from each other and also which may be identical to or 10 different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached-, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 15 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R24 and R25, which may be identical or different, represent a hydrogen atom or an alkyl, alkenyl or alkynyl 20 radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals, or alternatively R24 and R25 may optionally form, with the nitrogen atom to which they are attached, a 4- to . 7 25 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, N-alkyl and N-C(O)alkyl, and optionally substituted with one or more -substituents, which may be identical or different, chosen from halogen atoms and OH, 30 alkyl, alkoxy and oxo radicals; WO 2006/010641 PCT/EP2005/008720 222 R26 represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; 5 R27, which may be identical to or different from -R26, represents the same values as R26; R26 and R27 may also optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero 10 atoms, which may be identical or different, chosen from 0, S, N , N-alkyl and -N-C(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; 15 R28, which may be identical to or different from R26, represents the same values as R26; R29, which may be identical to or different from R26, represents the same values as R26; R30, which may be identical to or different from R26, 20 represents the same values as R26; n represents the integers 0, 1 and 2; the said products of formula (I) being in any possible racemic, enantiomeric and diastereoisomeric isomer form, and also the addition salts with mineral' acids and 25 organic acids or with mineral bases and organic bases of the said products of formula (I). 2)Products of formula (I) as defined in claim 1 in which WO 2006/010641 PCT/EP2005/008720 223 p represents the integers-0, 1 and 2, A represents aryl, heteroaryl or a monocyclic or bicyclic fused carbocyclic or heterocyclic 5- to 11-membered radical, all these radicals optionally being substituted 5 with one- or more. substituents, which may be identical or different,.chosen from the values of R3; X represents a -single bond or the following divalent radicals: -N(R6)-; -0-; -C(O)-; -S(O)n-; -N(R6)-C(O)-; -N(R6)-C'(0)-N(R6')-; -N(R6)-C(S)-N(R6')-; -N(R6)-C(O)0-; 10 -N(R6)-SO2-; -N(R6)-SO2-N~(R6')-; -C(O)-N(R6)-; -S02-NR6-; and -C.(O)0-; Ll representsthe following divalent radicals: alkylene, alkenylene, alkynylene and cycloalkylene, all optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R7; phenylene -and heteroarylene, these last two radicals optionally substituted with one or more substituents chosen from the values of R8; The radical NR1R2 is such that: 20 either Rl and R2, which may be identical' or different, are such that: Rl represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl, all optionally substituted with one or more substituents, which may be identical or different, 25 chosen from the values of R7; aryl, heteroaryl, arylalkyl and heteroarylalkyl in which each of the aromatic rings may optionally be substituted with one or more substituents, which may be identical or different, chosen from the values of R8; -S02R9; -C(0)R9; -C(O)OR9; 30 -C(0)NR1OR11, -C(S)NR1OR11 and -SO2NR1OR11; WO 2006/010641 PCT/EP2005/008720 224 and R2 represents a hydrogen atom; alkyl, alkenyl, alkynyl and cycloalkyl, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 5 or R1 and R2 form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, NR12 and S, and optionally substituted with one or more 10 substituents, which may be identical or different, chosen from the values of R7; or NRl with Li or NR2 with L, together form a 4- to 8 membered heterocycle - optionally containing one or more other hetero atoms, which may be identical or different, 15 chosen from 0, N, NR12 and S, and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R3 represents a hydrogen atom; a halogen atom; hydroxyl; alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy and 20 alkylenedioxy, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; -NR13Rl4; -C(O)R13; -S(O)nR13; -C(O)OR13; -C(O)NR15R16; -S(O)nNR15Rl6; SF5; nitro; cyano; 4- to 7-membered heterocycloalkyl 25 optionally substituted with one or more radicals, which may be identical or different, chosen from halogen- atoms and alkyl, alkoxy or oxo radicals; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or 30 different, chosen from the values of R8; WO 2006/010641 PCT/EP2005/008720 225 being noted that when A represents a mono or bicyclic fused ll-membered radical, R3 represents in more oxo, R4, R4', R4'' and R4''', which may be identical or different, are chosen from the values defined below for 5 R4; R4 represents a hydrogen atom; a halogen atom; an alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; 10 aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8; oxo; it being understood that two substituents from among R4, R4' and R4'' may form, with the carbon atom(s) to 15 which they are attached, a 3- to 10-membered ring optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12; L2 is chosen from a single bond; an alkylene; alkenylene; alkynylene; cycloalkylene; -0-; -NR17-; -C(O)- and S02 20 radical; Y represents a saturated, partially saturated or unsaturated N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted 25 with one or more substituents, which may be identical or different, chosen from the values of R5; R5 represents a hydrogen atom; a halogen atom; an alkyl, alkenyl, alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be 30 identical or different, chosen from the values of R7; WO 2006/010641 PCT/EP2005/008720 226 aryl, arylalkyl, heteroaryl and heteroarylalkyl, in which the aromatic rings are optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8; -OR18; -NR19R20; 5 NR19COR20; -NR19CONR19'R20; -NR19-S(0)2-R20; -NR19-S(0)2 NR19'R20; -COR18; COOR21; -CONR22R23; -S(O)nRl8; S02NR22R23; cyano; nitro; R6 is such that: either R6 represents a hydrogen atom; an alkyl, alkenyl, 10 alkynyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; aryl and heteroaryl, these last two. radicals optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R8; or R6 with NRlR2 together form a 4- to 8-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or 20 more substituents, which may be identical or different, chosen from the values of R7; or R6 with L1 together form a 4- to 8-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen, from 25 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R6', which may be identical to or different from R6, is chosen from the values of R6; WO 2006/010641 PCT/EP2005/008720 227 R7 represents a halogen atom; alkyl; cycloalkyle; cycloalkylalkyle; hydroxyl; alkoxy; cycloalkoxy; cyano; CF3; -N24R25; -NR26COR27; -NR26CONR26'R27; -NR26-S(O)2 R27; -NR26-S(0)2-NR26'R27; -COOR26; -COR26; -CO(NR24R25); 5 S(O)nR26; -S(O)2NR24R25; 4- to 7-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from OH and NH2 radicals, halogen atoms, and alkyl, alkoxy or oxo radicals; aryl optionally substituted with one or more 10 substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; heteroaryl, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and NH2, alkyl and alkoxy radicals; 15 phenoxy, optionally substituted with one. or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R8, which may be identical to or different from R7, represents the same values as R7 and in addition 20 represents halogen atoms; nitro; -OCF3; alkylenedioxy; difluoromethylenedioxy; benzyl optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; 25 R9, which' may be identical to or different from R6, represents the same values as R6; R10 and R11, which may be identical to or different from each other and also which may be identical to or -different from R6, are chosen from the same values as R6 30 and may optionally form, with the nitrogen atom to -which WO 2006/010641 PCT/EP2005/008720 228 they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, 5 which may be identical or different, chosen from the values of R7; R12 represents a hydrogen atom; an alkyl, alkenyl, alkynyl, cycloalkyl, alkylCO or alkylSO 2 radical, all optionally substituted with one or more substituents, 10 which may be identical or different, chosen from halogen atoms, OH, alkoxy and dialkylamino radicals; aryl and heteroaryl, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and 15 alkyl and alkoxy radicals; R13, which may be identical to or different from R6, represents the same values as R6; R14, which may be identical to or different from R13, represents the same values as R13 and also represents 20 C(O)R28; C(O)N28R29; S02R28 and S02NR28R29; R13 and R14 may optionally form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen 25 from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R15 and R16, which may be identical to or different from each other and also which may be identical to or WO 2006/010641 PCT/EP2005/008720 229 different from R13, are chosen from the same values as R13 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may 5 be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7; R17 represents a hydrogen atom, alkyl or cycloalkyl; 10 R18, which may be identical to or different from R6, represents the same values as R6; R19 and R20, which may be identical to or different from each other and also which may be identical to or different from R6, are chosen from the same values as R6 15 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, 20 which may be identical or different, chosen from the values'-of R7; R21, which may be identical -to or different from R13, represents the same values as R13 and also represents hydrogen; 25 R22 and R23, which