EP4626885A1

EP4626885A1 - Cyclobutyl substituted bicyclic compounds

Info

Publication number: EP4626885A1
Application number: EP23841500.4A
Authority: EP
Inventors: 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
Current assignee: Janssen Pharmaceutica NV
Priority date: 2022-11-30
Filing date: 2023-11-29
Publication date: 2025-10-08
Also published as: JP2025540682A; CN120359221A; WO2024114662A1

Abstract

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.

Description

CYCLOBUTYL SUBSTITUTED BICYCLIC COMPOUNDS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL; MLL1; KMT2A) result in aggressive acute leukemias across all age groups and still represent mostly incurable diseases emphasizing the urgent need for novel therapeutic approaches. 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.
MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in multiprotein complexes. Use of inducible loss-of-function alleles of Mll1 demonstrated that Mll1 plays an essential role in sustaining hematopoietic stem cells (HSCs) and developing B cells although its histone methyltransferase activity is dispensable for hematopoiesis.
Fusion of MLL with more than 60 different partners has been reported to date and has been associated with leukemia formation/progression. Interestingly, the SET (Su (var) 3–9, enhancer of zeste, and trithorax) domain of MLL is not retained in chimeric proteins but is replaced by the fusion partner. Recruitment of chromatin modifying enzymes like Dot1L and/or the pTEFb complex by the fusion partner leads to enhanced transcription and transcriptional elongation of MLL target genes including HOXA genes (e.g. HOXA9) and the HOX cofactor MEIS1 as the most prominent ones. Aberrant expression of these genes in turn blocks hematopoietic differentiation and enhances proliferation.
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) . Although 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. Furthermore, 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. Similarly, genetic disruption of 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. These studies also showed that menin is required for the maintenance of HOX gene expression by MLL fusion proteins. In addition, 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. Together with the observation that menin is not a requisite cofactor of MLL1 during normal hematopoiesis, these data validate the disruption of menin/MLL interaction as a promising new therapeutic approach for the treatment of MLL rearranged leukemia and other cancers with an active HOX/MEIS1 gene signature. For example, an internal partial tandem duplication (PTD) within the 5’ region of the MLL gene represents another major aberration that is found predominantly in de novo and secondary AML as well as myeloid dysplasia syndromes. Although the molecular mechanism and the biological function of MLL-PTD is not well understood, new therapeutic targeting strategies affecting the menin/MLL interaction might also prove effective in the treatment of MLL-PTD-related leukemias. Furthermore, castration-resistant prostate cancer has been shown to be dependent on the menin/MLL interaction.
MLL protein is also known as Histone-lysine N-methyltransferase 2A (KMT2A) protein in the scientific field (UniProt Accession #Q03164) .

