Cyclobutyl-substituted bicyclic compounds

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to medicaments useful for therapy and / or prophylaxis in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful for treating diseases such as cancer, including but not limited to leukemia. [Background technology]

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia genes (MLL; MLL1; KMT2A) cause aggressive acute leukemia across all age groups and still represent a largely incurable disease, highlighting the urgent need for novel therapeutic approaches. Acute leukemias harboring these chromosomal translocations of MLL represent lymphoid, myeloid, or biphenotypic disorders and comprise 5-10% of acute leukemias in adults and approximately 70% in infants.

[0003] MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in a multiprotein complex. Using an inducible loss-of-function allele of Mll1, we demonstrated that Mll1 plays a crucial role in hematopoietic stem cell (HSC) maintenance and B cell development, but its histone methyltransferase activity is dispensable for hematopoiesis.

[0004] Fusions of MLL with over 60 different partners have been reported to date and have been associated with leukemia formation / progression. Interestingly, the SET (Su(var)3-9, enhancer of zeste, and trithorax) domain of MLL is not retained in 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 enhances the transcription and transcription elongation of MLL target genes, most notably HOXA genes (e.g., HOXA9) and the HOX cofactor MEIS1. Aberrant expression of these genes then blocks hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the Multiple Endocrine Neoplasia type 1 (MEN1) gene, is ubiquitously expressed and primarily localized in the nucleus. It has been shown to interact with numerous proteins and, therefore, to be involved in various cellular processes. The best-understood function of menin is its role as an oncogenic cofactor for MLL fusion proteins. Menin interacts with two motifs within the N-terminal fragment of MLL, MBM1 (menin-binding motif 1) and MBM2, which are conserved in all fusion proteins. The menin / MLL interaction provides a novel interaction surface for lens epithelium-derived growth factor (LEDGF). While MLL directly binds to LEDGF, menin is essential for stable interaction between MLL and LEDGF and for gene-specific chromatin recruitment of the MLL complex via the PWWP domain of LEDGF. Furthermore, numerous genetic studies have demonstrated that menin is strictly required for oncogenic transformation by MLL fusion proteins, suggesting that the menin / MLL interaction is an attractive therapeutic target. For example, conditional deletion of Men1 blocks leukocyte formation in myeloid progenitor cells ectopically expressing MLL fusions. Similarly, genetic disruption of the menin / MLL fusion interaction by loss-of-function mutations abolishes the oncogenic properties of MLL fusion proteins, prevents leukemia development in vivo, and relieves the differentiation block of MLL-transformed leukemic blasts. These studies also demonstrate that menin is required for maintaining HOX gene expression by MLL fusion proteins. In addition, small molecule inhibitors of the menin / MLL interaction have been developed, suggesting the druggable potential of this protein / protein interaction and demonstrating efficacy in preclinical models of AML. Together with the observation that menin is not an essential cofactor for MLL1 during normal hematopoiesis, these data demonstrate that disruption of the menin / MLL interaction represents a promising new therapeutic approach for treating MLL-rearranged leukemias and other cancers with an active HOX / MEIS1 gene signature.For example, intragenic partial tandem duplication (PTD) within the 5' region of the MLL gene represents another major abnormality found primarily in de novo and secondary AML and myelodysplastic syndromes. Although the molecular mechanisms and biological functions of MLL-PTD are not fully understood, novel therapeutic targeting strategies affecting the menin / MLL interaction may also prove effective in treating MLL-PTD-associated leukemia. Furthermore, castration-resistant prostate cancer has been shown to be dependent on the menin / MLL interaction.

[0006] The MLL protein is also known in the scientific community as histone-lysine N-methyltransferase 2A (KMT2A) protein (UniProt accession number Q03164). Summary of the Invention [Means for solving the problem]

[0007] The present invention relates to a compound of formula (I)

[0008] [ka] [In the formula, R 1a is hydrogen, cyano, halo, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 , -C(=O)-OC 1~4 Alkyl-NR 22a R 22b , -C(=O)-OC 1~4 Alkyl,

[0009] [ka] represents R 1b represents hydrogen, F, or Cl; R 2a But hydrogen, halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 represents alkyl, R 2b is hydrogen or C 1~4 represents alkyl, R 2c is hydrogen or C 1~4 represents alkyl, R 3 But hydrogen, C 1~6 Alkyl or C 3~6 Cycloalkyl-substituted C 1~6 represents alkyl, R 4 But hydrogen, C 1~6 Alkyl, R 6 , Het 1 , R 6 and Het 1 C substituted with one substituent selected from the group consisting of 1~6 represents alkyl, R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl, R 6 But C 3~6 Cycloalkyl, or C 1~4 Alkyl, -OC 1~4 Alkyl or Het 2 C substituted with one or two substituents each independently selected from the group consisting of 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, where the S atom(s) may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, where the S atom(s) may be substituted to form S(=O) or (=O)2, wherein the heterocyclyl optionally contains, on 1 or 2 carbon atoms, halo, C 1~4substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, oxo, and —OH; Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a —C(=O)—C bond on one nitrogen atom; 1~4 is substituted with alkyl, R 18 But C 1~6 Alkyl or C 3~6 represents cycloalkyl, R 19 is hydrogen or C 1~6 represents alkyl, or R 18 and R 19 together to form -CH2-CH2-CH2- Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, and the monocyclic 5- or 6-membered aromatic ring is optionally selected from the group consisting of C 1~4 Alkyl, C 3~6 substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R xa and R xb are independently hydrogen, Het 3 , C 3~6 Cycloalkyl, and C 1~6 alkyl, and optionally, the C 3~6 Cycloalkyl and the C 1~6 Alkyl is -OH, -OC 1~4 Alkyl, -C 1~4 Alkyl-OH, Halo, CF3, C 3~6 Cycloalkyl, Het 3 , and NR 11c R 11dor substituted with 1, 2, or 3 substituents each independently selected from the group consisting of or R xa and R xb together with the N atom to which they are attached to form one N atoms and optionally selected from O, S, and N; The S atom forms a 4-7 membered monocyclic fully or partially saturated heterocyclyl containing one additional heteroatom, which may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally be C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and Halo and OR 23 C substituted with 1, 2, or 3 substituents selected from the group consisting of 1~4 substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R xa and R xb taken together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains C 1~4 Alkyl, halo, -OH, -OC 1~4 Alkyl, cyano, and halo and OR 23 C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of 1~4 substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R 23 is hydrogen or C optionally substituted with 1, 2, or 3 halo 1~4 represents alkyl] This invention relates to novel compounds of the formula: and their tautomeric and stereoisomeric forms.

[0010] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0011] Additionally, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use as a medicament, and also to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of cancer, including, but not limited to, leukemia.

[0012] In certain embodiments, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment or prevention of cancer.

[0013] In specific embodiments, the cancer is selected from leukemia, hi some embodiments, leukemias include acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), MLL-rearranged leukemia, MLL-PTD leukemia, MLL-amplified leukemia, MLL-positive leukemia, leukemia exhibiting a HOX / MEIS1 gene expression signature, and the like.

[0014] In particular, the compounds according to the present invention and pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemia, particularly nucleophosmin (NPM1) mutant leukemia, such as NPM1c.

[0015] In certain embodiments, the compounds of formula (I) and their pharmaceutically acceptable salts and solvates may have improved metabolic stability properties.

[0016] In certain embodiments, the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may reduce tumor growth, for example, tumors harboring MLL (KMT2A) gene rearrangements / alterations and / or NPM1 mutations.

[0017] 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 pharmaceutical agent for use in the treatment or prevention of cancer, including but not limited to leukemia.

[0018] Furthermore, the present invention relates to a process for preparing a pharmaceutical composition according to the present invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

[0019] The present invention also relates to a product comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and an additional pharmaceutical agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, including but not limited to leukemia. DETAILED DESCRIPTION OF THE INVENTION

[0020] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0021] As used herein, the prefix "C x~y " (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1~6 An alkyl group contains 1 to 6 carbon atoms, and so on.

[0022] As used herein, "C" as a group or part of a group 1~4 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, and the like.

[0023] Similarly, as used herein, "C" as a group or part of a group 1~6The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0024] As used herein, "C" as a group or part of a group 3~6 The term "cycloalkyl" defines a saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] It will be apparent to those skilled in the art that S(=O)2 or SO2 represents a sulfonyl moiety.

[0026] It will be apparent to one skilled in the art that CO or C(=O) represent a carbonyl moiety.

[0027] Non-limiting examples of "monocyclic 5- or 6-membered aromatic rings containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety" include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or 1,2-dihydro-2-oxo-4-pyridinyl.

[0028] Those skilled in the art will recognize that a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and a carbonyl moiety is

[0029] [ka] It will be understood that these include, but are not limited to:

[0030] The term "monocyclic N-linked 4-7 membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N'" defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing at least one nitrogen atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, which is attached to the remainder of the molecule of formula (I) via a nitrogen atom. Examples are N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked 1,4-diazepanyl, and N-linked piperidinyl. Two R groups that together with the N atom to which they are attached form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N are similarly defined, except that the hydrocarbon radical can be fully or partially saturated.

[0031] The term "monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N" defines a fully saturated cyclic hydrocarbon radical having 4 to 7 ring members and containing 1, 2, or 3 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, C-linked piperidinyl, C-linked azepanyl, and C-linked 1,2,3,6-tetrahydro-pyridinyl.

[0032] For clarity, a 4- to 7-membered fully or partially saturated heterocyclyl has 4 to 7 ring members, including the heteroatom.

[0033] Within the context of this invention, bicyclic 6-11 membered fully saturated heterocyclyl groups include fused, spiro and bridged bicyclic rings.

[0034] A fused bicyclic group is two rings that share two atoms and a bond between those atoms.

[0035] A spiro bicyclic group is two rings joined at a single atom.

[0036] A bridged bicyclic group is two rings that have three or more atoms in common.

[0037] Examples of bicyclic C-bonded 6-11 membered fully saturated heterocyclyls containing 1, 2, or 3 heteroatoms each independently selected from O, S, and N include:

[0038] [ka] These include, but are not limited to:

[0039] Examples of two R groups that together with the N atom to which they are attached form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl containing one N atom and optionally one additional heteroatom selected from O, S, and N include:

[0040] [ka] These include, but are not limited to:

[0041] The substituents may be, for example,

[0042] [ka] Whenever represented by a chemical structure such as "----" represents the bond to the remainder of the molecule of formula (I).

[0043] When any variable occurs more than one time in any constituent, each definition is independent.

