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WO2018050686A1 - Inhibiteurs spiro bicycliques de l'interaction ménine-mll - Google Patents

Inhibiteurs spiro bicycliques de l'interaction ménine-mll Download PDF

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Publication number
WO2018050686A1
WO2018050686A1 PCT/EP2017/073004 EP2017073004W WO2018050686A1 WO 2018050686 A1 WO2018050686 A1 WO 2018050686A1 EP 2017073004 W EP2017073004 W EP 2017073004W WO 2018050686 A1 WO2018050686 A1 WO 2018050686A1
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Prior art keywords
group
optionally substituted
4alkyl
hydrogen
fluoro
Prior art date
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PCT/EP2017/073004
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English (en)
Inventor
Patrick René ANGIBAUD
Vineet PANDE
Barbara HERKERT
Daniel Jason KROSKY
Olivier Alexis Georges QUEROLLE
Isabelle Noëlle Constance PILATTE
Aaron Nathaniel PATRICK
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Priority to LTEP17768428.9T priority Critical patent/LT3512857T/lt
Priority to HRP20210514TT priority patent/HRP20210514T1/hr
Priority to DK17768428.9T priority patent/DK3512857T3/da
Priority to CN201780056188.3A priority patent/CN109689663B/zh
Priority to AU2017326487A priority patent/AU2017326487B2/en
Priority to ES17768428T priority patent/ES2872003T3/es
Priority to BR112019004691A priority patent/BR112019004691A2/pt
Priority to MX2019002962A priority patent/MX392051B/es
Priority to CA3033239A priority patent/CA3033239A1/fr
Priority to SI201730700T priority patent/SI3512857T1/sl
Priority to EP17768428.9A priority patent/EP3512857B1/fr
Priority to US16/331,606 priority patent/US11220517B2/en
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to EA201990699A priority patent/EA201990699A1/ru
Priority to KR1020197008627A priority patent/KR102493644B1/ko
Priority to JP2019535974A priority patent/JP6975791B2/ja
Publication of WO2018050686A1 publication Critical patent/WO2018050686A1/fr
Priority to IL265233A priority patent/IL265233B/en
Anticipated expiration legal-status Critical
Priority to US17/536,899 priority patent/US12084462B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to spiro bicyclic compounds, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplasia syndrome (MDS) and diabetes.
  • MDS myelodysplasia syndrome
  • Acute leukemias harboring these chromosomal translocations of MLL represent as lymphoid, myeloid or biphenotypic disease and constitute 5 to 10% of acute leukemias in adults and approximately 70% in infants (Marschalek, Br J Haematol 2011. 152(2), 141-54; Tomizawa et al, Pediatr Blood Cancer 2007. 49(2), 127-32).
  • MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes.
  • HSCs hematopoietic stem cells
  • H3K4 lysine 4
  • Use of inducible loss-of- function alleles of Mill demonstrated that Mill plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for hematopoiesis (Mishra et al, Cell Rep 2011. 7(4), 1239-47).
  • Menin which is encoded by the Multiple Endocrine Neoplasia type 1 (MEN1) gene is expressed ubiquitously and is predominantly localized in the nucleus. It has been shown to interact with numerous proteins and is, therefore, involved in a variety of cellular processes. The best understood function of menin is its role as an oncogenic cofactor of MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL that is retained in all fusion proteins, MBM1 (menin-binding motif 1) and MBM2 (Thiel et al, Bioessays 2012. 34, 771-80). Menin/MLL interaction leads to the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF).
  • LEDGF lens epithelium-derived growth factor
  • MLL directly binds to LEDGF
  • menin is obligatory for the stable interaction between MLL and LEDGF and the gene specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF
  • menin is strictly required for oncogenic transformation by MLL fusion proteins suggesting the menin/MLL interaction as an attractive therapeutic target.
  • conditional deletion of Menl prevents leukomogenesis in bone marrow progenitor cells ectopically expressing MLL fusions (Chen et al, Proc Natl Acad Sci 2006. 103, 1018-23).
  • menin/MLL fusion interaction by loss-of- function mutations abrogates the oncogenic properties of the MLL fusion proteins, blocks the development of leukemia in vivo and releases the differentiation block of MLL-transformed leukemic blasts.
  • menin is required for the maintenance of HOX gene expression by MLL fusion proteins (Yokoyama et al, Cell 2005. 123, 207-18).
  • small molecule inhibitors of menin/MLL interaction have been developed suggesting druggability of this protein/protein interaction and have also demonstrated efficacy in preclinical models of AML (Borkin et al., Cancer Cell 2015. 27, 589-602; Cierpicki and Grembecka, Future Med Chem 2014.
  • the present invention concerns novel compounds of Formula (I)
  • R 1 is selected from the group consisting of CF , CH 2 F, CHF 2 , and CF 3 ;
  • R 2 is selected from the group consisting of hydrogen and CH 3 ;
  • L 1 represents a 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms provided that it is N-linked to the thienopyrimidinyl heterocycle;
  • L 2 -R 3 is selected from (a), (b), (c), (d), (e), (f) or (g), wherein
  • L 2 is selected from the group consisting of >S0 2 , >CR 4a R 4b , and -CHR 4a CHR 5 -;
  • R 4b is selected from the group consisting of hydrogen and methyl; or R 4a and R 4b together with the carbon atom to which they are attached form a C 3 -5cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom; wherein
  • R 10a , R 10b and R 11 are each independently selected from the group consisting of hydrogen; Ci- 4 alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10- membered saturated spirocarbobicyclic system; or
  • L 2 is selected from the group consisting of >CR 4c R 4d and -CHR 4c CHR 5a -, wherein R 4c , R 4d , and R 5a are each independently selected from the group consisting of hydrogen and Ci_ 4 alkyl; and
  • R 3 is selected from the group consisting of R and R ; wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of Ci- 6 alkyl optionally substituted with a -OH or a -NH 2 substituent; and -OCi-6alkyl; or
  • (c) ⁇ L 2 -R 3 is Ci- 6 alkyl optionally substituted with one, two or three fluoro substituents; or
  • L 2 is O and R 3 is selected from the group consisting of C 3 - 6 alkyl optionally substituted with one, two or three fluoro substituents; Ar; Het 1 ; Het 2 ; a 7- to 10- membered saturated spirocarbobicyclic system; -CH 2 -Ar; -CH 2 -Het 1 ; -CH 2 -Het 2 ; and -CH 2 -(a 7- to 10-membered saturated spirocarbobicyclic system); when L 2 is linked to a carbon atom of L 1 ; or
  • L 2 -R 3 is -0-CHR 5 -R 3 when L 2 is linked to a carbon atom of L 1 , wherein
  • R 16a , R 16b and R 17 are each independently selected from the group consisting of hydrogen; Ci-4alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and
  • R 3 is selected from the group consisting of hydrogen; Ci-4alkyl optionally substituted with one, two, or three fluoro substituents; -CN; Ar, Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system; or
  • R 18 is selected from the group consisting of hydrogen; Ci-4alkyl optionally substituted with a fluoro or a -CN substituent; and C 2 -4alkyl substituted with a substituent selected from the group consisting of -OR 19 and -NR 20a R 20b ; wherein
  • R 21a , R 21b and R 22 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • R 18a is selected from the group consisting of hydrogen, fluoro and Ci-4alkyl
  • R 18b is selected from the group consisting of fluoro, -OCi-4alkyl, and Ci-4alkyl optionally substituted with 1, 2 or 3 fluoro substituents; or
  • R 18a and R 18b are bound to the same carbon atom and together form a C3- 5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom or
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isoxazolyl; or a bicyclic heteroaryl selected from the group consisting of imidazothiazolyl, imidazo imidazolyl, benzo furanyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, indazoly
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, myelodysplasia syndrome (MDS) and diabetes.
  • MDS myelodysplasia syndrome
  • the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer.
  • said cancer is selected from leukemias, myeloma or a solid tumor cancer (e.g. prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma, etc.).
  • leukemias myeloma or a solid tumor cancer (e.g. prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma, etc.).
  • the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocyte leukemias (T-PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exhibiting HOXIMEIS1 gene expression signatures etc.
  • the invention also relates to the use of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use
  • the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof.
  • the invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.
  • a product comprising a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.
  • MDS myelodysplastic syndrome
  • the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, as defined herein, or a pharmaceutical composition or combination as defined herein.