may be identical to or different from each other and also which may be identical to or different from R6, are chosen from the same values as R6 and may optionally form, with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle WO 2006/010641 PCT/EP2005/008720 230 optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR12 and optionally substituted with one or more substituents, which may be identical or different, chosen from the 5 values of R7; R24 and R25, which may be identical or different, represent an alkyl, alkenyl or alkynyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH 10 and alkoxy radicals, or alternatively R24 and R25 may optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, N-alkyl and 15 N-C(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; R26 represents a hydrogen atom or an alkyl, alkenyl or 20 alkynyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; R27, which may be identical to or different from R26, represents the same values as R26; 25 R26 and R27 may also optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N , N-alkyl and N-C(O)alkyl, and optionally 30 substituted with one or more substituents, which may be WO 2006/010641 PCT/EP2005/008720 231 identical or different, chosen from halogen atoms and OH, alkyl, alkoxy and oxo radicals; R28, which may be identical to or different from R26., represents the same values as R26; 5 R29, which may be identical to or different from R26, represents the same values as R26; R30, which may be identical to or different from R26, represents the same values as R26; n represents the integers 0, 1 and 2; 10 the said products of formula (I) - being in any possible racemic, enantiomeric and diastereoisomeric isomer form, and also the addition salts with mineral acids and organic acids or with mineral bases and organic bases of the said products of formula (I). 15 3) Products of formula (I) as defined in any one of the other claims corresponding to formula (Ia): R a II L a R 2 a R 3 as .Xa Aa 0 O N O [CR 4 a"R 4 a"')p N( R2a R 4 a R 4 a' Yas Rea in which: p represents the integers 0, 1 and 2, 20 Aa represents phenyl, heteroaryl and a monocyclic or bicyclic fused carbocyclic or heterocyclic 5- to 11- WO 2006/010641 PCT/EP2005/008720 232 membered radical, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R3a; Xa represents a single bond or the following divalent 5 radicals: -N(R6a)-; -0-; -C(O)-; -S(0)n-; -N(R6a) C(0)-; -N(R6a)-C(0)-N(R6'a)-; -N(R6a)-SO2-; -C(0) N(R6a)-; -S02-NR6a-; Lla represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or more 10 substituents chosen from the values of R7a; the 'radical NRlaR2a is such that: either Rla and R2a, which may be identical or different, are such that: Rla represents a hydrogen atom; alkyl and cycloalkyl, 15 these last two radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; aryl, heteroaryl, arylalkyl and heteroarylalkyl in which each of the aromatic rings may be optionally substituted with 20 one or more substituents, which may be identical or different, chosen from the values of R8a; and R2a represents a hydrogen atom, alkyl and cycloalkyl, these last two radicals being optionally substituted with one or more substituents, which may be identical or 25 different, chosen from the values of R7a ; or Ria and R2a form, together with the nitrogen atom' to which they are attached, a 4- to 10-membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, WO 2006/010641 PCT/EP2005/008720 233 NR12a and S and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; or NRla with Lla or NR2a with Lla together form a 4- to 5 8-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R3a represents a hydrogen atom, a halogen atom; an alkyl, cycloalkyl, alkoxy or alkylenedioxy radical, all 10 optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; -NR13aRl4a; -C(O)Rl3a; -S (0),Rl3a; -C (0) NR15aRl6a; -S (0),NR15aR16a; aryl and heteroaryl, these last two radicals being optionally substituted with 15 one or more substituents,. which may be identical or different, chosen from the values of R8a; R4a, R4a', R4a'' and R4a''', which may be identical or different, are chosen from the values defined below for R4a; 20 R4a represents a hydrogen atom, a halogen atom (F), an alkyl or cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; it being understood that two substituents from among R4a, R4a' and 25 R4a'' may form, with the carbon atom(s) to which they are attached, a 3- to 7-membered ring optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and N-alkyl; L2a is chosen from a single bond; alkylene; WO 2006/010641 PCT/EP2005/008720 234 cycloalkylene; -0- and -NR17a-; Ya represents an N-heterocycle optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S and N and optionally 5 substituted with one or more substituents, which may be identical or different, chosen from the values of R5a; R5a represents a hydrogen atom, a halogen atom, an alkyl or cycloalkyl radical, optionally substituted with one or more substituents, which may be identical or different, 10 chosen from the values of R7a; aryl, arylalkyl, heteroaryl and heteroarylalkyl, in which the aromatic rings are optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8a; -OR18a; -NR19aR20a; -NR19aCOR20a; 15 -NR19aCONR19'aR20a; -NR19a-S(0)2-R20a; -NR19a-S(O)2 NR19a'R20a; -COR18a; COOR21a; -CONR22aR23a; -S(O)nRl8a; SO2NR22aR23a; cyano; R6a is such that: either R6a represents a hydrogen atom or an alkyl or 20 cycloalkyl radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; or R6a with NRlaR2a together form a 5- to 7-membered heterocycle optionally substituted with one or more 25 substituents, which may be identical or different, chosen from the values of R7a; or R6a with Lla together form a 5- to 7-membered heterocycle optionally substituted with one or more WO 2006/010641 PCT/EP2005/008720 235 substituents, which may be identical or different, chosen from the values of R7a; R6a', which may be identical to or different from R6a, is chosen from the values of R6a, 5 R7a represents a halogen atom (F); an alkyl; hydroxyl (OH); alkoxy; cycloalkoxy; cyano radical; -CF3; -N24aR25a; -NR26aCOR27a; -NR26aCONR26a'R27a; -NR26a S(0)2-R27a; -NR26a-S(0)2-NR26a'R27a; -COOR26a; -COR26a; -CO(NR24aR25a); S(O)nR26a; -S(0)2NR24aR25a; a 4- to 7 10 membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from OH and NH2 radicals, halogen atoms (F), and alkyl, alkoxy or oxo radicals; aryl optionally substituted with one or more substituents, which may be 15 identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; heteroaryl, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and NH2, alkyl and alkoxy radicals; phenoxy, optionally 20 substituted with one or more substituents, which may -be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R8a, which may be identical to or different from R7a, represents the same values as R7a and also represents 25 halogen atoms (Cl, Br or I) and -OCF3, alkylenedioxy and difluoromethylenedioxy radicals; R12a represents a hydrogen atom or an alkyl, cycloalkyl, alkylCO or alkylSO 2 radical, all optionally substituted with one or more substituents, which may be identical or WO 2006/010641 PCT/EP2005/008720 236 different, chosen from' halogen atoms (F) and alkoxy radicals; R13a represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be 5 identical or different, chosen from the values of R7a; a phenyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and alkyl and alkoxy radicals; a. 5- or 6-membered heteroaryl radical optionally 10 substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and alkyl and alkoxy radicals; R14a represents an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R7a; C(0)R28a; R13a and R14a may optionally form, together with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more 20 hetero atoms, which may be identical or different, chosen from 0, S, N and Nalkyl and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R15a and R16a, which may be identical to or different 25 from each other and also identical to or different from R13a, are chosen from the same values as R13a and may optionally form, with the nitrogen atom to which they .are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atdms which may be 30 identical or different, chosen from 0, S, N and NR12A and WO 2006/010641 PCT/EP2005/008720 237 optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R17a represents a hydrogen atom or an alkyl or cycloalkyl 5 radical; R18a, which may be identical to or different from R6, represents the same values as R6; R19a represents a hydrogen atom or an alkyl or cycloalkyl radical; 10 R20a represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; aryl and heteroaryl, optionally substituted with one or more substituents, which may be 15 identical or different, chosen from the values of R8a;. R19a and R20a, which may be identical to or different from each other, may also form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more hetero atoms, which may 20 be identical or different, chosen from 0, S, N and NR12a and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R21a, which may be identical to or different from R13a, 25 is chosen from the values of R13a and also represents a hydrogen atom; R22a and R23a, which may be identical to or different from each other and identical to or different from R6a, WO 2006/010641 PCT/EP2005/008720 238 are chosen from the values of R6a and may also form, with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more hetero atoms, which may be identical or different,.chosen 5 from 0, S, N and NR12a and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7a; R24a and R25a, which may be identical or different, represent an alkyl radical optionally