[0044] When any variable occurs more than one time in any formula (eg, formula (I)), each definition is independent.

[0045] It will be apparent to one of skill in the art that when a moiety (e.g., a heterocyclyl or a monocyclic 5- or 6-membered aromatic ring) is substituted with two or more substituents (e.g., 1, 2, or 3 substituents) selected from a group, each substituent can be independently selected from that group, even if not explicitly stated.

[0046] Generally, whenever the term "substituted" is used herein, unless otherwise specified or clear from the context, it means that one or more hydrogens, specifically 1 to 4 hydrogens, more specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, and more preferably 1 hydrogen, on the atom or radical designated in the expression "substituted" are replaced with a selection from the designated group, provided that the normal valences are not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to withstand isolation to a useful degree of purity from the reaction mixture (post-reaction isolation, for example, purification by silica gel chromatography). In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.

[0047] Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. "Stable compound," in this context, is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (post-reaction isolation, e.g., purification by silica gel chromatography).

[0048] Those skilled in the art will understand that the term "optionally substituted" means that the atom or radical designated in the expression using "optionally substituted" may be substituted or unsubstituted (which means substituted or unsubstituted, respectively).

[0049] When two or more substituents are present on a moiety, they may replace hydrogen atoms on the same atom, or they may replace hydrogen atoms on different atoms in the moiety, unless otherwise stated or apparent from the context.

[0050] In the context of the present invention, "saturated" means "fully saturated" unless otherwise specified.

[0051] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be attached to the remainder of the molecule of formula (I) through any available ring carbon atom (C-bonded) or nitrogen atom (N-bonded).

[0052] Unless otherwise specified or apparent from the context, aromatic rings and heterocyclyl groups may be optionally substituted on carbon and / or nitrogen atoms where possible, depending on the embodiment.

[0053] 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 object of treatment, observation, or experiment.

[0054] The term "therapeutically effective amount," as used herein, means that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including alleviation or reversal of the symptoms of the disease or disorder being treated.

[0055] The term "composition" is intended to encompass a product containing specified ingredients in specified amounts, and any product that results directly or indirectly from combining specified ingredients in specified amounts.

[0056] As used herein, the term "treatment" is intended to refer to any process that can slow, hinder, inhibit, or halt the progression of a disease, although it does not necessarily indicate complete elimination of all symptoms.

[0057] As used herein, the term "compounds of the invention" or "compounds according to the invention" is meant to include compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

[0058] As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedge bonds or hashed wedge bonds, or otherwise shown as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer or a mixture of two or more stereoisomers.

[0059] Above and below, the term "compounds of formula (I)" is meant to include its tautomers and its stereoisomeric forms.

[0060] Above and below the terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably.

[0061] The present invention includes all stereoisomers of the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0062] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0063] Atropisomers (or atropoisomers) are stereoisomers with specific spatial configurations resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

[0064] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related as mirror images. If the compound contains double bonds, the substituents may be in either the E or Z configuration.

[0065] Substituents on a divalent cyclic saturated or partially saturated radical can have either the cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents can be in either the cis or trans configuration.

[0066] Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0067] The meanings of all terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to those skilled in the art.

[0068] Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane-polarized light. For example, resolved enantiomers whose absolute configuration is not known can be designated (+) or (-) depending on the direction they rotate plane-polarized light.

[0069] When a particular stereoisomer is specified, 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 specified, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is specified, for example, as E, this means that the compound is substantially free of the Z isomer; and when a compound of formula (I) is specified, for example, as cis, this means that the compound is substantially free of the trans isomer.

[0070] Some of the compounds according to formula (I) may also exist in their tautomeric forms. Such forms, to the extent possible, are intended to be included within the scope of the present disclosure, although not explicitly shown in formula (I) above. Thus, a single compound may exist in both stereoisomeric and tautomeric forms.

[0071] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting a free acid form or a 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, and then removing the solvent or medium using standard techniques (for example, in vacuo, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present disclosure in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0072] The pharmaceutically acceptable salts referred to above or below are meant to include the therapeutically active non-toxic acid and base salt forms which the compounds of formula (I) and their solvates are able to form.

[0073] 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, propanoic acid, hydroxyacetic 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 forms can be converted to the free base form by treatment with an appropriate base.

[0074] Compounds of formula (I) or solvates thereof containing acidic protons may be converted into their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0075] Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, cesium, magnesium, calcium salts, and the like, salts with organic bases such as primary, secondary, and tertiary aliphatic amines and aromatic amines, for example, 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-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, base forms can be converted to the free base forms by treatment with acid.

[0076] The term "prodrug" includes any compound that, following oral or parenteral administration, especially oral administration, is metabolized in vivo to a more active(er) form in an experimentally detectable amount and within a predetermined time period (e.g., within a 0.5 to 24 hour dosing interval, or, for example, within a 6 to 24 hour dosing interval (i.e., 1 to 4 times daily)). For the avoidance of doubt, the term "parenteral" administration includes all modes of administration other than oral administration, in particular intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.

[0077] Prodrugs can be prepared by modifying functional groups present on a compound such that the modification is cleaved in vivo when the prodrug is administered to a mammalian subject. The modification is typically accomplished by synthesizing the parent compound with a prodrug substituent. In general, prodrugs include compounds in which a hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0078] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases.

[0079] The term solvates comprises the solvent addition forms, as well as the salts thereof, which the compounds of formula (I) are able to form. Examples of such solvent addition forms are, for example, hydrates, alcoholates, etc.

[0080] The compounds of the present invention prepared by the processes described below may be synthesized in the form of mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. A method for separating the enantiomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates includes liquid chromatography using chiral stationary phases. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparative methods. These methods will advantageously employ enantiomerically pure starting materials.

[0081] As used herein, the term "enantiomerically pure" means that the product contains at least 80% by weight of one enantiomer and no more than 20% by weight of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and no more than 10% by weight of the other enantiomer. In the most preferred embodiment, the term "enantiomerically pure" means that the composition contains at least 99% by weight of one enantiomer and no more than 1% of the other enantiomer.

[0082] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to those enumerated herein, but due to the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant atom found in nature).

[0083] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring or synthetically produced, at natural abundance or in isotopically enriched form, are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and 2 H, 3 H,11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br and other isotopes of iodine. Preferably, the isotope is 2 H, 3 H, 11 C. 13 C, and 18 Preferably, the isotope is selected from the group 2 H, 3 H, 11 C, and 18 F. More preferably, the isotope is selected from the group 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, deuterium compounds and 13 C-enriched compounds are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0084] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) can be useful, for example, in substrate tissue distribution assays. 3 H) and carbon-l4( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2Substitutions such as with hydroxypropyl methyl ... 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies. PET imaging in cancer finds utility in helping to localize and identify tumors, stage disease, and determine appropriate treatments. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy. In addition, target-specific PET radiotracers can be used as biomarkers to investigate and evaluate pathologies, for example, by measuring target expression and treatment response.

[0085] The present invention particularly relates to compounds of formula (I) as defined herein, wherein: R 1a -C(=O)-NR xa R xb represents R 1b represents F, R 2a is hydrogen or C 1~4 represents alkyl, R 2b represents hydrogen, R 2c represents hydrogen, R 3 But hydrogen, C 1~6 Alkyl or C 3~6 Cycloalkyl-substituted C 1~6 represents alkyl, R 4 But hydrogen, C 1~6 Alkyl, R 6 , Het 1 , R 6 and Het1 C substituted with one substituent selected from the group consisting of 1~6 represents alkyl, R 5a and R 5b are each independently hydrogen or C 1~4 represents alkyl, R 6 But C 3~6 Cycloalkyl or -OC 1~4 Alkyl or Het 2 C substituted with one or two substituents each independently selected from the group consisting of 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, and the S atoms may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, and the S atoms may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a total of 1, 2, 3, or 4 C atoms on 1 or 2 carbon atoms; 1~4 is substituted with alkyl, Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has a —C(=O)—C bond on one nitrogen atom; 1~4 is substituted with alkyl, R xa and R xb But C 1~6 represents alkyl] and the tautomeric and stereoisomeric forms thereof, and the pharmaceutically acceptable salts and solvates thereof.

[0086] The present invention particularly relates to compounds of formula (I) as defined herein, wherein: R 1a -C(=O)-NR xa R xb represents R 1b represents F, R 2a is hydrogen or C 1~4 represents alkyl, R 2b represents hydrogen, and R 2c represents hydrogen, and R 3 represents hydrogen, R 4 But C 1~6 Alkyl, R 6 , Het 1 , R 6 and Het 1 C substituted with one substituent selected from the group consisting of 1~6 represents alkyl, R 5a and R 5b represents hydrogen, R 6 But C 3~6 represents cycloalkyl, Het 1 are each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally contain a total of 1, 2, 3, or 4 C atoms on 1 or 2 carbon atoms. 1~4 is substituted with alkyl, R xa and R xb But C 1~6 represents alkyl] and the tautomeric and stereoisomeric forms thereof, and the pharmaceutically acceptable salts and solvates thereof.

[0087] The present invention particularly relates to compounds of formula (I) as defined herein, wherein: R 1a -C(=O)-NR xa R xb represents R 1b represents F, R 2a But hydrogen, C 1~4 represents alkyl, R 2b represents hydrogen, and R 2c represents hydrogen, and R 3 represents hydrogen, R 4 But C 1~6 Alkyl, R 6 , Het 1 , R 6 and Het 1 C substituted with one substituent selected from the group consisting of 1~6 represents alkyl, R 5a and R 5b represents hydrogen, R 6 But C 3~6 represents cycloalkyl, Het 1 are each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally contain a total of 1, 2, 3, or 4 C atoms on 1 or 2 carbon atoms. 1~4 is substituted with alkyl, R xa and R xb But C 1~6 represents alkyl] and the tautomeric and stereoisomeric forms thereof, and the pharmaceutically acceptable salts and solvates thereof.

[0088] The present invention particularly relates to compounds of formula (I) as defined herein, wherein: R 1a -C(=O)-NR xa R xb represents R 1b represents F, R 2a But C 1~4 represents alkyl, in particular methyl, R 2b represents hydrogen, and R 2c represents hydrogen, and R 3 represents hydrogen, R 4 But one Het 1 C replaced with 1~6 represents alkyl, R 5a and R 5b represents hydrogen, R 6 But C 3~6 represents cycloalkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms, each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally have one C 1~4 is substituted with alkyl, R xa and R xb But C 1~6 represents alkyl] and the tautomeric and stereoisomeric forms thereof, and the pharmaceutically acceptable salts and solvates thereof.