  • 'halo ' or 'halogen' as used herein represents fluoro, chloro, bromo and iodo.
  • Ci- 6 alkyl group contains from 1 to 6 carbon atoms
  • C3- 6 cycloalkyl group contains from 3 to 6 carbon atoms, and so on.
  • 'Ci-4alkyl' as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • 'C2-4alkyl' as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 2 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
  • 'Ci_6alkyl' as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for Ci-4alkyl and n-pentyl, n-hexyl, 2-methylbutyl and the like.
  • the term 'C3-6alkyl' as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 3 to 6 carbon atoms such as n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl and the like.
  • 'C3-5cycloalkyl' as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl and cyclopentyl.
  • 'spirobicyclic' as used herein as group or part of a group represents cyclic systems wherein two cycles are joined at a single atom. Examples of these systems are 7- to 10-membered saturated spiroheterobicyclic systems containing one or two N-atoms, wherein one of the nitrogen atoms is always linked to the thienopyrimidinyl heterocycle in the compounds of Formula (I) as defined herein.
  • Such spirocyclic systems include, but are not limited to systems resulting from the combination of e.g. piperidine, pyrrolidine, azetidine, and cyclobutane rings. Examples of such systems include, but are not limited to (a), (b), (c), (d), (e), (f) and (g) below and the like
  • Examples of 7- to 10-membered saturated spirocarbobicyclic systems include, but are not limited to
  • 'substituted' is used in the present invention, it is meant, unless otherwise indicated or clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using 'substituted' are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
  • substituents When two or more substituents are present on a moiety they may, where possible and unless otherwise indicated or clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.
  • a substituent on a heterocyclyl group may replace any hydrogen atom on a ring carbon atom or on a ring heteroatom.
  • 'saturated' means 'fully saturated', if not otherwise specified.
  • a 'non-aromatic group' embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.
  • the term 'fully saturated' refers to rings where there are no multiple bonds between ring atoms.
  • a 'non-aromatic heterocyclyl' is a non-aromatic monocyclic or bicyclic system, unless otherwise specified, having for example, 3 to 12 ring members, more usually 5 to 10 ring members.
  • monocyclic groups are groups containing 4 to 7 ring members, more usually, 5 or 6 ring members.
  • bicyclic groups are those containing 8 to 12, more usually 9 or 10 ring members.
  • Non-limiting examples of monocyclic heterocyclyl systems containing at least one heteroatom selected from nitrogen, oxygen or sulfur (N, O, S) include, but are not limited to 4- to 7-membered heterocyclyl systems such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and tetrahydro-2H-thiopyranyl 1,1 -dioxide, in particular azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, and thiomorpholiny.
  • indolyl indolinyl .
  • each can be bound to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked), and may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to the embodiments.
  • Examples of a C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen atom include, but are not limited to, azetidinyl, pyrrolidinyl and piperidinyl, bound to the rest of the molecule through an available carbon atom.
  • '— ' represents the bond of attachment to the remainder of the molecule of Formula (I).
  • Lines (such as '— ') drawn into ring systems indicate that the bond may be attached to any of the suitable ring atoms.
  • Het 1 and Het 2 may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or nitrogen atom as appropriate, if not otherwise specified. It will be clear that a saturated cyclic moiety may, where possible, have substituents on both carbon and N-atoms, unless otherwise is indicated or is clear from the context.
  • L 2 is >CR 4a R 4b , this is equivalent to L is ⁇ C ⁇ .
  • L 2 is >CR 4a R 4b wherein both R 4a and R 4b are hydrogen.
  • each definition is independent.
  • the term 'subject' as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g. cat, dog, primate or human
  • a human who is or has been the object of treatment, observation or experiment.
  • 'therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • composition' is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treatment' is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • the invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Atropisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.
  • Diastereomers are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.
  • Substituents on bivalent cyclic saturated or partially saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.
  • the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate base or acid, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter- ion, for example using a suitable ion exchange resin.
  • the pharmaceutically acceptable salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base salt forms which the compounds of Formula (I) and solvates thereof, are able to form.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, cesium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the salt form can be converted by treatment with acid into the free acid form.
  • solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form.
  • solvent addition forms are e.g. hydrates, alcoholates and the like.
  • the compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures.
  • a manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable salts, and solvates thereof involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).
  • isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, n C, 13 C, 14 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, S, 18 F, 36 C1, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 2 H, 3 H, n C and 18 F. More preferably, the radioactive isotope is 2 H.
  • deuterated compounds are intended to be included within the scope of the present invention.
  • Certain isotopically-labeled compounds of the present invention may be useful for example in substrate tissue distribution assays. Tritiated ( 3 H) and carbon- 14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • R 2 is selected from hydrogen or deuterium, in particular deuterium.
  • L 2 can be >C( 2 H) 2 .
  • Positron emitting isotopes such as 15 0, 13 N, n C and 18 F are useful for positron emission tomography (PET) studies.
  • PET imaging in cancer finds utility in helping locate and identify tumours, stage the disease and determine suitable treatment.
  • Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets.
  • Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumour cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127).
  • target-specific PET radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi: 10.1016/j.canlet.2016.05.008).
  • the present invention relates in particular to compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the embodiments, wherein also the following compound and pharmaceutically acceptable addition salts, and solvates thereof, are excluded:
  • the present invention relates in particular to compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the embodiments, wherein the intermediates and compounds described in WO2017/112768, in as far as they are covered by the present invention, are excluded.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1 is CF 3 ;
  • R 2 is selected from the group consisting of hydrogen and CH 3 ;
  • L 1 represents a 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms provided that it is N-linked to the thienopyrimidinyl heterocycle;
  • L 2 -R 3 is selected from (a), (b), (c), (d), (f) or (g), wherein
  • L 2 is selected from the group consisting of>CR 4a R 4b , and -CHR 4a CHR 5 -;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 5 is selected from the group consisting of hydrogen; -OR 6 ; and Ci-4alkyl;
  • R 4b is selected from the group consisting of hydrogen and methyl; or R 4a and R 4b together with the carbon atom to which they are attached form a C 3- 5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom; wherein
  • R 6 , R 7a , R 7b , R 8 , R 9a and R 9b are each independently selected from the group consisting of hydrogen; and C 2 _4alkyl substituted with a substituent selected from the group consisting of -OR 11 and -NR 10a R 10b ; wherein
  • R 10a , R 10b and R 11 are each independently selected from the group consisting of hydrogen; and Ci-4alkyl; and
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10- membered saturated spirocarbobicyclic system; or
  • L 2 is >CR 4c R 4d , wherein R 4c and R 4d are hydrogen; and R 12a
  • R 3 is R 12c ; wherein R 12a , R 12b , and R 12c are Ci-ealkyl 1; or
  • ⁇ L 2 -R 3 is Ci- 6 alkyl optionally substituted with one, two or three fluoro substituents; or
  • L 2 is O and R 3 is -CH 2 -Ar; or
  • R 18 is selected from the group consisting of hydrogen; and Ci-4alkyl;
  • R 18a is selected from the group consisting of hydrogen, and fluoro
  • R 18b is selected from the group consisting of fluoro, -OCi-4alkyl, and Ci-4alkyl optionally substituted with 1, 2 or 3 fluoro substituents; or
