Cyclobutyl substituted bicyclic compounds

Abstract

The present invention relates to agents useful in the treatment and / or prophylaxis in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer, including but not limited to leukemia.

Description

Technical Field

[0001] The present invention relates to an agent that can be used for the treatment and / or prevention of mammals, a pharmaceutical composition containing such a compound, and their use as a menin / MLL protein / protein interaction inhibitor that can be used for treating diseases such as cancer, including but not limited to leukemia. Background Art

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL; MLL1; KMT2A) result in aggressive acute leukemias in all age groups and still predominantly present as incurable diseases highlighting the urgent need for novel therapeutic approaches. Acute leukemias with these MLL chromosomal translocations present as lymphoid, myeloid or biphenotypic diseases and account for 5% to 10% of adult acute leukemias and approximately 70% in infants.

[0003] MLL is a histone methyltransferase that methylates histone H3 at lysine 4 (H3K4) and functions in a multiprotein complex. Use of an inducible loss-of-function allele of Mll1 has shown that Mll1 plays an important role in maintaining hematopoietic stem cells (HSCs) and developing B cells, although its histone methyltransferase activity is not necessary for hematopoiesis.

[0004] To date, more than 60 different fusion partners have been reported for MLL and are associated with leukemia formation / progression. Interestingly, the SET (Su(var)3-9, enhancer of zeste and trithorax) domain of MLL is not retained in the chimeric protein but is replaced by the fusion partner. Recruitment of chromatin-modifying enzymes such as Dot1L and / or the pTEFb complex by the fusion partner results in enhanced transcription and transcriptional elongation of MLL target genes including the most prominent genes of the HOXA gene family (e.g., HOXA9) and the HOX cofactor MEIS1. Aberrant expression of these genes in turn blocks hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is ubiquitously expressed and mainly located in the nucleus. It has been shown to interact with many proteins and is thus 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 are retained in all fusion proteins, MBM1 (menin-binding motif 1) and MBM2. The menin / MLL interaction results in the formation of a new interaction surface for lens epithelium-derived growth factor (LEDGF). Although MLL binds directly to LEDGF, menin is essential for the stable interaction between MLL and LEDGF and for the gene-specific chromatin recruitment of the MLL complex through the PWWP domain of LEDGF. In addition, many genetic studies have shown that menin is required for oncogenic transformation by MLL fusion proteins, indicating that the menin / MLL interaction is an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukemogenesis in bone marrow progenitors ectopically expressing MLL fusions. Similarly, genetic disruption of the menin / MLL fusion interaction by loss-of-function mutations abrogates the oncogenic properties of MLL fusion proteins, blocks the development of leukemia in vivo, and releases the differentiation block of MLL-transformed leukemic blasts. These studies also suggest that menin is required for maintaining HOX expression by MLL fusion proteins. In addition, small molecule inhibitors of the menin / MLL interaction that pharmacologically demonstrate this protein / protein interaction have been developed and their efficacy has also been demonstrated in preclinical models of AML. Together with the observation that menin is not an essential cofactor of MLL1 during normal hematopoiesis, these data confirm that disruption of the menin / MLL interaction can be a promising new therapeutic approach for treating MLL-rearranged leukemias and other cancers with an active HOX / MEIS1 gene signature. For example, internal tandem duplications (PTDs) within the 5' region of the MLL gene represent another major aberration that occurs mainly in de novo and secondary AML and myelodysplastic syndromes. Although the molecular mechanisms and biological functions of MLL-PTDs have not been fully understood, novel therapeutic targeting strategies that affect the menin / MLL interaction may also prove effective in the treatment of MLL-PTD-related leukemias. In addition, castration-resistant prostate cancer has been shown to depend on the menin / MLL interaction

[0006] The MLL protein is also known as histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt accession number Q03164) in the scientific field. Detailed implementation mode

[0007] The present invention relates to novel compounds of formula (I),

[0008]

[0009] and their tautomers and stereoisomeric forms, wherein

[0010] R 1a represents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-O-C 1-4 alkyl-NR 22a R 22b , -C(=O)-O-C 1-4 alkyl,

[0011] R 1b represents hydrogen, F or Cl;

[0012] R 2a represents hydrogen, halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano or C 1-4 alkyl substituted with one, two or three halo substituents;

[0013] R 2b represents hydrogen or C 1-4 alkyl;

[0014] R 2c represents hydrogen or C 1-4 alkyl;

[0015] R 3 represents hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl-substituted C 1-6 alkyl;

[0016] R 4 represents hydrogen, C 1-6 alkyl, R 6 , Het 1 , C 6 alkyl substituted with a substituent selected from the group consisting of R 1 and Het 1-6 ;

[0017] R 5a and R 5b each independently represent hydrogen or C 1-4 alkyl;

[0018] R 6 represents C3-6 A cycloalkyl group or a C cycloalkyl group substituted by one or two substituents, where the one or two substituents are each independently selected from the group consisting of C 3-6 alkyl groups, -O-C 1-4 alkyl groups, or Het 1-4 groups; 2

[0019] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, where the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N, where the S atom can be substituted to form S(=O) or S(=O)2; where the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one, two, three, or four substituents each independently selected from the group consisting of halo, C 1-4 alkyl groups, oxo groups, and -OH;

[0020] Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom can be substituted to form S(=O) or S(=O)2; where the heterocyclic group is optionally substituted on one nitrogen by -C(=O)-C 1-4 alkyl groups.

[0021] R 18 represents C 1-6 alkyl groups or C 3-6 cycloalkyl groups;

[0022] R 19 represents hydrogen or C 1-6 alkyl groups;

[0023] Or R 18 and R 19 together form -CH2-CH2-CH2-;

[0024] Het represents a monocyclic 5- or 6-membered aromatic ring containing one, two, or three nitrogen atoms and optionally a carbonyl moiety; where the monocyclic 5- or 6-membered aromatic ring is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl groups, C 3-6 cycloalkyl groups, or cyano groups;

[0025] R xa and R xb ​Each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted with one, two or three substituents, each independently selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 cycloalkyl, Het 3 and NR 11c R 11d ;

[0026] Or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S and N; wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH and -O-C 1-4 alkyl, cyano and C substituted with one, two or three substituents selected from the group consisting of halo and OR 23 ; 1-4 alkyl;

[0027] Or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S and N, wherein said S atom can be substituted to form S(=O) or S(=O)2; wherein said heterocyclic group is optionally substituted with one, two or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano and C substituted with one, two or three substituents each independently selected from the group consisting of halo and OR 23 ; 1-4 alkyl;

[0028] R 23 represents hydrogen or C 1-4 alkyl optionally substituted with one, two or three halo;

[0029] And pharmaceutically acceptable salts and solvates thereof.

[0030] 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 solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0031] Furthermore, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof for use as a medicament, and to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of cancer, including but not limited to leukemia.

[0032] In one specific embodiment, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of cancer.

[0033] In one specific embodiment, the cancer is selected from leukemia. In some embodiments, these leukemias include acute leukemia, chronic leukemia, myeloid leukemia, myelocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemia showing HOX / MEIS1 gene expression signature, etc.

[0034] Specifically, the compounds and pharmaceutical compositions according to the present invention can be used for the treatment or prevention of leukemia, particularly leukemia with nucleophosmin (NPM1) mutations, such as NPM1c.

[0035] In one embodiment, the compound of formula (I), its pharmaceutically acceptable salts and solvates can have improved metabolic stability properties.

[0036] In one embodiment, the compound of formula (I), its pharmaceutically acceptable salts and solvates can reduce tumor growth, such as tumors carrying MLL (KMT2A) gene rearrangement / alteration and / or NPM1 mutations.

[0037] The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof in combination with an additional agent for the treatment or prevention of cancer, including but not limited to leukemia.

[0038] In addition, the present invention relates to a method for preparing a pharmaceutical composition according to the present invention, which is characterized by intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

[0039] The present invention also relates to a product comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and an additional agent, which is used as a combination preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, including but not limited to leukemia. Detailed Description

[0041] As used herein, the term "halo" or "halogen" means fluorine, chlorine, bromine and iodine.

[0042] As used herein, the prefix "C x-y " (wherein x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-6 alkyl groups contain from 1 to 6 carbon atoms, and so on.

[0043] As used herein as a group or part of a group, the term "C 1-4 alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

[0044] Similarly, as used herein as a group or part of a group, the term "C 1-6 alkyl" means a straight or branched chain fully saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0045] As used herein as a group or part of a group, the term "C 3-6 cycloalkyl" is defined as a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0046] It will be appreciated by those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0047] It will be appreciated by those skilled in the art that CO or C(=O) represents a carbonyl moiety.

[0048] Non-limiting examples of "a monocyclic 5- or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety" include but are not limited to pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1,2-dihydro-2-oxo-4-pyridyl.

[0049] Those skilled in the art 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

[0050]

[0051] The term "monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N" is defined as a fully saturated cyclic hydrocarbon group having 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 cyclic hydrocarbon group is linked to the remainder of the molecule of formula (I) through 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. The definition of two R groups that together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N is similar, but the hydrocarbon group may be fully saturated or partially saturated.

[0052] The term "monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two, or three heteroatoms each independently selected from O, S, and N" is defined as a fully saturated cyclic hydrocarbon group having 4 to 7 ring members and containing one, two, or three heteroatoms each independently selected from O, S, and N, such as 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, and C-linked piperidinyl, C-linked azepanyl, and C-linked 1,2,3,6-tetrahydro-pyridinyl.

[0053] For clarity, the 4- to 7-membered fully saturated or partially saturated heterocyclic group has 4 to 7 ring members, including heteroatoms.

[0054] In the context of the present invention, bicyclic 6- to 11-membered fully saturated heterocyclic groups include fused bicyclic, spiro bicyclic, and bridged bicyclic groups.

[0055] A fused bicyclic group is two rings that share two atoms and the bond between these atoms.

[0056] A spiro bicyclic group is two rings joined at a single atom.

[0057] A bridged bicyclic group is two rings that share more than two atoms.

[0058] Examples of bicyclic C-linked 6- to 11-membered fully saturated heterocyclic groups containing one, two, or three heteroatoms each independently selected from O, S, and N include but are not limited to

[0059]

[0060] etc.

[0061] Examples of the 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom each independently selected from O, S, and N formed by the two R groups together with the N atom to which they are attached include, but are not limited to

[0062]

[0063] etc.

[0064] Whenever a substituent is represented by a chemical structure, such as, for example

[0065] “----” represents a bond connecting to the remainder of the molecule of formula (I).

[0066] When any variable occurs more than once in any component, each definition is independent.

[0067] When any variable occurs more than once in any formula (such as formula (I)), each definition is independent.

[0068] It is clear to those skilled in the art that when a moiety (such as a heterocyclic group or a monocyclic 5- or 6-membered aromatic ring) is substituted by two or more substituents selected from a group (such as one, two, or three substituents), each substituent can be independently selected from the group, even if not explicitly mentioned.

[0069] Generally, unless otherwise specified or clear from the context, whenever the term “substituted” is used in the present invention, it means that one or more hydrogens, particularly 1 to 4 hydrogens, more particularly 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen on the atom or group indicated in the expression using “substituted” are replaced by a selection from the indicated group, provided that the normal valency is not exceeded and the substitution results in a chemically stable compound, i.e., a compound stable enough to withstand separation from the reaction mixture to useful purity (separated after the reaction, for example, purified by silica gel chromatography). In a specific embodiment, when the number of substituents is not explicitly specified, the number of substituents is one.