[0089] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 1a is hydrogen, Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0090] [ka] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0091] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 1a Het, -C(=O)-NR xa R xb , -S(=O)2-R 18 ,

[0092] [ka] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0093] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 1a -C(=O)-NR xa R xb , -S(=O)2-R 18 , or

[0094] [ka] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0095] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 1a -C(=O)-NR xa R xb , or

[0096] [ka] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0097] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 1a -C(=O)-NR xa R xband the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein

[0098] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R xa and R xb is hydrogen or C 1~6 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R represents an alkyl group;

[0099] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R xa and R xb But C 1~6 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R represents an alkyl group;

[0100] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R xa and R xb are not combined together] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0101] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 1b represents F or Cl] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0102] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 1b represents F] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0103] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 1b represents F and R2a is other than hydrogen, and R 2b represents hydrogen, and R 2c represents hydrogen] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0104] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 2a But C 1~4 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R represents an alkyl group;

[0105] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 2a represents methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0106] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 2a But, Halo, C 3~6 Cycloalkyl, C 1~4 Alkyl, -OC 1~4 C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents 1~4 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0107] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 2a represents other than hydrogen], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0108] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 3 represents hydrogen, R 4represents other than hydrogen], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0109] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 4 represents hydrogen, and R 3 represents other than hydrogen], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0110] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 4 But one Het 1 C replaced with 1~6 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0111] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 3 represents hydrogen, R 4 But one Het 1 C replaced with 1~6 and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0112] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 4 But one Het 1 C replaced with 1~6 represents alkyl, and Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms, each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally have one C 1~4substituted with alkyl, in particular methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0113] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: R 3 represents hydrogen, R 4 But one Het 1 C replaced with 1~6 represents alkyl, Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms, each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally have one C 1~4 substituted with alkyl, in particular methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0114] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5a represents hydrogen] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0115] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5b represents hydrogen] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0116] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5a and R 5b represents hydrogen] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0117] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5a and R 5b One of them is C 1~4 and the other represents alkyl and hydrogen; and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0118] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5a represents hydrogen, and R 5b But C 1~4 represents alkyl, in particular methyl] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0119] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein R 5b represents hydrogen, and R 5ba But C 1~4 represents alkyl, in particular methyl] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0120] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, and the S atom(s) may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, and the S atom(s) may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally contains a total of 1 or 2 C 1~4substituted with alkyl, in particular methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0121] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: Het 1 represents a monocyclic C-bonded 4- to 7-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, where the S atom(s) may be substituted to form S(=O) or S(=O)2, or a bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, where the S atom(s) may be substituted to form S(=O) or S(=O)2, and the heterocyclyl optionally has one C 1~4 substituted with alkyl, in particular methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0122] In one embodiment, the present invention provides a compound of formula (I) as referred to in any of the other embodiments, wherein: Het 1 represents a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2 or 3 heteroatoms, each independently selected from O, S, and N, and the S atom may be substituted to form S(=O) or S(=O)2, and the heterocyclyl may optionally have one C 1~4 substituted with alkyl, in particular methyl], and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0123] In one embodiment, the present invention provides a compound of formula (I) as mentioned in any of the other embodiments, wherein Het 1 is monocyclic] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0124] In one embodiment, the present invention provides a compound of formula (I) as mentioned in any of the other embodiments, wherein Het 1 is bicyclic] and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0125] In one embodiment, the present invention provides a compound of formula (I) as mentioned in any of the other embodiments, wherein Het 1 represents one of the following:

[0126] [ka] each optionally substituted as defined in any of the other embodiments], and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0127] In one embodiment, the present invention provides a compound of formula (I) as mentioned in any of the other embodiments, wherein Het 2 but,

[0128] [ka] and optionally substituted as defined in any of the other embodiments, and the pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof.

[0129] In certain embodiments, the present invention relates to a subgroup of Formula (I) as defined in the general reaction scheme.

[0130] In certain embodiments, the compound of formula (I) is an exemplified compound: its tautomeric and stereoisomeric forms, and any of the free bases, any pharmaceutically acceptable salts, and solvates thereof.

[0131] In certain embodiments, the compound of formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39.

[0132] In certain embodiments, the compound of Formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39, its tautomeric and stereoisomeric forms, and any pharmaceutically acceptable salts and solvates thereof.

[0133] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of any of the exemplified compounds.

[0134] The present invention provides 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 any of the exemplified compounds, its tautomeric and stereoisomeric forms, and pharmaceutical compositions selected from the group consisting of the free base, any pharmaceutically acceptable salt, and any solvate thereof.

[0135] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39.

[0136] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of formula (I) is selected from the group consisting of compounds 3, 8, 9, 11, 12, 13, 14, 26, 28, and 39, its tautomeric and stereoisomeric forms, and any pharmaceutically acceptable salts and solvates thereof.

[0137] In certain embodiments, the compound of formula (I) is Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0138] In certain embodiments, the compound of formula (I) is compound 3, or a pharmaceutically acceptable salt or solvate thereof.

[0139] In certain embodiments, the compound of Formula (I) is Compound 8, or a pharmaceutically acceptable salt or solvate thereof.

[0140] In certain embodiments, the compound of formula (I) is compound 9, or a pharmaceutically acceptable salt or solvate thereof.

[0141] In certain embodiments, the compound of formula (I) is compound 11, or a pharmaceutically acceptable salt or solvate thereof.

[0142] In certain embodiments, the compound of formula (I) is compound 12, or a pharmaceutically acceptable salt or solvate thereof.

[0143] In certain embodiments, the compound of formula (I) is compound 13, or a pharmaceutically acceptable salt or solvate thereof.

[0144] In certain embodiments, the compound of formula (I) is compound 14, or a pharmaceutically acceptable salt or solvate thereof.

[0145] In certain embodiments, the compound of Formula (I) is compound 26, or a pharmaceutically acceptable salt or solvate thereof.

[0146] In certain embodiments, the compound of Formula (I) is compound 28, or a pharmaceutically acceptable salt or solvate thereof.

[0147] In certain embodiments, the compound of Formula (I) is compound 39, or a pharmaceutically acceptable salt or solvate thereof.

[0148] All possible combinations of the above-described embodiments are considered to fall within the scope of the present invention.

[0149] Processes for preparing compounds of formula (I) In this section, and in all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and embodiments thereof defined herein.

[0150] The general preparation of some representative examples of compounds of formula (I) is described below, and in certain examples they are usually prepared from starting materials that are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are merely illustrative of examples of the present invention and are not intended to limit the present invention in any way.

[0151] Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the following general schemes, combined with standard synthetic processes commonly used by those skilled in the art.

[0152] Those skilled in the art will understand that in the reactions depicted in the schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, or carboxy groups) if these are desired in the final product to prevent their undesired participation in the reaction. Generally, conventional protecting groups (PG) can be used in accordance with standard practice. The protecting groups can be removed at a subsequent convenient stage using methods known in the art.

[0153] Those skilled in the art will appreciate that it may be advisable or necessary to carry out the reactions depicted in the schemes under an inert atmosphere, such as under an atmosphere of N2 gas.

[0154] It will be apparent to those skilled in the art that it may be necessary to cool the reaction mixture before working on the reaction (e.g., referring to the series of operations required to isolate and purify the product of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0155] Those skilled in the art will appreciate that heating the reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to reduce the overall reaction time.

[0156] Those skilled in the art will appreciate that the alternative chemical reaction sequences shown in the schemes below may also lead to the desired compounds of formula (I).

[0157] Those skilled in the art will appreciate that the intermediates and final compounds shown in the following schemes 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 a salt or solvate thereof. The intermediates and compounds described herein can be synthesized in the form of a mixture of tautomeric and stereoisomeric forms, which can be separated from one another according to art-known resolution procedures.

[0158] General synthetic scheme Scheme 1 In Scheme 1, PG represents a suitable protecting group such as, for example, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl, and X 1 represents a halogen, such as chloro, bromo, or iodo, or other leaving group, such as mesylate or tosylate; X 2 represents fluoro, chloro, bromo, or iodo, and all other variables are defined according to the scope of the present invention.

[0159] [ka]

[0160] In Scheme 1, the following reaction conditions apply: Step 1: 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, at a suitable temperature in the range of 80°C to 120°C; Process 2:R 2a But C 3~6 Cycloalkyl, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 If R is alkyl, it can be reacted in the presence of an alkyl or alkenyl boronic acid or boronic acid ester or alkyl trifluoroborate potassium salt, 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]dichloropalladium(II) (Pd(dppf)Cl2), in a suitable solvent such as dioxane or dimethylformamide and water, at a suitable temperature ranging from room temperature to 100°C. 2a When is methyl, a boron-containing reagent such as trimethylboroxine can be used in the presence of a suitable catalyst such as (Pd(dppf)Cl), in a suitable solvent such as dioxane or dimethylformamide and water, in the presence of an inorganic base such as potassium carbonate or cesium carbonate, at a reaction temperature between 80°C and 120°C; R 2a Ga-OC 1~4 If alkyl or cyano, in the presence of a suitable temperature between 60 and 150°C, in the presence of a sodium 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 organophosphine ligand such as dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (XPhos) or (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XantPhos), in the presence of potassium tert-butoxide, in a suitable solvent such as toluene or NMP. Step 3: at a suitable temperature between room temperature and 100°C, in the presence of a metal 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 H pressure, such as 1-3 bar; Step 4: in the presence of a suitable palladium catalyst, such as, for example, tris(dibenzylideneacetone)dipalladium, and a ligand, such as, for example, Xantphos, in the presence of an inorganic base, such as, for example, cesium carbonate, in a suitable solvent, such as, for example, 1,4-dioxane, at a suitable temperature, such as, for example, 80°C to 130°C; Step 5: in the presence of an acid such as hydrochloric acid, in a suitable solvent such as water or acetonitrile, at a suitable temperature of 40°C to 100°C; Step 6: in the presence of a reducing agent such as, for example, sodium cyanoborohydride or sodium triacetoxyborohydride, in the presence of a Lewis acid such as zinc chloride or a Bronsted acid such as acetic acid, in a suitable solvent such as, for example, dichloromethane, 1,2-dichloroethane or methanol, at a suitable temperature between room temperature and 80°C; Step 7: at a suitable temperature between 0°C and 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; Process 8:R 3 is other than hydrogen, C 1~6 Alkyl iodide or C 3~6 Cycloalkyl-substituted C 1~6 In the presence of a suitable electrophile such as an alkyl iodide; Step 9: When PG=Boc, in the presence of a suitable acid such as trifluoroacetic acid, in a suitable solvent such as dichloromethane, at a suitable temperature in the range of 0° C. to 40° C., such as room temperature. When PG is a different protecting group as defined herein, general deprotection conditions known to those skilled in the art can be used. Step 10: For 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, for example, sodium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent such as, for example, methanol, or dichloromethane, or 1,2-dichloroethane, optionally in the presence of zinc chloride or acetic acid or sodium acetate; for alkylation reactions using LG-Y: at a suitable temperature, for example, room temperature, in the presence of a suitable deprotonating agent, an inorganic base such as, for example, sodium hydride or potassium carbonate, or an amine base such as triethylamine, in a suitable aprotic solvent such as, for example, dimethylformamide, or dimethylsulfoxide, or acetonitrile.

