WO2020048830A1 - Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one - Google Patents
Composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one Download PDFInfo
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- WO2020048830A1 WO2020048830A1 PCT/EP2019/072879 EP2019072879W WO2020048830A1 WO 2020048830 A1 WO2020048830 A1 WO 2020048830A1 EP 2019072879 W EP2019072879 W EP 2019072879W WO 2020048830 A1 WO2020048830 A1 WO 2020048830A1
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- undecan
- carbonyl
- diazaspiro
- fluorophenyl
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- 0 O=*N(CC1)CCC1(CC(NC1)=O)[C@]1I Chemical compound O=*N(CC1)CCC1(CC(NC1)=O)[C@]1I 0.000 description 5
- XLHFGCJOTNLKKC-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F)=O XLHFGCJOTNLKKC-UHFFFAOYSA-N 0.000 description 2
- VSPMLBIEBIDJRZ-SSDOTTSWSA-N O=C(CC12CCNCC1)NC[C@H]2I Chemical compound O=C(CC12CCNCC1)NC[C@H]2I VSPMLBIEBIDJRZ-SSDOTTSWSA-N 0.000 description 2
- HNUPEFAHODNXJQ-UHFFFAOYSA-N CCOC(CC(CC1)(CCN1C(OC(C)(C)C)=O)C(c(c(F)c1)ccc1F)C#N)=O Chemical compound CCOC(CC(CC1)(CCN1C(OC(C)(C)C)=O)C(c(c(F)c1)ccc1F)C#N)=O HNUPEFAHODNXJQ-UHFFFAOYSA-N 0.000 description 1
- NXJLVQRHQUNGGK-UHFFFAOYSA-N O=C(C1(CCC1)c(cc1)ccc1F)N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F Chemical compound O=C(C1(CCC1)c(cc1)ccc1F)N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F NXJLVQRHQUNGGK-UHFFFAOYSA-N 0.000 description 1
- JJUDTOJICHJCEL-UHFFFAOYSA-N O=C(C1(CCCC1)c(cc1)ccc1F)N(CC1)CCC1(CC(NC1)=O)C1c1cc(F)ccc1 Chemical compound O=C(C1(CCCC1)c(cc1)ccc1F)N(CC1)CCC1(CC(NC1)=O)C1c1cc(F)ccc1 JJUDTOJICHJCEL-UHFFFAOYSA-N 0.000 description 1
- XICKBOVPKAGZGP-QHCPKHFHSA-N O=C(C1(CCCC1)c1ccccc1)N(CC1)CCC1(CC(NC1)=O)[C@@H]1c1ccccc1 Chemical compound O=C(C1(CCCC1)c1ccccc1)N(CC1)CCC1(CC(NC1)=O)[C@@H]1c1ccccc1 XICKBOVPKAGZGP-QHCPKHFHSA-N 0.000 description 1
- SSXOTKPZAUZYDP-UHFFFAOYSA-N O=C(C1(CCCCC1)c1ccccc1)N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F Chemical compound O=C(C1(CCCCC1)c1ccccc1)N(CC1)CCC1(CC(NC1)=O)C1c(cc1)ccc1F SSXOTKPZAUZYDP-UHFFFAOYSA-N 0.000 description 1
- QMUXWNQCIQWGRY-UHFFFAOYSA-N O=C(CC12CCNCC1)NCC2c(cc1)ccc1Cl Chemical compound O=C(CC12CCNCC1)NCC2c(cc1)ccc1Cl QMUXWNQCIQWGRY-UHFFFAOYSA-N 0.000 description 1
- WNLWCHGPXGQANJ-UHFFFAOYSA-N O=C(CC12CCNCC1)NCC2c1ccccc1 Chemical compound O=C(CC12CCNCC1)NCC2c1ccccc1 WNLWCHGPXGQANJ-UHFFFAOYSA-N 0.000 description 1
- WNLWCHGPXGQANJ-ZDUSSCGKSA-N O=C(CC12CCNCC1)NC[C@H]2c1ccccc1 Chemical compound O=C(CC12CCNCC1)NC[C@H]2c1ccccc1 WNLWCHGPXGQANJ-ZDUSSCGKSA-N 0.000 description 1
- ATJVRZUWIFGHBA-UHFFFAOYSA-N OC(C1(CCCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O Chemical compound OC(C1(CCCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O ATJVRZUWIFGHBA-UHFFFAOYSA-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
- C07D471/02—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 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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 5-aryl-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) as described and defined herein, methods of preparing compounds of general formula (I), general formula (l-a), general formula (l-c) and general formula (l-d), 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 5-aryl-3,9-diazaspiro[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, and the use of 5-aryl-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (l-c) and general formula (l-d), which inhibit inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation.
