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WO2017109061A1 - Dérivés de spirocyclopropylamine utiles en tant qu'inhibiteurs d'histone déméthylases kdm1a - Google Patents

Dérivés de spirocyclopropylamine utiles en tant qu'inhibiteurs d'histone déméthylases kdm1a Download PDF

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WO2017109061A1
WO2017109061A1 PCT/EP2016/082360 EP2016082360W WO2017109061A1 WO 2017109061 A1 WO2017109061 A1 WO 2017109061A1 EP 2016082360 W EP2016082360 W EP 2016082360W WO 2017109061 A1 WO2017109061 A1 WO 2017109061A1
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cyclopropane
spiro
indane
amine
rans
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PCT/EP2016/082360
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Mario Varasi
Raffaella Amici
Florian Thaler
Ciro Mercurio
Paola Vianello
Maurizio PASI
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Ieo - Istituto Europeo Di Oncologia S.R.L.
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Publication of WO2017109061A1 publication Critical patent/WO2017109061A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Definitions

  • the present invention relates to spirocyclopropyl derivatives, pharmaceutical compositions containing such compounds and to their use in therapy.
  • Histone lysine demethylases represent attractive targets for epigenetic drugs, since their expression and/or activities are often misregulated in cancer (Varier, R. A. et al. Biochim. Biophys. Acta. 201 1 , 1815, 75-89).
  • a lysine can be mono-, di-, and tri-methylated and each modification, even on the same amino acid, can exert different biological effects.
  • Histone lysine demethylases can be grouped into two major families with different enzymatic mechanisms (Anand, R. et al. J. Biol. Chem. 2007, 282, 35425-35429; Metzger, E. et al. Nat. Struct. Mol. Biol. 2007, 14, 252-254).
  • Jumonji C Jumonji C
  • the demethylation reaction is carried out by JmjC domain proteins and where a conserved JmjC domain, the presence of Fe(ll) and a-ketoglutarate is required to generate formaldehyde and succinate and to allow the removal of mono-, di-, and trimethylated lysines.
  • KDM1A flavin dependent amino oxidase histone lysine demethylases
  • KDM1B also known as LSD2
  • KDM1A is a constituent in several chromatin-remodeling complexes and is often associated with the co-repressor protein CoREST. It recruits in this form other histone modifying enzymes such as histone deacetylases 1/2 (HDAC1/2) forming a multienzyme unit typically involved in gene repression regulation (Ballas, N. et al. Neuron 2001 , 31 , 353-365).
  • HDAC1/2 histone deacetylases 1/2
  • KDM1 A represents an interesting target for epigenetic drugs as supported by data related to its over-expression in solid and hematological tumors (Schulte, J. H. et al. Cancer Res. 2009, 69, 2065-2071 ; Lim, S. et al. Carcinogenesis 2010, 31 , 512-520; Hayami, S. et al. Int. J. Cancer 201 1 , 128, 574-586; Schildhaus, H. U. et al. Hum. Pathol. 201 1 , 42, 1667- 1675; Bennani-Baiti, I. M. et al. Hum. Pathol.
  • KDM1A in the control of other important cellular processes, such as DNA methylation (Wang, J. et al. Nat. Genet. 2009, 41 (1 ): 125-129), cell proliferation (Scoumanne, A. et al. J. Biol. Chem. 2007, 282, 15471 - 15475; Cho, H. S. et al. Cancer Res. 201 1 , 71 , 655-660), epithelial mesenchimal transition (Lin, T. et al. Oncogene. 2010, 29, 4896-4904), and chromosome segregation (Lv, S. et al. Eur. J. Cell Biol. 2010, 89, 557-563).
  • KDM1 A inhibitors were able to reactivate silenced tumor suppressor genes (Huang, Y. et al. Proc. Natl. Acad. Sci. U S A. 2007, 104, 8023-8028; Huang, Y. et al. Clin. Cancer Res. 2009, 15, 7217-7228), to target selectively cancer cells with pluripotent stem cells properties (Wang, J. et al. Cancer Res. 201 1 , 71 , 7238-7249), as well as to reactivate the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia (Schenk, T. et al. Nat Med. 2012, 18, 605-61 1 ).
  • KDM1 B The more recently discovered demethylase KDM1 B (LSD2) displays -similarly to KDM1A- specificity for mono- and di-methylated Lys4 of histone H3.
  • KDM1 B differently from KDM1A, does not bind CoREST and it has not been found up to now in any of KDM1A- containing protein complex (Karytinos, A. et al. J. Biol. Chem. 2009, 284, 17775-17782).
  • KDM1 B forms active complexes with euchromatic histone methyltransferases G9a and NSD3 as well as with cellular factors involved in transcription elongation.
  • KDM1 B has been reported to have a role as regulator of transcription elongation rather than that of a transcriptional repressor as proposed for KDM1A (Fang, R. et al. Mol. Cell 2010, 39, 222-233).
  • KDM1A and KDM1 B are both flavo amino oxidases dependent proteins sharing a FAD coenzyme-binding motif, a SWIRM domain and an amine oxidase domain, all of which are integral to the enzymatic activity of KDM1 family members. Moreover, both KDM1A and KDM1 B show a structural similarity with the monoamine oxidases MAO-A and MAO-B. Indeed, tranylcypromine, a MAO inhibitor used as antidepressive agent, was found to be also able to inhibit LSD1. The compound acts as an irreversible inhibitor forming a covalent adduct with the FAD cofactor. (Lee, M. G. et al. Chem. Biol. 2006, 13, 563; Schmidt, D. M. Z. et al. Biochemistry 2007, 46, 4408).
  • MAOs are well known targets for the treatment of diseases of the central nervous system, such as depression or Parkinson's disease.
  • inhibition of the MAOs are associated with side effects, among them tyramine-induced hypertensive crisis or the serotonin syndrome, which occurs in situation of concomintant use of MAO inhibitors and other serotoninergic drugs.
  • tyramine-induced hypertensive crisis or the serotonin syndrome which occurs in situation of concomintant use of MAO inhibitors and other serotoninergic drugs.
  • Oryzon Genomics S.A disclosed in WO2010/043721 , WO2010/084160, WO201 1/035941 , WO201 1/042217, and in WO2012/013728, cyclopropylaminoalkylamides, N-heterocyclyl-, aryl-, or heteroarylalkylcyclopropylamines with LSD1 , MAO-A and/or MAO-B inhibitory activity.
