Substitutive spiro derivatives

Abstract

The present invention relates to medicaments useful for the treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful in the treatment of diseases such as cancer, myelodysplastic syndromes (MDS) and diabetes.

Description

[Technical Field]

[0001] The present invention relates to pharmaceuticals useful for the treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and their use as menin / MLL protein / protein interaction inhibitors useful for the treatment of diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes. [Background technology]

[0002] Chromosomal rearrangements affecting the mixed lineage leukemia gene (MLL; MLL1; KMT2A) result in aggressive acute leukemia across all age groups, which remains largely incurable and highlight the urgent need for novel therapeutic approaches. Acute leukemia with these MLL chromosomal translocations presents as lymphoid, myeloid, or biphenotypic disorders and accounts for 5–10% of acute leukemia in adults and approximately 70% of acute leukemia in infants (Marschalek, Br J Haematol 2011.152(2),141-54; Tomizawa et al., Pediatr Blood Cancer 2007.49(2),127-32).

[0003] MLL is a histone methyltransferase that methylates histone H3 on lysine 4 (H3K4) and functions in a multiprotein complex. The use of an inducible loss-of-function allele of Mll1 demonstrated that Mll1 plays an essential role in the maintenance of hematopoietic stem cells (HSCs) and B cell development, but its histone methyltransferase activity is not essential for hematopoiesis (Mishra et al., Cell Rep 2014.7(4),1239-47).

[0004] Fusions of MLL with over 60 different partners have been reported to date and associated with leukemia development / progression (Meyer et al., Leukemia 2013.27, 2165-2176). Interestingly, the SET (Su(var)3-9, zeste enhancer, and trithorax) domains of MLL are not retained in the chimeric protein but are replaced by the fusion partner (Thiel et al., Bioessays 2012.34, 771-80). Recruitment of chromatin-modifying enzymes such as the Dot1L and / or pTEFb complex by the fusion partner results in enhanced transcription and transcriptional elongation of MLL target genes, most notably the HOXA gene (e.g., HOXA9) and the HOX cofactor MEIS1. Abnormal expression of these genes inhibits hematopoietic differentiation and enhances proliferation.

[0005] Menin, encoded by the multiple endocrine neoplasia type 1 (MEN 1) gene, is ubiquitously expressed and primarily localized within the nucleus. It has been shown to interact with numerous proteins and is therefore involved in a variety of cellular processes. Menin's best-understood function 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 retained in all fusion proteins (Thiel et al., Bioessays 2012.34, 771-80). The menin / MLL interaction results in the formation of a new interaction surface for lens epithelial 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 (Cermakova et al., Cancer Res 2014.15, 5139-51; Yokoyama & Cleary, Cancer Cell 2008.8, 36-46). Furthermore, numerous genetic studies have shown that menin is strictly required for oncogenic transformation by MLL fusion proteins, suggesting the menin / MLL interaction as an attractive therapeutic target. For example, conditional deletion of Men1 prevents leukocytosis in myeloid progenitor cells ectopically expressing MLL fusions (Chen et al., Proc Natl Acad Sci 2006.103, 1018-23). Similarly, loss-of-function mutations disrupting the menin / MLL fusion interaction suppress the oncogenic properties of the MLL fusion protein, prevent the development of leukemia in vivo, and release differentiation blocks in MLL-transformed leukemic blasts. These studies also demonstrated that menin is necessary for maintaining HOX gene expression by the MLL fusion protein (Yokoyama et al., Cell 2005.123,207-18).Furthermore, small molecule inhibitors of the menin / MLL interaction have been developed, suggesting the drug potential of this protein / protein interaction, and their efficacy has been demonstrated in preclinical models of AML (Borkin et al., Cancer Cell 2015.27, 589-602; Cierpicki and Grembecka, Future Med Chem 2014.6, 447-462). Combined with the observation that menin is not an essential cofactor of MLL 1 in normal hematopoiesis (Li et al., Blood 2013.122, 2039-2046), these data validate disruption of the menin / MLL interaction as a promising new therapeutic approach for treating MLL rearrangement leukemia and other cancers with an active HOX / MEIS1 gene signature. For example, internal 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 that influence menin / MLL interactions may also prove effective in treating MLL-PTD-associated leukemia. Furthermore, castration-resistant prostate cancer has been shown to be dependent on menin / MLL interactions (Malik et al., Nat Med 2015.21, 344-52).

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

[0007] Several references describe inhibitors targeting the menin-MLL interaction: International Publication No. 2011029054, J Med Chem 2016, 59, 892-913 describes the preparation of thienopyrimidine and benzodiazepine derivatives; International Publication No. 2014164543 describes thienopyrimidine and thienopyridine derivatives; Nature Chemical Biology March 2012, 8, 277-284 and Ren, J.; et al. Bioorg Med Chem Lett (2016), 26(18), 4472-4476 describe thienopyrimidine derivatives; J Med Chem 2014, 57, 1543-1556 describes hydroxy and aminomethylpiperidine derivatives; and Future Med Chem 2014,6,447-462 provides an overview of small molecules and peptide mimetic compounds, and International Publication No. 2016195776 describes flu[2,3-d]pyrimidine, 9H-purine, [1,3]oxazolo[5,4-d]pyrimidine, [1,3]oxazolo[4,5-d]pyrimidine, [1,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-b]pyridine, and thieno[2,3-d]pyrimidine derivatives. International Publication No. 2016197027 describes 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, pyrido[2,3-d]pyrimidine, and quinoline derivatives, while International Publication No. 2016040330 describes thienopyrimidine and thienopyridine compounds. International Publication No. 2017192543 describes piperidine as a menin inhibitor. International Publications No. 2017112768, 2017207387, 2017214367, 2018053267, and 2018024602 describe inhibitors of menin-MLL interaction. International Publication Nos. 2017161002 and 2017161028 describe menin-MLL inhibitors.International Publication Nos. 2018050686, 2018050684, and 2018109088 describe inhibitors of menin-MLL interaction. International Publication No. 2018226976 describes methods and compositions for inhibiting the interaction between menin and MLL protein. International Publication No. 2019060365 describes menin-MLL substitution inhibitors. Krivtsov et al., Cancer Cell 2019. No.6 Vol.36, 660-673, describes menin-MLL inhibitors.

[0008] International Publication No. 2020069027 discloses menin inhibitors. International Publication No. 2018175746 discloses methods for treating hematological malignancies and Ewing's sarcoma. International Publication No. 2020045334 discloses azabicyclo derivatives used in pharmaceutical compositions. International Publication No. 2019120209 discloses substituted heterocyclic compounds as menin / MLL protein / protein interaction inhibitors. Chinese Patent No. 111297863 discloses the use of menin mixed lineage leukemia (MLL) inhibitors. International Publication No. 2021121327 describes substituted linear spiro derivatives and their use as menin / MLL protein / protein interaction inhibitors. [Overview of the project]

[0009] The present invention relates to formula (I)

[0010] [ka] Novel compounds of the same, as well as their tautomers and stereoisomers [in the formula, R 1a This represents Het, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and optionally a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be C 3~6Cycloalkyl, cyano, and C 1~4 may be substituted with one or two additional substituents selected from the group consisting of; R 1b represents F or Cl; Y 1 is -CR 5a R 5b -, -O-, -S-, or -NR 5c -; R 2 is selected from the group consisting of hydrogen, halo, C 1~4 alkyl, -O-C 1~4 alkyl, and -NR 7a R 7b ; U represents N or CH; n1, n2, n3 and n4 are each independently selected from 1 and 2; X 1 represents CH, X 2 represents N; R 4 is C 1~5 alkyl;

[0011]

Chemical formula

[0012] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0013] Furthermore, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts or solvates thereof for use as pharmaceuticals, and to compounds of formula (I), pharmaceutically acceptable salts or solvates thereof for use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS) and diabetes.

[0014] In certain embodiments, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of cancer.

[0015] In certain embodiments, the cancer is selected from leukemia, myeloma, or solid tumor cancer (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma). In some embodiments, leukemias include acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell pre-lymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL reorganization leukemia, MLL-PTD leukemia, MLL amplification leukemia, MLL-positive leukemia, and leukemias exhibiting the HOX / MEIS1 gene expression signature.

[0016] The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, in combination with additional pharmaceuticals for use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS), and diabetes.

[0017] 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 homogeneously mixed with a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof.

[0018] The present invention also relates to a product comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof, and additional pharmaceuticals, as a combination formulation for simultaneous, separate, or sequential use in the treatment or prevention of cancer, myelodysplastic syndrome (MDS), and diabetes.

[0019] Furthermore, the present invention relates to a method for treating or preventing cell proliferation disorders in warm-blooded animals, comprising administering to the animal an effective amount of a compound of formula (I) as defined herein, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition or combination thereof. [Modes for carrying out the invention]

[0020] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo, and iodine.

[0021] When used in this specification, the prefix "C x~y (where x and y are integers) refers to the number of carbon atoms in a given group. Therefore, C 1~6 Alkyl alkyl groups contain 1 to 6 carbon atoms, for example.

[0022] "C" as used herein as a base or as part of a base 1~4 The term "alkyl" refers to linear or branched saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

[0023] "C" as used herein as a base or as part of a base 3~6 The term "cycloalkyl" defines saturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0024] "C" as used herein as a base or as part of a base 3~7 The term "cycloalkyl" defines saturated cyclic hydrocarbon radicals having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

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

[0026] It will be obvious to those skilled in the art that CO or C (=O) represents the carbonyl portion.

[0027] It will be obvious to those skilled in the art that groups such as -CRR- represent the following:

[0028] [ka] An example of such a base is -CR 5a R 5b - is

[0029] Bases such as -NR-

[0030] [ka] It will be obvious to those skilled in the art that this represents. An example of such a base is -NR 5c - is

[0031] The term “monocyclic carbon-bonded 4- to 7-membered fully saturated heterocycline” containing one nitrogen atom and optionally one or two additional heteroatoms independently selected from O, S, and N defines fully saturated cyclic hydrocarbon radicals having 4 to 7 ring members and containing at least one nitrogen atom and optionally one or two additional heteroatoms independently selected from O, S, and N, such as carbon-bonded azetidinyl, carbon-bonded pyrrolidinyl, carbon-bonded morpholinyl, and carbon-bonded piperidinyl. The term “monocyclic carbon-bonded 4- to 7-membered fully saturated heterocycline” containing one nitrogen atom and optionally one or two additional heteroatoms independently selected from O, S, and N is similarly defined, but bonded to the rest of the molecule of formula (I) via the nitrogen atom. Examples include N-bonded azetidinyl, N-bonded pyrrolidinyl, N-bonded morpholinyl, N-bonded thiomorpholinyl, N-bonded piperadinyl, N-bonded 1,4-diazepanyl, and N-bonded piperidinyl. It is similarly defined as a 4- to 7-membered monocyclic fully saturated heterocycline in which two R groups combine with the N atom to which they are bonded, and together with one N atom and optionally an additional heteroatom selected from O, S, and N.

[0032] The term "monocyclic C-bonded 4- to 7-membered fully saturated heterocycline containing 1, 2, or 3 heteroatoms independently selected from O, S, and N" defines fully saturated cyclic hydrocarbon radicals having 4 to 7 ring members and containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, such as C-bonded azetidinyl, C-bonded pyrrolidinyl, C-bonded morpholinyl, C-bonded tetrahydrofuranyl, C-bonded thiolanyl, C-bonded oxetanyl, C-bonded thietanyl, C-bonded tetrahydropyranyl, C-bonded tetrahydrothiopyranyl, and C-bonded piperidinyl. The term "monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing 2 N atoms and optionally 1 additional heteroatom selected from O, S, and N" defines fully saturated cyclic hydrocarbon radicals having 4 to 7 ring members and containing 2 nitrogen atoms and optionally 1 additional heteroatom selected from O, S, and N, such as N-bonded piperazinyl and N-bonded 1,4-diazepanyl.

[0033] To clarify, a 4- to 7-membered fully or partially saturated heterocyclyl has 4 to 7 ring members, including heteroatoms.

[0034] 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, pyridadinyl, pyrimidinyl, pyrazinyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1,2,4-triazinyl, 1,2-dihydro-2-oxo-5-pyrimidinyl, 1,2-dihydro-2-oxo-6-pyrimidinyl, 1,2-dihydro-2-oxo-4-pyrimidinyl, and 1,6-dihydro-6-oxo-3-pyrimidinyl.

[0035] Those skilled in the art will recognize that a five-membered or six-membered monocyclic aromatic ring containing one, two, or three nitrogen atoms and a carbonyl moiety is, but is not limited to,

[0036] [ka] You will understand that these are some of the points that can be raised.

[0037] Non-limiting examples of monocyclic carbon-bonded 5- or 6-membered aromatic rings containing one, two, or three heteroatoms, each independently selected from O, S, and N, include, but are not limited to, carbon-bonded pyrazolyl, carbon-bonded imidazolyl, carbon-bonded pyridinyl, carbon-bonded triazolyl, carbon-bonded pyridazinyl, carbon-bonded pyrimidinyl, carbon-bonded oxazolyl, carbon-bonded furanyl, carbon-bonded isothiazolyl, carbon-bonded thiazolyl, carbon-bonded thiadiazolyl, carbon-bonded oxadiazolyl, or carbon-bonded pyrazinyl.

[0038] In the context of the present invention, bicyclic C-bonded 6- to 11-membered fully saturated heterocyclyl groups include condensed, spiro, and bridging rings.

[0039] In the context of the present invention, the bicyclic N-bonded 6- to 11-membered fully saturated heterocyclyl groups include condensed, spiro, and bridging rings.

[0040] A fused bicyclic group is a set of two rings that share two atoms and the bond between them.

[0041] A spironicyclic group is a group of two rings bonded together at a single atom.

[0042] A bridging bicyclic group is a set of two rings that share three or more atoms.

[0043] Examples of bicyclic carbon-bonded 6- to 11-membered fully saturated heterocyclines containing one nitrogen atom independently selected from O, S, and N, and optionally one or two additional heteroatoms, include, but are not limited to,

[0044] [ka] These are some examples.

[0045] Examples of bicyclic carbon-bonded 6- to 11-membered fully saturated heterocyclines containing one, two, or three heteroatoms independently selected from O, S, and N include, but are not limited to,

[0046] [ka] These are some examples.

[0047] Examples of bicyclic N-bonded 6- to 11-membered fully saturated heterocyclines containing one N atom independently selected from O, S, and N, and optionally one or two additional heteroatoms, are, but are not limited to,

[0048] [ka] These are some examples.

[0049] Examples of fused bicyclic carbon-bonded 9 or 10-membered aromatic rings containing 1, 2, 3, or 4 heteroatoms, each independently selected from O, S, and N, are not limited to these, but

[0050] [ka] These are some examples.

[0051] substituents are chemical structures, for example

[0052] [ka] When represented by, "----" indicates a bond to the remainder of the numerator in equation (I).

[0053] If any variable occurs more than once in any component, each definition is independent.

[0054] If any variable occurs more than once in any expression (for example, expression (I)), then each definition is independent.

[0055] In this regard, it should be clear that a phrase such as "may be optionally substituted with one, two, or three substituents selected from the group consisting of" is equivalent to "may be optionally substituted with one, two, or three substituents independently selected from the group consisting of".

[0056] In general, whenever the term “substituted” is used in the present invention, unless otherwise specifically indicated or evident from the context, “substituted” means that one or more hydrogens on an atom or radical shown during expression, particularly 1 to 4 hydrogens, more specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, are replaced by a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound robust enough to withstand isolation from the reaction mixture to a useful purity. In certain embodiments, the number of substituents is 1 unless the number of substituents is explicitly specified.

[0057] Substituents and / or variable combinations are permissible only if such combinations result in a chemically stable compound. “Stable compound” means a compound that is robust enough to withstand isolation from the reaction mixture to a useful purity.

[0058] Those skilled in the art will understand that the term "optionally substituted" means that the atom or radical indicated in the expression using "optionally substituted" may or may not be substituted (meaning substituted or unsubstituted, respectively).

[0059] If two or more substituents are present on a part, they may replace hydrogen atoms on the same atom, or they may replace hydrogen atoms on different atoms in that part, unless otherwise indicated or evident from the context.

[0060] In the context of this invention, "saturated" means "fully saturated" unless otherwise specified.

[0061] Unless otherwise specified or evident from the context, the aromatic ring and heterocyclyl group may be attached to the rest of the molecule of formula (I) via any available ring carbon atoms (C bonds) or nitrogen atoms (N bonds).

[0062] Unless otherwise specified or evident from the context, the aromatic ring and heterocyclyl group may, if possible, be optionally substituted on carbon and / or nitrogen atoms as in the embodiment.

[0063] As used herein, the term “subject” means an animal, preferably a mammal (e.g., a cat, a dog, a primate, or a human), more preferably a human, that is or has been the subject of treatment, observation, or experimentation.

[0064] As used herein, the term “therapeutic dose” means the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue system, animal or human, including relief or reversal of symptoms of the disease or disorder being treated, as determined by researchers, veterinarians, physicians or other clinicians.

[0065] The term “composition” is intended to encompass products containing specific components in specific amounts, and any products obtained directly or indirectly from specific combinations of specific components in specific amounts.

[0066] As used herein, the term “treatment” is intended to refer to any process that can delay, interfere with, prevent or halt the progression of a disease, but does not necessarily mean the complete disappearance of all symptoms.

[0067] As used herein, the terms “(the) compound of the present invention” or “compound according to the present invention” mean the compound of formula (I), as well as its pharmaceutically acceptable salts and solvates.

[0068] When used herein, any chemical formula having a bond that is shown only as a solid line and not as a solid wedge bond or hashed wedge bond, or otherwise shown as having a specific arrangement (e.g., R, S) around one or more atoms, is intended to represent each possible stereoisomer or a mixture of two or more stereoisomers.

[0069] In the above and below, the term "compound of formula (I)" means including its tautomers and stereoisomers.

[0070] The terms "stereoisomer," "stereoisomeric form," and "stereochemical isomer form" used above and below are interchangeable.

[0071] The present invention comprises all stereoisomers of the compound of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0072] Enantiomers are stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0073] Atropisomers (or atropoiomers) are stereoisomers having a specific spatial configuration resulting from binding rotation around a single bond due to significant steric hindrance. All atropisomers of the compound of formula (I) are intended to be within the scope of this invention.

[0074] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers; that is, they are not related as mirror images. If a compound contains a double bond, the substituent can be in an E or Z configuration.

[0075] Substituents on a divalent cyclic saturated or partially saturated radical may have either a cis configuration or a trans configuration. For example, if the compound contains a disubstituted cycloalkyl group, the substituent may be in either a cis or trans configuration.

[0076] Therefore, the present invention always includes enantiomers, atrop isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, where chemically possible.

[0077] The meanings of all terms, namely enantiomer, atropisomer, diastereomer, racemate, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0078] The absolute configuration is determined according to the Cahn-Ingold-Prelog system. The configuration in asymmetric atoms is determined by either R or S. Decomposed stereoisomers whose absolute configuration is unknown are: They can be designated as (+) or (-) depending on the direction in which they rotate the plane polarization. For example, decomposed enantiomers whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction in which they rotate the plane polarization.

[0079] When a specific stereoisomer is identified, this means that the stereoisomer is substantially free from other stereoisomers, i.e., it is 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. Therefore, when a compound of formula (I) is identified, for example, as (R), this means that the compound is substantially free from the (S) isomer; when a compound of formula (I) is identified, for example, as E, this means that the compound is substantially free from the Z isomer; and when a compound of formula (I) is identified, for example, as cis, this means that the compound is substantially free from the trans isomer.

[0080] Some of the compounds according to formula (I) may also exist in their tautomerized forms. Such forms, to the extent possible, are not explicitly shown in formula (I) above, but are intended to be within the scope of the present invention. Thus, a single compound may exist in both stereoisomerized and tautomerized forms.

[0081] for example,

[0082] [ka] It also includes other tautomers.

[0083] [ka] for example,

[0084] [ka] It also includes other tautomers.

[0085] [ka]

[0086] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may 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 (e.g., by vacuum, by freeze-drying, or by filtration). Salts may also be prepared, for example, by exchanging a counterion of the compound of the present disclosure in salt form with another counterion using a suitable ion exchange resin.

[0087] The pharmaceutically acceptable salts referred to above or below include salt forms of therapeutically active, non-toxic acids and bases from which compounds of formula (I) and their solvates can be formed.

[0088] Suitable acids include, for example, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as 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, and pamoic acid. Conversely, the above salt forms can be converted to free salt forms by treatment with a suitable base.

[0089] Compounds of formula (I) containing acidic protons, or their solvates, may be converted to their non-toxic metal or amine salt forms by treatment with appropriate organic and inorganic bases.

[0090] Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, cesium, magnesium, and calcium salts; organic bases such as primary, secondary, and tertiary aliphatic amines and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline salts; benzathine, N-methyl-glucamine, hydravamin salts, and amino acid salts such as arginine and lysine. Conversely, base forms can be converted to free base forms by treatment with acid.

[0091] The term solvate includes the solubilated forms that a compound of formula (I) can form, as well as its salts. Examples of such solubilated forms include hydrates, alkoxides, and so on.

[0092] The compounds of the present invention, prepared by the processes described below, may be synthesized in the form of enantiomer mixtures, particularly racemic mixtures of enantiomers, which can be separated from each other by decomposition procedures known in the art. Methods for separating the enantiomer forms of the compound of formula (I), as well as its pharmaceutically acceptable salts and solvates, include liquid chromatography using a chiral stationary phase. The pure stereochemical isomers may also be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously employ enantiomerically pure starting materials.

[0093] As used herein, the term “enantiomerically pure” means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of another enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% by weight or less of another enantiomer. In the most preferred embodiment, the term “enantiomerically pure” means that the composition contains at least 99% by weight of one enantiomer and 1% by weight or less of another enantiomer.

[0094] The present invention also includes isotope-labeled compounds of the present invention that are identical to those enumerated herein, due to the fact that one or more atoms are replaced by atoms (or the most abundant atoms found in nature) having atomic masses or mass numbers different from those normally found in nature.

[0095] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring in their natural abundance or in isotopic-enriched forms, or produced synthetically, are intended within the scope of the compounds of the present invention. Exemplary isotopes that can be incorporated into the compounds of the present invention include those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. 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 Examples include Br. Preferably, the isotope is 2 H, 3 H, 11 C, and 18 Selected from group F. More preferably, the isotope is 2 This is H. In particular, deuterium compounds are included within the scope of the present invention.

[0096] Certain isotope-labeled compounds of the present invention (for example, 3 H and 14 (labeled with 1C) may be useful, for example, in substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) Isotopes are useful for their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2Substitution with H), for example, can lead to increased metabolic stability (e.g., increased half-life in vivo or reduced required dose), resulting in certain therapeutic benefits and therefore, depending on the situation, may be preferable. For example, 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as fluorine (F) are useful in positron emission tomography (PET) studies. PET imaging in cancer finds usefulness in determining tumor location and identification, disease stage, and appropriate treatment. Human cancer cells overexpress many receptors or proteins that are potential disease-specific molecular targets. Radiolabeled tracers that bind with high affinity and specificity to such receptors or proteins on tumor cells have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, Carlie L. et al. Tetrahedron Lett. 2016, 57(37), 4119-4127). Furthermore, target-specific PET radiotactic tracers can be used as biomarkers to investigate and evaluate pathology, for example, by measuring target expression and treatment response (Austin R. et al. Cancer Letters (2016), doi:10.1016 / j.canlet.2016.05.008).

[0097] The present invention relates, in particular, to compounds of formula (I) as defined herein, as well as their tautomers and stereoisomers [wherein, R 1a This represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and optionally a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be C 3~6 Cycloalkyl, cyano, and C 1~4 It may also be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R 1brepresents F or Cl; Y 1 -CR 5a R 5b -, -O-, -S-, or -NR 5c - represents; R 2 is hydrogen, halo, C 1~4 Alkyl, -OC 1~4 Alkyl and -NR 7a R 7b Selected from the group consisting of; U represents N or CH; n1, n2, n3, and n4 are selected independently from 1 and 2, respectively; X 1 CH represents X 2 represents N; R 4 C 1~5 alkyl;

[0098] [ka] It represents; R 5a , R 5b , R 5c , R 7a , and R 7b is hydrogen, C 1~4 Alkyl and C 3~6 Each is independently selected from the group consisting of cycloalkyl; R 3 Het 1 , Het 2 Cy 2 and -C 1~6 Alkyl-NR xc R xd Selected from the group consisting of; R xc Cy 1 ;Het 5 ;-C 1~6 Alkyl-Cy 1 ;-C 1~6 Alkyl-Het 3 ;-C 1~6 Alkyl-Het 4 ; or -C 1~6Represents alkylphenyl; R xd is hydrogen; C 1~4 alkyl; or halo, -OH, -OC 1~4 C is substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano. 1~4 Represents alkyl; Or, R xc and R xd These combine to form a 4-7 member monocyclic completely saturated heterocycline containing one N atom and optionally one additional heteroatom selected from O, S, and N, where the S atom may be substituted to form S(=O) or S(=O)2; and optionally the heterocycline may be halo, -OH, or -OC 1~4 It may be substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano; Het 1 This represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic 6-11 member fully saturated heterocycline containing an N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of, and the heterocyclyl may optionally have a halo, R on one or two carbon atoms. 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9bThey may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of and -OH; Het 2 R is on one nitrogen atom. 6a Represents a C-bonded pyrazolyl or triazolyl molecule substituted with; R 6 teeth, Het 3 ;-C(=O)-NH-R 8 ; Het 3 , Het 4 , Het 6a , Het 6b Cy 1 -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C may optionally be substituted with one or two substituents independently selected from the group consisting of alkyl groups. 1~6 alkyl; paste -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 C may optionally be substituted with one or two substituents independently selected from the group consisting of alkyl groups. 3~6 Cycloalkyl; -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl and -NH-S(=O)2-C 1~4 C may optionally be substituted with one substituent selected from the group consisting of alkyl groups. 1~4 Selected from the group consisting of alkyl groups; R 6a -NR 11a R 11b , Het 3a , and Het6a C substituted with one substituent selected from the group consisting of 1~6 Represents alkyl; R 8 -OH, halo, cyano, -NR 11a R 11b , Het 3a , and Het 6a C may optionally be substituted with one, two, or three substituents independently selected from each of the above. 1~6 Represents alkyl; Het 3 and Het 5 Each represents a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic 6-11 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have a carbon atom on one carbon atom, C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or may be substituted with an oxo; the heterocyclyl may, in some cases, have a C on one nitrogen atom. 1~4 It may also be substituted with alkyl groups; Het 3a and Het 5aEach of these independently represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have a carbon atom on one carbon atom, C 1~4 Alkyl, halo, -OH, -NR 11a R 11b or may be substituted with an oxo; the heterocyclyl may, in some cases, have a C on one nitrogen atom. 1~4 It may also be substituted with alkyl groups; Het 4 and Het 7 Each independently represents a monocyclic carbon-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms independently selected from O, S, and N; the 5-membered aromatic ring may optionally have a carbon atom on one nitrogen atom. 1~4 The ring may be substituted with alkyl groups; the 5- or 6-membered aromatic ring may, in some cases, be substituted with an -OH group on one carbon atom; Het 6a and Het 8 Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have a halo, -OH, oxo, on one or two carbon atoms. -(C=O)-NR 10a R 10b ,-OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, cyano, C1~4 Alkyl, -C 1~4 alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl groups; the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het 8a Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing two N atoms and optionally one additional heteroatom selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have a halo, -OH, oxo, on one or two carbon atoms. -(C=O)-NR 10a R 10b ,-OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, cyano, C 1~4 Alkyl, C 1~4 alkyl-OH, -OC 1~4 Alkyl, -O-(C=O)-NR 10a R 10b , and -O-(C=O)-C 1~4 The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl groups; the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het 6bThis represents a bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have C on one or two carbon atoms. 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups, and the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 -(C=O)-C 1~4 alkyl-OH, -C(=O)-C 1~4 Alkyl-OC 1~4 Alkyl, -C(=O)-C 1~4 Alkyl-NR 11a R 11b , and C 1~4 It may also be substituted on one nitrogen atom with a substituent selected from the group consisting of alkyl groups; Cy 1 -OH, -NH-C(=O)-C 1~4 Alkyl, C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, -S(=O)2-C 1~4 Alkyl and -OC 1~4 C may optionally be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. 3~6 Represents a cycloalkyl group; Cy 2 -NR 9a R 9b ;Het 6a ;Het 6b ; and Het 3a , Het 6a , Het 6b and NR 9a R9b C substituted with one or two substituents independently selected from the group consisting of 1~6 C is substituted with one or two additional substituents independently selected from the group consisting of alkyl groups. 3~7 Represents a cycloalkyl group; the C 3~7 Cycloalkyls may, depending on the case, be halo, R 6 , C 1~4 It may also be substituted with one or two additional substituents independently selected from the group consisting of alkyl and -OH; Cy 3 is C 3~7 Represents a cycloalkyl group; the C 3~7 The cycloalkyl group may, in some cases, be substituted with one, two, or three halo substituents; R 9a and R 9b is hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl; Het 5 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with one, two, or three substituents selected from the group consisting of and cyano 3~6 Cycloalkyl; and Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with one, two, or three substituents selected from the group consisting of and cyano 1~4 Each is independently selected from the group consisting of alkyl groups; R 11a , R 11b , R 13a , R 13b , R 15a , R 15b , R 17a , and R 17bis hydrogen and C 1~4 Each is independently selected from the group consisting of alkyl groups; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 Each is independently selected from the group consisting of cycloalkyl; R 14 Het 5a ;Het 8a ; or -NR 13a R 13b and Het 8a C substituted with one, two, or three substituents selected from the group consisting of 1~4 Represents alkyl; R 16 is -C(=O)-NR 17a R 17b -S(=O)2-C 1~4 Alkyl, Het 5 , Het 7 Or Het 8 [represents] This also relates to pharmaceutically acceptable salts and solvates thereof.