- Cancer is the second most prevalent cause of death in the United States, causing around 590,000 deaths in 2015. While significant progress has been made in identifying some of the likely underlying environmental and hereditary causes of cancer, there is a need for novel therapeutic approaches targeting cancer and related diseases.
- 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.
- YAP1/TAZ small molecule modulators have been described in Johnson R et al, Nature Reviews Drug Discovery, 2014, 13, 63-79 and in Stahn L.C., Characterization of Novel Inhibitors of the Hippo Signaling Pathway in Cancer Cells, Master Thesis, University Rostock, 2017. Dey A et al, (Trends in Cancer, Vol. 5, No. 5, 297-307, 2019) reported on compounds to modulate hippo pathway activity, among them compounds that inhibit YAP-TEAD interaction or decrease YAP expressions. 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.
- W020051 10992 relates to amido compounds as modulators of 1 1 -b hydroxyl steroid dehydrogenase type 1 (11 b HSD1 ) and/or mineralocorticoid receptor (MR).
- 1 1 -b hydroxyl steroid dehydrogenase type 1 11 b HSD1
- MR mineralocorticoid receptor
- WO2015096035 relates to spirocyclic compounds as inhibitors the Renal Outer Modulary Potassium Channel (ROMK).
- ROMK Renal Outer Modulary Potassium Channel
- W02009037168A1 relates to 3,9-diaza-spiro[5.5]undecane and 3,9-diaza-spiro[5.5]undecan-2- one compounds useful for the treatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
- WO2009135788A1 relates to 3,9-diaza-spiro[5.5]undecan-2-one compounds useful for thetreatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
- the state of the art does not describe the 5-aryl-3,9-diazaspiro[5.5]undecan-2-one compounds of general formulae (I) and (l-a) of the present invention as described and defined herein.
- 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 phenyl group
- phenyl, phenoxy, benzyl, benzyloxy and 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 and
- 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 or three times, each substituent independently selected from a halogen atom or 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 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,
- C 3 -C 4 -cycloalkyl and -N(R 3 )(R 4 ), represents a group selected from
- -U-V-W- represents a group selected from
- -X-Y-Z- represents a group selected from
- R 3 and R 4 represent, independently from each occurrence, a hydrogen atom or a group
- Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, C 2 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl,
- R 3 and R 4 together with the nitrogen to which they are attached represent a
- R 5 represents a Ci-C 4 alkyl group
- the present invention covers compounds of general
- R 1 represents a phenyl group
- phenyl, phenoxy, benzyl, benzyloxy and 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 and
- 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 or three times, each substituent independently selected from a halogen atom or 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 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,
- C 3 -C 4 -cycloalkyl and -N(R 3 )(R 4 ), represents a group selected from
- -U-V-W- represents a group selected from
- -X-Y-Z- represents a group selected from
- R 3 and R 4 represent, independently from each occurrence, a hydrogen atom or a group
- Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, C 2 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl,
- R 3 and R 4 together with the nitrogen to which they are attached represent a
- Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, C 2 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl,
- R 5 represents a C 1 -C 4 alkyl group
- the present invention covers compounds of general formula (l-c):
- R 1 represents a group selected from phenyl, 3-fluorophenyl and 4-fluorophenyl, and
- R 2 represents a group selected from wherein
- R 3 represents a group selected from phenyl, 2-fluorophenyl, 4-chlorophenyl,
- 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.
- Ci-C2-alkoxy (Ci-C2-alkoxy)-(C2-C3-alkyl)-
- a given part it is possible for a given part to be attached at any suitable position of said composite substituent, e.g. it is possible for the Ci-C 2 -alkoxy part to be attached to any suitable carbon atom of the C 2 -C3-alkyl part of said (Ci-C2-alkoxy)-(C 2 -C3-alkyl)- group.
- a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
- a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
- substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
- halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
- Ci-C 4 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or ferf-butyl group.
- said group has 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, propyl, or isopropyl group, more particularly 1 or 2 carbon atoms (“Ci-C2-alkyl”), e.g. a methyl or ethyl group.