  • Spiro[cyclopropane-2,1 '-indane]-1 -amine (CAS 1250204-62-6, Enamine Cat. Nbr. EN300- 149242), spiro[cyclopropane-2,1 '-tetralin]-1 -amine (CAS 1375474-45-5, Enamine Cat. Nbr. EN300-147284), spiro[chromane-4,2'-cyclopropane]-1 '-amine (CAS 1375474-45-5, Enamine Cat. Nbr. EN300-147140) are commercially available compounds, e.g. provided by Enamine, but no use has been associated to them.
  • A18.557.868, A18.557.869, A18.557.870, A18.576.368, A18.576.369, A18.576.370, A18.626.1 18, A18.626.1 19, A18.626.120) are disclosed in the Aurora Screening Library, but no use has been associated to them.
  • the present invention relates to substituted cyclopropylamine derivatives having highly potent inhibitory activities of the KDM1A enzyme and low inhibitory activity of monoamine oxidases (MAOs), useful in the prevention or therapy of diseases and conditions associated with the activity of the histone demethylases.
  • MAOs monoamine oxidases
  • spirocyclopropylamine compounds endowed with a potent KDM1A (LSD1 ) inhibitory activity, of general formula (I)
  • C1-C6 alkyi substituted by aryl or heteroaryl wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyi, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, OH and NH 2 ;
  • heterocydyl may be optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyi, C-i-C-6 alkyi substituted by aryl, aryl, or (CO)R 3 ;
  • heterocydyl optionally substituted by one or more substituents independently selected from the group consisting of Ci-C 6 alkyi, Ci-C 6 alkyi substituted by aryl;
  • aryl is aryl, wherein the aryl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci- Ce alkyi, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, or Ci-C 6 haloalkoxy
  • R 4 , R 5 are, independently, hydrogen; C1 -C6 alkyl; or R 4 and R 5 together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR 7 , O or S and being optionally substituted by NH 2 ;
  • R 6 , R 7 are, independently, hydrogen; or Ci-C 6 alkyl
  • the invention provides compounds of general formula (I) for the use as a medicament wherein aryl is phenyl.
  • the invention provides compounds of general formula (I)
  • X is a bond, oxygen or CH 2 ;
  • R is hydrogen, halogen, or R 2 -L-;
  • R is hydrogen
  • heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkyl substituted by phenyl, or
  • heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyl;
  • R 2 is phenyl, wherein the phenyl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, or Ci-C 6 haloalkoxy L is a single bond; -(CH 2 ) m -Y-(CH 2 ) n -; or (CO)NR 6 -;
  • n are, independently, zero or 1 ;
  • Y is oxygen
  • R 3 is C1-C-6 alkyl or phenyl
  • R 4 , R 5 are, independently, hydrogen; C 1 -C6 alkyl; or R 4 and R 5 together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR 7 ;
  • R 6 , R 7 are, independently, hydrogen; or Ci-C 6 alkyl
  • Particularly preferred compounds of general formula (I) for the use as a medicament include:
  • the invention provides the compounds of general formula (I) for use as KDM1 inhibitors.
  • the invention provides the compounds of general formula (I) for the use in the treatment and/or prevention of cancer, infectious diseases or a disease characterized by aberration of cellular energy metabolism, such as obesity.
  • the compounds of general formula (I) are for the use in the treatment and/or prevention of leukemia, non-small cell lung cancer, hepatocellular carcinoma, or glioblastomas. Still preferably the glioblastomas are giant cell glioblastoma or gliosarcoma.
  • a further embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I), together with a pharmaceutically acceptable excipient and/or diluent.
  • the pharmaceutical composition may further comprise at least one further therapeutic agent, preferably selected from the group consisting of histone deacetylase inhibitors, retinoid receptor modulators, anti-proliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, anti- angiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors, IGF1/insulin inhibitors or a chemotherapeutic agent.
  • the invention further provides a combination of the compound as defined above and a calorie restricted diet and/or a caloric restriction mimetic and/or at least one IGF1 /insulin inhibitor.
  • a calorie restricted diet means that the daily caloric intake is reduced by 10 to 100% and lasts for a period of about 24 hours to about 190 hours. The reduction is compared to a regular caloric intake per day.
  • Regular caloric intake per day is between 1200 Kcal and 3000 Kcal.
  • regular caloric intake per day (the range is based on age, sex and physical activity) is:
  • the IGF1/insulin inhibitor may be any known inhibitor, for instance as described in Clemmons DR, Nat. Rev. Drug Discov., 6, 821 -833, 2007, incorporated by reference.
  • the invention provides compounds of general formula (I)
  • the invention provides compounds of general formula (I) wherein aryl is phenyl.
  • the invention provides compounds of general formula (I)
  • X is a bond, oxygen or CH 2 ;
  • R is hydrogen, halogen, or R 2 -L-;
  • R is hydrogen
  • heterocyclyl substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C1-C6 alkyl, d-C-6 alkyl substituted by phenyl, or (CO)R 3 ;
  • heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyl;
  • R 2 is phenyl, wherein the phenyl may be optionally substituted by one, two or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, or Ci-C 6 haloalkoxy L is a single bond; -(CH 2 )m-Y-(CH 2 )n-; or (CO)NR 6 -;
  • n are, independently, zero or 1 ;
  • Y is oxygen;
  • R 3 is C-i-C-6 alkyl or phenyl;
  • R 4 , R 5 are, independently, hydrogen; C 1 -C6 alkyl; or R 4 and R 5 together with the nitrogen to which they are bound form a heterocyclic ring, optionally containing one or more further heteroatoms in the ring independently selected from NR 7 ;
  • R 6 , R 7 are, independently, hydrogen; or Ci-C 6 alkyl
  • Particularly preferred compounds of general formula (I) include:
  • aryl represents a mono or bicyclic aromatic ring system of, respectively, 6, 9 or 10 atoms, examples of such an aryl are phenyl, indenyl, indanyl and naphthyl and tetrahydronaphthalenyl.
  • Heteroaryl represents a mono or bicyclic heteroaromatic ring system of, respectively, 5 to 10 members, which contains one, two, three or four heteroatoms selected from nitrogen, oxygen or sulphur and one to nine carbon atoms.
  • heteroaryls include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[£>]thienyl, benzopyranyl, indazolyl, benzimidazolyl, purinyl, quinolyl, isoquinolyl, quinazolin
  • Heterocyclyl represents a mono or bicyclic saturated or partially saturated non-aromatic ring system of, respectively, 4 to 12 members, which contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulphur and three to eleven carbon atoms.
  • heterocycles include, but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxolyl, 2,3- dihydro-benzodioxinyl, benzoxazolyl, azepinyl, diazapinyl and tropinyl.