DESCRIPTION OF THE INVENTION

The present invention concerns novel compounds of Formula (I) ,
and the tautomers and the stereoisomeric forms thereof, wherein
R^1a represents hydrogen; cyano; halo; Het; -C (=O) -NR^xaR^xb; -S (=O) ₂-R¹⁸;
-C (=O) -O-C_1-4alkyl-NR^22aR^22b; -C (=O) -O-C_1-4alkyl;
R^1b represents hydrogen, F or Cl;
R^2a represents hydrogen, halo, C_3-6cycloalkyl, C_1-4alkyl, -O-C_1-4alkyl, cyano, or C_1-4alkyl substituted with one, two or three halo substituents;
R^2b represents hydrogen or C_1-4alkyl;
R^2c represents hydrogen or C_1-4alkyl;
R³ represents hydrogen, C_1-6alkyl, or C_1-6alkyl substituted with C_3-6cycloalkyl;
R⁴ represents hydrogen, C_1-6alkyl, R⁶, Het¹, C_1-6alkyl substituted with one subsituent selected from the group consisting of R⁶ and Het¹;
R^5a and R^5b each independently represent hydrogen or C_1-4alkyl;
R⁶ represents C_3-6cycloalkyl, or C_3-6cycloalkyl substituted with one or two substituents each independently selected from the group consisting of C_1-4alkyl, -O-C_1-4alkyl or Het²;
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, C_1-4alkyl, oxo, and -OH;
Het² represent a 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one nitrogen with -C (=O) -C_1-4alkyl;
R¹⁸ represents C_1-6alkyl or C_3-6cycloalkyl;
R¹⁹ represents hydrogen or C_1-6alkyl;
or R¹⁸ and R¹⁹ are taken together to form -CH₂-CH₂-CH₂-;
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_1-4alkyl, C_3-6cycloalkyl, or cyano;
R^xa and R^xb are each independently selected from the group consisting of hydrogen;
Het³; C_3-6cycloalkyl; and C_1-6alkyl; wherein optionally said C_3-6cycloalkyl and C_1-6alkyl are substituted with 1, 2 or 3 substituents each independently selected from the group consisting of -OH, -OC_1-4alkyl, -C_1-4alkyl-OH, halo, CF₃, C_3-6cycloalkyl, Het³, and NR^11cR^11d; or R^xa and R^xb are 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of C_1-4alkyl, halo, -OH, -O-C_1-4alkyl, cyano, and
C_1-4alkyl substituted with one, two or three substituents selected from the group consisting of halo and OR²³;
or R^xa and R^xb are 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 or two additional heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of C_1-4alkyl, halo, -OH, -O-C_1-4alkyl, cyano, and
C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo and OR²³;
R²³ represents hydrogen or C_1-4alkyl 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 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.
Additionally, 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.
In a particular embodiment, 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.
In a specific embodiment said cancer is selected from leukemias. In some embodiments, 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.
In particular, 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.
In an embodiment, compounds of Formula (I) and the pharmaceutically acceptable salts, and the solvates thereof, may have improved metabolic stability properties.
In an embodiment, 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.
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.
Furthermore, 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.
DETAILED DESCRIPTION OF THE INVENTION
The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.
The prefix ‘C_x-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C_1-6alkyl group contains from 1 to 6 carbon atoms, and so on. The term ‘C_1-4alkyl’ 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.
Similar, the term ‘C_1-6alkyl’ 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like.
The term ‘C_3-6cycloalkyl’ 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.
It will be clear for the skilled person that S (=O) ₂ or SO₂ represents a sulfonyl moiety.
It will be clear for the skilled person that CO or C (=O) represents a carbonyl moiety.
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.
The skilled person will understand that 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.
For clarity, the 4-to 7-membered fully or partially saturated heterocyclyls have from 4 to 7 ring members including the heteroatoms.
Within the context of this invention, 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.
Examples of 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
and the like.
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
and the like.
Whenever substituents are represented by chemical structure, such as for example
represents the bond of attachment to the remainder of the molecule of Formula (I) .
When any variable occurs more than one time in any constituent, each definition is independent. When any variable occurs more than one time in any formula (e.g. Formula (I) ) , each definition is independent.
It will be clear for a skilled person that when a moiety (for example a heterocyclyl or monocyclic 5-or 6-membered aromatic ring) is substituted with two or more substituents (for example one, two or three substituents) selected from a group, each substituent can be selected independently from said group, even if not explicitly mentioned.
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) . In a particular embodiment, when the number of substituents is not explicitly specified, the number of substituents is one.
Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. ‘Stable 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) .
The skilled person will understand that the term ‘optionally substituted’ means that the atom or radical indicated in the expression using ‘optionally substituted’ may or may not be substituted (this means substituted or unsubstituted respectively) .
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.
Within the context of this invention ‘saturated’ means ‘fully saturated’ , if not otherwise specified.
Unless otherwise specified or clear from the context, 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) .
Unless otherwise specified or clear from the context, aromatic rings and heterocyclyl goups, may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to the embodiments.
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.
The term “therapeutically effective amount” as used herein, 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.
The term “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.
The term “treatment” , as used herein, 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 term “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.
As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.
Hereinbefore and hereinafter, the term “compound (s) of Formula (I) ” is meant to include the tautomers thereof and the stereoisomeric forms thereof.
The terms “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 (or atropoisomers) 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 (or diastereoisomers) 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.
Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.
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. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomer is identified, this means that said 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. Thus, when a compound of Formula (I) is for instance specified as (R) , this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds according to Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention. It follows that a single compound may exist in both stereoisomeric and tautomeric form.
Pharmaceutically acceptable 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. butanedioic acid) , maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said 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. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term “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) ) . For the avoidance of doubt, the term “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. In general, 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.
Examples of 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.
The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such 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. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The term "enantiomerically pure" as used herein 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) .
All 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 ²H, ³H, ¹¹C, ¹³C, ¹⁴C , ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the isotope is selected from the group of ²H, ³H, ¹¹C, ¹³C and ¹⁸F. Preferably, the isotope is selected from the group of ²H, ³H, ¹¹C and ¹⁸F. More preferably, the isotope is ²H, ³H or ¹³C. More preferably, the isotope is ²H or ¹³C. More preferably, the isotope is ²H. In particular, deuterated compounds and ¹³C-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 (e.g., those labeled with ³H and ¹⁴C) may be useful for example in substrate tissue distribution assays. Tritiated (³H) and carbon-l4 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) 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 ¹⁵O, ¹³N, ¹¹C and ¹⁸F 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. Additionally, 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^1a represents -C (=O) -NR^xaR^xb;
R^1b represents F;
R^2a represents hydrogen or C_1-4alkyl;
R^2b represents hydrogen;
R^2c represents hydrogen;
R³ represents hydrogen, C_1-6alkyl, or C_1-6alkyl substituted with C_3-6cycloalkyl;
R⁴ represents hydrogen, C_1-6alkyl, R⁶, Het¹, C_1-6alkyl substituted with one subsituent selected from the group consisting of R⁶ and Het¹;
R^5a and R^5b each independently represent hydrogen or C_1-4alkyl;
R⁶ represents C_3-6cycloalkyl, or C_3-6cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -O-C_1-4alkyl or Het²;
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four C_1-4alkyl;
Het² represent a 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one nitrogen with -C (=O) -C_1-4alkyl;
R^xa and R^xb represent C_1-6alkyl;
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^1a represents -C (=O) -NR^xaR^xb;
R^1b represents F;
R^2a represents hydrogen or C_1-4alkyl;
R^2b represents hydrogen; R^2c represents hydrogen; R³ represents hydrogen;
R⁴ represents C_1-6alkyl, R⁶, Het¹, C_1-6alkyl substituted with one subsituent selected from the group consisting of R⁶ and Het¹;
R^5a and R^5b represent hydrogen;
R⁶ represents C_3-6cycloalkyl;
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four C_1- ₄alkyl;
R^xa and R^xb represent C_1-6alkyl;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^1a represents -C (=O) -NR^xaR^xb;
R^1b represents F;