[0099] The present invention relates, in particular, to compounds of formula (I) as defined herein, as well as their tautomers and stereoisomers [wherein, R 1a This represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and optionally a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be cyano and C. 1~4 It may also be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R 1b This represents F; Y 1 represents -O-; R 2 is hydrogen, U represents N; n1, n2, n3, and n4 are selected independently from 1 and 2, respectively; X 1 CH represents X 2 represents N; R 4 C 1~5 Alkyl; or

[0100] [ka] R 3 Het 1 and Cy 2 Selected from the group consisting of; Het 1 This represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of , and the heterocyclyl may optionally be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of oxo and -OH on one or two carbon atoms; R 6 and R 6a teeth, Het 4 ;Het 3 , Het 6a and Cy 1 C may optionally be substituted with one or two substituents independently selected from the group consisting of the above. 1~6 alkyl; and C3~6 Each is independently selected from the group consisting of cycloalkyl; R 8 However, -OC 1~6 Represents alkyl; Het 3 , Het 3a , Het 5 and Het 5a Each of these independently represents a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl may, in some cases, have a carbon atom on one carbon atom. 1~4 It may also be substituted with alkyl groups; Het 4 and Het 7 Each independently represents a monocyclic 5- or 6-membered aromatic ring with carbon bonds containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, or a fused bicyclic 9- or 10-membered aromatic ring with carbon bonds containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; the aromatic ring may optionally have a carbon atom on one nitrogen atom. 1~4 Alkyl or -(C=O)-OC 1~4 It may be substituted with alkyl; the aromatic ring may, depending on the case, be -OH, halo, C 1~4 Alkyl, -OC 1~4 Alkyl, -NR 11a R 11b , C 1~4 Alkyl-NR 11a R 11b -NH-C(=O)-C 1~4 Alkyl, cyano, -COOH, -NH-C(=O)-OC 1~4 Alkyl, -NH-C(=O)-NR 10a R 10b -(C=O)-OC 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, Het 8a , -C 1~4 Alkyl-Het 8a, Het 8b , Het 9 , and -C(=O)-NR 10a R 10b They may be substituted on one or two carbon atoms by a total of one or two substituents independently selected from the group consisting of; Het 6a , Het 8 and Het 8a Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have a halo, -OH, oxo, on one or two carbon atoms. -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 -(C=O)-NR 10a R 10b ,-OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH and -OC 1~4 The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents selected from the group consisting of alkyl groups; the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het 6b and Het 8b Each independently represents a bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have one or two carbon atoms, C 1~4Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups, and the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 , and C 1~4 It may also be substituted on one nitrogen atom with a substituent selected from the group consisting of alkyl groups; Het 9 Each independently represents a monocyclic carbon-bonded 5 or 6-membered aromatic ring containing one, two, or three heteroatoms selected from O, S, and N; the aromatic ring may have one or two carbon atoms on it. 1~4 It may also be substituted with alkyl groups; Cy 1 is -OH and C 1~4 C may optionally be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. 3~6 Represents a cycloalkyl group; Cy 2 is C 3~7 Represents a cycloalkyl group; the C 3~7 Cycloalkyls are sometimes R 6 , Het 6a , Het 6b , -NR 9a R 9b , -OH, and C 1~4 They may be substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl groups; Cy 3 is C 3~7 Represents a cycloalkyl group; the C 3~7 The cycloalkyl group may, in some cases, be substituted with one, two, or three halo substituents; R 9a and R 9b is hydrogen; C 1~4 Alkyl; C3~6 Cycloalkyl;-C(=O)-C 1~4 Alkyl;-C(=O)-C 3~6 Cycloalkyl; Het 5 ;Het 7 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ;and Halo, -OH, and -OC 1~4 C substituted with one, two, or three substituents selected from the group consisting of alkyl groups 1~4 Each is independently selected from the group consisting of alkyl groups; R 11a , R 11b , R 13a , R 13b , R 17a , and R 17b is hydrogen and C 1~4 Each is independently selected from the group consisting of alkyl groups; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 Each is independently selected from the group consisting of cycloalkyl; R 14 is OC 1~4 Alkyl;-OC 1~4 C substituted with one, two, or three substituents selected from the group consisting of alkyl and halo 3~6 Cycloalkyl; or -OC 1~4 Alkyl, -NR 13a R 13b C substituted with one, two, or three substituents selected from the group consisting of and cyano 1~4 Represents alkyl; R 16 is -C(=O)-NR 17a R 17b Or -S(=O)2-C 1~4 [Represents alkyl] This also relates to pharmaceutically acceptable salts and solvates thereof.

[0101] The present invention relates, in particular, to compounds of formula (I) as defined herein, as well as their tautomers and stereoisomers [wherein, R 1a This represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and optionally a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be cyano and C. 1~4 It may also be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R 1b represents F; Y 1 represents -O-; R 2 U represents hydrogen, and U represents N; n1, n2, n3, and n4 are selected independently from 1 and 2, respectively; X 1 CH represents X 2 represents N; R 4 C 1~5 Alkyl; or

[0102] [ka] It represents; R 3 Het 1 and Cy 2 Selected from the group consisting of; Het 1This represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; or a bicyclic 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents, each independently selected from the group consisting of oxo and -OH, on one or two carbon atoms; R 6 teeth, Het 3 , Het 6a and Cy 1 C may optionally be substituted with one or two substituents independently selected from the group consisting of the above. 1~6 alkyl; and C 3~6 Selected from the group consisting of cycloalkyl groups; R 6a Het 3a and Het 6a C substituted with one substituent selected from the group consisting of 1~6 Represents alkyl; Het 3 and Het 5 Each represents a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have a C on one carbon atom. 1~4 It may also be substituted with alkyl groups; Het3a A monocyclic carbon-bonded 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocyclyl may, in some cases, have a carbon atom on one carbon atom. 1~4 It may also be substituted with alkyl groups; Het 4 and Het 7 Each independently represents a monocyclic carbon-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms independently selected from O, S, and N; the 5-membered aromatic ring may optionally have a carbon atom on one nitrogen atom. 1~4 The ring may be substituted with alkyl groups; the 5- or 6-membered aromatic ring may, in some cases, be substituted with an -OH group on one carbon atom; Het 6a and Het 8 Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have a halo, -OH, oxo, on one or two carbon atoms. -(C=O)-NR 10a R 10b ,-OC 3~6 Cycloalkyl, -S(=O)2-C 1~4 Alkyl, cyano, C 1~4 Alkyl, -C 1~4 Alkyl-OH and -OC 1~4 The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl groups; the heterocyclyl may, in some cases, have one nitrogen atom. -C(=O)-C 1~4 Alkyl and -(C=O)-NR 10a R 10b It may also be substituted with substituents selected from the group consisting of; Het 6b This represents a bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; the heterocycline may optionally have C on one or two carbon atoms. 1~4 Alkyl, -OH, oxo, -(C=O)-NR 10a R 10b -NH-C(=O)-C 1~4 Alkyl, -NH-C(=O)-Cy 3 , and -OC 1~4 The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups, and the heterocyclyl may optionally be -C(=O)-C 1~4 Alkyl, -C(=O)-Cy 3 , and C 1~4 It may also be substituted on one nitrogen atom with a substituent selected from the group consisting of alkyl groups; Cy 1 is -OH and C 1~4 C may optionally be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. 3~6 Represents a cycloalkyl group; Cy 2 -NR 9a R 9b ;Het 6a ; and Het 6b C substituted with one or two substituents independently selected from the group consisting of 3~7 Represents cycloalkyl; and the C 3~7 Cycloalkyls are sometimes R 6 , C 1~4 It may also be substituted with one or two additional substituents independently selected from the group consisting of alkyl and -OH; Cy 3 is C 3~7 Represents a cycloalkyl group; the C 3~7 The cycloalkyl group may, in some cases, be substituted with one, two, or three halo substituents; R9a and R 9b is hydrogen; C 1~4 Alkyl, C 3~6 Cycloalkyl; Het 5 ;-C 1~4 Alkyl-R 16 ;-C(=O)-C 1~4 Alkyl-Het 3a ;-C(=O)-R 14 ; Halo, -OH, -OC 1~4 Alkyl, -NR 11a R 11b C substituted with one, two, or three substituents selected from the group consisting of and cyano 3~6 Cycloalkyl; and -OH and -OC 1~4 C substituted with one, two, or three substituents selected from the group consisting of alkyl groups 1~4 Each is independently selected from the group consisting of alkyl groups; R 11a , R 11b , R 13a , R 13b , R 17a , and R 17b is hydrogen and C 1~4 Each is independently selected from the group consisting of alkyl groups; R 10a and R 10b is hydrogen, C 1~4 Alkyl and C 3~6 Each is independently selected from the group consisting of cycloalkyl; R 14 This includes 1, 2, or 3 -NR 13a R 13b C substituted with substituents 1~4 Represents alkyl; R 16 is -C(=O)-NR 17a R 17b Or -S(=O)2-C 1~4 [Represents alkyl] This also relates to pharmaceutically acceptable salts and solvates thereof.

[0103] The present invention relates, in particular, to compounds of formula (I) as defined herein, as well as their tautomers and stereoisomers [wherein, R 1a This represents Het; Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms; the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5 or 6-membered aromatic ring may have one C 1~4 It may also be substituted with alkyl groups; R 1b represents F; Y 1 represents -O-; R 2 U represents hydrogen, and U represents N; n1 is 1, n2 is 2, n3 is 1, n4 is 1; X 1 CH represents X 2 represents N; R 4 represents isopropyl; R 3 is Cy 2 It represents; Het 6a This represents a monocyclic 4-7 member fully saturated heterocycline containing one nitrogen atom and a nitrogen bond; Het 6b This represents a condensed bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one additional heteroatom selected from O and N; the heterocycline optionally has -C(=O)-C on one nitrogen atom. 1~4 It may also be substituted with alkyl groups; Cy 2 Het 6a , Het 6b , and -NR 9a R 9b C substituted with one substituent selected from the group consisting of 3~7 Represents a cycloalkyl group; R 9a and R 9b However, each is independent of C 1~4 Selected from alkyl groups, This also relates to pharmaceutically acceptable salts and solvates thereof.

[0104] The present invention relates, in particular, to compounds of formula (I) as defined herein, as well as their tautomers and stereoisomers [wherein, R 1a This represents Het; Het is

[0105] [ka] It represents; R 1b represents F; Y 1 represents -O-; R 2 U represents hydrogen, and U represents N; n1 is 1, n2 is 2, n3 is 1, n4 is 1; X 1 CH represents X 2 represents N; R 4 represents isopropyl; R 3 is Cy 2 It represents; Het 6a This represents a monocyclic 4-7 member fully saturated heterocycline containing one nitrogen atom and a nitrogen bond; Het 6b This represents a condensed bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one additional heteroatom selected from O and N; the heterocycline optionally has -C(=O)-C on one nitrogen atom. 1~4 It may also be substituted with alkyl groups; Cy 2 Het 6a , Het 6b , and -NR 9a R 9b This represents a cyclobutyl molecule substituted with one substituent selected from the group consisting of; R 9a and R 9b However, each is independent of C 1~4 Selected from alkyl groups, This also relates to pharmaceutically acceptable salts and solvates thereof.

[0106] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 1b This represents F.

[0107] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 2 This represents hydrogen.

[0108] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1, and n4 is 1.

[0109] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 This represents -O-.

[0110] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, Y 1 represents -O-; U represents N.

[0111] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, where U represents N.

[0112] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, Y 1 represents -O-; U represents N; R 1b represents F; R 2 This represents hydrogen.

[0113] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, Y 1 represents -O-; U represents N; R 1b represents F; R 2 R represents hydrogen; 4 represents isopropyl.

[0114] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 4 represents isopropyl.

[0115] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 4 This represents the following expression

[0116] [ka]

[0117] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R4 isopropyl; or represents the following formula

[0118] [ka]

[0119] In embodiments, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 6 and R 6a teeth, Het 4 ;Het 3 and Cy 1 C may optionally be substituted with one or two substituents independently selected from the group consisting of the above. 1~6 Alkyl; and C 3~6 Each is independently selected from the group consisting of cycloalkyl; Het 3 , Het 3a , Het 5 and Het 5a Each of these independently represents a monocyclic 4-7 member fully saturated heterocycline containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2.

[0120] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, where Het represents the following formula

[0121] [ka]

[0122] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, where Het represents the following formula

[0123] [ka]

[0124] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het 1 This represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 -C(=O)-Cy 1 , and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of, and the heterocyclyl may optionally have a halo, R on one or two carbon atoms. 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b They may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of and -OH.

[0125] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het 1This represents a monocyclic 4-7 member fully saturated heterocycline containing one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 -C(=O)-Cy 1 and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of ; the heterocyclyl may, in some cases, be substituted on one or two carbon atoms with a total of one, two, three or four substituents independently selected from the group consisting of oxo and -OH.

[0126] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het 1 This represents a bicyclic carbon-bonded 6- to 11-membered fully saturated heterocycline containing at least one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 -C(=O)-Cy 1 , and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of, and the heterocyclyl may optionally have a halo, R on one or two carbon atoms. 6 , Het 6a , Het 6b , C 1~4 Alkyl, oxo, -NR 9a R 9b They may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of and -OH.

[0127] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het 1 This represents a bicyclic carbon-bonded 6- to 11-membered fully saturated heterocycline containing at least one N atom and optionally one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom may be substituted to form S(=O) or S(=O)2; The heterocycline may, in some cases, have R on one nitrogen atom. 6 -C(=O)-Cy 1 and -C(=O)-R 8 The heterocyclyl may be substituted with substituents selected from the group consisting of ; the heterocyclyl may, in some cases, be substituted on one or two carbon atoms with a total of one, two, three or four substituents independently selected from the group consisting of oxo and -OH.

[0128] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, solvates thereof, or any subgroup thereof as referred to in any of the other embodiments, R 6 Het 4 ;C 3~6 Cycloalkyl; and Het 3 and Cy 1 C may optionally be further substituted with one or two substituents independently selected from the group consisting of the above. 1~6 Selected from the group consisting of alkyl groups.

[0129] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 6 and R 6a teeth, Het 3 ;Het 4 ;-C(=O)-NH-Cy 1 ;-C(=O)-NH-R 8 ; Het 3 , Het 4 , Het 6a , Het 6b Cy 1 -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl-C 3~6 Cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C may optionally be substituted with one or two substituents independently selected from the group consisting of alkyl groups. 1~6 alkyl; paste -CN, -OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 Alkyl, as well as OH, -OC 1~4 Alkyl, -C(=O)-NH-C 1~4 Alkyl, -NH-S(=O)2-C 1~4 C may optionally be substituted with one substituent selected from the group consisting of alkyl groups. 1~4 C may optionally be substituted with one or two substituents independently selected from the group consisting of alkyl groups. 3~6 Each is independently selected from the group consisting of cycloalkyls.

[0130] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 6 teeth, Het 3 ;-C(=O)-NH-R 8 ; Het 3 , Het 4 , Het 6a , Het 6b Cy 1, -CN, -OH, -O-C 1~4 alkyl, -C(=O)-NH-C 1~4 alkyl, -C(=O)-NH-C 1~4 alkyl-C 3~6 cycloalkyl, -C(=O)-OH, -NR 11a R 11b , and -NH-S(=O)2-C 1~4 C optionally substituted with one or two substituents each independently selected from the group consisting of alkyl 1~6 alkyl; and -CN, -OH, -O-C 1~4 alkyl, -C(=O)-NH-C 1~4 alkyl, -NH-S(=O)2-C 1~4 alkyl, and OH, -O-C 1~4 alkyl, -C(=O)-NH-C 1~4 alkyl, -NH-S(=O)2-C 1~4 C optionally substituted with one substituent selected from the group consisting of alkyl 1~4 C optionally substituted with one or two substituents each independently selected from the group consisting of alkyl 3~6 selected from the group consisting of cycloalkyl; R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​C may optionally be substituted with one or two substituents independently selected from the group consisting of the above. 1~6 Each is independently selected from the group consisting of alkyl groups.

[0132] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein, R 6 Het 4 ;Het 3 , Het 6a , and Cy 1 C may optionally be substituted with one or two substituents independently selected from the group consisting of the above. 1~6 Selected from the group consisting of alkyl groups; R 6a Het 3a and Het 6a C substituted with one substituent selected from the group consisting of 1~6 Represents alkyl.

[0133] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, solvates thereof, or any subgroup thereof as referred to in any of the other embodiments, R 6 Het 4 ; and Het 3 and Cy 1 C, which may be further substituted with one or two substituents independently selected from the group consisting of the above. 1~6 Selected from the group consisting of alkyl groups.

[0134] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 1 teeth,

[0135] [ka] This represents a nitrogen optionally substituted with nitrogen as defined in any of the other embodiments.

[0136] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het 3 This represents the following expression

[0137] [ka]

[0138] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms; and the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be C 3~6 Cycloalkyl, cyano, and C 1~4 It may be substituted with one or two additional substituents selected from the group consisting of alkyl groups.

[0139] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms; and the monocyclic 5- or 6-membered aromatic ring contains 1 C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5-membered or 6-membered aromatic ring may be C 3~6 Cycloalkyl, cyano, and C 1~4 It may also be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R 1b This represents F.

[0140] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic 5 or 6-membered aromatic ring containing one or two nitrogen atoms; the monocyclic 5 or 6-membered aromatic ring contains one C 3~6 The cycloalkyl group is substituted, and the monocyclic 5- or 6-membered aromatic ring may optionally be substituted with a single cyanonucleotide.

[0141] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic 5 or 6-membered aromatic ring containing one or two nitrogen atoms; the monocyclic 5 or 6-membered aromatic ring contains one C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 5- or 6-membered aromatic ring may optionally be substituted with a single cyanonucleotide; R 1b This represents F.

[0142] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic six-membered aromatic ring containing one, two, or three nitrogen atoms; and the monocyclic six-membered aromatic ring contains one C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 6-membered aromatic ring may be C 3~6 Cycloalkyl, cyano, and C 1~4 It may be substituted with one or two additional substituents selected from the group consisting of alkyl groups.

[0143] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, wherein Het represents a monocyclic six-membered aromatic ring containing one, two, or three nitrogen atoms; and the monocyclic six-membered aromatic ring contains one C 3~6 It is substituted with a cycloalkyl group, and the monocyclic 6-membered aromatic ring may be C 3~6 Cycloalkyl, cyano, and C1~4 It may also be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R 1b This represents F.

[0144] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, where Het represents a monocyclic six-membered aromatic ring containing one, two, or three nitrogen atoms; the monocyclic six-membered aromatic ring contains one C 3~6 It is substituted with a cycloalkyl group.

[0145] In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as referred to in any of the other embodiments, and solvates thereof or any subgroup thereof, where Het represents a monocyclic six-membered aromatic ring containing one, two, or three nitrogen atoms; the monocyclic six-membered aromatic ring contains one C 3~6 It is substituted with a cycloalkyl group; R 1b This represents F.

[0146] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het is the following formula

[0147] [ka] Each represents, and depending on the case, one cyano or C 1~4 It may be substituted with alkyl.

[0148] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 Cy 2 It represents.

[0149] In one embodiment, the present invention relates to the compounds of formula (I), and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, as described in any of the other embodiments, wherein Cy 2 represents C 3~7 cycloalkyl; wherein the C 3~7 cycloalkyl is independently selected from the group consisting of Het 6a , Het 6b , and -NR 9a R 9b and is substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of

[0150] In one embodiment, the present invention relates to the compounds of formula (I), and their pharmaceutically acceptable salts and solvates, or any subgroup thereof, as described in any of the other embodiments, wherein Cy 2 represents C 3~7 cycloalkyl; wherein the C 3~7 cycloalkyl is independently selected from the group consisting of Het 6a and Het 6b and is substituted with 1 or 2 substituents each independently selected from the group consisting of

[0151] In one embodiment, the present invention relates to the compounds of formula (I) and pharmaceutically acceptable salts, and their solvates or any subgroup thereof, as mentioned in any of the other embodiments, wherein R 3 represents Cy<00​​​​​​​​​​​​​​​​This represents cyclobutyl as defined in any of the other embodiments.

[0153] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iy):

[0154] [ka] In the formula, R 3 This is defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0155] In one embodiment, the present invention relates to compounds of formula (I) as described in any of the other embodiments, as well as their pharmaceutically acceptable salts and solvates, or any subgroup thereof, wherein the compounds of formula (I) are limited to compounds of formula (Iz):

[0156] [ka] In the formula, Cy 2 This is defined for the compounds of formula (I) or any subgroup thereof as described in any of the other embodiments.

[0157] In one embodiment, the present invention relates to formula (Iz)

[0158] [ka] Novel compounds of the same, as well as their tautomers and stereoisomers [in the formula, Cy 2 C 3~7 Represents a cycloalkyl group; the C 3~7 Cycloalkyls have one or two carbon atoms, Het 6a , Het 6b , and -NR 9aR 9b It is substituted with one substituent selected from the group consisting of; R 9a and R 9b is hydrogen; C 1~4 Alkyl; C 3~6 Cycloalkyl;-C(=O)-C 1~4 Alkyl;-C(=O)-C 3~6 Cycloalkyl; -S(=O)2-C 1~4 Each is independently selected from the group consisting of alkyl groups; Het 6a This represents a monocyclic N-bonded 4-7 member fully saturated heterocycline containing one N atom; the heterocycline may optionally have -OC on one or two carbon atoms. 1~4 Alkyl;-OC 3~6 Cycloalkyl; -S(=O)2-C 1~4 Alkyl; and C 1~4 They may be substituted with a total of one, two, three, or four substituents independently selected from the group consisting of alkyl groups; Het 6b This represents a bicyclic N-bonded 6-11 member fully saturated heterocycline containing one N atom and optionally one additional heteroatom selected from O and N; the heterocycline optionally contains one -OC on one carbon atom. 1~4 It may be substituted with alkyl; if a second nitrogen atom is present in the heterocyclyl, the second nitrogen atom is -C(=O)-C 1~4 Alkyl and C 1~4 [Substituted with substituents selected from the group consisting of alkyl groups] This also relates to pharmaceutically acceptable salts and solvates thereof.

[0159] In one embodiment, the present invention relates to a subgroup of formula (I) defined in a general reaction scheme.

[0160] In one embodiment, the compound of formula (I) is the exemplified compound, Its tautomers and stereoisomers, The free base, any pharmaceutically acceptable salt, and any solvate thereof are selected from the group.

[0161] All possible combinations of the embodiments described above are considered to be included within the scope of the present invention.

[0162] Method for preparing the compound of formula (I) In this section, unless the context indicates otherwise, references to formula (I) in all other sections also include all other subgroups and their embodiments as defined herein.

[0163] The following describes the general preparation of some typical examples of the compound of formula (I), in which specific examples they are prepared from starting materials that are either commercially available or prepared by standard synthesis processes commonly used by those skilled in the field of organic chemistry. The following schemes are merely illustrative examples of the present invention and do not limit the present invention in any way.

[0164] Alternatively, the compounds of the present invention may also be prepared by similar reaction protocols, such as those described in the general scheme below, in combination with standard synthesis processes commonly used by those skilled in the art.

[0165] Those skilled in the art will understand that in the reactions described in the scheme, although this is not always explicitly stated, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, or carboxyl groups) if they are desirable in the final product to avoid undesirable involvement in the reaction. In general, conventional protecting groups can be used according to standard practices. Protecting groups can be removed at a convenient subsequent step using methods well known in the art.

[0166] Those skilled in the art will understand that in the reactions described in the scheme, it may be prudent or necessary to carry out the reactions under an inert atmosphere, such as an N2 gas atmosphere.

[0167] It will be obvious to those skilled in the art that it may be necessary to cool the reaction mixture before proceeding with the reaction (for example, a series of operations necessary to isolate and purify the products of a chemical reaction, such as quenching, column chromatography, and extraction).

[0168] Those skilled in the art will understand that heating a reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0169] Those skilled in the art will understand that another series of chemical reactions shown in the following scheme may also yield the desired compound of formula (I).

[0170] Those skilled in the art will understand that the intermediates and final compounds shown in the following scheme 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 salts or solvates thereof. The intermediates and compounds described herein can be synthesized in the form of a mixture of tautomers and stereoisomers, which can be separated from each other according to decomposition procedures known in the art.

[0171] Scheme 1 Generally, Y 1 is -O or -NR 5c - Y 1a Compounds of formula (I) limited to, and named herein as compounds of formula (Ia), (Ib), (Ic), (Id), and (Ie), can be prepared according to the following reaction scheme 1. In scheme 1, W 1 represents fluoro, chloro, bromo, or iodine; all other variables are defined in accordance with the scope of this invention.

[0172] [ka]

[0173] In Scheme 1, the following reaction conditions apply: Step 1: At a suitable temperature such as room temperature to 90°C, in the presence of a suitable base such as diisopropylethylamine, triethylamine, or sodium carbonate, and in a suitable solvent such as acetonitrile, dimethylformamide, or dichloromethane; Step 2: In a suitable temperature range of room temperature to 130°C, in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone; Alternatively, at a suitable temperature such as room temperature, in the presence of a suitable deprotonating agent, such as sodium hydride, in a suitable solvent, such as dimethyl sulfoxide; Alternatively, in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as room temperature, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU); Step 3: At a suitable temperature, e.g., room temperature, in the presence of a suitable catalyst, e.g., palladium charcoal (Pd / C), in a suitable solvent, e.g., methanol, under an H2 pressure, e.g., 1-3 bar, and optionally in the presence of a base, e.g., triethylamine; Alternatively, in the presence of a suitable catalyst, such as 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, such as sodium borohydride, a suitable base, such as N,N,N',N'-tetramethylethylenediamine, and a suitable solvent, such as tetrahydrofuran; Step 4: In a suitable temperature range of 100-130°C, in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone; Step 5: In a suitable temperature range of 100-130°C, in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone; Alternatively, at a suitable temperature in the range of 80-100°C, in the presence of a suitable catalyst, such as palladium acetate (Pd(OAc)2), a suitable ligand such as 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl, a suitable base such as cesium carbonate, or a suitable solvent such as dioxane; Step 6: In a suitable solvent, e.g., dioxane, in the presence of a suitable catalyst, e.g., palladium acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0)(Pd2dba3), and in the presence or absence of a suitable ligand, e.g., triphenylphosphine, at a suitable temperature of room temperature to 60°C;

[0174] Scheme 2 Generally, Y 1 is limited to -CH2-, R 2 is W 1 Compounds of formula (I), limited to those specified as compounds of formula (If), can be prepared according to the following reaction scheme 2. In scheme 2, all other variables are defined in accordance with the scope of the present invention.

[0175] [ka]

[0176] In Scheme 2, the following reaction conditions apply: Step 1: In a suitable solvent, e.g., tetrahydrofuran or dioxane, in the presence of a suitable catalyst, e.g., palladium acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), or tetrakis(triphenylphosphine)palladium(0), at a suitable temperature in the range of 60°C to 100°C.

[0177] Those skilled in the art will understand that starting from compound (If), it is possible to carry out chemistry similar to that reported in steps 3, 4, 5, and 6 of Scheme 1.

[0178] Scheme 3 Generally, Y1 ga-CR 5a R 5b - Limited to R 2 is W 1 Compounds of formula (I) (hereinafter referred to as compounds of formula (Ig)) limited to the above can be prepared according to the following reaction scheme 3. In scheme 3, R 5a and R 5b At least one of the elements is not hydrogen. All other variables are defined in accordance with the scope of this invention.

[0179] [ka]

[0180] In Scheme 3, the following reaction conditions apply: Step 1: At a suitable temperature in the range of 80°C to 200°C, optionally under microwave irradiation, in the presence of a suitable catalyst, such as palladium acetate (Pd(OAc)2), in the presence of a suitable ligand, such as triphenylphosphine or tricyclohexylphosphine, in a suitable solvent, such as dioxane, preferably under sealed conditions.

[0181] Those skilled in the art will understand that starting with compound (Ig), a chemistry similar to that reported in steps 3, 4, 5, and 6 of Scheme 1 can be carried out.

[0182] Scheme 4 Generally, the compound of formula (I), referred to as the compound of formula (Ib) in this specification, can be prepared alternatively according to the following reaction scheme 4. In scheme 4, PG 1 This represents a suitable protecting group such as tert-butyloxycarbonyl, LG 1 This is a leaving group such as chloro, bromo, iodine, or tosylate or mesylate. All other variables are defined as enumerated prior to or in accordance with the scope of this invention.

[0183] [ka]

[0184] In Scheme 4, the following reaction conditions apply: Step 1: At a suitable temperature such as room temperature to 90°C, in the presence of a suitable base such as diisopropylethylamine, triethylamine, or sodium carbonate, and in a suitable solvent such as acetonitrile, dimethylformamide, or dichloromethane; Step 2: In a suitable temperature range of room temperature to 130°C, in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone; Alternatively, at a suitable temperature such as room temperature, in the presence of a suitable deprotonating agent, such as sodium hydride, in a suitable solvent, such as dimethyl sulfoxide; Alternatively, in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as room temperature, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU); Step 3: At a suitable temperature, e.g., room temperature, in the presence of a suitable catalyst, e.g., palladium charcoal (Pd / C), in a suitable solvent, e.g., methanol, under an H2 pressure of e.g., 1-3 bar; Alternatively, in the presence of a suitable catalyst, such as 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex, a suitable reducing agent, such as sodium borohydride, a suitable base, such as N,N,N',N'-tetramethylethylenediamine, and a suitable solvent, such as tetrahydrofuran; Process 4:PG 1 If it is tert-butyloxycarbonyl, then it can be cleaved in a suitable temperature range, e.g., 0°C to room temperature, under suitable cleavage conditions, e.g., in the presence of an acid such as HCl or trifluoroacetic acid, and in a suitable solvent, e.g., acetonitrile or DCM or methanol (MeOH); Step 5: Leads to the final example (Ib), representing all types of reactions, such as reductive amination and nucleophilic substitution.

[0185] Those skilled in the art will understand that starting from intermediate XI, chemical reactions similar to those reported in steps 3, 4, 5, and 6 of Scheme 1 can be carried out.

[0186] Scheme 5 Generally, U is limited to N, and Y 1 However, Y is O 1b Compounds of formula (I), specifically those of formula (Iba), can be prepared according to the following reaction scheme 5. In scheme 5, PG 1 This represents a suitable protecting group, such as tert-butyloxycarbonyl, and W 2 represents a leaving group such as chloro, tosylate, or mesylate. All other variables are defined in accordance with the scope of this invention.