[0070] Combinations of substituents and / or variables are permitted only if such combinations result in a chemically stable compound. A “stable compound” in this context means a compound stable enough to withstand separation from the reaction mixture to useful purity (separated after the reaction, for example, purified by silica gel chromatography).

[0071] Those skilled in the art will understand that the term "optionally substituted" means that the atom or group indicated in the expression using "optionally substituted" may or may not be substituted (which means substituted or unsubstituted, respectively).

[0072] When there are two or more substituents on a moiety, where possible and unless otherwise specified or clear from the context, they may replace hydrogens on the same atom, or they may replace hydrogen atoms on different atoms in the moiety.

[0073] In the context of the present invention, if not otherwise stated, "saturated" means "fully saturated".

[0074] Unless otherwise specified or clear from the context, aromatic ring and heterocyclic group moieties may be attached to the remainder of the molecule of formula (I) through any available ring carbon atom (C - linked) or nitrogen atom (N - linked).

[0075] Unless otherwise specified or clear from the context, aromatic ring and heterocyclic group moieties may optionally be substituted on carbon and / or nitrogen atoms where possible according to the embodiments.

[0076] As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., a cat, dog, primate or human), more preferably a human who is or has been the subject of treatment, observation or experiment.

[0077] As used herein, the term "therapeutically effective amount" means the amount of an active compound or agent that elicits in a tissue system, animal or human the biological or pharmaceutical response (including alleviation or reversal of the symptoms of the disease or disorder being treated) that a researcher, veterinarian, physician or other clinician is seeking.

[0078] The term "composition" is intended to cover a product containing the specified amounts of the specified ingredients, as well as any product directly or indirectly obtained by combining the specified amounts of the specified ingredients.

[0079] As used herein, the term "treatment" is intended to refer to all processes in which there may be a slowing, interruption, arrest or stoppage of disease progression, but not necessarily to the complete elimination of all symptoms.

[0080] As used herein, the term "compounds of the present invention" or "compounds according to the present invention" means compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

[0081] As used herein, any chemical formula having only bonds shown as solid lines and not shown as solid wedges or hash wedges or otherwise represented as having a specific configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

[0082] In the foregoing and the following, the term "compound of formula (I)" is meant to include its tautomers and its stereoisomeric forms.

[0083] The terms "stereoisomer", "stereoisomeric form" or "stereochemical isomeric form" may be used interchangeably in the foregoing or the following.

[0084] The present invention includes all stereoisomers of the compounds of the present invention as pure stereoisomers or as mixtures of two or more stereoisomers.

[0085] 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 a racemic mixture.

[0086] Atropisomers (or atropoisomers) are stereoisomers having a specific spatial configuration that gives rise to 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.

[0087] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related to a mirror image. If a compound contains a double bond, the substituents may be in the E or Z configuration.

[0088] Substituents on a divalent cyclic saturated or partially saturated group may have a cis or trans configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

[0089] Accordingly, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, provided that they are chemically possible.

[0090] The meaning of all those terms, namely enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, is known to the person skilled in the art.

[0091] The absolute configuration is assigned according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is assigned as R or S. A resolved stereoisomer of unknown absolute configuration can be assigned as (+) or (-) according to the direction in which it rotates plane-polarized light. For example, a resolved enantiomer of unknown absolute configuration can be assigned as (+) or (-) according to the direction in which it rotates plane-polarized light.

[0092] When identifying a specific stereoisomer, this means that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2% and most preferably less than 1% of other stereoisomers. Thus, when a compound of formula (I) is designated as (R), for example, this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated as E, for example, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated as cis, for example, this means that the compound is substantially free of the trans isomer.

[0093] Some compounds according to formula (I) can also exist in their tautomeric forms. Although not explicitly indicated in formula (I) above, these forms are intended to be included within the scope of the present invention insofar as they may exist. It can be seen therefrom that a single compound can exist in the form of stereoisomers and tautomers.

[0094] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional methods, for example, by reacting the free acid or free base form with one or more equivalents of a suitable base or acid, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or the medium using standard techniques (e.g., vacuum, by lyophilization or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0095] The pharmaceutically acceptable salts mentioned above or below refer to the non-toxic acid and non-toxic base salt forms of the compounds of formula (I) and their solvates that are capable of forming and having therapeutic activity.

[0096] Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

[0097] Compounds of formula (I) containing acidic protons and their solvates can also be converted into their non-toxic metal or amine salt forms by treatment with suitable organic and inorganic bases.

[0098] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts (such as lithium, sodium, potassium, cesium, magnesium, calcium salts, etc.), salts with organic bases, such organic bases as 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; benzathine, N-methyl-D-glucamine, hydrabamine salts and salts with amino acids (such as, for example, arginine, lysine, etc.). Conversely, the salt form can be converted into the free acid form by treatment with an acid.

[0099] The term "prodrug" includes any compound that is metabolized in vivo to the (more) active form in an experimentally detectable amount within a predetermined time (e.g., within a dosing interval between 0.5 hour and 24 hours, or e.g., within a dosing interval between 6 hours and 24 hours (i.e., once to four times a day)) after oral or parenteral administration, especially oral administration. For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration, especially intravenous (IV), intramuscular (IM) and subcutaneous (SC) injection.

[0100] Prodrugs can be prepared by modifying the functional groups present on the compound such that the modification is cleaved in vivo when such prodrug is administered to a mammalian subject. These modifications are generally achieved by synthesizing the parent compound with a prodrug substituent. Generally, prodrugs include compounds in which a hydroxyl, amino, mercapto, carboxyl or carbonyl group is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, mercapto, carboxyl or carbonyl group, respectively.

[0101] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases.

[0102] The term solvate includes the solvent addition forms and their salts that the compounds of formula (I) are capable of forming. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0103] The compounds of the invention prepared by the methods described below can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, which mixtures can be separated from one another by resolution methods known in the art. The separation of the enantiomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomer forms can also be derived from the corresponding pure stereochemical isomer forms of the appropriate starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is required, the compounds will be synthesized by stereospecific preparative methods. These methods will advantageously employ optically pure starting materials.

[0104] As used herein, the term "optically pure" means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In the most preferred embodiment, the term "optically pure" means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.

[0105] The invention also encompasses isotopically labeled compounds of the invention which are identical to those described herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant atomic mass or mass number found in nature).

[0106] All isotopes and mixtures of isotopes of any specific atom or element as specified herein are contemplated within the scope of the compounds of the invention, whether occurring naturally or produced synthetically, whether in natural abundance or in isotopically enriched form. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82Br. Preferably, the isotope is selected from 2 H, 3 H, 11C, 13C, and 18F. Preferably, the isotope is selected from 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is 2 H, 3 H, or 13 C. More preferably, the isotope is 2 H, or 13 C. More preferably, the isotope is 2 H. In particular, deuterated compounds and compounds enriched in 13 C 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.

[0107] Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3 H and 14 C) can be used, for example, in substrate tissue distribution assays. Tritium ([[]] 3 3 H) and carbon-14 ([[]] 14 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., [[[]] 2 2 H) can provide certain therapeutic advantages due to greater metabolic stability (e.g., extended in vivo half-life or reduced dose requirements) and can therefore be preferred in some cases. Positron-emitting isotopes such as [[[]] 15 15 O, [[[]] 13 13 N, [[[]] 11 11 C, and [[[]] 18 18 F can be used in positron emission tomography (PET) studies. PET imaging in cancer can be used to help localize and identify tumors, stage the disease, and determine appropriate treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind to such receptors or proteins on tumor cells with high affinity and specificity have great potential for diagnostic imaging and targeted radionuclide therapy. Additionally, target-specific PET radiotracers can be used as biomarkers to examine and evaluate pathology by, for example, measuring target expression and treatment response.

[0108] The present invention particularly relates to compounds of formula (I) as defined herein, as well as their tautomeric and stereoisomeric forms, wherein

[0109] R 1a represents -C(=O)-NR xa R xb ;

[0110] R1b represents F;

[0111] R 2a represents hydrogen or C 1-4 alkyl;

[0112] R 2b represents hydrogen;

[0113] R 2c represents hydrogen;

[0114] R 3 represents hydrogen, C 1-6 alkyl or C 3-6 alkyl substituted by cycloalkyl; 1-6 alkyl;

[0115] R 4 represents hydrogen, C 1-6 alkyl, R 6 , Het 1 , substituted by a substituent selected from the group consisting of R 6 and Het 1 and consisting of C 1-6 alkyl;

[0116] R 5a and R 5b each independently represents hydrogen or C 1-4 alkyl;

[0117] R 6 represents C 3-6 cycloalkyl or C 3-6 cycloalkyl substituted by one or two substituents, each independently selected from the group consisting of -O-C 1-4 alkyl or Het 2 ;

[0118] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one, two, three or four C 1-4 alkyl;

[0119] Het 2represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one nitrogen with -C(=O)-C 1-4 alkyl;

[0120] R xa and R xb represents C 1-6 alkyl;

[0121] and pharmaceutically acceptable salts and solvates thereof.

[0122] The present invention particularly relates to compounds of formula (I) as defined herein, and their tautomeric and stereoisomeric forms, wherein

[0123] R 1a represents -C(=O)-NR xa R xb ;

[0124] R 1b represents F;

[0125] R 2a represents hydrogen or C 1-4 alkyl;

[0126] R 2b represents hydrogen;

[0127] R 2c represents hydrogen;

[0128] R 3 represents hydrogen;

[0129] R 4 represents C 1-6 alkyl, R 6 , Het 1 , C 6 alkyl substituted with a substituent selected from the group consisting of R 1 and Het 1-6 alkyl;

[0130] R 5a and R 5b represent hydrogen;

[0131] R 6 represents C 3-6 cycloalkyl;

[0132] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four C 1-4 alkyl substituents;

[0133] R xa and R xb represents C 1-6 alkyl;

[0134] and pharmaceutically acceptable salts and solvates thereof.

[0135] The present invention particularly relates to compounds of formula (I) as defined herein, and their tautomers and stereoisomeric forms, wherein

[0136] R 1a represents -C(=O)-NR xa R xb ;

[0137] R 1b represents F;

[0138] R 2a represents hydrogen, C 1-4 alkyl;

[0139] R 2b represents hydrogen;

[0140] R 2c represents hydrogen;

[0141] R 3 represents hydrogen;

[0142] R 4 represents C 1-6 alkyl, R 6 , Het 1 , substituted with a substituent selected from the group consisting of R 6 and Het 1 composed of C 1-6 alkyl;

[0143] R 5a and R 5b represent hydrogen;

[0144] R 6 represents C 3-6 cycloalkyl;

[0145] Het 1represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one or two carbon atoms with a total of one, two, three or four C 1-4 alkyl substitution;

[0146] R xa and R xb represents C 1-6 alkyl;

[0147] and pharmaceutically acceptable salts and solvates thereof.

[0148] The present invention particularly relates to compounds of formula (I) as defined herein, and their tautomers and stereoisomeric forms, wherein

[0149] R 1a represents -C(=O)-NR xa R xb ;

[0150] R 1b represents F;

[0151] R 2a represents C 1-4 alkyl, especially methyl;

[0152] R 2b represents hydrogen;

[0153] R 2c represents hydrogen;

[0154] R 3 represents hydrogen;

[0155] R 4 represents C 1 alkyl substituted by one Het 1-6 ;

[0156] R 5a and R 5b represent hydrogen;

[0157] R 6 represents C 3-6 cycloalkyl;

[0158] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted at one carbon atom with one C 1-4 alkyl substitution;

[0159] R xa and R xb represents C 1-6 alkyl;

[0160] and pharmaceutically acceptable salts and solvates thereof.