substituted with 10 one or more substituents, which may be identical or different, chosen from halogen atoms (F) and OH and alkoxy radicals, or alternatively R24a and R25a may optionally form, with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally 15 containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N , N-alkyl and N-C-(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and OH, alkyl, alkoxy or oxo 20 radicals; R26a represents a hydrogen atom or an alkyl radical optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and OH and alkoxy radicals; 25 R27a, which may be identical to or different from R26a, is chosen from the values of R26a; R26a and R27a, may also optionally form, with the nitrogen atom to which they are attached, a 4- to 7 membered heterocycle optionally containing one or more 30 hetero atoms, which may be identical or different, chosen WO 2006/010641 PCT/EP2005/008720 239 from 0, S, N, N-alkyl and N-C(O)alkyl, and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (F) and OH, alkyl, alkoxy or oxo radicals; 5 R28a, which may be identical to or different from R26a, is chosen from the values of R26a; R29a, which may be identical to or different from R26a, is chosen from the values of R26a; R30a, which may be identical to or different from R26a, 10 is chosen from the values of R26a; n represents the integers 0., 1 and 2; p represents the integers 0, 1 and 2; the said products of formula (Ia) being in all the possible racemic, enantiomeric and diastereoisomeric 15 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ia). 4) Products of formula (I) as defined in any one of the other claims such that p represents the integer 0, the 20 other substituents of the said products of formula (I) having any of the values defined in any one of the other claims. 5) Products of formula (I) as defined in any one of the other claims such that p represents the integer 1, the 25 other substituents of the said products of formula (I) having any of the values defined in any one of the other claims. 6) Products of formula (I) as defined in any one of the WO 2006/010641 PCT/EP2005/008720 240 other claims such that p represents the integer 2, the other substituents of the said products of formula (I) having any of the values defined in any one of the other claims. 5 7) Products of formula (I) or (Ia) according to the preceding claims, corresponding to formula (Ib): Rib N L 1 b 'R 2 b R 3 bN -Xb Ab 0 N 0 R 4 b N'L b (Ib) R 4 'b 12 Ybs in which Ab represents phenyl, heteroaryl or a carbocyclic or heterocyclic 7- to 11-membered cyclic 10 radical, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R3b; Xb represents a single bond or the following divalent radicals: -N(R6b)-; -0-; -C(O)-; -S(0)n-; -N(R6b)-C(0) 15 and -N(R6b)-S02-; Llb represents an alkylene radical containing 1 to 4 carbon atoms and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and OH and alkoxy radicals; 20 the radical NRlbR2b is such that: either Rlb and R2b, which may be identical or different, are such that: WO 2006/010641 PCT/EP2005/008720 241 Rlb represents a hydrogen atom or an alkyl or cycloalkyl radical, these last two radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; 5 aryl and heteroaryl, both optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R8b; and R2b represents a hydrogen atom or an alkyl or cycloalkyl radical, these last two radicals being 10 optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; or Rlb and R2b form, together with the nitrogen atom to which they are attached, a 4- to 10-membered heterocycle 15 optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; 20 or NRlb with LIb or NR2b with Llb together form a 4- to 8-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R7b; R3b represents a hydrogen atom, an alkyl, alkoxy (-OCH3) 25 or cycloalkyl radical, optionally substituted with one or more -substituents, which may be identical or different, chosen from F; OCF3; S(O)n-alkyl radicals, the alkyl residue containing 1 to 4 carbon atoms and being optionally substituted with one or more F; alkylamino, 30 optionally substituted with one or more F; dialkylamino, in which the two alkyl residues may optionally form, with WO 2006/010641 PCT/EP2005/008720 242 the nitrogen atom to which they are attached, a 4- to 10 membered heterocyclic radical. optionally containing one or morse other hetero atoms, which may be identical or different, chosen from 0, N., N-alkyl and S and optionally 5 substituted with one or more substituents, which may be identical or different, chosen from F and alkyl and alkoxy radicals; R4b and R4'b, which may be identical or different, represent a -hydrogen atom, a -halogen atom F and an alkyl 10 or cycloalkyl radical, optionally substituted with one or more F; it being understood that two substituents R4b may form, with the carbon atom to which they are attached, a 3- to 5-membered spirocyclic ring; L2b is chosen from a single bond and methylene; 15 Yb represents a monocyclic or bicyclic heteroaryl radical chosen from pyridyl, pyrimidinyl, pyridazine, pyrazine, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, 1H-pyrrolo[2,3-blpyridyl, furazanyl, 20 morpholinyl, pyrrolidinyl, 3H-imidazo- (4, 5b) -pyridine, 1H-pyrazolo-(3,4b)-pyridine, 1H-pyrazolo- (3,4d) pyrimidine, piperidyl, thienyl, indolyl, pyrrolyl, purinyl, benzoxazinyl, benzimidazolyl, these radicals being optionally substituted with one or more radicals 25 chosen from the values of R5b; R5b represents a hydrogen atom; a halogen atom; alkyl; cycloalkyl; -NHR20b; -. NHCOR20b; -NHCONR19bR20b; -NH-S (0) 2-R20b; R6b represents a hydrogen atom or an alkyl radical 30 containing from .1 to 4 carbon atoms; R6b and -NRlbR2b may optionally together form a 5- to 7 membered heterocycle optionally substituted with one or WO 2006/010641 PCT/EP2005/008720 243 more radicals, which may be identical or different, chosen from the values of R7b; R7b represents - a halogen atom ; hydroxyl; cyano; COOH; CF3; alkyl, alkoxy, alkylamino, dialkylamino, -NHCO 5 alkyl, -CO (NH-alkyl) and CO (Ndialkyl) in which the alkyl residues are optionally substituted with one or more substituents, which may be. identical or different, chosen from halogen atoms, OH and methoxy; an aryl radical optionally substituted with one or more substituents, 10 which may be identical or different, chosen -from halogen atoms and alkyl and alkoxy radicals; a 4- to 7-membered heterocycle; heteroaryl, optionally substituted with one or more substituents, which may be identical or different, chosen. from halogen atoms and NH2, alkyl and 15 alkoxy radicals; R8b, which may be identical to or different from R7b, is chosen from the values of R7b and in addition represents halogen atoms and -OCF3, alkylenedioxy and difluoromethylenedioxy radicals; 20 R19b represents a hydrogen atom or an alkyl or cycloalkyl radical; R20b represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or . more substituents, which may be identical or different, chosen 25 from the values of R7b; aryl and heteroaryl, optionally substituted with one or more substituents, which may be identical- or different, chosen from the values of R8b; R19b and R20b, which may be identical to or different from each other, may also form, with the nitrogen atom to WO 2006/010641 PCT/EP2005/008720 244 which they are attached, a 4- to 7-membered heterocycle. optionally containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and Nalkyl and optionally substituted with one or more substituents, 5 which may be identical or different, chosen from the values of R7b; .n represents the integers 0, 1 and 2; the said products of formula (Ib) being in all the possible racemic, enantiomeric and diastereoisomeric 10 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ib). 8) Products of formula (I), (Ia) or (Ib) according to the preceding claims, corresponding to formula (Ic): Rc LIc R 2 c RscN -Xc Ac O N O R 4 c o N (c R 4 'c 1 YcN 15 R5c in which A represents a phenyl, a 5 to 6-membered heteroaryl or a condensed heterocyclic ring system selected from the list: 1,2,3,4-tetrahydro-quinolin, 1,2,3,4-tetrahydro 20 isoquinolin, indolyl, 2,3-dihydro-1H-indolyl, 2,3 dihydro-1H-isoindolyl, 2,3-dihydro-benzothiazole, tetrahydroquinoline or tetrahydroisoquinoline, WO 2006/010641 PCT/EP2005/008720 245 all these radicals being optionally substituted with one or more substituents, which may be identical or different, chosen from alkyl, alkoxy, cycloalkyl, alkylamino and dialkylamino radicals, each alkyl radical 5 being optionally substituted with one or more substituents, which may be identical or different, chosen from F, -OCF3, SCF3 and SO2CF3 radicals; Xc represents a single bond or the following divalent radicals: -N(R6c)-; -0-; -C(O)-; and -N(R6c)-C(0)-; 10 Llc represents an alkylene radical containing 1 to 4 carbon atoms, optionally substituted with a hydroxyl radical; either Rlc and R2c, which may be identical or different, are such that: 15 Rlc represents an alkyl or cycloalkyl radical, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms; hydroxyl; alkoxy; cyano, free or esterified carboxyl, phenyl, 3- to 7-membered cycloalkyl, alkylamino, 20 dialkylamino, -NHCO-alkyl, -CO(NH-alkyl), CO(Ndialkyl) and saturated, partially saturated or unsaturated 5-, 6 or 7-membered heteroaryl radicals containing one or more hetero. atoms, which may be identical or different, chosen from 0, S, N, NH and N-alkyl and optionally substituted 25 with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl, NH2 and alkoxy radicals; or alternatively Rlc represents a phenyl radical or a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical,. itself 30 containing one or more hetero atoms chosen from 0, S, N, WO 2006/010641 