WO2024114662A1 - Composés bicycliques à substitution cyclobutyle - Google Patents

Composés bicycliques à substitution cyclobutyle Download PDF

Info

Publication number
WO2024114662A1
WO2024114662A1 PCT/CN2023/134909 CN2023134909W WO2024114662A1 WO 2024114662 A1 WO2024114662 A1 WO 2024114662A1 CN 2023134909 W CN2023134909 W CN 2023134909W WO 2024114662 A1 WO2024114662 A1 WO 2024114662A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
substituted
atom
het
Prior art date
Application number
PCT/CN2023/134909
Other languages
English (en)
Inventor
Ming Li
Wei Cai
Fabian HULPIA
Johannes Wilhelmus J. Thuring
Xiangjun DENG
Susan LEPRI
Chao Liang
Vineet PANDE
Zhen Sun
Zhigao Zhang
Original Assignee
Janssen Pharmaceutica Nv
Johnson & Johnson (China) Investment Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica Nv, Johnson & Johnson (China) Investment Ltd. filed Critical Janssen Pharmaceutica Nv
Publication of WO2024114662A1 publication Critical patent/WO2024114662A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, including but not limited to leukemia.
  • MLL mixed lineage leukemia gene
  • KMT2A mixed lineage leukemia gene
  • MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes.
  • H3K4 histone methyltransferase
  • H3K4 histone H3 on lysine 4
  • Mll1 plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for hematopoiesis.
  • 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. 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.
  • numerous genetic studies have shown that menin is strictly required for oncogenic transformation by MLL fusion proteins suggesting the menin/MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukomogenesis in bone marrow progenitor cells ectopically expressing MLL fusions.
  • 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.
  • 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.
  • MLL protein is also known as Histone-lysine N-methyltransferase 2A (KMT2A) protein in the scientific field (UniProt Accession #Q03164) .
  • KMT2A Histone-lysine N-methyltransferase 2A
  • the present invention concerns novel compounds of Formula (I) ,
  • R 1b represents hydrogen, F or Cl
  • R 2a represents hydrogen, halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted with one, two or three halo substituents;
  • R 2b represents hydrogen or C 1-4 alkyl
  • R 2c represents hydrogen or C 1-4 alkyl
  • R 3 represents hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with C 3-6 cycloalkyl;
  • R 4 represents hydrogen, C 1-6 alkyl, R 6 , Het 1 , C 1-6 alkyl substituted with one subsituent selected from the group consisting of R 6 and Het 1 ;
  • R 5a and R 5b each independently represent hydrogen or C 1-4 alkyl
  • R 6 represents C 3-6 cycloalkyl, or C 3-6 cycloalkyl substituted with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, -O-C 1-4 alkyl or Het 2 ;
  • R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl
  • R 19 represents hydrogen or C 1-6 alkyl
  • R 18 and R 19 are taken together to form -CH 2 -CH 2 -CH 2 -;
  • Het represents a monocyclic 5-or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein said monocyclic 5-or 6-membered aromatic ring is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, or cyano;
  • R xa and R xb are each independently selected from the group consisting of hydrogen;
  • R 23 represents hydrogen or C 1-4 alkyl optionally substituted with one, two or three halo; and the pharmaceutically acceptable salts and the solvates thereof.
  • 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, including but not limited to leukemia.
  • 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.
  • the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML) , Acute lymphoblastic leukemias (ALL) , MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exhibiting HOX/MEIS1 gene expression signatures etc.
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias, in particular nucleophosmin (NPM1) -mutated leukemias, e.g. NPM1c.
  • NPM1 nucleophosmin
  • compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof may have improved metabolic stability properties.
  • compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof may reduce tumor growth e.g., tumours harbouring MLL (KMT2A) gene rearrangements/alterations and/or NPM1 mutations.
  • KMT2A MLL
  • 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 in the treatment or prevention of cancer, including but not limited to leukemia.
  • 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, including but not limited to leukemia.
  • halo or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.
  • C x-y refers to the number of carbon atoms in a given group.
  • a C 1-6 alkyl group contains from 1 to 6 carbon atoms, and so on.
  • C 1-4 alkyl 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.
  • C 1-6 alkyl 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.
  • C 3-6 cycloalkyl as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Non-limiting examples of ‘monocyclic 5-or 6-membered aromatic rings containing one, two or three nitrogen atoms and optionally a carbonyl moiety’ include, but are not limited to pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1, 2-dihydro-2-oxo-4-pyridinyl.
  • a monocyclic 5-or 6-membered aromatic ring containing one, two or three nitrogen atoms and a carbonyl moiety includes, but is not limited to
  • the term ‘monocyclic N-linked 4-to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from O, S, and N’ defines a fully saturated, cyclic hydrocarbon radical having from 4 to 7 ring members and containing at least 1 nitrogen atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which is attached to the remainder of the molecule of formula (I) via a nitrogen atom.
  • Examples are N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked 1, 4-diazepanyl, and N-linked piperidinyl.