[0161] In one embodiment, the invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0162] R 1a represents hydrogen, Het, -C(=O)-NR xa R xb 、-S(=O)2-R 18 ,

[0163] In one embodiment, the invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0164] R 1a represents Het, -C(=O)-NR xa R xb 、-S(=O)2-R 18 ,

[0165] In one embodiment, the invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0166] R 1a represents -C(=O)-NR xa R xb 、-S(=O)2-R 18 , or

[0167] In one embodiment, the invention relates to compounds of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0168] R 1a represents -C(=O)-NR xa R xb , or

[0169] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0170] R 1a represents -C(=O)-NR xa R xb .

[0171] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb represent hydrogen or C 1-6 alkyl.

[0172] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa and R xb represent C 1-6 alkyl.

[0173] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R xa is not taken together with R xb .

[0174] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F or Cl.

[0175] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F.

[0176] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b represents F; R 2a is not hydrogen; R 2b represents hydrogen; R 2c represents hydrogen.

[0177] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2a represents C 1-4 alkyl.

[0178] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2a represents methyl.

[0179] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 represents halo, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, cyano or C 1-4 alkyl substituted with one, two or three halo substituents.

[0180] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2a is not hydrogen.

[0181] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents hydrogen and R 4 is not hydrogen.

[0182] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 represents hydrogen and R 3 is not hydrogen.

[0183] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 represents C 1 alkyl substituted with one Het 1-6 group.

[0184] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0185] R 3 represents hydrogen;

[0186] R 4 represents C 1 alkyl substituted by a Het 1-6 group.

[0187] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 4 represents C 1 alkyl substituted by a Het 1-6 group; wherein Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one carbon atom by a C 1-4 alkyl group, especially a methyl group.

[0188] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0189] R 3 represents hydrogen;

[0190] R 4 represents C 1 alkyl substituted by a Het 1-6 group;

[0191] wherein Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one carbon atom by a C 1-4 alkyl group, especially a methyl group.

[0192] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5a represents hydrogen.

[0193] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5b represents hydrogen.

[0194] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5a and R 5b represent hydrogen.

[0195] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5a and R 5b one of which represents C 1-4 alkyl and the other is hydrogen.

[0196] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5a represents hydrogen, and R 5b represents C 1-4 alkyl, especially methyl.

[0197] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 5b is hydrogen, and R 5ba represents C 1-4 alkyl, especially methyl.

[0198] In one embodiment, the present invention relates to the compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0199] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(═O) or S(═O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(═O) or S(═O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms by a total of one or two C 1-4 alkyl, especially methyl substitution.

[0200] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0201] Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one carbon atom by a C 1-4 alkyl group, especially methyl substituted.

[0202] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0203] wherein Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one carbon atom by a C 1-4 alkyl group, especially methyl substituted.

[0204] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 is monocyclic.

[0205] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 is bicyclic.

[0206] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 represents any of the following

[0207]

[0208] Each is optionally substituted as defined in any other embodiment.

[0209] In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 2 represents

[0210]

[0211] is optionally substituted as defined in any other embodiment.

[0212] In one embodiment, the present invention relates to a subgroup of formula (I) as defined in the general reaction scheme.

[0213] In one embodiment, the compounds of formula (I) are selected from the group consisting of: exemplary compounds,

[0214] their tautomeric and stereoisomeric forms,

[0215] and their free bases, any pharmaceutically acceptable salts and solvates.

[0216] In one embodiment, the compounds of formula (I) are selected from the group consisting of: compounds 3, 8, 9, 11, 12, 13, 14, 26, 28 and 39.

[0217] In one embodiment, the compounds of formula (I) are selected from the group consisting of: compounds 3, 8, 9, 11, 12, 13, 14, 26, 28 and 39;

[0218] their tautomeric and stereoisomeric forms,

[0219] and any pharmaceutically acceptable salts and solvates thereof.

[0220] 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 exemplary compound.

[0221] 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 exemplary compound,

[0222] their tautomeric and stereoisomeric forms,

[0223] and their free bases, any pharmaceutically acceptable salts and solvates.

[0224] 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: compound 3, 8, 9, 11, 12, 13, 14, 26, 28 and 39.

[0225] 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: compound 3, 8, 9, 11, 12, 13, 14, 26, 28 and 39;

[0226] its tautomeric and stereoisomeric forms;

[0227] and any pharmaceutically acceptable salts and solvates thereof.

[0228] In one embodiment, the compound of formula (I) is compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0229] In one embodiment, the compound of formula (I) is compound 3 or a pharmaceutically acceptable salt or solvate thereof.

[0230] In one embodiment, the compound of formula (I) is compound 8 or a pharmaceutically acceptable salt or solvate thereof.

[0231] In one embodiment, the compound of formula (I) is compound 9 or a pharmaceutically acceptable salt or solvate thereof.

[0232] In one embodiment, the compound of formula (I) is compound 11 or a pharmaceutically acceptable salt or solvate thereof.

[0233] In one embodiment, the compound of formula (I) is compound 12 or a pharmaceutically acceptable salt or solvate thereof.

[0234] In one embodiment, the compound of formula (I) is compound 13 or a pharmaceutically acceptable salt or solvate thereof.

[0235] In one embodiment, the compound of formula (I) is compound 14 or a pharmaceutically acceptable salt or solvate thereof.

[0236] In one embodiment, the compound of formula (I) is compound 26 or a pharmaceutically acceptable salt or solvate thereof.

[0237] In one embodiment, the compound of formula (I) is compound 28 or a pharmaceutically acceptable salt or solvate thereof.

[0238] In one embodiment, the compound of formula (I) is compound 39 or a pharmaceutically acceptable salt or solvate thereof.

[0239] All possible combinations of the above embodiments are considered to be included within the scope of the present invention.

[0240] Method for preparing the compound of formula (I)

[0241] In this section, as in all other sections, unless the context otherwise indicates, references to formula (I) also include all other subgroups and their examples as defined herein.

[0242] General preparations of some typical examples of the compounds of formula (I) are described below and in the examples and are generally prepared from starting materials that are commercially available or prepared by standard synthetic methods commonly used by those skilled in the art of organic chemistry. The following schemes are only intended to represent examples of the present invention and are in no way intended to limit the present invention.

[0243] Alternatively, the compounds of the present invention can also be prepared by combining similar reaction schemes as described in the general schemes below with standard synthetic methods commonly used by those skilled in the art.

[0244] Those skilled in the art will recognize that in the reactions described in the schemes, although this is not always explicitly shown, it may be desirable or necessary to protect the reactive functional groups (e.g., hydroxyl, amino or carboxyl groups) desired in the final product to avoid their undesired participation in the reaction. Generally, conventional protecting groups (PGs) can be used according to standard practice. The protecting groups can be removed using methods known in the art at a convenient subsequent stage.

[0245] Those skilled in the art will recognize that in the reactions described in the schemes, it may be desirable or necessary to conduct the reaction under an inert atmosphere, e.g., under a N2 - gas atmosphere.

[0246] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture (referring to a series of operations required to separate and purify the products of a chemical reaction, e.g., quenching, column chromatography, extraction) before work-up.

[0247] Those skilled in the art will recognize that heating the reaction mixture with stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to shorten the total reaction time.

[0248] Those skilled in the art will recognize that another sequence of the chemical reactions shown in the schemes below can also produce the desired compounds of formula (I).

[0249] Those skilled in the art will recognize that the intermediates and final compounds shown in the schemes below can be further functionalized according to methods well known to those skilled in the art. The intermediates and compounds described herein can be isolated in free form or as their salts or solvates. The intermediates and compounds described herein can be synthesized as mixtures of tautomeric and stereoisomeric forms, and the tautomeric and stereoisomeric forms can be separated from each other according to separation methods known in the art.

[0250] General synthetic scheme

[0251] Scheme 1

[0252] In Scheme 1, PG represents a suitable protecting group such as tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyl; X 1 represents a halogen such as chlorine, bromine or iodine, or other leaving groups such as mesylate or tosylate; X 2 represents fluorine, chlorine, bromine or iodine; all other variables are defined according to the scope of the present invention.

[0253]

[0254] In Scheme 1, the following reaction conditions are applied:

[0255] Step 1: At a suitable temperature in the range of 80 °C to 120 °C, in the presence of a diol reagent (such as ethylene glycol), in the presence of a Bronsted acid (such as p-toluenesulfonic acid), in a suitable aprotic solvent (such as toluene);

[0256] Step 2: When R 2a is a C 3-6 cycloalkyl, C 1-4 alkyl or C 1-4 alkyl substituted with one, two or three halogen substituents, at a suitable temperature in the range of room temperature to 100 °C, in the presence of an alkyl or alkenyl boronic acid or boronate or potassium alkyltrifluoroborate, in the presence of a suitable base such as potassium carbonate or cesium carbonate, in the presence of a suitable catalyst such as [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl2), in a suitable solvent such as di alkane or dimethylformamide and water. Alternatively, when R 2 is methyl, a boron-containing reagent (such as trimethylcyclotriboroxane) can be used in the presence of a suitable catalyst such as (Pd(dppf)Cl2), in a suitable solvent (such as di alkane or dimethylformamide and water), in the presence of an inorganic base such as potassium carbonate or cesium carbonate, at a reaction temperature of 80 °C to 120 °C;

[0257] When R2a is -O-C 1-4 is alkyl or cyano, at a suitable temperature of 60 °C - 150 °C, in the presence of sodium alkoxide or potassium alkoxide or CuCN or Zn(CN)₂, in the presence of a metal catalyst such as Pd₂(dba)₃ or Pd(dppf)Cl₂, in the presence of an organic phosphine ligand such as dicyclohexyl[2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine (XPhos) or (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos), in the presence of a base such as potassium tert-butoxide, in a suitable solvent such as toluene or NMP.

[0258] Step 3: At a suitable temperature from room temperature to 100 °C, in the presence of a metal reducing agent such as iron or zinc, in the presence of an inorganic salt such as ammonium chloride, in a suitable solvent such as an alcohol optionally mixed with water, such as a mixture of ethanol and water. Alternatively, at a suitable temperature (such as room temperature), in the presence of a suitable catalyst (such as palladium on carbon (Pd / C)), in a suitable solvent (such as ethyl acetate or methanol), under H₂ pressure (such as 1 bar to 3 bar);

[0259] Step 4: At suitable temperatures such as 80 °C and 130 °C, in the presence of a suitable palladium catalyst such as tris(dibenzylideneacetone)dipalladium and a ligand such as Xantphos, in the presence of an inorganic base such as cesium carbonate, in a suitable solvent such as 1,4-di alkane;

[0260] Step 5: At a suitable temperature of 40 °C to 100 °C, in the presence of an acid such as hydrochloric acid, in a suitable solvent such as water or acetonitrile;

[0261] Step 6: At a suitable temperature from room temperature to 80 °C, in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of a Lewis acid such as zinc chloride or a Brønsted acid such as acetic acid, in a suitable solvent such as dichloromethane, 1,2-dichloroethane or methanol;

[0262] Step 7: At a suitable temperature of 0 °C to 70 °C, in the presence of a reagent such as triphosgene or carbonyldiimidazole, in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, in a suitable aprotic solvent such as dichloromethane or tetrahydrofuran;

[0263] Step 8: When R 3 is not hydrogen; at a suitable temperature from 0 °C to room temperature, in the presence of a suitable base such as NaH, in the presence of a suitable electrophile such as C 1-6 alkyl iodide or C 3-6 alkyl iodide substituted by C 1-6 cycloalkyl;

[0264] Step 9: When PG = Boc, at a suitable temperature in the range of 0 °C to 40 °C (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 known to those skilled in the art can be used.