[0161] Scheme 2 In Scheme 2, X 2 represents fluoro, chloro, bromo, or iodo, and all other variables are defined according to the scope of the present invention.

[0162] [ka]

[0163] 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 others known in the art, in the presence of a base such as N,N-diisopropylethylamine, in a suitable solvent such as dimethylformamide, and the amine HNR xa R xb Alternatively, acid chlorides can be prepared by reacting a carboxylic acid with oxalyl chloride or thionyl chloride, optionally in a halogenated solvent such as dichloromethane, at temperatures ranging from 0° C. to room temperature. The amine HNR can then be reacted with the carboxylic acid, optionally in a solvent such as dichloromethane, and optionally in the presence of a tertiary amine such as N,N-diisopropylethylamine. xa R xb It may be reacted with

[0164] Scheme 3 In Scheme 3, PG represents a suitable protecting group such as, for example, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl, and X 1 represents a halogen, such as chloro, bromo, or iodo, or other leaving group, such as mesylate or tosylate; X 2 represents fluoro, chloro, bromo, or iodo, and all other variables are defined according to the scope of the present invention.

[0165] [ka]

[0166] In general, R 1a -C(=O)-NR xa R xb Compounds limited to can be prepared according to the following Reaction Scheme 3.

[0167] In Scheme 3, the following reaction conditions apply: Process 1:R 2b when is hydrogen, at a suitable temperature between room temperature and 80°C in the presence of a reducing agent such as, for example, sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent such as, for example, dichloromethane, 1,2-dichloroethane or methanol, optionally in the presence of zinc(II) chloride or acetic acid or sodium acetate; R 2b C 1~4 If it is alkyl, at a suitable temperature between 60 and 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, for example in the presence of zinc(II) chloride or titanium(IV) tetraisopropanolate. Step 2: at a suitable temperature between room temperature and 100°C, in the presence of a metal 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; Step 3: at a suitable temperature between 0°C and 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; Step 4: For example, at a suitable temperature such as 80°C to 130°C, in the presence of a suitable catalyst such as copper (Cu), in the presence of a base such as potassium carbonate or cesium carbonate, in a suitable aprotic solvent such as dimethylformamide or the like; alternatively, a copper(I) source such as CuI may 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 of 80°C to 150°C. Step 5: For example, 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 others known in the art, in the presence of a base such as N,N-diisopropylethylamine, in a suitable solvent such as dimethylformamide, and an amine HNR xa R xb Alternatively, the acid chloride can be prepared by reacting the acid intermediate with oxalyl chloride or thionyl chloride, optionally in a halogenated solvent such as dichloromethane, at temperatures ranging from 0° C. to room temperature. The amine HNR can then be reacted with the acid intermediate with oxalyl chloride or thionyl chloride, optionally in a solvent such as dichloromethane, and optionally in the presence of a tertiary amine such as N,N-diisopropylethylamine. xa R xb It may be reacted with Process 6:R 2a C 3~6 Cycloalkyl, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4if R is alkyl, in the presence of an alkyl or alkenyl boronic acid or boronic acid ester or alkyl trifluoroborate potassium salt, in the presence of a suitable base such as, for example, potassium carbonate or cesium carbonate, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), in a suitable solvent such as, for example, dioxane or dimethylformamide and water, at a suitable temperature in the range of room temperature to 100°C; 2a When is Me, a boron-containing reagent such as trimethylboroxine can be used in the presence of a suitable catalyst such as Pd(dppf)Cl2, in a suitable solvent such as dioxane or dimethylformamide and water, in the presence of an inorganic base such as potassium carbonate, at a reaction temperature between 80°C and 120°C; R 2a But C 3~6 Cycloalkyl, C 1~4 C substituted with alkyl or 1, 2, or 3 halo substituents 1~4 An additional step to achieve double bond reduction (if an alkenylboronic acid or boronic ester is used) to give an alkyl: 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 H pressure, for example, 1-3 bar, optionally in the presence of a base such as triethylamine.

[0168] Scheme 4 In Scheme 4, PG represents a suitable protecting group, for example, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyl, and PG 1 represents a suitable protecting group, such as, for example, tert-butyldimethylsilyl, and all other variables are defined according to the scope of the present invention.

[0169] [ka]

[0170] In Scheme 4, the following reaction conditions apply: Process 1:PG 1 is a silyl-containing protecting group, for example, at a suitable temperature such as 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, and in the presence of a base such as imidazole; Step 2: in the presence of a suitable acyl azide-forming reagent such as diphenylphosphoazide, in the presence of a suitable alcohol such as tert-butanol, 9-fluorenylmethanol, benzyl alcohol or 4-methoxybenzyl alcohol, in a suitable solvent such as toluene at a suitable temperature such as, for example, 80°C to 110°C; Step 3: at a suitable temperature, such as 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; Step 4: in the presence of a suitable oxidizing agent such as, for example, 2,2,6,6-tetramethylpiperidine 1-oxyl radical and (diacetoxyiodo)benzene, optionally in the presence of NaHCO3, in a suitable solvent such as, for example, dichloromethane or acetonitrile, at a suitable temperature such as, for example, 0°C to room temperature; Step 5: in the presence of a suitable Lewis acid such as titanium(IV) isopropoxide, in the presence of a suitable sulfinamide such as (R)-2-methyl-2-propanesulfinamide or (S)-2-methyl-2-propanesulfinamide or methyl-2-propanesulfinamide, in a suitable solvent such as tetrahydrofuran or 2-methyltetrahydrofuran, at a suitable temperature such as room temperature to 100°C; Step 6: A Grignard reagent (R 5a In the presence of organometallic reagents such as MgX; Step 7: in the presence of an acid such as hydrochloric acid in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 0°C to room temperature; alternatively, the deprotection can be carried out as follows: in the presence of molecular iodine in a suitable solvent such as a mixture of tetrahydrofuran and water at a suitable temperature such as 0°C to room temperature in the presence of a suitable base such as sodium carbonate, optionally in the presence of 4-dimethylaminopyridine.

[0171] It will be understood that, where appropriate functional groups are present, the compounds of the various formulae, or any intermediates used in their preparation, may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

[0172] The compounds of formula (I) may be synthesized in the form of racemic mixtures of enantiomers, which can be separated from one another according to art-known resolution procedures. Racemic compounds of formula (I) containing a basic nitrogen atom can be converted to the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. An alternative way to separate the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

[0173] In preparing compounds of the present invention, protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.

[0174] Pharmacology It has been found that the compounds of the present invention can block the interaction of menin with MLL proteins and oncogenic MLL fusion proteins themselves, or can be metabolized in vivo to a more active form (prodrug). Thus, compounds according to the present invention and pharmaceutical compositions comprising such compounds may be useful in the treatment or prevention, particularly the treatment, of diseases such as cancer, including but not limited to leukemia.

[0175] In particular, compounds according to the present invention and pharmaceutical compositions thereof may be useful for the treatment or prevention of cancer. According to one embodiment, cancers that may benefit from treatment with the menin / MLL inhibitors of the present invention include leukemia. In some embodiments, leukemia includes acute leukemia, chronic leukemia, myeloid leukemia, myeloid 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, leukemias exhibiting a HOX / MEIS1 gene expression signature, and the like.

[0176] In particular, the compounds according to the present invention and pharmaceutical compositions thereof may be useful in the treatment or prevention of leukemia, particularly nucleophosmin (NPM1) mutant leukemia, such as NPM1c.

[0177] In particular, the compounds according to the present invention and pharmaceutical compositions thereof are useful in the treatment of AML, particularly nucleophosmin (NPM1) mutant AML (i.e., NPM1 mut AML), more specifically, Abstract NPM1-mutant AML.

[0178] In particular, the compounds according to the present invention and pharmaceutical compositions thereof may be useful for treating or preventing MLL-rearranged leukemia, particularly MLL-rearranged AML or ALL.

[0179] In particular, the compounds according to the present invention and pharmaceutical compositions thereof may be useful for treating or preventing leukemia with an MLL gene alteration, particularly AML or ALL with an MLL gene alteration.

[0180] In particular, the compounds according to the present invention and pharmaceutical compositions thereof may be useful in the treatment or prevention of hematological cancers in subjects exhibiting NPM1 gene mutations and / or mixed lineage leukemia gene (MLL; MLL1; KMT2A) alterations, mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia, MLL-associated leukemia, MLL gene rearrangements / alterations or rearrangements / alterations, acute leukemia, chronic leukemia; and for inhibiting menin-MLL interaction when the MLL fusion protein target gene is HOX or MEIS1 in humans.

[0181] Thus, the present invention relates to compounds of formula (I), their tautomeric and stereoisomeric forms, and their pharmaceutically acceptable salts and solvates, for use as pharmaceuticals.

[0182] The present invention also 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 or solvate thereof, or a pharmaceutical composition, for the manufacture of a medicament.

[0183] The present invention also relates to a compound of formula (I) according to the present invention, a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use in the treatment, prevention, amelioration, control, or reduction of the risk of a disorder associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, wherein said treatment or prevention is affected or promoted by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.

[0184] The present invention also relates to the use of a compound of formula (I) according to the present invention, a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition, for the manufacture of a medicament for treating, preventing, ameliorating, controlling, or reducing the risk of a disorder associated with the interaction of menin with MLL proteins and oncogenic MLL fusion proteins in a mammal, including a human, wherein said treatment or prevention is affected or promoted by blocking the interaction of menin with MLL proteins and oncogenic MLL fusion proteins.

[0185] The present invention also relates to a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any one of the aforementioned diseases.

[0186] The present invention also relates to a compound of formula (I), a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any one of the aforementioned diseases.

[0187] The present invention also 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 treating or preventing any one of the aforementioned disease states.

[0188] The compounds of the present invention can be administered to mammals, preferably humans, to treat or prevent any one of the aforementioned diseases.

