WO2020048827A1 - Composés de la 1,3,9-triazaspiro[5.5]undécan-2-one - Google Patents
Composés de la 1,3,9-triazaspiro[5.5]undécan-2-one Download PDFInfo
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- WO2020048827A1 WO2020048827A1 PCT/EP2019/072875 EP2019072875W WO2020048827A1 WO 2020048827 A1 WO2020048827 A1 WO 2020048827A1 EP 2019072875 W EP2019072875 W EP 2019072875W WO 2020048827 A1 WO2020048827 A1 WO 2020048827A1
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- 0 *c1c(*)c(*)c(*)c(*)c1 Chemical compound *c1c(*)c(*)c(*)c(*)c1 0.000 description 3
- LEZGDAHGPWMQLQ-UHFFFAOYSA-N CC(C)(C(N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OCCCOC)NC1=O)=O)c1cccc(C(F)(F)F)c1 Chemical compound CC(C)(C(N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OCCCOC)NC1=O)=O)c1cccc(C(F)(F)F)c1 LEZGDAHGPWMQLQ-UHFFFAOYSA-N 0.000 description 2
- TVLTXIAAFFLCGI-VXPBITRUSA-N C/[O]=C\[C@@](C(F)(F)F)(C(N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OCc2ccccc2)NC1=O)=O)c1ccccc1 Chemical compound C/[O]=C\[C@@](C(F)(F)F)(C(N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OCc2ccccc2)NC1=O)=O)c1ccccc1 TVLTXIAAFFLCGI-VXPBITRUSA-N 0.000 description 1
- NSWWEUBOFJJNBQ-UHFFFAOYSA-N COCCCOc1cc(F)ccc1C(CN1)C(CC2)(CCN2C(Cc(cccc2)c2OC(F)(F)F)=O)NC1=O Chemical compound COCCCOc1cc(F)ccc1C(CN1)C(CC2)(CCN2C(Cc(cccc2)c2OC(F)(F)F)=O)NC1=O NSWWEUBOFJJNBQ-UHFFFAOYSA-N 0.000 description 1
- RLLMEIIVOZXUOT-UHFFFAOYSA-N O=C(Cc(cccc1)c1OC(F)(F)F)N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OC2CCC2)NC1=O Chemical compound O=C(Cc(cccc1)c1OC(F)(F)F)N(CC1)CCC1(C(CN1)c(ccc(F)c2)c2OC2CCC2)NC1=O RLLMEIIVOZXUOT-UHFFFAOYSA-N 0.000 description 1
- NBTRVTPOJIRGAX-UHFFFAOYSA-N O=C(NC1)NC2(CCNCC2)C1I Chemical compound O=C(NC1)NC2(CCNCC2)C1I NBTRVTPOJIRGAX-UHFFFAOYSA-N 0.000 description 1
- NBTRVTPOJIRGAX-ZCFIWIBFSA-N O=C(NC1)NC2(CCNCC2)[C@@H]1I Chemical compound O=C(NC1)NC2(CCNCC2)[C@@H]1I NBTRVTPOJIRGAX-ZCFIWIBFSA-N 0.000 description 1
- OJEBUJINTILKDK-GGYWPGCISA-N O=C([C@@H](C(F)(F)F)c1ccccc1)N(CC1)CCC1(C(CN1)c(cc2)ccc2F)NC1=O Chemical compound O=C([C@@H](C(F)(F)F)c1ccccc1)N(CC1)CCC1(C(CN1)c(cc2)ccc2F)NC1=O OJEBUJINTILKDK-GGYWPGCISA-N 0.000 description 1
- DQFIZJOTALDPJH-LMNIDFBRSA-N O[C@@](C(F)(F)F)(C(N(CC1)CCC1(C(CN1)c(cc2)ccc2F)NC1=O)=O)c1ccccc1 Chemical compound O[C@@](C(F)(F)F)(C(N(CC1)CCC1(C(CN1)c(cc2)ccc2F)NC1=O)=O)c1ccccc1 DQFIZJOTALDPJH-LMNIDFBRSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention covers 1 ,3,9-triazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
- the present invention covers 1 ,3,9-triazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) which inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation.