  • heterocyclic ring represents a mono or bicyclic saturated or partially saturated non- aromatic ring system of, respectively, 4 to 10 members, which contains one nitrogen and optionally one or more heteroatoms selected from nitrogen, oxygen, and sulphur.
  • heterocycles include, but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, azepinyl, diazapinyl and tropinyl.
  • halogen refers to fluoro, chloro, bromo, or iodo.
  • d-C-6 alkyl refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms.
  • Suitable examples of Ci-C 6 alkyl include methyl, ethyl, n-propyl, ispropyl, butyl, te/t-butyl, pentyl, and hexyl.
  • C-3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms. Suitable examples of C-3-6-cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C-i-C-6 alkoxy refers to a straight or branched O-C1 -C6 alkyl, where alkyl is as defined herein.
  • the "C1 -C6 alkoxy” group is preferably a linear or branched Ci-C 4 alkoxy group, more preferably a C1 -C2 alkoxy group.
  • C1 -C6 haloalkyi refers to a straight or branched hydrocarbon chain radical, which is substituted by one or more halogen atoms and having from one to six carbon atoms.
  • the "C1 -C6 haloalkyi” group is preferably a linear or branched Ci-C 4 haloalkyi group, more preferably a C1 -C2 haloalkyi group, being in particular CF 3 .
  • C-i-C-6 haloalkoxy refers to a straight or branched O-C-i-C-6 haloalkyi, where haloalkyi is as defined herein.
  • the "C-i-C-6 haloalkoxy” group is preferably a linear or branched Ci-C haloalkoxy group, more preferably a C1 -C2 haloalkoxy group, being in particular OCF 3 , OCHF 2 or OCH 2 F.
  • Pharmaceutically acceptable salts comprise conventional non-toxic salts obtained by salification of a compound of formula (I) with inorganic acids (e.g. hydrochloric, hydrobromic, sulphuric, or phosphoric acids), or with organic acids (e.g. acetic, propionic, succinic, benzoic, cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, maleic, malonic, fumaric, tartaric, citric, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or naphthalensulfonic acids).
  • inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, or phosphoric acids
  • organic acids e.g. acetic, propionic, succinic, benzoic, cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, mal
  • the compounds of formula (I) may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, EtOH and the like.
  • Compounds of formula (I) contain two or more asymmetric carbon atoms.
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated 3 H, and carbon-14 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • R and X are as defined above for fomula (I);
  • PG and PG 1 are protecting groups chosen among those known in the art. Examples of a suitable protecting group for PG may include methyl, ethyl etc. and examples for PG 1 may include a carbamate, for instance (1 ,3-benzodioxol-5-ylmethylamino)carbamate or (2- trimethylsilylethylamino)carbamate.
  • Compounds of formula A1 are known compounds or can be prepared by known methods, e.g. in case where R is R 2 -L, wherein R 2 is as defined above and L is (CH 2 ) p (CO)NR 6 - with p and R 6 as defined above, by reacting a compound of formula A1 , wherein R is NH 2 with a compound R 2 -CO-W, wherein W is a halogen atom, e.g. chloride or bromide in presence of a suitable base, for instance triethylamine (TEA), in an appropriate solvent, for example in tetrahydrofuran (THF) or toluene, at a temperature ranging from 0°C to the boiling point of the solvent.
  • a suitable base for instance triethylamine (TEA)
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • Compounds of formula A2 can be obtained by reacting triphenylmethylphosphonium bromide with a compound of formula A1 in presence of a suitable base, for instance potassium te/t-butoxide, in a suitable solvent, for instance THF or toluene, at a temperature ranging from 0°C to the boiling point of the solvent.
  • a suitable base for instance potassium te/t-butoxide
  • a suitable solvent for instance THF or toluene
  • a compound of formula A3 can be obtained by treating a compound of formula A2 with ethyl diazoacetate in presence of a suitable catalyst, which can be a Rh(ll) or copper based catalyst such as rhodium acetate, in a suitable solvent, for instance dichloromethane (DCM), at a temperature ranging from RT to the boiling point of the solvent.
  • a suitable catalyst which can be a Rh(ll) or copper based catalyst such as rhodium acetate
  • a suitable solvent for instance dichloromethane (DCM)
  • DCM dichloromethane
  • a compound of formula A4 can be obtained according to known methods, e.g. when the compound of formula A3 is a methyl or ethyl ester, by treatment of an ethyl ester with LiOH, NaOH or KOH in a suitable solvent, for example in ethanol/water, in THF ethanol/water, in methanol/water, or in a dioxane/ethanol/water mixture.
  • a suitable solvent for example in ethanol/water, in THF ethanol/water, in methanol/water, or in a dioxane/ethanol/water mixture.
  • the hydrolysis may be carried out at a temperature ranging from 0°C to the boiling point of the solvent.
  • the isocyanate compounds of formula A5 can be prepared by reacting a carboxylic acid of formula A4 with [azido(phenoxy)phosphoryl]oxybenzene in presence of a suitable base, for instance TEA, in a suitable solvent, for instance toluene, at a temperature ranging from 0°C to the boiling point of the solvent.
  • a suitable base for instance TEA
  • a suitable solvent for instance toluene
  • the isocyanate of formula A5 can be converted into a protected amine A6 by reacting with a suitable alcohol, for instance benzyl alcohol, 1 ,3-benzodioxol-5-ylmethanol or 2- trimethylsilylethanol, in in a suitable solvent, for instance toluene or THF, at a temperature ranging from RT to the boiling point of the solvent, forming a carbamate derivative.
  • a suitable alcohol for instance benzyl alcohol, 1 ,3-benzodioxol-5-ylmethanol or 2- trimethylsilylethanol
  • a suitable solvent for instance toluene or THF
  • the reaction may be carried out under microwave irradiation and a suitable base, such as TEA, may be added.
  • a suitable base such as TEA
  • the reaction is carried out under nitrogen atmosphere.
  • the protected amine A6, wherein X and PG is a defined above, and R is bromide or iodide, can be converted into a protected amine A6, wherein R is R 2 -(CH 2 ) p (CO)NR 6 and R 2 , p and R 6 as defined above, according to the Ullmann or the Buchwald-Hartwig type reaction.
  • a compound of formula A6 is treated with a compound of formula R 2 -(CH 2 ) P (CO)NR 6 -H in presence of a copper catalyst, for instance Cul, and a base, for example K 2 CO 3 , N,W-dimethylethane-1 ,2-diamine or 2-aminoethanol, in a suitable solvent, for example in dimethylacetamide or dioxane, at temperature ranging from room temperature to the boiling point of the solvent.