[0189] In view of the availability of compounds of formula (I), their tautomeric and stereoisomeric forms, and pharmaceutically acceptable salts and solvates thereof, methods are provided for treating warm-blooded animals, including humans, suffering from any one of the aforementioned diseases.

[0190] 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 man.

[0191] Therefore, the present invention also relates to a method for the treatment or prevention of any one of the aforementioned diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the invention.

[0192] Those skilled in the art will recognize that a therapeutically effective amount of a compound of the present invention is an amount sufficient to have therapeutic activity, and that this amount will vary depending, among other things, on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. An effective therapeutic daily dose is about 0.005 mg / kg to 100 mg / kg. The amount of a compound according to the present invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect may vary on an individual basis, for example, depending on the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

[0193] The present invention also provides compositions for preventing or treating the disorders mentioned herein, which compositions comprise 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.

[0194] While it is possible for an active ingredient (e.g., a compound of the present invention) to be administered alone, it is preferable to administer it as a pharmaceutical composition. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0195] The compounds of the invention can be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation containing a compound according to the invention and one or more additional therapeutic agents, as well as administration of a compound according to the invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.

[0196] Accordingly, one embodiment of the present invention relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anti-cancer agents as further active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.

[0197] The one or more other pharmaceutical agents and the compound according to the present invention can be administered simultaneously (e.g., in separate compositions or unit compositions) or sequentially in any order. In the latter case, the two or more compounds are administered within a period, amount, and manner sufficient to ensure that an advantageous or synergistic effect is achieved. It will be understood that the preferred method and order of administration, as well as the respective dosage amounts and regimes for each component of the combination, will depend on the particular other pharmaceutical agents and compounds of the present invention administered, their administration routes, the particular condition, particularly tumor, being treated, and the particular host being treated.

[0198] The following examples further illustrate the present invention. [Example]

[0199] Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively, could be synthesized by one skilled in the art by using well-known methods.

[0200] [Table 1]

[0201] As will be understood by those skilled in the art, compounds synthesized using the protocols as specified may exist as solvates, e.g., hydrates, and / or may contain residual solvents or trace impurities. Compounds or intermediates isolated as salt forms may be of integer stoichiometry, i.e., mono- or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the experimental section below is designated as an "HCl salt" without specifying the number of equivalents of HCl, this means that the number of equivalents of HCl was not determined. The same principle can be applied to, for example, "oxalates," "HCOOH salts" ("formates"), or

[0202] [ka] This also applies to all other salt forms mentioned in the experimental section, etc.

[0203] The stereochemical configuration about a center in some compounds may be designated "R" or "S" if the mixture has been separated and the absolute stereochemistry known, or if only one enantiomer has been obtained and the absolute stereochemistry known; for some compounds, the compound itself has been isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry has not been determined (even if the bonds are drawn stereospecifically), and the stereochemical configuration at the designated center may be designated "R" or "S." * R" or " * It is written as "S". * When a compound marked "R" is converted into another compound, the resulting compound's " * The "R" designation comes from the starting material.

[0204] For example, compound 16

[0205] [ka] It becomes clear that...

[0206] The stereochemical configuration of the two stereocenters is * Compounds designated by (e.g.,* R or * In S), the compound itself is isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry of the stereocenters has not been determined (even if the bonds are drawn stereospecifically). * The configuration of the first stereocenter designated by is * This is independent of the configuration of the second stereocenter designated by " * R" or " * S" are randomly assigned to such molecules. Similarly, the stereochemical configuration of the three stereocenters is * Compounds designated by (e.g., * R or * In S), the compound itself is isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry of the stereocenters has not been determined (even if the bonds are drawn stereospecifically). * The configuration of a stereocenter designated by is * This is independent of the configuration of other stereocenters specified by " * R" or " * S" is randomly assigned to such molecules.

[0207] For example, in the case of compound 26,

[0208] [ka] This means that the compound is:

[0209] [ka]

[0210] Those skilled in the art will appreciate that the above paragraphs regarding stereochemical configuration also apply to intermediates.

[0211] Those skilled in the art will understand that, even if not explicitly mentioned in the experimental protocols below, column chromatographic purification was typically followed by collection of desired fractions and evaporation of the solvent.

[0212] If stereochemistry is not specified, this means a mixture of stereoisomers or no determined stereochemistry, unless otherwise specified or clear from the context.

[0213] When a stereocenter is designated "RS," this means that a racemic mixture was obtained at the indicated center, unless otherwise stated.

[0214] A double bond designated EZ means that the compound / intermediate was obtained as a mixture of E and Z isomers.

[0215] Preparation of Intermediates and Compounds For intermediates that were used in the next reaction step as crude or as partially purified intermediates, in some cases no molar amount is stated for such intermediate in the next reaction step, or alternatively an estimated molar amount or theoretical molar amount is indicated in the reaction protocols set out below for such intermediate in the next reaction step.

[0216] Preparation of Intermediate 1:

[0217] [ka] 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 (approximately 12.3 g) as a brown solid, which was dissolved in THF (75 mL) and mixed with a solution of NaIO (2.9 g, 135.6 mmol) in HO (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 NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% EtOAc in hexanes (starting with 0% EtOAc-50% EtOAc) to give Intermediate 1 (6.0 g, 57.4% yield) as a yellow solid.

[0218] Preparation of intermediate 2:

[0219] [ka] To a mixture of intermediate 1 (4.3 g, 17.684 mmol) and trans tert-butyl (3-aminocyclobutyl)carbamate (CAS: 871014-19-6) (3.95 g, 21.2 mmol) in DCE (150 mL) was added acetic acid (0.1 mL) and NaBHCN (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 NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 25% EtOAc in hexane to give intermediate 2 (1.3 g, 18% yield) as a yellow solid.

[0220] The following intermediates were synthesized by a method similar to that described for intermediate 2:

[0221] [Table 2]

[0222] Preparation of intermediate 31:

[0223] [ka] A solution of intermediate 54 (400 mg, 1.15 mmol) and trans tert-butyl (3-aminocyclobutyl)carbamate (CAS: 871014-19-6) (258 mg, 1.38 mmol) in methanol (10 mL) was stirred at room temperature for 3 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 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). To this mixture were added sodium cyanoborohydride (200 mg, 3.2 mmol) and zinc(II) chloride (144 mg, 1.06 mmol). The solution was stirred at room temperature for 2 hours. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO (anhydrous), and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50% EA in petroleum ether to give Intermediate 31 (470 mg, purity 90%, yield 79.9%) as a yellow solid.

[0224] Preparation of intermediate 23:

[0225] [ka] To a mixture of intermediate 22 (500 mg, 1.329 mmol) in DCM (10 mL) was added trans tert-butyl(3-aminocyclobutyl)carbamate (297 mg, 1.595 mmol) and 0.1 mL of acetic acid at room temperature. The mixture was stirred at room temperature for 2 hours. Then, NaBHCN (167 mg, 2.658 mmol) was added. The mixture was continued to stir at room temperature for 3 hours. The mixture was diluted with 100 mL of water and extracted three times with EtOAc (100 mL). The combined layers were washed with brine, dried over NaSO, filtered, and concentrated, and the residue was purified by silica gel column chromatography eluting with 0%-50% EtOAc in petroleum ether to give intermediate 23 (501 mg, 68% yield) as a yellow solid.

[0226] Preparation of intermediate 3:

[0227] [ka] 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 powder (2.12 g, 37.88 mmol). The mixture was stirred at 80° C. for 1 hour. The mixture was filtered through a short pad of Celite®, diluted with water (100 mL), and extracted three times with EtOAc (30 mL). The combined organic phase was 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.

[0228] The following intermediates were synthesized by a method similar to that described for intermediate 3:

[0229] [Table 3]

[0230] Preparation of intermediate 4:

[0231] [ka] To a solution of intermediate 3 (2.7 g, 6.02 mmol, purity 82.8%) 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 and dried to give intermediate 4 (2.2 g, 91% yield) as a white solid.

[0232] [Table 4]

[0233] Preparation of Intermediate 5:

[0234] [ka] To a solution of intermediate 4 (2.1 g, 5.11 mmol) and 5-fluoro-2-iodobenzoic acid (2.04 g, 7.67 mmol) in DMF (100 mL) under nitrogen was added KCO (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.

[0235] [Table 5]

[0236] Preparation of Intermediate 6:

[0237] [ka] To a solution of crude intermediate 5 in DMF was added HATU (3.87 g, 10.18 mmol), DIEA (1.75 g, 13.57 mmol), and N-ethylpropan-2-amine (1.97 g, 22.62 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0%-5% MeOH in DCM to give intermediate 6 as a yellow solid.

[0238] [Table 6]

[0239] Preparation of intermediate 7:

[0240] [ka] To a solution of intermediate 6 (1.2 g, 1.9 mmol), trimethylboroxine (2.3 g, 17.75 mmol), and K2CO3 (736 mg, 5.32 mmol) in 1,4-dioxane (50 mL) and water (10 mL) under a nitrogen atmosphere was added Pd(dppf)Cl2 (130 mg, 0.018 mmol). The mixture was then heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted three times with DCM (30 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%-100% ethyl acetate in petroleum ether to give intermediate 7 (0.58 g, 56.5% yield) as a yellow solid.

[0241] [Table 7]

[0242] Preparation of intermediate 8:

[0243] [ka] To a solution of intermediate 7 (100 mg, 0.18 mmol) in dry DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil) (21 mg, 0.54 mmol) under a nitrogen atmosphere at 0° C. The mixture was stirred for 30 minutes at 0° C., followed by the addition of iodomethane (76 mg, 0.54 mmol). The resulting mixture was further stirred at 0° C. for 2 hours. 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%-10% methanol in dichloromethane to give intermediate 8 (60 mg, 60% yield) as a yellow solid.

[0244] [Table 8]

[0245] Preparation of intermediate 33:

[0246] [ka] To a solution of intermediate 32 (100 mg, 90% purity, 0.17 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (20 mg, 0.5 mmol). The solution was stirred at 0 °C for 30 min. Iodomethane (49 mg, 0.34 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 (anhydrous), and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 50% EA in petroleum ether to give intermediate 33 (50 mg, 90% purity, 48.7% yield) as a white solid.

[0247] Preparation of intermediate 17:

[0248] [ka] To a solution of intermediate 1 (4.2 g, 17.3 mmol) in toluene (20 mL) was added p-toluenesulfonic acid (3.65 g, 20.8 mmol) and ethane-1,2-diol (1.4 g, 22.5 mmol). The mixture was stirred at 120 °C overnight. After cooling to room temperature, water (30 mL) was added and the mixture was extracted with EtOAc (50 mL) three times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-6% EtOAc in petroleum ether to give intermediate 17 (3.3 g, 65.8% yield) as a white solid.