[0187] [ka]

[0188] In Scheme 5, the following reaction conditions apply: Step 1: In a suitable solvent, e.g., dimethylformamide, in the presence of a suitable base, e.g., potassium carbonate, at a suitable temperature, e.g., room temperature; Step 2: At a suitable temperature such as room temperature, in the presence of a suitable base such as lithium hydroxide, in a suitable solvent such as a mixture of tetrahydrofuran, ethanol, and water; Step 3: In a suitable solvent such as dichloroethane, in the presence of dibromoisocyanurate, at a suitable temperature such as room temperature; Process 4:W 2 If the substance is chloro, it is used in a suitable temperature range such as room temperature, in the presence of a chlorinating agent such as oxalyl chloride, in the presence of a catalytic amount of dimethylformamide, in the presence of a suitable base such as triethylamine, or in a suitable solvent such as dichloromethane; W 2If trifluoroethoxy is present, then in the presence or absence of 2,2,2-trifluoroethanol as a solvent, at a suitable temperature such as 65°C, in the presence of a molecular sieve, and with a suitable activator such as 1,3-dibromo-1,3,5-triazinan-2,4,6-trione; Step 5: At a suitable temperature such as room temperature, in the presence of a suitable base such as triethylamine or 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), in a suitable solvent such as dichloromethane or acetonitrile; Step 6: At a suitable temperature such as room temperature, in the presence of a suitable base such as triethylamine or 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), in a suitable solvent such as dichloromethane or acetonitrile; Process 7:PG 1 If it is tert-butyloxycarbonyl, then it can be cleaved in a suitable temperature range, e.g., 0°C to room temperature, under suitable cleavage conditions, e.g., in the presence of an acid such as HCl or trifluoroacetic acid, and in a suitable solvent, e.g., acetonitrile or DCM or methanol (MeOH); Step 8: Leading to the final example (Iba), representing all types of reactions such as reductive amination and nucleophilic substitution.

[0189] Scheme 6 In general, the intermediate of formula IIIa can be prepared according to the following reaction scheme 5. In scheme 5, PG 2 represents a suitable protecting group, such as benzyloxycarbonyl. All other variables are defined according to the scope of the present invention or as defined in the previous scheme.

[0190] [ka]

[0191] Step 1: At a suitable temperature, e.g., room temperature, in the presence of benzyl chloroformate, a suitable base, e.g., triethylamine, and a suitable solvent, e.g., dichloromethane; Process 2:PG 1If it is tert-butyloxycarbonyl, then it can be cleaved in a suitable temperature range, e.g., 0°C to room temperature, under suitable cleavage conditions, e.g., in the presence of an acid such as HCl or trifluoroacetic acid, and in a suitable solvent, e.g., acetonitrile or DCM or methanol (MeOH); Step 3: Represents all types of reactions, such as reductive amination and nucleophilic substitution leading to intermediate IIIa.

[0192] It will be understood that, given the presence of suitable functional groups, compounds of various formulas or any intermediates used in their preparation can be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Specific substitution techniques include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

[0193] The compound of formula (I) may be synthesized in the form of a racemic mixture of enantiomers, which can be separated from each other by decomposition procedures known in the art. A racemic compound of formula (I) containing a basic nitrogen atom may be converted to the corresponding diastereomer salt form by reaction with a suitable chiral acid. The diastereomer salt form is then separated, for example, by selective or fractional crystallization, and the enantiomer is liberated therefrom by alkali. An alternative method for separating the enantiomer form of the compound of formula (I) includes liquid chromatography using a chiral stationary phase. The pure stereochemical isomer may also be derived from the corresponding pure stereochemical isomer of a suitable starting material, provided that the reaction occurs stereospecifically.

[0194] In the preparation of the compounds of the present invention, protection of the remote functional group (e.g., primary or secondary amine) of the intermediate may be necessary. The need for such protection will vary depending on the properties 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 will be readily determined by those skilled in the art. For a general description of protecting groups and their use, see TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.

[0195] Pharmacology The compounds of the present invention have been found to block the interaction between menin and MLL proteins and oncogenic MLL fusion proteins. Therefore, the compounds of the present invention and pharmaceutical compositions containing such compounds may be useful in the treatment or prevention, particularly in the treatment, of diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

[0196] In particular, the compounds and pharmaceutical compositions according to the present invention may be useful for the treatment or prevention of cancer. According to one embodiment, cancers that may benefit from treatment with the menin / MLL inhibitor of the present invention include leukemia, myeloma, or solid tumor cancers (e.g., prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma). In some embodiments, leukemias include acute leukemia, chronic leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prelymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL rearrangement leukemia, MLL-PTD leukemia, MLL amplification leukemia, MLL-positive leukemia, and leukemias exhibiting the HOX / MEIS1 gene expression signature.

[0197] Accordingly, the present invention relates to compounds of formula (I) for use as pharmaceuticals, their tautomers and stereoisomers, and pharmaceutically acceptable salts and solvates thereof.

[0198] The present invention also relates to the use of a compound of formula (I), its tautomers or stereoisomers, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions according to the present invention, for the manufacture of pharmaceuticals.

[0199] The present invention also relates to a compound of formula (I), its tautomers or stereoisomers, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition according to the present invention, for use in treating, preventing, improving, controlling or reducing the risk of disorders associated with the interaction between menine and MLL proteins and oncogenic MLL fusion proteins in mammals, including humans, where the treatment or prevention thereof is affected or promoted by blocking the interaction between menine and MLL proteins and oncogenic MLL fusion proteins.

[0200] The present invention also relates to the use of a compound of formula (I), its tautomers or stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention, for the manufacture of a drug for treating, preventing, improving, controlling or reducing the risk of disorders associated with the interaction between menine and MLL protein and oncogenic MLL fusion protein in mammals, including humans, where the treatment or prevention thereof is affected or promoted by blocking the interaction between menine and MLL protein and oncogenic MLL fusion protein.

[0201] The present invention also relates to a compound of formula (I), its tautomer or stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of any one of the above-mentioned diseases.

[0202] The present invention also relates to a compound of formula (I), a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing any one of the diseases described herein.

[0203] The present invention also relates to the use of a compound of formula (I), its tautomer or stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a pharmacopoeia for the treatment or prevention of any one of the disease conditions described herein.

[0204] The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases described herein.

[0205] A method for treating a warm-blooded animal (including a human) suffering from any one of the diseases described herein is provided, taking into consideration the usefulness of the compound of formula (I), its tautomers and stereoisomers, and its pharmaceutically acceptable salts and solvates.

[0206] The method includes administering a therapeutically effective amount of a compound of formula (I), its tautomer or stereoisomer, or a pharmaceutically acceptable salt or solvate thereof to a warm-blooded animal, including a human, i.e., systemic or topical administration.

[0207] Accordingly, the present invention also relates to a method for treating or preventing any one of the diseases described herein, comprising administering a therapeutically effective amount of the compound according to the present invention to a patient in need thereof.

[0208] Those skilled in the art will recognize that a therapeutically effective dose of the compound of the present invention is sufficient to have therapeutic activity, and that this amount varies, among other things, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. The effective daily therapeutic dose will be about 0.005 mg / kg to 100 mg / kg. The amount of the compound of the present invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect may vary depending, for example, the specific compound, the route of administration, the age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also include administering the active ingredient in a regimen of 1 to 4 doses per day. In these treatment methods, the compound of the present invention is preferably formulated before administration.

[0209] The present invention also provides compositions for preventing or treating disorders referred to herein. The compositions comprise therapeutically effective amounts of a compound of formula (I), its tautomers or stereoisomers, or pharmaceutically acceptable salts or solvates thereof, and pharmaceutically acceptable carriers or diluents.

[0210] While it is possible to administer the active ingredient (for example, the compound of the present invention) alone, it is preferable to administer it as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising the compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to the recipient.

[0211] For example, the pharmaceutical composition is described in Gennaro et al. Remington's Pharmaceutical Sciences (18 th They can be prepared by any method well known in the field of pharmacy, using methods such as those described in (see, in particular, Part 8: Pharmaceutical preparations and their Manufacture) of Mack Publishing Company, 1990.

[0212] The compounds of the present invention may be used alone or in combination with one or more additional therapeutic agents. Combination therapy includes administering a single drug formulation containing the compounds of the present invention and one or more additional therapeutic agents, as well as administering the compounds of the present invention and each additional therapeutic agent in their own separate drug formulations.

[0213] 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 further comprising one or more anticancer agents as active ingredients, as a combination preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer.

[0214] One or more other pharmaceuticals and compounds according to the present invention may be administered simultaneously (e.g., in separate or single compositions) or sequentially in either order. In the latter case, the two or more compounds are administered for a sufficient period and in amounts and manner to ensure that a favorable or synergistic effect is achieved. It will be understood that the preferred method and order of administration of each component of the combination, as well as the respective dosages and administration plans, will depend on the specific other pharmaceuticals and compounds of the present invention being administered, their routes of administration, the specific condition being treated, particularly tumors, and the specific host being treated.

[0215] The following embodiments further illustrate the present invention. [Examples]

[0216] Several methods for preparing the compounds of the present invention are shown in the following examples. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification, or can be synthesized by those skilled in the art by using well-known methods.

[0217] [Table 1-1]

[0218] [Table 1-2]

[0219] [Table 1-3]

[0220] As will be understood by those skilled in the art, compounds synthesized using the indicated protocols may exist as solvates, e.g., hydrates, and / or may contain residual solvent or trace impurities. Compounds isolated in salt form may be integer stoichiometric, i.e., monostoichiometric, distoichiometric, or intermediate stoichiometric. Where intermediates or compounds in the following experimental sections are indicated as "HCl salts" without indicating the equivalent number of HCl, this means that the equivalent number of HCl could not be determined.

[0221] The stereochemical configuration of the center of some compounds can be named "R" or "S" when the mixture is separated, and for some compounds, the compound itself is isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry has not been determined (even if the bond is stereospecific), the indicated stereochemical configuration of the center is " * R" or " * It is named "S".

[0222] For example, compound 5

[0223] [ka] It should be clear that the following equation holds true.

[0224] [ka]

[0225] For example, compound 14

[0226] [ka] It should be clear that this is expressed by the following equation.

[0227] [ka]

[0228] For example, the stereochemical configuration of two stereocenters * (for example, * R or * In the case of compounds such as 214 and 215, indicated by S), the compound itself is isolated as a single stereoisomer and is enantiomerically pure, but the absolute stereochemistry of the stereocenter is not determined (even if the bond is stereospecifically described). In this case, the configuration of the first stereocenter is independent of the configuration of the second stereocenter in the same compound.

[0229] For example, regarding compound 214:

[0230] [ka] This is because the compound

[0231] [ka] It means that.

[0232] The above paragraph concerning stereochemical configuration also applies to intermediates.

[0233] As used herein, the term “enantiomerically pure” means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of another enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% by weight or less of another enantiomer. In the most preferred embodiment, the term “enantiomerically pure” means that the composition contains at least 99% by weight of one enantiomer and 1% by weight or less of another enantiomer.

[0234] Those skilled in the art will understand, even if not explicitly mentioned in the following experimental protocol, that typically, after column chromatography purification, the desired fraction is collected and the solvent is evaporated.

[0235] If the stereochemistry is not shown, this means that it is a mixture of stereoisomers, unless otherwise specified or evident from the context.

[0236] When a stereocenter is indicated by "RS," this means that a racemic mixture was obtained at the indicated center, unless otherwise specified.

[0237] Those skilled in the art will understand that, if an intermediate or compound is reported in a table, the methodology for synthesizing the desired intermediate / compound from the indicated starting materials may involve one or more reaction steps.

[0238] If two enantiomers, diastereomers, or isomers exist in the same cell in the following table (for example, compound 1a and compound 1b), those skilled in the art will understand that these intermediates or compounds can be separated from each other by using a suitable chromatographic method, such as SFC or reversed-phase separation.

[0239] Preparation of intermediates For intermediates used in subsequent reaction steps, either as crude or partially purified intermediates, the molar amount of such intermediates in the subsequent reaction step may not be mentioned, or an estimated or theoretical molar amount of such intermediates in the subsequent reaction step may be indicated in the reaction protocol described below.

[0240] Example A1 Preparation of intermediate 2:

[0241] [ka]

[0242] Benzyl chloroformate (6.03 g, 35.3 mmol) was added to a mixture of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (5.00 g, 23.6 mmol), TEA (16.5 mL, 117 mmol), and CH2Cl2 (50 mL) at 0°C (ice / water). Next, DMAP (57.5 mg, 0.471 mmol) was added to the above mixture. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 100:1~2:1) to obtain intermediate 2 (7.00 g, yield 83.7%) as yellow oil.

[0243] Preparation of intermediate 3:

[0244] [ka]

[0245] To a solution of intermediate 2 (25.0 g, 72.2 mmol) in dry dichloromethane (15 mL), trifluoroacetic acid (30 mL) was added. The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was suspended in an aqueous NaOH solution (4 g in H2O (40 mL)) and extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 3 (16.0 g) as a yellow oily substance.

[0246] Example A2 Preparation of intermediate 5

[0247] [ka]

[0248] To a solution of cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-cyclobutanecarboxylic acid (10.0 g, 46.5 mmol) in DMF (100 mL), HOBt (8.15 g, 60.3 mmol), EDCI (11.6 g, 60.5 mmol), and DIEA (30.0 mL, 182 mmol, 0.782 g / mL) were added at 0°C. Then, N,O-dimethylhydroxylamine hydrochloride (5.90 g, 60.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (500 mL). The mixture was washed with 1M HCl (150 mL), saturated NaHCO3 (100 mL x 2), and brine (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 5 (11.0 g, crude) as a white solid, which was used in the next step without further purification.

[0249] Preparation of intermediate 6

[0250] [ka]

[0251] To a solution of intermediate 5 (11.0 g, 6.97 mmol) in THF (100 mL), isopropyl magnesium chloride (64.0 mL, 128 mmol, 2 M in THF) was added dropwise at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 12 hours under an N2 atmosphere. The mixture was quenched with saturated NH4Cl (100 mL). The mixture was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: petroleum ether: ethyl acetate 1:0~5:1, TLC: petroleum ether: ethyl acetate = 5:1, Rf = 0.4) to obtain intermediate 6 (6.30 g) as a white solid.

[0252] Preparation of intermediate 7:

[0253] [ka]

[0254] To the solutions of intermediate 3 (2.80 g, 11.4 mmol) and intermediate 6 (3.00 g, 12.4 mmol) in MeOH (50 mL), acetic acid (1.50 g, 24.6 mmol) was added. The mixture was stirred at 45°C for 0.5 hours. Then, sodium cyanotrihydroborate (1.54 g, 24.5 mmol) was added. The mixture was stirred at 45°C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3 (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: dichloromethane:methanol 1:0 to 10:1, TLC: dichloromethane:methanol = 10:1, Rf = 0.5) to obtain intermediate 7 (3.40 g, purity 53.6% as measured by LCMS) as a colorless oil.

[0255] Preparation of intermediate 293:

[0256] [ka]

[0257] Intermediate 7 (10.0 g, 21.2 mmol) was processed using SFC (column: DAIEL CHIRALCEL OD (250 mm) * The mixture was separated using a 50 mm, 10 μm (50 mm, 10 μm) eluent (25% (v / v) supercritical CO2 in 0.1% NH3H2O ​​EtOH, flow rate: 200 mL / min) to obtain intermediate 293 (3.80 g, yield 38%) as a yellow oily substance.

[0258] Preparation of intermediate 8:

[0259] [ka]

[0260] To a solution of intermediate 7 (1.00 g, 2.12 mmol, purity 53.6%) in MeOH (50 mL), 1,1,2-trichloroethane (424 mg, 3.18 mmol) and Pd / C (500 mg, w / w% = 10% Pd-supported) were added. The mixture was stirred at 40°C for 4 hours under an H2 atmosphere (50 psi). The reaction mixture was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: dichloromethane: methanol (0.5% NH3.H2O) 1:0 to 3:1, TLC: dichloromethane: methanol (0.5% NH3.H2O) = 3:1, Rf = 0.4) to obtain intermediate 8 (380 mg, yield 99.1%) as a white solid.

[0261] Example A3 Preparation of intermediate 10:

[0262] [ka]

[0263] To a solution of 5-bromopyrimidine (30 g, 189 mmol) in 1000 mL of THF, cyclopropylmagnesium bromide (396 mL, 198 mmol, 0.5 M) was added at 0°C under an N2 atmosphere. After the addition, the reaction mixture was stirred at room temperature for 4 hours, and 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitride (42.8 g, 189 mmol) from 500 mL of THF was added dropwise to the reaction mixture at 0°C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, the residue was diluted with 200 mL of siRNA and 200 mL of water, then separated, the aqueous layer was extracted with siRNA (200 mL x 3), the combined extract was washed with 1N NaOH (200 mL x 2) and brine (200 mL), dried over Na2SO4, filtered, concentrated under vacuum, and the residue was purified by column chromatography (PE / siRNA 100 / 0~85 / 15) to obtain intermediate 10 (21.4 g, yield 55%) as a white solid.

[0264] The intermediates reported below were prepared starting from the corresponding starting materials, following a method similar to that described for intermediate 10:

[0265] [Table 2]

[0266] Preparation of intermediate 11:

[0267] [ka]

[0268] A mixture of intermediate 10 (16.4 g, 82.4 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (16.1 g, 103 mmol), Pd(dppf)Cl2 (3.56 g, 4.86 mmol), and Na2CO3 (2 M in water, 82.6 mL, 165 mmol) in dioxane (600 mL) was heated at 90°C for 3 hours. The reaction mixture was combined with another batch (prepared starting from 15 g of intermediate 10) for work-up and purification. The combined solution was filtered through a Celite® pad, and the filtrate was concentrated under vacuum. The residue was diluted with 200 mL of butyl and 200 mL of water, then separated, and the aqueous layer was extracted with butyl (200 mL x 3). The combined extracts were washed with brine (500 mL), dried over Na2SO4, filtered, concentrated under vacuum until 100 mL remained, filtered again to obtain intermediate 11 (20.0 g) as a brown solid. The filtrate was concentrated, and the residue was purified by column chromatography (PE / SiO2 100 / 0~50 / 50) to obtain intermediate 11 (10 g) as a brown solid. Total: 30.0 g of intermediate 11 (84% yield).

[0269] The intermediates reported below were prepared starting from the corresponding intermediate, following a method similar to that described for intermediate 11:

[0270] [Table 3]

[0271] Preparation of intermediate 12:

[0272] [ka]

[0273] K2CO3 (9.27 g, 67.1 mmol) was added to a solution of intermediate 11 (5.15 g, 22.4 mmol) and ethyl 6-chloro-1,2,4-triazine-5-carboxylate (5.60 g, 29.9 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (80 mL) and washed with H2O (40 mL x 2) and brine (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by FCC (elution with petroleum ether:ethyl acetate = 100:0~1:1) to obtain intermediate 12 (7.00 g, yield 59.1%) as a white solid.

[0274] The intermediates reported below were prepared starting from the corresponding intermediate, following a method similar to that described for intermediate 12:

[0275] [Table 4]

[0276] Preparation of intermediate 13:

[0277] [ka]

[0278] LiOH.H2O (3.85 g, 91.7 mmol) was added to the solution of intermediate 12 (7.00 g, 18.3 mmol) in THF (50 mL), H2O (10 mL), and EtOH (5 mL). The mixture was stirred at 25°C for 2 hours. The resulting solution was acidified to pH=5-6 with 0.5 M HCl and extracted with ethyl acetate (10 mL). The aqueous phase was extracted using Phenomenex Gemini-NX 150. * 30mm * The solution was purified by preparative high-performance liquid chromatography using a 5 μm eluent (eluent: (water (0.225% FA):ACN) 95:5~65:35 v / v). The pure fraction was collected, and volatile matter was removed under reduced pressure. The residue was freeze-dried to remove solvent residue, and intermediate 13 (3.85 g, yield 59.4%) was completely obtained as a white solid.

[0279] Alternative preparation of intermediate 13: A solution of intermediate 12 (1.80 g, crude product) in THF (30 mL) is prepared by adding LiOH . H2O (300 mg, 7.15 mmol) was added to a solution of H2O (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 3-4 with 1N HCl, then concentrated under reduced pressure to obtain a residue, which was purified by reverse-phase chromatography on a high-speed silica column (column: 80 g Agela C18, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient conditions: 5%B-40%B) to obtain intermediate 13 (1.40 g) as a white solid.

[0280] The intermediates reported below were prepared starting from the corresponding intermediate, following a method similar to that described for intermediate 13:

[0281] [Table 5]

[0282] Preparation of intermediate 298:

[0283] [ka]

[0284] To a mixture of 3,6-dichloropyridazine (20.0 g, 134 mmol) in DCM (660 mL) and H2O (600 mL), cyclopropanecarboxylic acid (23.0 g, 267 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dium tetrafluoroborate (95.0 g, 268 mmol), and TFA (10.0 mL, 135 mmol) were added under an N2 atmosphere at 25°C. The resulting mixture was stirred at 25°C for 5 minutes, and then AgNO3 (68.0 mL, 27.2 mmol, 0.4 M in H2O) was added. The resulting mixture was stirred under an N2 atmosphere at 55°C for 10 hours. After cooling to room temperature, the reaction mixture was quenched with 2N NaOH (90 mL), extracted with Depositphotos (500 mL x 3), and the combined organic layer was dried over Na2SO4. After filtration and concentration, the crude residue was separated and subjected to preparative HPLC (YMC-Triart Prep C18 250). * 50mm * The solution was purified using a 10 μm atmosphere (mobile phase A: water (0.225% formic acid), mobile phase B: ACN, flow rate: 100 mL / min, gradient conditions from 15% B to 55% B). The desired fraction was collected and freeze-dried to obtain intermediate 298 (6.00 g, yield 24%) as a colorless oil.

[0285] Preparation of intermediates 299 and 300:

[0286] [ka]

[0287] To a solution of intermediate 298 (6.00 g, 28.6 mmol) in MeOH (50 mL), sodium methanolate (7.72 g, 143 mmol) was gradually added under an N2 atmosphere at 25°C, and the reaction mixture was stirred at this temperature for 0.5 hours. The resulting mixture was quenched with 1N HCl (100 mL) to adjust the pH to 7 and extracted with SiO2 (135 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain a colorless oily mixture consisting of intermediate 299 and intermediate 300 (5.6 g, crude), which was used directly in the next step without further purification.

[0288] Preparation of intermediate 301:

[0289] [ka]

[0290] A mixture of intermediates 299 and 300 (5.60 g, crude) was dissolved in dioxane (120 mL) and H2O (24 mL). (5-fluoro-2-hydroxyphenyl)boronic acid (9.63 g, 61.7 mmol), Na2CO3 (9.82 g, 92.6 mmol), and Pd(PPh3)4 (1.78 g, 1.54 mmol) were added. The resulting mixture was stirred at 90°C for 8 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by FCC (PE to PE / SiO=3 / 1) to obtain intermediate 301 (1.20 g) as a white solid.

[0291] Preparation of intermediate 302:

[0292] [ka]

[0293] To a solution of intermediate 301 (1.80 g, 6.92 mmol) in ACN (40 mL), cerium(III) chloride (2.56 g, 10.4 mmol) and NaI (1.56 g, 10.4 mmol) were added. The resulting mixture was stirred at 70°C for 8 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was washed with SiO2 (30 mL x 2). The filtrate was concentrated under reduced pressure, and the crude residue was purified by FCC (PE to pure SiO2) to obtain intermediate 302 (1.4 g, yield 74%) as a white solid.

[0294] Preparation of intermediate 14:

[0295] [ka]

[0296] 1,3-Dibromo-1,3,5-Triadinane-2,4,6-Trione (1.22 g, 4.25 mmol) was added to a solution of intermediate 13 (1.00 g, 2.83 mmol) in DCE (20 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was quenched with H2O (1 mL), filtered, and the filtrate was washed with CH2Cl2 (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by FCC (eluting with ethyl acetate:methanol = 100:0 to 10:1) to obtain intermediate 14 (600 mg, yield 60.8%) as a yellow solid.

[0297] Alternative preparation of intermediate 14: To a solution of intermediate 13 (700 mg, 1.98 mmol) in DCE (30 mL), 1,3-dibromo-1,3,5-triazinan-2,4,6-trione (900 mg, 3.14 mmol) was added. The resulting mixture was stirred at room temperature for 0.5 hours. The suspension was isolated by filtration. The filtered cake was purified by FCC (siRNA:MeOH = 10:1) to obtain intermediate 14 (500 mg, yield 73%) as a light brown solid.

[0298] Preparation of intermediate 15:

[0299] [ka]

[0300] To a solution of intermediate 14 (200 mg, 0.615 mmol) in CH2Cl2 (10 mL), oxalyl chloride (134 μL, 1.23 mmol), followed by 2 drops of DMF, were added at room temperature. The mixture was stirred at this temperature for 1.5 hours. The mixture was concentrated under reduced pressure to obtain intermediate 15 (200 mg, crude) as a brown solid, which was used directly in the next reaction step.

[0301] Example A4 Preparation of intermediate 17:

[0302] [ka]

[0303] HATU (99.5 g, 262 mmol) was gradually added to a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50.0 g, 218 mmol), N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol), and Et3N (90.9 mL, 654 mmol) in dichloromethane (500 mL) at 0°C (ice / water). The reaction mixture was stirred at room temperature for 12 hours, then concentrated to dryness under reduced pressure. The residue was diluted with water (1500 mL) and extracted with dichloromethane (500 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the crude product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0~1:1) to obtain intermediate 17 (54 g) as a yellow oily substance.

[0304] The intermediates reported below were prepared starting from the corresponding intermediate or starting material, in a manner similar to that described for intermediate 17:

[0305] [Table 6]

[0306] Preparation of intermediate 18:

[0307] [ka]

[0308] Intermediate 17 (54.0 g, 198 mmol) and THF (500 mL) were added to a 1 L three-necked round-bottom flask. Then, i-PrMgCl (198 mL, 397 mmol, 2 M in THF) was added dropwise to the mixture under N2 at 0°C (ice / water). The mixture was stirred for 10 hours while being heated to room temperature, then poured into water (2000 mL) and extracted with SiO2 (1000 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was then placed in silica gel FCC (eluent: petroleum ether: ethyl acetate 1:0~2:1, TLC: petroleum ether: ethyl acetate = 2:1, R f The intermediate 18 (19.2g) was purified using a method involving a concentration of 0.6) and obtained as a yellow oily substance.

[0309] The intermediates reported below were prepared starting from the corresponding intermediate, following a method similar to that described for intermediate 18:

[0310] [Table 7]

[0311] Example A5 Preparation of intermediate 22:

[0312] [ka]

[0313] To a solution of intermediate 3 (6.00 g, 24.4 mmol) and intermediate 18 (6.22 g, 24.4 mmol) in dry methanol (180 mL), ZnCl2 (6.64 g, 48.7 mmol) was added. The reaction mixture was heated and stirred at 65°C for 3 hours, then NaBH3CN (4.59 g, 73.1 mmol) was added. The reaction mixture was stirred at 65°C for 12 hours. Then, an additional amount of intermediate 18 (6.22 g, 24.4 mmol) was added, and the reaction mixture was stirred at 65°C for a further 20 hours. The reaction mixture was cooled to room temperature, suspended in saturated NaHCO3 (180 mL), and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with SiO2 (50 mL). The filtrate was extracted with SiO2 (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was then collected in silica gel FCC (eluent: petroleum ether: ethyl acetate 1:0~0:1, TLC: petroleum ether: ethyl acetate = 0:1, R f The intermediate 22 (9.80 g) was purified using a method involving a concentration of 0.3) to obtain a colorless oily substance.

[0314] Preparation of intermediates 23 and 24: Intermediate 23:

[0315] [ka] Intermediate 24:

[0316] [ka]

[0317] Intermediate 22 (50.0 g, 103 mmol) was further purified by SFC using DAIEL CHIRALPAK AD (fixed composition elution: i-PrOH (containing 0.1% 25% NH3 aqueous solution): supercritical CO2, 25%:75%~25%:75% (v / v)). The pure fraction was recovered, and volatile substances were removed under reduced pressure to obtain intermediate 23 (22 g, yield 44%) as a yellow oily substance, and intermediate 24 (23 g, yield 46%) as a yellow oily substance.

[0318] Preparation of intermediate 26:

[0319] [ka]

[0320] HCl / 1,4-dioxane (10 mL, 40 mmol) was added to a solution of intermediate 23 (1.0 g, 2.1 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and then NH3H2O ​​(5 mL; concentrated, typically 25-28%) was added to the mixture. The residue was suspended in water (10 mL), the mixture was frozen using dry ice / acetone, and then freeze-dried to obtain intermediate 26 (900 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0321] Preparation of intermediate 27:

[0322] [ka]

[0323] TEA (1.3 mL, 9.3 mmol) was added to a solution of intermediate 26 (900 mg, crude) in dichloromethane (10 mL). Oxetane-3-carbaldehyde (310 mg, 14 mmol) was added to the above solution and stirred at room temperature for 0.5 hours. Then, NaBH(OAc)3 (1.5 g, 7.1 mmol) was added to the above solution and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated NaHCO3 (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was then processed using Waters Xbridge Prep OBD C18 150. * 40mm *The product was purified by preparative HPLC using 10 μm and water (0.05% ammonium hydroxide v / v) / ACN at 100 / 0 to 20 / 80 (v / v) to obtain a pure product. The product was suspended in water (10 mL), the mixture was frozen using dry ice / acetone, and then freeze-dried to obtain intermediate 27 (500 mg) as a colorless oil.

[0324] Preparation of intermediate 28:

[0325] [ka]

[0326] Intermediate 27 (500 mg, 1.10 mmol) and dried Pd / C (150 mg, w / w% = 10% Pd loading) were suspended in THF (30 mL). The reaction mixture was stirred at 45°C for 4 hours under H2 (50 Psi). The suspension was filtered through a Celite® pad and washed with THF (50 mL). The filtrate was concentrated to dryness under reduced pressure to obtain intermediate 28 (350 mg) as a colorless oil, which was used in the next step without further purification.

[0327] Example A6 Preparation of intermediate 25:

[0328] [ka]

[0329] Dried Pd / C (1 g) was added to a mixture of intermediate 23 (7.5 g, 15 mmol), 1,1,2-trichloroethane (2.3 mL, 25 mmol), and MeOH (200 mL) under Ar. The mixture was stirred at 40°C for 4 hours under H2 (50 psi). The mixture was filtered, and the phytolate was concentrated to dryness to obtain intermediate 25 as a white solid (5.8 g, HCl salt, 97% yield).