  • R 18a and R 18b are bound to the same carbon atom and together form a C3- 5 cycloalkyl; or
  • Ar is phenyl which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -OR 24 , and Ci-4alkyl optionally substituted with -OR 26 ;
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, and isoxazolyl; or a bicyclic heteroaryl selected from the group consisting of indolyl, imidazopyridinyl; each of which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN, -OR 24 , and Ci-4alkyl optionally substituted with a substituent selected from the group consisting of -CN, -OR 26 , and -NR 27a R 27b ; and
  • Het 2 is a non-aromatic heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN, and Ci-4alkyl optionally substituted with -OR 26 ; wherein
  • R 24 , R 26 , R 27a , and R 27b are each independently selected from the group consisting of hydrogen; Ci-4alkyl; and C 2 -4alkyl substituted with -NR 28a R 28b ; wherein
  • R 28a and R 28b are hydrogen
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • L 2 is selected from the group consisting of >S0 2 , >CR 4a R 4b , and -CHR 4a CHR 5 -;
  • R 4b is selected from the group consisting of hydrogen and methyl; or >CR 4a R 4b form a >C3- 5 cycloalkanediyl or a >C-linked 4- to 6-membered heterocyclediyl containing an oxygen atom; wherein
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10- membered saturated spirocarbobicyclic system; or
  • L 2 is selected from the group consisting of >CR 4c R 4d and -CHR 4c CHR 5a -, wherein R 4c , R 4d , and R 5a are each independently selected from the group consisting of hydrogen and Ci-4alkyl; and
  • R 3 is selected from the group consisting of R R 1' 2"c and
  • R 12a , R 12b , and R 12c are each independently selected from the group consisting of Ci- 6 alkyl optionally substituted with a -OH or a -NH 2 substituent; or
  • ⁇ L 2 -R 3 is Ci- 6 alkyl optionally substituted with one, two or three fluoro substituents; or
  • L 2 is O and R 3 is selected from the group consisting of Ar, Het 1 ; -CH 2 -Ar, -CH 2 -Het 1 , and -CH 2 -(a 7- to 10-membered saturated spirocarbobicyclic system); when L 2 is linked to a carbon atom of L 1 : or
  • R 18 is hydrogen
  • Het 2 is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl; wherein
  • R 26 , R 27a , and R 27b are each independently selected from the group consisting of hydrogen and Ci_4alkyl; and the pharmaceutically acceptable salts and the solvates thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1 is selected from the group consisting of CH 3 , CH 2 F, CHF 2 , and CF 3 ;
  • R 2 is selected from the group consisting of hydrogen and CH 3 ;
  • L 1 represents a 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms provided that it is N-linked to the thienopyrimidinyl heterocycle;
  • L 2 -R 3 is selected from (a), (b), (d), (e), or (f), wherein
  • L 2 is selected from the group consisting of >S0 2 , >CR 4a R 4b , and -CHR 4a CHR 5 -;
  • Ci-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR 8 , and ⁇ M R ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
  • R 4b is selected from the group consisting of hydrogen and methyl; or R 4a and R 4b together with the carbon atom to which they are attached form a C 3 -5cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom; wherein
  • R 10a , R 10b and R 11 are each independently selected from the group consisting of hydrogen; Ci- 4 alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10- membered saturated spirocarbobicyclic system; or
  • L 2 is selected from the group consisting of >CR 4c R 4d and -CHR 4c CHR 5a -, wherein
  • R 4c , R 4d , and R 5a are each independently selected from the group consisting of hydrogen and Ci_ 4 alkyl;
  • R 3 is selected from the group consisting of R and R ; wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of Ci- 6 alkyl optionally substituted with a -OH or a -NH 2 substituent; and -OCi-6alkyl; or
  • L 2 is O and R 3 is selected from the group consisting of C 3 - 6 alkyl optionally substituted with one, two or three fluoro substituents; Ar; Het 1 ; Het 2 ; a 7- to 10- membered saturated spirocarbobicyclic system; -CH 2 -Ar; -CH 2 -Het 1 ; -CH 2 -Het 2 ; and -CH 2 -(a 7- to 10-membered saturated spirocarbobicyclic system); when L 2 is linked to a carbon atom of L 1 ; or
  • R 16a , R 16b and R 17 are each independently selected from the group consisting of hydrogen; Ci-4alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and
  • R 3 is selected from the group consisting of hydrogen; Ci-4alkyl optionally substituted with one, two, or three fluoro substituents; -CN; Ar, Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system; or
  • R 18 is selected from the group consisting of hydrogen; Ci-4alkyl optionally substituted with a fluoro or a -CN substituent; and C 2 -4alkyl substituted with a substituent selected from the group consisting of -OR 19 and -NR 20a R 20b ; wherein
  • R 21a , R 21b and R 22 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • R 18a is selected from the group consisting of hydrogen, fluoro and Ci-4alkyl
  • R 18b is selected from the group consisting of fluoro, -OCi-4alkyl, and Ci-4alkyl optionally substituted with 1, 2 or 3 fluoro substituents
  • R 18a and R 18b are bound to the same carbon atom and together form a C3- 5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom;
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, thiadiazolyl, and isoxazolyl; or a bicyclic heteroaryl selected from the group consisting of imidazothiazolyl, imidazo imidazolyl, benzo furanyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, indazoly
  • R 28a , R 28b and R 29 are each independently selected from the group consisting of hydrogen; Ci-4alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and the pharmaceutically acceptable salts and the solvates thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1 is CF 3 ;
  • R 4b is selected from the group consisting of hydrogen and methyl
  • R 7a and R 7b are each independently selected from the group consisting of hydrogen; Ci-4alkyl; and C 2 -4alkyl substituted with a substituent selected from the group consisting of -OR 1 1 and -NR 10a R 10b ; wherein
  • R 10a , R 10b and R 1 1 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10- membered saturated spirocarbobicyclic system; or
  • L 2 is >CR 4c R 4d , wherein R 4c and R 4d are each independently selected from the group consisting of hydrogen and Ci-4alkyl; and
  • R 3 is selected from the group consisting of R and R ; wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of Ci- 6 alkyl optionally substituted with a -NH 2 substituent; or
  • (c) ⁇ L 2 -R 3 is Ci- 6 alkyl optionally substituted with one, two or three fluoro substituents; or
  • L 2 is O and R 3 is selected from the group consisting of Ar, Het 1 , -CH 2 -Ar, -CH 2 -Het 1 , and -CH 2 -(a 7- to 10-membered saturated spirocarbobicyclic system); when L 2 is linked to a carbon atom of L 1 ; or
  • Ar is phenyl optionally substituted with a halo substituent
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5- thiazolyl
  • a bicyclic heteroaryl selected from imidazopyridinyl, in particular imidazo[l ,2-a]pyridinyl; each of which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo and Ci_4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR 26 , -NR 27a R 27b , and -C( 0)NR 27a R 27b ; and
  • Het 2 is a non-aromatic heterocyclyl selected from azetidinyl, pyrrolidinyl and piperidinyl; wherein
  • R 26 , R 27a , and R 27b are each independently selected from the group consisting of hydrogen and Ci_4alkyl; and the pharmaceutically acceptable salts and the solvates thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1 is CF 3 ;
  • L 1 represents a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (a), (b), (c), (d), (e), (f) an
  • a represents the position of linkage to the thienopyrimidinyl heterocycle
  • L 2 is >CH 2 ; and R 3 is selected from the group consisting of Ar, Het 1 , and a 7- to 10-membered saturated spirocarbobicyclic system; or
  • Ar is phenyl optionally substituted with a halo substituent
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of 4-, 5- or 6- pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, and 4- or 5- thiazolyl; or a bicyclic heteroaryl selected from imidazopyridinyl, in particular imidazo[l ,2-a]pyridinyl; each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo and Ci-4alkyl; and the pharmaceutically acceptable salts and the solvates thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1 is CF 3 ;
  • R 2 is hydrogen
  • L 1 represents a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (a), (b), (c), (d), (e), (f) an
  • a represents the position of linkage to the thienopyrimidinyl heterocycle
  • L 2 is >CH 2 ; and R 3 is selected from the group consisting of Ar, Het 1 , and a 7- to 10-membered saturated spirocarbobicyclic system; or
  • Ar is phenyl optionally substituted with a halo substituent
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of 4-, 5- or 6- pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, and imidazolyl; or a bicyclic heteroaryl selected from imidazopyridinyl, in particular imidazo[l,2-a]pyridinyl; each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo and Ci-4alkyl; and the pharmaceutically acceptable salts and the solvates thereof.