- Rho GTPases belong to the larger family of Ras GTPases, consisting of over 50 proteins with related characteristics. Rho GTPases are master regulators for signal transduction from the extracellular matrix to the cytoplasm and nucleus. They are involved in the regulation of cell proliferation, survival and differentiation by modulating cytoskeletal structure and properties of cell adhesion. Abberant Rho GTPase activity is observed in human cancer. Members of the pathway are therefore potential therapeutic targets. Activity of Rho GTPases is regulated by protein prenylation (farnesylation and geranylgeranylation) of the CAAX box motif. Prenylated Rho GTPases are primed for membrane localization and subsequent activon.
- GGTase II is selective for Rab proteins and shows a different Mode of Action compared to GGTase I and FTase.
- GGTase I inhibition reduces tumor formation of lung cancer as well as myeloproliferative disease and that the anti-tumor effect depended on the inhibition of protein geranyl-geranylation Sjogren AKM et al, J. Clin. Invest. 1 17:1294-1304 (2007).
- Rho GTPases A recently discovered downstream target of Rho GTPases are YAP1 and TAZ (gene name WWTR1 ). It has been shown that geranylgeranylated Rho GTPases such as RhoA activate downstream YAP1/TAZ in breast cancer (Mi W et al Oncogene 2015). YAP1 and TAZ (gene name WWTR1 ) are two highly related transcriptional coactivators that are frequently aberrantly activated in human cancers (Zanconato F, Cancer Cell. 2016 783-803). YAP1/TAZ are important for the activation of several hallmarks of cancer (Harvey KF, Nat Rev Cancer. 2013 246-57).
- YAP1/TAZ shuttle between the cytoplasm and the cells ' nucleus, where they interact with TEAD transcription factors1 -4 (TEAD1 -4) to activate target genes important for cell survival and cell cycle progression (S. Piccolo Physiol. Rev., 2014 1287-1312. Zanconato F, et al. Nat Cell Biol. 2015 1218-27).
- Abberant YAP1/TAZ expression induces cell proliferation (Zhao B Genes Dev., 2007, 2747-2761 ).
- high levels of YAP1/TAZ can overcome the induction of programmed cell death and apoptosis by upregulation of anti- apoptotic proteins (Rosenbluh J. Cell, 2012. 1457-1473).
- YAP1/TAZ also confers Cancer Stem Cells (CSC) traits and are required for CSC expansion within tumors (Cordenonsi M. Cell, 201 1 , 759-772). In line with this, the ability to initiate tumor formation and induce metastasis depends on YAP1/TAZ (Bartucci M, Oncogene, 2015, 681-690 Lau AN EMBO J. 2014, 468-481 ). Blockade of YAP1/TAZ function by RNAi-mediated knockdown reduces the viability of several cancer cells in vitro (Pan J Oncol. Rep., 2012 179-185).
- CSC Cancer Stem Cells
- YAP1/TAZ may represent promising targets for therapeutic intervention of various diseases with uncontrolled cell proliferation, including cancer.
- the present invention relates to chemical compounds that have been found to
- GGTase I inhibitors have been developed (reviewed in Ullah N et al Current Cancer Drug Targets 2016, 16, 563-571 ), but no GGTase I inhibitor is currently approved for treatment of patients.
- WO-03017939 WO-2010088457.
- GGTI-2418 US 2012/0035184 A1 .ln cancer cell lines, GGTase I inhibitors cause cell cycle arrest in G0/G1 phase via blockade of cyclin- dependent kinases downstream of Rho Sun J et al, J. Biol. Chem., 1999, 274, 6930-; Vogt A et al, J. Biol. Chem., 1997, 272, 27224-27229.
- Cyclic peptides inhibiting the YAP1 -TEAD protein-protein interaction have been described in Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998.
- a peptide mimicking VGLL4 function has been proposed to act as a YAP1 antagonist in preclinical models of gastric cancer in Jiao S, et al., Cancer Cell, 2014, 25, 166- 180.
- a number of publications report inhibitors of YAP1 , for example, the Tankyrase inhibitor XAV939 (Wang et al., Cell Reports, 2015, 13, 524-532) is reported to target YAP1 for cancer treatment.