[0265] Step 10: In the case of reductive amination reactions using aldehydes or ketones: at a suitable temperature in the range of room temperature to 70 °C, in the presence of a suitable reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride), in a suitable solvent (such as methanol or dichloromethane or 1,2-dichloroethane), optionally in the presence of zinc chloride or acetic acid or sodium acetate; in the case of alkylation reactions using LG-Y: at a suitable temperature (such as room temperature), in the presence of a suitable deprotonating inorganic base (such as sodium hydride or potassium carbonate or an amine base such as triethylamine), in a suitable aprotic solvent (such as dimethylformamide or dimethyl sulfoxide or acetonitrile).

[0266] Scheme 2

[0267] In Scheme 2, X 2 represents fluorine, chlorine, bromine or iodine; all other variables are defined according to the scope of the present invention.

[0268]

[0269] In Scheme 2, the following conditions are applied: at a suitable temperature such as room temperature, in the presence of a suitable condensing reagent such as 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other compounds known in the art, in the presence of a base such as N,N-diisopropylethylamine, in a suitable solvent such as dimethylformamide, in the presence of the amine HNR xa R xb ; alternatively, the acyl chloride can be prepared by reacting a carboxylic acid with oxalyl chloride or thionyl chloride, optionally in a halogenated solvent (such as dichloromethane), at a temperature in the range of 0 °C to room temperature. Then the intermediate acyl chloride can be reacted with the amine HNR xa R xb optionally in a solvent (such as dichloromethane) and optionally in the presence of a tertiary amine (such as N,N-diisopropylethylamine);

[0270] Scheme 3

[0271] In Scheme 3; PG represents a suitable protecting group, such as tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyl; X 1represents a halogen such as chlorine, bromine or iodine, or another leaving group such as mesylate or tosylate; X 2 represents fluorine, chlorine, bromine or iodine; all other variables are defined according to the scope of the present invention.

[0272]

[0273] Generally, wherein R 1a is limited to -C(=O)-NR xa R xb The compound of can be prepared according to the following Reaction Scheme 3.

[0274] In Scheme 3, the following reaction conditions are applied:

[0275] Step 1: When R 2b is hydrogen, at a suitable temperature from room temperature to 80 °C, in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane, 1,2-dichloroethane or methanol, optionally in the presence of zinc(II) chloride or acetic acid or sodium acetate;

[0276] When R 2b is C 1-4 alkyl, at a suitable temperature from 60 - 120 °C, in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, in a suitable solvent such as toluene or methanol, in the presence of zinc(II) chloride or titanium(IV) tetraisopropoxide.

[0277] Step 2: At a suitable temperature from room temperature to 100 °C, in the presence of a metal reducing agent such as iron or zinc, in the presence of an inorganic salt such as ammonium chloride, in a suitable solvent such as ethanol and water;

[0278] Step 3: At a suitable temperature from 0 °C to 70 °C, in the presence of a reagent such as triphosgene or carbonyldiimidazole, in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, in a suitable aprotic solvent such as dichloromethane or tetrahydrofuran;

[0279] Step 4: At a suitable temperature (such as 80 °C and 130 °C), in the presence of a suitable catalyst (such as copper (Cu)), in the presence of a base (such as potassium carbonate or cesium carbonate), in a suitable aprotic solvent (such as dimethylformamide, etc.); alternatively, a copper(I) source (such as CuI) can be used, 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 from 80 °C to 150 °C;

[0280] Step 5: At a suitable temperature such as room temperature, in the presence of a suitable condensing reagent such as 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or other compounds known in the art, in the presence of a base such as N,N-diisopropylethylamine, in a suitable solvent such as dimethylformamide, in the presence of the amine HNR xa R xb ; Alternatively, the acyl chloride can 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 the range of 0 °C to room temperature. Then the intermediate acyl chloride can react with the amine HNR xa R xb , optionally in a solvent (such as dichloromethane) and optionally in the presence of a tertiary amine (such as N,N-diisopropylethylamine).

[0281] Step 6: When R 2a is a cycloalkyl, C 3-6 alkyl or C 1-4 alkyl substituted with one, two or three halogen substituents, at a suitable temperature in the range of room temperature to 100 °C, in the presence of an alkyl or alkenyl boronic acid or boronate or potassium alkyltrifluoroborate, in the presence of a suitable base such as potassium carbonate or cesium carbonate, in the presence of a suitable catalyst such as [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)Cl2), in a suitable solvent such as di 1-4 alkane or dimethylformamide and water; Alternatively, when R is Me, a boron-containing reagent (such as trimethylcyclotriboroxane) can be used in a suitable solvent (such as di 2a alkane or dimethylformamide and water), in the presence of an inorganic base such as potassium carbonate, in the presence of a suitable catalyst such as Pd(dppf)Cl2, at a reaction temperature of 80 °C to 120 °C; The additional step for achieving double bond reduction to obtain R

[0282] (when using an alkenyl boronic acid or boronate) is that for C 2 cycloalkyl, C 3-6 alkyl or C 1-4 alkyl substituted with one, two or three halogen substituents: at a suitable temperature (such as room temperature), in the presence of a suitable catalyst (such as palladium on carbon (Pd / C)), in a suitable solvent (such as methanol), under H2 pressure (such as 1 bar to 3 bar), optionally in the presence of a base (such as triethylamine). 1-4

[0283] Scheme 4

[0284] ​In Scheme 4, PG represents a suitable protecting group, such as a suitable protecting group, for example, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyl; PG 1 represents a suitable protecting group, for example, tert-butyldimethylsilyl; all other variables are defined according to the scope of the present invention.

[0285]

[0286] In Scheme 4, the following reaction conditions are applied:

[0287] Step 1: When PG 1 is a silyl-containing protecting group; at a suitable temperature, for example, 0 °C to 80 °C, in a suitable solvent such as N,N-dimethylformamide, in the presence of a silylating agent such as tert-butyldimethylsilyl chloride, in the presence of a base such as imidazole;

[0288] Step 2: At a suitable temperature, for example, 80 °C to 110 °C, in a suitable solvent such as toluene, in the presence of a suitable acyl azide forming agent such as diphenylphosphoryl azide, in the presence of a suitable alcohol such as tert-butanol, 9-fluorenylmethanol, benzyl alcohol or 4-methoxybenzyl alcohol;

[0289] Step 3: At a suitable temperature, for example, 0 °C to 50 °C, in a suitable solvent such as tetrahydrofuran, in the presence of a deprotecting reagent such as tetrabutylammonium fluoride, optionally in the presence of acetic acid;

[0290] Step 4: At a suitable temperature, for example, 0 °C to room temperature, in a suitable solvent such as dichloromethane or acetonitrile, in the presence of a suitable oxidant such as 2,2,6,6-tetramethylpiperidin-1-oxyl group and (diacetoxyiodo)benzene, optionally in the presence of NaHCO3;

[0291] Step 5: At a suitable temperature, such as room temperature to 100 °C, in a suitable solvent such as tetrahydrofuran or 2-methyltetrahydrofuran, in the presence of a suitable Lewis acid, for example, titanium(IV) isopropoxide, in the presence of a suitable sulfinamide, for example, (R)-2-methyl-2-propanesulfinamide or (S)-2-methyl-2-propanesulfinamide or methyl-2-propanesulfinamide;

[0292] Step 6: At a suitable temperature, such as -78 °C to room temperature, in a suitable solvent such as tetrahydrofuran or diethyl ether, in the presence of an organometallic reagent such as a Grignard reagent (R 5a MgX);

[0293] Step 7: At a suitable temperature, such as 0 °C to room temperature, in a suitable solvent such as 1,4-di In an alkane, in the presence of an acid such as hydrochloric acid; alternatively, deprotection can be carried out as follows: at a suitable temperature such as 0 °C to 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.

[0294] It should be understood that in the presence of suitable functional groups, compounds of various formulas or any intermediates used in their preparation can be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction or cleavage reactions. Specific substitution methods include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

[0295] The compounds of formula (I) can be synthesized in the form of a racemic mixture of enantiomers, and the mixture can be separated from each other according to the resolution methods known in the art. The racemic compounds of formula (I) containing a basic nitrogen atom can be converted into the corresponding diastereomeric salt form by reaction with a suitable chiral acid. Subsequently, the diastereomeric salt form is separated, for example, by selective or fractional crystallization, and the enantiomers are released therefrom by a base. An alternative way to separate the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemical isomer forms can also be derived from the corresponding pure stereochemical isomer forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0296] In the preparation of the compounds of the present invention, it may be necessary to protect the terminal functional groups of the intermediates (e.g., primary or secondary amines). The need for such protection will vary depending on the nature of the terminal functional group and the conditions of the preparation method. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Those skilled in the art can readily determine the need for such protection.

[0297] Pharmacology

[0298] It has been found that the compounds of the present invention block the interaction of menin with the MLL protein and the oncogenic MLL fusion protein itself, or can undergo metabolism in vivo to a (more) active form (prodrug). Accordingly, the compounds of the present invention and pharmaceutical compositions containing such compounds can be used for the treatment or prevention, particularly the treatment of diseases such as cancer, including but not limited to leukemia.

[0299] Specifically, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing cancer. According to one embodiment, cancers that can benefit from treatment with the menin / MLL inhibitors of the present invention include leukemia. In some embodiments, these leukemias include acute leukemia, chronic leukemia, myeloid leukemia, myelocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemia showing HOX / MEIS1 gene expression signature, and the like.

[0300] Specifically, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing leukemia, particularly leukemia with nucleophosmin (NPM1) mutation, such as NPM1c.

[0301] Specifically, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing AML, particularly AML with nucleophosmin (NPM1) mutation (i.e., NPM1 mut AML), more particularly AML with abstract NPM1 mutation.

[0302] Specifically, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing MLL-rearranged leukemia, particularly MLL-rearranged AML or ALL.

[0303] Specifically, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing leukemia with MLL gene alteration, particularly AML or ALL with MLL gene alteration.

[0304] In particular, the compounds and pharmaceutical compositions thereof according to the present invention can be used for treating or preventing leukemia showing NPM1 gene mutation and / or mixed lineage leukemia gene (MLL; MLL1; KMT2A) alteration, mixed lineage leukemia (MLL), MLL-related leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia, leukemia related to MLL, rearrangement / alteration of the MLL gene or rearrangement / alteration of the MLL gene, acute leukemia, chronic leukemia; and hematological cancers of a subject for inhibiting menin-MLL interaction, wherein the MLL fusion protein target gene is human HOX or MEIS1.

[0305] Accordingly, the present invention relates to compounds of formula (I), their tautomeric and stereoisomeric forms, and their pharmaceutically acceptable salts and solvates for use as a medicament.

[0306] The invention further relates to the use of a compound of formula (I) according to the invention, a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof for the manufacture of a medicament.

[0307] The invention further relates to a compound of formula (I) according to the invention, a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof for treating, preventing, ameliorating, controlling or reducing the risk of a disorder in a mammal (including a human) associated with the interaction of menin with MLL protein and oncogenic MLL fusion proteins, wherein the treatment or prevention of the disorder affects or promotes by blocking the interaction of menin with MLL protein and oncogenic MLL fusion proteins.

[0308] Furthermore, the invention relates to the use of a compound of formula (I) according to the invention, a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt, solvate or pharmaceutical composition thereof for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of a disorder in a mammal (including a human) associated with the interaction of menin with MLL protein and oncogenic MLL fusion proteins, wherein the treatment or prevention of the disorder affects or promotes by blocking the interaction of menin with MLL protein and oncogenic MLL fusion proteins.