  • a copper catalyst for instance Cul
  • a base for example K 2 CO 3 , N,W-dimethylethane-1 ,2-diamine or 2-aminoethanol
  • a suitable solvent for example in dimethylacetamide or dioxane
  • the reaction may be carried out under microwave irradiation.
  • the reaction is carried out under nitrogen atmosphere.
  • a compound of formula A6 is treated with a compound of formula R 2 -(CH 2 ) p (CO)NR 6 -H in presence of a catalyst, for instance palladium or a palladium salt, for example palladium (II) acetate and tris(dibenzylideneacetone)dipalladium(0), and a phosphine ligand, for instance triphenylphosphine, tri(o-tolyl)phosphine, 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl) (BINAP), and a base, for example C-S2CO3, in a suitable solvent, for example dioxane, toluene or THF, at temperature ranging from room temperature to the boiling point of the solvent.
  • a catalyst for instance palladium or a palladium
  • the carbamate may be hydrolysed providing a compound of formula (I) by reaction with an acid, for instance hydrobromic acid (HBr) or hydrochloric acid (HCI), in a suitable solvent, for instance acetic acid, THF or diethylether (Et 2 O), at a temperature ranging from 0°C to the boiling point of the solvent.
  • an acid for instance hydrobromic acid (HBr) or hydrochloric acid (HCI)
  • a suitable solvent for instance acetic acid, THF or Et 2 O
  • R is Ci-C 6 alkyl; d-C 6 alkyl substituted by C 3 - C6 cycloalkyl; C 1 -C6 alkyl substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, OH and NH 2 ; C 1 -C6 alkyl substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkyl substituted by aryl, aryl, or (CO)R 3 ; C 3 -C 6 cycloalkyl optionally substituted by NH 2 ; heterocyclyl optionally substituted
  • R and X are as defined above for fomula (I);
  • R 8 is d-C-6 alkyi; d-C-6 alkyi substituted by C 3 -C 6 cycloalkyl; Ci-C 6 alkyi substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyi, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, C-I -C6 haloalkoxy, OH and NH 2 ; C-i-C-6 alkyi substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C-i-C-6 alkyi, C-i-C-6 alkyi substituted by aryl, aryl, or COR 3 ; C 3 -C 6 cycloalkyl optionally substituted by
  • R 9 is C 1 -C5 alkyi; C 1 -C5 alkyi substituted by C 3 -C 6 cycloalkyl; C 1 -C5 alkyi substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, Ci-C 6 alkyi, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, OH and NH 2 ; C-i- C5 alkyi substituted by heterocyclyl, wherein the heterocyclyl may be optionally substituted by one or more substituents independently selected from the group consisting of C 1 -C6 alkyi, Ci-C 6 alkyi substituted by aryl, aryl, or COR 3 ; R 0 is hydrogen or R 9 and R 0 form together with the carbon atom to which they are bound a C 3 -
  • Reaction of a compound of formula B1 with a compound of formula R 8 -W (B2) can be carried in a suitable solvent (e.g. DMF) in the presence of a suitable base (e.g. NaH).
  • a suitable solvent e.g. DMF
  • a suitable base e.g. NaH
  • the reaction may be carried out at a temperature between 0°C to the boiling point of the solvent.
  • said chemical group may be protected and deprotected according to known methods (e.g. a protecting group is a te/t-butyloxycarbonyl group).
  • compounds of general formula (I), wherein R is other than hydrogen or -CH 2 (CO)NR 4 R 5 may be prepared according to Scheme B by reaction of a compound of formula B1 with a compound of formula R 9 -CO- R 0 (B3), preferably under nitrogen atmosphere, in a suitable organic solvent (e.g. dichloroethane, CH 2 CI 2 , MeOH, EtOH, DMF or tetrahydrofuran) at a temperature between about 0°C and 70°C in the presence of a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • a suitable organic solvent e.g. dichloroethane, CH 2 CI 2 , MeOH, EtOH, DMF or tetrahydrofuran
  • a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • Compounds of formula B1 may be for example prepared according to Scheme A.
  • the compounds of the present invention are useful in the prevention or treatment of tumor type diseases, including but not limited to: acute and chronic myeloid leukaemia, acute and chronic lymphoblastic leukaemia, myelodysplastic syndromes, multiple myeloma, Hodgkin's disease, non- Hodgkin's lymphomas, cutaneous and peripheral T-cell lymphoma, adult T-cell leukemia, large B-cell lymphoma; mammary tumors; pulmonary tumors and pleural mesotheliomas, adenocarcinoma, non-small lung cancer, small-cell lung cancer; skin tumors including basal cell carcinomas (basaliomas), melanomas, squamous cell carcinoma, Kaposi's sarcoma, keratocanthomas; osteosarcomas, fibrosarcomas, rhabdomyosarcomas, neuroblastomas, glioblastomas, cerebral tumors
  • tumor type diseases including but not limited
  • the compounds of the invention are also useful in the prevention or treatment of infections, including, but not limited to, infections caused by protozoa, fungi, phytotoxic agents, viruses and parasites, for example HIV or herpes virus infections.
  • the compounds of the invention are also useful in the prevention or treatment of diseases characterized by aberration of cellular energy metabolism, such as obesity (Hino S. et al. Nat Commun. 2012, doi: 10.1038/ncomms1755).
  • the compounds of formula (I) can also be used in combination with additional agents, in particular anti-tumor and differentiating agents, either by separate administrations, or by including the two active principles in the same pharmaceutical formulation.