[0249] Preparation of intermediate 19:

[0250] [ka] To a solution of 5-fluoro-2-iodobenzoic acid (5 g, 17.857 mmol) in DCM (100 mL) was added oxalyl chloride (2.493 g, 19.642 mmol) dropwise at 0° C., followed by DMF (130 mg, 1.786 mmol). After stirring at 0° C. for 2 h, the mixture was concentrated to remove the solvent. The residue was dissolved in DCM (100 mL) and added dropwise to a mixture of diisopropylamine (2.761 mL, 19.642 mmol) and triethylamine (6.932 mL, 53.570 mmol) in DCM (100 mL) at 0° C. The resulting mixture was further stirred for 4 h while slowly warming to room temperature. Water (100 mL) was then added, the organic phase was separated, and the aqueous phase was extracted twice with DCM (200 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to give Intermediate 19 (4.9 g, 80% yield) as a pale yellow solid.

[0251] Preparation of intermediate 29:

[0252] [ka] To a solution of 5-fluoro-2-iodobenzoic acid (20 g, 71.43 mmol) in DCM (150 mL) was added oxalyl chloride (9.97 g, 78.57 mmol) dropwise at 0° C., followed by DMF (499 mg, 6.82 mmol). After stirring at 0° C. for 2 h, 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 h while slowly warming to room temperature. Water (200 mL) was then 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 give the crude product, which was further purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to give Intermediate 29 (16.7 g, 69% yield) as a white solid.

[0253] Preparation of intermediate 21:

[0254] [ka] To a mixture of intermediate 20 (3 g, 14.983 mmol) and intermediate 19 (6.278 g, 17.980 mmol) in dioxane (50 mL), CsCO (9.764 g, 29.966 mmol), Xantphos (0.866 g, 1.498 mmol), and Pd(dba) (0.686 g, 0.749 mmol) were added at room temperature. The mixture was stirred at 120 °C for 20 h. 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 NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% EtOAc in petroleum ether to give intermediate 21 (5.0 g, 83% yield) as a yellow oil.

[0255] [Table 9]

[0256] Preparation of intermediate 30:

[0257] [ka] To a mixture of 4-(1,3-dioxolan-2-yl)pyridin-3-amine (4.2 g, 22.747 mmol) and Intermediate 29 (9.148 g, 27.296 mmol) in dioxane (50 mL) was added CsCO (14.823 g, 45.494 mmol), Xantphos (1.315 mg, 2.275 mmol), and Pd(dba) (1.041 g, 1.137 mmol) at room temperature. The mixture was stirred at 120 °C for 20 h. The residue was diluted with 300 mL of water and extracted three times with EtOAc (500 mL). The combined organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% EtOAc in petroleum ether to give the intermediate (6.5 g, 70% yield) as a yellow oil.

[0258] Preparation of intermediate 22:

[0259] [ka] To a mixture of intermediate 21 (5 g, 11.831 mmol) in acetonitrile (10 mL) was added hydrochloric acid (10 mL, 4N in water) at room temperature. The mixture was continued to stir at 50° C. for 2 hours. The mixture was diluted with 300 mL of water and extracted three times with EtOAc (300 mL). The organic phase was washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% EtOAc in petroleum ether to give intermediate 22 (3.6 g, 87.6% yield) as a yellow solid.

[0260] [Table 10]

[0261] Preparation of intermediate 54:

[0262] [ka] To a mixture of intermediate 30 (6.5 g, 16.536 mmol) in acetonitrile (10 mL) was added hydrochloric acid (10 mL, 4N in water) at room temperature. The mixture was continued to stir at 50 °C for 2 hours. 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, dried over NaSO, filtered, and concentrated. Silica gel column chromatography eluting with 0%-50% EtOAc in petroleum ether to give intermediate 54 (4.7 g, 86.2% yield) as a yellow solid.

[0263] Preparation of intermediate 24:

[0264] [ka] To a solution of intermediate 23 (400 mg, 0.68 mmol), triethylamine (353 mg, 3.41 mmol) in DCM (20 mL) was added a solution of triphosgene (128 mg, 0.41 mmol) in 20 mL of DCM dropwise over 20 min. After stirring at 20° C. for 5 h, the mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with 50%-100% EtOAc in petroleum ether to give intermediate 24 (207 mg, 55.07% yield) as a yellow solid.

[0265] [Table 11]

[0266] Preparation of intermediate 32:

[0267] [ka] To a solution of intermediate 31 (250 mg, 90% purity, 0.45 mmol) and TEA (136 mg, 1.35 mmol) in THF (10 mL) was added bis(trichloromethyl)carbonate (67 mg, 0.23 mmol) at 0 °C for 0.5 h under a nitrogen atmosphere. The resulting mixture was stirred at 30 °C for 2 h. The reaction mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over NaSO (anhydrous), and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 50% EA in petroleum ether to give intermediate 32 (130 mg, 90% purity, 49.4% yield) as a yellow solid.

[0268] Preparation of intermediate 41:

[0269] [ka] To a solution of intermediate 40 (100 mg, 0.410 mmol) in methanol (5 mL) under nitrogen was added Pd / C (10% w / w) (50 mg) and the mixture was kept under H gas at 1 bar pressure for 16 h at room temperature. The reaction was filtered through Celite® and evaporated to dryness to give intermediate 41 (85 mg) as a crude product, which was used in the next step without further purification.

[0270] Preparation of intermediate 35:

[0271] [ka] To a solution of compound 60 (200 mg, 0.32 mmol) in acetonitrile (5 mL) was added 1 M aqueous hydrochloric acid (1.3 mL), and the mixture was stirred at 50 °C for 10 minutes. 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, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 5% MeOH in DCM to give intermediate 35 (130 mg, 70.31% yield) as a white solid.

[0272] Preparation of Compound 1:

[0273] [ka] Intermediate 7 (160 mg, 0.29 mmol) was added to 4N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then basified with aqueous NaOH (1 M) to pH 10. The mixture was extracted three times with DCM (20 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-10% methanol in dichloromethane to give compound 1 (54 mg, 43% yield) as a yellow oil.

[0274] [Table 12]

[0275] Preparation of Compound 3:

[0276] [ka] 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) (66 mg, 0.311 mmol). The mixture was stirred at room temperature for 1 h, evaporated, and the residue was purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane to give compound 3 (43 mg, 73% yield) as a yellow solid.

[0277] [Table 13-1]

[0278] [Table 13-2]

[0279] [Table 13-3]

[0280] [Table 13-4]

[0281] [Table 13-5]

[0282] Preparation of Compound 8:

[0283] [ka] 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) (82 mg, 0.39 mmol). The solution was stirred at room temperature for 2 hours. 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 NaSO, and filtered. The residue was purified by preparative HPLC (SunFire C18 150 × 19 mm × 5 μm column, mobile phase A: water (0.1% NHHCO), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, gradient: 25% B to 65% B) to give compound 8 (15 mg, 21.1% yield) as a white solid.

[0284] Preparation of Compound 9:

[0285] [ka] To a solution of compound 1 (200 mg, 0.39 mmol) in 1,2-dichloroethane (5 mL), 4-methyltetrahydro-2H-pyran-4-carbaldehyde (57 mg, 0.43 mmol), acetic acid (0.05 mL), and NaBH(OAc) (251 mg, 1.16 mmol) were added under ice-water bath. The reaction mixture was stirred at room temperature for 4 hours. It was poured into saturated aqueous NaHCO and extracted twice with DCM (10 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography eluting with 0%-5% methanol in 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 length, 5 μm; mobile phase: MeOH:DCM:DEA = 90:10:0.2 at 30 mL / min) to give compound 9 (90 mg, 22.58% yield) as a white solid.

[0286] Preparation of Compound 11:

[0287] [ka] To a solution of compound 1 (1.3 g, 2.66 mmol), tetrahydro-4H-pyran-4-one (327 mg, 3.19 mmol) in methanol (5 mL) in a sealed tube was added NaBHCN (513 mg, 7.99 mmol) and ZnCl (371 mg, 2.66 mmol). After stirring at 65 °C for 16 h, the mixture was filtered, and the filtrate was concentrated to give the crude compound, which was purified by silica gel column chromatography eluting with 0%-12% methanol in dichloromethane 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 length, 10 μm; mobile phase: MeOH:DCM:DEA = 90:10:0.2 at 30 mL / min; temperature: 38 °C) to give compound 11 (820 mg, 58.06% yield) as a white solid.

[0288] Preparation of Compound 12:

[0289] [ka] To a mixture of compound 1 (50 mg, 0.108 mmol) in 1,2-dichloroethane (5 mL) was added cyclobutanecarbaldehyde (18 mg, 0.216 mmol) at room temperature. The mixture was stirred at room temperature for 2 minutes. Then, NaBH(OAc) (68 mg, 0.324 mmol) was added. The mixture was continued to stir at room temperature for 3 hours. 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 NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% ethyl acetate in 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 from 10% B to 65% B) to give compound 12 (15 mg, 25.9% yield) as a white solid.

[0290] Preparation of Compound 13:

[0291] [ka] To a mixture of compound 1 (50 mg, 0.108 mmol) in 1,2-dichloroethane (5 mL) was added pivalaldehyde (19 mg, 0.216 mmol) at room temperature. The mixture was stirred at room temperature for 2 minutes. Then, NaBH(OAc) (68 mg, 0.324 mmol) was added to the mixture. The mixture was continued to stir at room temperature for 3 hours. 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 NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-50% ethyl acetate in 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%).

[0292] Preparation of Compound 14:

[0293] [ka] To a solution of compound 59 (50 mg, 0.10 mmol) in 1,2-dichloroethane (5 mL), tetrahydro-2H-pyran-4-carbaldehyde (18 mg, 0.15 mmol), acetic acid (0.05 mL), and NaBH(OAc) (67 mg, 0.30 mmol) were added under ice-water bath cooling. The reaction mixture was stirred at room temperature for 4 hours, poured into saturated aqueous NaHCO, 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 the crude product, which was purified by silica gel column chromatography eluting with 0%-8% methanol in dichloromethane to give compound 14 (12 mg, 22% yield) as a white solid.