[0309] The invention further relates to a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of any one of the diseases mentioned above.

[0310] The invention further relates to a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of any one of the diseases mentioned above.

[0311] The invention further relates to the use of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of any one of the disorders mentioned above.

[0312] The compounds of the invention can be administered to a mammal, preferably a human, for the treatment or prevention of any one of the diseases mentioned above.

[0313] In view of the utility of the compounds of formula (I), their tautomeric and stereoisomeric forms, as well as their pharmaceutically acceptable salts and solvates, a method for treating warm-blooded animals (including humans) suffering from any one of the diseases mentioned above is provided.

[0314] The method comprises administering (i.e., systemically or locally) a therapeutically effective amount of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, to a warm-blooded animal, including a human.

[0315] Accordingly, the present invention also relates to a method for treating or preventing any of the diseases mentioned above, which method comprises administering a therapeutically effective amount of a compound according to the present invention to a patient in need thereof.

[0316] Those skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is an amount sufficient to have a therapeutic activity, and this amount will vary particularly according to the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. The effective daily dose for treatment will be from about 0.005 mg / kg to 100 mg / kg. The amount of the compound according to the present invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect can vary according to the circumstances, for example, according to the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated.

[0317] The present invention also provides a composition for preventing or treating the disorders mentioned herein. The composition comprises a therapeutically effective amount of a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0318] Although the active ingredient can be administered alone, it is preferably in the form of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition, which pharmaceutical composition comprises a compound according to the present invention and 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 harmless to its recipient.

[0319] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administering a single pharmaceutical dosage formulation containing a compound according to the present invention and one or more additional therapeutic agents, and administering the compound according to the present invention and each additional therapeutic agent in their respective separate pharmaceutical dosage formulations.

[0320] Accordingly, one embodiment of the present invention relates to a product which comprises a compound according to the present invention as a first active ingredient and one or more anti-cancer agents as additional active ingredients, for use simultaneously, separately or sequentially in the treatment of a patient suffering from cancer as a combination formulation.

[0321] One or more other agents and the compounds according to the invention can be administered simultaneously (e.g., in a separate or single composition) or sequentially in any order. In the latter case, two or more compounds will be administered over a period of time and in an amount and manner sufficient to ensure an advantageous or synergistic effect. It should be understood that the preferred method and order of administration of each component of the combination, as well as the corresponding dosage and regimen, will depend on the particular other agent and the compound of the invention being administered, their route of administration, the specific medical condition, in particular the tumor being treated and the particular host being treated.

[0322] The following examples further illustrate the invention.

[0323] Examples

[0324] Several methods for preparing the compounds of the invention are illustrated in the following examples. Unless otherwise stated, all starting materials are commercially available and can be used without further purification, or alternatively can be synthesized by those skilled in the art using well-known methods.

[0325]

[0326]

[0327] As will be understood by those skilled in the art, the compounds synthesized using the shown schemes can exist as solvates, such as hydrates, and / or contain residual solvent or minor impurities. Compounds or intermediates isolated as salt forms can be of integer stoichiometric, i.e., mono- or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the following experimental section is represented as an "HCl salt" without indicating the equivalent amount of HCl, this means that the equivalent amount of HCl has not been determined. The same principle applies to all other salt forms mentioned in the experimental section, such as "oxalate", "HCOOH salt" ("formate") or

[0328] When the absolute stereochemistry is known when separating a mixture, or when only one enantiomer is obtained and the absolute stereochemistry is known, the stereochemical configuration at the center in some compounds can be named "R" or "S"; for certain compounds, when the absolute stereochemistry is not determined (even if the bonds are clearly stereodrawn), the stereochemical configuration at the designated center is designated as "*R" or "*S", even though the compound itself has been isolated as a single stereoisomer and is optically pure. In the case of converting a compound designated as "*R" into another compound, the "*R" of the resulting compound indicates its origin from the starting material.

[0329] For example, it is clear that Compound 16

[0330] is

[0331]

[0332] For compounds in which the stereochemistry of two stereocenters is represented by * (e.g., *R or *S), the absolute stereochemistry of the stereocenters is undetermined (even if the bonds are drawn stereospecifically), although the compound itself has been isolated as a single stereoisomer and is optically pure. In such cases, the configuration of the first stereocenter represented by * in the same compound is independent of the configuration of the second stereocenter represented by *. For such molecules, "*R" or "*S" is randomly assigned. Similarly, for compounds in which the stereochemistry of three stereocenters is represented by * (e.g., *R or *S), the absolute stereochemistry of the stereocenters is undetermined (even if the bonds are drawn stereospecifically), although the compound itself has been isolated as a single stereoisomer and is optically pure. In such cases, the configuration of the stereocenters represented by * in the same compound is independent of the configuration of the other stereocenters represented by *. For such molecules, "*R" or "*S" is randomly assigned.

[0333] For example, for Compound 26

[0334]

[0335] This means that the compound is

[0336]

[0337] One skilled in the art will recognize that the above paragraphs regarding stereochemistry also apply to intermediates.

[0338] One skilled in the art will recognize that even when not explicitly mentioned in the following experimental protocols, after purification by column chromatography, the desired fractions are collected and the solvent is evaporated.

[0339] In the absence of indication of stereochemistry, this means that it is a mixture of stereoisomers or of undetermined stereochemistry, unless otherwise specified or clear from the context.

[0340] Unless otherwise specified, when a stereocenter is denoted by "RS", this means that a racemic mixture is obtained at the specified center.

[0341] A double bond denoted by EZ means that the compound / intermediate is obtained as a mixture of the E isomer and the Z isomer.

[0342] Preparation of intermediates and compounds

[0343] For intermediates that are used as crude products or as partially purified intermediates in the next reaction step, in some cases, the molar amount of such intermediates is not mentioned in the next reaction step, or alternatively the estimated or theoretical molar amount of such intermediates in the next reaction step is indicated in the following reaction scheme.

[0344] Preparation of Intermediate 1 :

[0345]

[0346] 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 °C for 3 h. After cooling to room temperature, the mixture was poured into 100 mL of water. The precipitated solid was filtered and dried to give the intermediate as a brown solid (about 12.3 g), which was dissolved in THF (75 mL) and mixed with a solution of NaIO4 (2.9 g, 135.6 mmol) in H2O (75 mL) at room temperature. After stirring for 20 h, the reaction mixture was diluted with 100 mL of water and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc / hexane (starting from 0% EtOAc to 50% EtOAc) to give intermediate 1 as a yellow solid (6.0 g, 57.4% yield)

[0347] Preparation of Intermediate 2 :

[0348]

[0349] To a mixture of intermediate 1 (4.3 g, 17.684 mmol) and tert-butyl (trans-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 at room temperature for 2 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (120 mL * 3). The combined organic phases were washed with brine (300 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 25% EtOAc / hexane to give intermediate 2 as a yellow solid (1.3 g, 18% yield).

[0350] Synthesize the following intermediates by a method similar to that described for Intermediate 2

[0351]

[0352]

[0353] Preparation of Intermediate 31 :

[0354]

[0355] A solution of intermediate 54 (400 mg, 1.15 mmol) and tert-butyl (3-aminocyclobutyl)carbamate (CAS: 871014-19-6) (258 mg, 1.38 mmol) in methanol (10 mL) was stirred at room temperature for 3 h. The reaction 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 in vacuo to give a yellow oil, which was dissolved in methanol (10 mL). Sodium cyanoborohydride (200 mg, 3.2 mmol) and zinc(II) chloride (144 mg, 1.06 mmol) were added to the mixture. The solution was stirred at room temperature for 2 h. 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 anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 50% EA / petroleum ether to give intermediate 31 as a yellow solid (470 mg, 90% purity, 79.9% yield).

[0356] Preparation of Intermediate 23 :

[0357]

[0358] To a mixture of intermediate 22 (500 mg, 1.329 mmol) in DCM (10 mL) at room temperature was added tert-butyl (3-aminocyclobutyl)carbamate (297 mg, 1.595 mmol) and 0.1 mL of acetic acid. And the mixture was stirred at room temperature for 2 h. Then, NaBH3CN (167 mg, 2.658 mmol) was added. And the mixture was stirred at room temperature for an additional 3 h. The mixture was diluted with 100 mL of water and extracted three times with EtOAc (100 mL). The combined layers were washed with brine and dried over Na2SO4, filtered and concentrated, and the residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc / petroleum ether to give intermediate 23 as a yellow solid (501 mg, 68% yield).

[0359] Preparation of Intermediate 3 :

[0360]

[0361] To a solution of intermediate 2 (3.04 g, 7.58 mmol) in ethanol (50 mL) and water (10 mL) was added ammonium chloride (2.6 g, 37.88 mmol) and iron powder (2.12 g, 37.88 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was filtered through a short pad of , diluted with water (100 mL), and extracted three times with EtOAc (30 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give intermediate 3 (3.04 g, crude) as a yellow solid.

[0362] Synthesize the following intermediates by a method similar to that described for Intermediate 3

[0363]

[0364] Preparation of Intermediate 4 :

[0365]

[0366] 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 to room temperature, the precipitate was filtered off and dried to give intermediate 4 (2.2 g, 91% yield) as a white solid.

[0367] Synthesize the following intermediates by a method similar to that described for Intermediate 4

[0368]

[0369] Preparation of Intermediate 5 :

[0370]

[0371] Under nitrogen, 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) were added K2CO3 (2.12 g, 0.73 mmol) and copper powder (328 mg, 5.11 mmol). After stirring at 120 °C for 16 h, the mixture was cooled to room temperature and used in the next step without further purification.

[0372] Synthesize the following intermediates by a method similar to that described for Intermediate 5

[0373]

[0374] Preparation of Intermediate 6 :

[0375]

[0376] To the solution of crude intermediate 5 in DMF, HATU (3.87 g, 10.18 mmol), DIEA (1.75 g, 13.57 mmol) and N-ethylpropane-2-amine (1.97 g, 22.62 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, the filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with 0% to 5% MeOH / DCM to obtain intermediate 6 as a yellow solid.

[0377] Synthesize the following intermediates by a method similar to that described for Intermediate 6

[0378]

[0379] Preparation of Intermediate 7 :

[0380]

[0381] Under nitrogen atmosphere, intermediate 6 (1.2 g, 1.9 mmol), trimethylboroxine (2.3 g, 17.75 mmol) and K2CO3 (736 mg, 5.32 mmol) were added to 1,4-dihydro- ... Pd(dppf)Cl2(130mg, 0.018mmol) was added to a solution of 1,2-dihydro-1,4-dihydro-1,4-dihydro-2-nitropropene (50mL) and water (10mL). The mixture was then heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (100mL), and extracted three times with DCM (30mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with 0% to 100% ethyl acetate / petroleum ether to obtain intermediate 7 (0.58g, 56.5 yield) as a yellow solid.

[0382] Synthesize the following intermediates by a method similar to that described for Intermediate 7

[0383]

[0384] Preparation of Intermediate 8 :

[0385]

[0386] To a solution of intermediate 7 (100 mg, 0.18 mmol) in dry DMF (10 mL) at 0 °C under a nitrogen atmosphere was added sodium hydride (60% dispersed in mineral oil) (21 mg, 0.54 mmol). The mixture was stirred at 0 °C for 30 min, followed by the addition of methyl iodide (76 mg, 0.54 mmol). The resulting mixture was further stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted three times with EtOAc (20 mL). 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 0% to 10% methanol / dichloromethane, to give intermediate 8 (60 mg, 60% yield) as a yellow solid.