  • Two R groups taken together to form together with the N-atom to which they are attached a 4-to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from O, S, and N, are defined similar but the hydrocarbon radical can be fully or partially saturated.
  • the term ‘monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N’ defines a fully saturated, cyclic hydrocarbon radical having from 4 to 7 ring members and containing one, two or three heteroatoms each independently selected from O, S, and N, such as for example C-linked azetidinyl, C-linked pyrrolidinyl, C-linked morpholinyl, C-linked tetrahydrofuranyl, C-linked thiolanyl, C-linked oxetanyl, C-linked thietanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked piperidinyl, C-linked azepanyl, and C-linked 1, 2, 3, 6-tetrahydro-pyridinyl.
  • the 4-to 7-membered fully or partially saturated heterocyclyls have from 4 to 7 ring members including the heteroatoms.
  • bicyclic 6-to 11-membered fully saturated heterocyclyl groups include fused, spiro and bridged bicycles.
  • Fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.
  • Spiro bicyclic groups are two cycles that are joined at a single atom.
  • Bridged bicyclic groups are two cycles that share more than two atoms.
  • bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N include, but are not limited to
  • Examples of two R groups taken together to form together with the N-atom to which they are attached a 6-to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from O, S, and N, include, but are not limited to
  • each definition is independent.
  • each definition is independent.
  • substituted in general, whenever the term ‘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 (isolation after a reaction e.g. purification by silica gel chromatography) .
  • the number of substituents is one.
  • Solid compound is in this context meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (isolation after a reaction e.g. purification by silica gel chromatography) .
  • 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.
  • saturated means ‘fully saturated’ , if not otherwise specified.
  • aromatic rings and heterocyclyl goups can be attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked) .
  • aromatic rings and heterocyclyl goups may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to the embodiments.
  • subject 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
  • terapéuticaally 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.
  • compound (s) of the (present) invention or “compound (s) according to the (present) invention” as used herein, is meant to include the compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof.
  • stereoisomers , “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
  • 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.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2%and most preferably less than 1%, of the other stereoisomers.
  • a compound of Formula (I) is for instance specified as (R)
  • a compound of Formula (I) is for instance specified as E
  • this means that the compound is substantially free of the Z isomer
  • a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • 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.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids
  • 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.
  • prodrug includes any compound that, following oral or parenteral administration, in particular oral administration, is metabolised in vivo to a (more) active form in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 0.5 and 24 hours, or e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily) ) .
  • parenteral administration includes all forms of administration other than oral administration, in particular intravenous (IV) , intramuscular (IM) , and subcutaneous (SC) injection.
  • Prodrugs may be prepared by modifying functional groups present on a compound in such a way that the modifications are cleaved in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases.
  • 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.
  • 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.
  • 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, 11 C, 13 C, 14 C , 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the isotope is selected from the group of 2 H, 3 H, 11 C, 13 C and 18 F.
  • the isotope is selected from the group of 2 H, 3 H, 11 C and 18 F. More preferably, the isotope is 2 H, 3 H or 13 C. More preferably, the isotope is 2 H or 13 C. More preferably, the isotope is 2 H.
  • deuterated compounds and 13 C-enriched compounds are intended to be included within the scope of the present invention. In particular, 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-l4 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • 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.
  • Positron emitting isotopes such as 15 O, 13 N, 11 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.
  • Radiolabelled 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.
  • target-specific PET radiotracers may be used as biomarkers to examine and evaluate pathology, by for example, measuring target expression and treatment response.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1b represents F
  • R 2a represents hydrogen or C 1-4 alkyl
  • R 2b represents hydrogen
  • R 2c represents hydrogen
  • R 3 represents hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with C 3-6 cycloalkyl;
  • R 4 represents hydrogen, C 1-6 alkyl, R 6 , Het 1 , C 1-6 alkyl substituted with one subsituent selected from the group consisting of R 6 and Het 1 ;
  • R 5a and R 5b each independently represent hydrogen or C 1-4 alkyl
  • R 6 represents C 3-6 cycloalkyl, or C 3-6 cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -O-C 1-4 alkyl or Het 2 ;
  • R xa and R xb represent C 1-6 alkyl
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1b represents F
  • R 2a represents hydrogen or C 1-4 alkyl
  • R 4 represents C 1-6 alkyl, R 6 , Het 1 , C 1-6 alkyl substituted with one subsituent selected from the group consisting of R 6 and Het 1 ;
  • R 5a and R 5b represent hydrogen
  • R 6 represents C 3-6 cycloalkyl
  • R xa and R xb represent C 1-6 alkyl;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 1b represents F
  • R 2a represents hydrogen; C 1-4 alkyl
  • R 4 represents C 1-6 alkyl, R 6 , Het 1 , C 1-6 alkyl substituted with one subsituent selected from the group consisting of R 6 and Het 1 ;
  • R 5a and R 5b represent hydrogen
  • R 6 represents C 3-6 cycloalkyl
  • R xa and R xb represent C 1-6 alkyl
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • R 1b represents F
  • R 2a represents C 1-4 alkyl; in particular methyl
  • R 4 represents C 1-6 alkyl substituted with one Het 1 ;
  • R 5a and R 5b represent hydrogen
  • R 6 represents C 3-6 cycloalkyl
  • R xa and R xb represent C 1-6 alkyl
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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 xa and R xb represent hydrogen or C 1-6 alkyl.