  • Another embodiment of the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
  • R 1 is CF 3 ;
  • R 2 is hydrogen
  • L 1 is a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (a), (b), (c), (d), (e), (f) and (g) as defined herein;
  • L 1 is a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (a), (b), (c), (d), (e), and (f) as defined herein;
  • L 1 is a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (c) and (e); (f) L 2 is >CH 2 ;
  • L 2 is >CH 2 ; and R 3 is selected from the group consisting of Ar, Het 1 , and a 7- to 10- membered saturated spirocarbobicyclic system;
  • R 18 is selected from the group consisting of hydrogen; Ci-4alkyl optionally substituted with a fluoro or -CN substituent; and C 2 -4alkyl substituted with a substituent selected from the group consisting of -OR 19 and -NR 20a R 20b ; wherein
  • R 21a , R 21b and R 22 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • Ar is phenyl optionally substituted with one or two independently selected halo substituents
  • Ar is phenyl optionally substituted with one halo substituent
  • (k) Ar is phenyl
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridazinyl, 4-, 5- or 6-pyrimidinyl, and pyrazinyl; or is a bicyclic heteroaryl selected from imidazopyridinyl, in particular imidazo[l,2-a]pyridinyl; each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo and Ci-4alkyl;
  • Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridazinyl, 4- , 5- or 6-pyrimidinyl, and pyrazinyl, each of which may be optionally substituted with a halo substituent;
  • Het 1 is a bicyclic heteroaryl selected from imidazopyridinyl, in particular imidazo[l,2-a]pyridinyl-6-yl or imidazo[l,2-a]pyridinyl-2-yl;
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1 is CF 3 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1 is CF 3 , and wherein R 2 is hydrogen.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceut ically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is phenyl optionally subst ituted according to any of the other embodiments.
  • the present invent ion relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein L 2 is l inked to a carbon atom of
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein— L 2 -R 3 is (a).
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceut ically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein— L 2 -R 3 is (b).
  • the present invention relates to those compounds of Formula (I) and the pharmaceut ically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein— L 2 -R 3 is (c).
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (d).
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutical ly acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (e).
  • the present invention relates to those compounds of Formula (I) and the pharmaceut ical ly acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is ( f).
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (g).
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceut ically acceptable salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a); (b), (d), (e) or (f); and R 4a is other than hydrogen.
  • the present invent ion relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein — L 2 -R 3 is (a) or (f); and R 4a is other than hydrogen.
  • the present invent ion relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein— L 2 -R 3 is (a); and R 4a is other than hydrogen.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein — L 2 -R 3 is (a); and when L 2 is linked to a nitrogen atom of L 1 then R 4a is other than hydrogen.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a) or (f); and when L 2 is linked to a nitrogen atom of L 1 then R 4a is other than hydrogen.
  • the present inv ention relates to those compounds of Formula ( I ) and the pharmaceut ically acceptable salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a), (b), (d), (e) or (f); and when L 2 is linked to a nitrogen atom of L 1 then R 4a is other than hydrogen.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solv ates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein L 1 represents
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solv ates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a); R 3 is Het 1 or Het 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solv ates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a); R 3 is Het 1 .
  • the present inv ention relates to those compounds of Formula (I) and the pharmaceutical ly acceptable salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein ⁇ L 2 -R 3 is (a); R 3 is Het 1 ; and Het 1 is azetidinyl optionally substituted as defined in any of the other embodiments.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Ar is phenyl which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, -CN,
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is selected from the group consisting of >CR 4a R 4b , and -CHR 4a CHR 5 -;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 5 is selected from the group consisting of hydrogen; -OR 6 ; -NR 7a R 7b ;
  • Ci-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR 8 , and
  • R 4b is selected from the group consisting of hydrogen and methyl
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 4b is hydrogen
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 4b is hydrogen
  • R 3 is selected from the group consisting of Ar, and Het 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is selected from the group consisting of >CR 4a R 4b , and -CHR 4a CHR 5 -;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 5 is selected from the group consisting of hydrogen; -OR 6 ; -NR 7a R 7b ;
  • Ci-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR 8 , and
  • R 4b is selected from the group consisting of hydrogen and methyl
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R is hydrogen;
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 4b is hydrogen
  • R 3 is selected from the group consisting of Ar, and Het 2 .
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is selected from the group consisting of >CR 4a R 4b , and -CHR 4a CHR 5 -; wherein L 2 is linked to a nitrogen atom of L 1 ;
  • R 4a is C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
  • R 5 is selected from the group consisting of hydrogen; -OR 6 ; -NR 7a R 7b ;
  • Ci-4alkyl optionally substituted with a substituent selected from the group consisting of fluoro, -CN, -OR 8 , and
  • R 4b is selected from the group consisting of hydrogen and methyl
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 4a is C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
  • R 4b is hydrogen
  • R 3 is selected from the group consisting of Ar, Het 1 , Het 2 , and a 7- to 10-membered saturated spirocarbobicyclic system.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • L 2 is >CR 4a R 4b ;
  • L 2 is linked to a nitrogen atom of L 1 ;
  • R 4a is C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
  • R 4b is hydrogen
  • R 3 is selected from the group consisting of Ar, and Het 2 .
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein L 2 is linked to a nitrogen atom ofL 1 .
  • the present inv ention relates to those compounds of Formula (I) and the pharmaceut ically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • ⁇ L 2 -R 3 is selected from the group consisting of
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • — 2 -R 3 is selected from the group consisting of
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as ment ioned in any of the other embodiments, wherein
  • L 1 represents a N-linked 7- to 10-membered saturated spiroheterobicyclic system containing one or two N-atoms selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), and (i)
  • a represents the position of linkage to the thienopyrimidinyl heterocycle.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het 2 is monocyclic heterocyclyl optionally substituted with one, two, or three substituents as described in the other embodiments.
  • the present invention relates to those compounds of Formula ( I ) and the pharmaceutically acceptable salts, and the solvates thereof or any subgroup thereof as ment ioned in any of the other embodiments, wherein Het 2 is a non-aromatic heterocyclyl selected from azetidinyl, oxetanyl, tetrahydrofuranyl, piperidinyl,
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • Het 2 is a non-aromatic heterocyclyl selected from
  • Particular compounds of Formula (I) are compounds 82, 84, 273, and 274, including the stereoisomeric forms, the pharmaceutically acceptable salts thereof, in particular the hydrochloride salts thereof, and the solvates thereof.
  • Particular compounds of Formula (I) are compounds 82, 84, 273, and 274.
  • the compound of Formula ( I ) is selected from the group consisting of any of the exemplified compounds,
  • references to Formula (I) also include all other sub-groups and examples thereof as defined herein.
  • compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • reaction work-up refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
  • microwave heating may be used instead of conventional heating to shorten the overall reaction time.
  • Scheme 1 represents L 1 as a 7- to 10-membered saturated spiroheterobicyclic system containing two N-atoms and which is N-linked to the thienopyrimidinyl heterocycle, LG 1 and LG 2 each represent a suitable leaving group, such as for example halo or methanesulfonyl; PG 1 represents a suitable protecting group, such as for example tert-butyloxycarbonyl; R 3a -PG 2 represents an R 3 as defined in Formula (I) with an appropriate protecting group, such as for example tert- butyloxycarbonyl, when the R 3 substituent bears an amino group.
  • the X in formula (XI) represents CH or N (in formula (XI) L 2 can be linked to a carbon or a N-atom). All other variables in Scheme 1 are defined according to the scope of the present invention.
  • a suitable temperature such as ranged from rt to 90 °C, in the presence of a suitable base such as for example diisopropylethylamine, in a suitable solvent such as for example acetonitrile or isopropanol or ethanol;
  • a suitable base such as for example diisopropylethylamine
  • a suitable solvent such as for example acetonitrile or isopropanol or ethanol
  • cleavage conditions such as for example an acid such as HCl or trifluoroacetic acid in a suitable solvent such as acetonitrile or dichloromethane when PG 1 is tert-butyloxycarbonyl;
  • a suitable temperature such as for example room temperature in a suitable solvent such as acetic acid
  • a suitable temperature such as for example room temperature or reflux, in the presence of a suitable base such as for example potassium carbonate or 1,8- Diazabicyclo[5.4.0]undec-7-ene, in a suitable solvent such as for example acetonitrile or DMSO;
  • a suitable base such as for example potassium carbonate or 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • a suitable solvent such as for example acetonitrile or DMSO
  • a suitable temperature such as for example room temperature or 90 °C, in the presence of a suitable base such as for example potassium carbonate or 1,8- Diazabicyclo[5.4.0]undec-7-ene, in a suitable solvent such as for example acetonitrile or DMSO;
  • a suitable base such as for example potassium carbonate or 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • a suitable solvent such as for example acetonitrile or DMSO
  • reaction temperature range such as for example from 0 °C to room temperature
  • suitable cleavage conditions such as for example an acid such as HC1 or trifluoroactic acid in a suitable solvent such as acetonitrile or dichloromethane when PG 2 is tert-butyloxycarbonyl.