- Ci-C4-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-C 4 -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 4 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-C 4 -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 4 -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 4 -alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C 4 -aikyl)-0-, in which the term“Ci-C 4 -alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert- butoxy.
- Ci-C 4 -haloalkoxy means a linear or branched, saturated, monovalent Ci-C 4 -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-C 4 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
- C2-C 4 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3 or 4 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, prop-1 -en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, 1 -methylprop-1 -enyl, or a buta-1 ,3-dienyl group.
- C2-C -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3 or 4 carbon atoms.
- Said C 2 -C 4 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl”), but-1 -ynyl, but-2-ynyl, but-3-ynyl, 1 -methylprop-2-ynyl, group.
- 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 -cycloalkyl”), e.g. a cyclopropyl or cyclobutyl group.
- Cs-Ce-cycloalkyloxy means a saturated, monovalent group of formula (C 3 -C 6 -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
- 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.
- a 4-membered ring such as azetidinyl, for example
- 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.
- 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
- 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.
- C1 -C4 as used in the present text, e.g. in the context of the definition of “Ci-C 4 -alkyl”, “Ci-C 4 -haloalkyl”, “Ci-C 4 -hydroxyalkyl”, “Ci-C 4 -alkoxy” or “Ci-C 4 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 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.
- C1 -C4" encompasses Ci , C2, C3, C 4 , C1 -C4, C1 -C3, C1 -C2, C2-C4, C2-C3, and C3-C4;
- C2-C4 encompasses C 2 , C 3 , C 4 , C 2 -C 4 , C2-C3, and C 3 -C 4 ;
- C3-C6 encompasses C3, C 4 , C5, Ce, C3-C6, C3-C5, C3-C4, C 4 -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.
- such 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-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-fert-butyl-
- the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), general formula (l-a), general formula (l-c) and general formula (l-d), particularly deuterium-containing compounds of general formula (I), general formula (l-a), general formula (l-c) and general formula (l-d).
- 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), general formula (l-a), general formula (l-c) and general formula (l-d) is defined as a compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) 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 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, 1 , 124
- isotopes 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, 1 , 124
- the isotopic variant(s) of the compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) preferably contain deuterium (“deuterium-containing compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d)”).
- deuterium-containing compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) preferably contain deuterium (“deuterium-containing compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d)”).
- Isotopic variants of the compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies.
- Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d).
- Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d).
- These isotopic variants of the compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) are useful for in vivo imaging applications.
- Deuterium-containing and 13 C- containing compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
- Isotopic variants of the compounds of general formula (I), general formula (l-a), general formula (l-c) and general formula (l-d) 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.
- a variety of 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), general formula (l-a), general formula (l-c) or general formula (l-d) is defined as a compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d), 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), general formula (l-a), general formula (l-c) or general formula (l-d) 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), general formula (l-a), general formula (l-c) or general formula (l-d) 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), general formula (l-a), general formula (l-c) or general formula (l-d) 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.
- deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
- the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased.
- the potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels.
- a compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) may have multiple potential sites of attack for metabolism.
- deuterium-containing compounds of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d) 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), general formula (l-a), general formula (l-c) or general formula (l-d) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), general formula (l-a), general formula (l-c) or general formula (l-d), 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), general formula (l-a), general formula (l-c) or general formula (l-d) 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 formulae (I) and (l-c) 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.
- 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. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
- 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.
- the compounds of the present invention may exist as tautomers.