R^2a represents hydrogen; C_1-4alkyl;
R^2b represents hydrogen; R^2c represents hydrogen; R³ represents hydrogen;
R⁴ represents C_1-6alkyl, R⁶, Het¹, C_1-6alkyl substituted with one subsituent selected from the group consisting of R⁶ and Het¹;
R^5a and R^5b represent hydrogen;
R⁶ represents C_3-6cycloalkyl;
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four C_1- ₄alkyl;
R^xa and R^xb represent C_1-6alkyl;
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^1a represents -C (=O) -NR^xaR^xb;
R^1b represents F;
R^2a represents C_1-4alkyl; in particular methyl;
R^2b represents hydrogen; R^2c represents hydrogen; R³ represents hydrogen;
R⁴ represents C_1-6alkyl substituted with one Het¹;
R^5a and R^5b represent hydrogen;
R⁶ represents C_3-6cycloalkyl;
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one carbon atom with one C_1-4alkyl;
R^xa and R^xb represent C_1-6alkyl;
and the pharmaceutically acceptable salts and the solvates thereof.
In an embodiment, 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^1a represents hydrogen; Het; -C (=O) -NR^xaR^xb; -S (=O) ₂-R¹⁸;
In an embodiment, 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^1a represents Het; -C (=O) -NR^xaR^xb; -S (=O) ₂-R¹⁸;
In an embodiment, 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^1a represents -C (=O) -NR^xaR^xb; -S (=O) ₂-R¹⁸; or
In an embodiment, 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^1a represents -C (=O) -NR^xaR^xb; or
In an embodiment, 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^1a represents -C (=O) -NR^xaR^xb.
In an embodiment, 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_1-6alkyl.
In an embodiment, 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_1-6alkyl.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment, 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_1-4alkyl.
In an embodiment, 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.
In an embodiment, 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_3-6cycloalkyl, C_1- ₄alkyl, -O-C_1-4alkyl, cyano, or C_1-4alkyl substituted with one, two or three halo substituents.
In an embodiment, 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.
In an embodiment, 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 R³ represents hydrogen, and R⁴ is other than hydrogen.
In an embodiment, 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 R⁴ represents hydrogen, and R³ is other than hydrogen.
In an embodiment, 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 R⁴ represents C_1-6alkyl substituted with one Het¹.
In an embodiment, 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
R³ represents hydrogen;
R⁴ represents C_1-6alkyl substituted with one Het¹.
In an embodiment, 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 R⁴ represents C_1-6alkyl substituted with one Het¹; wherein Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one carbon atom with one C_1-4alkyl, in particular methyl.
In an embodiment, 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
R³ represents hydrogen;
R⁴ represents C_1-6alkyl substituted with one Het¹;
wherein Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one carbon atom with one C_1-4alkyl, in particular methyl.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment, 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.
In an embodiment, 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_1-4alkyl and the other one is hydrogen.
In an embodiment, 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_1-4alkyl, in particular methyl.
In an embodiment, 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_1-4alkyl, in particular methyl.
In an embodiment, 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
Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one or two C_1-4alkyl, in particular methyl.
In an embodiment, 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 Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one carbon atom with one C_1-4alkyl, in particular methyl.
In an embodiment, 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 Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one carbon atom with one C_1-4alkyl, in particular methyl.
In an embodiment, 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 Het¹ is monocylic.
In an embodiment, 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 Het¹ is bicyclic.
In an embodiment, 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 Het¹ represents any of the following
each optionally substituted as defined in any of the other embodiments.
In an embodiment, 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 Het² represents
optionally substituted as defined in any of the other embodiments.
In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
tautomers and stereoisomeric forms thereof,
and the free bases, any pharmaceutically acceptable salts, and the solvates thereof.
In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39.
In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39;
tautomers and stereoisomeric forms thereof,
and any pharmaceutically acceptable salts, and the solvates thereof.
The present invention also relates to 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 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,
tautomers and stereoisomeric forms thereof,
and the free bases, any pharmaceutically acceptable salts, and the solvates thereof.
The present invention also relates to 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 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;
tautomers and stereoisomeric forms thereof,
and any pharmaceutically acceptable salts, and the solvates thereof.
In an embodiment the compound of Formula (I) is compound 1 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 3 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 8 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 9 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 11 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 12 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 13 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 14 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 26 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 28 or a pharmaceutically acceptable salt or solvate thereof.
In an embodiment the compound of Formula (I) is compound 39 or a pharmaceutically acceptable salt or solvate thereof.
All possible combinations of the above indicated embodiments are considered to be embraced within the scope of the invention.
METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I)
In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.
The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
Alternatively, 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.
The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. In general, conventional protecting groups (PG) can be used in accordance with standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N₂-gas atmosphere.
It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before 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) .
The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.
The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I) .
The skilled person will realize that 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.
General Synthetic Schemes
Scheme 1
In scheme 1, PG represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl; X¹ represents a halogen such as chloro, bromo or iodo, or other leaving groups such as mesylate or tosylate; X² represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
In Scheme 1, the following reaction conditions apply:
Step 1: at a suitable temperature in a range between 80℃ and 120℃, 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;
Step 2: when R^2a is C_3-6cycloalkyl, C_1-4alkyl, or C_1-4alkyl substituted with one, two or three halo substituents, at a suitable temperature in a range between room temperature and 100℃, 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) Cl₂) in a suitable solvent such as for example dioxane or dimethylformamide and water. Alternatively, when R^2a is methyl, a boron containing reagent such as trimethyl boroxine can be used in the presence of a suitable catalyst such as (Pd (dppf) Cl₂) 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℃ and 120℃;
When R^2a is -O-C_1-4alkyl or cyano, at a suitable temperature between 60-150℃, 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 Pd₂ (dba) ₃ or Pd (dppf) Cl₂, in the presence of 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) , in the presence of 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℃, 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. Alternatively, 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 H₂ pressure such as for example from 1 to 3 bar;
Step 4: at a suitable temperature such as for example 80℃ and 130℃, 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;
Step 5: at a suitable temperature between 40℃ and 100℃, in the presence of an acid such as for example hydrochloric acid in a suitable solvent such as for example water or acetonitrile;
Step 6: at a suitable temperature between room temperature and 80℃, in the presence of a reductant such as for example sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of a Lewis acid such as for example zinc chloride or a Bronsted acid such as acetic acid, in a suitable solvent such as for example dichloromethane, 1, 2-dichloroethane or methanol;
Step 7: at a suitable temperature between 0℃ to 70℃, 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;
Step 8: when R³ is other than hydrogen; at a suitable temperature between 0℃ 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_1-6alkyliodide, or C_1-6alkyliodide substituted with C_3- ₆cycloalkyl;
Step 9: when PG = Boc, at a suitable temperature in a range between 0℃ and 40℃, such as room temperature, in the presence of a suitable acid such as trifluoroacetic acid, in a suitable solvent, such as dichloromethane. When 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℃, 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; In the case of an alkylation reaction employing 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 amine base such as triethylamine in a suitable aprotic solvent such as for example dimethylformamide or dimethylsulfoxide or acetonitrile.
Scheme 2
In scheme 2, X² represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