  • a suitable temperature such as for example at room temperature, eventually in the presence of a suitable base such as for example trimethylamine or a suitable acid such as for example acetic acid, in a suitable solvent such as for example anhydrous dichloromethane, dichloroethane or tetrahydropyrane;
  • a suitable base such as for example trimethylamine or a suitable acid such as for example acetic acid
  • a suitable solvent such as for example anhydrous dichloromethane, dichloroethane or tetrahydropyrane;
  • a suitable temperature for example room temperature
  • a suitable reducing agent such as for example NaBH(OAc) 3
  • a suitable solvent such as dichloromethane, dichloroethane or tetrahydropyran
  • Steps 6 and 7 can conveniently be performed as a one-pot procedure.
  • step 6 and 7 can be performed in the presence of a suitable acid such as for example acetic acid, a suitable catalyst such as platinium oxide, in a suitable solvent such as for example ethanol at a suitable temperature such as for example 60°C;
  • a suitable acid such as for example acetic acid
  • a suitable catalyst such as platinium oxide
  • a suitable solvent such as for example ethanol
  • suitable temperature such as for example 60°C;
  • reagent of Formula (XI) represents CH or N, and L 2 and R 3 are as defined according to the scope of the invention.
  • Reagents of Formula (XI) are either commercially available or can be prepared by methods known to the skilled person from commercially available starting materials, e.g. by appropriate protection/deprotection steps and functional group interconversion, from starting materials, such as 2-azaspiro[3.3]heptan-6-ol (CAS[1256352-97-2]).
  • a suitable temperature such as for example at reflux temperature, in the presence of acetic anhydride and a suitable base such as for example trimethylamine, in a suitable solvent such as for example toluene;
  • a suitable temperature such as for example at reflux temperature, in the presence of a suitable base such as potassium hydroxide, in a suitable solvent such as for example ethanol;
  • a suitable temperature such as for example room temperature or 45°C, in the presence of titanium (IV) ethoxide or titanium (IV) isopropoxide, in a suitable solvent such as for example tetrahydropyrane, dichloroethane or a mixture of dichloroethane and methanol;
  • a suitable temperature such as for example room temperature
  • a suitable acid such as for example trifluoroacetic acid
  • a suitable solvent such as for example tetrahydropyrane
  • a suitable temperature such as for example room temperature
  • a suitable reducting agent such as for example sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable solvent such as for example tetrahydropyrane, dichloroethane or a mixture of dichloroethane and methanol
  • Steps 1 and 2 can be performed as a one-pot procedure.
  • a suitable temperature such as for example room temperature or 45°C, in the presence of titanium (IV) ethoxide or titanium (IV) isopropoxide, in a suitable solvent such as for example tetrahydropyran;
  • Steps 1 and 2 can be performed as a one-pot procedure.
  • a suitable temperature such as for example room temperature
  • a suitable acid coupling agent such as for example l-[bis(dimethylamino)methylene]- lH-benzotriazoliumhexafiuorophosphate(l-)3-oxide (HBTU) or 1- [Bis(dimethy lamino)methy lene] - 1 H- 1 ,2 , 3 -triazo lo [4 , 5 -b]pyridinium 3 -oxide hexafluorophosphate (HATU), in the presence of a suitable base such as for example N-ethyl-N-(l-methylethyl)-2-propanamine (DIPEA), in a suitable solvent such as N,N- d i m e t h y 1 f o m a m i d e (DMF);
  • DIPEA N-ethyl-N-(l-methylethyl)-2-propan
  • a suitable temperature for example room temperature, in the presence of a suitable base such as for example potassium carbonate, in a suitable solvent such as for example acetonitrile.
  • the compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • Suitable amino -protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
  • NH- Pg amino -protecting groups
  • the compounds of the present invention block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins. Therefore the compounds according to the present invention and the pharmaceutical compositions comprising such compounds may be useful for the treatment or prevention, in particular treatment, of diseases such as cancer, myelodysplasia syndrome (MDS) and diabetes.
  • diseases such as cancer, myelodysplasia syndrome (MDS) and diabetes.
  • a solid tumor cancer e.g. prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma and glioblastoma, etc.
  • the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML), Chronic myelogenous leukemias (CML), Acute lymphoblastic leukemias (ALL), Chronic lymphocytic leukemias (CLL), T cell prolymphocyte leukemias (T- PLL), Large granular lymphocytic leukemia, Hairy cell leukemia (HCL), MLL- rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exphibiting HOXIMEIS1 gene expression signatures etc.
  • AML acute myelogeneous leukemias
  • CML Chronic myelogenous leukemias
  • ALL Acute lymphoblastic leukemias
  • the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, for use as a medicament.
  • the invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.
  • the present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.
  • the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, the treatment or prevention of which is affected or facilitated by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.
  • the invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore.
  • the invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore.
  • the invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.
  • the compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.
  • Said method comprises the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, to warm-blooded animals, including humans.
  • administration i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, to warm-blooded animals, including humans.
  • the invention also relates to a method for the treatment or prevention of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.
  • a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient.
  • the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.
  • An effective therapeutic daily amount would be from about 0.005 mg/kg to 100 mg/kg, in particular 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
  • a particular effective therapeutic daily amount might be 1 mg/kg body weight, 2 mg/kg body weight, 4 mg/kg body weigth, or 8 mg/kg body weight.
  • the amount of a compound according to the present invention, also referred to herein as the active ingredient, which is required to achieve a therapeutically effect may vary on case- by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to administration.
  • suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
  • compositions for preventing or treating the disorders referred to herein comprising a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture).
  • a therapeutically effective amount of the particular compound, in base form or salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot- on or as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
  • the compounds are preferably orally administered.
  • the exact dosage and frequency of administration depends on the particular compound of Formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
  • said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.
  • a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • the one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular condition, in particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
  • the weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1/10 to 10/1 , more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
  • 'ACN or 'MeCN' means acetonitrile
  • 'DCM' means dichloromethane
  • 'DIPEA' means ⁇ , ⁇ -diisopropylethylamine
  • 'DIPE or 'DiPE means diisopropyl ether
  • 'h' means hours(s)
  • 'min' means minute(s)
  • 'DMF' means dimethylformamide
  • 'DSC means differential scanning calorimetry
  • 'TEA or 'Et 3 N' means triethyl amine
  • 'Et 2 0' means diethyl ether
  • 'EtOAc' or 'EA' means ethyl acetate
  • 'EtOH' means ethanol
  • 'HPLC means High-performance Liquid Chromatography
  • 'iPrOH' means isopropyl alcohol
  • 'LC/MS' means Liquid Chromatography/Mass Spectrometry
  • aq.' means saturated aqueous.
  • 'AcCP means acetyl chloride
  • 'AcOH' or 'HOAc' means acetic acid
  • 'BOC or 'Boc' means tert- butyloxycarbonyi
  • 'Celite ® ' means diatomaceous earth
  • 'CH O H-f means ammonium acetate
  • 'COMU®' means (l-Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate
  • 'C0 2 ' means carbon dio ide
  • 'DCE' means dichloroethane
  • 'DMAP' means dimethylaminopyridine
  • 'DMSO' means dimethyl sulfoxyde
  • DBU * means 1,8- diazabicyclo[5.4.0]undecene-7
  • 'EtMgBr' means ethyl magnesium bromide
  • 'Et 2 0' means diethyl ether
  • 'EtOAc' means ethyl acetate
  • 'Et 3 N' or 'TEA' means triethylamine
  • 'EtOH' means ethanol
  • 'h' means hours(s)
  • 'HATU' means 0-(7-Azabenzotriazoi-l-yl)-N,N,N,N- t et ra me t h y 1 u o n i u m hexafluorophosphate
  • 'HC1' means hydrochloric acid
  • 'HOBT' means N-Hydroxybenzotrizole monohydrate
  • ⁇ 2 0' means water
  • 'iPrMgCP means isopropyl magnesium chloride
  • 'iPrNH 2 ' means isoprapylamine
  • compounds synthesised using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.
  • Compounds isolated as a salt form may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry.
  • the stereochemical configuration for centres in some compounds may be designated "R” or "5"' when the mixture(s) was separated; for some compounds, the
  • stereospecifically although the compound is enantiomerically pure at the indicated centre.