  • additional agents include:
  • histone deacetylase inhibitors for example, but not limited to SAHA, PXD101 , JNJ- 26481585, SB939, ITF-2357, LBH589, PCI-24781 , valproic acid, butyric acid, MS-275, MGCD0103 and FK-228);
  • retinoid receptor modulators such as 13-c/s-retinoic acid, 9-c/s-retinoic acid, bexarotene, alitretinoin, or tretinoin; vitamin D;
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example platin derivatives like c/s-platin, carboplatin, oxaliplatin, lobaplatin, satraplatin, nedaplatin, heptaplatin; nitrogen mustard such as chlorambucil, melphalan, chlormethine, cyclophosphamide, ifosfamide, trofosfamide, uramustine, bendamustine, estramustine; busulphan, temozolomide or nitrosoureas); antimetabolites (for example antifolates such as aminopterin, methotrexate, pemetrexed, raltitrexed); purines such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine; pyrimidines like capecitabine, cylating agents
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, liarozole or cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha-reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifen
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function for example growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibodies figitumumab (CP- 751 ,871 ), cixutumumab (IMC-A12), dalotuzumab (MK-0646; h7C10), ganitumab (AMG 479), R1507 and MEDI-573 (IGF1 -IFG2)), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors (for example the tyrosine kinase inhibitors against IGF-1 R linsitinib (OSI-906), BMS-754807, BVP 51004, or XL228) and serine/threonine kinase inhibitors, for example enzastaurin
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab, lenalidomide or thalidomide;
  • cell cycle inhibitors including for example CDK inhibitors (for example but not limited to flavopiridol, roscovitine) and other inhibitors of cell cycle checkpoints; inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation;
  • proteasome inhibitors for example lactacystin, bortezomib, epoxomicin
  • HSP90 inhibitors for example but not limited to AT-13387, KOS-953, KOS-1022, CNF-1010, CNF-2024, SNX 5422, STA-9090, NVP-HSP990, NVP-AUY922, PU-H17 and XL -888
  • Selective COX-2 inhibitors for example celecoxib
  • non selective NSAIDs for example diclofenac, flurbiprofen, ibuprofen, ketoprofen, or naproxen.
  • a compound of general formula (I) can be used in combination with radiation therapy.
  • a compound of general formula (I) may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • CAF cyclophosphamide, doxorubicin and 5-fluorouracil
  • AC doxor
  • the invention also provides pharmaceutical compositions comprising one or more compounds of formula (I) and one or more pharmaceutically acceptable excipient and/or diluent.
  • the pharmaceutical compositions can be chosen on the basis of the treatment requirements.
  • Such compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable, or infusible liquid solutions, suspensions, or suppositories.
  • Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • the oral solid compositions can be prepared by conventional methods of blending, filling or tableting.
  • the blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers.
  • Such operations are conventional.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents.
  • Oral formulations also include conventional slow-release formulations such as enterically coated tablets or granules.
  • composition for administration by inhalation can be delivered from an insufflator or a nebulizer pressurized pack.
  • parenteral administration fluid unit dosages can be prepared, containing the compound and a sterile vehicle.
  • the compound can be either suspended or dissolved, depending on the vehicle and concentration.
  • the parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilising by filtration, filling suitable vials and sealing.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle.
  • the composition can be frozen after having filled the vials and removed the water under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions may be tablets, lozenges, pastilles, or gel.
  • the compounds can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • suppositories or retention enemas e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres.
  • ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights.
  • Creams are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol.
  • Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • transdermal delivery comprises conventional aqueous and non- aqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches.
  • the compounds of the present invention may be employed alone as a sole therapy or in combination with other therapeutic agents (see the list of additional agents is as indicated previously and comprises also standard chemotherapeutic agents) for the treatment of the above-mentioned conditions.
  • the combination can be administered as separate compositions (simultaneous, sequential) of the individual components of the treatment or as a single dosage form containing both agents.
  • the active ingredients may be separately formulated into single-ingredient preparations of one of the above-described forms and then provided as combined preparations, which are given at the same time or different times, or may be formulated together into a two- or more- ingredient preparation.
  • Compounds of general formula (I) may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The determination of optimum dosages for a particular patient is well known to one skilled in the art.
  • compositions are normally accompanied by written or printed instructions for use in the treatment in question.
  • DIPEA A/,A/-diisopropylethylamine
  • DMF dimethylformamide
  • MAO A (monoamine oxidase A)
  • MAO B (monoamine oxidase B)
  • the 1 H-NMR spectra were acquired with a Varian 500 MHz instrument.
  • the chemical shifts are expressed in parts per million (ppm, ⁇ units).
  • the coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).
  • the LC-MS analyses were carried out on a Waters Acquity UPLC or Waters Acquity UPLC H-Class linked to with a SQD Single quadrupole (Waters) using an Acquity UPLC BEH C18 (50 x 2.1 mm, 1.7 ⁇ ) or Acquity UPLC HSS T3 (50 x 2.1 mm, 1 .8 ⁇ ) column.
  • Phase A was composed by either Milli-Q water/CH 3 CN 95/5 + 0.07% formic acid or Milli-Q water + 0.07% formic acid; Phase B by CH 3 CN + 0.05% formic acid; flow rate: 0.6 mL/min; UV detection (DIODE array) from 210 to 400 nm; ESI+ detection in the 100-2000 m/z range.
  • the structure of all intermediates and final products was confirmed by NMR and LC-MS analysis. The yields were calculated assuming that products were 100% pure if not stated otherwise.
  • ethyl spiro[cyclopropane-2,1 '-indane]-1 - carboxylate as a colorless oil (3.51 g, 65%).
  • the obtained ethyl spiro[cyclopropane-2,1 '- indane]-1 -carboxylate is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS).
  • ethyl 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.555 g (2.65 mmol) of 5-bromo-1 -methylene-indane (Intermediate 3).
  • the obtained ethyl 5'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of the two different isomers regarding to the cyclopropyl ring (CIS and TRANS).
  • 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.800 g (2.71 mmol) of ethyl 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 8).
  • the obtained 5'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS).
  • 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid was prepared according to the procedure described for Intermediate 13, starting from 0.950 g (3.22 mmol) of ethyl 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate (Intermediate 9).
  • the obtained 6'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylic acid is a mixture of two different isomers regarding to the cyclopropyl ring (CIS and TRANS).
  • the reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form.
  • the c/ ' s and trans isomers were determined by NMR (NOE) analysis.
  • the reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cydopropyl ring) in their racemic form.
  • the cis and trans isomers were determined by NMR (NOE) analysis.
  • N-[trans-2-aminospiro[cvclopropane-1,3'-indanel-5'-yllbenzamide hvdrochoride 0.022 g (74%) of N-[£rans-2-aminospiro[cyclopropane-1 ,3'-indane]-5'-yl]benzamide hydrochoride was prepared according to the procedure described for Example 2, Step 3, starting from 0.040 g (0.095 mmol) of 2-trimethylsilylethyl N-[trans-6'- benzamidospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate.
  • Example 5 frans-5'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide and Example 6: c;s-5'-Bromospiro[cyclopropane-2,1'-indane]-1 -amine hydrobromide
  • the reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form.
  • the cis and trans isomers were determined by NMR (NOE) analysis.