PCT/EP2005/008720 246 NH and N-alkyl, and optionally substituted with one or more radicals chosen from halogen atoms and alkyl, NH2 and alkoxy radicals; and R2c represents a hydrogen atom or an alkyl or 5 cycloalkyl radical optionally substituted with one or more halogen atoms; or Rlc and R2c form, together with the nitrogen atom to which they are attached, a 4- to 7-membered heterocycle optionally containing one or more other hetero atoms, 10 which may be identical or different, chosen from 0, N, NH, N-alkyl and S and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, CF3 and free or esterified carboxyl radicals; 15 or NRlc with Llc or NR2c with LlC together form a 4- to 7-membered heterocycle optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms,- and 'alkyl, alkoxy and free or esterified carboxyl radicals; 20 L2c is chosen from a single bond and methylene; R4c and R4'c, which may be identical or different, represent a hydrogen atom, an alkyl or cycloalkyl radical optionally substituted with one or more halogen atoms; it being understood that two substituents R4c may form, with 25 the carbon atom to which they are attached, a 3-membered to 5-membered spirocyclic ring ; Yc represents a heteroaryl 'radical chosen from pyrid-4-. yl, pyrimidin-4-yl, quinolin-4-yl, isoquinolin-5-yl; azaindol-4-yl and quinazolin-4-yl, these radicals being WO 2006/010641 PCT/EP2005/008720 247 optionally substituted with one or more substituents, which may be identical or different, chosen from the values of R5c; R5c represents a hydrogen atom, ,a halogen atom; an alkyl, 5 cycloalkyl, NH2, -NH-cycloalkyl, -NHCO-alkyl, -NHCO cycloalkyl, -NHCONH-alkyl or -NHCON(dialkyl) radical, the alkyl and cycloalkyl residues being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms (F) and 10 alkoxy, morpholinyl, piperidyl, piperazinyl, N-methyl piperazinyl and COOH radicals; NH-aryl, NH-heteroaryl, -NHCO-aryl and -NHCO-heteroaryl in which the aromatic residues are optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and 15 COOH radicals; R6c represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms; R6c and NRlcR2c may optionally together form a 5- to 7 membered heterocycle optionally substituted with one or 20 more radicals, which may be identical or different, chosen from halogen atoms (F) and alkyl and alkoxy radicals, the said products of formula (Ic) being in all the possible racemic, enantiomeric and diastereoisomeric 25 isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ic). 9) Products of formula (I) according to the preceding 30 claims in which WO 2006/010641 PCT/EP2005/008720 248 A represents a phenyl, 2,3-dihydro-lH-indolyl, or indolyl radical optionally substituted with one or more radicals chosen from the values of R3, X represents a single bond, -NH-alk-, alkylene, -0-, 5 Nalk-CO-, -NH-CO, -NH-CO-alk-, -NH-CO-NH-, -CO-NH-, -S02,-NR6d or -CO-, Ll represents a single bond, an alkylene radical containing 1 to 5 carbon atoms optionally substituted with a hydroxyl radical, an cycloalkylalkyl radical, a 10 phenyl radical, Rl and R2, which may be identical or different, are such that: either RI represents a hydrogen atom, an alkyl radical optionally substituted with one or more radicals chosen 15 from halogen atoms and hydroxyl, alkoxy, NH2, NH.(alk) , N(alk)2, cyano, free or esterified carboxyl, phenyl and 3- to 7-membered cycloalkyl radicals and a saturated, partially saturated. or unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with 20 one or ..more alkyl radicals and containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH and N-alkyl, or R1 represents a 3- to 7-membered cycloalkyl radical, a phenyl radical or a saturated, partially saturated or 25 unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with one or more alkyl radicals and containing one or more hetero atoms chosen from 0, S, N, NH and N-alkyl, and R2 represents a hydrogen atom or an alkyl radical, WO 2006/010641 PCT/EP2005/008720 249 or R1 and R2 form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4- to 7-membered heterocyclic radical optionally containing one or more other hetero atoms chosen from-0, S, N, NH and N-alkyl, 5 this radical formed by R1 and R2 with N being itself optionally substituted with one or more radicals chosen from alkyl, halogen, NH2, NH(alk), N(alk)2, CF3 and free or esterified carboxyl radicals, all the above alkyl and alkoxy radicals being linear or 10 branched and containing up to 6 carbon atoms, or NRiR2 forms with Li a saturated or unsaturated 4- to 10-membered heterocycle containing at least one nitrogen atom andoptionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, this radical 15 formed by NR1R2 with Li being itself optionally substituted with one or more radicals chosen from alkyl, cycloalkyl and free or esterified carboxyl radicals, R3 represents one or more substituents of the ring A, which may be identical or different, chosen from a 20 hydrogen atom and an alkyl or alkoxy radical containing up to 4 carbon atoms, optionally substituted with one or more F; alkyl-S(O)n optionally substituted by F; OCF3;SO2CF2; or SCF3; with n representing 0 or 2; R4 and R4', which may be identical or different, are 25 chosen from a hydrogen atom and an alkyl radical containing up to 4 carbon atoms, R6 represents a hydrogen atom, an acyl radical optionally substituted with one or more F or an alkyl radical containing from 1 to 4 carbon atoms, WO 2006/010641 PCT/EP2005/008720 250 L2 represents an alkylene radical, Y2 represents a quinolyl, pyridyl or pyrimidinyl radical, optionally substituted by NIH2; the said products of formula (I) being in all the 5 possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 10) Products of formula (I) according to the preceding 10 claims, corresponding to formula (Id): /Rd N Lid R 2 d R 3 d AdXd o N 0 R 4 d N-L d R 4 1 d 12 Yd,, R 5 d in which Ad represents a phenyl or indolyl radical optionally substituted with one or more radicals chosen from the values of R3d, 15 Xd represents -0-, -NH-CO, -NR6 or -CO-, Lld represents an alkylene radical containing 1 to 3 carbon atoms optionally substituted with a hydroxyl radical, Rld and R2d, which may be identical or different, are 20 such that: WO 2006/010641 PCT/EP2005/008720 251 either Rld represents an alkyl radical optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, cyano, free or esterified carboxyl, phenyl and 3- to 7-membered cycloalkyl radicals 5 and a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with one or more alkyl radicals and containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N, NH and 10 N-alkyl, or R2d represents a 3- to 7-membered cycloalkyl radical, a phenyl radical or a saturated, partially saturated or unsaturated 4- to 7-membered heterocyclic radical, itself optionally substituted with one or more alkyl radicals 15 and containing one or more hetero atoms chosen from 0, S, N, NH and N-alkyl, and R2d represents a hydrogen atom or an alkyl radical, or Rld and R2d form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4- to 7-membered 20 heterocyclic radical optionally containing one or more other hetero atoms chosen from 0, S, N, NH and N-alkyl, this radical formed by RIa and R2d with N bein4 itself optionally substituted with one or more radicals chosen from alkyl, CF3 and free or esterified carboxyl radicals, 25 all the above alkyl and alkoxy radicals being linear or branched and containing up to 6 carbon atoms, or NRldR2d forms with Lld a saturated or unsaturated 4 to 8-membered heterocycle containing at least one nitrogen atom and optionally containing one or more other 30 hetero atoms chosen from 0, S, N, NH and N-alkyl, this WO 2006/010641 PCT/EP2005/008720 252 radical formed by NRldR2d with Lld being itself optionally substituted with one or more radicals chosen from alkyl and free or esterified carboxyl radicals, R3d represents one or more substituents of the ring Ad, 5 which may be identical or different, chosen from a hydrogen atom and an alkyl or alkoxy radical containing up to 4 carbon atoms, optionally substituted with one or more F; alkyl-S(O)n optionally substituted by F; OCF3;SO2CF2; or SCF3; with n representing 0 or 2; 10 R4d and R4'd, which may be identical or different, are chosen from 'a hydrogen atom and an alkyl radical containing up to 4 carbon atoms, L2d represents an alkylene radical, Y2d represents a quinolyl, pyridyl or pyrimidinyl 15 radical, the said products of formula (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition -salts with mineral and organic acids or with mineral and organic bases of 20 the said products of formula (Id). 11) Products of formula (I), (Ia), (Ib), (Ic) or (Id) as defined in any one of the preceding claims in which, when A represents a phenyl radical, then Xd represents -0-, NR6 or -NH-CO, the other substituents of the said 25 products of formula (I), (Ia), (Ib), (Ic) or (Id) having the meanings defined in any one of the preceding claims, the said products of formula (I), (Ia), (Ib), (Ic) or (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition 30 salts with mineral and organic acids or with mineral and WO 2006/010641 PCT/EP2005/008720 253 organic bases of the said products of formula (I), (Ia), (Ib), (Ic) or (Id). 