[0387] Synthesize the following intermediates by a method similar to that described for Intermediate 8

[0388]

[0389] Preparation of Intermediate 33 :

[0390]

[0391] To a solution of intermediate 32 (100 mg, 90% purity, 0.17 mmol) in THF (3 mL) was added NaH (60% dispersed in mineral oil) (20 mg, 0.5 mmol). The solution was stirred at 0 °C for 30 minutes. Then methyl iodide (49 mg, 0.34 mmol) was added to the reaction mixture and stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 (anhydrous) and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with 50% EA / petroleum ether, to give intermediate 33 (50 mg, 90% purity, 48.7% yield) as a white solid.

[0392] Preparation of Intermediate 17 :

[0393]

[0394] 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 overnight at 120 °C. After cooling to room temperature, water (30 mL) was added, and the mixture was extracted three times with EtOAc (50 mL). 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 0% to 6% EtOAc / petroleum ether, to give Intermediate 17 as a white solid (3.3 g, 65.8% yield).

[0395] Preparation of Intermediate 19 :

[0396]

[0397] At 0 °C, oxalyl chloride (2.493 g, 19.642 mmol) was added dropwise to a solution of 5-fluoro-2-iodobenzoic acid (5 g, 17.857 mmol) in DCM (100 mL), followed by DMF (130 mg, 1.786 mmol). After stirring for 2 hours at 0 °C, the mixture was concentrated to remove the solvent. The residue was dissolved in DCM (100 mL) and added dropwise at 0 °C to a mixture of diisopropylamine (2.761 mL, 19.642 mmol) and triethylamine (6.932 mL, 53.570 mmol) in DCM (100 mL). The resulting mixture was further stirred for 4 hours while gradually warming to room temperature. Then, water (100 mL) was added, the organic phase was separated, and the aqueous phase was extracted twice with DCM (200 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was further purified by silica gel column chromatography, eluting with 10% EtOAc / petroleum ether, to give Intermediate 19 as a pale yellow solid (4.9 g, yield: 80%).

[0398] Preparation of Intermediate 29 :

[0399]

[0400] At 0 °C, oxalyl chloride (9.97 g, 78.57 mmol) was added dropwise to a solution of 5-fluoro-2-iodobenzoic acid (20 g, 71.43 mmol) in DCM (150 mL), and then DMF (499 mg, 6.82 mmol) was added dropwise. After stirring at 0 °C for 2 hours, the mixture was concentrated to remove the solvent. The residue was dissolved in 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 °C. The resulting mixture was further stirred for 4 hours while gradually warming to room temperature. Then, water (200 mL) was added, the organic phase was separated, and the aqueous phase was extracted three times with EA (500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a crude product, which was further purified by silica gel column chromatography, eluting with 10% EtOAc / petroleum ether, to give Intermediate 29 as a white solid (16.7 g, yield: 69%).

[0401] Preparation of Intermediate 21 :

[0402]

[0403] At room temperature, Cs2CO3 (9.764 g, 29.966 mmol), Xantphos (0.866 g, 1.498 mmol), and Pd2(dba)3 (0.686 g, 0.749 mmol) were added to a mixture of Intermediate 20 (3 g, 14.983 mmol) and Intermediate 19 (6.278 g, 17.980 mmol) in dodecane (50 mL). The mixture was stirred continuously at 120 °C for 20 hours. After cooling to room temperature, the mixture was diluted with 300 mL of water and extracted three times with EtOAc (500 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc / petroleum ether, to give Intermediate 21 as a yellow oil (5.0 g, yield 83%).

[0404] Synthesize the following intermediates by a method similar to that described for Intermediate 21

[0405]

[0406] Preparation of Intermediate 30 :

[0407]

[0408] At room temperature, Cs2CO3 (14.823 g, 45.494 mmol), Xantphos (1.315 mg, 2.275 mmol), and Pd2(dba)3 (1.041 g, 1.137 mmol) were added 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 dichloromethane (50 mL). The mixture was stirred at 120 °C for 20 h. The mixture was diluted with 300 mL of water and extracted three times with EtOAc (500 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc / petroleum ether, to afford the Intermediate as a yellow oil (6.5 g, 70% yield).

[0409] Preparation of Intermediate 22 :

[0410]

[0411] At room temperature, hydrochloric acid (10 mL, 4 N in water) was added to a mixture of Intermediate 21 (5 g, 11.831 mmol) in acetonitrile (10 mL). The mixture was stirred at 50 °C for 2 h. The mixture was diluted with 300 mL of water and extracted three times with EtOAc (300 mL). The combined phases were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc / petroleum ether, to afford Intermediate 22 as a yellow solid (3.6 g, 87.6% yield).

[0412] Synthesize the following intermediates by a method similar to that described for Intermediate 22

[0413]

[0414] Preparation of Intermediate 54 :

[0415]

[0416] ​At room temperature, hydrochloric acid (10 mL, 4 N in water) was added to a mixture of Intermediate 30 (6.5 g, 16.536 mmol) in acetonitrile (10 mL). The mixture was stirred continuously at 50 °C for 2 h. The mixture was diluted with 300 mL of water and extracted three times with EtOAc (300 mL). The combined layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated. Silica column chromatography was performed, eluting with 0% to 50% EtOAc / petroleum ether to give Intermediate 54 (4.7 g, 86.2% yield) as a yellow solid.

[0417] Preparation of Intermediate 24 :

[0418]

[0419] To a solution of Intermediate 23 (400 mg, 0.68 mmol) and triethylamine (353 mg, 3.41 mmol) in DCM (20 mL) was added dropwise a 20 mL DCM solution of triphosgene (128 mg, 0.41 mmol) over 20 min. After stirring at 20 °C for 5 h, the mixture was concentrated to give a crude product, which was purified by silica column chromatography, eluting with 50% to 100% EtOAc / petroleum ether to give Intermediate 24 (207 mg, 55.07% yield) as a yellow solid.

[0420] Synthesize the following intermediates by a method similar to that described for Intermediate 24

[0421]

[0422]

[0423] Preparation of Intermediate 32 :

[0424]

[0425] Under a nitrogen atmosphere at 0 °C, bis(trichloromethyl) carbonate (67 mg, 0.23 mmol) was added to a solution of Intermediate 31 (250 mg, 90% purity, 0.45 mmol) and TEA (136 mg, 1.35 mmol) in THF (10 mL) over 0.5 h. The resulting mixture was stirred at 30 °C for 2 h. The reaction mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica column chromatography, eluting with 50% EA / petroleum ether to give Intermediate 32 (130 mg, 90% purity, 49.4% yield) as a yellow solid.

[0426] Preparation of Intermediate 41 :

[0427]

[0428] Under nitrogen, Pd / C (10% w / w) (50 mg) was added to a solution of intermediate 40 (100 mg, 0.410 mmol) in methanol (5 mL). And the mixture was kept at room temperature for 16 h under a pressure of 1 bar of H2 gas. The reaction was carried out filtered, evaporated to dryness, and the intermediate 41 (85 mg) as a crude product was obtained, which was used in the next step without further purification.

[0429] Preparation of Intermediate 35 :

[0430]

[0431] 1M aqueous hydrochloric acid (1.3 mL) was added to a solution of compound 60 (200 mg, 0.32 mmol) in acetonitrile (5 mL), and the mixture was stirred at 50 °C for 10 min. After cooling to room temperature, 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 twice with EtOAc (10 mL). The combined organic phases were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 5% MeOH / DCM, to give intermediate 35 (130 mg, 70.31% yield) as a white solid.

[0432] Preparation of Compound 1 :

[0433]

[0434] Intermediate 7 (160 mg, 0.29 mmol) was added to a solution of 4N HCl in 1,4- dioxane (10 mL), and the mixture was stirred at room temperature for 2 h. Then the mixture was basified to pH 10 with aqueous NaOH solution (1M). The mixture was extracted three times with DCM (20 mL). 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 0% to 10% methanol / dichloromethane, to give compound 1 (54 mg, 43% yield) as a yellow oil.

[0435] Synthesize the following compounds by a method similar to that described for Compound 1

[0436]

[0437] Preparation of Compound 3 :

[0438]

[0439] To a solution of Compound 1 (50 mg, 0.11 mmol) in DCE (10 mL) was 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 0% to 10% methanol / dichloromethane to give Compound 3 as a yellow solid (43 mg, 73% yield).

[0440] Synthesize the following compounds by a method similar to that described for Compound 3

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] Preparation of Compound 8 :

[0447]

[0448] 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 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO 4(s) dried and filtered. The residue was purified by preparative HPLC (column: SunFire C18 150 * 19 mm * 5 um, mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, gradient condition: 25% B to 65% B) to give Compound 8 as a white solid (15 mg, 21.1% yield).

[0449] Preparation of Compound 9 :

[0450]

[0451] Under an ice-water bath, 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) were added to a solution of Compound 1 (200 mg, 0.39 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 4 hours. It was poured into saturated aqueous NaHCO3 and extracted twice with DCM (10 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography, eluting with 0% to 5% methanol / dichloromethane to give the desired product (200 mg) as a white solid. The product was further purified by chiral preparative HPLC (column: IE 4.6 cm I.D. * 25 cm L, 5 um; mobile phase: MeOH:DCM:DEA = 90:10:0.2, 30 mL / min) to give Compound 9 (90 mg, 22.58% yield) as a white solid.

[0452] Preparation of Compound 11 :

[0453]

[0454] In a sealed tube, NaBH3CN (513 mg, 7.99 mmol) and ZnCl 2( (371 mg, 2.66 mmol) were added to a solution of Compound 1 (1.3 g, 2.66 mmol) and tetrahydro-4H-pyran-4-one (327 mg, 3.19 mmol) in methanol (5 mL). After stirring at 65 °C for 16 h, the mixture was filtered, and the filtrate was concentrated to obtain a crude compound, which was purified by silica gel column chromatography, eluting with 0% to 12% methanol / dichloromethane solution to give the desired product (1.3 g) as a white solid. The product was further purified by chiral preparative HPLC (column: IE 5.0 cm I.D. * 25 cm L, 10 um; mobile phase: MeOH:DCM:DEA = 90:10:0.2, 30 mL / min; temperature: 38 °C) to give Compound 11 (820 mg, 58.06% yield) as a white solid.

[0455] Preparation of Compound 12 :

[0456]

[0457] At room temperature, cyclobutanecarbaldehyde (18 mg, 0.216 mmol) was added to a mixture of compound 1 (50 mg, 0.108 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc)3 (68 mg, 0.324 mmol) was added. The mixture was stirred at room temperature for an additional 3 h. The mixture was diluted with 30 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% ethyl acetate / petroleum ether, to give the product (40 mg) as a yellow oil. The product was further purified by preparative 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 to 65% B) to give compound 12 (15 mg, yield 25.9%) as a white solid.

[0458] Preparation of Compound 13 :

[0459]

[0460] At room temperature, pivalaldehyde (19 mg, 0.216 mmol) was added to a mixture of compound 1 (50 mg, 0.108 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc)3 (68 mg, 0.324 mmol) was added to the mixture. The mixture was stirred at room temperature for an additional 3 h. The mixture was diluted with 30 mL of water and extracted with EtOAc (30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 50% ethyl acetate / petroleum ether, to give the product (30 mg) as a yellow oil. The product was further purified by preparative 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 to 65% B) to give compound 13 (10 mg, purity 95.7%, yield 18%).