[0294] Preparation of Compound 10:

[0295] [ka] To a solution of compound 3 (50 mg, 0.09 mmol) in methanol (2 mL) was added formaldehyde (68 mg, 0.84 mmol, 37% w / w in water) and NaBH(OAc) (54 mg, 0.25 mmol) while cooling in an ice-water bath. The reaction mixture was stirred at room temperature for 4 h, then poured into saturated aqueous NaHCO and extracted twice with DCM (20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography eluting with 0%-12% methanol in dichloromethane to give compound 10 (12 mg, 24.14% yield) as a yellow solid.

[0296] Preparation of compounds 15, 16, and 17:

[0297] [ka] To a mixture of compound 1 (140 mg, 0.319 mmol) in MeOH (5 mL) were added 3,3-dimethyltetrahydro-4H-pyran-4-one (122.475 mg, 0.956 mmol) and ZnCl (65.119 mg, 0.478 mmol). After stirring the mixture at 60 °C for 0.5 h, NaBHCN (40.033 mg, 0.637 mmol) was added, and the mixture was continued to stir at 50 °C for 3 h. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO and extracted three times with DCM (10 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, 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% NHOH + 10 mM NHHCO), mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient conditions: 50% B - 60%) to give compound 15 (130 mg, yield 71%) as a yellow solid.

[0298] 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 CO, B: MeOH + 0.1% NHOH, A:B = 90:10 at 11 mL / min, column temperature: 45 °C).

[0299] 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).

[0300] Preparation of compounds 26, 27, 33, 34:

[0301] [ka] To a mixture of compound 1 (660 mg, 1.502 mmol) in MeOH (10 mL), 3-methyltetrahydro-4H-pyran-4-one (CAS: 119124-53-7) (514.195 mg, 4.505 mmol) and ZnCl (306.991 mg, 2.252 mmol) were added at room temperature. The mixture was stirred at room temperature for 0.5 hours. Then, NaBHCN (188.727 mg, 3.003 mmol) was added, and the mixture was continued to stir at 50 °C for 2 hours. The mixture was washed with saturated aqueous NaHCO and brine, dried, filtered, and concentrated. The mixture was purified by preparative HPLC (Waters XBridge C8 5 μm, 19 × 150 mm column, mobile phase A: water (0.1% NH OH + 10 mM NH HCl), mobile phase B: acetonitrile, flow rate: 17 mL / min, gradient conditions: 29% B - 34% B). The first and second fractions were collected separately and further purified. The first fraction was further purified by preparative SFC (stationary phase: CHIRALPAK AD 5 μm, 10 × 250 mm column, mobile phase A: supercritical CO , B: EtOH:MeOH (3:1) + 0.1% NH OH, A:B = 85:15 at 11 mL / min, column temperature: 45 °C). 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 CO, B: EtOH + 0.1% NH OH, A:B = 88:12 at 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.

[0302] [Table 14-1]

[0303] [Table 14-2]

[0304] [Table 14-3]

[0305] [Table 14-4]

[0306] [Table 14-5]

[0307] Preparation of Compound 21:

[0308] [ka] 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 hours. The mixture was concentrated in vacuo. The residue was diluted with aqueous NaOH (1 M, 50 mL) and extracted three times with DCM (30 mL). The combined organic phases were dried over NaSO and filtered. The filtrate 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 μm, mobile phase A: water (containing 0.1% NHHCO), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, gradient: 10% B to 40% B to give compound 21 (15 mg, 37.6% yield) as a yellow solid.

[0309] Preparation of Compound 28:

[0310] [ka] A mixture of intermediate 33 (500 mg, 0.09 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at room temperature for 2 hours. 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 layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: SunFire C18 150 × 19 mm × 5 μm, mobile phase A: water (0.1% NHHCO), mobile phase B: acetonitrile, flow rate: 15 mL / min, gradient condition: 10% B to 45% B) to give compound 28 (15 mg, yield 36) as a white solid.

[0311] Preparation of compounds 29 and 30:

[0312] [ka] 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) (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 (36 mg, 34.90% yield) as the formate salt, which was further separated by chiral preparative HPLC (column: IA 4.6 cm i.d. × 25 cm length, 5 μm; mobile phase: hexane:EtOH:DEA = 70:30:0.2 at 30 mL / min; temperature: 38 °C). The first fraction was collected as compound 29 (7 mg, 19% yield) as a white solid, and the second fraction was collected as compound 30 (10 mg, 27% yield) as a white solid.

[0313] [Table 15]

[0314] Preparation of Compound 39:

[0315] [ka] To a mixture of compound 59 (100 mg, 0.209 mmol) in 1,2-dichloroethane (5 mL) was added tetrahydro-4H-pyran-4-one (42 mg, 0.419 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Then, NaBH(OAc) (81 mg, 0.628 mmol) was added to the mixture. The mixture was continued to stir at room temperature for 3 hours. 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 NaSO, filtered, and concentrated. Silica gel column chromatography eluting with 0%-50% ethyl acetate in petroleum ether to give the product (50 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 39 (26 mg, 95.1% purity by LCMS, 23.1% yield) as a white solid.

[0316] Preparation of Compound 58:

[0317] [ka] 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, and concentrated. The remaining compound 58 (60 mg, crude) was used in the next step without further purification.

[0318] Preparation of Compound 59:

[0319] [ka] 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 under vacuum. The residue was dissolved in water (5 mL). The pH was adjusted to about 10 with 1 M NaOH (aqueous) solution. 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.

[0320] [Table 16]

[0321] LCMS (Liquid Chromatography / Mass Spectrometry) General Procedure High Performance Liquid Chromatography (HPLC) measurements were performed using the LC pump, diode-array (DAD) or UV detector, and column specified in each method. Additional detectors were included if necessary (see methods table below).

[0322] The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data collection was performed with appropriate software.

[0323] Compounds were analyzed by their experimental retention times (R t ) and ions. Unless otherwise specified in the tables of data, the reported molecular ions are [M+H]+ (protonated molecule) and / or [MH] - (deprotonated molecule). If the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH4] + , [M+HCOO] - For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained for the lowest isotopic mass. All results are obtained with experimental uncertainties typically associated with the methods used.

[0324] Hereinafter, "SQD (Single Quadrupole Detector)" means a single quadrupole detector, "RT (room temperature)" means room temperature, "BEH (bridged ethylsiloxane / silica hybrid)" means a bridged ethylsiloxane / silica hybrid, "HSS (High Strength Silica)" means high-strength silica, and "DAD" means a diode array detector.

[0325] [Table 17-1]

[0326] [Table 17-2]

[0327] [Table 18-1]

[0328] [Table 18-2]

[0329] NMR: NMR method Several NMR experiments were performed at ambient temperature (298.6 K) using a Bruker Avance III 400 spectrometer equipped with a BBO 400 MHz S1 5 mm probehead with z-gradients, operating at 400 MHz for protons and 100 MHz for carbon, using an internal deuterium lock. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are in Hz.

[0330] Some NMR experiments were performed at ambient temperature (298.6 K) using a Varian 400-MR spectrometer equipped with a Varian 400 4NUC PFG probehead with z-gradients, operating at 400 MHz for protons and 100 MHz for carbon, using an internal deuterium lock. Chemical shifts (δ) are reported in parts per million (ppm). J values ​​are in Hz.

[0331] Several NMR experiments were performed at ambient temperature (298.6 K) using a Varian 400-VNMRS spectrometer equipped with a Varian 400 ASW PFG probehead with z-gradients, operating at 400 MHz for protons and 100 MHz for carbon, using an internal deuterium lock. Chemical shifts (d) are reported in parts per million (ppm). J values ​​are in Hz.

[0332] [Table 19]

[0333] Pharmacological part 1) Menin / MLL homogenous time-resolved fluorescence (HTRF) assay To an untreated white 384-well microtiter plate, 40 nL of 200x test compound in DMSO and 4 μL of 2x terbium-chelate-labeled menin (preparation described below) in assay buffer (40 mM Tris·HCl, pH 7.5, 50 mM NaCl, 1 mM DTT (dithiothreitol), and 0.05% Pluronic F-127) were added. After incubation of the test compound and terbium-chelate-labeled menin for 30 min at ambient temperature, 4 μL of 2x FITC-MBM1 peptide (FITC-β-alanine-SARWRFPARPGT-NH2) ("FITC (fluorescein isothiocyanate)" in assay buffer 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 menin·FITC-MBM1 complex present in the assay mixture is determined by measuring the homogeneous time-resolved fluorescence (HTRF) of the terbium / FITC donor / acceptor fluorophore pair at ambient temperature using an EnVision microplate reader (excitation 337 nm / terbium emission 490 nm / FITC emission 520 nm). The fluorescence resonance energy transfer (HTRF) value is calculated as the ratio of the fluorescence emission intensities of the FITC and terbium fluorophores (F em 520nm / F em The binding assay is expressed as a 490 nm (490 nm). The final concentrations of reagents in the binding assay are 200 pM terbium chelate-labeled menin, 75 nM FITC-MBM1 peptide, and 0.5% DMSO in assay buffer. Dose-response titration of test compounds is typically performed using an 11-point, 4-fold serial dilution scheme starting at 10 μM.

[0334] Compound potency was determined by first calculating the % inhibition at each compound concentration according to Equation 1: Inhibition % = (((HC-LC)-(HTRF 化合物 -LC)) / (HC-LC)) × 100 (Equation 1) where LC and HC are the HTRF values ​​of the assay in the presence or absence of a saturating concentration of a compound that competes with FITC-MBM1 for binding to menin, and HTRF 化合物 (where ≈ 0.05 is the HTRF value measured in the presence of the test compound). HC and LC HTRF values ​​represent the average of at least 10 replicate experiments per plate. For each test compound, the % inhibition values ​​were plotted against the logarithm of the test compound concentration, and the IC was determined by fitting these data to Equation 2. 50 Get the value: Inhibition % = bottom + (top - bottom) / (1 + 10^((logIC 50 -log[compound])×h))(Formula 2) where bottom and top are the lower and upper asymptote of the dose-response curve, respectively, and IC 50 is the concentration of compound that inhibits the signal by 50%, and h is the Hill coefficient).

[0335] Preparation of terbium cryptate labeling of menin: Menin (a.a.1-610-6xHis tag, 2.3 mg / mL in 20 mM Hepes (2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid), 80 mM NaCl, 5 mM DTT (dithiothreitol), pH 7.5) was labeled with terbium cryptate as follows: 200 µg of menin was buffer-exchanged into 1x Hepes buffer. 6.67 µM menin was incubated with an 8-fold molar excess of NHS (N-hydroxysuccinimide)-terbium cryptate at room temperature for 40 min. Half of the labeled protein was purified from free label by running the reaction on a NAP5 column with elution buffer (0.1 M Hepes, pH 7 + 0.1% BSA (bovine serum albumin)). The remaining half was eluted with 0.1 M phosphate buffered saline (PBS), pH 7. 400 μL of eluate was collected for each, aliquoted, and frozen at −80° C. The final concentrations of terbium-labeled menin protein were 115 μg / mL in Hepes buffer and 85 μg / mL in PBS buffer, respectively.