  • 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 xa and R xb represent C 1-6 alkyl.
  • 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 xa and R xb are not taken together.
  • 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 1b represents F or Cl.
  • 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 1b represents 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 R 1b represents F; R 2a is other than hydrogen; R 2b represents hydrogen; R 2c represents hydrogen.
  • 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 2a represents C 1-4 alkyl.
  • 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 2a represents methyl.
  • 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 2a represents halo, C 3-6 cycloalkyl, C 1- 4 alkyl, -O-C 1-4 alkyl, cyano, or C 1-4 alkyl substituted with one, two or three halo substituents.
  • 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 2a is other than hydrogen.
  • 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 3 represents hydrogen, and R 4 is other than hydrogen.
  • 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 4 represents hydrogen, and R 3 is other than hydrogen.
  • 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 4 represents C 1-6 alkyl substituted with one Het 1 .
  • 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 3 represents hydrogen
  • R 4 represents C 1-6 alkyl substituted with one Het 1 .
  • 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 3 represents hydrogen
  • R 4 represents C 1-6 alkyl substituted with one Het 1 ;
  • 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 5a represents hydrogen.
  • 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 5b represents hydrogen.
  • 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 5a and R 5b represent hydrogen.
  • 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 of R 5a and R 5b represents C 1-4 alkyl and the other one is hydrogen.
  • 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 5a represents hydrogen, and R 5b represents C 1-4 alkyl, in particular methyl.
  • 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 5b represents hydrogen, and R 5ba represents C 1-4 alkyl, in particular methyl.
  • 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
  • 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 1 is monocylic.
  • 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 1 is bicyclic.
  • 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 1 represents any of the following
  • 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 represents
  • the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
  • the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
  • the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39.
  • the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39;
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39;
  • the compound of Formula (I) is compound 1 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 3 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 8 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 9 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 11 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 12 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 13 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 14 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 26 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 28 or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I) is compound 39 or a pharmaceutically acceptable salt or solvate thereof.
  • 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.
  • 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.
  • intermediates and final compounds shown in the Schemes below may be further functionalized according to methods well-known by the person skilled in the art.
  • the intermediates and compounds described herein can be isolated in free form or as a salt, or a solvate thereof.
  • the intermediates and compounds described herein may be synthesized in the form of mixtures of tautomers and stereoisomeric forms that can be separated from one another following art-known resolution procedures.
  • PG represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl;
  • X 1 represents a halogen such as chloro, bromo or iodo, or other leaving groups such as mesylate or tosylate;
  • X 2 represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
  • Step 1 at a suitable temperature in a range between 80°C and 120°C, in the presence of a diol reagent such as for example ethylene glycol, in the presence of a Bronsted acid such as for example p-toluenesulfonic acid in a suitable aprotic solvent such as for example toluene;
  • a diol reagent such as for example ethylene glycol
  • a Bronsted acid such as for example p-toluenesulfonic acid
  • a suitable aprotic solvent such as for example toluene
  • Step 2 when R 2a is C 3-6 cycloalkyl, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halo substituents, at a suitable temperature in a range between room temperature and 100°C, in the presence of alkyl or alkenyl boronic acid or boronic ester or potassium alkyltrifluoroborate salt, in the presence of a suitable base such as for example potassium carbonate or cesium carbonate, in the presence of a suitable catalyst such as [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl 2 ) in a suitable solvent such as for example dioxane or dimethylformamide and water.
  • a suitable temperature in a range between room temperature and 100°C
  • a suitable base such as for example potassium carbonate or cesium carbonate
  • a suitable catalyst such as [1, 1'-Bis (diphenylphosphino
  • a boron containing reagent such as trimethyl boroxine can be used in the presence of a suitable catalyst such as (Pd (dppf) Cl 2 ) in a suitable solvent such as for example dioxane or dimethylformamide and water in the presence of an inorganic base such as potassium carbonate or cesium carbonate at a reaction temperature between 80°C and 120°C;
  • a suitable catalyst such as (Pd (dppf) Cl 2
  • a suitable solvent such as for example dioxane or dimethylformamide
  • an inorganic base such as potassium carbonate or cesium carbonate at a reaction temperature between 80°C and 120°C
  • R 2a is -O-C 1-4 alkyl or cyano
  • a suitable temperature between 60-150°C, in the presence of sodium or potassium alkoxide or CuCN or Zn (CN) 2 , in the presence of a metal catalyst such as for example Pd 2 (dba) 3 or Pd (dppf) Cl 2
  • an organic phosphine ligand such as for example dicyclohexyl [2′, 4′, 6′-tris (propan-2-yl) [1, 1′-biphenyl] -2-yl] phosphane (XPhos) or (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphane) (Xantphos)
  • a base such as for example potassium tert-butoxide in a suitable solvent such as toluene or NMP.