  • the absolute stereochemistry of the stereocentres is undetermined (even if the bonds are drawn stereospecifically), although the compound itself has been isolated as a single stereoisomer and is enant iomerically pure.
  • the configuration of the first stereocentre is independent of the configuration of the second stereocentre in the same compound.
  • enantiomerically pure means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of the other enantiomer. Preferably the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment the term “enantiomerically pure” means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.
  • Acetic anhydride (1 mL, 10.7 mmol) was added dropwise at rt, to a solution of 2-amino- 5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide (2 g, 8.92 mmol) in toluene (50 mL) and trimethylamine (6.2 mL, 44.6 mmol).
  • the solution was heated at reflux for 5h, poured into water, extracted with EtOAc, and washed with brine (x2).
  • the organic layer was dried over MgS04, filtered and evaporated to dryness, the crude product was taken- up with Et 2 0 and the precipitate was filtered to provide 1.5 g of intermediate 13 (yield 63% / brown solid).
  • intermediate 41 Under a N 2 flow, at rt, to a solution of intermediate 11 (250 mg, 0.76 mmol) in DCM (12 mL) was added intermediate 42 (246 mg, 0.91 mmol). The mixture was stirred at room temperature for 3h. The mixture was cooled to 5°C, NaBH(OAc) 3 (323 mg, 1.52 mmol) was added and the mixture was stirred at rt overnight. Then, it was poured into ice water and the layers were separated. The aqueous layer was extracted with DCM. The organic layers were combined, washed with brine then dried over MgS0 4 , evaporated. The residue was crystallized from Et 2 0 and pentane. The white precipitate was filtered off and dried under vaccum yielding 55mg (yield 100%) of intermediate 41.
  • intermediate 53(349 mg, 1.37 mmol) and Ti(OiPr) 4 (436 ⁇ ,, 1.83 mmol) were added to a solution of intermediate 11 (300 mg, 0.914 mmol) in THF (6 mL). The solution was stirred at 50°C for 5 hours then, at rt overnight. The reaction mixture was cooled to 5°C and 2N iPrMgCl in THF (2.28 mL, 4.57 mmol) was added dropwise. The reaction mixture was allowed to rise slowly to rt and stirred overnight . The reaction mixture was diluted with EtOAc and poured onto a 10% aqueous solution of K2CO3.
  • Fraction 1 was purified by reverse phase (YMC-actus Triart CI 8 10 ⁇ 30* 150 mm, mobile phase: gradient from 65% NH4HCO3 0.2%, 35% ACN to 25% NH4HCO3 0.2%, 75%) ACN). The fractions containing the product were collected and the solvent was evaporated. The residue (160 mg; colourless oil) was freeze-dried with water-ACN to give 90 mg (6%>) of white solid compound 61.
  • intermediate 69 was purified by chiral SFC (Chiralpak IG 5 ⁇ 250*20 mm, mobile phase: 65% C0 2 , 35% iPrOH (0.3% iPrNH 2 )). The pure fractions were collected and the solvent was evaporated to give 4.07 g of intermediate 69a (46%>, yellow foam) and 4.29 g of intermediate 69b (48%>, yellow foam).
  • the intermediate 70a was prepared by using an analogous method as described for the alternative preparation of intermediate 11, starting from the respective starting material intermediate 69a.
  • Reaction mixture 1 In a sealed tube, a solution of intermediate 78 (2 equivalents), intermediate 11 (100 mg; 0.305 mmol) and Ti(OiPr) 4 (6 equivalents)in EtOH (0.2 mL) was heated at 45°C for 1 hour. The mixture was cooled down to room temperature, diluted with EtOH (3 mL) and NaBH 4 (2 equivalents) was added. The reaction mixture was stirred at room temperature for 4 hours indicating, according to LC/MS the formation of 60% of intermediate 77
  • Reaction mixture 2 and 3 The reaction was performed twice on the same quantity : In a sealed tube, a solution of intermediate 78 (2 equivalents), intermediate 11 (450 mg; 1.37 mmol) and Ti(OiPr) 4 (6 equivalents) in EtOH (0.9 mL) was heated at 45°C for 1 hour. The mixture was cooled down to room temperature, diluted with EtOH (13 mL) and NaBH 4 (2 equivalents) was added. The reaction mixture was stirred at room temperature for 18 hours. The three reaction mixtures were diluted with EtOAc and poured onto a mixture of 10% K2CO3 and brine. The suspension was sonicated for 30 min and filtered through a pad of Celite ® .
  • the impure fraction of intermediate 77 was further purified by achiral SFC
  • reaction mixture was cooled to room temperature, poured out onto a mixture of iced water and a saturated aqueous NH 4 C1 solution, and extracted with EtOAc. The organic layer was decanted, dried over MgSC ⁇ , filtered and evaporated to dryness yielding 4.7 g of intermediate 72 (quantitative).
  • HBTU 210 mg; 0.555 mmol
  • BOC-L-proline 119 mg; 0.555 mmol
  • DIPEA 0.48 mL; 2.775 mmol
  • DMF 10 mL
  • intermediate 10b 200 mg was added and the solution was stirred at room temperature all over the weekend.
  • the reaction mixture was poured into iced water, basified with a 10% aqueous solution of K2CO3 and extracted with EtOAc. The organic layer was washed by water, dried over MgS04, filtered and evaporated to dryness.
  • the enantiomers were separated via chiral SFC (stationary phase: Lux Cellulose-4 5 ⁇ 250*21.2mm, mobile phase: C0 2 /MeOH (0.3% iPrNH 2 ): 70/30).
  • the product containing fractions were collected and evaporated to dryness yielding 80 mg (yield 31 %) of a first eluted fraction Fl and 81 mg (yield 31%) of a second eluted fraction F2.
  • intermediate 11 200 mg, 0.51 mmol
  • intermediate 16 220 mg, 1.08 mmol
  • K2CO3 221.4 mg, 1.53 mmol
  • the mixture was heated to 90 °C and stirred overnight.
  • Water (10 mL) and DCM (10 mL) were added to the reaction mixture.
  • the organic phase was separated, the aqueous layer was extracted with DCM (10 mL).
  • the residue was purified by chromatography over silica gel (stationary phase: irregular SiOH 15-40 ⁇ 24g, mobile phase: DCM/MeOH (+10% NH 4 OH): gradient from 97/3 to 90/10.
  • the pure fractions were collected and evaporated to dryness.
  • the residue was freeze-dried with acetonitrile/water: 20/80 yielding 0.057 g (15% yield) of compound 36.
  • the compounds in the Table below were prepared by using an analogous method as described for the preparation of compound 36, starting from the respective starting materials.
  • the residue was purified by chromatography over silica gel (irregular SiOH, lOg; mobile phase: gradient from 3% MeOH, 97% DCM to 10% MeOH, 90% DCM). The fractions containing the product were collected and evaporated to dryness yielding 144 mg of an impure fraction 1.
  • a second purification was performed (irregular SiOH, 40g; mobile phase: 0.5% NH 4 OH, 95% DCM, 5% MeOH). The fractions containing the product were collected and evaporated to dryness yielding 43 mg of an impure fraction 2.
  • Fraction 2 was purified again by chromatography over silica gel (irregular SiOH, lOg; mobile phase: gradient from 3% MeOH, 97% DCM to 10% MeOH, 90% DCM). The fractions containing the product were collected and evaporated to dryness. The resulting residue was taken up with diisopropyl ether. The solid was filtered and dried yielding 17 mg of compound 108.
  • the residue was purified by chromatography over silica gel (stationary phase: irregular bare silica 40g, mobile phase: NH 4 OH/DCM/MeOH: 0.2/98/2).
  • the residue was dissolved in 5 mL of ACN, 2eq of 4N HCl in dioxane (1 17 ⁇ ; 0.47 mmol) was added dropwise at 10°C.
  • Et 2 0 was added and after 30mn, the solution was evaporated to dryness, Et 2 0 was added and a precipitate was filtered and dried yielding 38 mg of compound 58 (HCl salt).
  • the residue was purified by chromatography over silica gel (irregular SiOH, 24g; mobile phase: NH 4 OH/MeOH/DCM: gradient from 0/0/100 to 0.7/7/93). The pure fractions were collected and evaporated to dryness. The residue was freeze-dried from water/ ACN (80/20; 10 mL) yielding 155 mg of compound 63 (56% yield).