[0330] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 25:

[0331] [Table 8]

[0332] Example A7 Preparation of intermediate 1:

[0333] [ka]

[0334] Pyridinium-p-toluenesulfonic acid (2.16 g, 8.61 mmol) was added to a solution of methyl 1-hydroxycyclopropane carboxylate (10.0 g, 86.1 mmol) and 3-4-dihydropyran (7.68 g, 91.3 mmol) in DCM (100 mL). After addition, the reaction mixture was stirred overnight at 20°C. The reaction mixture was washed with H2O (70 mL) and saturated brine aqueous solution (50 mL), dried on sodium sulfate, and concentrated under vacuum to obtain oil. The oil was purified by FCC (PE:EA = 10:1) to obtain intermediate 1 (13.5 g, yield 78%) as a colorless oil.

[0335] Preparation of intermediate 4:

[0336] [ka]

[0337] A solution of LiAlH4 (2.00 g, 52.7 mmol) in 80 mL of THF was added to a solution of intermediate 1 (8.00 g, 40.0 mmol) in 20 mL of THF under a N2 atmosphere at 0°C. After the addition, the reaction mixture was stirred at 0°C for 2 hours. After the reaction mixture was cooled to 0°C, water (2 mL), 10% NaOH aqueous solution (2 mL), water (6 mL), and 20 g of Na2SO4 were sequentially added to the reaction mixture. The resulting mixture was filtered. The filtered cake was washed with THF (80 mL), and the combined filtrate was concentrated under reduced pressure to obtain the labeled intermediate 3A (6.23 g, yield 81%) as a colorless oil.

[0338] Preparation of intermediate 9:

[0339] [ka]

[0340] Dess-Martin periodinane (16.0 g, 37.7 mmol) was added to a 100 mL solution of intermediate 4 (4.00 g, 23.2 mmol) in DCM. After addition, the reaction mixture was stirred at 15°C for 1.5 hours. The reaction mixture was diluted with 50 mL of DCM and stirred with 60 mL of saturated NaHCO3 and 60 mL of saturated Na2S2O3 for 10 minutes. The mixture was then extracted three times with DCM (50 mL). Brine (100 mL) was then added to separate the organic layer and the brine layer. The combined organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to obtain intermediate 9 (2.98 g, 70% yield) as a pale yellow oil.

[0341] Example A8 Preparation of intermediate 29:

[0342] [ka]

[0343] TEA (363 mg, 3.59 mmol) was added to a solution of compound 3 (240 mg, crude) and intermediate 9 (500 mg, 2.94 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 10 minutes, and then NaBH3CN (300 mg, 4.77 mmol) was added little by little. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 29 (250 mg, crude) as a light brown oil (which was used directly in the next reaction step without further purification).

[0344] Example A9 Preparation of intermediate 30:

[0345] [ka]

[0346] At room temperature, tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1.27 g; 5.96 mmol) and triethylamine (1.7 mL; 11.93 mmol) were added to a solution of trichlorotriazine (1.1 g; 5.96 mmol) in DCM (40 mL). The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted with DCM. The organic layer was washed with water and brine, dried, filtered, and concentrated. The residue was combined with Et2O. The precipitate was filtered and dried to obtain 1.76 g of intermediate 30 (81%).

[0347] Preparation of intermediate 31:

[0348] [ka]

[0349] A mixture of intermediate 30 (3.25 g; 9.017 mmol), intermediate 11 (2.18 g; 9.468 mmol), and cesium carbonate (3.23 g; 9.919 mmol) in DMF (100 mL) was stirred overnight at room temperature. The solution was cooled to room temperature, poured into cold water, and extracted with phenylethylamine. The organic layer was decanted, washed with water, then brine, dried over MgSO4, filtered, and evaporated to dryness. The residue (5.8 g) was purified by silica gel chromatography (irregular SiOH, 40 g + 80 g; mobile phase: gradient from 40% phenylethylamine, 60% heptane to 100% phenylethylamine, 0% heptane). The pure fraction was recovered and evaporated to dryness, yielding 3.41 g of (68%) intermediate 31 and 600 mg of an impure fraction, which was collected together with another impure fraction (700 mg) from a reaction carried out with 1 g of intermediate 30. The resulting residue was purified by silica gel chromatography (irregular SiOH, 24 g + 24 g; mobile phase: gradient from 40% SiOH, 60% heptane to 100% SiOH, 0% heptane). The pure fraction was recovered and evaporated to dryness to obtain an additional 1.04 g of intermediate 31.

[0350] Preparation of intermediate 32:

[0351] [ka]

[0352] A mixture of intermediate 31 (500 mg; 0.902 mmol) and Pd / C (144 mg; 0.135 mmol) in MeOH (25 mL) and triethylamine (125 μL; 0.902 mmol) was hydrogenated for 40 minutes under a pressure of H2 (1 bar). The catalyst was removed by filtration through a Celite® pad and washed with DCM. The filtrate was washed with water, decanted, filtered through Chromabond®, and evaporated to dryness. The residue (520 mg) was analyzed by silica gel chromatography (irregular SiOH, 24 g; mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.5% NH4OH, 5% MeOH, 95% DCM). The pure fraction was recovered and evaporated to dryness to obtain 300 mg (64%) of intermediate 32.

[0353] Alternative preparation: A mixture of intermediate 31 (13.60 g, 24.58 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.00 g, 1.23 mmol), sodium borohydride (1.58 g, 41.73 mmol), and N,N,N',N'-tetramethylethylenediamine (6.3 mL, 41.73 mmol) in THF (280 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water (250 mL) and extracted with SiO2 (4 × 250 mL). The combined organic layer was washed with water (600 mL) and brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (mobile phase: SiO2 / petroleum ether 10:1). The pure fraction was recovered and evaporated to dryness to obtain 10.4 g (79%) of intermediate 32 as a pale yellow oily substance.

[0354] Preparation of intermediate 33:

[0355] [ka]

[0356] TFA (1 mL; 13.067 mmol) was added to a solution of intermediate 32 (300 mg; 0.577 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ACN and evaporated to dryness several times. The residue was then dissolved in DCM and basicized with diluted 15% NH4OH aqueous solution. The organic layer was decanted, washed again with water, filtered through Chromabond®, and evaporated to dryness to obtain 245 mg of intermediate 33.

[0357] Preparation of intermediate 34:

[0358] [ka]

[0359] Under N2 conditions, a solution of triethylamine (4.65 mL; 26.13 mmol) was added to a 50 mL solution of 2-methyl-1-(4-piperidinyl)-1-propanone (450 mg; 0.23 mmol) and oxetane-3-carbaldehyde (1 g; 5.22 mmol) in dimethylamine (DCM). The reaction mixture was stirred at room temperature for 15 minutes, then NaBH(OAc)3 (3.32 g; 15.7 mmol) was added gradually, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with DCM (twice), and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue (1.4 g) was purified by silica gel chromatography (stationary phase: irregular SiOH 15-40 μm 40 g, mobile phase: gradient from 100% heptane, 0% SiOH to 80% heptane, 20% SiOH) to obtain 0.88 g of (75%) intermediate 34.

[0360] Example A10 Preparation of intermediate 35:

[0361] [ka]

[0362] To a solution of 3,3-dimethoxycyclobutanecarboxylic acid (12.0 g, 75 mmol) in DCM (145 mL), T3P (100 mL, 50% in 168 mmol, 168 mmol, 168 mmol) and DIEA (64 mL, 372 mmol) were added at 0°C. Then, N,O-dimethylhydroxylamine hydrochloride (8.8 g, 89.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into a saturated solution of NaHCO3, and toluene was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain intermediate 35 (16.0 g, crude), which was used in the next step without further purification.

[0363] Preparation of intermediate 36:

[0364] [ka]

[0365] The reaction was carried out twice on 15.7 g of intermediate 35, and the reaction media from each step were mixed for workup and purification. To a solution of intermediate 35 (15.7 g, 77.7 mmol) in THF (420 mL), isopropyl magnesium chloride (178.5 mL, 232 mmol, 2 M in THF) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was stirred at room temperature under an N2 atmosphere for 12 hours, and then poured into ice water and a 10% aqueous solution of NH4Cl. The resulting mixture was then divided into two parts. nd The mixture obtained from the reaction was combined with the intermediate, and the combined mixture was extracted with siRNA. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (mobile phase: heptane:siRNA 9:1). The pure fraction was recovered and evaporated until dry to obtain 22 g (76%) of intermediate 36 as a colorless oil.

[0366] Example A11 Intermediate 37, 37a( * S) and 37b( * Preparation of R):

[0367] [ka]

[0368] The reaction was carried out twice, once with 5.09 g of intermediate 33 and once with 10.9 g of intermediate 33. The resulting crude mixtures were combined for workup and purification. Intermediate 33 (5.09 g; 12.14 mmol), intermediate 36 (2.26 g; 12.14 mmol), AcOH (764 μL; 13.35 mmol), and NaBH3CN (763 mg; 12.14 mmol) were mixed in MeOH (50 mL) and stirred overnight at 50°C. The two reaction mixtures were combined and poured into a 10% aqueous solution of K2CO3. DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (3×). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The crude product was purified by silica gel chromatography (mobile phase: 100% DCM~95% DCM, 5% MeOH, 0.5% NH4OH). The pure fraction was collected, and the solvent was evaporated to obtain 7.84 g of intermediate 37. This residue was combined with other batches obtained from the same reaction performed on 10.9 g of intermediate 33. The resulting intermediate 37 (18 g) was then treated with chiral SFC (CHIRALPAK AD-H 5 μm 250 * The solution was purified using a 30 mm substrate with a mobile phase of 78% CO2 and 22% EtOH (0.3% iPrNH2). The pure fraction was collected, and the solvent was evaporated to obtain 9.04 g of intermediate 37a. * S)(ee 100%) and 8.88g of intermediate 37b( * R) was obtained as a grayish-white foam (ee 98.9%).

[0369] Preparation of intermediates 38, 38a, and 38b:

[0370] [ka]

[0371] At 5°C, TFA (4 mL; 52.7 mmol) was added dropwise to intermediate 37 (1.55 g; 2.63 mmol) in a solution in DCM (40 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basicized with a 30% aqueous solution of NH4OH at 0-5°C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain 1.4 g (100%) of intermediate 38 as a grayish-white foam.

[0372] [ka]

[0373] The reaction is carried out with 4.44g of intermediate 37b ( * The procedure was carried out twice on R), and the resulting mixtures were combined for post-treatment. At 5°C, TFA (11.5 mL; 150.6 mmol) is mixed with intermediate 37b ( * The solution in DCM (110 mL) was added dropwise to R) (4.44 g; 7.53 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was combined with the mixture obtained from the second reaction, and the combined mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basicized with a 30% aqueous solution of NH4OH at 0-5°C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain 7.87 g (96%) of intermediate 38b( * R) was obtained as a grayish-white foam.

[0374] [ka]

[0375] At 5°C, TFA (13 mL; 170 mmol) is mixed with intermediate 37a ( *The mixture was added dropwise to a solution of (5g; 8; 48 mmol) in DCM (130 mL), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with ACN and evaporated to dryness. The residue was dissolved in DCM and basicized with a 30% aqueous solution of NH4OH at 0-5°C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain 4.6 g (100%) of intermediate 38a( * S) was obtained as a grayish-white foam.

[0376] Example A12 Preparation of intermediate 39:

[0377] [ka]

[0378] NaBH3CN (278 mg; 4.42 mmol) was added to a mixture of intermediate 38b (1.2 g; 2.21 mmol), tert-butyl-diphenyl-(4-piperidyloxy)silane (2.4 g; 7.1 mmol), and AcOH (126 μL; 2.21 mmol) in MeOH (65 mL). The reaction mixture was then heated at 60 °C for 48 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). The pure fraction was collected and evaporated to dryness, yielding 1.09 g (57%) of intermediate 39( * R) was obtained.

[0379] Example A13 Preparation of intermediate 40:

[0380] [ka]

[0381] To a solution of 2,3-dichloropyridine (6.0 g, 40.54 mmol) in N-methyl-2-pyrrolidinone (54 mL) in THF (210 mL), ferric acetylacetonate (530 mg, 1.50 mmol) was added. Then, cyclopropylmagnesium bromide (47 mL, 46.63 mmol) was added at 0°C. After stirring at room temperature for 1 hour, a further amount of cyclopropylmagnesium bromide (23 mL, 23.313 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl. The solid was filtered off, and the filtrate was extracted with siRNA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: ethyl acetate / hexane, 1:20) to obtain 3.0 g (48% yield) of intermediate 40 as a pale yellow oil.

[0382] Preparation of intermediate 41:

[0383] [ka]

[0384] To a solution of intermediate 40 (4.5 g, 29.30 mmol) in 1,4-dioxane (90 mL), 4-fluoro-2-hydroxyphenylboronic acid (4.6 g, 29.30 mmol), Pd(amphos)Cl2 (1.0 g, 1.46 mmol), and Na2CO3 (30 mL, 2 M in water) were added. After stirring at 90°C for 2 hours, the reaction mixture was cooled to room temperature, quenched with water, and extracted with SiO2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: ethyl acetate / hexane, 1:2) to obtain 5.5 g (yield 81.1%) of intermediate 41 as a yellow solid.

[0385] Preparation of intermediate 42:

[0386] [ka]

[0387] To a solution of intermediate 41 (5.5 g, 24.0 mmol) in THF (137 mL), intermediate 30 (8.6 g, 24.0 mmol) and DBU (3.6 g, 24.0 mmol) were added. After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with SiO2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: ethyl acetate / hexane, 1:1) to obtain 8.8 g (yield 63.5%) of intermediate 42 as a yellow solid.

[0388] Preparation of intermediate 43:

[0389] [ka]

[0390] Intermediate 42 (6.7 g, 12.12 mmol) in THF (167 mL) was mixed with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (989 mg, 1.21 mmol), sodium borohydride (779 mg, 20.60 mmol), and N,N,N',N'-tetramethylethylenediamine (2.4 g, 20.60 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with SiO2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: ethyl acetate / hexane, 2:3) to obtain 6.1 g (yield 95.5%) of intermediate 43 as a yellowish-brown solid.

[0391] Preparation of intermediate 44:

[0392] [ka]

[0393] At 0°C, TFA (16 mL; 212 mmol) was added to a solution of intermediate 43 (7.33 g; 14.1 mmol) in DCM (150 mL), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 40 mL of water, and the solution was basicized with a 15% aqueous solution of NH4OH. The aqueous layer was collected in DCM ( * 3) Extraction was performed. The organic layer was decanted, washed again with brine, dried with MgSO4, filtered, and evaporated to dryness to obtain 6.3 g of intermediate 44, which was used in the next step without further purification.

[0394] Intermediate 45, 45a ( * R) and 45b( * Preparation of S):

[0395] [ka]

[0396] A mixture of intermediate 44 (5 g; 11.2 mmol), intermediate 36 (2.51 g; 13.5 mmol), AcOH (707 μL; 12.4 mmol), and NaBH3CN (2.1 g; 34 mmol) in MeOH (47 mL) was stirred overnight at 50°C. The reaction mixture was poured into a 10% aqueous solution of K2CO3, and DCM was added. This mixture was extracted with DCM (3 ×). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The crude product was purified by silica gel chromatography (mobile phase: 99% DCM, 1% i-PrOH ~ 88% DCM, 12% i-PrOH). The pure fraction was collected and the solvent was evaporated. This residue (4.6 g) was subjected to chiral SFC (CHIRALPAK AD-H 5 μm 250 * The solution was purified using a 30 mm substrate with mobile phases of 85% CO2 and 15% EtOH (0.3% iPrNH2). The pure fraction was collected, and the solvent was evaporated to obtain 1.98 g (30%) of intermediate 45a. * R)(ee 100%) and 2.09g (31%) intermediate 45b( * S) was obtained as a grayish-white foam (ee 99.4%).

[0397] Intermediate 46a( * R) and 46b( * Preparation of S):

[0398] [ka]

[0399] At 5°C, TFA (5.1 mL; 67 mmol) is mixed with intermediate 45a ( * The reaction mixture was added dropwise to a solution of R) (1.98 g; 3.36 mmol) in DCM (76 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM and basicized with a 30% aqueous solution of NH4OH at 0-5°C. The mixture was stirred at room temperature for 1 hour. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain intermediate 46a( * R) 1.90g (100%) was obtained.

[0400] At 5°C, TFA (5.4 mL; 71 mmol) is mixed with intermediate 45b ( * Add (2.09 g; 3.55 mmol) of S) dropwise to a solution in DCM (81 mL), and stir the reaction mixture at room temperature for 2 hours. Evaporate the reaction mixture to dryness. Dissolve the residue in DCM and basicize with a 30% aqueous solution of NH4OH at 0-5°C. Stir the mixture at room temperature for 1 hour. Decant the organic layer, wash with water, dry over MgSO4, filter, and evaporate the solvent to obtain intermediate 46b( * S) 1.95 g (97%) was obtained.

[0401] Example A14 Preparation of intermediate 47:

[0402] [ka]

[0403] A mixture of 2-chloro-3-cyclopropylpyridine (5 g; 32.55 mmol), 5-fluoro-2-hydroxyphenylboronic acid pinacol ester (10.1 mL; 48.82 mmol), and potassium fluoride (9.46 g; 162.75 mmol) in dioxane (125 mL) and water (30 mL). The reaction mixture was degassed and Sphos Pd G2 (469 mg; 0.65 mmol) was added. The reaction mixture was then heated at 100 °C for 2 hours. The mixture was cooled to RT and then poured into water. Ether was added, and the reaction mixture was filtered through a celite® pad. The organic layer was decanted, washed with brine, then with water, dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from Et2O. The precipitate was filtered and dried to obtain 6.8 g (91%) of intermediate 47.

[0404] Preparation of intermediate 48:

[0405] [ka]

[0406] To a solution of intermediate 47 (5.6 g, 15.7 mmol) in THF (180 mL), intermediate 30 (3.6 g, 15.7 mmol) and DBU (4.9 mL, 33 mmol) were added. After stirring at room temperature for 72 hours, the reaction mixture was quenched with water and extracted with SiO2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase: gradient from 0.1% NH4OH, 1% MeOH, 99% DCM to 0.3% NH4OH, 3% MeOH, 97% DCM) to obtain 6.4 g (74%) of intermediate 48.

[0407] Preparation of intermediate 49:

[0408] [ka]

[0409] Intermediate 48 (6.4 g, 11.58 mmol) in THF (300 mL) was mixed with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (956 mg, 1.16 mmol), sodium borohydride (875 mg, 24 mmol), and N,N,N',N'-tetramethylethylenediamine (3.5 mL, 23.14 mmol). After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography column (mobile phase from 0.1% NH4OH, 1% MeOH, 99% DCM) to obtain 3 g (50% yield) of intermediate 49.

[0410] Preparation of intermediate 50:

[0411] [ka]

[0412] At 0°C, TFA (8.9 mL; 73.28 mmol) was added to a solution of intermediate 49 (3 g; 5.78 mmol) in DCM (90 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 40 mL of water, and the solution was basicized with a 15% aqueous solution of NH4OH. The aqueous layer was collected in DCM ( * 3) Extraction was performed. The organic layer was decanted, washed again with brine, dried with MgSO4, filtered, and evaporated to dryness to obtain 2.4 g of intermediate 50, which was used in the next step without further purification.

[0413] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 50:

[0414] [Table 9]

[0415] Intermediate 51, 51a ( * R), 51b(* Preparation of S):

[0416] [ka]

[0417] The solutions of intermediate 50 (1.3g; 3.1 mmol), intermediate 36 (0.752g; 4.08 mmol), AcOH (178 μL; 3.11 mmol), and NaBH3CN (0.29g; 4.66 mmol) in MeOH (50 mL) were stirred overnight at 50°C. The reaction mixture was poured into a 10% aqueous solution of K2CO3, and DCM was added. This mixture was extracted with DCM (3×). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The crude product was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, % MeOH, 99% DCM to 0.1% NH4OH, 5% MeOH, 95% DCM). The pure fraction was collected and the solvent was evaporated. This residue (1.2 g) was subjected to chiral SFC (CHIRALPAK AD-H 5 μm 250 * The solution was purified using a 30 mm substrate with mobile phases of 70% CO2 and 30% i-PrOH (0.3% iPrNH2). The pure fraction was collected, and the solvent was evaporated to obtain 464 mg (25%) of intermediate 51a. * R)(ee100%) and 476mg(26%) intermediate 51b( * S) was obtained as an off-white (ee100%) solid.

[0418] Intermediate 52a ( * R), 52b( * Preparation of S):

[0419] [ka]

[0420] At 5°C, TFA (1.2 mL; 15.76 mmol) is mixed with intermediate 51a ( *The reaction mixture was added dropwise to a solution of R) (464 mg; 0.79 mmol) in DCM (16 mL), and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM and basicized with a 10% aqueous solution of K2CO3. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain intermediate 52a ( * R) 400 mg (94%) was obtained.

[0421] At 5°C, TFA (1.2 mL; 15.76 mmol) is mixed with intermediate 51b ( * The reaction mixture was added dropwise to a solution of (476 mg; 0.81 mmol) in DCM (15 mL), and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM and basicized with a 10% aqueous solution of K2CO3. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain intermediate 52b( * S) 430 mg (98%) was obtained.

[0422] The intermediates reported below were prepared starting from the corresponding intermediates, following the same method as described for intermediates 52a and 52b:

[0423] [Table 10] Example A15 Preparation of intermediate 53:

[0424] [ka]

[0425] Under a nitrogen atmosphere, tert-butylchlorodimethylsilane (2.9 g, 19.3 mmol) and 1H-imidazole (1.66 g, 24.3 mmol) were added to a solution of 3-hydroxycyclobutane-1-carboxylic acid (1.13 g, 9.7 mmol) in THF (15 mL). The reaction mixture was stirred overnight at room temperature. The reaction product was filtered to remove insoluble matter, washed with DCM, and then concentrated under vacuum to obtain 2.9 g of intermediate 53. The intermediate was used in the next step without further purification.

[0426] Preparation of intermediate 54:

[0427] [ka]

[0428] A solution of K2CO3 (141 mg; 1 mmol) in water (2.2 mL) was added to a solution of intermediate 53 (913 mg; 2.54 mmol) in MeOH (6.5 mL) and THF (2.2 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated. The reaction mixture was cooled to 0°C in an ice bath. Then, aqueous HCl (1.5 N) was added dropwise until the pH < 2. The mixture was extracted twice with HCl. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to obtain 493 mg (79%) of intermediate 54, which was used directly in the next step without further purification.

[0429] Preparation of intermediate 55:

[0430] [ka]

[0431] Intermediate 54 (261 mg; 1 mmol), EDCI (307 mg; 1.6 mmol), N,O-dimethylhydroxylamine hydrochloride (156 mg; 1.6 mmol), then DMAP (6.5 mg; 0.054 mmol) and DIPEA (0.75 mL; 4.3 mmol) were mixed in DCM (6 mL) and stirred overnight at room temperature. The reaction mixture was diluted with DCM (10 mL), washed with aqueous HCl (1N) (2 × 5 mL) and water (10 mL), and then washed with saturated NaHCO3 solution (2 × 10 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness to obtain 144 mg of intermediate 55 (45%), which was used directly in the next step without further purification.

[0432] Preparation of intermediate 56:

[0433] [ka]

[0434] Under a nitrogen atmosphere at 0°C, isopropylmagnesium chloride (2.3 mL; 3 mmol, 1.3 M in THF) was added to a solution of intermediate 55 (144 mg; 0.5 mmol) in THF, and the mixture was dried (5 mL). The reaction mixture was stirred at 0°C for 1 hour. Then, the solution was slowly heated to room temperature and stirred for 2 hours. The reaction mixture was poured into ice water, and RINKAN was added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness to obtain 117 mg (86%) of intermediate 56.

[0435] Preparation of intermediate 57:

[0436] [ka]

[0437] Intermediate 33 (140 mg; 0.33 mmol), intermediate 56 (117 mg; 0.43 mmol), AcOH (19 μL, 0.33 mmol), and NaBH3CN (47 mg; 0.75 mmol) were mixed in MeOH (5 mL) and stirred overnight at 50°C. The reaction mixture was poured into a saturated solution of NaHCO3 and DCM was added. This mixture was extracted with DCM (3 ×). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The crude product (258 mg) was purified by silica gel chromatography (mobile phase: gradient from 99% DCM, 1% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fraction was recovered, and the solvent was evaporated to obtain 104 mg (46%) of intermediate 57.

[0438] Example A16 Preparation of intermediate 59:

[0439] [ka]

[0440] 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (900 mg; 3.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (400 mg; 4.1 mmol) were mixed in 15 mL of DCM. HATU (2.1 g; 5.6 mmol) and DIPEA (0.96 mL; 5.6 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water. Saturated aqueous NaHCO3 solution and DCM were added. The organic layer was separated, dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue (2.26 g) was purified by silica gel chromatography (mobile phase: gradient from 80% heptane, 20% siRNA to 40% heptane, 60% siRNA). The pure fraction was recovered, and the solvent was evaporated to obtain 1 g (100%) of intermediate 59.

[0441] Intermediate 60, reported below, was prepared according to a similar method starting from 1-boc-1-azaspiro[3.3]heptane-6-carboxylic acid.

[0442] [Table 11]

[0443] Preparation of intermediate 61:

[0444] [ka]

[0445] Under a nitrogen atmosphere at 0°C, isopropyl magnesium chloride (29 mL; 37.3 mmol, 1.3 M in THF) was added to a solution of intermediate 59 (2.12 g; 7.46 mmol) in THF solution and dried (36 mL). The reaction mixture was stirred at 0°C for 1 hour. The solution was then slowly heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with a 10% aqueous solution of NH4Cl and pharmaceutically acceptable ammonium compounds were added. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue (1.9 g) was purified by silica gel chromatography (mobile phase: gradient from 80% heptane, 20% ammonium compounds to 40% heptane, 60% ammonium compounds). The pure fraction was recovered, and the solvent was evaporated to obtain 1.47 g (74%) of intermediate 61.

[0446] Intermediate 62, reported below, was prepared according to a similar method starting from intermediate 60.

[0447] [Table 12]

[0448] Example A17 Intermediate 58, reported below, was prepared starting from intermediate 38b and methyl-3-methylpyrrolidine-3-carboxylate, following the same method as the preparation of compound 7.

[0449] [Table 13]

[0450] Preparation of intermediate 67:

[0451] [ka]

[0452] Lithium hydroxide (101 mg; 2.41 mmol) was added to a solution of intermediate 58 (270 mg; 0.4 mmol) in THF (25 mL) and water (3 mL). The mixture was stirred overnight at room temperature and then concentrated to dryness. The crude product was then separated over Et2O and filtered to obtain 280 mg of intermediate 67, which was used directly in the next step without further purification.

[0453] Example A18 Preparation of intermediate 68:

[0454] [ka]

[0455] (NH4)2S2O8 (15 g; 65.73 mmol) and AgNO3 (8.5 g; 50 mmol) were added to water (150 mL) and cyclopropanecarboxylic acid (2.1 mL; 26.47 mmol), followed by the addition of 5-bromo-2-chloropyrimidine (5 g; 25.85 mmol) and CH3CN (150 mL). The reaction mixture was stirred at room temperature for 72 hours and quenched by slowly adding ice water. HCl was added, followed by the addition of saturated NaCl solution. The solution was filtered through a celite® layer, then extracted with HCl (2 × 500 mL), dried over MgSO4, filtered, and concentrated. The residue (5.83 g) was purified by silica gel chromatography (mobile phase: 40% DCM, 60% heptane). The pure fraction was recovered, and the solvent was evaporated until dry to obtain 3.05 g (51%) of intermediate 68.

[0456] Preparation of intermediate 69:

[0457] [ka]

[0458] At room temperature, TBACN (1.75 g; 6.52 mmol) and DABCO (0.72 g; 6.42 mmol) were added to a solution of intermediate 68 (1 g; 4.28 mmol) in MeCN (20 mL), and the solution was stirred at room temperature for 2 hours. The solution was poured into cold water, and the product was extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue (1.6 g) was purified by silica gel chromatography (mobile phase gradient 0% DCM, 100% heptane to 30% DCM, 70% heptane). The pure fraction was recovered, and the solvent was evaporated until dry to obtain 860 mg (90%) of intermediate 69.

[0459] Preparation of intermediate 70:

[0460] [ka]

[0461] A pre-degassed mixture of intermediate 69 (860 mg; 3.84 mmol), 5-fluoro-2-hydroxyphenylboron pinacol ester (1.3 g; 5.46 mmol), and potassium fluoride (1.1 g; 18.93 mmol) in 1,4-dioxane (20 mL) was mixed with water (3.9 mL) and SPhos Pd G2 (56 mg; 0.08 mmol). The mixture was heated in a Schlenk apparatus at 100 °C for 2.30 hours. The mixture was cooled to room temperature and poured into water. Ether was added, and the mixture was filtered through a celite® pad. The organic layer was decanted, washed with brine, then with water, dried over MgSO4, filtered, and evaporated to dryness. The residue (2.12 g) was purified by silica gel chromatography (mobile phase: gradient from 100% DCM, 0% MeOH to 98% DCM, 2% MeOH). The pure fraction was recovered, and the solvent was evaporated until dry, yielding 630 mg (64%) of intermediate 70.

[0462] Preparation of intermediate 71:

[0463] [ka]

[0464] The solutions of intermediate 70 (2 g; 7.835 mmol), intermediate 30 (2.8 g; 7.77 mmol), and DBU (5.7 mL; 38.94 mmol) in THF (100 mL) were stirred at room temperature for 24 hours. The solutions were poured into cold water, and the product was extracted with SiO2. The organic layer was separated, dried over MgSO4, filtered, and evaporated to dryness. The residue (5 g) was purified by silica gel chromatography (mobile phase: 0.1% NH4OH, 99% DCM, 1% MeOH). The pure fraction was collected, and the solvent was evaporated until dry. Chiral SFC (stationary phase: CHIRALPAK IC 5 μm 250 * A second purification (3.5 g) was performed via a 30 mm (mobile phase: 50% CO2, 50% MeOH). The pure fraction was collected, and the solvent was evaporated until dry to obtain 2.6 g (57%) of intermediate 71.