12) Products of formula -(I) as defined in any one of Claims 1 to 11, the names of which are given hereinbelow: 5 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 morpholin-4-yl-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 10 (dimethyl-morpholin-4-yl)-acetamide trifluoroacetate 2-Cyclopentylamino-N-[ 5 -(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 15 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2- (2,2,2 trifluoro-ethylamino)-acetamide trifluoroacetate - 2-Diethylamino-N-['5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylrethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate 20 - -N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 thi6morpholin-4-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 25 pyrrolidin-1-yl-acetamids trifluoroacetate WO 2006/010641 PCT/EP2005/008720 254 - - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (4 methyl-piperazin-1-yl)-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 piperidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2 [(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 15 [(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2 hydroxy-ethylamino)-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 methoxy-ethylamino)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate 25 - 2-(Cyanomethyl-amino)-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 255 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate. - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 10 - N-[5-(.4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate - ({[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] 15 methyl}-amino)-acetic acid methyl ester; compound with trifluoro-acetic acid - 2 -( 2 ,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-acetamide; compound with 20 trifluoro-acetic acid - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4,4 dimethyl-piperidin-1-yl)-acetamide - N-[5-( 4 , 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(4 trifluoromethyl-piperidin-1-yl)-acetamide WO 2006/010641 PCT/EP2005/008720 256 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [1,4]oxazepan-4-yl-acetamide - 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyll methyl}-pyrrolidine-3-carboxylic acid methyl ester - 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyll-acetamide 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 fluoro-ethylamino)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2-[(2 15 methoxy-ethyl)-methyl-amino]-acetamide - ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyll-amino)-acetic acid trifluoroacetate 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 20 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 morpholin-4-yl-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 257 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 (dimethyl-morpholin-4-yl)-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(4 methyl-piperazin-1-yl)-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 piperidin-1-yl-propionamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-3 thiomorpholin-4-yl-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 15 pyrrolidin-1-yl-propionamide trifluoroacetate - 3-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl]-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3-(2,2,2 trifluoro-ethylamino)-propionamide; compound with trifluoro-acetic acid - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy 25 phenyll-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 258 - N-[5-( 4 , 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-morpholin-4-yl acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-isopropyl-phenyl]-2-piperidin-1-yl acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-(4-methyl piperazin-1-yl)-acetamide trifluoroacetate 10 - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] acetamide trifluoroacetate - 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] 15 acetamide trifluoroacetate - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)-2-isopropyl phenyl]-acetamide trifluoroacetate - 2 -Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 20 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2-isopropyl phenyl]-acetamide trifluoroacetate - 1-Methyl-piperidine-4-carboxylic acid [5-(4,4-dimethyl 2,5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-amide, trifluoro-acetate 25 - 3-[3-( 2 -Cyclopentylamino-ethoxy)-4-methoxy-phenyl]-5,5 dimethyl-l-quinolin-4-ylmethyl- imidazolidine-2,4-dione WO 2006/010641 PCT/EP2005/008720 259 - 3- (3-{2-[ (Furan-2-ylmethyl) -amino] -ethoxy}-4-methoxy -phenyl) -5, 5-dimethyl---quinolin-4- ylmethyl imidazolidine-2, 4-dione - 3-{3-[2-(2-flydroxy-l-phenyl-ethylamino) -ethoxy] -4 5 methoxy-phenyl}-5, 5-dimethyl-1-quinolin- 4-ylmethyl imidazolidine-2, 4-dione - 3- [3,3-Dimethyl--(2-morpholin-4-yl-acetyl) -2,3 dihydro-1H-indol-6-yl] -5, 5-dimethyl-1- quinolin-4 ylmethyl-imidazolidine-2, 4-dione 10 - 3-[3,3-Dimethyl-1-(2-thiomorpholin-4-yl-acetyl)-2,3 dihydro-1H-indol-6-yl] -5, 5-ckimethyl- 1-quinolin-4 ylmethyl'imiclazolidine-2, 4-dione - 3-{ 4 -Methoxy-3-[2-(2-morpholin-4-yl-ethylamino) ethoxyl -phenyi}-5, 5-dimethyl-1-quinolin-4- ylmethyl 15 imiclazolidine-2, 4-dione - 3-f4-Methoxy-3- (2-pyrrolidin-1-yl-ethoxy) -phenyllj-5,5 dimethyl-l-quinolin-4-ylmethyl- imidazolidine-2, 4-dione - 3- (4-Methoxy-3-{2- II(pyridin-2-ylmethyl) -amino] -ethoxyl phenyl) -5, 5-dimethyl-1-quinolin-4- ylmethyl 20 imidazolidine-2, 4-dione - 3-f 4-Methoxy-3- [2- (tetrahydro-pyran-4-ylanino) -ethoxy] phenyl}-5, 5-dimethyl-1-quinolin-4-, ylmethyl imidazolidine-2, 4-diane - 3-{4-Methoxy-3-[2- (1-methyl-piperidin-4-ylamino) 25 ethoxy] -phenyl}-5, 5-dimethyl-1-quinolin- 4-ylmethyl imidazolidine-2, 4-dione WO 2006/010641 PCT/EP2005/008720 260 - 3-{3-[2-Hydroxy-3- (tetrahydro-pyran-4-ylamino) propoxyl -4-methoxy-phenyl}-5, 5-dimethyl-1- quinolin- 4 ylmethyl-imidazolidine- 2 ,4-dione - 3-{3-[2-Hydroxy-3-(pyridin-4-ylamino)-propoxy]- 4 5 methoxy-phenyl}-5, 5-dimethyl-1-quinolin- 4-ylmethyl imidazolidine-2,4-dione - 3-3-[2-Hydroxy-3-(1-methyl-piperidin-4-ylamino) propoxyl-4-methoxy-phenyll-5,5-dimethyl- l-quinolin- 4 ylmethyl-imidazolidine- 2 ,4-dione 10 the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 15 13) Products of formula (I) as defined in any one of Claims 1 to 11, the names of which are given hereinbelow: - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl) -2-trifluoromethoxy- phenyll -2 morpholin-4-yl-acetamide 20 - N- [5- (4, 4-Dimethyl-2, 5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 (dimethyl-morpholin-4-yl) -acetamide trifluoroacetate - 2-Cyclopentylamino-N- [5- (4, 4-dimethyl-2, 5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2 25 trifluoromethoxy-phenyl]-acetamide trifluoroacetate - N-[5- (4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2,2,2 trifluoro-ethylamino)-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 261 - 2-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyl]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 5 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 thiomorpholin-4-yl-acetamide trifluoroacetate - .N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 pyrrolidin-1-yl-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy-- phenyl]-2-(4 methyl-piperazin-1-yl)-acetamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 15 piperidin-1-yl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-2-ylmethyl)-amino]-acetamide trifluoroacetate. - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-3-ylmethyl)-amino]-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [(pyridin-4-ylmethyl)-amino]-acetamide trifluoroacetate 25 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (2 hydroxy-ethylamino)-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 262 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-(2 methoxy-ethylamino)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 5 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyll-acetamide trifluoroacetate - 2-.(Cyanomethyl-amino)-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl]-acetamide trifluoroacetate 10 - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -2- (4 methyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl) -2- (4 15 methyl-[1,4]diazepan-1-yl)-acetamide trifluoroacetate - 2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1- yl)-2 trifluoromethoxy-phenyl-acetamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-.(1,2,2 trimethyl-propylamino)-acetamide trifluoroacetate - ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-amino)-acetic acid methyl ester; compound with 25 trifluoro-acetic acid - 2-(2,2-Difluoro-ethylamino)-N-[5-(4,4-dimethyl-2,5 dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2- WO 2006/010641 PCT/EP2005/008720 263 trifluoromethoxy-phenyl]-acetamide; compound with trifluoro-acetic acid - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2- (4,4 5 dimethyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2-(4 trifluoromethyl-piperidin-1-yl)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 10 imidazolidin-1-yl)-2-trifluoromethoxy- phenyll-2 [1,4]oxazepan-4-yl-acetamide 1-{[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-pyrrolidine-3-carboxylic acid methyl ester 15 - 2-Azetidin-1-yl-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyll-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy-. phenyl]-2-(2 20 fluoro-ethylamino)-acetamide - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-2-[(2 methoxy-ethyl)-methyl-amino]-acetamide - ({ [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 25 imidazolidin-1-yl)-2-trifluoromethoxy- phenylcarbamoyl] methyl}-amino)-acetic acid trifluoroacetate WO 2006/010641 PCT/EP2005/008720 264 - 2-Cyclohexylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyl-acetamide trifluoroacetate - - 2-Cyclopropylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 5 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyll-acetamide trifluoroacetate N-[5-(4',4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 morpholin-4-yl-propionamide trifluoroacetate 10 N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl inidazolidin-1-yl)-2-trifluoromethoxy-. phenyll-3 (dimethyl-morpholin-4-yl)-propionamide trifluoroacetate N [5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl] -3- (4 15 methyl-piperazin-1-yl)-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 piperidin-1-yl-propionamide trifluoroacetate - N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 20 imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 thiomorpholin-4-yl-propionamide trifluoroacetate N-[5-(4,4-Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3 pyrrolidin-1-yl-propionamide trifluoroacetate 25 - 3-Cyclopentylanino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)- 2 trifluoromethoxy-phenyll-propionamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 265 - N-[5- (4, 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-trifluoromethoxy- phenyl]-3- (2,2,2 trifluoro-ethylamino)-propionamide; compound with trifluoro-acetic acid 5 - 3-Diethylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2- trifluoromethoxy phenyll-propionamide trifluoroacetate - N-[5-( 4 , 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-morpholin-4-yl 10 acetamide trifluoroacetate - N-[5-(4, 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl imidazolidin-1-yl)-2-isopropyl-phenyl]-2-piperidin-1-yl acetamide trifluoroacetate - N-[5-( 4 , 4 -Dimethyl-2,5-dioxo-3-pyridin-4-ylmethyl 15 imidazolidin-1-yl)-2-isopropyl-phenyl]-2-(4-methyl piperazin-1-yl)-acetamide trifluoroacetate - 2-Dimethylamino-N-[5-( 4 ,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] acetamide trifluoroacetate 20 - 2-Diethylamino-N-[5-( 4 ,4-dimethyl-2,5-dioxo-3-pyridin 4-ylmethyl-imidazolidin-1-yl)-2-isopropyl-phenyl] acetamide trifluoroacetate - '2-tert-Butylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl)-2-isopropyl 25 phenyl]-acetamide trifluoroacetate WO 2006/010641 PCT/EP2005/008720 266 - 2-Cyclopentylamino-N-[5-(4,4-dimethyl-2,5-dioxo-3 pyridin-4-ylmethyl-imidazolidin-1-yl) - 2-isopropyl phenyl]-acetamide trifluoroacetate - 1-Methyl-piperidine-4-carboxylic acid [5-(4,4-dimethyl 5 2,5-dioxo-3-pyridin-4-ylmethyl- imidazolidin-1-yl)-2 trifluoromethoxy-phenyl]-amide, trifluoro-acetate - 3- [3- (2-Cyclopentylamino-ethoxy) -4-methoxy-phenyl] -5,5 dimethyl-l-quinolin-4-ylmethyl- imidazolidine-2,4-dione - 3-(3-{2-[(Furan-2-ylmethyl)-amino]-ethoxy}-4-methoxy 10 phenyl)-5,5-dimethyl-l-quinolin-4- ylmethyl imidazolidine-2,4-dione - 3-{3-[2-(2-Hydroxy-l-phenyl-ethylamino)-ethoxy]-4 methoxy-phenyl}-5,5-dimethyl-1-quinolin- 4-ylmethyl imidazolidine-2,4-dione 15 - 3-[3,3-Dimethyl-l- (2-morpholin-4-yl-acetyl)-2,3 dihydro-lH-indol-6-yl]-5,5-dimethyl-l- quinolin-4 ylmethyl-imidazolidine-2, 4-dione - 3-[3,3-Dimethyl-l-(2-thiomorpholin-4-yl-acetyl)-2,3 dihydro-lH-indol-6-yl]-5,5-dimethyl- l-quinolin-4 20 ylmethyl-imidazolidine-2,4-dione the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of, 25 the said products of formula (I). 14) As medicinal products, the products of formula (I) as defined in any one of Claims 1 to 11, and also prodrugs thereof, the said products of formula (I) being WO 2006/010641 PCT/EP2005/008720 267 in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral and organic acids or with mineral and organic bases of 5 the said products of formula (I) 15) As medicinal products, the products of formula (Ia), (Ib), , (Ic) or (Id) as defined in the preceding claims, and also prodrugs thereof, the said products of formula (Ia), (Ib), (Ic) or (Id) being in all the possible 10 racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Ia), (Ib), (Ic) or (Id). 15 16) As medicinal products, the products as defined in Claim 12 or 13, and also prodrugs thereof, and also the pharmaceutically acceptable addition salts of these products with mineral and organic acids or with mineral and organic bases. 20 17) Pharmaceutical compositions containing, as -active principle, at least one of the medicinal products as defined in Claims 14 to 16. 18) Pharmaceutical compositions according to Claim 17, characterized in that they are used as medicinal 25 products, in particular for cancer chemotherapy., 19) Pharmaceutical compositions according to Claim 18, containing, in addition to the active principles, other chemotherapy medicinal products for combating cancer. 20) Use of products of formula (I) as' defined in any one 30 of the claims, or of pharmaceutically acceptable salts of WO 2006/010641 PCT/EP2005/008720 268 the said products of formula (I), for the preparation of medicinal products for inhibiting the activity of protein kinases and especially of a protein kinase. 21) Use of products of formula (I) as defined in the 5 preceding claim, or of pharmaceutically acceptable salts of the said products of formula (I) in which the protein kinase is a protein tyrosine kinase. 22) Use of products of formula (I) as defined in any one of the claims, or of pharmaceutically acceptable salts of 10 the said. products of formula (I), in which the protein kinase is chosen from the following group: IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Fltl-3, FAK, Src, Abl, cKit, cdkl-9, Auroral-2, cdc7, Akt, Pdk, S6K, Jnk, IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2, CDK7, CDK2 15 et EGFR. 23) Use of products of formula (I) as defined in any one of the claims, or of pharmaceutically acceptable salts of the said products of formula (I), in which the protein kinase is chosen from the following group: IGF1, cdc7, 20 Auroral-2, Src, Jnk, FAK, KDR, IR, Tie2, CDK7, CDK2 et EGFR. 24) Use of products of formula (I) as defined in any one of the claims, or of pharmaceutically acceptable salts of the said products of formula (I), in which the protein 25 kinase is IGF1R. 25) Use of products of formula (I) as defined in any one of the claims, or of pharmaceutically acceptable salts of the said products of formula (I), in which the protein kinase is FAK or AKT. 30 26) Use.of products of formula (I) as defined in any one WO 2006/010641 PCT/EP2005/008720 269 of the claims, or of pharmaceutically acceptable salts of the said products of formula (I), in which the protein kinase is in a cell culture. 27) Use of products of formula (I) as defined in any one 5 of the claims, or of pharmaceutically acceptable salts of the said products of formula (I), in which the protein kinase is in a mammal. 28) Use of products of formula (I) as defined in any one of the claims or of pharmaceutically acceptable salts of 10 the said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease characterized by deregulation of the activity of a protein kinase. 29) Use of products of formula (I) according to the 15 preceding claim in which the disease to be prevented or treated is in a mammal. 30) Use of products of formula (I) as defined in anyone of the claims or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a 20 medicinal product for preventing or treating a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, 25 thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related macula degeneration oncology diseases and cancer. 31) Use of products of formula (I) as defined in any one 30 of the claims or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a WO 2006/010641 PCT/EP2005/008720 270 medicinal product for treating oncology diseases. 32) Use of products of formula (I) as defined in any one of the claims or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a 5 medicinal product for treating cancer. 33) Use of products of formula (I) according to the preceding claim, in which the disease to be treated is a cancer of solid tumours. 34) Use of products of formula (I) according to the 10 preceding claim, in which the disease to be treated is a cancer that is resistant to cytotoxic agents. 35) Use of products of formula (I) as defined in any one of the claims, or of pharmaceutically acceptable salts of the said products of formula (I) , for the preparation of 15 a medicinal product for treating cancers, among which are breast cancer, stomach cancer, cancer of the colon, lung cancer, cancer of the ovaries, cancer of the uterus, brain cancer, cancer of the kidney, cancer of the larynx, cancer of the lymphatic system, cancer of the thyroid, 20 cancer, of the urogenital tract, cancer of the tract including the seminal vesicle and prostate, bone cancer, cancer of the pancreas and melanomas. 36) Use of products of formula (I) according to the preceding claim, in which the disease to be treated is a 25 breast cancer, cancer of the colon or lung cancer. 37) Use of products of formula (I) as defined in any one of the claims or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of a medicinal product for cancer chemotherapy. WO 2006/010641 PCT/EP2005/008720 271 38) Use of products of formula (I) as defined in any one of the claims or of pharmaceutically acceptable salts of the said products of formula (I) for the preparation of medicinal.products for cancer chemotherapy, used alone or 5 in combination. 39) Use of products of formula (I) as defined in any one of the claims or of pharmaceutically acceptable salts of the said products of formula. (I) for the preparation of medicinal products for use alone or in combination with 10 chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents. 40) Use of products of formula (I) according to the. preceding claim, in which the therapeutic agents .may be commonly used antitumour agents. 15 41) Products of formula (I) as defined in any one, of the claims, as protein kinase inhibitors, the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts of the said products of formula (I) 20 with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases, and also the prodrugs thereof. 42) Products of formula (I), (Ia), (Ib) or (Ic) -as defined in any one of the claims, as IGFlR inhibitors. 25 43) Products of formula (Id) as defined in the preceding claims, as IGFlR inhibitors.