  • the residue was purified by chromatography over silica gel (irregular SiOH, 24g; mobile phase: NH 4 OH/MeOH/DCM gradient from 0/0/100 to 0.7/7/93). The pure fractions were collected and evaporated to dryness. The residue was purified a second time by chromatography over silica gel (irregular SiOH, lOg; mobile phase: EtO Ac/heptane: gradient from 60/40 to 80/20). The pure fractions were collected and evaporated to dryness. The residue was crystallized from DIPE yielding, after drying under vacuum at 50°C, 100 mg of compound 64 (53% yield).
  • intermediate 35 (211 mg; 1.37 mmol) and Ti(OiPr) 4 (436 ⁇ ; 1.83 mmol) were added to a solution of intermediate 11 (300 mg; 0.914 mmol) in THF (6 mL). The solution was stirred at 50°C for 5 hours then at rt overnight. The reaction mixture was cooled to 5°C and isopropyl magnesium chloride 2M in THF (2.28 mL; 4.57 mmol) was added drop wise. The reaction mixture was allowed to rise slowly to rt and stirred overnight. The reaction mixture was diluted with EtOAc and poured onto a 10% aqueous solution of K2CO3. The precipitate was removed by filtration over Celite ® .
  • COMPOUND 313 Diastereoisomer B (mixture of 2 compounds (RS and SR) or (RR and SS)):
  • Co 312 Diastereoisomer A (RR and SS) or (RS and SR)
  • Reaction mixture 1 A solution of 3-methyl-l-(6-oxaspiro[4.5]dec-9-yl)-l-Butanone (1.5 eq.), intermediate 11 (100 mg; 0.285 mmol), Ti(OiPr) 4 (1.6 eq.) in ethanol (0.25 mL) was stirred for 2 hours at 45°C. Ethanol (3 mL) was added and NaBH 4 (2 eq.) was added. The reaction mixture was stirred at room temperature for 18 hours.
  • Reaction mixture 2 A solution of 3-methyl-l-(6-oxaspiro[4.5]dec-9-yl)-l-Butanone (546 mg; 2.436 mmol; 2eq), intermediate 11 (400 mg; 1.22 mmol), Ti(OiPr) 4 (580 ⁇ ; 1.95 mmol) in ethanol (1 mL) was stirred for 2 hours at 45°C. Ethanol (12 mL) was added and NaBH 4 (92 mg; 2.436 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours.
  • the two reaction mixtures were gathered and diluted with EtOAc, poured onto a 10% aqueous solution of K2CO3 and filtered through a pad of Celite ® .
  • the organic layer was decanted, washed with brine, dried over MgS0 4 , filtered and evaporated to dryness.
  • the residue was purified by chromatography over silica gel (irregular SiOH, 24g; mobile phase: gradient from 0% NH 4 OH, 0% MeOH, 100% DCM to 0.9% NH 4 OH, 9% MeOH, 91 ) DCM). The desired fractions were collected and evaporated to dryness.
  • Compound 156 was purified by reverse phase (YMC-actus Triart CI 8 10 ⁇ 30* 150 mm, mobile phase: gradient from 50% NH 4 HC0 3 0.2%, 50% ACN to 0% NH 4 HC0 3 0.2%), 100%) ACN). The pure fractions were collected and the solvent was evaporated to give 66 mg of compound 157 (colourless oil) and 264 mg of compound 156 (8%; colourless oil).
  • the residue was purified by chromatography over silica gel (irregular SiOH, 24 g; mobile phase: gradient from 100% DCM to 10% MeOH (+10%NH 4 OH), 90%) DCM). The pure fractions were collected and evaporated to dryness.
  • the hydrochloride salt was prepared: The residue (110 mg, 38%) was dissolved in ACN and HCl 4N in 1,4-dioxane (2eq.) was added. The solution was evaporated to dryness and taken up several times with ACN. The residue was crystallized from Et 2 0 yielding 120 mg of compound 184 (HCl salt).
  • the compound in the Table below were prepared by using an analogous method as described for the preparation of compound 184, starting from the respective starting materials.
  • the residue was purified by chromatography over silica gel (irregular SiOH, lOg; mobile phase: gradient from 0% NH40H, 0% MeOH, 100% DCM to 0.5% NH4OH, 5% MeOH, 95% DCM). The pure fractions were collected and evaporated to dryness. The residue was freeze dried from water/ ACN (80/20; 10 mL) yielding 73 mg (56%>) of compound 289.
  • the compounds in the Table below were prepared by using an analogous method as described for the preparation of compound 289, starting from the respective starting materials. The most relevant minor deviations are indicated in the column Yield.
  • Compound 273 can also be prepared from intermediate 71a using the same procedure.
  • Compound 200 can also be prepared from intermediate 71b using the same procedure.
  • the compounds in the table below were prepared using an analogous method as described for the preparation of compound 273 starting from the respective starting materials.
  • the enantiomers were separated by chiral SFC (CHIRALPAK IC 5 ⁇ 250x20mm; mobile phase: 50% C0 2 , 50% MeOH (+2% iPrNH 2 )). The fractions containing each enantiomer were collected, evaporated to dryness and purified by reverse phase chromatography (YMC-actus Triart-C18 ⁇ 30* 150mm; mobile phase: gradient from 75% NH4HCO3 0.2%, 25% ACN to 35% NH4HCO3 0.2%, 65% ACN). The pure fractions were collected, evaporated to dryness and freeze dried from ACN/water (20/80) yielding 21 mg (17%) of compound 201 and 23 mg (19%>) of compound 202.
  • the residue was purified by chromatography over silica gel (irregular SiOH, 12g; mobile phase: gradient from 100% DCM, 0% MeOH to 95% DCM, 5% MeOH, 0.3% NH 4 OH). The fractions were collected and evaporated to dryness.
  • the residue 300 mg was purified a second time by reverse phase chromatography (YMC-actus Triart CI 8 ⁇ 30* 150mm; mobile phase: gradient from 65% NH4HCO3 0.2% aq, 35% ACN to 25% NH4HCO3 0.2%) aq, 75%) ACN).
  • the pure fractions were collected, evaporated to dryness yielding 104 mg of compound 224.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne des agents pharmaceutiques utiles pour la thérapie et/ou la prophylaxie chez un mammifère, et en particulier des composés spiro bicycliques, une composition pharmaceutique comprenant de tels composés, et leur utilisation en tant qu'inhibiteurs d'interactions ménine/protéine MLL/protéine, utiles pour le traitement de maladies telles que le cancer, le syndrome myélodysplasique (MDS) et le diabète.