[0465] Preparation of intermediate 72:

[0466] [ka]

[0467] A mixture in dry THF (100 mL) containing intermediate 71 (2.6 g; 4.49 mmol) and TMEDA (1 mL; 6.71 mmol) was degassed by N2 bubbling. Next, Pd(dppf)Cl2.DCM (415 mg; 0.50 mmol) and NaBH4 (260 mg; 6.87 mmol) were added. The reaction mixture was stirred overnight at 50°C in a sealed glass container. The solution was cooled, poured into cooling water, and SiO was added. This mixture was filtered through a Celite® pad. The product was extracted with SiO. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (mobile phase: gradient from 100% DCM, 0% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fraction was collected, and the solvent was evaporated until dry, yielding 1.84 g (75%) of intermediate 72.

[0468] Preparation of intermediate 73:

[0469] [ka]

[0470] The solutions of intermediate 72 (3 g; 5.51 mmol) and TFA (9 mL; 117.5 mmol) in DCM (90 mL) were stirred overnight at room temperature. The solutions were evaporated to dryness, the mixture was poured into cold water, basicized with NH4OH, and the product was extracted with SiO2. The organic layer was dried over MgSO4, filtered, and evaporated to dryness to obtain 2.49 g of intermediate 73, which was used directly for the next step.

[0471] Preparation of intermediate 74:

[0472] [ka]

[0473] Under N2 conditions at room temperature, a mixture of intermediate 73 (2 g; 4.5 mmol), intermediate 36 (1.1 g; 5.91 mmol), and AcOH (260 μL; 4.55 mmol) in MeOH (60 mL) was mixed with NaBH3CN (424 mg; 6.75 mmol), and the reaction mixture was heated overnight at 60 °C. The reaction mixture was cooled and poured into a mixture of 10% aqueous K2CO3 and SiO2. The mixture was extracted with SiO2 (3 ×). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by silica gel chromatography (2.6 g) (mobile phase: 100% DCM, gradient from 0% MeOH (+10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fraction was recovered, and the solvent was evaporated until dry to obtain 450 mg (16% in two steps) of intermediate 74.

[0474] Preparation of intermediate 75:

[0475] [ka]

[0476] At 5°C, TFA (1.2 mL; 15.7 mmol) was added dropwise to a solution of intermediate 74 (450 mg; 0.73 mmol) in DCM (12 mL), and the reaction mixture was stirred at room temperature for 3 hours. MeCN was added, and the solution was evaporated to dryness. The residue was dissolved in RINKAN and basicized with a 30% aqueous solution of NH4OH at 0-5°C. The organic layer was decanted, washed with water, dried over MgSO4, filtered, and the solvent was evaporated to obtain intermediate 75, 414 mg (99%), which was used directly in the next step.

[0477] Example A19 Preparation of intermediate 76:

[0478] [ka]

[0479] In a 1 L Schlenk round-bottom flask, 0.5 M cyclopropyl zinc bromide (100 mL; 50 mmol) in THF was added dropwise to a pre-degassed solution of 4-bromo-3-chloropyridine (6.41 g; 33.33 mmol) and Pd(PPh3)4 (1.93 g; 1.67 mmol) in THF (200 mL). The reaction mixture was heated at 65 °C for 18 hours. The reaction mixture was cooled to room temperature, neutralized with a 10% aqueous solution of K2CO3, and extracted with Et2O (twice). The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 80 g; mobile phase: gradient from 10% HCl, 90% heptane to 20% HCl, 80% heptane). The pure fraction was recovered and evaporated to dryness to obtain 3.93 g (77%) of intermediate 76.

[0480] Preparation of intermediate 77:

[0481] [ka]

[0482] In a Schlenk round-bottom flask, a pre-degassed mixture of intermediate 76 (3.91 g; 25.4 mmol), 5-fluoro-2-hydroxyphenylboron pinacol ester (7.88 g; 33.09 mmol), potassium fluoride (7.39 g; 127 mmol), and SPhos Pd G2 (366 mg; 0.509 mmol) in dioxane (80 mL) and water (27 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, diluted with SiO2, and poured into water. The organic layer was decanted, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was left to stand over the weekend. The residue was dissolved in DCM, the precipitate was filtered, washed with Et2O, and dried to obtain 4.86 g (83%) of intermediate 77.

[0483] Example A21 Preparation of intermediate 81:

[0484] [ka]

[0485] In a sealed tube, di-μ-iodobis(tri-t-butylphosphino)dipalladium(I) (180 mg; 207 μmol) was added to a mixture of 5-bromo-6-chloro-nicotinonitrile (1.8 g; 8.3 mmol) and cyclopropyl zinc bromide 0.5 M THF (17 mL; 8.7 mmol) solution in dry THF (34 mL). The reaction mixture was stirred at room temperature for 1 hour and quenched with a few drops of water. MgSO4 and celite were added, and the solvent was removed under vacuum to obtain a dry load, which was purified by chromatography using silica gel (irregular SiOH, 80 g; mobile phase: heptane / siRNA gradient from 95:5 to 80:20). The fractions containing the product were combined and evaporated under vacuum to obtain 1.06 g (72%) of intermediate 81 as a brown oil, which crystallized when stored at room temperature.

[0486] Preparation of intermediate 82:

[0487] [ka]

[0488] Under a flow of N2, Cs2CO3 (7.92 g; 24.3 mmol), followed by Pd(PPh3)4 (1.40 g; 1.22 mmol), was added to a stirred solution of intermediate 81 (2.17 g; 12.1 mmol) and 5-fluoro-2-hydroxyphenyl)boronic acid (4.17 g; 26.7 mmol) in a mixture of water (9.5 mL) and dioxane (28.6 mL). The reaction mixture was degassed with N2 and then stirred at 90°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with SiO2, and water was added. The organic layer was decanted, washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (irregular SiOH, 80 g, dry load; mobile phase: heptane / SiO2, gradient from 95 / 5 to 70 / 30). When the fractions containing the product were combined and evaporated, 2.41 g (78%) of intermediate 82 was obtained as a yellow solid.

[0489] Example A22 Preparation of intermediate 83:

[0490] [ka]

[0491] In a Schlenk flask, the solution of 5-bromo-4-hydroxy-nicotinonitrile (2.00 g; 10.1 mmol), 2-benzyloxy-5-fluorophenylboronic acid (3.09 g; 12.6 mmol), and K3PO4 (3.20 g; 15.1 mmol) in a mixture of dioxane (40 mL) and H2O (13.3 mL) was purged with nitrogen. CatacXium A Pd G3 (439 mg; 603 μmol) was added. The reaction mixture was again purged with nitrogen and stirred at 80°C for 17 hours. The reaction mixture was poured into water and extracted twice with the mixture DCM / MeOH (98:2). The organic layers were combined, dried over MgSO4, filtered, and evaporated to dryness. The residue was heated in i-PrOH (8 mL) and cooled to room temperature. The precipitate was filtered, washed with diethyl ether, and dried under vacuum to obtain 854 mg of intermediate 83 (27%) as a yellow solid.

[0492] Preparation of intermediate 84:

[0493] [ka]

[0494] A mixture of intermediate 83 (854 mg; 2.67 mmol) in MeCN (10 mL) was treated with POCl3 (2.03 mL; 21.9 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was then cooled to room temperature, quenched with a 10% aqueous solution of K2CO3, and extracted by DCM. The organic layer was dried over MgSO4, filtered, and evaporated under vacuum to obtain 914 mg (quantitative) of intermediate 84 as a yellow solid.

[0495] Preparation of intermediate 85:

[0496] [ka]

[0497] The solution of intermediate 84 (914 mg; 2.70 mmol), cyclopropylboronic acid (464 mg; 5.40 mmol), and K3PO4 (859 mg; 4.05 mmol) in a mixture of dioxane (11 mL) and H2O (3.6 mL) was purged with nitrogen. CatacXium A Pd G3 (117 mg; 0.162 mmol) was added. The reaction mixture was again purged with nitrogen and stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic mixture was washed with water and then brine, dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography (irregular SiOH, 40 g, dry load; mobile phase: gradient heptane / ethyl acetate, 85 / 15 to 70 / 30). The fractions containing the product were combined and evaporated to obtain 471 mg (51%) of intermediate 85 as a yellow, rubbery solid.

[0498] Preparation of intermediate 86:

[0499] [ka]

[0500] The solutions of intermediate 85 (450 mg; 1.31 mmol) and ammonium formate (412 mg; 6.53 mmol) in EtOH (7.6 mL) were treated with charcoal-supported palladium (278 mg; 0.131 mmol) and stirred at 75°C for 45 minutes. The reaction mixture was cooled to room temperature, diluted with DCM, and filtered through a Celite® pad. The filtrate was evaporated under vacuum to obtain the residue, which was purified by silica gel chromatography (irregular SiOH, 12 g; mobile phase: gradient DCM / MeOH 100 / 0 to 98 / 2). The fractions containing the product were combined and evaporated to obtain 190 mg of intermediate 86 (57%) as a yellow foam.

[0501] Example A23 Preparation of intermediate 87:

[0502] [ka]

[0503] A mixture of 2,3-dichloropyrazine (5.0 g; 33.562 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.64 g; 33.562 mmol), and Pd(amphos)Cl2 (2.38 g; 3.356 mmol) in 1,4-dioxane (100 mL) was mixed with a solution of sodium carbonate (2 M in water; 50.3 mL). The resulting mixture was stirred at 80°C for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA at 100 / 0 to 80 / 20). The fractions containing the product were combined and evaporated to obtain 3.0 g of intermediate 87 (57%) as a colorless oil.

[0504] Preparation of intermediate 88:

[0505] [ka]

[0506] A mixture of intermediate 87 (1.21 g, 7.762 mmol) and tetrakis(triphenylphosphine)palladium (370 mg; 0.323 mmol) in 1,4-dioxane (50 mL) was mixed with a solution of sodium carbonate (10 mL; 1 M in water), and the reaction was stirred at 90°C for 3.5 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with SiO2. The combined organic layer was washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether 2:1). The fractions containing the product were combined and evaporated to obtain 1.25 g of intermediate 88 (84%) as a pale yellow solid.

[0507] Example A24 Preparation of intermediate 89:

[0508] [ka]

[0509] To a stirred solution of 5-bromo-2,4-dimethoxypyrimidine (10.0 g; 45.66 mmol) in 1,4-dioxane, cyclopropylboronic acid (4.71 g; 65.74 mmol), sodium carbonate (2 M in water, 50 mL), and dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (3.23 g; 219.04 mmol) were added. The reaction mixture was stirred overnight at room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE:ethyl:93:7). The fractions containing the product were combined and evaporated to obtain 4.3 g of intermediate 89 (50%) as a colorless oil.

[0510] Preparation of intermediate 90:

[0511] [ka]

[0512] Sodium iodide (12.0 g; 79.91 mmol) was added to a stirred solution of intermediate 89 (4.8 g; 26.64 mmol) in MeCN (96 mL). The reaction mixture was cooled to 0°C, and chlorotrimethylsilane (8.7 g; 79.91 mmol) was added. After stirring overnight at room temperature, the reaction mixture was quenched with water and stirred for 15 minutes. The solid was filtered and dried under vacuum to obtain 3.0 g of intermediate 90 (yield 73%) as a yellow solid.

[0513] Preparation of intermediate 91:

[0514] [ka]

[0515] 3.5 g (23.00 mmol) of intermediate 90 was added to 300 mL of phosphorus oxychloride with 0.70 mL of N,N-dimethylformamide. After stirring at 100°C for 2 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in a small amount of DMF, poured into ice water, and subsequently extracted with SiO2. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4.2 g of intermediate 91 (96%) as a yellow oil.

[0516] Preparation of intermediate 92:

[0517] [ka]

[0518] To a stirred solution of intermediate 91 (5.4 g; 28.56 mmol) in 1,4-dioxane (162 mL), (5-fluoro-2-hydroxyphenyl)boronic acid (4.45 g; 28.56 mmol), tetrakis(triphenylphosphine)palladium (1.65 g; 1.43 mmol), and sodium bicarbonate (2 M in water, 54 mL) were added. After stirring at 80°C for 2 hours under a nitrogen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE:ethyl acetate 3:1). The fractions containing the product were combined and evaporated to obtain 2.7 g of intermediate 92 (purity 29%, 81% as evaluated by LC-MS) as a pale yellow solid.

[0519] Preparation of intermediate 93:

[0520] [ka]

[0521] To a stirred solution of intermediate 92 (1.0 g; 2.08 mmol) in MeOH (55 mL), Et3N (382 mg; 3.78 mmol) and 10% Pd / C (683 mg) were added. After stirring for 30 minutes under a hydrogen stream (1 atm) at room temperature, the catalyst was filtered off. The filtrate cake was washed with methanol. The collected filtrate was concentrated under reduced pressure to obtain 550 mg of intermediate 93 (62%).

[0522] Example A25 Preparation of intermediate 94:

[0523] [ka]

[0524] To a stirred solution of 4,5-dibromopyridazine-3(2H)-one (50 g; 196.95 mmol) in THF (300 mL), p-toluenesulfonic acid (3.4 g; 19.694 mmol) and 3,4-dihydro-2H-pyran (82.8 g; 988.72 mmol) were added. After stirring overnight at 60°C, the reaction mixture was quenched with water, and siRNA was extracted. The combined organic layer was washed with water, then brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / siRNA 81 / 19). The fractions containing the product were combined and evaporated to obtain 65 g of intermediate 94 (83%) as a pale yellow solid.

[0525] Preparation of intermediate 95:

[0526] [ka]

[0527] To a stirred solution of intermediate 94 (25 g; 73.97 mmol) in 1,2-dimethoxyethane (200 mL), sodium borohydride (5.6 g; 147.93 mmol) was added at 0°C. After stirring at room temperature for 18 hours, the reaction mixture was cooled to 0°C, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA 70 / 30). The fractions containing the product were combined and evaporated to obtain 2.3 g of intermediate 95 (12%) as a white solid.

[0528] Preparation of intermediate 96:

[0529] [ka]

[0530] A mixture of intermediate 95 (2.7 g, 10.42 mmol), (5-fluoro-2-hydroxyphenyl)boronic acid (1.6 g; 10.42 mmol), and Pd(PPh3)4 (1.2 g; 1.042 mmol) in dioxane (50 mL) was mixed with sodium carbonate solution (20 mL; 2 M in water). After stirring at 90°C for 5 hours, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0~80 / 20). The fractions containing the product were combined and evaporated to obtain 2.46 g of intermediate 96 (78%) as a yellow solid.

[0531] Preparation of intermediate 97:

[0532] [ka]

[0533] A mixture of intermediate 96 (2.46 g; 8.47 mmol), benzyl chloride (2 mL; 16.95 mmol), and K2CO3 (5.9 g; 42.37 mmol) in acetone (50 mL) was stirred overnight at 60°C. The mixture was quenched with water and extracted with siRNA. The combined organic layer was washed with water, then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The filtrate was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0~80 / 20). The fractions containing the product were combined and evaporated to obtain 2.0 g of intermediate 97 (60%) as a yellow oil.

[0534] Preparation of intermediate 98:

[0535] [ka]

[0536] Intermediate 97 (2.0 g; 5.26 mmol) was dissolved in hydrochloric acid (37% in water, 5 mL) and methanol (15 mL) and stirred at 50°C for 1 hour. The solution was concentrated under reduced pressure. The residue was dissolved in Et2O. The precipitate was filtered and dried under vacuum to obtain 1.0 g of intermediate 98 (64%) as a yellow solid.

[0537] Preparation of intermediate 99:

[0538] [ka]

[0539] A solution of intermediate 98 (1 g; 3.38 mmol) in phosphorus oxychloride (15 mL) was stirred at 100°C for 2 hours. The solution was concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA 100 / 0~30 / 70). The fractions containing the product were combined and evaporated to obtain 600 mg of intermediate 99 (52%) as a yellow oil.

[0540] Preparation of intermediate 100:

[0541] [ka]

[0542] To a solution of intermediate 99 (200 mg; 0.64 mmol) in THF (7.0 mL), palladium(II) acetate (14 mg; 0.06 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (52 mg; 0.13 mmol) were added. The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0°C, and cyclopropylzinc bromide (0.5 M in THF; 1.9 mL; 0.95 mmol) was added dropwise. After stirring overnight at room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (irregular SiOH, 40 g; mobile phase: petroleum ether: ethyl acetate 70%: 30%). The fractions containing the product were combined and evaporated to obtain 150 mg of intermediate 100 (67%) as a light brown oil.

[0543] Preparation of intermediate 101:

[0544] [ka]

[0545] To a solution of intermediate 100 (150 mg; 0.47 mmol) in MeOH (10 mL), 10% Pd / C (150 mg; 0.14 mmol) was added. After stirring at room temperature for 1 hour under a hydrogen atmosphere (2-3 atm), the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain 100 mg of intermediate 101 (88%) as a light brown solid.

[0546] Example A26 Preparation of intermediate 102:

[0547] [ka]

[0548] 3,4-Dihydro-2H-pyran (28 mL; 306.5 mmol) was added at room temperature to a mixture of 4-chloropyridazine-3(2H)-one (10 g; 76.61 mmol) and p-toluenesulfonic acid (1.4 g; 7.67 mmol in THF (200 mL)). The mixture was stirred overnight at 70°C. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (mobile phase: PE / EA: 100 / 0~30 / 70). The fractions containing the product were combined and evaporated to obtain intermediate 102 16 g (84%) as a yellow solid.

[0549] Preparation of intermediate 103:

[0550] [ka]

[0551] A mixture of intermediate 102 (5 g; 23.29 mmol), cyclopropylboronic acid (2.1 g; 24.46 mmol), and Pd(amphos)Cl2 (1.65 g; 2.33 mmol) in 1,4-dioxane (75 mL) and a solution of 2 M sodium carbonate aqueous solution (25 mL) was stirred at 90°C for 5 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0~30 / 70). The fractions containing the product were combined and evaporated to obtain 3.5 g of intermediate 103 (67%) as a yellow solid.

[0552] Preparation of intermediate 104:

[0553] [ka]

[0554] Intermediate 103 (10.0 g; 45.40 mmol) was dissolved in hydrochloric acid (37% in water, 50 mL) and methanol (150 mL) and stirred at 50°C for 1 hour. The solution was evaporated under reduced pressure. The residue was dissolved in water. The resulting solution was adjusted to pH=7 with NaOH (2 M in water) and extracted with (MeOH / DCM = 1 / 10). The combined organic layers were dried over Na2SO4. The solid was filtered off. The filtrate was concentrated under reduced pressure to obtain 5.2 g of intermediate 104 (76%) as a yellow solid.

[0555] Preparation of intermediate 105:

[0556] [ka]

[0557] A solution of intermediate 104 (12.1 g; 88.14 mmol) in acetonitrile (200 mL) was mixed with a solution of POCl3 (41.1 mL; 440.69 mmol). After stirring at 50°C for 1.5 hours, the solution was slowly poured into ice water (200 mL). The resulting solution was adjusted to pH=7 using a saturated aqueous solution of Na2CO3 and extracted with ethyl acetate. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA: 100 / 0~30 / 70). The fractions containing the product were combined and evaporated to obtain 9.0 g of intermediate 105 (61%) as a yellow oil.

[0558] Preparation of intermediate 106:

[0559] [ka]

[0560] Intermediate 105 (9 g; 58.22 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13.86 g; 58.22 mmol), Pd(PPh3)4 (3.36 g; 2.91 mmol), and a mixture of 1,4-dioxane (130 mL) in a sodium carbonate solution (43.9 mL; 2 M) were stirred at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: PE / EA: 100 / 0~30 / 70). The fractions containing the product were combined and evaporated to obtain 13 g of intermediate 106 (86%) as a pale yellow solid.

[0561] Example A27 Preparation of intermediate 107:

[0562] [ka]

[0563] To a solution of 5-bromopyridazine-4-amine (7.7 g; 44.25 mmol) in 1,4-dioxane (130 mL), cyclopropylboronic acid (5.7 g; 66.38 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.7 g; 6.64 mmol), and sodium carbonate solution (2 M in water; 66.4 mL; 132.8 mmol) were added. The resulting mixture was stirred at 90°C for 36 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (120 g; mobile phase: dichloromethane / methanol 95% / 5%). When the fractions containing the product were combined and evaporated, 2.5 g of intermediate 107 (39%) was obtained as a red oil.

[0564] Preparation of intermediate 108:

[0565] [ka]

[0566] To a solution of intermediate 107 (2.5 g; 18.50 mmol) in acetonitrile (50 mL), cupric bromide (3.31 g; 14.80 mmol) and isoamyl nitrite (2.73 mL; 20.35 mmol) were added. The resulting mixture was stirred at 70°C for 2.5 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (60 g; mobile phase: petroleum ether / ethyl acetate 50 / 50). The fractions containing the product were combined and evaporated to obtain 1.6 g of intermediate 108 (42%) as a yellow oil.

[0567] Preparation of intermediate 109:

[0568] [ka]

[0569] To a solution of intermediate 108 (1.6 g; 8.04 mmol) in 1,4-dioxane (24 mL), (5-fluoro-2-hydroxyphenyl)-boronic acid (1.38 g; 8.84 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (570 mg; 0.80 mmol), and sodium carbonate solution (2 M in water; 12.1 mL, 24.11 mmol) were added. The resulting mixture was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (irregular SiOH, 60 g; mobile phase: PE / EA: 100 / 0~0 / 100). The fractions containing the product were combined and evaporated to obtain 1.3 g of intermediate 109 (62%) as a red solid.

[0570] Example A28 Preparation of intermediate 110:

[0571] [ka]

[0572] A stirred solution of 2-bromo-6-methoxypyridine (16.8 g; 89.35 mmol) in 1,4-dioxane (450 mL) was added to (2-(benzyloxy)-5-fluorophenyl)boronic acid (22 g; 89.35 mmol), Pd(PPh3)4 (5.1 g; 34.69 mmol), and sodium carbonate (168 mL; 2 M). The reaction mixture was stirred under a nitrogen atmosphere at 90°C for 2 hours, quenched with water, and extracted with ethyl acetate. The combined organic layer was washed with water, then brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution system: PE:EA 98:2). The fractions containing the product were combined and evaporated to obtain 26 g of intermediate 110 (94%) as a colorless oil.

[0573] Preparation of intermediate 111:

[0574] [ka]

[0575] To a stirred solution of intermediate 110 (23.0 g; 74.353 mmol) in acetonitrile (400 mL), p-toluenesulfonic acid monohydrate (17.0 g; 89.24 mmol) and lithium iodide (20.0 g; 148.71 mmol) were added. After stirring at 80°C for 1 hour, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution system: PE:EA 50:50). The fractions containing the product were combined and evaporated to obtain 23.0 g of intermediate 111 (90%) as a gray solid.

[0576] Preparation of intermediate 112:

[0577] [ka]

[0578] To a stirred solution of intermediate 111 (6.0 g; 20.32 mmol) in acetonitrile (60 mL), potassium cyclopropyl trifluoroborate (9.0 g; 60.9 mmol), cupric acetate (923 mg; 5.08 mmol), o-phenanthroline (458 mg; 2.540 mmol), potassium carbonate (5.6 g; 40.64 mmol), and water (18 mL) were added. After stirring overnight at 70°C under an oxygen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then by (PE:EA:35:65). The fractions containing the product were combined and evaporated to obtain 2.9 g of intermediate 112 (39%) as a grayish-white solid.

[0579] Preparation of intermediate 113:

[0580] [ka]

[0581] To a stirred solution of intermediate 112 (1.0 g, 2.98 mmol) in acetonitrile (15 mL), iodotrimethylsilane (17.9 g, 89.45 mmol) was added. After stirring overnight at room temperature, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH 96:4). The fractions containing the product were combined and evaporated to obtain 630 mg of intermediate 113 (83%) as a dark brown solid.

[0582] Example A29 (All remaining intermediates) Preparation of intermediate 114:

[0583] [ka]

[0584] To a solution of 5-bromo-2-methoxypyrimidine (23.8 g, 0.13 mol) in diethyl ether (950 mL) and THF (170 mL), cyclopropylmagnesium bromide (133 mL, 0.13 mol, 1 M in THF) was added at 0°C. After stirring at room temperature for 1 hour, the resulting mixture was quenched with water (2.3 mL, 0.13 mol), followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (28.6 g, 0.13 mol, dissolved in 70 mL of tetrahydrofuran). The resulting mixture was stirred overnight at room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: ethyl acetate / hexane (1 / 10)). The pure fraction was recovered and evaporated to dryness, yielding the desired intermediate 114, 12.0 g (40%), as a yellow solid.

[0585] Preparation of intermediate 115:

[0586] [ka]

[0587] To a solution of intermediate 114 (2.0 g, 8.73 mmol) in 1,4-dioxane (100 mL), (5-fluoro-2-hydroxyphenyl)boronic acid (1.6 g, 10.48 mmol), tetrakis(triphenylphosphine)palladium (500 mg, 0.44 mmol), and sodium carbonate solution (17.5 mL, 1 M water, 17.5 mmol) were added. After stirring at 90°C for 2 hours, the reaction mixture was cooled to room temperature, quenched with water, and extracted with SiO2. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (mobile phase: SiO2 / hexane, 2 / 3). The pure fraction was recovered and evaporated to dryness, yielding 1.4 g of the desired intermediate 115 (63%) as a pale yellow solid.

[0588] Preparation of intermediate 116:

[0589] [ka]

[0590] Intermediate 30 (2.1 g, 5.76 mmol) and DBU (877 mg, 5.76 mmol) were added to a solution of intermediate 115 (1.5 g, 5.76 mmol) in THF (45 mL). The resulting solution was stirred at room temperature for 48 hours, then quenched with water and extracted with SiO2. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (mobile phase: ethyl acetate / hexane: 1 / 1). The pure fraction was recovered and evaporated to dryness, yielding 3.0 g of the desired intermediate 116 (purity 78% and 87% by LC / MS) as a yellow solid.

[0591] Preparation of intermediate 117:

[0592] [ka]

[0593] To a solution of intermediate 116 (2.9 g, 5.0 mmol) in MeOH (175 mL), palladium-activated carbon (10% palladium-activated carbon, 67% water) (1.6 g, 1.49 mmol) was added. After stirring at room temperature for 1 hour under a hydrogen atmosphere (1 atm), the resulting mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to obtain 2.7 g (96%) of the desired intermediate 117 as a yellow solid.

[0594] Preparation of intermediate 118:

[0595] [ka]

[0596] To a solution of intermediate 117 (2.2 g, 4.0 mmol) in DCM (70 mL), TFA (24 mL) was added at 0°C. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 9 with NaOH solution (1 M in water). The resulting solution was extracted eight times through DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1.6 g (81%) of the desired intermediate 118 as a white solid.

[0597] Preparation of intermediate 232:

[0598] [ka]

[0599] To a solution of tert-butyl 3-nitrocyclobutane carboxylate (1.00 g, 4.72 mmol) (synthesis is described in U.S. Patent Application Publication No. 20170283406(A1)) and methyl acrylate (0.840 g, 9.76 mmol) in ACN (10 mL), DBU (1.45 g, 9.53 mmol) was added at 0°C, and the mixture was stirred at the same temperature for 20 minutes. The reaction product was quenched with saturated NH4Cl aqueous solution (20 mL), and the mixture was extracted with siRNA (30 mL x 2). The combined organic layer was washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the crude residue was purified by FCC (PE:EA = 100:0~80:20) to obtain intermediate 232 (0.8 g, yield 59%) as a colorless oil.

[0600] Preparation of intermediate 233:

[0601] [ka]

[0602] To a mixture of intermediate 232 (1.58 g, 5.50 mmol) and nickel(II) chloride hexahydrate (1.2 g, 5.05 mmol) in MeOH (40 mL), NaBH4 (0.95 g, 25.1 mmol) was slowly added in three portions at -10 °C. The mixture was stirred at the same temperature for 3 hours. The reaction product was quenched with K2CO3 aqueous solution (0.416 g / mL) at 0 °C. The resulting mixture was stirred at 0 °C for 3 hours, and then stirred further at room temperature for another 2 hours. The mixture was passed through a Celite® pad, and the filtrate was concentrated under vacuum to obtain intermediate 233 (0.87 g, crude), which was used directly in the next step without further purification.

[0603] Preparation of intermediate 234:

[0604] [ka]

[0605] A solution of intermediate 233 (0.5 g, 2.22 mmol) in HCl / dioxane (7 mL, 4 M) was stirred at room temperature for 12 hours. The mixture was concentrated under vacuum to obtain intermediate 234 (350 mg, crude) as a white solid, which was used directly in the next step without further purification.

[0606] Preparation of intermediate 250:

[0607] [ka]

[0608] Boc2O (7.79 g, 35.7 mmol) was added to a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (1.00 g, 8.92 mmol), tert-butyl 4-iodopiperidine-1-carboxylate (4.71 g, 17.8 mmol), 2,2'-bipyridine (696 mg, 4.46 mmol), nickel(II) acetylacetonate (916 mg, 3.57 mmol), MgCl2 (2.55 g, 26.8 mmol), zinc powder (4.00 g, 61.2 mmol), 4 ÅMS (10.0 g), and DIEA (4.5 mL, 27.2 mmol) in THF / DMF (100 mL / 30 mL) under an Ar atmosphere at 25 °C. After the addition, the reaction mixture was stirred at 25 °C for 60 hours. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (150 mL x 2). The combined layers were washed with brine (200 mL) and dried over anhydrous sodium 2SO4. After filtration and concentration, the residue was purified by column chromatography (ethyl acetate / PE = 0-15%) to obtain intermediate 250 (560 mg, yield 16%) as a colorless oil.

[0609] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 250:

[0610] [Table 14]

[0611] Preparation of intermediate 237:

[0612] [ka]

[0613] NaH (71 mg, 1.8 mmol, 60% in mineral oil) was added to a solution of tert-butyl 5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (200 mg, 0.884 mmol) in THF (8 mL) cooled to 0°C under an N2 atmosphere. The reaction mixture was stirred at this temperature for 1 hour. Next, MeI (1.48 g, 10.4 mmol) was added dropwise to the reaction mixture at 0°C, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated NH4Cl (10 mL) aqueous solution and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain intermediate 237 (210 mg, crude) as a brown oily substance, which was used directly in the next step without further purification.

[0614] The intermediates reported below were prepared starting from the corresponding commercially available starting materials, following a method similar to that described for intermediate 237:

[0615] [Table 15]

[0616] Preparation of intermediate 238:

[0617] [ka]

[0618] Intermediate 237 (210 mg, 0.874 mmol) was added to a solution of TFA (0.5 mL) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain intermediate 238 (300 mg, crude) as a brown oil, which was used directly in the next step without further purification.