[0461] Preparation of Compound 14 :

[0462]

[0463] Under ice-water bath cooling, tetrahydro-2H-pyran-4-carbaldehyde (18 mg, 0.15 mmol), acetic acid (0.05 mL), and NaBH(OAc)3 (67 mg, 0.30 mmol) were added to a solution of compound 59 (50 mg, 0.10 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 4 h. It was poured into saturated aqueous NaHCO3 and extracted twice with DCM (10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography, eluting with 0% to 8% methanol / dichloromethane, to afford compound 14 (12 mg, 22% yield) as a white solid.

[0464] Preparation of Compound 10 :

[0465]

[0466] Formaldehyde (68 mg, 0.84 mmol, 37% w / w aqueous solution) and NaBH(OAc)3 (54 mg, 0.25 mmol) were added to a solution of compound 3 (50 mg, 0.09 mmol) in methanol (2 mL) while cooling in an ice-water bath. The reaction mixture was stirred at room temperature for 4 h, then poured into saturated aqueous NaHCO3 and extracted twice with DCM (20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography, eluting with 0% to 12% methanol / dichloromethane, to afford compound 10 (12 mg, 24.14% yield) as a yellow solid.

[0467] Preparation of Compounds 15, 16, and 17 :

[0468] Compound 15

[0469] Compound 16

[0470] Compound 17

[0471] 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) and ZnCl2 (65.119 mg, 0.478 mmol). The mixture was stirred at 60 °C for 0.5 h, then NaBH3CN (40.033 mg, 0.637 mmol) was added, and the mixture was stirred at 50 °C for 3 h. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO3 and extracted three times with DCM (10 mL). 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 5 μm, 19*150 mm, mobile phase A: water (0.1% NH4OH + 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient conditions: 50% B to 60% B) to give compound 15 (130 mg, 71% yield) as a yellow solid.

[0472] Compound 15 (110 mg) was further purified by preparative SFC (stationary phase: column CHIRALPAK AD-H 5 μm 10*250 mm, mobile phase: A: supercritical CO2, B: MeOH + 0.1% NH4OH, A:B = 90:10, 11 mL / min, column temperature: 45 °C).

[0473] The first fraction was collected as compound 16 (35 mg, 32% yield), and the second fraction was collected as compound 17 (32 mg, 29% yield).

[0474] Preparation of Compounds 26, 27, 33, and 34 :

[0475] Compound 26

[0476] Compound 27

[0477] Compound 33

[0478] Compound 34

[0479] At room temperature, 3-methyltetrahydro-4H-pyran-4-one (CAS: 119124-53-7) (514.195 mg, 4.505 mmol) and ZnCl2 (306.991 mg, 2.252 mmol) were added to a mixture of Compound 1 (660 mg, 1.502 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 0.5 h. Then, NaBH3CN (188.727 mg, 3.003 mmol) was added, and the mixture was further stirred at 50 °C for 2 h. The mixture was washed with saturated aqueous NaHCO3 and brine, dried, filtered, and concentrated. The mixture was purified by preparative HPLC (column: Waters XBridge C8 5 μm, 19*150 mm, mobile phase A: water (0.1% NH4OH + 10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient condition: 29% B to 34% B). The first fraction and the second fraction were collected separately and further purified. The first fraction was further purified by preparative SFC (stationary phase: column CHIRALPAK AD 5 μm 10*250 mm, mobile phase: A: supercritical CO2, BEtOH:MeOH (3:1) + 0.1% NH4OH, A:B = 85:15, 11 mL / min, column temperature: 45 °C), and the first peak was collected as Compound 26 and the second peak was collected as Compound 27. The second fraction was further purified by preparative SFC (stationary phase: column CHIRALPAK AD-H 5 μm 10*250 mm, mobile phase: A: supercritical CO2, B EtOH + 0.1% NH4OH, A:B = 88:12, 11 mL / min, column temperature: 45 °C), and the first peak was collected as Compound 33 and the second peak was collected as Compound 34.

[0480] Synthesize the following compounds by a method similar to that described for Compound 15

[0481]

[0482]

[0483]

[0484]

[0485] Preparation of Compound 21 :

[0486]

[0487] A mixture of intermediate 32 (50 mg, 0.09 mmol) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was diluted with aqueous NaOH solution (1 M, 50 mL) and extracted three times with DCM (30 mL). The combined organic phases were dried over Na2SO4 and filtered. The residue was concentrated in vacuo to give the crude product, which was purified by preparative HPLC under the following conditions (column: SunFire C18 150*19 mm*5 um, mobile phase A: water (containing 0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, gradient condition: 10% B to 40% B) to give compound 21 as a yellow solid (15 mg, 37.6% yield).

[0488] Preparation of Compound 28 :

[0489]

[0490] A mixture of intermediate 33 (500 mg, 0.09 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. 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, filtered and concentrated. The residue was purified by preparative HPLC (column: SunFire C18 150*19 mm*5 um, mobile phase A: water (containing 0.1% NH4HCO3), mobile phase B: acetonitrile, flow rate: 15 mL / min, gradient condition: 10% B to 45% B) to give compound 28 as a white solid (15 mg, 36% yield). 4(s) Compound 29:

[0491] Preparation of Compounds 29 and 30 :

[0492] Compound 30:

[0493] Compound 30:

[0494] 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 °C for 16 h, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative 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 as formate (36 mg, 34.90% yield), which was further purified by chiral preparative HPLC (column: IA 4.6 cm I.D.*25 cm L, 5 μm; mobile phase: Hex:EtOH:DEA = 70:30:0.2, 30 mL / min; temperature: 38 °C). The first fraction was collected as compound 29 as a white solid (7 mg, 19% yield), and the second fraction was collected as compound 30 as a white solid (10 mg, 27% yield).

[0495] Synthesize the following compounds by a method similar to that described for Compounds 29 and 30

[0496]

[0497] Preparation of Compound 39 :

[0498]

[0499] To a mixture of compound 59 (100 mg, 0.209 mmol) in 1,2-dichloroethane (5 mL) at room temperature was added tetrahydro-4H-pyran-4-one (42 mg, 0.419 mmol). And the mixture was stirred at room temperature for 2 h. Then NaBH(OAc)3 (81 mg, 0.628 mmol) was added to the mixture. The mixture was stirred at room temperature for an additional 3 h. The mixture was diluted with 30 mL of water and extracted three times with EtOAc (30 mL). The combined layers were washed with brine, dried over Na2SO4, filtered and concentrated. Silica column chromatography was performed, eluting with 0% to 50% ethyl acetate / petroleum ether to give the product as a yellow oil (50 mg). The product was further purified by preparative 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 as a white solid (26 mg, LCMS purity 95.1%, yield 23.1%).

[0500] Preparation of Compound 58 :

[0501]

[0502] 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 in vacuo. The residue was dissolved in water (5 mL). The pH was adjusted to 8 - 9 with saturated aqueous sodium carbonate. The mixture was extracted three times with EtOAc (10 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue, compound 58 (60 mg, crude), was used in the next step without further purification.

[0503] Preparation of Compound 59 :

[0504]

[0505] To a solution of intermediate 24 (260 mg, 0.376 mmol) in DCM (5 mL) was added TFA (1 mL). After stirring at room temperature for 2 h, the solvent was removed in vacuo. The residue was dissolved in water (5 mL). The pH was adjusted to approximately 10 with 1 M aqueous NaOH. The mixture was extracted twice with DCM (10 mL), and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give compound 59 (180 mg, crude) as a yellow solid, which was used in the next step without purification.

[0506] Synthesize the following compounds by a method similar to that described for Compound 59

[0507]

[0508] LCMS (Liquid Chromatography / Mass Spectrometry)

[0509] General procedure

[0510] High - performance liquid chromatography (HPLC) measurements are performed using an LC pump, a diode array (DAD) or UV detector, and a column as specified in the corresponding method. If required, additional detectors are included (see the method in the table below).

[0511] The flow from the column is fed into a mass spectrometer (MS) equipped with an atmospheric pressure ionization source. Adjustment parameters (e.g., scan range, dwell time,...) are set so as to obtain ions that allow the identification of the nominal monoisotopic molecular weight (MW) of the compound within the knowledge of a person skilled in the art. Data acquisition is carried out using appropriate software.

[0512] By experimental retention time (Rt ) and ions are used to describe compounds. If not otherwise specified in the data sheet, the reported molecular ion corresponds to [M+H] + (protonated molecule) and / or [M-H] - (deprotonated molecule). In cases where the compound cannot be directly ionized, the type of adduct is specified (i.e., [M+NH4] + 、[M+HCOO] - etc.). For molecules with a multi-isotope pattern (Br, Cl), the reported values are those obtained for the lowest isotope mass. All results are obtained with the experimental uncertainties typically associated with the methods used.

[0513] Hereinafter, "SQD" refers to a single quadrupole detector, "RT" refers to room temperature, "BEH" refers to a bridged ethyl siloxane / silica mixture, "HSS" refers to high-intensity silica, and "DAD" refers to a diode array detector.

[0514] Table 1a: LCMS method code (flow rate in mL / min; column temperature (T) in °C; run time in minutes). "TFA" refers to trifluoroacetic acid; "FA" means formic acid 。

[0515]

[0516]

[0517]

[0518] Table 1b: LCMS and melting point data. Co.No. refers to the compound number; R t refers to the retention time in min 。

[0519]

[0520]

[0521] NMR :

[0522] NMR - method

[0523] Some NMR experiments were carried out at ambient temperature (298.6 K) using a Bruker Avance III 400 spectrometer, with internal deuterium lock and equipped with a BBO 400 MHz S1 5 mm probe with z-gradient and operating at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.

[0524] Some NMR experiments were carried out at ambient temperature (298.6 K) using a Varian 400-MR spectrometer, with internal deuterium lock and equipped with a Varian 400 4NUC PFG probe with z-gradient and operating at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (δ) were reported in parts per million (ppm). J values were expressed in Hz.

[0525] Some NMR experiments were carried out at ambient temperature (298.6 K) using a Varian 400-VNMRS spectrometer, with internal deuterium lock and equipped with a Varian 400ASW PFG probe with z-gradient and operating at 400 MHz for protons and 100 MHz for carbon. Chemical shifts (d) were reported in parts per million (ppm). J values were expressed in Hz.

[0526]

[0527]

[0528] Pharmacology section

[0529] 1) Menin / MLL homogeneous time - resolved fluorescence (HTRF) assay

[0530] To an untreated white 384-well microtiter plate was added 40 nL of a DMSO solution of the 200X test compound and 4 μL of a 2X terbium chelate-labeled menin (prepared below) assay buffer (40 mM Tris·HCl, pH 7.5, 50 mM NaCl, 1 mM DTT (dithiothreitol), and 0.05% Pluronic F-127). After incubating the test compound and terbium chelate-labeled menin at ambient temperature for 30 min, an assay buffer containing 4 μL of 2X FITC-MBM1 peptide (FITC-β-alanine-SARWRFPARPGT-NH2) (“FITC” refers to fluorescein isothiocyanate) was added, the microtiter plate was centrifuged at 1000 rpm for 1 min, and the assay mixture was incubated at ambient temperature for 15 min. The relative amount of the menin·FITC-MBM1 complex present in the assay mixture was determined by measuring the homogeneous time-resolved fluorescence (HTRF) of the terbium / FITC donor / acceptor fluorophore pair using an EnVision microplate reader at ambient temperature (excitation wavelength 337 nm / terbium emission wavelength 490 nm / FITC emission wavelength 520 nm). The degree of fluorescence resonance energy transfer (HTRF value) was expressed as the ratio of the fluorescence emission intensities of the FITC and terbium fluorophores (F em 520nm / F em(490 nm). The final concentrations of the reagents in the assay were 200 pM terbium chelate-labeled menin, 75 nM FITC-MBM1 peptide, and 0.5% DMSO in the assay buffer. A dose-response titration of the test compound was performed using an 11-point, four-fold serial dilution scheme, typically starting at 10 μM.