- Peptide 17 has been reported to inhibit the YAP1 -TEAD protein-protein interaction (Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998 and Zhou et al., FASEB J., 2015, 29, 724-732).
- Verteporfin has also reported to be a YAP1 inhibitor (Szeto et al., J. Am. Soc. Nephrol., 2016, 27, 31 17-3128 and Liu-Chittenden et al., Gens Dev., 2012, 26, 1300-1305).
- Latrunculin A, Blebbistatin, Y27632 and ML7 have been reported to inhibit YAP1 nuclear localization as well as YAP1 and TEAD activity (see Nature Reviews Drug Discovery, 2014, 13, 63-79).
- WO20191 18973A1 describes 1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer.
- W02005075484 A2 discloses 1 -oxa-3,8-diazaspiro[4.5]decan-2-one and 1 -oxa-3,9-diazaspiro- [5.5]undecan-2-one compounds, which modulate the chemokine CCR5 receptors.
- W02002092604 A1 discloses 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one derivatives and its use as antagonists of the neurokinin receptor.
- W02003057698 A2 discloses spiroazacyclic compounds as monoamine receptor modulators.
- the compounds of the present invention have surprisingly been found to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation, and may therefore be used for the treatment or prophylaxis of hyperproliferative disorders, such as cancer, for example.
- GTTase I geranylgeranyltransferase I
- the present invention covers compounds of general formula (I):
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci -Ce-alkyl C2-C6-alkenyl, C2-C6-alkynyl, C3-Ce-cycloalkyl,
- n represents an integer of 2, 3, 4 or 5
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci -C 2 -alkoxy, C 3 -C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Cs-Ce-cycloalkyl, C4-C7-cycloalkenyl, C 4 -C 7 -hydroxycycloalkenyl, (Ci-C 2 -alkoxy)-(C3-C 6 -alkenyl)-,
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- (5- or 6-membered heteroaryl)oxy- group and (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, phenyl, phenyl-(Ci-C 2 -alkyl)-, -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
- -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(Ci-C 3 -alkyl)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 3 and R 4 together with the carbon atom to which they are attached represent a
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -hydroxyalkyl,
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
- optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3 or 4, in particular 1 , 2 or 3.
- an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
- ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
- halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
- Ci-Ce-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, fert-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
- said group has 1 , 2, 3 or 4 carbon atoms (“Ci-C 4 -alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or fert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group, more particularly 1 or 2 carbon atoms (“Ci-C2-alkyl”), e.g. a methyl or ethyl group.
- Ci-C 4 -alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or fert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl
- Ci-Ce-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is defined supra , and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 .2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1 -hydroxypropan-2-yl,
- Ci-C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
- said halogen atom is a fluorine atom.
- Ci-C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.
- Ci-C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term“Ci-Ce-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
- Ci-C 6 -haloalkoxy means a linear or branched, saturated, monovalent Ci-C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
- said halogen atom is a fluorine atom.
- Said Ci-Ce-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
- Ci-Ce-cyanoalkoxy means a linear or branched, saturated, monovalent
- Ci-C 6 -alkoxy group as defined supra, in which group one of the hydrogen atoms is replaced with a cyano group. Particularly, said group contains 1 , 2, 3 or 4 carbon atoms
- Ci-C 4 -cyanoalkoxy (“Ci-C 4 -cyanoalkoxy”).
- Said Ci-C 4 -cyanoalkoxy group is, for example, a cyanomethoxy, 1 -cyanoethoxy, 2-cyanoethoxy, 1 -cyanopropoxy, 2-cyanopropoxy, 3-cyanopropoxy,
- C2-C6-hydroxyalkoxy means a linear or branched, saturated, monovalent
- C2-C 6 -alkoxy group as defined supra, in which group one of the hydrogen atoms is replaced with a hydroxy group.
- group one of the hydrogen atoms is replaced with a hydroxy group.
- said group contains 2, 3 or 4 carbon atoms
- C 2 -C 4 -hydroxyalkoxy (“C 2 -C 4 -hydroxyalkoxy”).
- Said C 2 -C 4 -hydoxyalkoxy group is, for example, a 2-hydroxyethoxy,
- C2-C6-alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, it being understood that in the case in which said alkenyl group contains two double bonds, then it is possible for said double bonds to be conjugated with each other, or to form an allene.