[0336] MENIN protein sequence (SEQ ID NO: 1): MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNVPELTFQPSPAPDPPGGLTYFPVADLSIIAALYARFTAQIRGAVDLSLYPREGGVSSRELVKKVSDVIWNSLSRSYFKDRAHIQSLFSFITGTKLDS SGVAFAVVGACQALGLRDVHLALSEDHAWVVFGPNGEQTAEVTWHGKGNEDRRGQTVNAGVAERSWLYLKGSYMRCDRKMEVAFMVCAINPSIDLHTDSLELLQLQQKLLWLLYDLGHLERYPMALGNLADLEELEPTPGRPDPLTLYHKGIAS AKTYYRDEHIYPYMYLAGYHCRNRNVREALQAWADTATVIQDYNYCREDEEIYKEFFEVANDVIPNLLKEAASLLEAGEERPGEQSQGTQSQGSALQDPECFAHLLRFYDGICKWEEGSPTPVLHVGWATFLVQSLGRFEGQVRQKVRIVSREA EAAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTGQGAVSGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQSEKMKGMKELLVATKINSSAIKLQLTAQSQVQMKKQKVSTPSDYTLSFLKRQRKGLHHHHHH

[0337] 2a) Proliferation assay The antiproliferative effects of menin / MLL protein / protein interaction inhibitor test compounds 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, which have an NPM1c gene mutation, were also tested. MLL-rearranged cell lines (e.g., MOLM14) and NPM1c-mutated cell lines exhibit a stem cell-like HOXA / MEIS1 gene expression signature. To exclude compounds that exhibit general cytotoxic effects, KO-52 was used as a control cell line containing two MLL (KMT2A) wild-type alleles.

[0338] 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). KO-52 and OCI-AML3 cell lines were grown 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). During culture, cells were maintained at 0.3–2.5 million cells / ml and not more than 20 passages.

[0339] To evaluate antiproliferative effects, 200 MOLM14 cells, 200 OCI-AML3 cells, or 300 KO-52 cells were seeded in 200 μL of medium per well of a 96-well round-bottom ultra-low attachment plate (Costar, catalog no. 7007). Cell seeding numbers were selected based on growth curves to ensure linear growth throughout the experiment. Test compounds were added at different concentrations, and DMSO content was normalized to 0.3%. Cells were incubated at 37°C and 5% CO for 8 days. Spheroid-like growth was measured in real time by live-cell imaging (IncuCyteZOOM, Essenbio, 4x objective) with image acquisition on day 8. Confluence (%), as a measure of spheroid size, was determined using the integrated analysis tool.

[0340] To determine the effect of test compounds over time, the confluence in each well was calculated as a measure of spheroid size. The confluence of the highest dose of reference compound was used as a baseline for LC (Low control), and the confluence of DMSO-treated cells was used as 0% cytotoxicity (High Control, HC).

[0341] Absolute IC as a percentage change in confluence as follows: 50 The values ​​were calculated: LC = low control: cells treated with, for example, 1 μM of the cytotoxic agent staurosporine, or cells treated with, for example, a high concentration of a surrogate reference compound HC = High control: average confluence (%) (DMSO-treated cells) Effectiveness % = 100 - (100 x (sample - LC) / (HC - LC))

[0342] IC was measured using GraphPad Prism (version 7.00). 50 was calculated. A dose-response equation was used for plots of % effect versus Log10 compound concentration, with a variable slope and a maximum fixed at 100% and a minimum fixed at 0%.

[0343] 2b) MEIS1 mRNA expression assay MEIS1 mRNA expression upon compound treatment was examined using the Quantigene Singleplex assay (Thermo Fisher Scientific). This technology allows for direct quantification of mRNA targets using probes hybridizing to predetermined target sequences of interest, and signals are detected using the Envision Multimode plate reader (PerkinElmer). The MOLM14 cell line was used for this experiment. Cells were seeded at 3,750 cells / well in a 96-well plate in the presence of increasing concentrations of compound. After 48 hours of incubation with compound, cells were lysed in lysis buffer and incubated at 55°C for 45 minutes. Cell lysates were mixed with a human MEIS1-specific capture probe or a human RPL28 (ribosomal protein L28)-specific probe as a normalization control, as well as a blocking probe. The cell lysates were then transferred to a custom assay hybridization plate (Thermo Fisher Scientific) and incubated at 55°C for 18–22 hours. The plate was then washed to remove unbound material, followed by the sequential addition of preamplifier, amplifier, and labeled probe. Signal (= gene number) was measured on the Envision Multimode plate reader. IC was determined by dose-response modeling using appropriate software. 50For all non-housekeeper gene responses, equal numbers were corrected for background and relative expression. For each sample, each test gene signal (background subtracted) was divided by the normalized gene signal (RPL28: background subtracted). Fold changes were 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 calculated as IC 50 was used to calculate.

[0344] [Table 20-1]

[0345] [Table 20-2]

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R １ａ is hydrogen, cyano, halo, Het, -C(=O)-NR ｘａ R ｘｂ , -S(=O) ２ -R １８ , -C(=O)-OC １～４ Alkyl-NR ２２ａ R ２２ｂ , -C(=O)-OC １～４ Alkyl, 【Chemistry 2】 represents R １ｂ represents hydrogen, F, or Cl; R ２ａ But hydrogen, halo, C ３～６ Cycloalkyl, C １～４ Alkyl, —O—C １～４ C substituted with alkyl, cyano, or 1, 2, or 3 halo substituents １～４ represents alkyl, R ２ｂ is hydrogen or C １～４ represents alkyl, R ２ｃ is hydrogen or C １～４ represents alkyl, R ３ But hydrogen, C １～６ Alkyl, or C ３～６ Cycloalkyl-substituted C １～６ represents alkyl, R ４ But hydrogen, C １～６ Alkyl, R ６ , Het １ , R ６ and Het １ C substituted with one substituent selected from the group consisting of １～６ represents alkyl, R ５ａ and R ５ｂ are each independently hydrogen or C １～４ represents alkyl, R ６ But C ３～６ cycloalkyl, or C １～４ Alkyl, —O—C １～４ Alkyl or Het ２ C substituted with one or two substituents each independently selected from the group consisting of ３～６ represents cycloalkyl, Het １ are each independently selected from O, S, and N, and the S atom is S(=O) or S(=O) ２ or a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, wherein the S atom is S(═O) or S(═O) ２ and wherein the heterocyclyl is optionally substituted on one or two carbon atoms with halo, C １～４ substituted with a total of 1, 2, 3, or 4 substituents each independently selected from the group consisting of alkyl, oxo, and —OH; Het ２ is an N atom and optionally each independently selected from O, S, and N, wherein the S atom is S(=O) or S(=O) ２ and one or two additional heteroatoms, which may be optionally substituted on one nitrogen to form -C(=O)-C １～４ is substituted with alkyl, R １８ But C １～６ Alkyl or C ３～６ represents cycloalkyl, R １９ is hydrogen or C １～６ represents alkyl, or R １８ and R １９ together, -CH ２ -CH ２ -CH ２ - forms, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and, optionally, a carbonyl moiety, said monocyclic 5- or 6-membered aromatic ring optionally being selected from the group consisting of C １～４ Alkyl, C ３～６ substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl, cycloalkyl, or cyano; R ｘａ and R ｘｂ are each independently hydrogen, Het ３ , C ３～６ Cycloalkyl, and C １～６ alkyl, and optionally, ３～６ Cycloalkyl and the C １～６ The alkyl is —OH, —OC １～４ Alkyl, —C １～４ Alkyl-OH, Halo, CF ３ , C ３～６ Cycloalkyl, Het ３ , and N.R. １１ｃ R １１ｄ or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of or R ｘａ and R ｘｂ together with the N atom to which they are attached, one N atom and optionally selected from O, S, and N, wherein the S atom is S(=O) or S(=O) ２ and one additional heteroatom, optionally substituted to form a 4- to 7-membered monocyclic fully or partially saturated heterocyclyl containing １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents selected from the group consisting of １～４ substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; or R ｘａ and R ｘｂ together with the N atom to which they are attached, form one N atom and optionally each independently selected from O, S, and N, wherein the S atom is S(=O) or S(=O) ２ and one or two additional heteroatoms, which may be optionally substituted to form a 6- to 11-membered bicyclic fully or partially saturated heterocyclyl, １～４ Alkyl, halo, —OH, —O—C １～４ Alkyl, cyano, and halo and OR ２３ C substituted with 1, 2, or 3 substituents each independently selected from the group consisting of １～４ substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl; R ２３ is hydrogen or C optionally substituted with 1, 2, or 3 halo １～４ represents alkyl] or a tautomeric or stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof.

2. R １ａ is -C(=O)-NR ｘａ R ｘｂ represents R １ｂ represents F, R ２ａ is hydrogen or C １～４ represents alkyl, R ２ｂ represents hydrogen, R ２ｃ represents hydrogen, R ６ But C ３～６ cycloalkyl, or —O—C １～４ Alkyl or Het ２ C substituted with one or two substituents each independently selected from the group consisting of ３～６ represents cycloalkyl, Het １ are each independently selected from O, S, and N, and the S atom is S(=O) or S(=O) ２ or a monocyclic C-bonded 4-7 membered fully saturated heterocyclyl containing 1, 2, or 3 heteroatoms, each independently selected from O, S, and N, wherein the S atom is S(═O) or S(═O) ２ and wherein the heterocyclyl optionally has a total of 1, 2, 3, or 4 C atoms on 1 or 2 carbon atoms. １～４ is substituted with alkyl, Het ２ is an N atom and optionally each independently selected from O, S, and N, wherein the S atom is S(=O) or S(=O) ２ and one or two additional heteroatoms, which may be optionally substituted on one nitrogen to form -C(=O)-C １～４ is substituted with alkyl, R ｘａ and R ｘｂ But C １～６ The compound of claim 1 , wherein the compound represents alkyl.

3. R １ｂ 2. The compound of claim 1, wherein represents F.

4. R ２ａ is C １～４ 4. The compound of claim 1, 2, or 3, wherein the compound represents alkyl.

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

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

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

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

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