[0531] Compound potency was determined by first calculating the percent inhibition of each compound concentration according to Equation 1:

[0532] Percent inhibition = (((HC - LC) - (HTRF 化合物 - LC)) / (HC - LC)) * 100 (Equation 1) where LC and HC are the HTRF values measured in the presence or absence of a saturating concentration of a compound that competes with FITC-MBM1 for binding to menin, and HTRF 化合物 is the HTRF value measured in the presence of the test compound. The HC and LC HTRF values represent the average of at least 10 parallel determinations per plate. For each test compound, the percent inhibition values were plotted against the logarithm of the test compound concentration, and the IC 50 value was determined by fitting this data to Equation 2:

[0533] Percent inhibition = bottom + (top - bottom) / (1 + 10^((logIC 50 - log[compound]) * h)) (Equation 2) where bottom and top are the lower and upper asymptotes of the dose-response curve, IC 50 is the compound concentration that produces 50% signal inhibition, and h is the Hill coefficient.

[0534] Preparation of Terbium Cryptate-Labeled Menin: Menin (20 mM Hepes (2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid), 80 mM NaCl, 5 mM DTT (dithiothreitol), pH 7.5) containing 2.3 mg / mL a.a 1-610-6xhis tag) was labeled with terbium cryptate as follows. 200 μg Menin was buffer-exchanged into 1x Hepes buffer. 6.67 μM Menin was incubated with an 8-fold molar excess of NHS (N-hydroxysuccinimide)-cryptate at room temperature for 40 minutes. Half of the labeled protein was purified from the free label by running the reaction over a NAP5 column with elution buffer (0.1 M Hepes, pH 7 + 0.1% BSA (bovine serum albumin)). The other half was eluted with 0.1 M phosphate-buffered saline (PBS) (pH 7). 400 μL eluate was collected per fraction, aliquoted, and frozen at -80 °C. The final concentration of the terbium-labeled Menin protein was 115 μg / mL in Hepes buffer and 85 μg / mL in PBS buffer, respectively.

[0535] MENIN protein sequence (SEQ ID NO:1) :

[0536] MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNVPELTFQPSPAPDPPGGLTYFPVADLSIIAALYARFTAQIRGAVDLSLYPREGGVSSRELVKKVSDVIWNSLSRSYFKDRAHIQSLFSFITGTKLDSSGVAFAVVGACQALGLRDVHLALSEDHAWVVFGPNGEQTAEVTWHGKGNEDRRGQTVNAGVAERSWLYLKGSYMRCDRKMEVAFMVCAINPSIDLHTDSLELLQLQQKLLWLLYDLGHLERYPMALGNLADLEELEPTPGRPDPLTLYHKGIASAKTYYRDEHIYPYMYLAGYHCRNRNVREALQAWADTATVIQDYNYCREDEEIYKEFFEVANDVIPNLLKEAASLLEAGEERPGEQSQGTQSQGSALQDPECFAHLLRFYDGICKWEEGSPTPVLHVGWATFLVQSLGRFEGQVRQKVRIVSREAEAAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTGQGAVSGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQSEKMKGMKELLVATKINSSAIKLQLTAQSQVQMKKQKVSTPSDYTLSFLKRQRKGLHHHHHH

[0537] 2a) Proliferation assay

[0538] The antiproliferative effects of test compounds that inhibit the menin / MLL protein / protein interaction were evaluated in human leukemia cell lines. The cell line MOLM14 has an MLL translocation and expresses the MLL fusion protein MLL-AF9 and the wild-type protein from the second allele, respectively. OCI-AML3 cells carrying the NPM1c gene mutation were also tested. MLL-rearranged cell lines (such as MOLM14) and NPM1c-mutated cell lines exhibit a stem cell-like HOXA / MEIS1 gene expression signature. KO-52 was used as a control cell line containing two wild-type alleles of MLL (KMT2A) to exclude compounds that show general cytotoxic effects.

[0539] MOLM14 cells were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10% heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg / ml gentamicin (Gibco). The KO-52 and OCI-AML3 cell lines were propagated in α-MEM (Sigma Aldrich) supplemented with 20% heat-inactivated fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich), and 50 μg / ml gentamicin (Gibco). Cells were maintained at 300,000 - 2,500,000 cells / ml during culture and were passaged no more than 20 times.

[0540] To evaluate the anti-proliferative effect, 200 MOLM14 cells, 200 OCI-AML3 cells, or 300 KO-52 cells were seeded in 200 μl of medium / well in a 96-well round-bottom ultra-low attachment plate (Costar, catalog number 7007). The cell seeding number was selected based on the growth curve to ensure linear growth throughout the experiment. Different concentrations of the test compound were added and the DMSO content was normalized to 0.3%. The cells were incubated at 37 °C and 5% CO2 for 8 days. Images were acquired on day 8 by live cell imaging (IncuCyte ZOOM, Essenbio, 4x objective) to measure spheroid-like growth in real time. Confluence (%), as a measure of spheroid size, was determined using the integrated analysis tool.

[0541] To determine the effect of the test compound over time, the confluence in each well was calculated as a measure of spheroid size. The confluence of the highest dose of the reference compound was used as the baseline for LC (low control), and the confluence of DMSO-treated cells was used as 0% cytotoxicity (high control, HC).

[0542] Absolute IC 50 values were calculated as the percentage change in confluence as follows:

[0543] LC = low control: cells treated with a cytotoxic agent such as 1 μM staurosporine,

[0544] or cells treated with an alternative reference compound at a high concentration

[0545] HC = high control: average confluence (%) (DMSO-treated cells)

[0546] % effect = 100 - (100 * (sample - LC) / (HC - LC))

[0547] GraphPad Prism (version 7.00) was used to calculate IC 50。The dose-response equation is used to plot % effect against Log10 compound concentration with a variable slope, fixing the maximum value at 100% and the minimum value at 0%.

[0548] 2b) MEIS1 mRNA expression assay

[0549] MEIS1 mRNA expression after compound treatment was detected by Quantigene Singleplex assay (Thermo Fisher Scientific). This technique allows direct quantification of mRNA targets using probes that hybridize to defined target sequences, and signals are detected using an Envision multimode plate reader (PerkinElmer). The MOLM14 cell line was used for this experiment. Cells were seeded at 3750 cells / well in 96-well plates in the presence of increasing concentrations of the compound. After incubation with the compound for 48 h, the cells were lysed in lysis buffer and incubated at 55 °C for 45 min. The cell lysates were mixed with human MEIS1-specific capture probes or human RPL28 (ribosomal protein L28)-specific probes (as a normalization control) and blocking probes. The cell lysates were then transferred to a custom assay hybridization plate (Thermo Fisher Scientific) and incubated at 55 °C for 18 to 22 h. Subsequently, the plates were washed to remove unbound material, followed by sequential addition of preamplifier, amplifier, and labeled probes. Signals (= gene counts) were measured using an Envision multimode plate reader. IC was calculated by dose-response modeling using appropriate software 50 。For all non-housekeeping genes, reaction equal counts corrected for background and relative expression were used. For each sample, the signal of each test gene (minus background) was divided by the signal of the normalization gene (RPL28: minus background). Fold change was calculated by dividing the normalized value of the treated sample by the normalized value of the DMSO-treated sample. The fold change for each target gene was used to calculate IC 50 。

[0550] Table 3. Biological data - HTRF assay, proliferation assay, and MEIS1 mRNA expression assay

[0551]

[0552]

Claims

1. A compound of formula (I) or a tautomeric or stereoisomeric form thereof, wherein R 1a represents hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 , - C(=O)-O-C 1-4 alkyl-NR 22a R 22b 、-C(=O)-O-C 1-4 alkyl R 1b represents H, F or Cl; R 2a represents hydrogen, a halogen group, C 3-6 cycloalkyl, C 1-4 alkyl, -O-C 1-4 alkyl, a cyano group or C substituted with one, two or three halogen substituents 1-4 alkyl; R 2b represents hydrogen or C 1-4 alkyl; R 2c represents hydrogen or C 1-4 alkyl; R 3 represents hydrogen, C 1-6 alkyl or C substituted by C 3-6 cycloalkyl-substituted C 1-6 alkyl; R 4 represents hydrogen, C 1-6 alkyl, R 6 , Het 1 , and C 6 alkyl substituted with a substituent selected from the group consisting of R 1 and Het 1-6 ; R 5a and R 5b each independently represents hydrogen or C 1-4 alkyl; R 6 represents C 3-6 cycloalkyl or C 3-6 cycloalkyl substituted by one or two substituents, said one or two substituents being each independently selected from the group consisting of C 1-4 alkyl, -O-C 1-4 alkyl or Het 2 consisting of; Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four substituents each independently selected from the group consisting of: halo, C 1-4 alkyl, oxo and -OH; Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by -C(=O)-C 1-4 alkyl; R 18 represents C 1-6 alkyl or C 3-6 cycloalkyl; R 19 represents hydrogen or C 1-6 alkyl; or R 18 and R 19 together 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 1-4 alkyl, C 3-6 cycloalkyl or cyano; R xa and R xb each independently selected from the group consisting of: hydrogen, Het 3 , C 3-6 cycloalkyl, and C 1-6 alkyl; wherein optionally, said C 3-6 cycloalkyl and C 1-6 alkyl are substituted with one, two or three substituents each independently selected from the group consisting of: -OH, -OC 1-4 alkyl, -C 1-4 alkyl-OH, halo, CF3, C 3-6 cycloalkyl, Het 3 and NR 11c R 11d ; or R xa and R xb together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one additional heteroatom selected from O, S, and N; wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted with one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, and -O-C 1-4 alkyl, cyano, and C 23 alkyl substituted with one, two, or three substituents selected from the group consisting of halo and OR 1-4 alkyl; or R xa and R xb together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully saturated or partially saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted by one, two, or three substituents selected from the group consisting of C 1-4 alkyl, halo, -OH, -O-C 1-4 alkyl, cyano, and C 23 alkyl substituted by one, two, or three substituents each independently selected from the group consisting of halo and OR 1-4 alkyl; R 23 represents hydrogen or a C 1-4 alkyl group optionally substituted with one, two or three halogen groups; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, wherein R 1a represents -C(=O)-NR xa R xb ; R 1b represents F; R 2a represents hydrogen or C 1-4 alkyl; R 2b represents hydrogen; R 2c represents hydrogen; R 6 represents C 3-6 cycloalkyl or C-cycloalkyl substituted by one or two substituents 3-6 wherein each of the one or two substituents is independently selected from the group consisting of -O-C 1-4 alkyl or Het 2 ; Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; or represents a bicyclic C-linked 6- to 11-membered fully saturated heterocyclic group containing one, two or three heteroatoms each independently selected from O, S and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one or two carbon atoms with a total of one, two, three or four C 1-4 alkyl groups; Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclic group containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein the S atom can be substituted to form S(=O) or S(=O)2; wherein the heterocyclic group is optionally substituted on one nitrogen by -C(=O)-C 1-4 alkyl; R xa and R xb represent C 1-6 alkyl groups.

3. The compound according to claim 1, wherein R 1b represents F.

4. The compound according to claim 1, 2 or 3, wherein R 2a represents C 1-4 alkyl.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.

6. A method for preparing the pharmaceutical composition according to claim 5, the method comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound according to any one of claims 1 to 4.

7. The compound according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5, the compound or pharmaceutical composition for use as a medicament.

8. The compound according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5, the compound or pharmaceutical composition for use in the prevention or treatment of cancer.

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