类似技术:

---

公开号 | 公开日 | 专利标题

---

EP1773808B1|2011-02-16|Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors

---

CN107406426B|2020-11-20|Cyclic ureas as ROCK inhibitors

---

US20080021029A1|2008-01-24|Substituted Cyclic Urea Derivatives, Preparation Thereof And Pharmaceutical Use Thereof As Kinase Inhibitors

---

US7482370B2|2009-01-27|Compounds for the treatment of inflammatory disorders

---

EP1599464B1|2010-09-22|Novel cyclic urea derivatives, preparation method thereof and pharmaceutical use of same as kinase inhibitors

---

US20070259891A1|2007-11-08|Heterocycle-Substituted Cyclic Urea Derivatives, Preparation Thereof And Pharmaceutical Use Thereof As Kinase Inhibitors

---

EP1487822B1|2007-08-01|Pyrrole-2,5-dione derivatives and their use as gsk-3 inhibitors

---

US9738630B2|2017-08-22|Inhibitors of lysine methyl transferase

---

US8541572B2|2013-09-24|Compounds for the treatment of inflammatory disorders

---

US20040248884A1|2004-12-09|Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors

---

US20070004684A1|2007-01-04|Alpha-Carbolines as CDK-1 inhibitors

---

US20090082329A1|2009-03-26|Novel Sulphur-Containing Cyclic Urea Derivatives, Preparation Thereof and Pharmaceutical Use Thereof as Kinase Inhibitors

---

KR101421852B1|2014-07-22|Imidazole derivatives as casein kinase inhibitors

---

EP0970070A1|2000-01-12|Phthalazines with angiogenesis inhibiting activity

---

US20090082379A1|2009-03-26|Novel Cyclic Urea Derivatives, Preparation Thereof and Pharmaceutical Use Thereof as Kinase Inhibitors

---

JP2005538962A|2005-12-22|Phenylaminopyrimidine and its use as a Rho-kinase inhibitor