[0619] The intermediates reported below were prepared starting from the corresponding intermediate or a commercially available starting material, in a manner similar to that described for intermediate 238:

[0620] [Table 16]

[0621] Preparation of intermediate 242:

[0622] [ka]

[0623] A mixture of tert-butyl 3-amino-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.47 mmol) and TEA (1.0 mL, 7.42 mmol) in THF (15 mL), cooled to 0°C, was added to a solution of bis(trichloromethyl) carbonate (800 mg, 2.70 mmol) in THF (5 mL) under an N2 atmosphere. The reaction mixture was stirred at 0°C for 0.5 hours, and then stirred at room temperature for a further 3 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (30 mL) and extracted with SiO2 (20 mL x 3). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was removed under vacuum to obtain intermediate 242 (600 mg, crude) as a red solid, which was used directly in the next step without further purification.

[0624] Preparation of intermediate 252:

[0625] [ka]

[0626] DIC (5.0 g, 39.6 mmol) was added to a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (4.0 g, 35.7 mmol), 2-hydroxyisoindoline-1,3-dione (6.50 g, 39.8 mmol), and DMAP (450 mg, 3.68 mmol) in DCM (100 mL). The resulting mixture was stirred overnight at 25°C. The reaction mixture was filtered through a Celite® pad, and the filtrate was concentrated under vacuum to obtain the crude product, which was purified by FCC (PE:Â=10:1) to obtain intermediate 252 (7.7 g, yield 84%) as a white solid.

[0627] Preparation of intermediate 253:

[0628] [ka]

[0629] Anhydrous ACN (20 mL) and THF (30 mL) were added to a mixture of intermediate 252 (3.0 g, 11.7 mmol), 3,3-dimethoxycyclobutane-1-carboxylic acid (3.75 g, 23.4 mmol), Ni(BPhen)Cl2·2DMF (710 mg, 1.16 mmol), zinc powder (2.40 g, 36.7 mmol), benzoic anhydride (5.30 g, 23.4 mmol), MgCl2 (1.67 g, 17.7 mmol), and LiBr (1.02 g, 11.7 mmol) using a syringe under an N2 atmosphere. The resulting mixture was stirred overnight at 25°C. The mixture was diluted with SiO2 (200 mL), washed with 1N NaOH (100 mL x 2) and brine (50 mL x 2), and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by FCC (PE:EA = 10:1) to obtain intermediate 253 (1.40 g, yield 57%) as a colorless oil.

[0630] Preparation of intermediate 254:

[0631] [ka]

[0632] To a solution of tert-butyl(3-hydroxycyclobutyl)carbamate (900 mg, 4.81 mmol), 1H-imidazole (982 mg, 14.4 mmol), and Ph3P (2.52 g, 9.61 mmol) in toluene (15 mL), I2 (1.83 g, 7.21 mmol) was added. The mixture was stirred at 110 °C for 1 hour. After cooling to room temperature, the mixture was diluted with SiO2 (50 mL), washed with brine (20 mL x 2), and further dried over anhydrous Na2SO4. After filtration and concentration, the crude residue was purified by FCC (PE:EA = 5:1) to obtain intermediate 254 (620 mg, yield 43%) as a white solid.

[0633] Preparation of intermediate 267:

[0634] [ka]

[0635] A suspension of LiAlH4 (1.17 g, 30.8 mmol) in THF (10 mL) cooled to -10°C was added dropwise to a solution of cis-3-hydroxy-3-methylcyclobutanecarboxylic acid (1.00 g, 7.68 mmol) in THF (5 mL). The resulting mixture was slowly warmed to 25°C and stirred for 2 hours. The reaction product was quenched with water (10 mL). The mixture was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel FCC (PE:EA 1:0~0:1) to obtain intermediate 267 (550 mg, yield 62%) as a colorless oil.

[0636] Preparation of intermediate 268:

[0637] [ka]

[0638] To a solution of intermediate 267 (200 mg, 1.72 mmol) in DCM (10 mL), TEA (0.74 mL, 5.3 mmol, 0.73 g / mL) was added at 0°C. Then, MsCl (750 mg, 6.54 mmol) was added dropwise at 0°C. The mixture was slowly warmed to 20°C and stirred for 1 hour. The mixture was washed with water (1 mL), and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel FCC (PE:EA 1:0~1:2) to obtain intermediate 268 (150 mg, yield 45%) as a colorless oil.

[0639] Preparation of intermediate 269:

[0640] [ka]

[0641] To a solution of cis-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)methanol (500 mg, 2.31 mmol), TEA (1 mL, 7 mmol), and DMAP (57 mg, 0.47 mmol) in DCM (10 mL) cooled to 0°C, TsCl (500 mg, 2.62 mmol) was added gradually. The resulting mixture was slowly warmed to room temperature and stirred for 12 hours. The mixture was poured into H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by FCC (PE:siRNA = 1:0 to 10:1) to obtain intermediate 269 (700 mg, yield 82%) as a white solid.

[0642] The intermediates reported below were prepared starting from the corresponding commercially available starting materials, following a method similar to that described for intermediate 269:

[0643] [Table 17]

[0644] Preparation of intermediate 270:

[0645] [ka]

[0646] A mixture of compound 3 (600 mg, 1.07 mmol), intermediate 269 (500 mg, 1.35 mmol), K2CO3 (230 mg, 1.66 mmol), and KI (36 mg, 0.22 mmol) in ACN (10 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by FCC (DCM:MeOH = 1:0~15:1) to obtain intermediate 270 (700 mg, yield 80%) as a white solid.

[0647] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 270:

[0648] [Table 18]

[0649] Preparation of intermediate 273:

[0650] [ka]

[0651] To a solution of cyclopropanecarboxamide (3.00 g, 35.3 mmol) in toluene (30 mL), N,N-dimethylformamide dimethylacetal (8.40 g, 70.5 mmol) was added. The mixture was stirred at 120 °C for 2 hours. After cooling to room temperature, the mixture was concentrated under vacuum to obtain intermediate 273 (5.0 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0652] Preparation of intermediate 274:

[0653] [ka]

[0654] A solution of 5-fluoro-2-methoxyaniline (10.0 g, 70.9 mmol) in 12M HCl (30 mL) and H2O (15 mL) was stirred at 0°C for 20 minutes, and then a solution of NaNO2 (6.36 g, 92.2 mmol) in H2O (15 mL) was slowly added at 0°C. The resulting mixture was slowly warmed to 25°C and stirred for 1 hour. Next, SnCl2 (26.9 g, 142 mmol) in HCl (30 mL) was added at -20°C, and the mixture was stirred at -20°C for 2 hours. The mixture was basicized with NaOH (2 M) at -20°C to adjust the pH to 12. After slowly warming to room temperature, the mixture was extracted with DCM (500 mL), washed with brine (200 mL x 3), and further dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to obtain intermediate 274 (7.5 g, crude) as a brown oily substance, which was used directly in the next step without further purification.

[0655] Preparation of intermediate 275:

[0656] [ka]

[0657] Intermediate 273 (5.00 g, crude) was added at 0°C to a solution of intermediate 274 (5.50 g, crude) in AcOH (50 mL). The resulting mixture was heated to room temperature and stirred for 12 hours. The mixture was basicized with NaOH (2 M) to adjust the pH to 12 and extracted with SiO (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by silica gel FCC (PE:EA, 1:0 to 2:1) to obtain intermediate 275 (3.0 g) as a brown solid.

[0658] Preparation of intermediate 276:

[0659] [ka]

[0660] To a solution of intermediate 275 (3.00 g, 12.9 mmol) in DCM (30 mL), BBr3 (3.60 mL, 38.1 mmol) was slowly added at -78°C under an N2 atmosphere. The mixture was stirred at -78°C for 1 hour, and then stirred at room temperature for 12 hours. The mixture was basicized with NaOH (2 M) to adjust the pH to 12 and extracted with DCM (200 mL). The organic layer was washed with brine (100 mL x 3). The combined aqueous phase was extracted again with DCM (100 mL x 3 times), and the combined organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by silica gel FCC (1:0 to 1:1 PE:siRNA) to obtain intermediate 276 (1.90 g, yield 66%) as a brown solid.

[0661] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 276:

[0662] [Table 19]

[0663] Preparation of intermediate 280:

[0664] [ka]

[0665] Intermediate 279 (450 mg, 1.13 mmol) was dissolved in THF (15 mL), and then isoamyl nitrite (0.55 mL, 4.1 mmol) was added. The reaction mixture was heated at 65°C for 3 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the crude product was purified by FCC (EA:PE, 1:10 to 1:3) to obtain intermediate 280 (200 mg, yield 46%) as a yellow oily substance.

[0666] Preparation of intermediate 294:

[0667] [ka]

[0668] A mixture of intermediate 13 (3.5 g, 9.91 mmol), molecular sieve (6.0 g, 4 Å), and 2,2,2-trifluoroethanol (30 mL) was first purged three times with Ar gas and stirred at 65°C for 3 hours. Then, 1,3-dibromo-1,3,5-triazinan-2,4,6-trione (5.69 g, 19.8 mmol) was added to the mixture at 25°C, and the mixture was further stirred at 65°C for 8 hours. After cooling to room temperature, the mixture was filtered through a Celite® pad and concentrated under reduced pressure to obtain the crude product, which was purified by FCC (eluent:PE:EA, 1:0 to 3:1) to obtain intermediate 294 (1.8 g, yield 45%) as a yellow oil.

[0669] The intermediates reported below were prepared starting from the corresponding intermediates, following a method similar to that described for intermediate 294:

[0670] [Table 20]

[0671] Preparation of intermediate 285:

[0672] [ka]

[0673] To a solution of DCM (150 mL) and MeOH (150 mL) containing 5-fluoro-2-methoxybenzoic acid (10.0 g, 58.8 mmol) cooled to 0°C, TMSCH2N2 (88.0 mL, 176 mmol, 2 M in hexane) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by FCC (PE:Â=10:1 to 3:1) to obtain intermediate 285 (12 g, purity 89%, yield 99%) as a yellow oil.

[0674] Preparation of intermediate 286:

[0675] [ka]

[0676] A mixture of intermediate 285 (4.00 g, 21.7 mmol) and hydrazine hydrate (2.02 mL, 65.0 mmol) in EtOH (10 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum to obtain intermediate 286 (2.9 g, crude) as a white solid, which was used directly in the next step without further purification.

[0677] Preparation of intermediate 287:

[0678] [ka]

[0679] To a solution of intermediate 286 (2.80 g, 15.2 mmol) in ACN (60 mL), N,N-dimethylformamide dimethyl acetal (1.85 mL, 19.8 mmol) was added, and the reaction mixture was stirred at 50°C for 1 hour. Next, cyclopropanamine (5.27 mL, 76.0 mmol) from ACN (10 mL) was added to the mixture, followed by the addition of AcOH (1.74 mL, 30.4 mmol). The reaction mixture was further stirred at 120°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was separated by preparative HPLC (Welch Xtimate C18 150).* 40mm * The solution was purified using a 10 μm column and eluent: water (0.2% formic acid)-ACN, 15% ACN to 45% ACN v / v). The desired fraction was recovered and freeze-dried to obtain intermediate 287 (465 mg, yield 10%) as a white solid.

[0680] Preparation of intermediate 303

[0681] [ka]

[0682] Intermediate 3 (15 g, 60.900 mmol) was stirred in methanol (300 mL), to which intermediate 36 (13.61 g, 73.080 mmol) and acetic acid (4.02 g, 66.990 mmol) were added. After stirring at room temperature for 0.5 hours, sodium borohydride cyanohydride (7.65 g, 121.800 mmol) was added. After stirring overnight at 50 °C, the reaction mixture was quenched with potassium carbonate solution (10% in water) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (EA / PE, 0%EA~50%) to obtain 17.8 g (yield 69%) of the desired compound as a pale yellow oil.

[0683] Preparation of intermediates 304 and 305

[0684] [ka]

[0685] 170 g of benzyl 2-(1-(3,3-dimethoxycyclobutyl)-2-methylpropyl)-2,6-diazaspiro[3.4]octane-6-carboxylate was purified by SFC under the following conditions: Column: CHIRALPAK IG, 5 *25 cm, 10 μm; mobile phase A: CO2, mobile phase B: EtOH:ACN:DCM = 1:1:1; flow rate: 150 mL / min; gradient: 40% B; 220 nm; retention time 1 = 4.45 min; retention time 2 = 5.88 min; injection volume: 3.8 mL; runs: 237, yielding two fractions.

[0686] Intermediate 304 was obtained as a pale yellow oily substance in fraction A (67.0 g, 39% yield, retention time 1:5.88 min).

[0687] Fraction B: Intermediate 305 in 65 g as pale yellow oil (38% yield, retention time 2:4.45 min).

[0688] Preparation of intermediate 306

[0689] [ka]

[0690] To a solution of intermediate 304 (15 g, 36.010 mmol) in methanol (300 mL), palladium-activated carbon (10% palladium) (8 g, 7.517 mmol) was added. The mixture was then stirred under hydrogen (2-3 atm) at room temperature for 5 hours. The mixture was diluted with methanol and filtered through Celite®. The filtrate was evaporated under reduced pressure to obtain 9.5 g of intermediate 306 as a yellow oily substance.

[0691] Preparation of intermediate 307

[0692] [ka]

[0693] A solution of 3,5,6-trichloro-1,2,4-triazine (9.4 g, 50.99 mmol) in dichloromethane (100 mL) was added to a mixture of intermediate 306 (12.0 g, 42.49 mmol) and triethylamine (12 mL, 84.98 mmol) in dichloromethane (150 mL) under nitrogen at 0°C. After stirring under nitrogen at room temperature for 3 hours, the mixture was quenched with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure to obtain 17.3 g (83% yield) of intermediate 307 as a yellow solid.

[0694] Preparation of intermediate 308

[0695] [ka]

[0696] To a solution of 4-bromo-5-chloro-2-methylpyridine (8.8 g, 42.62 mmol) in tetrahydrofuran (90 mL), tetrakis(triphenylphosphine)palladium (2.5 g, 2.13 mmol) was added. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour, and then cyclopropylzinc(II) bromide (340 mL, 0.5 M in THF) was added. After stirring under a nitrogen atmosphere at 65°C for 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified with 100 g of silica gel (eluent: petroleum ether-ethyl acetate 75%:25%) to obtain 7.2 g (yield 97%) of intermediate 308 as a yellow solid.

[0697] Preparation of intermediate 309

[0698] [ka]

[0699] To a stirred solution of intermediate 308 (7.2 g, 42.95 mmol) in 1,4-dioxane (216 mL), (5-fluoro-2-hydroxyphenyl)boronic acid (8.0 g, 51.54 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (1.5 g, 2.15 mmol), and aqueous sodium carbonate solution (2 M in water, 72 mL) were added. After stirring under a nitrogen atmosphere at 100°C for 3 hours, the reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified with 100 g of silica gel (eluent: petroleum ether - ethyl acetate 70%:30%) to obtain 5.8 g (yield 54%) of intermediate 309 as a yellow solid.

[0700] Preparation of intermediate 310

[0701] [ka]

[0702] Intermediate 309 (3.0 g, 12.33 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (3.9 g, 25.90 mmol) were added to a solution of intermediate 307 (4.3 g, 9.87 mmol) in tetrahydrofuran (80 mL). After stirring at room temperature for 3 days, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified with 100 g of silica gel (eluent: petroleum ether-ethyl acetate 34%:66%) to obtain 5.0 g (64% yield) of intermediate 310 as a green solid.

[0703] Preparation of intermediate 311

[0704] [ka]

[0705] To a solution of intermediate 310 (5.3 g, 8.32 mmol) in tetrahydrofuran (100 mL), sodium borohydride (535 mg, 14.14 mmol), N,N,N',N'-tetramethylethylenediamine (1.6 g, 14.14 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (680 mg, 0.83 mmol) were added under a nitrogen atmosphere. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified with 100 g of silica gel (eluent: dichloromethane-methanol 93%:7%) to obtain 4.9 g (yield 88%) of intermediate 311 as a brown solid.

[0706] Preparation of intermediate 312

[0707] [ka]

[0708] To a solution of intermediate 311 (4.9 g, 8.13 mmol) in acetone (80 mL), p-toluenesulfonic acid (7.0 g, 40.65 mmol) and water (40 mL) were added. The resulting mixture was stirred overnight at 65°C. After cooling to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (100 g, eluent: dichloromethane-methanol 98%:2%) to obtain 4.2 g of intermediate 312 (purity 88%, yield 81% as assessed by LC-MS) as a yellow solid.

[0709] Preparation of intermediate 313

[0710] [ka]

[0711] To a solution of 3-bromo-2-chloro-5-methylpyridine (16.0 g, 79.55 mmol) in tetrahydrofuran (160 mL), cyclopropylzinc(II) bromide (350.0 mL, 175,000 mmol, 0.5 M in THF) and tetrakis(triphenylphosphine)palladium (4.6 g, 3.98 mmol) were added. After stirring at 65°C for 10 hours under a nitrogen atmosphere, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using 320 g of silica gel (eluent: petroleum ether-ethyl acetate / 0%~10%) to obtain 12 g of intermediate 313 (purity 82.8%, yield 75%, as assessed by LC / MS) as a colorless oil.

[0712] Preparation of intermediate 314

[0713] [ka]

[0714] To a solution of intermediate 313 (15.0 g, 89.48 mmol) in 1,4-dioxane (420 mL) and water (140 mL), 5-fluoro-2-hydroxyphenylboronic acid (16.74 g, 107.4 mmol), sodium carbonate (28.45 g, 268.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (10.34 g, 8.95 mmol) were added. The resulting mixture was stirred under nitrogen at 100°C for 18 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography using 320 g of silica gel (eluent: petroleum ether-ethyl acetate / 0%~100%) to obtain the crude product. When the crude product was polished in ethyl acetate / petroleum ether in a 1:10 ratio, 18.0 g (82% yield) of intermediate 314 was obtained as a grayish-white solid.

[0715] Preparation of intermediate 315

[0716] [ka]

[0717] Intermediate 314 (8.8 g, 36.25 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (11.0 mL, 75.52 mmol) were added to a solution of intermediate 307 (13.0 g, 30.21 mmol) in tetrahydrofuran (400.0 mL). After stirring at room temperature for 3 days, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using 100 g of silica gel (eluent: petroleum ether-ethyl acetate / 0%~100%) to obtain two fractions of intermediate 315.

[0718] Fraction A: 8.89 g (purity 97.5% as evaluated by LC-MS; yield 45%) as a white solid.

[0719] Fraction B: 2.5g (purity 88.7%, yield 11%) as a yellow solid.

[0720] Preparation of intermediate 316

[0721] [ka]

[0722] To a solution of intermediate 315 (7.89 g, 12.38 mmol) in tetrahydrofuran (160.0 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (506 mg, 0.62 mmol), sodium borohydride (796 mg, 21.05 mmol), and N,N,N',N'-tetramethylethylenediamine (3.2 mL, 21.05 mmol) were added. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using 120 g of silica gel (eluent: petroleum ether-ethyl acetate: 0%~100%) to obtain 6.0 g (yield 81%) of intermediate 316 as a yellow solid.

[0723] Preparation of intermediate 317

[0724] [ka]

[0725] To a solution of intermediate 316 (5.4 g, 8.96 mmol) in dichloromethane (26.0 mL), trifluoroacetic acid (78.0 mL) was added at 0°C. The resulting mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure. The residue was quenched with saturated sodium bicarbonate solution and then extracted three times with dichloromethane. The organic layers were combined, washed with brine, and dried over sodium sulfate. The solid was filtered off. The filtrate was concentrated under reduced pressure to obtain 4.0 g (80% yield) of intermediate 317 as a yellow solid.

[0726] Preparation of intermediate 318

[0727] [ka]

[0728] Acetic anhydride (375 mg, 3.67 mmol) was added to a solution consisting of (trans)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (750 mg, 2.48 mmol), Et3N (1.0 g, 9.9 mmol), and DCM (20 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was partitioned into H2O (30 mL) and DCM (30 mL). The aqueous phase was extracted with DCM (20 mL x 3), the combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain 600 mg (95% yield) of intermediate 318 (a mixture of trans compounds) as a yellow solid.

[0729] Preparation of intermediate 319

[0730] [ka]

[0731] TFA (1.3 mL, 18 mmol) was added to a solution of DCM (15 mL) containing intermediate 318 (600 mg, 2.36 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product as a yellow oil, which was dissolved in water (20 mL). The pH of the mixture was adjusted to 10 using NH3·H2O, and then freeze-dried to obtain 500 mg (crude) of intermediate 319 (trans mixture) as a yellow solid, which was used in the next step without further purification.

[0732] Preparation of intermediate 320

[0733] [ka]

[0734] A stirring bar, 5-bromo-2-methylpyrimidine (36.0 g, 208 mmol), and dried tetrahydrofuran (250 mL) were added to a 2 L three-necked round-bottom flask. The mixture was then cooled to 0°C in an ice bath and purged three times with nitrogen. Cyclopropylmagnesium bromide (500 mL, 250 mmol, 0.5 M in THF) was added dropwise over 2 hours. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 1.5 hours. The mixture was again cooled to 0°C in an ice bath. A solution of DDQ (47.2 g, 208 mmol) in dried tetrahydrofuran (250 mL) was added dropwise to the mixture over 1.5 hours. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for a further 16 hours. 400 mL of EtAOc and 50 mL of saturated NH4Cl were added to the reaction mixture and stirred for 0.5 hours. The reaction mixture was filtered through celite® and washed with dimethyl phosphate (100 mL x 3). This organic phase was concentrated under reduced pressure. The residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 20:1) to obtain 24.31 g (55% yield) of intermediate 320 as a yellow oily substance.

[0735] Preparation of intermediate 321

[0736] [ka]

[0737] Pd(dppf)Cl2 (4.17 g, 5.70 mmol) was added to a mixture of intermediate 320 (24.3 g, 114 mmol), 5-fluoro-2-hydroxyphenyl)boronic acid (21.3 g, 137 mmol), and Na2CO3 (24.18 g, 228 mmol) in dioxane (300 mL) / H2O (60 mL). The mixture was stirred at 90°C for 16 hours under an inert atmosphere. The reaction mixture was cooled to room temperature, filtered through a celite® pad, and washed with HCl (50 mL x 2). The filtrate was concentrated under vacuum, and the residue was dissolved in HCl (300 mL). The mixture was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in HCl (30 mL), stirred for 30 minutes, filtered, and washed with HCl (10 mL x 2). The filtered cake was recovered and dried to obtain 22.3 g (78% yield) of intermediate 321 as a pale solid.

[0738] Preparation of intermediate 322

[0739] [ka]

[0740] DBU (2.94 g, 19.3 mmol) was added to a solution in THF (200 mL) consisting of intermediate 307 (7.0 g, 16.3 mmol) and intermediate 321 (3.98 g, 16.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned into H2O (200 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 3 times), the combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. This was mixed with another crude product (2 g) and purified by FCC (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 7.0 g of intermediate 322 (based on 8 g of intermediate 307, with an overall yield of 53%) as a yellow solid.

[0741] Preparation of intermediate 323

[0742] [ka]

[0743] Pd(dppf)Cl2·DCM (540 mg, 0.661 mmol) was added under N2 conditions to a solution of intermediate 322 (6.0 g, 9.4 mmol), NaBH4 (620 mg, 16.4 mmol), TMEDA (2.1 g, 18 mmol), and THF (150 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned into H2O (300 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (150 mL x 3), the combined extract was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. This was mixed with another crude product (1.2 g) and purified by FCC (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 4.5 g of intermediate 323 (66% overall yield from 7 g of intermediate 322) as a yellow solid.

[0744] Preparation of intermediate 324

[0745] [ka]

[0746] TFA (9.6 mL, 129 mmol) was added to a solution of intermediate 323 (4.0 g, 6.6 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into 10% K₂CO₃ aqueous solution (300 mL) and extracted with dichloromethane (200 mL x 3). The combined organic extracts were washed with brine (300 mL), NaHCO₃ aqueous solution (300 mL), and H₂O (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to obtain 3.3 g (84% yield) of intermediate 324 as a yellow solid, which was used in the next step without further purification.

[0747] Preparation of intermediate 325

[0748] [ka]

[0749] To a solution of 4-bromo-6-methylpyridazine-3(2H)-one (5.00 g, 26.45 mmol) in tetrahydrofuran (100 mL), 3,4-dihydro-2H-pyran (9.65 mL, 105.82 mmol) and p-toluenesulfonic acid (455 mg, 2.65 mmol) were added. The resulting mixture was stirred overnight at 70°C. The reaction product was quenched with water and then extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~20%EA) to obtain 4.2 g of intermediate 325 (yield 52%, purity 89.2% based on LCMS) as a yellow solid.

[0750] Preparation of intermediate 326

[0751] [ka]

[0752] To a solution of intermediate 325 (8.30 g, 24.62 mmol; 81% purity (based on LC-MS)) in 1,4-dioxane (120 mL), cyclopropylboronic acid (2.33 g, 27.08 mmol), Pd(amphos)Cl2 (871 mg, 1.23 mmol), and sodium carbonate (40 mL, 2 M water, 80.00 mmol) were added. The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. After cooling to room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~13%EA) to obtain 3.4 g of intermediate 326 (50% yield, 84.7% purity based on LC-MS) as a yellow oil.

[0753] Preparation of intermediate 327

[0754] [ka]

[0755] To a solution of intermediate 326 (2.40 g, 8.61 mmol, purity 84.7% based on LC-MS) in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added. The resulting mixture was stirred at 50°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water and adjusted to pH=7 with ammonium hydroxide (33% in water). The mixture was extracted five times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 870 mg (yield 58%) of intermediate 327 as a yellow solid.

[0756] Preparation of intermediate 328

[0757] [ka]

[0758] To a solution of intermediate 327 (2.46 g, 16.38 mmol) in acetonitrile (50 mL), POCl3 (7.6 mL, 81.90 mmol) was added. After stirring overnight at 50°C, the reaction solution was slowly poured into ice water. The resulting solution was adjusted to pH=7 with NaOH solution (2 M in water) and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO4. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~30%EA) to obtain 2.1 g of intermediate 328 as a yellow oil.

[0759] Preparation of intermediate 329

[0760] [ka]

[0761] A mixture of intermediate 328 (5.0 g, 29.65 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.06 g, 29.65 mmol), and Pd(PPh3)4 (1.71 g, 1.48 mmol) in 1,4-dioxane (75 mL) was mixed with sodium carbonate solution (25 mL, 2 M water, 50.00 mmol) and stirred at 90°C for 3 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~60%EA) to obtain 6.0 g of intermediate 329 as a yellow solid.

[0762] Preparation of intermediate 330

[0763] [ka]

[0764] Intermediate 329 (5.45 g, 22.31 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (6.94 mL, 46.47 mmol) were added to a solution of intermediate 307 (8 g, 18.6 mmol) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature over the weekend. The reaction product was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~90%EA) to obtain 7.56 g of intermediate 330 (yield 62%) as a yellow solid.

[0765] Preparation of intermediate 331

[0766] [ka]

[0767] To a solution of intermediate 330 (7.26 g, 10.92 mmol) in THF (140 mL), Pd(dppf)Cl2 (446 mg, 0.55 mmol), NaBH4 (702 mg, 18.57 mmol), and TMEDA (2.78 mL, 18.57 mmol) were added. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction product was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (EA / PE, 0%EA~91%EA) to obtain 416 mg of intermediate 331 (yield 65%) as a yellow solid.

[0768] Preparation of intermediate 332

[0769] [ka]

[0770] To a solution of intermediate 331 (500 mg, 0.75 mmol) in acetone (7.5 mL) and water (2.5 mL), TsOH (649 mg, 3.77 mmol) was added. After stirring overnight at 65°C, the reaction product was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 480 mg of intermediate 332 (98% yield) as a brown solid.

[0771] Preparation of intermediate 333

[0772] [ka]

[0773] Intermediate 283 (2.7 g, 6.58 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.21 g, 6.56 mmol) in DCM (100 mL) were stirred at 25°C for 10 minutes, and TEA (2.74 mL, 19.7 mmol) was added. The mixture was stirred at 25°C for 10 hours. The mixture was poured into water (100 mL x 2) and extracted with dichloromethane (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by FCC (eluent:dichloromethane:methanol = 1:0~10:1) to obtain intermediate 333 as a yellow solid (3.32 g, yield 81.7%).

[0774] Preparation of intermediate 336

[0775] [ka]

[0776] The solution of intermediate 5 (9.91 g, 38.364 mmol) in anhydrous THF (191.8 mL) was cooled to 0°C. 3.4 M MeMgBr (25.952 mL, 3.4 M, 88.236 mmol) in THF was slowly added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred over the weekend. The reaction mixture was quenched by adding saturated ammonium chloride solution. The aqueous phase was extracted several times with diethyl ether. The organic extracts were combined, dried on magnesium sulfate, filtered, and concentrated to obtain the crude substance (8 g, yield 97.775%). The substance was purified by FCC (silica gel, 10%-30% EA in n-heptane) to obtain compound 336 (1.16 g, yield 14.2%) as a white powder.

[0777] Preparation of intermediate 338

[0778] [ka]

[0779] 2-chloro-1,3-thiazole-5-carboxylic acid (0.5 g, 3.057 mmol) was dissolved in ethyl acetate (5.2 mL) and treated with 50% T3P in ethyl acetate (4.41 mL) and acethydrazide (226 mg, 3.057 mmol). The resulting solution was stirred at 70°C over the weekend. The reaction mixture was hydrolyzed and extracted with ethyl acetate (3×). The combined organic phase was washed with brine. Volatile components were removed using a rotary evaporator. The substance was analyzed by HPLC and NMR, revealing intermediate 338 (240 mg, 39% yield) containing T3P impurities. This substance was used without further purification.

[0780] Preparation of intermediate 339

[0781] [ka]

[0782] tBuXPhos Pd G3 (36.5 mg, 0.046 mmol) was added under an argon atmosphere to a solution of compound 1a (250 mg, 0.459 mmol), 5-chloro-1-(4-methoxybenzyl)-1,8-naphthyrizine-2(1H)-one (262 mg, 0.871 mmol), and NaOtBu (132 mg, 1.37 mmol) in 1,4-dioxane (8 mL). The mixture was stirred under microwave at 100 °C for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and washed with H2O (10 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by silica gel flash column chromatography (eluent:dichloromethane:methanol = 1:0-10:1) to obtain intermediate 339 (180 mg, yield 37.06%) as a yellow oil.