  • Step 3 at a suitable temperature between room temperature and 100°C, in the presence of a metal reductant such as for example iron or zinc, in the presence of an inorganic salt such as for example ammonium chloride in a suitable solvent such as an alcohol optionally mixed with water, such as for example a mixture of ethanol and water.
  • a suitable temperature such as room temperature, in the presence of a suitable catalyst such as for example palladium on charcoal (Pd/C) , in a suitable solvent such as ethyl acetate or methanol, under H 2 pressure such as for example from 1 to 3 bar;
  • Step 4 at a suitable temperature such as for example 80°C and 130°C, in the presence of a suitable palladium catalyst such as for example tris (dibenzylideneacetone) dipalladium and a ligand such as for example Xantphos, in the presence of an inorganic base such as cesium carbonate, in a suitable solvent such as for example 1, 4-dioxane;
  • a suitable palladium catalyst such as for example tris (dibenzylideneacetone) dipalladium and a ligand such as for example Xantphos
  • an inorganic base such as cesium carbonate
  • a suitable solvent such as for example 1, 4-dioxane
  • Step 5 at a suitable temperature between 40°C and 100°C, in the presence of an acid such as for example hydrochloric acid in a suitable solvent such as for example water or acetonitrile;
  • an acid such as for example hydrochloric acid
  • a suitable solvent such as for example water or acetonitrile
  • Step 7 at a suitable temperature between 0°C to 70°C, in the presence of a reagent such as for example triphosgene or carbonyldiimidazole, in the presence of a tertiary amine such as for example triethylamine or diisopropylethylamine in a suitable aprotic solvent such as for example dichloromethane or tetrahydrofuran;
  • a reagent such as for example triphosgene or carbonyldiimidazole
  • a tertiary amine such as for example triethylamine or diisopropylethylamine
  • a suitable aprotic solvent such as for example dichloromethane or tetrahydrofuran
  • Step 8 when R 3 is other than hydrogen; at a suitable temperature between 0°C to room temperature, in the presence of as suitable base, such as for example NaH, in the presence of a suitable electrophile, such as a C 1-6 alkyliodide, or C 1-6 alkyliodide substituted with C 3- 6 cycloalkyl;
  • as suitable base such as for example NaH
  • a suitable electrophile such as a C 1-6 alkyliodide, or C 1-6 alkyliodide substituted with C 3- 6 cycloalkyl
  • a suitable acid such as trifluoroacetic acid
  • a suitable solvent such as dichloromethane.
  • PG is a different protecting group as defined herein, general deprotection conditions may be used, known to those skilled in the art.
  • Step 10 in the case of a reductive amination reaction employing an aldehyde or a ketone: at a suitable temperature in a range between room temperature and 70°C, in the presence of a suitable reducing agent such as for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent such as for example methanol or dichloromethane or 1, 2-dichloroethane, optionally in the presence of zinc chloride or acetic acid or sodium acetate;
  • a suitable reducing agent such as for example sodium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable solvent such as for example methanol or dichloromethane or 1, 2-dichloroethane, optionally in the presence of zinc chloride or acetic acid or sodium acetate
  • LG-Y at a suitable temperature such as for example room temperature, in the presence of a suitable deprotonating agent inorganic base such as for example sodium hydride or potassium carbonate, or an
  • X 2 represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
  • the following conditions apply: at a suitable temperature such as for example room temperature, in the presence of a suitable condensation reagent such as 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) , or others well known in the art, in the presence of a base such as N, N-diisopropylethylamine, in a suitable solvent such as dimethylformamide and in the presence of an amine HNR xa R xb ;
  • the acid chloride may be prepared by reacting the carboxylic acid with oxalyl chloride or thionyl chloride optionally in a halogenated solvent such as dichloromethane at a temperature in a range between 0°C and room temperature.
  • the intermediate acid chloride may then be reacted with the amine HNR xa R xb optionally in a solvent such as dichloromethane and optionally in the presence of a tertiary amine such as N, N-diisopropylethylamine;
  • PG represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl
  • X 1 represents a halogen such as chloro, bromo or iodo, or other leaving groups such as mesylate or tosylate
  • X 2 represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
  • Step 1 when R 2b is hydrogen, at a suitable temperature between room temperature and 80°C, in the presence of a reductant such as for example sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as for example dichloromethane, 1, 2-dichloroethane or methanol, optionally in the presence of zinc (II) chloride or acetic acid or sodium acetate;
  • a reductant such as for example sodium cyanoborohydride or sodium triacetoxyborohydride
  • a suitable solvent such as for example dichloromethane, 1, 2-dichloroethane or methanol
  • R 2b is C 1-4 alkyl
  • a reductant such as for example sodium cyanoborohydride or sodium borohydride in a suitable solvent such as for example toluene or methanol
  • zinc (II) chloride or titanium (IV) tetraisopropanolate in the presence of zinc (II) chloride or titanium (IV) tetraisopropanolate.