In Scheme 2 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^xaR^xb; Alternatively 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℃ and room temperature. The intermediate acid chloride may then be reacted with the amine HNR^xaR^xb optionally in a solvent such as dichloromethane and optionally in the presence of a tertiary amine such as N, N-diisopropylethylamine;
Scheme 3
In scheme 3; PG represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl; X¹ represents a halogen such as chloro, bromo or iodo, or other leaving groups such as mesylate or tosylate; X² represents fluoro, chloro, bromo or iodo; all other variables are defined according to the scope of the present invention.
In general, compounds wherein R^1a is limited to -C (=O) -NR^xaR^xb, can be prepared according to the following reaction Scheme 3.
In Scheme 3, the following reaction conditions apply:
Step 1: when R^2b is hydrogen, at a suitable temperature between room temperature and 80℃, 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;
When R^2b is C_1-4alkyl, at a suitable temperature between 60-120 ℃, in the presence of a reductant such as for example sodium cyanoborohydride or sodium borohydride in a suitable solvent such as for example toluene or methanol, in the presence of zinc (II) chloride or titanium (IV) tetraisopropanolate.
Step 2: at a suitable temperature between room temperature and 100℃, 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;
Step 3: at a suitable temperature between 0℃ to 70℃, 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;
Step 4: at a suitable temperature such as for example 80℃ and 130℃, 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; Alternatively 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℃ and 150℃;
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^xaR^xb; Alternatively 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 ⁰C and room temperature. The intermediate acid chloride may then be reacted with the amine HNR^xaR^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_3-6cycloalkyl, C_1-4alkyl, or C_1-4alkyl substituted with one, two or three halo substituents, at a suitable temperature in a range between room temperature and 100℃, 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) Cl₂) in a suitable solvent such as for example dioxane or dimethylformamide and water; Alternatively, when R^2a is Me, a boron containing reagent such as trimethyl boroxine can be used in the presence of a suitable catalyst such as Pd (dppf) Cl₂ in a suitable solvent such as for example dioxane or dimethylformamide and water in the presence of an inorganic base such as potassium carbonate at a reaction temperature between 80℃ and 120℃;
An additional step to achieve the double bond reduction (when alkenyl boronic acid or boronic ester is used) to obtain R^2a is C_3-6cycloalkyl, C_1-4alkyl, or C_1-4alkyl 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 H₂ pressure such as for example from 1 to 3 bar, optionally in the presence of a base such as triethylamine.
Scheme 4
In scheme 4, PG represents a suitable protecting group such as represents a suitable protecting group, such as for example tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl; PG¹ represents a suitable protecting group such as for example tert-butyldimethylsilyl; all other variables are defined according to the scope of the present invention.
In Scheme 4, the following reaction conditions apply:
Step 1: when PG¹ is a silyl containing protecting group; at a suitable temperature, such as for example between 0℃ and 80℃, 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;
Step 2: at a suitable temperature, such as for example between 80℃ and 110℃, 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;
Step 3: at a suitable temperature, such as from example between 0℃ and 50℃, 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;
Step 4: at a suitable temperature, such as for example between 0℃ 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 NaHCO₃, in a suitable solvent such dichloromethane or acetonitrile;
Step 5: at a suitable temperature, such as between room temperature and 100℃, 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;
Step 6: at a suitable temperature, such as between -78℃ 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^5aMgX) ;
Step 7: at a suitable temperature, such as between 0℃ and room temperature, in a suitable solvent such as 1, 4-dioxane, in the presence of an acid, such as hydrochloric acid; Alternatively, the deprotection can be performed as follows: at a suitable temperature, such as between 0℃and room temperature, in a suitable solvent such as a mixture of tetrahydrofuran and water, in the presence of molecular iodine, in the presence of a suitable base, such as sodium carbonate, optionally in the presence of 4-dimethylaminopyridine.
It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.
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.
In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc) , benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc) . The need for such protection is readily determined by one skilled in the art.
PHARMACOLOGY
It has been found that 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.
In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment or prevention of cancer. According to one embodiment, cancers that may benefit from a treatment with menin/MLL inhibitors of the invention comprise leukemias. In some embodiments, 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.
In particular, 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.
In particular, 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.
In particular, 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.
In particular, 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.
In particular, 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.
Hence, 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.
Also, 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.
In view of the utility of the compounds of Formula (I) , the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts, and the solvates thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from 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.
Therefore, 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.
One skilled in the art will recognize that 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.
The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions 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.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The 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.
Therefore, 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.
The following examples further illustrate the present invention.
EXAMPLES
Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.
As understood by a person skilled in the art, 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. When 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.
For example, it will be clear that Compound 16
For compounds wherein the stereochemical configuration of two stereocentres is indicated by * (e.g. *R or *S) , 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 enantiomerically pure. In this case, the configuration of the first stereocentre indicated by *is independent of the configuration of the second stereocentre indicated by *in the same compound. “*R” or “*S” is assigned randomly for such molecules. Similar for compounds wherein the stereochemical configuration of three stereocentres is indicated by * (e.g. *R or *S) , 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 enantiomerically pure. In this case, the configuration of the stereocentres indicated by *are independent of the configuration of the other stereocentres indicated by *in the same compound. “*R” or “*S” is assigned randomly for such molecules.
For example, for Compound 26
this means that the compound is
A skilled person will realize that the paragraphs above about stereochemical configurations, also apply to intermediates.
A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected, and the solvent was evaporated.
In case no stereochemistry is indicated, this means it is a mixture of stereoisomers or undetermined stereochemistry, unless otherwise is indicated or is clear from the context.
When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained at the indicated center, unless otherwise indicated.
A double bond indicated with EZ means the compound/intermediate was obtained as a mixture of E and Z isomers.
Preparation of Intermediates and Compounds
For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.
Preparation of Intermediate 1:
To a solution of 3-bromo-4-methyl-5-nitropyridine (10 g, 46.078 mmol) in DMF (50 mL) was added 1, 1-dimethoxy-N, N-dimethylmethanamine (13 mL) . The mixture was stirred at 90 ℃ for 3 h. After cooled down to rt, the mixture was poured into 100 mL water. The precipitated solid was filtered and dried to afford an intermediate (～12.3g) as a brown solid, which was dissolved in THF (75 mL) was mixed with a solution of NaIO₄ (2.9 g, 135.6 mmol) in H₂O (75 mL) at r.t., After stirred for 20 hrs, the reaction mixture was diluted by 100 mL water and extracted with EtOAc (100mL x 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in hexanes from 0%to 50% (starting with 0%EtOAc to 50%EtOAc) to provide Intermediate 1 (6.0 g, yield 57.4%) as a yellow solid.
Preparation of Intermediate 2:
To a mixture of Intermediate 1 (4.3 g, 17.684 mmol) and trans tert-butyl (3-aminocyclobutyl) carbamate (CAS: 871014-19-6) (3.95 g, 21.2 mmol) in DCE (150 mL ) was added acetic acid (0.1 mL) and NaBH₃CN (2.22 g, 35.367 mmol) . The reaction mixture was stirred for 2 hours at room temperature. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (120 mL*3) . The combined organic phase was washed with brine (300 mL) , dried over Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 25%EtOAc in hexanes to afford Intermediate 2 (1.3 g, 18%yield) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 2
Preparation of Intermediate 31:
To a solution of Intermediate 54 (400 mg, 1.15 mmol) and trans tert-butyl (3-aminocyclobutyl) carbamate (CAS: 871014-19-6) (258 mg, 1.38 mmol) in methanol (10 mL ) was stirred for 3 hrs at rt. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over Na₂SO₄ (anhydrous) and filtered. The filtrate was concentrated under vacuum to give a yellow oil which was dissolved in methanol (10 mL ) . To this mixture, sodium cyanoborohydride (200 mg, 3.2 mmol) and zinc (II) chloride (144 mg, 1.06 mmol) were added. The solution was stirred at rt for 2 hours. Then, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄ (anhydrous) and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 50%EA in petroleum ether to give Intermediate 31 (470 mg, 90%purity, 79.9%yield) as a yellow solid.