---

JP2009532375A|2009-09-10|Kinase inhibitor

---

US20090105216A1|2009-04-23|3- | 2-indolinone derivates and their use as cell proliferation inhibitors

---

HU0104994A2|2002-04-29|Substituted |benzoheteroaryl compounds, process for their preparation and medicaments containing them

同族专利:

---

公开号 | 公开日

---

BRPI0512681A|2008-04-01|

---

DE602005026395D1|2011-03-31|

---

CN101031559A|2007-09-05|

---

EP1621536A1|2006-02-01|

---

JP2008508228A|2008-03-21|

---

CA2571323A1|2006-01-02|

---

MA28732B1|2007-07-02|

---

IL180286D0|2007-07-04|

---

PE20060383A1|2006-06-06|

---

AT498618T|2011-03-15|

---

WO2006010641A2|2006-02-02|

---

EP1773808B1|2011-02-16|

---

EA011088B1|2008-12-30|

---

WO2006010641A3|2006-10-26|

---

UY29039A1|2006-02-24|

---

TW200616973A|2006-06-01|

---

EP1773808A2|2007-04-18|

---

KR20070038529A|2007-04-10|

---

AR050269A1|2006-10-11|

---

EA200700141A1|2007-08-31|

---

US20080004300A1|2008-01-03|

---

NO20071067L|2007-04-26|

---

US7759379B2|2010-07-20|

---

MX2007001024A|2007-04-16|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

FR2476087B1|1980-02-18|1983-07-18|Roussel Uclaf||

---

US5411981A|1991-01-09|1995-05-02|Roussel Uclaf|Phenylimidazolidines having antiandrogenic activity|

---

FR2671348B1|1991-01-09|1993-03-26|Roussel Uclaf|NOVEL PHENYLIMIDAZOLIDINES, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|

---

DE19540027A1|1995-10-27|1997-04-30|Gruenenthal Gmbh|Substituted imidazolidine-2,4-dione compounds as active pharmaceutical ingredients|

---

DE19732928C2|1997-07-31|2000-05-18|Gruenenthal Gmbh|Use of substituted imidazolidine-2,4-dione compounds as pain relievers|

---

FR2796945B1|1999-07-30|2002-06-28|Sod Conseils Rech Applic|NOVEL DERIVATIVES OF HYDANTOINS, THIOHYDANTOINS, PYRIMIDINEDIONES AND THIOXOPYRIMIDINONES, PROCESSES FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS|

---

US6114365A|1999-08-12|2000-09-05|Pharmacia & Upjohn S.P.A.|Arylmethyl-carbonylamino-thiazole derivatives, process for their preparation, and their use as antitumor agents|

---

AU2002951247A0|2002-09-06|2002-09-19|Alchemia Limited|Compounds that interact with kinases|

---

US7354933B2|2003-01-31|2008-04-08|Aventis Pharma Sa|Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

FR2850652B1|2003-01-31|2008-05-30|Aventis Pharma Sa|NOVEL CYCLIC UREA DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF KINASES|

---

US7256208B2|2003-11-13|2007-08-14|Bristol-Myers Squibb Company|Monocyclic N-Aryl hydantoin modulators of androgen receptor function|

---

EP1621535A1|2004-07-27|2006-02-01|Aventis Pharma S.A.|Substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

EP1621539A1|2004-07-27|2006-02-01|Aventis Pharma S.A.|Heterocycle -substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|US7354933B2|2003-01-31|2008-04-08|Aventis Pharma Sa|Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

EP1621539A1|2004-07-27|2006-02-01|Aventis Pharma S.A.|Heterocycle -substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

EP1621535A1|2004-07-27|2006-02-01|Aventis Pharma S.A.|Substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

FR2896504B1|2006-01-23|2012-07-13|Aventis Pharma Sa|NOVEL CYCLIC UREA DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF KINASES|

---

FR2896503B1|2006-01-23|2012-07-13|Aventis Pharma Sa|NOVEL CYCLIC UREA SULFUR DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF KINASES|

---

EP2125750B1|2007-02-26|2014-05-21|Vitae Pharmaceuticals, Inc.|Cyclic urea and carbamate inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

TW200946520A|2008-05-01|2009-11-16|Vitae Pharmaceuticals Inc|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

CA2723039A1|2008-05-01|2009-11-05|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

EP2324018B1|2008-07-25|2013-09-04|Boehringer Ingelheim International GmbH|Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1|

---

EP2291370B1|2008-05-01|2013-11-27|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

WO2009017671A1|2007-07-26|2009-02-05|Vitae Pharmaceuticals, Inc.|Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1|

---

US8242111B2|2008-05-01|2012-08-14|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1|

---

AR069207A1|2007-11-07|2010-01-06|Vitae Pharmaceuticals Inc|CYCLIC UREAS AS INHIBITORS OF THE 11 BETA - HIDROXI-ESTEROIDE DESHIDROGENASA 1|

---

JP5490014B2|2007-12-11|2014-05-14|ヴァイティーファーマシューティカルズ，インコーポレイテッド|11β-hydroxysteroid dehydrogenase type 1 cyclic urea inhibitor|

---

TW200934490A|2008-01-07|2009-08-16|Vitae Pharmaceuticals Inc|Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1|

---

JP5490020B2|2008-01-24|2014-05-14|ヴァイティーファーマシューティカルズ，インコーポレイテッド|Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1|

---

JP5734666B2|2008-02-11|2015-06-17|ヴァイティー ファーマシューティカルズ，インコーポレイテッド|1,3-oxaazepan-2-one and 1,3-diazepan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase 1|

---

EP2254872A2|2008-02-15|2010-12-01|Vitae Pharmaceuticals, Inc.|Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1|

---

US20110105504A1|2008-03-18|2011-05-05|Vitae Pharmaceuticals ,Inc.|Inhibitors Of 11beta-Hydroxysteroid Dehydrogenase Type 1|

---

US8680093B2|2009-04-30|2014-03-25|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

US20100331320A1|2009-04-30|2010-12-30|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

CA2729998A1|2008-07-25|2010-01-28|Boehringer Ingelheim International Gmbh|Inhibitors of 11beta-hydroxysteroid dehydrogenase 1|

---

CA2744946A1|2009-02-04|2010-08-12|Boehringer Ingelheim International Gmbh|Cyclic inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1|

---

TW201039034A|2009-04-27|2010-11-01|Chunghwa Picture Tubes Ltd|Pixel structure and the method of forming the same|

---

EP2440537A1|2009-06-11|2012-04-18|Vitae Pharmaceuticals, Inc.|Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure|

---

JP5749263B2|2009-07-01|2015-07-15|ヴァイティー ファーマシューティカルズ，インコーポレイテッド|Cyclic inhibitor of 11β-hydroxysteroid dehydrogenase 1|

---

US20120315244A1|2009-09-30|2012-12-13|President And Fellows Of Harvard College|Methods for Modulation of Autophagy Through the Modulation of Autophagy-Inhibiting Gene Products|

---

US8933072B2|2010-06-16|2015-01-13|Vitae Pharmaceuticals, Inc.|Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use|

---

WO2011161128A1|2010-06-25|2011-12-29|Boehringer Ingelheim International Gmbh|Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders|

---

CA2813671A1|2010-11-02|2012-05-10|Boehringer Ingelheim International Gmbh|Pharmaceutical combinations for the treatment of metabolic disorders|

---

AU2015324111B2|2014-09-29|2021-04-01|Chemocentryx, Inc.|Processes and intermediates in the preparation of C5aR antagonists|

法律状态:
2009-08-13| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|

优先权:

---

申请号 | 申请日 | 专利标题

---

EP04291904.3||2004-07-27||

---

EP04291904A|EP1621536A1|2004-07-27|2004-07-27|Amino cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---

PCT/EP2005/008720|WO2006010641A2|2004-07-27|2005-07-25|Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors|

---