  • Step 2 at a suitable temperature between room temperature and 100°C, in the presence of a metal reductant such as for example iron or zinc, in the presence of an inorganic salt such as for example ammonium chloride in a suitable solvent such as for example ethanol and water;
  • a metal reductant such as for example iron or zinc
  • an inorganic salt such as for example ammonium chloride in a suitable solvent such as for example ethanol and water;
  • Step 3 at a suitable temperature between 0°C to 70°C, in the presence of a reagent such as for example triphosgene or carbonyldiimidazole, in the presence of a tertiary amine such as for example triethylamine or diisopropylethylamine in a suitable aprotic solvent such as for example dichloromethane or tetrahydrofuran;
  • a reagent such as for example triphosgene or carbonyldiimidazole
  • a tertiary amine such as for example triethylamine or diisopropylethylamine
  • a suitable aprotic solvent such as for example dichloromethane or tetrahydrofuran
  • Step 4 at a suitable temperature such as for example 80°C and 130°C, in the presence of a suitable catalyst such as copper (Cu) , in the presence of a base such as potassium carbonate or cesium carbonate, in a suitable aprotic solvent such as dimethylformamide or the like;
  • a suitable catalyst such as copper (Cu)
  • a base such as potassium carbonate or cesium carbonate
  • a suitable aprotic solvent such as dimethylformamide or the like
  • a copper (I) source may be used, such as CuI in the presence of a suitable diamine ligand, such as trans-N, N'-dimethylcyclohexane-1, 2-diamine in the presence of an inorganic base, such as potassium carbonate in an aprotic solvent such as dimethylformamide at a temperature between 80°C and 150°C;
  • Step 5 at a suitable temperature such as for example room temperature, in the presence of a suitable condensation reagent such as 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) , or others well known in the art, in the presence of a base such as N, N-diisopropylethylamine, in a suitable solvent such as dimethylformamide and in the presence of an amine HNR xa R xb ;
  • the acid chloride may be prepared by reacting the acid intermediate with oxalyl chloride or thionyl chloride optionally in a halogenated solvent such as dichloromethane at a temperature in a range between 0 0 C and room temperature.
  • a suitable condensation reagent such as 2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hex
  • the intermediate acid chloride may then be reacted with the amine HNR xa R xb optionally in a solvent such as dichloromethane and optionally in the presence of a tertiary amine such as N, N-diisopropylethylamine.
  • Step 6 when R 2a is C 3-6 cycloalkyl, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halo substituents, at a suitable temperature in a range between room temperature and 100°C, in the presence of alkyl or alkenyl boronic acid or boronic ester or potassium alkyltrifluoroborate salt, in the presence of a suitable base such as for example potassium carbonate or cesium carbonate, in the presence of a suitable catalyst such as [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl 2 ) in a suitable solvent such as for example dioxane or dimethylformamide and water;
  • a boron containing reagent such as trimethyl boroxine can be used in the presence of a suitable catalyst such as Pd (dppf) Cl 2 in a suitable solvent such as for example
  • R 2a is C 3-6 cycloalkyl, C 1-4 alkyl, or C 1-4 alkyl substituted with one, two or three halo substituents: at a suitable temperature such as room temperature, in the presence of a suitable catalyst such as palladium on charcoal (Pd/C) , in a suitable solvent such as methanol, under H 2 pressure such as for example from 1 to 3 bar, optionally in the presence of a base such as triethylamine.
  • a suitable temperature such as room temperature
  • a suitable catalyst such as palladium on charcoal (Pd/C)
  • a suitable solvent such as methanol
  • H 2 pressure such as for example from 1 to 3 bar
  • a base such as triethylamine
  • PG represents a suitable protecting group such as represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl;
  • PG 1 represents a suitable protecting group such as for example tert-butyldimethylsilyl; all other variables are defined according to the scope of the present invention.