Preparation of Intermediate 23:
To a mixture of Intermediate 22 (500 mg, 1.329 mmol) in DCM (10 mL) was added trans tert-butyl (3-aminocyclobutyl) carbamate (297 mg, 1.595 mmol) and 0.1 mL acetic acid at rt. And the mixture was stirred at rt for 2 h. Then, NaBH₃CN (167 mg, 2.658 mmol) was added. And the mixture continued to stir at rt for 3 h. The mixture was diluted by 100 mL water and extracted with EtOAc (100 mL) three times. The combined layers were washed by brine and dried over Na₂SO₄, filtered and concentrated, the residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 50%to provide Intermediate 23 (501 mg, yield 68 %) as a yellow solid.
Preparation of Intermediate 3:
To a solution of intermediate 2 (3.04 g, 7.58 mmol) in ethanol (50 mL) and water (10 mL) were added ammonium chloride (2.6 g, 37.88 mmol) and iron powder (2.12 g, 37.88 mmol) . The mixture was stirred at 80 ℃ for 1 h. The mixture was filtered through a short pad of diluted with water (100 mL) , and extracted with EtOAc (30 mL) three times. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, the filtrate was concentrated under vacuum to give Intermediate 3 (3.04 g, crude) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 3
Preparation of Intermediate 4:
To a solution of Intermediate 3 (2.7 g, 6.02 mmol, 82.8%purity) in THF (50 mL) was added CDI (2.93 g, 18.06 mmol) . The mixture was refluxed for 2 h. After the mixture was cooled down to rt, and the precipitate was filtered and dried to give Intermediate 4 (2.2 g, 91%yield) as a white solid.
The following intermediates were synthesized by an analogous method as described for intermediate 4
Preparation of Intermediate 5:
To a solution of Intermediate 4 (2.1 g, 5.11 mmol) and 5-fluoro-2-iodobenzoic acid (2.04 g, 7.67 mmol) in DMF (100 mL) , under nitrogen, were added K₂CO₃ (2.12 g, 0.73 mmol) and copper powder (328 mg, 5.11 mmol) . After stirring at 120 ℃ for 16 hrs, the mixture was cooled to room temperature and the mixture was used in the next step without further purification.
The following intermediates were synthesized by an analogous method as described for Intermediate 5
Preparation of Intermediate 6:
To a solution of crude Intermediate 5 in DMF were added HATU (3.87 g, 10.18 mmol) , DIEA (1.75 g, 13.57 mmol) and N-ethylpropan-2-amine (1.97 g, 22.62 mmol) . The mixture was stirred at rt for 1 h. The mixture was diluted with water and extracted with ethyl acetate (50 mL) three times. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, the filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with MeOH in DCM from 0%to 5%to afford Intermediate 6 as a yellow solid
The following intermediates were synthesized by an analogous method as described for Intermediate 6
Preparation of Intermediate 7:
To a solution of Intermediate 6 (1.2 g, 1.9 mmol) , trimethylboroxine (2.3 g, 17.75 mmol) and K₂CO₃ (736 mg, 5.32 mmol) in 1, 4-dioxane (50 mL) and water (10 mL) was added Pd (dppf) Cl₂ (130 mg, 0.018 mmol) under nitrogen atmosphere. Then the mixture was heated at 100 ℃ for 16 hrs. The reaction mixture was cooled down to rt and diluted with water (100 mL) and extracted with DCM (30 mL) three times. The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0%to 100%to afford Intermediate 7 (0.58 g, 56.5 yield) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 7
Preparation of Intermediate 8:
To a solution of Intermediate 7 (100 mg, 0.18 mmol) in dry DMF (10 mL) was added sodium hydride (60%dispersion in mineral oil) (21 mg, 0.54 mmol) at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 0 ℃ for 30 min followed by addition of iodomethane (76 mg, 0.54 mmol) . The resulting mixture was further stirred at 0 ℃ for 2 h. The reaction mixture was quenched with aq. saturated NH₄Cl solution, and extracted with EtOAc (20 mL) three times. The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 %to 10%to afford the Intermediate 8 (60 mg, 60%yield) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 8
Preparation of Intermediate 33:
To a solution of Intermediate 32 (100 mg, 90%purity, 0.17 mmol) in THF (3 mL ) was added NaH (60%dispersion in mineral oil) (20 mg, 0.5 mmol) . The solution was stirred at 0 ℃ for 30 minutes. To the reaction mixure was then added iodomethane (49 mg, 0.34 mmol) and stirring was continued for 2hrs at rt. The reaction mixture was quenched with aq. saturated NH₄Cl solution and extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄ (anhydrous) and filtered. The filtrate was concentrated under vacuum. The result residue was purified by silica gel column chromatography eluting with 50%EA in petroleum ether to give Intermediate 33 (50 mg, 90%purity, 48.7%yield) as a white solid.
Preparation of Intermediate 17:
To a solution of Intermediate 1 (4.2 g, 17.3 mmol) in toluene (20 mL) was added p-toluenesulfonic acid (3.65 g, 20.8 mmol) and ethane-1, 2-diol (1.4 g, 22.5 mmol) . The mixture was stirred at 120 ℃ overnight. After cooling down to rt, water (30 mL) was added and the mixture was extracted with EtOAc (50 mL) three times. The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 6%to give Intermediate 17 (3.3 g, 65.8%yield) as a white solid.
Preparation of Intermediate 19:
To a solution of 5-fluoro-2-iodobenzoic acid (5 g, 17.857 mmol) in DCM (100 mL) was added oxalylchloride (2.493 g, 19.642 mmol) dropwise at 0 ℃ and then, DMF (130 mg, 1.786 mmol) was added dropwise. After stirring at 0 ℃ for 2 hours the mixture was concentrated to remove the solvent. The residue was dissolved with DCM (100 mL) and added dropwise to a mixture of diisopropylamine (2.761 mL, 19.642 mmol) and triethylamine (6.932 mL, 53.570 mmol) in DCM (100 mL) at 0 ℃. The resulting mixture was further stirred for 4 hours while slowly warmed to rt. Then, water (100 mL) was added, the organic phase was separated, and the aqueous phase extracted with DCM (200 mL) twice. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the crude product which was further purified by silica gel column chromatography eluting with 10%EtOAc in petroleum ether to give the Intermediate 19 (4.9 g yield: 80%) as a light yellow solid.
Preparation of Intermediate 29:
To a solution of 5-fluoro-2-iodobenzoic acid (20 g, 71.43 mmol) in DCM (150 mL) was added oxalylchloride (9.97 g, 78.57 mmol) dropwise at 0 ℃ and then DMF (499 mg, 6.82 mmol) was added dropwise. After stirring at 0 ℃ for 2 hours the mixture was concentrated to remove the solvent. The residue was dissolved with DCM (100 mL) and added dropwise to a mixture of N-ethylpropan-2-amine (6.85 g, 78.57 mmol ) and triethylamine (64 mL) in DCM (150 mL) at 0 ℃. The resulting mixture was further stirred for 4 hours while slowly warmed to rt. Then, water (200 mL) was added, the organic phase was separated, and the aqueous phase was extracted with EA (500 mL) three times. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the crude product which was further purified by silica gel column chromatography eluting with 10%EtOAc in petroleum ether to give Intermediate 29 (16.7 g yield: 69%) as a white solid.
Preparation of Intermediate 21:
To a mixture of Intermediate 20 (3 g, 14.983 mmol) and Intermediate 19 (6.278 g, 17.980 mmol) in dioxane (50 mL) was added Cs₂CO₃ (9.764 g, 29.966 mmol) , Xantphos (0.866 g, 1.498 mmol) and Pd₂ (dba) ₃ (0.686 g, 0.749 mmol) at rt. The mixture was continued to stir at 120 ℃ for 20 hrs. After cooling down to rt, the mixture was diluted by 300 mL water and extracted with EtOAc (500 mL) three times. The combine organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 50%to provide Intermediate 21 (5.0 g, yield 83%) as a yellow oil.
The following intermediates were synthesized by an analogous method as described for Intermediate 21
Preparation of Intermediate 30:
To a mixture of 4- (1, 3-dioxolan-2-yl) pyridin-3-amine (4.2 g, 22.747 mmol) and intermediate 29 (9.148 g, 27.296 mmol) in dioxane (50 mL) was added Cs₂CO₃ (14.823 g, 45.494 mmol) , Xantphos (1.315 mg, 2.275 mmol) and Pd₂ (dba) ₃ (1.041 g, 1.137 mmol ) at rt. The mixture was stirred 120 ℃ for 20 hrs. The mixture was diluted by 300 mL water and extracted with EtOAc (500 mL) three times. The combine organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 50%to provide Intermediate (6.5 g, yield 70 %) as a yellow oil.
Preparation of Intermediate 22:
To a mixture of Intermediate 21 (5 g, 11.831 mmol) in acetonitrile (10 mL) was added hydrochloric acid (10 mL, 4N in water) at rt. The mixture was continued to stir at 50 ℃ for 2 h. The mixture was diluted by 300 mL water and extracted with EtOAc (300 mL) three times. The combined phase was washed by sat. aq. NaCl solution, dried over Na₂SO₄, filtered and concentrated. the residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 50%to provide Intermediate 22 (3.6 g, yield 87.6 %) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 22
Preparation of Intermediate 54:
To a mixture of Intermediate 30 (6.5 g, 16.536 mmol) in acetonitrile (10 mL) was added hydrochloric acid (10 mL, 4N in water) at rt. The mixture was continued to stir at 50 ℃ for 2 hrs. The mixture was diluted by 300 mL water and extracted with EtOAc (300 mL) three times. The combined layers were washed by sat. aq. NaCl solution and dried over Na₂SO₄ filtered and concentrated. silica gel column chromatography eluting with EtOAc in petroleum ether from 0%to 50%to provide Intermediate 54 (4.7 g, yield 86.2%) as a yellow solid.
Preparation of Intermediate 24:
To a solution of Intermediate 23 (400 mg, 0.68 mmol) , triethylamine (353 mg, 3.41 mmol) in DCM (20 mL) was added a solution of triphosgene (128 mg, 0.41 mmol) in 20 mL of DCM dropwise over 20 min. After stirring at 20 ℃ for 5hrs, the mixture was concentrated to give crude product which was purified by silica gel column chromatography eluting with EtOAc in petroleum ether from 50%to 100%to give Intermediate 24 (207 mg, 55.07%yield) as a yellow solid.
The following intermediates were synthesized by an analogous method as described for Intermediate 24
Preparation of Intermediate 32:
To a solution of Intermediate 31 (250 mg, 90%purity, 0.45 mmol) and TEA (136 mg, 1.35 mmol) in THF (10 mL) was added bis (trichloromethyl) carbonate (67 mg, 0.23 mmol ) at 0 ℃for 0.5 h under nitrogen atmosphere. The reasulting mixture was stirred at 30 ℃ for 2 hours. The reaction mixture was extracted with ethyl acetate (200 mL x 3) . The combined organic layers were washed with brine (300 mL) , dried over Na₂SO₄ (anhydrous) and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography eluting with 50%EA in petroleum ether to Intermediate 32 (130 mg, 90%purity, 49.4%yield) as a yellow solid.
Preparation of Intermediate 41:
To a solution of Intermediate 40 (100 mg, 0.410 mmol) in methanol (5 mL) was added Pd/C (10%w/w) (50 mg) under nitrogen. and the mixture was kept under H2 gas at a pressure of 1 bar at rt for 16 hrs. The reaction was filtered over evaporated to dryness to afford Intermediate 41 (85 mg) as a crude product which was used in next step without further purification.
Preparation of Intermediate 35:
To a solution of compound 60 (200 mg, 0.32 mmol) in acetonitrile (5 mL) was added 1 M aqueous hydrochloric acid solution (1.3 mL) , the mixture was stirred at 50 ℃ for 10 min. After cooling down to rt, the solvent was removed. Water (10 mL) and EtOAc (10 mL) were added to the residue. The organic phase was separated, and the aqueous phase was extracted with EtOAc (10 mL) twice. The combined organic phase was washed by sat. aq. NaCl, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 5%MeOH in DCM to give Intermediate 35 (130 mg, 70.31%yield) as a white solid.
Preparation of Compound 1:
Intermediate 7 (160 mg, 0.29 mmol) was added to 4N HCl in 1, 4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. Then the mixture was basified with NaOH aq. solution (1M) to pH ～ 10. The mixture was extracted with DCM (20 mL) three times. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0%to 10%to afford Compound 1 (54 mg, 43%yield) as a yellow oil.
The following Compounds were synthesized by an analogous method as described for Compound 1
Preparation of Compound 3:
To a solution of Compound 1 (50 mg, 0.11 mmol) in DCE (10 mL) were added tetrahydro-2H-pyran-4-carbaldehyde (12 mg, 0.11 mmol) and NaBH (OAc) ₃ (66 mg, 0.311 mmol) . The mixture was stirred at room temperature for 1 h, the mixture was evaporated, and the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 to 10%to afford Compound 3 (43 mg, 73%yield) as a yellow solid.
The following Compounds were synthesized by an analogous method as described for Compound 3
Preparation of Compound 8:
To a mixture of Compound 1 (60 mg, 0.13 mmol) and cyclohexanone (38 mg, 0.39 mmol) in 1, 2-dichloroethane (3 mL) was added acetic acid (0.1 mL) and NaBH (OAc) ₃ (82 mg, 0.39 mmol) . The solution was stirred at room temperature for 2 hours. The mixture was diluted with water (50mL) and extracted with ethyl acetate (40 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over Na₂SO₄ (s) and filtered. The reside was purified by Prep-HPLC (Column: SunFire C18 150*19mm*5um, Mobile Phase A: water (0.1%NH₄HCO₃) , Mobile Phase B: acetonitrile, UV: 214 nm, Flow rate: 15 mL/min, gradient condition from 25%B to 65%B) to Compound 8 (15 mg, 21.1%yield) as a white solid.
Preparation of Compound 9:
To a solution of Compound 1 (200 mg, 0.39 mmol) in 1, 2-dichlorethane (5 mL) were added 4-methyltetrahydro-2H-pyran-4-carbaldehyde (57 mg, 0.43 mmol) , acetic acid (0.05 mL) and NaBH (OAc) ₃ (251 mg, 1.16 mmol) under ice-water bath. The reaction mixture was stirred at room temperature for 4 hours. It was poured into aqueous saturated NaHCO₃ solution and extracted with DCM (10 mL) twice, the organic layers were washed with brine (20 mL) , dried over Na₂SO₄ (s) , filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 %to 5 %to give the desired product (200 mg) as a white solid. The product was further purified by chiral Prep. HPLC (Column: IE 4.6 cm I.D. *25 cm L, 5um; Mobile Phase: MeOH: DCM: DEA = 90: 10: 0.2 at 30 mL/min) to afford Compound 9 (90 mg, 22.58%yield) as a white solid.
Preparation of Compound 11:
In a sealed tube, to a solution of Compound 1 (1.3 g, 2.66 mmol) , tetrahydro-4H-pyran-4-one (327 mg, 3.19 mmol) in methanol (5 mL) were added NaBH₃CN (513 mg, 7.99 mmol) and ZnCl₂ (371 mg, 2.66 mmol) . After stirring at 65 ℃ for 16h, the mixture was filtered, and the filtrate was concentrated to give crude compound, which was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 %to 12 %to give the desired product (1.3 g) as a white solid. The product was further purified by chiral Prep. HPLC (Column: IE 5.0 cm I.D. *25 cm L, 10um; Mobile Phase: MeOH: DCM: DEA = 90: 10: 0.2 at 30 mL/min; Temp: 38 ℃) to afford Compound 11 (820 mg, 58.06%yield) as a white solid.
Preparation of Compound 12:
To a mixture of Compound 1 (50 mg, 0.108 mmol) in 1, 2-dichloroethane (5 mL) was added cyclobutanecarbaldehyde (18 mg, 0.216 mmol) at rt. The mixture was stirred at rt for 2 hrs. Then NaBH (OAc) ₃ (68 mg, 0.324 mmol) was added. And the mixture continued to stir at rt for 3 hrs. The mixture was diluted by 30 mL water and extracted with EtOAc (30mL) three times. The combined layers were washed by brine and dried over Na₂SO₄ and concentrated. 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 μm 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.
Preparation of Compound 13:
To a mixture of Compound 1 (50 mg, 0.108 mmol) in 1, 2-dichloroethane (5 mL) was added pivalaldehyde (19 mg, 0.216 mmol) at rt. The mixture was stirred at rt for 2 hrs. Then NaBH (OAc) ₃ (68 mg, 0.324 mmol) was added to the mixture. The mixture was continued to stir for 3 h at rt. The mixture was diluted with 30 mL water and extracted with EtOAc (30mL) three times. The combined layers were washed by brine and dried over Na₂SO₄ and concentrated. The residue was purified by by silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0 %to 50 %to provide product (30 mg) as a yellow oil. The product was further purified by prep_HPLC (Column: Xbridge C18 (5 μm 19 *150 mm) , Mobile Phase A: Water (0.1 %ammoniumbicarbonate) , Mobile Phase B: acetonitrile, Flow rate: 15 mL /min, Gradient: 10%B to 65 %B) to give Compound 13 (10 mg, purity 95.7%, yield 18 %) .
Preparation of Compound 14:
To a solution of Compound 59 (50 mg, 0.10 mmol) in 1, 2-dichlorethane (5 mL) were added tetrahydro-2H-pyran-4-carbaldehyde (18 mg, 0.15 mmol) , acetic acid (0.05 mL) and NaBH (OAc) ₃ (67 mg, 0.30 mmol) under ice-water bath cooling. The reaction mixture was stirred at rt for 4 hrs. It was poured into saturated NaHCO₃ aqueous solution and extracted with DCM (10 mL) twice. The organic layers were washed with brine (20 mL) , dried over sodium sulfate (s) , filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 %to 8 %to give Compound 14 (12 mg, 22%yield) as a white solid.
Preparation of Compound 10:
To a solution of Compound 3 (50 mg, 0.09 mmol) in methanol (2 mL) were added formaldehyde (68 mg, 0.84 mmol, 37%w/w in water) and NaBH (OAc) ₃ (54 mg, 0.25 mmol) while being cooled in an ice-water bath. The reaction mixture was stirred at rt for 4 hours and then poured into aq. sat. NaHCO₃ solution and extracted with DCM (20 mL) twice, the combined organic phase was washed with brine (30 mL) , dried over anhydrous Na₂SO₄ (s) , filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography eluting with methanol in dichloromethane from 0 %to 12 %to give Compound 10 (12 mg, 24.14%yield) as a yellow solid.
Preparation of Compound 15, 16, 17:
Compound 15
Compound 16
Compound 17
To a mixture of Compound 1 (140 mg, 0.319 mmol) in MeOH (5 mL) was added 3, 3-dimethyltetrahydro-4H-pyran-4-one (122.475 mg, 0.956 mmol) , ZnCl₂ (65.119 mg, 0.478 mmol) . The mixture was stirred at 60 ℃ for 0.5 h before NaBH₃CN (40.033 mg, 0.637 mmol) was added, and the mixture continue stirred at 50 ℃ for 3hrs. After cooling down to rt, the mixture was quenched with sat. aq. NaHCO₃ solution and extracted with DCM (10 mL) three times. The combined organic phases were washed with brine (30 mL) , dried over anhydrous Na₂SO₄ (s) , filtered and concentrated. The mixture was purified by preparative-HPLC (Column: Waters XBridge C8 5μm, 19*150mm, Mobile Phase A: water (0.1%NH₄OH+10 mM NH₄HCO₃) , Mobile Phase B: acetonitrile, Flow rate: 17 mL/min, gradient condition from 50%B to 60%) to afford Compound 15 (130 mg, 71%yield) as a yellow solid.
Compound 15 (110 mg) was further purified by Prep SFC (Stationary phase: Column CHIRALPAK AD-H 5μm 10*250mm, Mobile phase: A: Supercritical CO₂, B MeOH+0.1%NH₄OH, A: B = 90: 10 at 11 mL/min, Column Temp: 45 ℃)
The first fraction was collected as Compound 16 (35 mg, 32%yield) , the second fraction was collected as Compound 17 (32 mg, 29%yield) .
Preparation of Compound 26, 27, 33, 34:
Compound 26
Compound 27
Compound 33
Compound 34
To a mixture of Compound 1 (660 mg, 1.502 mmol) in MeOH (10 mL) was added 3-methyltetrahydro-4H-pyran-4-one (CAS: 119124-53-7) (514.195 mg, 4.505 mmol) , ZnCl₂ (306.991 mg, 2.252 mmol) at rt. The mixture was stirred at rt for 0.5 hrs. Then NaBH₃CN (188.727 mg, 3.003 mmol) was added, and the mixture was continued to stir at 50 ℃ for 2 hrs. The mixture was washed with sat. aq. NaHCO₃ and brine, dried, filtered and concentrated. The mixture was purified by preparative-HPLC (Column: Waters XBridge C8 5μm, 19*150mm, Mobile Phase A: water (0.1%NH₄OH+10 mM NH₄HCO₃) , 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. The first fraction was further purified by Prep SFC (Stationary phase: Column CHIRALPAK AD 5μm 10*250mm, Mobile phase: A: Supercritical CO₂, B EtOH: MeOH (3: 1) +0.1%NH₄OH, A: B =85: 15 at 11 mL/min, Column Temp: 45 ℃) and the first peak was collected as Compound 26, the second peak was collected as Compound 27. The second fraction was further purified by Prep SFC (Stationary phase: Column CHIRALPAK AD-H 5μm 10*250mm, Mobile phase: A: Supercritical CO₂, B EtOH+0.1%NH₄OH, A: B =88: 12 at 11 mL/min, Column Temp: 45 ℃) and the first peak was collected as Compound 33, the second peak was collected as Compound 34.
The following Compounds were synthesized by an analogous method as described for Compound 15
Preparation of Compound 21:
A mixture of Intermediate 32 (50 mg, 0.09 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 2h at r. t. The mixture was concentrated under vacuum. The residue was diluted with aqueous NaOH solution (1 M, 50 mL) and extracted with DCM (30 mL) three times. The combined organic phase was dried over Na₂SO₄ (s) and filtered. The filtrate was concentrated under vacuum to give the crude which was purified by Prep-HPLC with the following conditions (Column: SunFire C18 150*19mm*5um, Mobile Phase A: water (containing 0.1%NH₄HCO₃) , Mobile Phase B: acetonitrile, UV: 214 nm, Flow rate: 15 mL/min, gradient condition from 10%B to 40%B) to Compound 21 (15 mg, 37.6%yield) as a yellow solid.