  • Example 12 /V-[frans-2-Aminospiro[cyclopropane-1 ,4'-tetralin]-6'-yl]benzamide hydrochloride
  • the reaction mixture was cooled with ice, quenched by adding aqueous saturated NaHC0 3 and the product was extracted with DCM. The organic phase was dried over Na 2 S0 4 , filtered and the solution concentrated with nitrogen. The solution was cooled with ice, then 0.034 ml (0.24 mmol) of TEA and 0.050 g (0.23 mmol) of di-te/t-butyl dicarbonate were added under nitrogen. The solution was stirred at r.t overnight. The reaction mixture was diluted with DCM, washed with brine, dried and concentrated.
  • Example 17 c;s-5'-Bromo-/V-(4-piperidylmethyl)spiro[cyclopropane-2,1'-indane]-1 - amine dihydrochloride
  • Example 18 frans-/V-(4-Piperidylmethyl)spiro[cyclopropane-2,1'-tetralin]-1 -amine dihydrochloride
  • 0.040 ml (0.29 mmol) of TEA were added to a solution of 0.060 g (0.29 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 11 ) in 3 ml of dry MeOH under nitrogen. Then, 0.061 g (0.29 mmol) of te/t-butyl 4-formylpiperidine-1 -carboxylate was added and the reaction mixture was stirred at r.t. for 3.5 h. 0.017 g (0.43 mmol) of NaBH 4 was then carefully added, and the mixture was stirred at r.t. for 1 h.
  • the reaction was quenched with water and extracted with EtOAc. The organic phase was dried over Na 2 S0 4 , filtered and the solvent was evaporated. The residue was solubilised in 7 ml of DCM, the solution was cooled with ice and 0.050 ml (0.36 mmol) of TEA and 0.075 g (0.34 mmol) of di-te/t-butyl dicarbonate were added under nitrogen. The solution was stirred at r.t for 1 h, then kept in the freezer overnight. The reaction mixture was diluted with DCM, washed with brine, dried and concentrated.
  • Example 20 fra/7S-6 , -Bromo-A -(4-piperidylmethyl)spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride
  • 0.031 g (83%) of irans-6'-Bromo-A/-(4-piperidylmethyl)spiro[cyclopropane-2,1 '-indane]-1 - amine dihydrochloride was prepared according to the procedure described for Example 16, Step 2. starting from 0.040 g (0.092 mmol) of te/t-butyl 4-[[[trans-6'- bromospiro[cyclopropane-2, 1 '-indane]-1 -yl]amino]methyl]piperidine-1 -carboxylate.
  • 0.013 ml (0.095 mmol) of TEA was added to a solution of 0.020 g (0.095 mmol) of trans- spiro[cyclopropane-2,1 '-tetralin]-1 -amine hydrochloride (Example 10) in 1 ml of dry MeOH under nitrogen. Then, 9.7 ⁇ (0.095 mmol) of benzaldehyde was added and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was ice-cooled and 0.0056 g (0.14 mmol) of NaBH 4 was added, and the mixture was stirred at r.t. for further 1 h.
  • Example 8 0.036 g (56%) of irans-N-(cyclopropylmethyl)spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 21 , starting from 0.050 g (0.26 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8).
  • Example 25 fra/7S-A -[2-(4-Piperidyl)ethyl]spiro[cyclopropane-2,1'-indane]-1 -amine dihydrochloride
  • Example 8 0.018 g (36%) of irans-N-[2-(4-piperidyl)ethyl]spiro[cyclopropane-2,1 '-indane]-1 -amine dihydrochloride was prepared according to the procedure described for Example 20, starting from 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride (Example 8).
  • Example 26 1 -Methyl-/V-[frans-spiro[cyclopropane-2,1'-indane]-1 -yl]piperidin-4- amine dihydrochloride
  • 0.021 ml (0.15 mmol) of TEA and 0.018 ml (0.15 mmol) of 1 -methylpiperidin-4-one were added under nitrogen to a solution of 0.030 g (0.15 mmol) of £rans-spiro[cyclopropane- 2,1 '-indane]-1 -amine hydrochloride (Example 8) in 2 ml of dry MeOH.
  • the mixture was stirred at r.t. for 3 h.
  • the solution was then treated with 0.048 g (0.21 mmol) of NaBH(OAc)3 at 0°C and the mixture was stirred at r.t. overnight.
  • the reaction mixture was cooled with ice, quenched by adding 3 ml of 0.1 M NaOH and the product was extracted with EtOAc. The EtOAc extract was dried over Na 2 SO 4 , filtered and the solution concentrated.
  • the crude mixture was purified by flash chromatography (eluent: DCM/MeOH/30% NH 4 OH aq. 95:5:0.5).
  • the resulting oil (15 mg) was solubilized in Et 2 O/MeOH (1.5 ml/0.5 ml), the solution was cooled with ice and 2 M HCI in Et 2 O was added (0.088 ml, 0.18 mmol). A solid separated and the mixture was then allowed to reach r.t. and stirred overnight.
  • Example 28 8-Methyl-A -[fra/7S-spiro[cyclopropane-2,1'-indane]-1 -yl]-8- azabicyclo[3.2.1]octan-3-amine dihydrochloride
  • Example 29 frans-/V4-[frans-Spiro[cyclopropane-2,1'-indane]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride and
  • Example 30 c/s-/V4-[frans-Spiro[cyclopropane-2,1'- indane]-1 -yl]cyclohexane-1 ,4-diamine dihydrochloride
  • trans-tert-B utyl ⁇ /-[4- [[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]amino]cyclohexyl]carbamate required a further purification (eluent: DCM/MeOH 97:3) and was obtained as a yellow oil that partially solidified on-standing (53 mg, 29%).
  • Example 32 1 -(4-Methylpiperazin-1 -yl)-2-[[frans-spiro[cyclopropane-2,1'-indane]-1 - yl]amino]ethanone dihydrochloride
  • 0.380 ml (0.380 mmol) of 1 M NaOH was added at 0°C to a solution of 0.030 g (0.076 mmol) of ⁇ /-[(1 -acetyl-4-piperidyl)methyl]-2,2,2-trifluoro-A/-[irans-spiro[cyclopropane-2, 1 '- indane]-1 -yl]acetamide in 0.6 ml of EtOH and the solution was stirred at r.t. for 5 h. The reaction mixture was concentrated. The concentrated solution was then partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and evaporated.
  • the solution was then treated with 0.050 g (0.22 mmol) of NaBH(OAc) 3 at 0°C and the mixture was stirred at r.t. overnight. A further portion of 0.050 g (0.22 mmol) of NaBH(OAc) 3 was added to the ice-cooled reaction and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was cooled with ice, quenched by adding water and the product was extracted with EtOAc. The EtOAc extract was dried over Na2SO 4 , filtered and the solution was concentrated.