- Said alkenyl group is, for example, an ethenyl (or“vinyl”), prop-2-en-1 -yl (or“allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or“isopropenyl”),
- C2-C 6 -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2, 3 Oder 4 carbon atoms (“C 2 -C4-alkynyl”).
- Said C2-C 6 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl”), but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-
- Cs-Ce-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms.
- Said C3-C 6 -cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
- said group has 3 or 4 carbon atoms (“C3-C 4 -cycloalkyr’), e.g. a cyclopropyl or cyclobutyl group.
- C4-C7-cycloalkenyl means a monocyclic hydrocarbon ring which contains 4, 5, 6 or 7 carbon atoms and one double bond. Particularly, said ring contains 5 or 6 carbon atoms (“Cs-Ce-cycloalkenyl”).
- Said Cs-Ce-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyll group.
- C 4 -C7-hydroxycycloalkenyr means a monocyclic hydrocarbon ring which contains 4, 5, 6 or 7 carbon atoms and one double bond, in which group the term“C 4 -C7-cycloalkenyl” is as defined supra , and in which group one hydrogen atom is replaced with a hydroxy group.
- said ring contains 5 or 6 carbon atoms (“Cs-Ce-hydroxycycloalkenyl”) e.g. a hydroxycyclopentenyl or hydroxycyclohexenyl group.
- C3-C 6 -cycloalkyloxy means a saturated, monovalent group of formula (C3-C6-cycloalkyl)-0-, in which the term “Cs-Ce-cycloalkyl” is as defined supra , e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
- the term“4- to 7-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S.
- Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,1 -dioxidothiolanyl,
- a 6-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperaziny
- (4- to 7-membered heterocycloalkyl)oxy means a monocyclic, saturated heterocycloalkyl of formula (4- to 7-membered heterocycloalkyl)-0- in which the term“4- to 7- membered heterocycloalkyl” is as defined supra.
- heterocycloalkenyl means a monocyclic, unsaturated, non aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series N, O and S.
- Said heterocycloalkenyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 2,5-dihydro-1 /-/-pyrrolyl, [1 ,3]dioxolyl, 4/-/-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4/-/-[1 ,4]thiazinyl.
- nitrogen containing 4- to 7-membered heterocycloalkyl group means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one ring nitrogen atom and optionally one further ring heteroatom from the series N, O and S.
- Said nitrogen containing 4- to 7-membered heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, for example; or a 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or
- 1 .3-thiazolidinyl for example; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.
- 5- or 6-membered heteroaryl means a monovalent aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom.
- Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
- a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl
- (5- or 6-membered heteroaryl)oxy means a monovalent aromatic group of formula (5- or 6-membered heteroaryl)-0- in which the term “5- or 6-membered heteroaryl” is as defined supra.
- heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g .: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
- pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
- Ci-C 6 as used in the present text, e.g. in the context of the definition of “Ci-Ce-alkyl”, “Ci-Ce-haloalkyl”, “Ci-Ce-hydroxyalkyl”, “Ci-C 6 -alkoxy” or “Ci-C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
- C 3 -C 6 as used in the present text, e.g. in the context of the definition of “Cs-Ce-cycloalkyl” or “C3-C 6 -cycloalkyloxy”, means a cycloalkyl group or cycloalkyloxy group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
- Ci-Ce encompasses Ci , C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1 -C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
- C2-C6 encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
- C 1 -C 4 encompasses Ci , C 2 , C 3 , C 4 , C 1 -C 4 , C 1 -C3, C 1 -C 2 , C 2 -C 4 , C 2 -C3, and C 3 -C 4 ;
- C 2 -C 4 encompasses C 2 , C 3 , C 4 , C 2 -C 4 , C 2 -C3, and C 3 -C 4 ;
- C3-C6 encompasses C3, C4, C5, Ce, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Cs-Ce.
- the term“leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
- a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
- the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I) and general formula (l-a), particularly deuterium-containing compounds of general formula (I) and general formula (l-a).
- Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
- Isotopic variant of the compound of general formula (I) and general formula (l-a) is defined as a compound of general formula (I) or general formula (l-a) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
- the expression“unnatural proportion” means a proportion of such isotope which is higher than its natural abundance.