Preparation of Compound 28:
A mixture of Intermediate 33 (500 mg, 0.09 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at rt for 2hrs. The mixture was concentrated under vacuum. The residue was diluted with NaOH solution (1 mol/L, 50 mL) and extracted with DCM (40 mL*3) . The combined organic layers were dried over Na₂SO₄ (s) , filtered and concentrated. The reside was purified by Prep-HPLC (Column: SunFire C18 150*19mm*5um, Mobile Phase A: water (containing 0.1% NH₄HCO₃) , Mobile Phase B: acetonitrile, Flow rate: 15 mL/min, gradient condition from 10%B to 45%B) to give Compound 28 (15 mg, 36 yield) as a white solid.
Preparation of Compound 29, 30:
Compound 29:
Compound 30:
To a solution of Intermediate 35 (100 mg, 0.14 mmol) and 1- (piperazin-1-yl) ethan-1-one (23 mg, 0.17 mmol) in methanol (3 mL) was added NaBH (OAc) ₃ (154 mg, 0.71 mmol) . After stirring at 20 ℃ for 16h, the mixture was filtered, and the filtrate was concentrated to give crude product, which was purified by Prep-HPLC (Column: Xbridge C18 (5 μm 19 *150 mm) , Mobile Phase A: Water (containing 0.1 %HCOOH) , Mobile Phase B: acetonitrile, Flow rate: 15 mL /min, Gradient: 20-50 % (%B) ) ) to give the racemic mixture (36 mg, 34.90%yield) as formate salt which was further separated by chiral Prep. HPLC (Column: IA 4.6 cm I.D. *25 cm L, 5um; Mobile Phase: Hex: EtOH: DEA = 70: 30: 0.2 at 30 mL/min; Temp: 38 ℃) . The first fraction was collected as Compound 29 (7 mg, 19%yield) as a white solid and the second fraction was collected as Compound 30 (10 mg, 27%yield) as a white solid.
The following Compounds were synthesized by an analogous method as described for Compound 29 &Compound 30
Preparation of Compound 39:
To a mixture of Compound 59 (100 mg, 0.209 mmol) in 1, 2-dichloroethane (5 mL) was added tetrahydro-4H-pyran-4-one (42 mg, 0.419 mmol) at rt. And the mixture was stirred at rt for 2 hrs. Then NaBH (OAc) ₃ (81 mg, 0.628 mmol) was added to the mixture. And the mixture was continued to stir at rt for 3 hrs. The mixture was diluted by 30 mL water and extracted with EtOAc (30mL) three times. The combined layers were washed by brine, dried over Na₂SO₄, filtered and concentrated. silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0 %to 50 %to provide the product (50 mg) as a yellow oil. The product was further purified by prep-HPLC (Column: Xbridge C18, 5 μm 19 *150 mm, Mobile Phase A: Water (0.1 %ammonium bicarbonate) , Mobile Phase B: acetonitrile, Flow rate: 15 mL /min, Gradient: 10 %B -65 %B) ) to give Compound 39 (26 mg, purity 95.1 %from LCMS, yield 23.1 %) as a white solid.
Preparation of Compound 58:
To a solution of Intermediate 14 (80 mg, 0.148 mmol) in DCM (3 mL) was added TFA (1 mL) . The reaction was stirred at room temperature for 0.5 h. The solvent was removed under vacuum. The residue was dissolved in water (5 mL) . The pH was adjusted to 8～9 with aqueous saturated sodium carbonate solution. The mixture was extracted with EtOAc (10 mL) three times, and the combined organic phase was washed with brine, dried over Na₂SO₄ (s) and concentrated. The residue Compound 58 (60 mg, crude) was used for next step without further purification.
Preparation of Compound 59:
To a solution of Intermediate 24 (260 mg, 0.376 mmol) in DCM (5 mL) , was added TFA (1 mL) . After stirring at RT for 2h. T The solvent was removed under vacuum. The residue was dissolved in water (5 mL) . The pH was adjusted to ～10 with 1 M NaOH (aq) solution. The mixture was extracted with DCM (10 mL) twice, and the combined organic layers were washed with brine (20 mL) , dried over Na₂SO₄ (s) , filtered and concentrated to afford the Compound 59 (180 mg, crude) as a yellow solid which was used in the next step without purification.
The following Compounds were synthesized by an analogous method as described for Compound 59
LCMS (Liquid chromatography/Mass spectrometry)
General procedure
The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below) .
Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW) . Data acquisition was performed with appropriate software.
Compounds are described by their experimental retention times (R_t) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] ⁺(protonated molecule) and/or [M-H] ^- (deprotonated molecule) . In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH₄] ⁺, [M+HCOO] ^-, etc…) . For molecules with multiple isotopic patterns (Br, Cl. . ) , the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.
Table 1a: LCMS Method codes (Flow expressed in mL/min; column temperature (T) in ℃; Run time in minutes) . “TFA” means trifluoroacetic acid; “FA” means formic acid.
Table 1b: LCMS and melting point data. Co. No. means compound number; R_t means retention time in min.
NMR:
NMR-Methods
Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer at ambient temperature (298.6 K) , using internal deuterium lock and equipped with BBO 400MHz S1 5 mm probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm) . J values are expressed in Hz.
Some NMR experiments were carried out using a Varian 400-MR spectrometer at ambient temperature (298.6 K) , using internal deuterium lock and equipped with Varian 400 4NUC PFG probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm) . J values are expressed in Hz.
Some NMR experiments were carried out using a Varian 400-VNMRS spectrometer at ambient temperature (298.6 K) , using internal deuterium lock and equipped with Varian 400 ASW PFG probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm) . J values are expressed in Hz.
PHARMACOLOGICAL PART
1) Menin/MLL homogenous time-resolved fluorescence (HTRF) assay
To an untreated, white 384-well microtiter plate was added 40 nL 200X test compound in DMSO and 4 μL 2X terbium chelate-labeled menin (vide infra for preparation) in assay buffer (40 mM Tris·HCl, pH 7.5, 50 mM NaCl, 1 mM DTT (dithiothreitol) and 0.05%Pluronic F-127) . After incubation of test compound and terbium chelate-labeled menin for 30 min at ambient temperature, 4 μL 2X FITC-MBM1 peptide (FITC-β-alanine-SARWRFPARPGT-NH₂) ( “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 μM.
Compound potencies were determined by first calculating %inhibition at each compound concentration according to equation 1:
%inhibition = ( ( (HC -LC) - (HTRF^compound -LC) ) / (HC -LC) ) *100 (Eqn 1)
Where 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, and 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. For each test compound, %inhibition values were plotted vs. the logarithm of the test compound concentration, and the IC₅₀ value derived from fitting these data to equation 2:
%inhibition = Bottom + (Top-Bottom) / (1+10^ ( (logIC₅₀-log [cmpd] ) *h) ) (Eqn 2)
Where Bottom and Top are the lower and upper asymptotes of the dose-response curve, respectively, IC₅₀ is the concentration of compound that yields 50%inhibition of signal and h is the Hill coefficient.
Preparation of Terbium cryptate labeling of Menin: 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 μg of Menin was buffer exchanged into 1x Hepes buffer. 6.67 μM Menin was incubated with 8-fold molar excess NHS (N-hydroxysuccinimide) -terbium cryptate for 40 minutes at room temperature. Half of the labeled protein was purified away from free label by running the reaction over a NAP5 column with elution buffer (0.1M Hepes, pH 7 + 0.1%BSA (bovine serum albumin) ) . The other half was eluted with 0.1M phosphate buffered saline (PBS) , pH7.400 μl of eluent was collected for each, aliquoted and frozen at -80℃. The final concentration of terbium-labeled Menin protein was 115 μg/mL in Hepes buffer and 85 μg/mL in PBS buffer, respectively.
MENIN Protein Sequence (SEQ ID NO: 1) :
2a) Proliferation assay
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 50μg/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 50μg/ml gentamycin (Gibco) . Cells were kept at 0.3 –2.5 million cells per ml during culturing and passage numbers did not exceed 20.
In order to assess the anti-proliferative effects, 200 MOLM14 cells, 200 OCI-AML3 cells or 300 KO-52 cells were seeded in 200μl media per well in 96-well round bottom, ultra-low attachment plates (Costar, catalogue number 7007) . Cell seeding numbers were chosen based on growth curves to ensure linear growth throughout the experiment. Test compounds were added at different concentrations and the DMSO content was normalized to 0.3%. Cells were incubated for 8 days at 37℃ and 5%CO₂. Spheroid like growth was measured in real-time by live-cell imaging (IncuCyteZOOM, Essenbio, 4x objective) acquiring images at day 8. Confluence (%) as a measure of spheroid size was determined using an integrated analysis tool.
In order to determine the effect of the test compounds over time, the confluence in each well as a measure of spheroid size, was calculated. Confluence of the highest dose of a reference compound was used as baseline for the LC (Low control) and the confluence of DMSO treated cells was used as 0%cytotoxicity (High Control, HC) .
Absolute IC₅₀ values were calculated as percent change in confluence as follows:
LC = Low Control: cells treated with e.g. 1 μM of the cytotoxic agent staurosporin, or e.g. cells treated with a high concentration of an alternative reference compound
HC = High Control: Mean confluence (%) (DMSO treated cells)
%Effect = 100 - (100* (Sample-LC) / (HC-LC) )
GraphPad Prism (version 7.00) was used to calculate the IC₅₀. 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%.
2b) MEIS1 mRNA expression assay
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℃. Cell lysates were mixed with human MEIS1 specific capture probe or human RPL28 (Ribosomal Protein L28) specific probe as a normalization control, as well as blocking probes. Cell lysates were then transferred to the custom assay hybridization plate (Thermo Fisher Scientific) and incubated for 18 to 22 hours at 55℃. Subsequently, plates were washed to remove unbound materials followed by sequential addition of preamplifiers, amplifiers, and label probe. Signals (= gene counts) were measured with a Multimode plate reader Envision. IC₅₀s were calculated by dose-response modelling using appropriate software. For all non-housekeeper genes response equal counts corrected for background and relative expression. For each sample, 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 IC₅₀s.
Table 3. Biological data –HTRF assay, proliferation assay, and MEIS1 mRNA expression assay