  • Step 1 when PG 1 is a silyl containing protecting group; at a suitable temperature, such as for example between 0°C and 80°C, in a suitable solvent such as N, N-dimethylformamide, in the presence of a silylating agent such as tert-butyldimethylsilylchloride, in the presence of a base such as imidazole;
  • a suitable solvent such as N, N-dimethylformamide
  • a silylating agent such as tert-butyldimethylsilylchloride
  • Step 2 at a suitable temperature, such as for example between 80°C and 110°C, in a suitable solvent, such as toluene, in the presence of a suitable acyl azide forming reagent such as diphenyl phosphorazide, in the presence of a suitable alcohol, such as tert-butanol, 9-fluorenylmethanol, benzylalcohol or 4-methoxybenzylalcohol;
  • a suitable temperature such as for example between 80°C and 110°C
  • a suitable solvent such as toluene
  • a suitable acyl azide forming reagent such as diphenyl phosphorazide
  • a suitable alcohol such as tert-butanol, 9-fluorenylmethanol, benzylalcohol or 4-methoxybenzylalcohol
  • Step 3 at a suitable temperature, such as from example between 0°C and 50°C, in a suitable solvent, such as tetrahydrofuran in the presence of a deprotection reagent, such as tetrabutylammonium fluoride, optionally in the presence of acetic acid;
  • a suitable solvent such as tetrahydrofuran
  • a deprotection reagent such as tetrabutylammonium fluoride
  • Step 4 at a suitable temperature, such as for example between 0°C and room temperature, in the presence of a suitable oxidant, such as 2, 2, 6, 6-tetramethylpiperidine 1-oxyl radical and (diacetoxyiodo) benzene, optionally in the presence of NaHCO 3 , in a suitable solvent such dichloromethane or acetonitrile;
  • a suitable oxidant such as 2, 2, 6, 6-tetramethylpiperidine 1-oxyl radical and (diacetoxyiodo) benzene, optionally in the presence of NaHCO 3
  • a suitable solvent such dichloromethane or acetonitrile
  • Step 5 at a suitable temperature, such as between room temperature and 100°C, in a suitable solvent, such as tetrahydrofuran or 2-methyltetrahydrofuran, in the presence of a suitable Lewis acid, such as for example, titanium (IV) isopropoxide, in the presence of a suitable sulfinamide, such as (R) -2-methyl-2-propanesulfinamide or (S) -2-methyl-2-propanesulfinamide or methyl-2-propanesulfinamide;
  • a suitable solvent such as tetrahydrofuran or 2-methyltetrahydrofuran
  • a suitable Lewis acid such as for example, titanium (IV) isopropoxide
  • Step 6 at a suitable temperature, such as between -78°C and room temperature, in a suitable solvent, such as tetrahydrofuran or diethylether, in the presence of an organometallic reagent, such as a Grignard reagent (R 5a MgX) ;
  • a suitable solvent such as tetrahydrofuran or diethylether
  • Step 7 at a suitable temperature, such as between 0°C and room temperature, in a suitable solvent such as 1, 4-dioxane, in the presence of an acid, such as hydrochloric acid;
  • a suitable temperature such as between 0°Cand room temperature
  • a suitable solvent such as a mixture of tetrahydrofuran and water
  • molecular iodine in the presence of a suitable base, such as sodium carbonate, optionally in the presence of 4-dimethylaminopyridine.
  • 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
  • acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc) acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc) , benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc) .
  • Boc t-butoxycarbonyl
  • Fmoc 9-fluorenylmethyleneoxycarbonyl
  • the compounds of the present invention block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins per se, or can undergo metabolism to a (more) active form in vivo (prodrugs) . 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, including but not limited to leukemia.
  • cancers that may benefit from a treatment with menin/MLL inhibitors of the invention comprise leukemias.
  • the leukemias include acute leukemias, chronic leukemias, myeloid leukemias, myelogeneous leukemias, lymphoblastic leukemias, lymphocytic leukemias, Acute myelogeneous leukemias (AML) , Acute lymphoblastic leukemias (ALL) , MLL-rearranged leukemias, MLL-PTD leukemias, MLL amplified leukemias, MLL-positive leukemias, leukemias exhibiting HOX/MEIS1 gene expression signatures etc.
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias, in particular nucleophosmin (NPM1) -mutated leukemias, e.g. NPM1c.
  • NPM1 nucleophosmin
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of AML, in particular nucleophosmin (NPM1) -mutated AML (i.e., NPM1 mut AML) , more in particular abstract NPM1-mutated AML.
  • NPM1 -mutated AML i.e., NPM1 mut AML
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of MLL-rearranged leukemias, in particular MLL-rearranged AML or ALL.
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemias with MLL gene alterations, in particular AML or ALL with MLL gene alterations.
  • compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of hematological cancer in a subject exhibiting NPM1 gene mutations and/or mixed lineage leukemia gene (MLL; MLL1; KMT2A) alterations, mixed lineage leukemia (MLL) , MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia, leukemia associated with a MLL, rearrangement/alteration or a rearrangement/alteration of the MLL gene, acute leukemia, chronic leukemia; and for inhibiting a menin-MLL interaction, where the MLL fusion protein target gene is HOX or MEIS1 in human.
  • MLL mixed lineage leukemia gene
  • 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, 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.
  • An effective therapeutic daily amount would be from about 0.005 mg/kg to 100 mg/kg.
  • 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.
  • 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.
  • 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.
  • 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. It will be appreciated that 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.
  • compounds synthesized using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.
  • Compounds or intermediates isolated as a salt form may be integer stoichiometric i.e. mono-or di-salts, or of intermediate stoichiometry.
  • HCl salt an intermediate or compound in the experimental part below is indicated as ‘HCl salt’ without indication of the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined.