- the natural abundances of isotopes to be applied in this context are described in“Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1 ), 217-235, 1998.
- isotopes examples include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 1 1 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, respectively.
- the isotopic variant(s) of the compounds of general formula (I) or general formula (l-a) preferably contain deuterium (“deuterium-containing compounds of general formula (I) or general formula (l-a)”).
- deuterium-containing compounds of general formula (I) or general formula (l-a) are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
- Positron emitting isotopes such as 18 F or 1 1 C may be incorporated into a compound of general formula (I) or general formula (l-a). These isotopic variants of the compounds of general formula (I) or (l-a) are useful for in vivo imaging applications.
- Deuterium-containing and 13 C-containing compounds of general formula (I) or general formula (l-a) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
- Isotopic variants of the compounds of general formula (I) and general formula (l-a) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
- a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
- deuterium from D 2 0 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
- Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a direct route for incorporation of deuterium.
- Metal catalysts i.e. Pd, Pt, and Rh
- deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons.
- deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
- deuterium-containing compound of general formula (I) or general formula (l-a) is defined as a compound of general formula (I) or general formula (l-a), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than the natural abundance of deuterium, which is about 0.015%.
- the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
- the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) or general formula (l-a) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed.
- physicochemical properties such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am
- a compound of general formula (I) or general formula (l-a) may have multiple potential sites of attack for metabolism.
- deuterium-containing compounds of general formula (I) or general formula (l-a) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
- the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) or general formula (l-a) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I) or general formula (l-a), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
- the present invention concerns a deuterium-containing compound of general formula (I) or general formula (l-a) having 1 , 2, 3 or 4 deuterium atoms, particularly with 1 , 2 or 3 deuterium atoms.
- stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- the compounds of the present invention of the structural formula (I) optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres.
- Preferred isomers are those which produce the more desirable biological activity.
- Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
- the purification and the separation of such materials can be accomplished by standard techniques known in the art.
- the optical isomers can be obtained by resolution of the mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
- the optically active bases or acids are then liberated from the separated diastereomeric salts.
- Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
- Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
- a different process for separation of optical isomers involves the use of chiral chromatography (e.g ., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
- Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
- the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
- the present invention includes all possible diastereomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, it is possible for the compounds of the present invention to exist as tautomers. For example, the compounds of the present invention contain a cyclic urea moiety and can exist as tautomers, or even a mixture in any amount of the tautomers:
- the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
- the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen atom of the compounds of the present invention is oxidised.
- the present invention includes all such possible N-oxides.
- the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
- the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, dimethylsulfoxide, tetrahydrofuran, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
- the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
- Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
- “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the present invention.
- pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
- a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or“mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
- an alkali metal salt for example a sodium or potassium salt
- an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
- acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
- alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
- the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
- in vivo hydrolysable ester means an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
- suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1- Ce alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce alkanoyloxymethyl esters, e.g.
- esters pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkyloxy-carbonyloxy-Ci-C 6 alkyl esters, e.g. 1 - cyclohexyloxycarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1 ,3-dioxolen- 2-onylmethyl; and Ci-Ce-alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present invention.
- An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
- inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
- a-acyloxyalkyl ethers include acetoxym ethoxy and 2,2- dimethylpropionyloxymethoxy.
- a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted alkanoyl, benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), N,N-dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
- the present invention covers all such esters.
- the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
- the present invention also includes prodrugs of the compounds according to the invention.
- prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C4-alkyl Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C 4 -alkoxy,
- n represents an integer of 2, 3 or 4,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and C1-C2- alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and pyridinyl, which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 3 -C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 - alkoxy, C 2 -C6-hydroxyalkoxy, (Ci-C 2 -alkoxy)-(C 2 -C 4 -alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-, hydroxy, (R 5 )(R 6 )N-(C 2 -C 3 -alkoxy)-, (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- and -C( 0)OR 7 ,
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl are Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl,
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of general formula (l-a):
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 4 -alkyl Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy,
- n represents an integer of 2, 3 or 4,
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkoxy, C3-C4-cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and Ci-C 2 - alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and pyridinyl
- phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group and
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 - alkoxy, C 2 -C 6 -hydroxyalkoxy, (Ci-C 2 -alkoxy)-(C 2 -C 4 -alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R 5 )(R 6 )N-(C 2 -C3-alkoxy)-, (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C( 0)OR 7 ,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl, C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl, R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group seleceted from
- Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl are Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl,
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of general formula (I), supra , in which :
- R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
- X 2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C 4 -alkoxy,
- n represents an integer of 2, 3 or 4,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and Ci-C 2 -alkoxy, wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C 4 -haloalkyl group, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X 6 represents a hydrogen atom or a halogen atom,
- R 2 represents a group selected from phenyl, naphthyl and pyridinyl
- phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C4-alkyl C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C 4 -alkoxy, C2-C 6 -hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C 4 -alkoxy)-,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- Ci-C 4 -alkyl and C3-C 4 -cycloalkyl are Ci-C 4 -alkyl and C3-C 4 -cycloalkyl
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a group wherein " * " represents the point of attachment to the rest of the molecule
- X 2 represents a hydrogen atom or a group selected from
- Ci-C4-alkyl Ci-C 4 -alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-,
- (4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
- (4- to 7-membered heterocycloalkyl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C2-alkyl Ci-C2-hydroxyalkyl, hydroxy and oxo,
- phenyl part of said phenyl-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl and Ci-C2-alkoxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a halogen atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom,
- R 2 represents a group selected from phenyl and naphthyl
- phenyl and naphthyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 4 -alkyl, Ci-C 4 -haloalkyl and Ci-C 4 -haloalkoxy
- R 3 represents a hydrogen atom or a group selected from
- Ci-C 4 -alkyl Ci-C 4 -alkoxy, C2-C 6 -hydroxyalkoxy and hydroxy
- R 4 represents a hydrogen atom or a group selected from
- Ci-C 4 -alkyl and Ci-C 4 -haloalkyl are Ci-C 4 -alkyl and Ci-C 4 -haloalkyl
- the present invention covers compounds of general formula (I), supra , in which: R 1 represents a group wherein " * " represents the point of attachment to the rest of the molecule,
- X 2 represents a hydrogen atom or a group selected from
- X 3 represents a hydrogen atom
- X 4 represents a fluorine atom
- X 5 represents a hydrogen atom
- X 6 represents a hydrogen atom
- R 2 represents a group selected from
- R 3 represents a hydrogen atom or a group selected from
- R 4 represents a hydrogen atom or a group selected from methyl and trifluoromethyl, and tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a group selected from
- R 2 represents a group selected from
- R 3 represents a hydrogen atom or a group selected from
- R 4 represents a hydrogen atom or a group selected from methyl and trifluoromethyl, and tautomers, hydrates, solvates, and salts thereof, and mixtures of same.
- the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of: 5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 ,3,9-triazaspiro[5.5]- undecan-2-one (mixture of stereoisomers),
- the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of: (5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 ,3,9- triazaspiro[5.5]undecan-2-one, (5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 ,3,9-triazaspiro-
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci -Ce-alkyl C2-C 6 -alkenyl, C2-C 6 -alkynyl, C3-C 6 -cycloalkyl,
- Ci-Ce-hydroxyalkyl (Ci-C2-alkoxy)-(Ci -Ce-alkyl)-, Ci-Ce-haloalkyl,
- Ci-Ce-cyanoalkoxy phenyl, 5- or 6-membered heteroaryl
- n represents an integer of 2, 3, 4 or 5
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci -C 2 -alkoxy, C 3 -C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
- (5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci -Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C4-C7-cycloalkenyl, C 4 -C7-hydroxycycloalkenyl, (Ci-C 2 -alkoxy)-(C 3 -C 6 -alkenyl)-,
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, phenyl, phenyl-(Ci-C 2 -alkyl)-, -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
- cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(Ci-C3-alkyl)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group seleceted from
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of formula (l-a), supra , in which:
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Cs-Ce-cycloalkyl,
- Ci-Ce-hydroxyalkyl (Ci-C 2 -alkoxy)-(Ci-C 6 -alkyl)-, Ci-C 6 -haloalkyl,
- n represents an integer of 2, 3, 4 or 5
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy,
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci -Ce-alkyl C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 4 -C 7 -cycloalkenyl, C 4 -C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C 3 -C6-alkenyl)-,
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, phenyl, phenyl-(Ci-C 2 -alkyl)-, -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
- -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(Ci-C 3 -alkyl)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -hydroxyalkyl,
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of formula (l-a), supra , in which:
- R 1 represents a group selected from phenyl and naphtyl
- phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl,
- Ci-C 6 -hydroxyalkyl (Ci-C 2 -alkoxy)-(Ci-C 6 -alkyl)-, Ci-C 6 -haloalkyl,
- Ci-C 6 -alkoxy (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkoxy)-, C 2 -C 6 -hydroxyalkoxy,
- n represents an integer of 2, 3, 4 or 5
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- Ci-Ce-alkyl C2-C6-alkenyl, C2-C6-alkynyl, Cs-Ce-cycloalkyl, C 4 -C7-cycloalkenyl, C 4 -C 7 -hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C 6 -alkenyl)-,
- 5- or 6-membered heteroaryl or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C2-alkyl Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C2-alkyl Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
- (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C4-alkyl C 2 -C4-alkenyl, C 2 -C4-alkynyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C 4 -haloalkyl, phenyl, phenyl-(Ci-C 2 -alkyl)-, -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
- -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C2-alkyl Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
- cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(Ci-C3-alkyl)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
- R 3 and R 4 together with the carbon atom to which they are attached represent a
- cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of formula (l-a), supra , in which:
- R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
- X 2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C 4 -alkyl, Ci -C 4 -hydroxyalkyl, Ci -C 4 -haloalkyl, Ci -C 4 -alkoxy,
- n represents an integer of 2, 3 or 4,
- (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl and Ci-C2-alkoxy, wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group, wherein X 6 represents a hydrogen atom or a halogen atom,
- R 2 represents a group selected from phenyl, naphthyl and pyridinyl
- phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
- 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
- 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
- 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
- R 3 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 - alkoxy, C 2 -C6-hydroxyalkoxy, (Ci-C 2 -alkoxy)-(C 2 -C 4 -alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-, hydroxy, (R 5 )(R 6 )N-(C 2 -C 3 -alkoxy)-, (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- and -C( 0)OR 7 ,
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
- (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and oxo, and
- (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
- R 4 represents a hydrogen atom, a halogen atom, or a group selected from
- Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
- R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
- Ci-C 4 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 4 -alkyl and C 3 -C 4 -cycloalkyl
- R 5 and R 6 together with the nitrogen to which they are attached represent a
- R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
- R 8 represents a Ci-C 4 -alkyl group
- the present invention covers compounds of formula (l-a), supra , in which:
- R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
- X 2 represents a hydrogen atom or a group selected from
- (4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
- (4- to 7-membered heterocycloalkyl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
- Ci -C 2 -alkyl Ci -C 2 -hydroxyalkyl, hydroxy and oxo,
- phenyl part of said phenyl-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl and Ci-C 2 -alkoxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a halogen atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom,
- R 2 represents a group selected from phenyl and naphthyl
- phenyl and naphthyl group is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from
- R 3 represents a hydrogen atom or a group selected from
- Ci -C 4 -alkyl Ci -C 4 -alkoxy, C2-C 6 -hydroxyalkoxy and hydroxy
- R 4 represents a hydrogen atom or a group selected from
- Ci -C 4 -alkyl and Ci-C 4 -haloalkyl are Ci-C 4 -alkyl and Ci-C 4 -haloalkyl
- the present invention covers compounds of formula (l-a), supra , in which:
- R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
Abstract
La présente invention porte sur des composés de la 1,3,9-triazaspiro[5.5]undécan-2-one de formule générale (I) et de formule générale (I-a) : (I) et (I-a), dans lesquelles R1, R2, R3 et R4 sont tels que définis dans la description, sur des procédés de préparation desdits composés, des composés intermédiaires utiles pour la préparation desdits composés, des compositions et des associations pharmaceutiques comprenant lesdits composés et l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques pour le traitement et/ou la prophylaxie de maladies, en particulier de troubles hyperprolifératifs, en monothérapie ou en association avec d'autres principes actifs.
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