  • Example 36 fra/7S-A -[(1 -Methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'-indane]- 1 -amine dihydrochloride
  • the solution was treated with 0.106 g (0.476 mmol) of NaBH(OAc) 3 at 0°C and the mixture was stirred at r.t. for 3.5 h.
  • the reaction mixture was cooled with ice, quenched by adding water, the pH of the aqueous layer was adjusted to 7-8 with NaHC0 3 and the product was extracted with EtOAc.
  • 0.017 g (42%) of irans-A/-[(1 -methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]-1 - amine dihydrochloride was prepared according to the procedure described for Example 35, Step 2, starting from 0.042 g (0.1 1 mmol) of 2,2,2-trifluoro-A/-[(1 -methyl-4- piperidyl)methyl]-A/-[irans-spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide.
  • Example 37 frans-/V-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- indane]-1 -amine dihydrochloride
  • reaction mixture was filtered through a sintered glass to eliminate most of the inorganic salts and the solvent was removed under vacuum.
  • the residue was partitioned between EtOAc and water, the pooled organic phases were washed with brine, dried over Na 2 S0 4 , filtered and the solvent removed under vacuum.
  • the residue was purified by flash chromatography (eluent: DCM/MeOH/30% NH 4 OH aq.
  • Example 33 0.008 g (30%) of irans-N-[(1 -phenethyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-indane]- 1 -amine dihydrochloride was prepared according to the procedure described for Example 36, starting from 0.033 g (0.072 mmol) of 2,2,2-trifluoro-N-(4-piperidylmethyl)-N-[irans- spiro[cyclopropane-2,1 '-indane]-1 -yl]acetamide trifluoroacetate (Example 33, Step 2).
  • Example 39 fra/7S-A -[2-(4-Piperidyl)ethyl]spiro[cyclopropane-2,1'-tetralin]-1 -amine dihydrochloride
  • Example 40 fra/7S-A 4-[fra/7S-Spiro[cyclopropane-2,1 '-tetralin]-1 -yl]cyclohexane-1 ,4- diamine dihydrochloride and
  • Example 41 c;s-/V4-[irans-Spiro[cyclopropane-2,1'- tetralin]-1 -yl]cyclohexane-1 ,4-diamine dihydrochloride
  • Example 42 frans-/V-[(1 -Methyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'-tetralin]- 1 -amine dihydrochloride
  • Example 43 frans-/V-[(1 -Phenethyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- tetralin]-1 -amine dihydrochloride
  • the solution was treated with 0.1 1 g (0.50 mmol) of NaBH(OAc)3 at 0°C and the mixture was stirred at r.t. overnight.
  • the reaction mixture was then cooled with ice, quenched by adding water, the pH of the aqueous layer was adjusted to 7-8 with NaHC03 and the product was extracted with EtOAc.
  • the EtOAc extract was washed with brine, dried over Na2SO 4 , filtered and the solution was concentrated under reduced pressure.
  • Example 44 frans-/V-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1'- tetralin]-1 -amine dihydrochloride
  • Step 2 trans-N-[( 1 -lsopropyl-4-piperidyl)methyllspiro[cvclopropane-2, 1 '-tetralinl-1 -amine dihydrochloride
  • irans-N-[(1 -lsopropyl-4-piperidyl)methyl]spiro[cyclopropane-2,1 '-tetralin]-1 - amine dihydrochloride was prepared according to the procedure described for Example 42, Step 4. starting from 0.0610 g (0.149 mmol) of 2,2,2-trifluoro-N-[(1 -isopropyl-4- piperidyl)methyl]-N-[irans-spiro[cyclopropane-2,1 '-tetralin]-1 -yl]acetamide.
  • Example 45 1 -(4-Methylpiperazin-1 -yl)-2-[[fra/7S-spiro[cyclopropane-2,1'-tetralin]-1 - yl]amino]ethanone dihydrochloride
  • ethyl 4'-bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate was prepared according to the procedure described for Intermediate 7, starting from 0.773 g (3.70 mmol) of 4-bromo-1 -methylene-indane (Intermediate 29).
  • the obtained ethyl 4'- bromospiro[cyclopropane-2,1 '-indane]-1 -carboxylate is a mixture of the two different isomers regarding to the cyclopropyl ring (CIS and TRANS).
  • reaction mixture was evaporated and the residue was purified by flash chromatography (eluent: DCM/EtOAc from 100:1 to 95:5) to give two products, the trans- isomer and the c/s-isomer (regarding the cyclopropyl ring) in their racemic form.
  • the cis and trans isomers were determined by analogy to 1 ,3-benzodioxol-5-ylmethyl N-[cis-5'- bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate and 1 ,3-benzodioxol-5-ylmethyl N- [irans-5'-bromospiro[cyclopropane-2,1 '-indane]-1 -yl]carbamate, Example 5, Step 1.
  • the frans-isomer, Intermediate 36 was obtained as an off-white solid (0.279 g, 39%).
  • the reaction gave two products, the c/s-isomer and the frans-isomer (regarding the cyclopropyl ring) in their racemic form.
  • the cis and trans isomers were identified by NMR (NOE) analysis of the corresponding amino derivatives.
  • the aqueous layer was ice-cooled, brought to a basic pH of about 9 with 1 N NaOH, and extracted with Et 2 O (60 ml x 3).
  • the combined organic phases containing the free amine were washed with brine, dried over Na 2 S0 4 and the solution was filtered
  • the organic phase was cooled with ice and 2 N HCI in Et 2 0 (2.93 ml) was added dropwise.
  • a white solid along with a yellow oil separated and the mixture was then allowed to reach r.t.
  • the mixture was evaporated, the residue was taken up with Et 2 0 and concentrated again. The residue was then triturated with Et 2 0 (80 ml) and MeOH (2 ml).
  • (+)-irans-spiro[cyclopropane-2,1 '-indane]-1 -amine hydrochloride was prepared according to the procedure described for Example 50, starting from 0.594 g (1.93 mmol) of (+)-(2R)-2-methoxy-2-phenyl-N-[irans-spiro[cyclopropane-2,1 '-indane]-1 - yl]acetamide (Intermediate 41 ).
  • the demethylase activity was estimated under aerobic conditions and at RT by measuring the release of H 2 O 2 produced during the catalytic process by the Amplex® UltraRed detection system coupled with peroxidase assay. Briefly, a fixed amount of KDM1A/CoRest complex was incubated at RT for 15 minutes in the absence and/or the presence of various concentrations of inhibitor (e.g. from 0 to 100 ⁇ , depending on the inhibitor strength) and of Amplex® UltraRed detection system coupled with peroxidase assay. The inhibitors were tested twice in duplicates at each concentration. Tranylcypromine (Sigma) was used as control.