[0783] Preparation of intermediate 340 (1-(benzyloxy)-4-fluoro-2-nitrobenzene):

[0784] [ka]

[0785] Benzyl bromide (4 mL, 33.418 mmol) was added to a solution of DMF (50 mL) containing 4-fluoro-2-nitro (5 g, 31.827 mmol) and Cs2CO3 (20.74 g, 63.653 mmol) at room temperature for 6 hours.

[0786] Upon completion (TLC), the reaction mixture was diluted with HCl (100 mL) and washed with water (200 mL). The layers were separated, and the aqueous layer was extracted with HCl (3 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (0 to 10% HCl in heptane) to obtain intermediate 340 (1-(benzyloxy)-4-fluoro-2-nitrobenzene) (7.85 g, yield 99%) as a concentrated yellow oil.

[0787] Preparation of intermediate 341 (2-benzyloxy-5-fluoroaniline):

[0788] [ka]

[0789] A mixture of intermediate 340 (1 g, 4.045 mmol) and NH4Cl (2.15 g, 40.196 mmol) in EtOH (30 mL) was mixed with zinc powder (2.63 g, 40.208 mmol) at ambient temperature, and the mixture was then heated to 50°C overnight. The mixture was diluted with HCl and filtered through a Celite® pad, and the solvent was removed under reduced pressure. The residue was partitioned between HCl (50 mL) and water. The aqueous layer was extracted with HCl (2 × 25 mL). The combined organic layers were washed with water and brine, dried on anhydrous MgSO4, and swiftly evaporated to obtain intermediate 340 (2-benzyloxy-5-fluoro-aniline) (875 mg, 99% yield) as a brown oil.

[0790] Preparation of intermediate 342 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarboxamide):

[0791] [ka]

[0792] To a solution of intermediate 341 (2-benzyloxy-5-fluoroaniline) (1.37 g, 6.306 mmol) and Et3N (2.64 mL, 19.92 mmol) in anhydrous dichloromethane (20 mL), 0° cyclopropane carbonyl chloride (0.7 mL, 7.57 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour.

[0793] After completion (TLC), the reaction mixture was diluted with dichloromethane (100 mL) and washed with water (100 mL). The aqueous layer was extracted with dichloromethane (30 mL x 2), the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (0 to 60% Â in heptane) to obtain intermediate 342 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarboxamide) (1.55 g, yield 86%) as a colorless solid.

[0794] Preparation of intermediate 343 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarbothioamide):

[0795] [ka]

[0796] To a solution of intermediate 342 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarboxamide) (1 g, 3.505 mmol) in 1,4-dioxane (30 mL), Lawson's reagent (0.8 g, 1.963 mmol) was added, and the resulting mixture was heated at 100°C for 6 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by flash column chromatography (0 to 15% ELISA in heptane) to obtain intermediate 343 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarbothioamide) (0.815 g, 77%) as a pale yellow solid.

[0797] Preparation of intermediate 344 (4-(2-benzyloxy-5-fluorophenyl)-3-cyclopropyl-5-methyl-1,2,4-triazole):

[0798] [ka]

[0799] Hydrazine hydrate (0.28 mL, 2.883 mmol) was added dropwise at ambient temperature to a stirred solution of intermediate 343 (N-(2-benzyloxy-5-fluorophenyl)cyclopropanecarbothioamide) (790 mg, 2.622 mmol) in THF (20 mL). After 60 minutes, the solution was concentrated under reduced pressure, and the residue was treated with triethyl orthoacetate (5 mL). The mixture was heated at 80°C for 30 minutes, cooled to ambient temperature, and concentrated under reduced pressure. The residue was treated with ice-cold dilute ammonia water (15 mL) and water (25 mL), and extracted with siRNA (70 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and rotated to evaporate. The residue was purified by flash column chromatography (0 to 100% ethyl acetate in heptane) to obtain intermediate 344 (4-(2-benzyloxy-5-fluorophenyl)-3-cyclopropyl-5-methyl-1,2,4-triazole) (530 mg, yield 62%) as a creamy, fluffy solid.

[0800] Preparation of intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenol):

[0801] [ka]

[0802] Pd / C (10%) (27 mg) was added to a solution of intermediate 344 (4-(2-benzyloxy-5-fluorophenyl)-3-cyclopropyl-5-methyl-1,2,4-triazole) (200 mg, 0.62 mmol) in methanol (50 mL) and maintained overnight for hydrogenation at ambient temperature. Upon completion (TLC), the catalyst was filtered through a Celite® bed, washed several times with MeOH, and the combined organic layers were concentrated under vacuum to obtain intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenol) (135 mg, yield 93%) as a colorless solid.

[0803] Preparation of intermediate 346 (7-[3-chloro-6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenoxy]-1,2,4triazine-5-yl]-2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octane):

[0804] [ka]

[0805] A mixture of intermediate 307 (130 mg, 0.3 mmol), intermediate 345 (2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenol) (70 mg, 0.3 mmol), and DBU (0.225 mL, 1.5 mmol) in THF (4 mL) was stirred at room temperature for 48 hours. Upon completion, the reaction mixture was diluted with HCl (30 mL) and washed with water. The layers were separated, and the aqueous layer was extracted with HCl (2 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, and rotated to evaporate. The crude compound was purified by flash column chromatography (0 to 70% n-heptane in HCl) to obtain intermediate 346 (60 mg, yield 31%) as a colorless oil.

[0806] Preparation of intermediate 347 (7-[6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenoxy]-1,2,4triazine-5-yl]-2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3.4]octane):

[0807] [ka]

[0808] The solution of intermediate 346 (60 mg, 0.0957 mmol) and N,N,N',N'-tetramethylethylenediamine (50 μL, 0.335 mmol) in THF (10 mL) was degassed for 5 minutes, then Pd(dppf)Cl2.DCM (12 mg, 0.0144 mmol) and NaBH4 (26 mg, 0.67 mmol) were added, the mixture was purged with nitrogen (3 times), and stirred at room temperature for 18 hours. The reaction mixture was quenched with a 10% aqueous solution of K2CO3, and then extracted with dichloromethane (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, evaporated under vacuum, and purified by flash column chromatography (with 0 to 3% MeOH in dichloromethane as the eluent) to obtain intermediate 347 (30 mg, 52% yield) as a colorless, cottony solid as a mixture of atropisomers.

[0809] Preparation of intermediate 348 (3-[(1R)-1-[7-[6-[2-(3-cyclopropyl-5-methyl-1,2,4-triazole-4-yl)-4-fluorophenoxy]-1,2,4triazine-5-yl]-2,7-diazaspiro[3,4]octan-2-yl]-2-methylpropyl]cyclobutanone):

[0810] [ka]

[0811] To a solution of intermediate 347 (252 mg, 0.425 mmol) in anhydrous dichloromethane (3 mL), TFA (0.65 mL, 8.5 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with dichloromethane. The organic layer was saturated, and the NaHCO3 was dried over MgSO4, filtered, and evaporated under vacuum to obtain intermediate 348 (233 mg) as a cream-colored, cottony solid, a mixture of atropisomers.

[0812] Preparation of intermediate 349 (5-cyclopropyl-3-methyl-isoxazole):

[0813] [ka]

[0814] A mixture of EtOH containing 1-cyclopropylbutane-1,3-dione (5 g, 39.634 mmol) and NH2OH.HCl (3.31 g, 47.56 mmol) was heated at 130°C for 5 minutes under microwave irradiation. Water (25 mL) was added to the mixture, and it was then extracted with HCl (three times). The organic layer was separated, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was subjected to flash column purification (0 to 90% HCl in heptane as eluent) to obtain 5-cyclopropyl-3-methyl-isoxazole as the major positional isomer (2.4 g, 44%). The positional isomer mixture was used in the next step without separation.

[0815] Preparation of intermediate 350 (4-bromo-5-cyclopropyl-3-methyl-isoxazole):

[0816] [ka]

[0817] N-bromosuccinimide (1.532 g, 8.607 mmol) was added to a solution of intermediate 349 (0.5 g, 4.06 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 4 hours.

[0818] Upon completion (LCMS), water was added to the reaction mixture and extracted with diethyl ether (3 × 25 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was subjected to flash column purification (0 to 90% ethyl phosphate in heptane as the eluent) to obtain intermediate 350 as the major positional isomer, 600 mg, 73%.

[0819] Preparation of intermediate 351 (5-cyclopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole):

[0820] [ka]

[0821] Intermediate 350 (6 g, 29.696 mmol) was dissolved in THF (250 mL) and cooled to -78°C under N2. n-BuLi (2.5 M in hexane) (17.8 mL, 2.5 M, 44.5 mmol) was slowly added to the solution and then stirred at -78°C for 30 minutes. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoborolane (7.27 mL, 35.635 mmol) was added to the reaction mixture and stirred for a further 2 hours at -78°C, then warmed to room temperature and stirred overnight. The reaction was quenched by adding a saturated NH4Cl solution. The mixture was then extracted with ELISA, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (0 to 5% SiO in heptane as the eluent), yielding intermediate 51 (5 g, 67%) as a positional isomer mixture.

[0822] Preparation of intermediate 352 (5-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-3-methyl-isoxazole):

[0823] [ka]

[0824] To a solution of intermediate 351 (1.823 g, 7.316 mmol) and 2-bromo-4-fluoro-1-methoxybenzene (1 g, 4.877 mmol) in dioxane (250 mL), saturated NaHCO3 (50 mL) was added, and the mixture was degassed for 10 minutes. [Ph3P]4Pd (1.127 g, 0.975 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. Dichloromethane and water were added to the mixture, and the layers were separated. The aqueous layer was washed with dichloromethane (2 ×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash column chromatography (0 to 70% siRNA in heptane as eluent) to obtain 5-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-3-methylisoxazole (0.65 g, 53%).

[0825] Preparation of intermediate 353 (2-(5-cyclopropyl-3-methyl-isoxazole-4-yl)-4-fluorophenol):

[0826] [ka]

[0827] A solution of intermediate 352 (150 mg, 0.607 mmol) in dichloromethane (10 mL) was cooled to a temperature of 5–10°C. Boron tribromide (169 μL, 1.82 mmol) was added dropwise. The resulting reaction mixture was then stirred at 0°C for 2.5 hours. Water (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash column chromatography (0–70% ethyl acetate in heptane as eluent) to obtain intermediate 353 (70 mg, 49%).

[0828] Preparation of intermediate 354 (4-[2-[[3-chloro-5-[2-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3,4]octan-7-yl]-1,2,4triazine-6-yl]oxy]-5-fluorophenyl]-5-cyclopropyl-3-methyl-isoxazole):

[0829] [ka]

[0830] A mixture of intermediates 307 (700 mg, 1.626 mmol), 353 (392 mg, 1.678 mmol), and DBU (1.2 mL, 8.13 mmol) in THF (90 mL) was stirred at room temperature for 72 hours. Upon completion, the reaction mixture was diluted with dichloromethane (100 mL) and washed with water. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous MgSO4, and rotated to evaporate. The residue was purified by flash column chromatography (0 to 2% MeOH in dichloromethane) to obtain intermediate 354 (380 mg, yield 37%).

[0831] Preparation of intermediate 355 (5-cyclopropyl-4-[5-fluoro-2-[[5-[2-[(1 R)-1-(3,3-dimethoxycyclobutyl)-2-methyl-propyl]-2,7-diazaspiro[3,4]octan-7-yl]-1,2,4triazine-6-yl]oxy]phenyl]-3-methyl-isoxazole):

[0832] [ka]

[0833] Pd / C (10%) (45 mg) was added at ambient temperature to a solution of intermediate 354 (260 mg, 0.415 mmol) and thiophene (0.10 mL, 0.4 M, 0.041 mmol) in MeOH (50 mL), and the mixture was stirred under H2 (1 atm) for 1 hour. After completion (LCMS), the mixture was filtered through dikalyte, and the solvent was evaporated under vacuum to obtain intermediate 355 (100 mg, 41%).

[0834] Preparation of intermediate 356 (3-[(1R)-1-[7-[6-[2-(5-cyclopropyl-3-methylisoxazole-4-yl)-4-fluorophenoxy]-1,2,4triazine-5-yl]-2,7-diazaspiro[3,4]octan-2-yl]-2-methylpropyl]cyclobutanone):

[0835] [ka]

[0836] To a solution of intermediate 355 (300 mg, 0.51 mmol) in anhydrous dichloromethane (30 mL), trifluoroacetic acid (0.775 mL, 10.123 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then diluted with dichloromethane. The organic layer was washed with a 10% aqueous solution of Na2CO3, then dried over anhydrous MgSO4, filtered, and evaporated under vacuum to obtain intermediate 356 in quantitative yield.

[0837] Preparation of compounds Compound 1:

[0838] [ka]

[0839] To a solution of compound 490 (250 mg, 0.388 mmol) in CH2Cl2 (3 mL), TFA (2.0 mL, 26 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 13 with an aqueous solution of NaOH (2 M). The resulting mixture was then extracted with CH2Cl2 (10 mL x 2). The combined organic extract was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain compound 1 (185 mg, crude) as a yellow oily substance, which was used in the next step without further purification.

[0840] The compounds reported below were prepared starting from the corresponding intermediates, following a method similar to that described for compound 1:

[0841] [Table 21-1]

[0842] [Table 21-2]

[0843] [Table 21-3]

[0844] Alternative preparations of compound 1a and compound 1b

[0845] [ka]

[0846] The reaction was carried out twice with 6 g of compound 490. The resulting crude mixtures were combined for workup and purification. To a solution of compound 490 (6 g, 9.4 mmol) in CH2Cl2 (150 mL), TFA (14 mL, 186 mmol) was added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH=13 with NaOH (2 M) aqueous solution. The resulting mixture of both reactions was then extracted with CH2Cl2 (10 mL × 2). The combined organic extract was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue (10.1 g) was placed on chiral SFC (stationary phase: Chiralpak IG 5 μm 250 * The experiment was conducted using a 30 mm microscope with a mobile phase of 60% CO2 and a 40% mixture of EtOH / iPrOH / DCM (40 / 40 / 20 v / v / v (+3.0% iPrNH2)). The pure fraction was collected, and the solvent was evaporated under vacuum to obtain 3.8 g of compound 1a and 3.8 g of compound 1b.

[0847] Preparation of compound 2:

[0848] [ka]

[0849] Compound 1 (150 mg, crude) and acetic acid (36 μL, 0.63 mmol) were dissolved in CH2Cl2 (5 mL), to which T3P (403 mg, 0.633 mmol, 50% purity) and DIEA (147 μL, 0.828 mmol) were added. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with CH2Cl2 (20 mL). The mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: ACE 5 C18-AR 150). * 30mm * The compound was purified using a 5 μm mobile phase (A: water (10 mM NH4HCO3)-ACN, B: acetonitrile, flow rate: 30 mL / min, gradient conditions from 25%B to 55%B). The pure fraction was collected, the solvent was evaporated under vacuum to obtain the residue, which was then partitioned into acetonitrile (2 mL) and water (8 mL). The solution was freeze-dried to obtain compound 2 (60.0 mg) as a white powder.

[0850] 1 H NMRCDCl3(Varian_400MHz):δ8.93(br.s.,1H),8.46(s,1H),8.40(br.s.,1H),7.49- 7.31(m,1H),7.26-7.18(m,1H),7.16-7.08(m,1H),6.02(br.s.,0.2H),5.60(br.s.,0 .6H),4.26-4.12(m,1H),3.80-3.42(m,4H),3.19-2.99(m,3H),2.52-2.35(m,2H),2. 08-1.98(m,3H),1.94(s,3H),1.89-1.55(m,6H),1.19-0.94(m,3H),0.92-0.62(m,7H) 19 F NMR(376MHz,CDCl3):-115.85(s,1F)

[0851] The compounds reported below were prepared according to a method similar to that described for compound 2, which started from compound 1:

[0852] [Table 22]

[0853] Preparation of compound 2a:

[0854] [ka]

[0855] The reaction was carried out twice with 1.7 g of compound 1a. The resulting crude mixtures were combined for workup and purification. To a solution of compound 1a (1.7 g, 3.12 mmol) and acetic acid (0.4 mL, 7.1 mmol) in DCM (25 mL), T3P (4.3 mL, 7.2 mmol, 50% purity) and DIEA (1.7 mL, 9.4 mmol) were added. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with DCM. The combined mixture of both reactants was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: gradient from 0.1% NH4OH, 5% MeOH, 95% DCM to 0.1% NH4OH, 8% MeOH, 92% DCM). The pure fraction was collected, and the solvent was evaporated under vacuum to obtain the residue, which was partitioned into acetonitrile (2 mL) and water (8 mL). The solution was lyophilized to obtain compound 2a (1.69; 46%) as a white powder.

[0856] 1 H NMR(500MHz,DMSO-d6)δppm8.80-9.02(m,1H),8.41(brs,2H),7.98(brd,J=7.2H z,1H),7.52-7.63(m,1H),7.39-7.50(m,2H),3.95(dq,J=16.2,8.2Hz,1H),3.37- 3.83(m,4H),3.05(brs,3H),2.84-2.99(m,1H),2.13-2.31(m,2H),1.89-2.03(m, 3H),1.78-1.88(m,1H),1.65-1.77(m,5H),1.50-1.64(m,2H),0.61-1.18(m,10H)

[0857] Alternative preparations of compound 2a and compound 2b:

[0858] [ka]

[0859] Compound 2 (30 mg, 0.051 mmol) was subjected to SFC (column: DAIEL CHIRALCEL OD-H (250 mm) *Separation was performed using a 30 mm, 5 μm filter (eluent: 0.1% NH3H2O ​​EtOH with 30% (v / v) supercritical CO2, flow rate: 50 mL / min). The desired fraction was collected, and the solvent was evaporated under vacuum. The residue was redissolved in ACN and water, and freeze-dried to obtain compound 2a (13 mg, yield 43%) and compound 2b (11 mg, yield 37%), both as white powders.

[0860] Preparation of compound 303:

[0861] [ka]

[0862] To a solution of compound 1a (100 mg, 0.184 mmol) and cyclopropanecarboxylic acid (36.2 mg, 0.420 mmol) in DCM (5 mL), T3P (268 mg, 0.421 mmol, 50% in Â) and DIEA (118 mg, 0.913 mmol) were added. The resulting mixture was stirred at 25°C for 12 hours. The mixture was extracted with DCM (10 mL), H2O (10 mL), and brine (10 mL). After drying with Na2SO4, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to preparative HPLC (column: Phenomenex Gemini-NX 150). * 30mm * The compound was purified using a 5 μm mobile phase (A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), B: ACN, flow rate: 30 mL / min, gradient conditions from 40% B to 70%). The desired fraction was collected and freeze-dried to obtain compound 303 (50 mg, yield 44%) as a white powder.

[0863] 1H NMRCDCl3(Bruker_400MHz):δ8.94(s,1H),8.46(s,1H),8.44-8.34(m,1H),7.39(s,1H), 7.26-7.18(m,1H),7.17-7.08(m,1H),6.31-5.68(m,1H),4.29-4.13(m,1H),3.82-3.30(m ,4H),3.26-2.91(m,4H),2.56-2.35(m,2H),2.20-1.93(m,4H),1.80-1.55(m,4H),1.36- 1.22(m,1H),1.20-1.03(m,2H),1.02-0.91(m,3H),0.91-0.79(m,7H),0.76-0.64(m,2H).

[0864] The compounds reported below were prepared starting from a suitable starting material (e.g., compound 1a or another suitable starting material) in a manner similar to that described for compound 2a or compound 303:

[0865] [Table 23-1]

[0866] [Table 23-2]

[0867] [Table 23-3]

[0868] [Table 23-4]

[0869] [Table 23-5]

[0870] Preparation of compound 508

[0871] [ka]

[0872] To a solution of intermediate 14 (500 mg, 1.54 mmol) in DMF (0.1 mL) in DCM (30 mL), oxalyl dichloride (1.05 g, 8.27 mmol) was added at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure (below 35°C) to obtain a residue. The residue was dissolved in DCM (30 mL), and TEA (5.0 mL, 35.9 mmol) was added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 3 minutes. DCM (2 mL) containing intermediate 25 (600 mg, 1.55 mmol) was added dropwise at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (50 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by FCC (PE:Â=1:3 to 0:1) to obtain compound 508 (260 mg, yield 18%) as a white solid.

[0873] Preparation of Compound 3

[0874] [ka]

[0875] To a solution of compound 508 (260 mg, 0.395 mmol) in dioxane (5 mL), 4 M HCl / dioxane (3.00 mL, 12 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to obtain compound 3 (240 mg, crude HCl salt) as a light brown solid (no further purification was required).

[0876] Preparation of compound 4:

[0877] [ka]

[0878] To a solution of intermediate 29 (370 mg, crude) in DCM (3 mL), 4 M HCl / dioxane (0.2 mL, 0.8 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated. The resulting residue was first subjected to preparative HPLC (column: Waters Xbridge Prep OBD C18 150). * 40mm * Preparative HPLC (10 μm, mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 30% B to 80% B) followed by preparative HPLC (column: Boston Prime C18 150) * 30mm * The compound was purified using a 5 μm mobile phase (A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3), B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 55%B to 85%B). The pure fraction was collected and freeze-dried to obtain compound 4 (8.00 mg, yield 2%) as a white powder.

[0879] 1 H NMRCDCl3(Bruker-400MHz):δ8.93(s,1H),8.46(s,1H),8.38(s,1H),7.38(s,1H),7.22(d,J=8.0Hz,1H),7.12(d,J=6.4Hz,1H),3.38-3.8 7(m,5H),2.93-3.27(m,6H),2.44(s,2H),2.01(d,J=7.2Hz,3H),1.33-1.91(m,11H),1.11(brs,2H),0.67-0.99(m,8H),0.30-0.40(m,2H)

[0880] Preparation of compound 5:

[0881] [ka]

[0882] PyBrOP (108 mg, 0.232 mmol) was added to a solution of intermediate 14 (50 mg; 0.15 mmol), intermediate 28 (61 mg, 0.16 mmol), TEA (0.12 mL, 0.88 mmol), and DMF (0.5 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was purified by preparative high-performance liquid chromatography using a Phenomenex Gemini-NX 150 × 30 mm × 5 μm (eluent: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) / 65 / 35~41 / 59 v / v ACN). The pure fraction was collected, freeze-dried, and completely removed solvent residue to obtain compound 5 (7.64 mg) as a white solid.

[0883] 1 H NMRCDCl3(Varian_400MHz):δ8.93(s,1H),8.46(s,1H),8.38(s,1H),7.37(br.s,1H),7.25-7.18( m,1H),7.15-7.09(m,1H),4.83-4.73(m,2H),4.40(t,J=6.4Hz,2H),3.75-3.42(m,4H),3.41-3.16( m,2H),3.16-3.03(m,3H),3.03-2.93(m,1H),2.81-2.73(m,2H),2.69-2.62(m,2H),2.05-1.99(m,2 H),1.88-1.76(m,4H),1.56-1.39(m,4H),1.37-1.28(m,1H),1.16-1.03(m,2H),0.98-0.63(m,8H).

[0884] Preparation of compound 6:

[0885] [ka]

[0886] Sodium cyanoborohydride (30 mg; 0.477 mmol) was added to a mixture of intermediate 33 (100 mg; 0.238 mmol), intermediate 34 (107 mg; 0.477 mmol), and acetic acid (14 μL; 0.238 mmol) in MeOH (5 mL), and the reaction mixture was heated at 70 °C for 60 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was decanted, filtered through Chromabond®, and evaporated to dryness. The residue (190 mg) was purified by silica gel chromatography (irregular SiOH, 4 g + 4 g; mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 1% NH4OH, 10% MeOH, 90% DCM). The pure fraction was recovered and evaporated to dryness to obtain 54 mg of the substance, which was freeze-dried (10 mL; 20% ACN, 80% water) to obtain 52 mg (yield 35%) of compound 6.

[0887] The compounds in the table below were prepared by SFC separation of compound 6.

[0888] [Table 24]

[0889] Preparation of Compound 7 and Compound 8:

[0890] [ka]

[0891] NaBH3CN (139 mg; 2.21 mmol) is used as intermediate 38b ( *R) (600 mg; 1.1 mmol), dimethylamine solution (2.76 mL; 5.52 mmol; 2 M in THF), and a mixture of MeOH (30 mL) containing AcOH (63 μL; 1.1 mmol) were added. The reaction mixture was then heated at 60°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). The pure fraction was collected and evaporated to dryness. The residue (650 mg) was filtered using achiral SFC (CHIRALPAK AD-H 5 μm 250 * The compound was purified using a 30 mm substrate with a mobile phase of 82% CO2 and 18% EtOH (0.3% iPrNH2). The pure fraction was recovered, and the solvent was evaporated to obtain 425 mg of compound 7 as a white foam and 62 mg of compound 8 as a colorless oil. Compound 7 was freeze-dried with water-ACN to obtain 420 mg (66%) of the final compound as a white solid.

[0892] compound 7 1 H NMR(500MHz,DMSO-d6)δppm8.92(br,1H)8.41(brs,2H)7.57(brs,1H)7.46(brd,J=7.6Hz,2H)3.40-3.79(m,4H)2.89-3.14(m,4H) 2.27-2.38(m,1H)2.05(m,2H)1.97(s,9H)1.72-1.87(m,2H)1.61(m,2H)1.45(q,J=9.6Hz,1H)1.01(m,3H)0.82(brt,J=6.0Hz,7H)

[0893] The compounds reported below are suitable starting materials (e.g., intermediate 38( * Compound 7 was prepared according to a method similar to that reported for the preparation of compound 7 starting from R) or other suitable starting material:

[0894] [Table 25-1]

[0895] Table 25-2

[0896] Table 26-1

[0897] Table 26-2

[0898] Table 26-3

[0899] Table 26-4

[0900] Table 26-5

[0901] Table 26-6

[0902] Table 26-7

[0903] Table 26-8

[0904] Table 26-9

[0905] Table 26-10

[0906] Table 26-11

[0907] Table 26-12

[0908] Table 26-13

[0909] Table 26-14

[0910] Table 26-15

[0911] Table 26-16

[0912] Table 26-17

[0913] Table 26-18

[0914] Table 26-19

[0915] The compounds reported below require a suitable starting material (e.g., intermediate 38a( * Starting from S) or other suitable starting material, compound 7 was prepared according to a method similar to that reported for the preparation of compound 7:

[0916] [Table 27-1]

[0917] [Table 27-2]

[0918] [Table 27-3]

[0919] [Table 27-4]

[0920] [Table 27-5]

[0921] [Table 27-6]

[0922] [Table 27-7]

[0923] [Table 27-8]

[0924] [Table 27-9]

[0925] [Table 27-10]

[0926] [Table 27-11]

[0927] [Table 27-12]

[0928] The compounds reported below were prepared according to a method similar to that reported for the preparation of compound 7, starting from a suitable starting material (e.g., intermediate 38b or other suitable starting material). Standard cleavage of protecting groups was applied where necessary:

[0929] [Table 28-1]

[0930] [Table 28-2]

[0931] [Table 28-3]

[0932] [Table 28-4]

[0933] [Table 28-5]

[0934] [Table 28-6]

[0935] Preparation of Compound 331 and Compound 332:

[0936] [ka]

[0937] NaBH3CN (433 mg, 6.89 mmol) was added to a solution consisting of intermediate 249a (800 mg, 1.38 mmol), (S)-3-methoxypyrrolidine hydrochloride (418 mg, 4.13 mmol), MeOH (10 mL), and AcOH (0.237 mL). The mixture was stirred at 60°C for 12 hours. After cooling to room temperature, the mixture was adjusted to pH=8 using NH3H2O ​​and purified by preparative HPLC using a Phenomenex Gemini 150 mm × 25 mm × 10 μm column (eluent: H2O containing 30%~60% (v / v) ACN and 0.05% NH3H2O). The desired fractions were collected and lyophilized to obtain compound 331 (321 mg, yield 36%) and compound 332 (49 mg, yield 5%) as white solids.

[0938] Compound 331: 1 H NMRMethanol-d4(Varian_400MHz):δ9.01-8.85(m,1H),8.29(s,1H),7.63-7.47(m,1H),7.45-7.2 8(m,2H),7.21-7.07(m,1H),4.02-3.90(m,1H),3.88-3.68(m,2H),3.64-3.43(m,2H),3.29-3.16(m ,7H),2.81-2.70(m,1H),2.70-2.60(m,2H),2.60-2.53(m,1H),2.49-2.39(m,1H),2.26-2.13(m,3 H),2.11-1.96(m,4H),1.86-1.66(m,5H),1.08-0.98(m,2H),0.97-0.86(m,6H),0.83-0.75(m,2H).

[0939] Compound 332: 1 H NMRMethanol-d4(Varian_400MHz):δ9.00-8.87(m,1H),8.30(s,1H),7.60-7.48(m,1H),7.45 -7.32(m,2H),7.19-7.10(m,1H),4.03-3.92(m,1H),3.85-3.69(m,2H),3.67-3.57(m,1H),3.5 6-3.45(m,1H),3.30-3.14(m,7H),2.95-2.86(m,1H),2.81-2.53(m,4H),2.32-2.16(m,2H),2 .15-1.97(m,6H),1.89-1.66(m,4H),1.08-0.98(m,2H),0.96-0.85(m,6H),0.84-0.74(m,2H).

[0940] The compounds reported below are intermediate 249a( * Starting from S), compounds 331 and 332 were prepared according to a method similar to that described:

[0941] [Table 29-1]

[0942] [Table 29-2]

[0943] [Table 29-3]

[0944] [Table 29-4]

[0945] [Table 29-5]

[0946] [Table 29-6]

[0947] The compounds reported below are intermediate 249b( * Starting from R), it was prepared according to a method similar to that described for compound 331:

[0948] [Table 30-1]

[0949] [Table 30-2]

[0950] Preparation of compound 9:

[0951] [ka]

[0952] NaBH3CN (162 mg; 2.58 mmol) is used as intermediate 38b ( * R) (700 mg; 1.288 mmol), 4-(methylsulfonyl)piperidine (1.05 g; 6.438 mmol), and AcOH (74 μL; 1.3 mmol) were added to a mixture in MeOH (41 mL). The reaction mixture was then heated at 60 °C for 24 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). The pure fraction was collected and evaporated to dryness. The residue (684 mg) was freeze-dried over water-ACN to obtain 655 mg (73%) of the final compound 9.