PCT/EP2017/073004 2016-09-14 2017-09-13 Inhibiteurs spiro bicycliques de l'interaction ménine-mll Ceased WO2018050686A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
EP17768428.9A EP3512857B1 (fr) 2016-09-14 2017-09-13 Inhibiteurs spiro-bicyclique de menin-mll-interaction
DK17768428.9T DK3512857T3 (da) 2016-09-14 2017-09-13 Spiro-bicykliske inhibitorer af menin-mll-interaktion
CN201780056188.3A CN109689663B (zh) 2016-09-14 2017-09-13 Menin-mll相互作用的螺二环抑制剂
AU2017326487A AU2017326487B2 (en) 2016-09-14 2017-09-13 Spiro bicyclic inhibitors of menin-MLL interaction
ES17768428T ES2872003T3 (es) 2016-09-14 2017-09-13 Inhibidores espirobicíclicos de la interacción de menina-MLL
BR112019004691A BR112019004691A2 (pt) 2016-09-14 2017-09-13 inibidores bicíclicos em espiro da interação menina-mll
MX2019002962A MX392051B (es) 2016-09-14 2017-09-13 Inhibidores espirobiciclicos de la interaccion de menina-mll
CA3033239A CA3033239A1 (fr) 2016-09-14 2017-09-13 Inhibiteurs spiro bicycliques de l'interaction menine-mll
SI201730700T SI3512857T1 (sl) 2016-09-14 2017-09-13 Spiro biciklični zaviralci interakcije menin-MLL
LTEP17768428.9T LT3512857T (lt) 2016-09-14 2017-09-13 Menin-mll sąveikos spirobicikliniai inhibitoriai
HRP20210514TT HRP20210514T1 (hr) 2016-09-14 2017-09-13 Spiro biciklički inhibitori interakcije menin-mll
US16/331,606 US11220517B2 (en) 2016-09-14 2017-09-13 Spiro bicyclic inhibitors of menin-MLL interaction
EA201990699A EA201990699A1 (ru) 2016-10-05 2017-09-13 Спиробициклические ингибиторы взаимодействия менин–mll
KR1020197008627A KR102493644B1 (ko) 2016-09-14 2017-09-13 메닌-mll 상호작용의 스피로 바이사이클릭 억제제
JP2019535974A JP6975791B2 (ja) 2016-09-14 2017-09-13 メニン−ｍｌｌ相互作用のスピロ二環式阻害剤
IL265233A IL265233B (en) 2016-09-14 2019-03-07 Spiro-cyclic inhibitors of the menin-mll interaction
US17/536,899 US12084462B2 (en) 2016-09-14 2021-11-29 Spiro bicyclic inhibitors of menin-MLL interaction

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US201662394295P 2016-09-14 2016-09-14
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10077271B2 (en) 2015-06-04 2018-09-18 Kura Oncology, Inc. Methods and compositions for inhibiting the interaction of menin with MLL proteins
US10246464B2 (en) 2014-09-09 2019-04-02 The Regents Of The University Of Michigan Thienopyrimidine and thienopyridine compounds and methods of use thereof
WO2019120209A1 (fr) * 2017-12-20 2019-06-27 Janssen Pharmaceutica Nv Inhibiteurs spiro exo-aza de l'interaction ménine-mll
WO2020032105A1 (fr) 2018-08-08 2020-02-13 大日本住友製薬株式会社 Dérivé de pipéridine ponté optiquement actif
WO2020045334A1 (fr) 2018-08-27 2020-03-05 大日本住友製薬株式会社 Dérivé azabicyclique optiquement actif
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US10611778B2 (en) 2016-09-14 2020-04-07 Janssen Pharmaceutica Nv Fused bicyclic inhibitors of menin-MLL interaction
US10745409B2 (en) 2016-12-15 2020-08-18 Janssen Pharmaceutica Nv Azepane inhibitors of menin-MLL interaction
US10752639B2 (en) 2016-03-16 2020-08-25 Kura Oncology, Inc. Bridged bicyclic inhibitors of menin-MLL and methods of use
US10781218B2 (en) 2016-03-16 2020-09-22 Kura Oncology, Inc. Substituted inhibitors of menin-MLL and methods of use
US10815241B2 (en) 2018-08-27 2020-10-27 Sumitomo Dainippon Pharma Co., Ltd. Optically active azabicyclo ring derivative
WO2021060453A1 (fr) * 2019-09-27 2021-04-01 大日本住友製薬株式会社 Dérivé d'amine secondaire optiquement actif réticulé
JPWO2019189732A1 (ja) * 2018-03-30 2021-04-08 大日本住友製薬株式会社 光学活性な架橋型環状２級アミン誘導体
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WO2022237626A1 (fr) 2021-05-08 2022-11-17 Janssen Pharmaceutica Nv Dérivés spiro substitués
WO2022237627A1 (fr) 2021-05-08 2022-11-17 Janssen Pharmaceutica Nv Dérivés spiro substitués
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US11542248B2 (en) 2017-06-08 2023-01-03 Kura Oncology, Inc. Methods and compositions for inhibiting the interaction of menin with MLL proteins
US11649251B2 (en) 2017-09-20 2023-05-16 Kura Oncology, Inc. Substituted inhibitors of menin-MLL and methods of use
WO2024033479A1 (fr) * 2022-08-11 2024-02-15 Remynd N.V. Dérivés d'(aza)spiroheptane pour le traitement de troubles neurodégénératifs
US11944627B2 (en) 2017-03-24 2024-04-02 Kura Oncology, Inc. Methods for treating hematological malignancies and Ewing's sarcoma
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
US12060365B2 (en) 2018-12-06 2024-08-13 Daiichi Sankyo Company, Limited Cycloalkane-1,3-diamine derivative
US12084462B2 (en) 2016-09-14 2024-09-10 Janssen Pharmaceutica Nv Spiro bicyclic inhibitors of menin-MLL interaction

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029054A1 (fr) 2009-09-04 2011-03-10 The Regents Of The University Of Michigan Compositions et méthodes de traitement de la leucémie
WO2014164543A1 (fr) 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Compositions comprenant des composés thiénopyrimidine et thiénopyridine et procédés d'utilisation associés
WO2017112768A1 (fr) 2015-12-22 2017-06-29 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732636B (zh) * 2014-12-30 2020-04-21 广东东阳光药业有限公司 杂芳化合物及其在药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029054A1 (fr) 2009-09-04 2011-03-10 The Regents Of The University Of Michigan Compositions et méthodes de traitement de la leucémie
WO2014164543A1 (fr) 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Compositions comprenant des composés thiénopyrimidine et thiénopyridine et procédés d'utilisation associés
WO2017112768A1 (fr) 2015-12-22 2017-06-29 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
AUSTIN R. ET AL., CANCER LETTERS, 2016
BORKIN ET AL., CANCER CELL, vol. 27, 2015, pages 589 - 602
CERMAKOVA ET AL., CANCER RES, vol. 15, 2014, pages 5139 - 51
CHARRON, CARLIE L. ET AL., TETRAHEDRON LETT., vol. 57, no. 37, 2016, pages 4119 - 4127
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 885275-27-4
CHEN ET AL., PROC NATL ACAD SCI, vol. 103, 2006, pages 1018 - 23
CIERPICKI; GREMBECKA, FUTURE MED CHEM, vol. 6, 2014, pages 447 - 462
FUTURE MED CHEM, vol. 6, 2014, pages 447 - 462
GENNARO ET AL.: "Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
J MED CHEM, vol. 57, 2014, pages 1543 - 1556
J MED CHEM, vol. 59, 2016, pages 892 - 913
JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 3, 2016, pages 892 - 913
LI ET AL., BLOOD, vol. 122, 2013, pages 2039 - 2046
MALIK ET AL., NAT MED, vol. 21, 2015, pages 344 - 52
MARSCHALEK, BR, J HAEMATOL, vol. 152, no. 2, 2011, pages 141 - 54
MEYER ET AL., LEUKEMIA, vol. 27, 2013, pages 2165 - 2176
MISHRA ET AL., CELL REP, vol. 7, no. 4, 2011, pages 1239 - 47
NATURE CHEMICAL BIOLOGY, vol. 8, March 2012 (2012-03-01), pages 277 - 284
REN, J. ET AL., BIOORG MED CHEM LETT, 2016, Retrieved from the Internet <URL:http://dx.doi.org/10.1016/j.bmcl.2016.07.074>
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2007, WILEY, HOBOKEN
THIEL ET AL., BIOESSAYS, vol. 34, 2012, pages 771 - 80
TOMIZAWA ET AL., PEDIATR BLOOD CANCER, vol. 49, no. 2, 2007, pages 127 - 32
YOKOYAMA ET AL., CELL, vol. 123, 2005, pages 207 - 18
YOKOYAMA; CLEARY, CANCER CELL, vol. 8, 2008, pages 36 - 46

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WO2022237626A1 (fr) 2021-05-08 2022-11-17 Janssen Pharmaceutica Nv Dérivés spiro substitués
WO2022237627A1 (fr) 2021-05-08 2022-11-17 Janssen Pharmaceutica Nv Dérivés spiro substitués
WO2022253167A1 (fr) 2021-06-01 2022-12-08 Janssen Pharmaceutica Nv Dérivés de phényl-1h-pyrrolo [2, 3-c] pyridine substitués
WO2022253289A1 (fr) 2021-06-03 2022-12-08 Janssen Pharmaceutica Nv Pyridazines ou 1,2,4-triazines substituées par des amines spirocycliques
WO2022262796A1 (fr) 2021-06-17 2022-12-22 Janssen Pharmaceutica Nv Sel de bésylate (r)-n-éthyl-5-fluoro-n-isopropyl-2-((5-(2-(6-((2-méthoxyéthyl)(méthyl)amino)-2-m éthylhexan-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl)oxy)benzamide pour le traitement de maladies telles que le cancer
WO2024033479A1 (fr) * 2022-08-11 2024-02-15 Remynd N.V. Dérivés d'(aza)spiroheptane pour le traitement de troubles neurodégénératifs
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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