  • the same principle will also apply to all other salt forms referred to in the experimental part, such as e.g. ‘oxalate salt’ , ‘HCOOH salt’ ( ‘formate salt’ ) , or
  • the stereochemical configuration for centers in some compounds may be designated “R” or “S” when the mixture (s) was separated and absolute stereochemistry was known, or when only one enantiomer was obtained and absolute stereochemistry was known; for some compounds, the stereochemical configuration at indicated centers has been designated as “*R” or “*S” when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. In case a compound designated as “*R” is converted into another compound, the “*R” indication of the resulting compound is derived from its starting material.
  • the residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0 %to 50 %to provide the product (40 mg) as a yellow oil.
  • the product was further purified by prep_HPLC (Column: Xbridge C18 (5 ⁇ m 19 *150 mm) , Mobile Phase A: Water (0.1 %ammonium bicarbonate) , Mobile Phase B: acetonitrile, Flow rate: 15 mL /min, Gradient from 10%B to 65%B) to give Compound 12 (15 mg, yield 25.9%) as a white solid.
  • the first fraction was collected as Compound 16 (35 mg, 32%yield)
  • the second fraction was collected as Compound 17 (32 mg, 29%yield) .
  • the mixture was purified by preparative-HPLC (Column: Waters XBridge C8 5 ⁇ m, 19*150mm, Mobile Phase A: water (0.1%NH 4 OH+10 mM NH 4 HCO 3 ) , Mobile Phase B: acetonitrile, Flow rate: 17 mL/min, gradient condition from 29%B to 34%B) .
  • the first fraction and second fraction were collected separately and further purified.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • SQL Single Quadrupole Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • HSS High Strength Silica
  • DAD Diode Array Detector
  • Table 1b LCMS and melting point data. Co. No. means compound number; R t means retention time in min.
  • FITC-MBM1 peptide (FITC- ⁇ -alanine-SARWRFPARPGT-NH 2 ) ( “FITC” means fluorescein isothiocyanate) in assay buffer was added, the microtiter plate centrifuged at 1000 rpm for 1 min and the assay mixtures incubated for 15 min at ambient temperature.
  • the relative amount of menin ⁇ FITC-MBM1 complex present in an assay mixture is determined by measuring the homogenous time-resolved fluorescence (HTRF) of the terbium/FITC donor /acceptor fluorphore pair using an EnVision microplate reader (ex. 337 nm/terbium em. 490 nm/FITC em. 520 nm) at ambient temperature.
  • the degree of fluorescence resonance energy transfer (the HTRF value) is expressed as the ratio of the fluorescence emission intensities of the FITC and terbium fluorophores (F em 520 nm/F em 490 nm) .
  • the final concentrations of reagents in the binding assay are 200 pM terbium chelate-labeled menin, 75 nM FITC-MBM1 peptide and 0.5%DMSO in assay buffer. Dose-response titrations of test compounds are conducted using an 11 point, four-fold serial dilution scheme, starting typically at 10 ⁇ M.
  • %inhibition ( ( (HC -LC) - (HTRF compound -LC) ) / (HC -LC) ) *100 (Eqn 1)
  • LC and HC are the HTRF values of the assay in the presence or absence of a saturating concentration of a compound that competes with FITC-MBM1 for binding to menin
  • HTRF compound is the measured HTRF value in the presence of the test compound.
  • HC and LC HTRF values represent an average of at least 10 replicates per plate.
  • IC 50 is the concentration of compound that yields 50%inhibition of signal and h is the Hill coefficient.
  • Menin (a. a1-610-6xhis tag, 2.3 mg/mL in 20mM Hepes (2- [4- (2-Hydroxyethyl) -1-piperazinyl] ethane sulfonic acid) , 80 mM NaCl, 5mM DTT (Dithiothreitol) , pH 7.5) was labeled with terbium cryptate as follows. 200 ⁇ g of Menin was buffer exchanged into 1x Hepes buffer. 6.67 ⁇ M Menin was incubated with 8-fold molar excess NHS (N-hydroxysuccinimide) -terbium cryptate for 40 minutes at room temperature.
  • NHS N-hydroxysuccinimide
  • MENIN Protein Sequence (SEQ ID NO: 1) :
  • the anti-proliferative effect of menin/MLL protein/protein interaction inhibitor test compounds was assessed in human leukemia cell lines.
  • the cell line MOLM14 harbors a MLL translocation and expresses the MLL fusion protein MLL-AF9, respectively, as well as the wildtype protein from the second allele.
  • OCI-AML3 cells that carry the NPM1c gene mutation were also tested.
  • MLL rearranged cell lines (e.g. MOLM14) and NPM1c mutated cell lines exhibit stem cell-like HOXA/MEIS1 gene expression signatures.
  • KO-52 was used as a control cell line containing two MLL (KMT2A) wildtype alleles in order to exclude compounds that display general cytotoxic effects.
  • MOLM14 cells were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10%heat-inactivated fetal bovine serum (HyClone) , 2 mM L-glutamine (Sigma Aldrich) and 50 ⁇ g/ml gentamycin (Gibco) .