- the compounds of the present invention contain a piperidin-2-one moiety and can exist as a lactam, or a lactim, or even a mixture in any amount of the two tautomers, namely :
- 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. For example, see S. M. Berge, et al.“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
- 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- C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C 6 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-C 6 -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 phenyl group
- R 2 represents a group selected from phenyl and pyridinyl
- phenyl and pyridinyl 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 -alkoxy represents a group selected from
- -U-V-W- represents a group selected from
- -X-Y-Z- represents a group selected from
- R 5 represents a C 1 -C 4 alkyl group
- R 1 represents a phenyl group
- R 2 represents a group selected from phenyl and pyridinyl
- phenyl and pyridinyl 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 -alkoxy represents a group selected from
- -U-V-W- represents a group selected from
- -X-Y-Z- represents a group selected from
- R 5 represents a C 1 -C 4 alkyl group
- the present invention covers compounds of general formula (l-a):
- R 1 represents a phenyl group
- R 2 represents a group selected from phenyl and pyridinyl
- phenyl and pyridinyl 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 -alkoxy up selected from
- -U-V-W- represents a group selected from
- R 5 represents a C 1 -C 4 alkyl group
- the present invention covers compounds of general formula (l-a):
- R 1 represents a phenyl group
- R 2 represents a group selected from phenyl and pyridinyl
- phenyl and pyridinyl 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 -alkoxy represents a group selected from
- -U-V-W- represents a group selected from
- -CH 2 -CH CH-, -0-(CH 2 ) 2 - and -CH 2 -0-CH 2 -, and
- -X-Y-Z- represents a group selected from
- R 5 represents a C 1 -C 4 alkyl group
- the present invention covers compounds of general formula (l-a), supra , in which:
- R 1 represents a phenyl group
- R 2 represents a phenyl group
- each substituent independently selected from a bromine atom or a chlorine atom or a fluorine atom or a group selected from methyl, trifluoromethyl and methoxy represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group i optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- R 5 represents an ethyl group
- the present invention covers compounds of general formula (l-a), supra , in which:
- R 1 represents a phenyl group
- R 2 represents a phenyl group
- each substituent independently selected from a bromine atom or a chlorine atom or a fluorine atom or a group selected from methyl, trifluoromethyl and methoxy represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 )3- and -(CH 2 ) 2 -0-, which group is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- R 5 represents an ethyl group
- the present invention covers compounds of general formula (l-a), supra , in which:
- R 1 represents a group selected from
- phenyl 4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,
- R 2 represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- the present invention covers compounds of general formula (l-a), supra , in which:
- R 1 represents a group selected from
- phenyl 4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,
- R 2 represents a group selected from
- -L-M- represents a -(CH 2 ) 2 - group
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
- the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
- the present invention covers compounds of general formula (l-a), supra , which are selected from the group consisting of:
- the present invention covers compounds of general formula (l-a), supra , which are selected from the group consisting of:
- the present invention covers compounds of general formula (l-d),
- R 1 represents a group selected from phenyl, 3-fluorophenyl and 4-fluorophenyl, and
- R 2 represents a group selected from wherein
- R 3 represents a group selected from phenyl, 2-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, 3,5-dimethylphenyl and 4-methoxyphenyl, or tautomers, hydrates, or solvates, or mixtures of same,
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a phenyl group
- R 2 represents a phenyl group, which is optionally substituted, one or two times, each substituent independently selected from a bromine atom or a chlorine atom or a fluorine atom or a group selected from methyl, trifluoromethyl and methoxy, represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- R 5 represents an ethyl group
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a phenyl group
- R 2 represents a phenyl group
- each substituent independently selected from a bromine atom or a chlorine atom or a fluorine atom or a group selected from methyl, trifluoromethyl and methoxy represents a group selected from
- -L-M- represents a -(CH 2 ) 2 - group
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group ft) is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- R 5 represents an ethyl group
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a group selected from
- phenyl 4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,
- R 2 represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group is optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- the present invention covers compounds of general formula (I), supra , in which:
- R 1 represents a group selected from
- phenyl 4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-fluoro-2-methylphenyl,
- R 2 represents a group selected from
- 3-methoxyphenyl represents a group selected from
- -X-Y-Z- represents a group selected from -(CH 2 ) 3 - and -(CH 2 ) 2 -0-, which group optionally substituted one or two times, each substituent independently selected from a methyl, a hydroxy and an oxo group,
- the present invention covers compounds of general formula (l-a), supra , in which:
- R 1 represents a phenyl group
- Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkinyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, C 3 -C6-cycloalkyloxy, phenyl, phenoxy, benzyl, benzyloxy, -SH, -S-(Ci-C 4 -alkyl), -S( 0)-(Ci-C 4 -alkyi),
- phenyl, phenoxy, benzyl, benzyloxy and 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 and
- 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 or three times, each substituent independently selected from a halogen atom or a group selected from
Abstract
La présente invention concerne des composés 5-aryl-3,9-diazaspiro[5.5]undécan-2-one de formule générale (I) et de formule générale (l-a) : dans lesquelles A, R1 et R2 sont tels que définis dans la description, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques destinées au traitement et/ou à la prophylaxie de maladies, et des composés de formule générale (l-c) et de formule générale (l-d) : dans lesquelles R1 et R2 sont tels que définis dans la description, destinés au traitement et/ou à la prophylaxie de maladies, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques.
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