  • Compounds 1 , 3, 4, 6, 7, 10, 21 , 45, 47 and 49 exhibit IC 50 values of less than 10 ⁇
  • compounds 5, 8, 15, 17-19, 22-24, 26-28, 30, 31 , 34, 39-44, 46 and 48 exhibit IC 50 values of less than 1 ⁇
  • compounds 9, 14, 16, 20, 25, 29, 32, 33, 35-38 exhibit an IC50 value of less than 0.1 ⁇ .
  • Tranylcypromine exhibits an IC 50 value of 12.9 ⁇ 3.2 ⁇ .
  • the MAO Glo Assay from Promega (cat. V1402, Promega, Madison, Wl) was used to measure the effect of inhibitors on MAO A and MAO B activity. Human recombinant MAO A and MAO B were expressed in Pichia pastoris and purified as published (Binda C. et al. Proc. Natl. Acad. Sci. USA, 2003, 9750-9755). The assay was performed at RT in 50 ⁇ _ (25 ⁇ _ reaction solution + 25 ⁇ _ detection reagent) in 96 well half area white plates (cat. 3693, Corning, Corning, NY).
  • Luminescence was measured after 20 min incubation in the dark using a microplate reader (Infinite F200, Tecan Group, Switzerland) with an integration time of 0.25 s per well. 50 nM MAO A or 125 nM MAO B were incubated with five different inhibitor concentrations (from 0.004 ⁇ to 100 ⁇ ) for 15 min at RT in Promega MAO Buffer or Promega MAO B Buffer (MAO Glo Assay kit, catalogue number V1402, Promega, Madison, Wl). After 30 min of incubation the reaction was stopped with the Promega detection reagent. All compounds were tested twice and IC 50 values were calculated using GraphPad Prism version 4.0 (GraphPad Software, San Diego, CA).
  • Compounds 14, 15, 18-20, 29, 30, 32, 33, 36 and 37 were at least 10 times more active against KDM1A (LSD1) compared to both MAO A and MAO B.

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Abstract

La présente invention concerne des composés de spirocyclopropylamine dotés d'une puissante activité inhibitrice de KDM1A (LSD1), où X, R et R1 sont tels que définis dans la description, des compositions pharmaceutiques contenant de tels composés et leur utilisation en thérapie.
PCT/EP2016/082360 2015-12-23 2016-12-22 Dérivés de spirocyclopropylamine utiles en tant qu'inhibiteurs d'histone déméthylases kdm1a WO2017109061A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9809541B2 (en) 2015-12-29 2017-11-07 Mirati Therapeutics, Inc. LSD1 inhibitors
JP2018505169A (ja) * 2015-01-30 2018-02-22 ジェネンテック， インコーポレイテッド 治療用化合物およびその使用
WO2018083189A1 (fr) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarqueurs pour déterminer la sensibilité à des inhibiteurs de lsd1
CN108440491A (zh) * 2018-03-30 2018-08-24 郑州大学 含有多个螺碳的螺-环丙基对二烯酮类化合物及其制备方法
US10059668B2 (en) 2015-11-05 2018-08-28 Mirati Therapeutics, Inc. LSD1 inhibitors
WO2019025588A1 (fr) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Méthodes de traitement des altérations du comportement
WO2020011731A1 (fr) * 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020157069A1 (fr) * 2019-01-28 2020-08-06 NodThera Limited Composés amino hétérocycliques et leurs utilisations
WO2020188089A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble d'hyperactivité avec déficit de l'attention au moyen d'inhibiteurs de kdm1a tels que le composé vafidemstat
WO2020188090A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble de la personnalité borderline
WO2021004610A1 (fr) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarqueurs et procédés pour le traitement personnalisé d'un cancer du poumon à petites cellules au moyen d'inhibiteurs de kdm1a
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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WO2012013728A1 (fr) * 2010-07-29 2012-02-02 Oryzon Genomics S.A. Inhibiteurs de déméthylase lsd1 base d'aryclcyclopropylamine et leur utilisation médicale

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WO2012013728A1 (fr) * 2010-07-29 2012-02-02 Oryzon Genomics S.A. Inhibiteurs de déméthylase lsd1 base d'aryclcyclopropylamine et leur utilisation médicale

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018505169A (ja) * 2015-01-30 2018-02-22 ジェネンテック， インコーポレイテッド 治療用化合物およびその使用
US10059668B2 (en) 2015-11-05 2018-08-28 Mirati Therapeutics, Inc. LSD1 inhibitors
US9809541B2 (en) 2015-12-29 2017-11-07 Mirati Therapeutics, Inc. LSD1 inhibitors
US10233152B2 (en) 2015-12-29 2019-03-19 Mirati Therapeutics, Inc. LSD1 inhibitors
WO2018083189A1 (fr) 2016-11-03 2018-05-11 Oryzon Genomics, S.A. Biomarqueurs pour déterminer la sensibilité à des inhibiteurs de lsd1
WO2019025588A1 (fr) 2017-08-03 2019-02-07 Oryzon Genomics, S.A. Méthodes de traitement des altérations du comportement
EP4512473A2 (fr) 2017-08-03 2025-02-26 Oryzon Genomics, S.A. Procédés de traitement d'altérations de comportement
CN108440491A (zh) * 2018-03-30 2018-08-24 郑州大学 含有多个螺碳的螺-环丙基对二烯酮类化合物及其制备方法
CN112334192A (zh) * 2018-07-12 2021-02-05 Ucb生物制药有限责任公司 作为il-17调节剂的螺环茚满类似物
US11458124B2 (en) 2018-07-12 2022-10-04 UCBBiopharma Srl Spirocyclic indane analogues as IL-17 modulators
WO2020011731A1 (fr) * 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020157069A1 (fr) * 2019-01-28 2020-08-06 NodThera Limited Composés amino hétérocycliques et leurs utilisations
WO2020188089A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble d'hyperactivité avec déficit de l'attention au moyen d'inhibiteurs de kdm1a tels que le composé vafidemstat
WO2020188090A1 (fr) 2019-03-20 2020-09-24 Oryzon Genomics, S.A. Procédés de traitement d'un trouble de la personnalité borderline
WO2021004610A1 (fr) 2019-07-05 2021-01-14 Oryzon Genomics, S.A. Biomarqueurs et procédés pour le traitement personnalisé d'un cancer du poumon à petites cellules au moyen d'inhibiteurs de kdm1a
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

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