  • KO-52 and OCI-AML3 cell lines were propagated in alpha-MEM (Sigma Aldrich) supplemented with 20%heat-inactivated fetal bovine serum (HyClone) , 2 mM L-glutamine (Sigma Aldrich) and 50 ⁇ g/ml gentamycin (Gibco) .
  • Cells were kept at 0.3 –2.5 million cells per ml during culturing and passage numbers did not exceed 20.
  • LC Low Control: cells treated with e.g. 1 ⁇ M of the cytotoxic agent staurosporin, or e.g. cells treated with a high concentration of an alternative reference compound
  • GraphPad Prism (version 7.00) was used to calculate the IC 50 .
  • Dose-response equation was used for the plot of %Effect vs Log10 compound concentration with a variable slope and fixing the maximum to 100%and the minimum to 0%.
  • MEIS1 mRNA expression upon treatment of compound was examined by Quantigene Singleplex assay (Thermo Fisher Scientific) .
  • This technology allows for direct quantification of mRNA targets using probes hybridizing to defined target sequences of interest and the signal is detected using a Multimode plate reader Envision (PerkinElmer) .
  • the MOLM14 cell line was used for this experiment. Cells were plated in 96-well plates at 3, 750 cells/well in the presence of increasing concentrations of compounds. After incubation of 48 hours with compounds, cells were lysed in lysis buffer and incubated for 45 minutes at 55°C.
  • each test gene signal background subtracted was divided by the normalization gene signal (RPL28: background subtracted) .
  • Fold changes were calculated by dividing the normalized values for the treated samples by the normalized values for the DMSO treated sample. Fold changes of each target gene were used for the calculation of IC 50 s.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des agents pharmaceutiques utiles pour la thérapie et/ou la prophylaxie chez un mammifère, une composition pharmaceutique comprenant de tels composés, et leur utilisation en tant qu'inhibiteurs d'interaction ménine/protéine MLL/protéine, utiles pour le traitement de maladies telles que le cancer, comprenant sans caractère limitatif, la leucémie.
PCT/CN2023/134909 2022-11-30 2023-11-29 Composés bicycliques à substitution cyclobutyle WO2024114662A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022135436 2022-11-30
CNPCT/CN2022/135436 2022-11-30

Publications (1)

Publication Number Publication Date
WO2024114662A1 true WO2024114662A1 (fr) 2024-06-06

Family

ID=84901475

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/134909 WO2024114662A1 (fr) 2022-11-30 2023-11-29 Composés bicycliques à substitution cyclobutyle

Country Status (1)

Country Link
WO (1) WO2024114662A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018053267A1 (fr) * 2016-09-16 2018-03-22 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2021011428A1 (fr) * 2019-07-12 2021-01-21 Gb005, Inc. Inhibiteurs de kinase hétérocycliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018053267A1 (fr) * 2016-09-16 2018-03-22 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2021011428A1 (fr) * 2019-07-12 2021-01-21 Gb005, Inc. Inhibiteurs de kinase hétérocycliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAI HUANRONG ET AL.: "Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021)", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 32, no. 5, 11 March 2022 (2022-03-11), GB, pages 507 - 522, XP093029977, ISSN: 1354-3776, DOI: 10.1080/13543776.2022.2045947 *

Similar Documents

Publication Publication Date Title
WO2021121327A1 (fr) Dérivés spiro à chaîne droite substitués
WO2022253167A1 (fr) Dérivés de phényl-1h-pyrrolo [2, 3-c] pyridine substitués
WO2018109088A1 (fr) Inhibiteurs d'azépane de l'interaction ménine-mll
WO2022237720A1 (fr) Multithérapies
CN115698023A (zh) 作为mcl-1抑制剂的大环2-氨基-3-氟-丁-3-烯酰胺
WO2022237719A1 (fr) Polythérapies
AU2022272692A1 (en) Substituted spiro derivatives
WO2024114662A1 (fr) Composés bicycliques à substitution cyclobutyle
AU2022275192A1 (en) Substituted spiro derivatives
WO2024114658A1 (fr) Dérivés de 1-phényl-3, 4-dihydropyrido[3,4-d]pyrimidin-2-one substitués
US11530226B2 (en) Azepane inhibitors of menin-MLL interaction
WO2023193790A1 (fr) Formes cristallines d'un inhibiteur de l'interaction ménine/mll
WO2022253289A1 (fr) Pyridazines ou 1,2,4-triazines substituées par des amines spirocycliques
WO2024114664A1 (fr) Associations comprenant un inhibiteur de ménine-mll et au moins un autre agent thérapeutique
WO2024114666A1 (fr) Combinaisons comprenant un inhibiteur de ménine-mll et un inhibiteur de bcl-2
CN118255774A (en) Substituted straight-chain spiro derivatives
CN118255773A (en) Substituted straight-chain spiro derivatives
CN118251398A (en) Macrocyclic 2-amino-but-3-enamides as MCL-1 inhibitors
EA046212B1 (ru) Азепановые ингибиторы взаимодействия менин–mll