Claims

A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein

R^1a represents hydrogen; cyano; halo; Het; -C (=O) -NR^xaR^xb; -S (=O) ₂-R¹⁸;

-C (=O) -O-C_1-4alkyl-NR^22aR^22b; -C (=O) -O-C_1-4alkyl;

R^1b represents hydrogen, F or Cl;

R^2a represents hydrogen, halo, C_3-6cycloalkyl, C_1-4alkyl, -O-C_1-4alkyl, cyano, or C_1-4alkyl substituted with one, two or three halo substituents;

R^2b represents hydrogen or C_1-4alkyl;

R^2c represents hydrogen or C_1-4alkyl;

R³ represents hydrogen, C_1-6alkyl, or C_1-6alkyl substituted with C_3-6cycloalkyl;

R⁴ represents hydrogen, C_1-6alkyl, R⁶, Het¹, C_1-6alkyl substituted with one subsituent selected from the group consisting of R⁶ and Het¹;

R^5a and R^5b each independently represent hydrogen or C_1-4alkyl;

R⁶ represents C_3-6cycloalkyl, or C_3-6cycloalkyl substituted with one or two substituents each independently selected from the group consisting of C_1-4alkyl, -O-C_1-4alkyl or Het²;

Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four substituents each independently selected from the group consisting of halo, C_1-4alkyl, oxo, and -OH;

Het² represent a 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one nitrogen with -C (=O) -C_1-4alkyl;

R¹⁸ represents C_1-6alkyl or C_3-6cycloalkyl;

R¹⁹ represents hydrogen or C_1-6alkyl;

or R¹⁸ and R¹⁹ are taken together to form -CH₂-CH₂-CH₂-;

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_1-4alkyl, C_3-6cycloalkyl, or cyano;

R^xa and R^xb are each independently selected from the group consisting of hydrogen;

Het³; C_3-6cycloalkyl; and C_1-6alkyl; wherein optionally said C_3-6cycloalkyl and C_1-6alkyl are substituted with 1, 2 or 3 substituents each independently selected from the group consisting of -OH, -OC_1-4alkyl, -C_1-4alkyl-OH, halo, CF₃, C_3-6cycloalkyl, Het³, and NR^11cR^11d;

or R^xa and R^xb are 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of C_1-4alkyl, halo, -OH, -O-C_1-4alkyl, cyano, and

C_1-4alkyl substituted with one, two or three substituents selected from the group consisting of halo and OR²³;

or R^xa and R^xb are 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 or two additional heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted with one, two or three substituents selected from the group consisting of C_1-4alkyl, halo, -OH, -O-C_1-4alkyl, cyano, and

C_1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo and OR²³;

R²³ represents hydrogen or C_1-4alkyl optionally substituted with one, two or three halo; or a pharmaceutically acceptable salt or a solvate thereof.
The compound according to claim 1, wherein

R^1a represents -C (=O) -NR^xaR^xb;

R^1b represents F;

R^2a represents hydrogen or C_1-4alkyl;

R^2b represents hydrogen;

R^2c represents hydrogen;

R⁶ represents C_3-6cycloalkyl, or C_3-6cycloalkyl substituted with one or two substituents each independently selected from the group consisting of -O-C_1-4alkyl or Het²;

Het¹ represents a monocyclic C-linked 4-to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; or a bicyclic C-linked 6-to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one or two carbon atoms with in total one, two, three or four C_1-4alkyl;

Het² represent a 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, wherein said S-atom might be substituted to form S (=O) or S (=O) ₂; wherein said heterocyclyl is optionally substituted on one nitrogen with -C (=O) -C_1-4alkyl;

R^xa and R^xb represent C_1-6alkyl.
The compound according to claim 1, wherein R^1b represents F.
The compound according to claim 1, 2 or 3, wherein R^2a represents C_1-4alkyl.
A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.
A process for preparing a pharmaceutical composition as defined in claim 5 comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound according to any one of claims 1 to 4.
A compound as claimed in any one of claims 1 to 4 or a pharmaceutical composition as claimed in claim 5 for use as a medicament.
A compound as claimed in any one of claims 1 to 4 or a pharmaceutical composition as claimed in claim 5 for use in the prevention or treatment of cancer.