[0953] 1 H NMR(500MHz,DMSO-d6)δppm8.95(br,1H)8.41(brs,2H)7.57(brd,J=3.4Hz,1H)7.41-7.49(m,2H)3.39-3.79(m,4H)2.85-3.15(m,10 H)2.38-2.47(m,1H)2.02-2.16(m,2H)1.96(brd,J=9.8Hz,5H)1.80-1.89(m,1H)1.41-1.78(m,8H)1.00(m,3H)0.82(t,J=6.2Hz,7H)

[0954] Preparation of compound 10 and compound 33:

[0955] [ka] The piperidine moiety is a single cis isomer (the specific cis isomer is yet to be determined).

[0956] [ka] The piperidine moiety is a single cis isomer (the specific cis isomer is yet to be determined).

[0957] NaBH3CN (40.7 mg; 0.65 mmol) is used as intermediate 38b ( * A mixture of MeOH (15 mL) containing R) (176.1 mg; 0.33 mmol), cis-3-fluoropiperidine-4-ol (201.6 mg; 1.30 mmol), and AcOH (19 μL; 0.32 mmol) was added. The reaction mixture was then heated at 60°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.1% NH4OH, 12% MeOH, 88% DCM). The pure fraction was collected and evaporated to dryness. The residue (650 mg) was etched into an achiral SFC (CHIRALPAK AD-H 5 μm 250 *The compounds were purified using a 30 mm substrate with a mobile phase of 80% CO2 and 20% EtOH (0.3% iPrNH2). The pure fraction was collected and the solvent was evaporated. After lyophilization with a water-ACN mixture, 29 mg (14%) of compound 10 and 25 mg (12%) of compound 33 were obtained.

[0958] Compound 10: 1 H NMR(500MHz,DMSO-d6)δppm8.88-8.97(m,1H),8.41(brs,2H),7.57(brs,1H),7.47(brd,J=7.5Hz,2H),4.89(d,J=4.7Hz,1H), 4.43-4.60(m,1H),3.38-3.79(m,6H),2.87-3.14(m,5H),1.39-2.32(m,15H),1.00(brd,J=6.9Hz,3H),0.83(brt,J=5.8Hz,7H)

[0959] Preparation of Compound 12 and Compound 13

[0960] [ka]

[0961] NaBH3CN (35 mg; 0.55 mmol) is used as intermediate 38b ( *(R) (150 mg; 0.28 mmol), (3S)-3-methylpyrrolidine-3-ol (140 mg; 1.38 mmol), and AcOH (16 μL; 0.28 mmol) were added to a mixture in MeOH (9 mL). The reaction mixture was then heated at 60 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0.3% NH4OH, 3% MeOH, 97% DCM to 1% NH4OH, 10% MeOH, 90% DCM). The pure fraction was collected and evaporated to obtain a mixture of 130 mg of compound 12 and compound 13. The residue (130 mg) was purified by reverse-phase filtration (mobile phase: gradient from 65% NH4CO3 (0.2%), 35% ACN to 25% NH4CO3 (0.2%), 75% ACN). The pure fraction was recovered, evaporated to dryness, and freeze-dried with water-ACN to obtain 80 mg (46%) of the final compound 12 as a white solid.

[0962] compound 12 1 H NMR(400MHz,DMSO-d6)δppm8.88-8.96(m,1H),8.41(brs,2H),7.57(brd,J=2 .0Hz,1H),7.41-7.51(m,2H),4.45(s,1H),3.38-3.77(m,4H),2.88-3.20(m, 4H),2.58-2.64(m,1H),2.36-2.44(m,1H),2.32(s,3H),1.90-2.08(m,4H),1 .46-1.90(m,8H),1.21(s,3H),0.90-1.07(m,3H),0.82(dd,J=6.8,3.1Hz,7H)

[0963] Preparation of Compound 14 and Compound 15

[0964] [ka]

[0965] NaBH3CN (35 mg; 0.55 mmol) is used as intermediate 38b ( * R) (150 mg; 0.28 mmol), hexahydro-1H-flu[3,4-C]pyrrole (156 mg; 1.38 mmol), and AcOH (16 μL; 0.28 mmol) were added to a mixture in MeOH (9 mL). The reaction mixture was then heated at 60 °C for 48 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0.3% NH4OH, 3% MeOH, 97% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). The pure fraction was recovered and evaporated to obtain 79 mg, which was freeze-dried with water-ACN to obtain 79 mg (44%) of compound 14 as a white solid, and a mixture of compound 14 and compound 15 of 95 mg (which was not further purified).

[0966] compound 14 1 H NMR(500MHz,DMSO-d6)δppm8.88-8.98(m,1H),8.36-8.46(m,2H),7.56(brd,J=4.1Hz ,1H),7.41-7.50(m,2H),3.66-3.76(m,3H),3.39-3.63(m,4H),3.35(brdd,J=8.5,3.7 Hz,3H),2.88-3.16(m,4H),2.62-2.68(m,2H),2.53-2.61(m,2H),2.34-2.48(m,4H), 2.14-2.22(m,2H),1.48-2.11(m,12H),0.91-1.05(m,3H),0.82(dd,J=6.9,4.9Hz,7H)

[0967] Preparation of Compound 16 and Compound 17

[0968] [ka]

[0969] NaBH3CN (139 mg; 2.21 mmol) is used as intermediate 38b ( * Compound 16 (600 mg; 1.1 mmol), 4-methoxypiperidine (636 mg; 5.52 mmol), and AcOH (64 μL; 1.1 mmol) were added to a mixture of MeOH (15 mL). The reaction mixture was then heated at 60 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with DCM (3×), dried over MgSO4, filtered, and evaporated until dry. The residue was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.1% NH4OH, 6% MeOH, 94% DCM). The pure fraction was recovered and evaporated to dryness, yielding 355 mg of compound 16 and 155 mg of a mixture of compound 16 and compound 17. Compound 16 (355 mg) was further purified by reverse-phase chromatography (mobile phase: gradient from 40% NH4CO3 (0.2%), 60% ACN to 10% NH4CO3 (0.2%), 90% ACN). The pure fraction was recovered and evaporated to dryness, yielding 264 mg of compound 16. This was freeze-dried with water-ACN, yielding a final compound of 250 mg (35%) as a white solid.

[0970] compound 16 1 H NMR(400MHz,DMSO-d6)δppm8.88-8.98(m,1H),8.41(brs,2H),7.57(brs,1H), 7.40-7.50(m,2H),3.39-3.79(m,4H),3.20(s,3H),2.88-3.16(m,6H),2.36-2. 43(m,1H),2.00-2.18(m,2H),1.70-2.00(m,10H),1.55-1.67(m,2H),1.46(q, J=9.7Hz,1H),1.29-1.40(m,2H),1.00(brs,3H),0.82(brdd,J=6.9,3.9Hz,7H)

[0971] Preparation of compound 18:

[0972] [ka]

[0973] Compound 18 is intermediate 38b ( * Starting from R) and pyrrolidine, compound 18 was prepared using the same procedure as that used for the synthesis of compounds 12 and 13. 40 mg (36%) of compound 18 was obtained.

[0974] Preparation of compound 20 and compound 21:

[0975] [ka]

[0976] Compounds 20 and 21 are used to form intermediate 38b ( * Starting from R) and 2-oxa-6-azaspiro[3.3]heptane, the compounds were prepared using the same procedure as that used for the synthesis of compounds 7 and 8. 45 mg (26%) of compound 20 and 45 mg (26%) of compound 21 were obtained.

[0977] compound 20 1 H NMR(500MHz,DMSO-d6)δppm8.93(brs,1H),8.41(brs,2H),7.57(brs,1H),7.37-7.49(m,2H),4.56(s,4H),3.39-3.82(m,4H),3.13-3.23(m,4) H),2.85-3.12(m,4H),2.71-2.83(m,1H),1.84-2.07(m,5H),1.68-1.8 3(m,2H),1.51-1.67(m,2H),1.42(q,J=9.8Hz,1H),0.62-1.09(m,10H)

[0978] Preparation of compound 22:

[0979] [ka]

[0980] TBAF (11.5 mL; 11.3 mmol; 1 M in THF) was added to a solution of intermediate 39 (1.09 g; 1.26 mmol) in MeTHF (25 mL), and the reaction mixture was stirred at room temperature for 24 hours. The mixture was poured into a 10% aqueous solution of K2CO3. The organic layer was extracted with ELISA (3×), dried over MgSO4, filtered, and evaporated until dry. The residue (1.36 g) was purified by silica gel chromatography (mobile phase: gradient from 0% NH4OH, 0% MeOH, 100% DCM to 0.7% NH4OH, 7% MeOH, 93% DCM). The pure fraction was collected and evaporated to dryness. The residue (604 mg) was purified by reversed-phase chromatography (mobile phase: gradient from 75% NH4CO3 (0.2%), 25% ACN to 35% NH4CO3 (0.2%), 65% ACN). The pure fraction was recovered, evaporated to dryness, and freeze-dried with water-ACN to obtain 313 mg (40%) of compound 22 as a white solid.

[0981] Preparation of Compound 313 and Compound 314:

[0982] [ka]

[0983] ZnCl2 (450 mg, 3.30 mmol) was added to the solutions of intermediates 236 (200 mg, 1.02 mmol) and 33 (450 mg, 1.07 mmol) in MeOH (10 mL). The mixture was stirred at 70°C for 2 hours. Next, NaBH3CN (200 mg, 3.18 mmol) was added. The resulting mixture was stirred at 70°C for a further 2 hours. After cooling to room temperature, the mixture was quenched with water and filtered. The filtrate was evaporated to obtain the crude product, which was then subjected to preparative HPLC (column: Phenomenex Gemini NX-C 18 75). * 30mm *The solution was purified using a 3µm mobile phase (A: H2O (0.05% NH3H2O ​​+ 10 mM NH4HCO3), B: ACN, with a gradient from 35%B to 65%B). The pure fraction was recovered and freeze-dried to obtain a 100 mg residue, which was then processed using SFC (DAICEL CHIRALPAK AD-H (250 mm)). * The mixture was further purified using a 30 mm, 10 μm (mobile phase: A: supercritical CO2, B: 0.1% NH3H2O ​​EtOH, A:B = 50:50, 80 mL / min) filter. The desired fraction was collected, and volatile substances were removed under vacuum. The residue was resuspended in water (10 mL) and freeze-dried to obtain compound 313 (23 mg, 4% yield) and compound 314 (30 mg, 5% yield) as white powders.

[0984] The compounds reported below were prepared starting from a suitable intermediate, following a method similar to that described for compounds 313 and 314:

[0985] [Table 31-1]

[0986] [Table 31-2]

[0987] Preparation of compound 347:

[0988] [ka]

[0989] Compound 1a (150 mg, 0.275 mmol), N,N-dimethylacrylamide (55 mg, 0.56 mmol), and TEA (110 mg, 1.09 mmol) were added to a 10 mL sealed tube, followed by the addition of EtOH (5 mL). The mixture was stirred at 70 °C for 12 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum to obtain compound 347 (200 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0990] The compounds reported below were prepared starting from compound 1a, following a method similar to that described for compound 347:

[0991] [Table 32]

[0992] Preparation of compound 357:

[0993] [ka]

[0994] Formic acid (0.2 mL, 5.3 mmol) was added dropwise to a solution of intermediate 270 (350 mg, 0.462 mmol) in ACN (3 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was preparatively HPLC (Welch Xtimate C18 150). * 30mm * The compound was purified using a 5 μm medium, mobile phase A: water containing 0.225% formic acid, mobile phase B: ACN, gradient conditions: 8%B to 30%B v / v). The desired fraction was recovered and freeze-dried to obtain compound 357 (305 mg, yield 87%) as a white solid.

[0995] The compounds reported below were prepared starting from the corresponding intermediates, following a method similar to that described for compound 357:

[0996] [Table 33]

[0997] Preparation of compound 23:

[0998] [ka]

[0999] NaBH3CN (46 mg; 0.74 mmol) is used as intermediate 46b ( * 200 mg; 0.37 mmol) of 4-(methylsulfonyl)piperidine (301 mg; 1.84 mmol) and 21 μL; 0.36 m...

Claims

1. The following formula (I): 【Chemistry 1】 Compounds of the same, or tautomers or stereoisomers thereof [in the formula, R １ａ This represents Het, Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms and which may contain a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C ３～６ It is substituted with a cycloalkyl group, and the monocyclic five-membered or six-membered aromatic ring is C ３～６ Cycloalkyl, cyano, and C １～４ It may be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R １ｂ represents F or Cl; Y １ represents -CR ５ａ R ５ｂ -, -O-, -S-, or -NR ５ｃ -; R ２ is hydrogen, halo, C １～４ Alkyl, -O-C １～４ Alkyl and -NR ７ａ R ７ｂ Selected from the group consisting of; U represents N or CH; n1, n2, n3, and n4 are each independently selected from 1 and 2; X １ represents CH, X ２ represents N; R ４ C １～５ Alkyl; or the following formula: 【Chemistry 2】 It represents a base represented by; R ５ａ , R ５ｂ , R ５ｃ , R ７ａ , and R ７ｂ is hydrogen, C １～４ Alkyl and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R ３ Het １ , Het ２ Cy ２ and -C １～６ Alkyl-NR ｘｃ R ｘｄ Selected from the group consisting of; R ｘｃ Cy １ ; Het ５ ;-C １～６ Alkyl-Cy １ ;-C １～６ Alkyl-Het ３ ;-C １～６ Alkyl-Het ４ ; or -C １～６ Represents alkylphenyl; R ｘｄ is hydrogen; C １～４ Alkyl; or halo, -OH, -O-C １～４ C is substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano compounds. １～４ Represents alkyl; Or, R ｘｃ and R ｘｄ These together, along with the N atom to which they are bonded, form a 4- to 7-membered monocyclic completely saturated heterocycline containing one N atom and one additional heteroatom selected from O, S, and N, where the S atom is substituted with S(=O) or S(=O). ２ They may form a heterocycline, -OH, -O-C １～４ It may be substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano; Het １ This is a monocyclic 4-7 member fully saturated heterocycline containing one N atom and each independently containing one or two additional heteroatoms selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond that contains one N atom and may each independently contain one or two additional heteroatoms selected from O, S and N, wherein the S atom is substituted with S(=O) or S(=O) ２ Represents a bicyclic C-bonded 6-11 member fully saturated heterocycline that may form a , and the heterocycline has R on one nitrogen. ６ , -C(=O)-Cy １ , and -C(=O)-R ８ The heterocyclyl may be substituted with substituents selected from the group consisting of, and the heterocyclyl may have a halo, R on one or two carbon atoms. ６ , Het ６ａ , Het ６ｂ , C １～４ Alkyl, oxo, -NR ９ａ R ９ｂ They may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of and -OH; Het ２ represents a C-bonded pyrazolyl or triazolyl; R on one nitrogen atom ６ａ It is also fine if it is replaced with; R ６ and R ６ａ is Het ３ ; Het ４ ; -C(=O)-NH-Cy １ ; -C(=O)-NH-R ８ ; Het ３ Het ４ Het ６ａ Het ６ｂ Cy １ ; -CN, -OH, -O-C １～４ alkyl, -C(=O)-NH-C １～４ alkyl, -C(=O)-NH-C １～４ alkyl-C ３～６ cycloalkyl, -C(=O)-OH, -NR １１ａ R １１ｂ and -NH-S(=O) ２ -C １～４ alkyl, which may be independently substituted by one or two substituents selected from the group consisting of １～６ alkyl; and; -CN, -OH, -O-C １～４ alkyl, -C(=O)-NH-C １～４ alkyl, -NH-S(=O) ２ -C １～４ alkyl, and, OH, O-C １～４ alkyl, -C(=O)-NH-C １～４ alkyl and -NH-S(=O) ２ -C １～４ alkyl, which may be substituted by one substituent selected from the group consisting of １～４ alkyl, which may be independently substituted by one or two substituents selected from the group consisting of ３～６ cycloalkyl; each independently selected from the group consisting of; R ８ is -O-C １～６ alkyl, C １～６ alkyl; or -OH, halo, cyano, -NR １１ａ R １１ｂ , Het ３ａ and Het ６ａ and is substituted with 1, 2 or 3 substituents each independently selected from １～６ alkyl; Het ３ , Het ３ａ , Het ５ and Het ５ａ Each is a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ Represents a bicyclic C bond 6-11 member fully saturated heterocycline which may form a C bond; the heterocycline has a C bond on one carbon atom. １～４ Alkyl, Halo, -OH, -NR １１ａ R １１ｂ , or may be substituted with an oxo; the heterocyclyl has a C on one nitrogen atom. １～４ It may also be substituted with alkyl; Het ４ and Het ７ Each independently represents a monocyclic 5- or 6-membered aromatic ring with carbon bonds containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, or a condensed bicyclic 9- or 10-membered aromatic ring with carbon bonds containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; the aromatic ring has a carbon atom on one nitrogen atom. １～４ Alkyl or -(C=O)-O-C １～４ It may be substituted with alkyl groups; the aromatic ring may have -OH, halo, and C on 11 or 2 carbon atoms. １～４ Alkyl, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, -COOH, -NH-C(=O)-O-C １～４ Alkyl, -NH-C(=O)-Cy ３ , -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, -NH-S (=O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ , and -C(=O)-NR １０ａ R １０ｂ They may be substituted with a total of one or two substituents independently selected from the group consisting of; Het ６ａ , Het ８ and Het ８ａ Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and possibly one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a halo, -OH, oxo, -NH-C(=O)-C on one or two carbon atoms; １～４ Alkyl, -NH-C(=O)-Cy ３ , -(C=O)-NR １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S (=O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, -C １～４ Alkyl-OH,-O-C １～４ Alkyl, -O-(C=O)-NR １０ａ R １０ｂ , and -O-(C=O)-C １～４ The heterocyclyl may be substituted with a total of one, two, three, or four substituents independently selected from the group consisting of alkyl groups, wherein the heterocyclyl has -C(=O)-C substituents on one nitrogen atom. １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ It may also be substituted with substituents selected from the group consisting of; Het ６ｂ and Het ８ｂ Each independently represents a bicyclic N-bonded 6- to 11-membered fully saturated heterocycline containing one N atom and possibly one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a C on one or two carbon atoms. １～４ Alkyl, -OH, oxo, -(C=O)-NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , and -O-C １～４ The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups; the heterocyclyl may have -C(=O)-C substituents on one nitrogen atom. １～４ Alkyl, -C(=O)-Cy ３ -(C=O)-C １～４ Alkyl-OH,-C(=O)-C １～４ Alkyl-O-C １～４ Alkyl, -C(=O)-C １～４ Alkyl-NR １１ａ R １１ｂ , and C １～４ They may be substituted with substituents selected from the group consisting of alkyl groups; Het ９ This represents a monocyclic 5- or 6-membered aromatic ring with carbon bonds containing one, two, or three heteroatoms independently selected from O, S, and N, or a fused bicyclic 9- or 10-membered aromatic ring with carbon bonds containing one, two, or three heteroatoms independently selected from O, S, and N; the aromatic ring has a carbon atom on one nitrogen atom. １～４ It may be substituted with alkyl; the aromatic ring may have -OH, halo, and C on one or two carbon atoms. １～４ They may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups; Cy １ is -OH, -NH-C(=O)-C １～４ Alkyl, C １～４ Alkyl, -NH-S (=O) ２ -C １～４ Alkyl, -S (=O) ２ -C １～４ Alkyl and -O-C １～４ C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. ３～６ Represents a cycloalkyl group; Cy ２ is C ３～７ Represents cycloalkyl; the above C ３～７ Cycloalkyl is halo, R ６ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , -OH, C １～４ Alkyl, and Het ３ａ , Het ６ａ , Het ６ｂ , and -NR ９ａ R ９ｂ C is substituted with one or two substituents independently selected from the group consisting of the following: １～４ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl groups; Cy ３ is C ３～７ Represents cycloalkyl; the above C ３～７ The cycloalkyl group may be substituted with one, two, or three halo substituents; R ９ａ and R ９ｂ is hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; -C(=O)-C １～４ Alkyl; -C(=O)-C ３～６ Cycloalkyl; -S (=O) ２ -C １～４ Alkyl; Het ５ ;Het ７ ;-C １～４ Alkyl-R １６ ;-C(=O)-C １～４ Alkyl-Het ３ａ ;-C(=O)-R １４ ; Halo, -OH, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ C substituted with one, two, or three substituents selected from the group consisting of and cyano ３～６ Cycloalkyl; and; halo, -OH, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ C substituted with one, two, or three substituents selected from the group consisting of and cyano １～４ Each is independently selected from the group consisting of alkyl groups, R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １５ａ , R １５ｂ , R １７ａ , and R １７ｂ is hydrogen and C １～４ Each is independently selected from the group consisting of alkyls; R １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R １４ Het ５ａ ;Het ７ ;Het ８ａ ;-O-C １～４ Alkyl; -C(=O)NR １５ａ R １５ｂ ;-O-C １～４ C substituted with one, two, or three substituents selected from the group consisting of alkyl and halo ３～６ Cycloalkyl; or -O-C １～４ Alkyl, -NR １３ａ R １３ｂ Halo, Cyano, -OH, Het ８ａ , and Cy １ C substituted with one, two, or three substituents selected from the group consisting of １～４ Represents alkyl; R １６ is -C(=O)-NR １７ａ R １７ｂ , -S (=O) ２ -C １～４ Alkyl, Het ５ , Het ７ Or Het ８ [Represents] or a pharmaceutically acceptable salt or solvate thereof.

2. Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms, and which may contain a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C ３～６ It is substituted with a cycloalkyl group, and the monocyclic five-membered or six-membered aromatic ring is C ３～６ Cycloalkyl, cyano, and C １～４ It may be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R ２ is hydrogen, halo, C １～４ Alkyl, -O-C １～４ Alkyl and -NR ７ａ R ７ｂ Selected from the group consisting of; R ５ａ , R ５ｂ , R ５ｃ , R ７ａ , and R ７ｂ is hydrogen, C １～４ Alkyl and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R ３ Het １ , Het ２ Cy ２ and -C １～６ Alkyl-NR ｘｃ R ｘｄ Selected from the group consisting of; R ｘｃ Cy １ ;Het ５ ;-C １～６ Alkyl-Cy １ ;-C １～６ Alkyl-Het ３ ;-C １～６ Alkyl-Het ４ ; or -C １～６ Represents alkylphenyl, R ｘｄ is hydrogen; C １～４ Alkyl; or halo, -OH, -O-C １～４ C is substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano compounds. １～４ Represents alkyl; Or, R ｘｃ and R ｘｄ These combine to form a 4- to 7-membered monocyclic completely saturated heterocycline, which together with the N atom to which they are bonded, may contain one N atom and one additional heteroatom selected from O, S, and N, where the S atom is substituted with S(=O) or S(=O). ２ They may form a heterocycline, -OH, -O-C １～４ It may be substituted with one, two, or three substituents selected from the group consisting of alkyl and cyano; Het １ This is a monocyclic 4-7 member fully saturated heterocycline containing one N atom and each independently containing one or two additional heteroatoms selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond that contains an N atom and may each independently contain one or two additional heteroatoms selected from O, S and N, wherein the S atom is substituted with S(=O) or S(=O) ２ Represents a bicyclic C-bonded 6-11 member completely saturated heterocycline that may form a bicyclic C bond; The aforementioned heterocycline has R on one nitrogen atom. ６ and -C(=O)-R ８ The heterocyclyl may be substituted with substituents selected from the group consisting of, and the heterocyclyl may have a halo, R on one or two carbon atoms. ６ , Het ６ａ , Het ６ｂ , C １～４ Alkyl, oxo, -NR ９ａ R ９ｂ They may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of and -OH; Het ２ R on one nitrogen atom ６ａ Represents a C-linked pyrazolyl or triazolyl that is substituted with; R ６ Het ３ ;-C(=O)-NH-R ８ ;Het ３ , Het ４ , Het ６ａ , Het ６ｂ Cy １ , -CN, -OH, -OC １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl-C ３～６ Cycloalkyl, -C(=O)-OH, -NR １１ａ R １１ｂ , and -NH-S (=O) ２ -C １～４ C may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. １～６ Alkyl; and; -CN, -OH, -O-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl, -NH-S (=O) ２ -C １～４ Alkyl, and OH, -O-C １～４ Alkyl, -C(=O)-NH-C １～４ Alkyl and -NH-S (=O) ２ -C １～４ C may be substituted with one substituent selected from the group consisting of alkyl groups. １～４ C may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. ３～６ Represents a cycloalkyl group; R ６ａ -NR １１ａ R １１ｂ , Het ３ａ , and Het ６ａ A C substituted with one substituent selected from the group consisting of １～６ Represents alkyl; R ８ -OH, halo, cyano, -NR １１ａ R １１ｂ , Het ３ａ , and Het ６ａ C may be substituted with one, two, or three substituents independently selected from each of the above. １～６ Represents alkyl; Het ３ and Het ５ Each is a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond containing one, two, or three heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ Represents a bicyclic C bond 6-11 member fully saturated heterocycline which may form a C bond; the heterocycline has a C bond on one carbon atom. １～４ Alkyl, Halo, -OH, -NR １１ａ R １１ｂ , or may be substituted with an oxo; the heterocyclyl may have a C on one nitrogen atom. １～４ It may also be substituted with alkyl; Het ３ａ and Het ５ａ Each is a monocyclic 4-7 member fully saturated heterocycline containing one N atom and one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond that contains one N atom and may contain one or two additional heteroatoms independently selected from O, S and N, wherein the S atom is substituted with S(=O) or S(=O) ２ Represents a bicyclic C bond 6-11 member fully saturated heterocycline which may form a C bond; the heterocycline has a C bond on one carbon atom. １～４ Alkyl, Halo, -OH, -NR １１ａ R １１ｂ , or may be substituted with an oxo; the heterocyclyl may have a C on one nitrogen atom. １～４ It may also be substituted with alkyl; Het ４ and Het ７ Each independently represents a monocyclic carbon-bonded 5- or 6-membered aromatic ring containing 1, 2, or 3 heteroatoms independently selected from O, S, and N; the 5-membered aromatic ring has a carbon atom on one nitrogen atom. １～４ It may be substituted with alkyl; the 5 or 6-membered aromatic ring may be substituted with -OH on one carbon atom; Het ６ａ and Het ８ Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and possibly one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a halo, -OH, oxo, -(C=O)-NR on one or two carbon atoms. １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S (=O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, -C １～４ Alkyl-OH,-O-C １～４ Alkyl, -O-(C=O)-NR １０ａ R １０ｂ , and -O-(C=O)-C １～４ The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl groups; the heterocyclyl is -C(=O)-C １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het ８ａ Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing two N atoms and possibly an additional heteroatom selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a halo, -OH, oxo, -(C=O)-NR on one or two carbon atoms. １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S (=O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, C １～４ Alkyl-OH,-O-C １～４ Alkyl, -O-(C=O)-NR １０ａ R １０ｂ , and -O-(C=O)-C １～４ The heterocyclyl may be substituted with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl groups; the heterocyclyl is -C(=O)-C １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het ６ｂ This represents a bicyclic N-bonded 6- to 11-membered fully saturated heterocycline containing one N atom, each independently containing one or two additional heteroatoms selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a C on one or two carbon atoms. １～４ Alkyl, -OH, oxo, -(C=O)-NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , and -O-C １～４ The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups, and the heterocyclyl is -C(=O)-C １～４ Alkyl, -C(=O)-Cy ３ -(C=O)-C １～４ Alkyl-OH,-C(=O)-C １～４ Alkyl-O-C １～４ Alkyl, -C(=O)-C １～４ Alkyl-NR １１ａ R １１ｂ , and C １～４ It may also be substituted on one nitrogen atom with a substituent selected from the group consisting of alkyl groups; Cy １ is -OH, -NH-C(=O)-C １～４ Alkyl, C １～４ Alkyl, -NH-S (=O) ２ -C １～４ Alkyl, -S (=O) ２ -C １～４ Alkyl and -O-C １～４ C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. ３～６ Represents a cycloalkyl group; Cy ２ -NR ９ａ R ９ｂ ;Het ６ａ ;Het ６ｂ ; and Het ３ａ , Het ６ａ , Het ６ｂ and NR ９ａ R ９ｂ C substituted with one or two substituents independently selected from the group consisting of １～６ C may be substituted with one or two substituents independently selected from the group consisting of alkyl groups. ３～７ Represents cycloalkyl; the above C ３～７ Cycloalkyl is halo, R ６ , C １～４ It may also be substituted with one or two additional substituents independently selected from the group consisting of alkyl and -OH; Cy ３ is C ３～７ Represents cycloalkyl; the above C ３～７ The cycloalkyl group may be substituted with one, two, or three halo substituents; R ９ａ and R ９ｂ is hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; Het ５ ;-C １～４ Alkyl-R １６ ;-C(=O)-C １～４ Alkyl-Het ３ａ ;-C(=O)-R １４ ; Halo, -OH, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ C substituted with one, two, or three substituents selected from the group consisting of and cyano ３～６ Cycloalkyl; and; halo, -OH, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ C substituted with one, two, or three substituents selected from the group consisting of and cyano １～４ Each is independently selected from the group consisting of alkyl groups, R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １５ａ , R １５ｂ , R １７ａ , and R １７ｂ is hydrogen and C １～４ Each is independently selected from the group consisting of alkyls; R １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R １４ Het ５ａ ;Het ８ａ ; or -NR １３ａ R １３ｂ and Het ８ａ C substituted with one, two, or three substituents selected from the group consisting of １～４ Represents alkyl; R １６ is -C(=O)-NR １７ａ R １７ｂ , -S (=O) ２ -C １～４ Alkyl, Het ５ , Het ７ Or Het ８ The compound according to claim 1, which represents the compound described in claim 1.

3. Het represents a monocyclic 5- or 6-membered aromatic ring containing 1, 2, or 3 nitrogen atoms, and which may contain a carbonyl moiety; the monocyclic 5- or 6-membered aromatic ring contains 1 C ３～６ It is substituted with a cycloalkyl group, and the monocyclic five-membered or six-membered aromatic ring is cyano and C １～４ It may be substituted with one or two additional substituents selected from the group consisting of alkyl groups; R １ｂ This represents F; Y １ represents -O-; R ２ is hydrogen, U represents N; n1, n2, n3, and n4 are each independently selected from 1 and 2; R ４ However, C １～５ Alkyl; or the following formula: 【Transformation 3】 It represents a base represented by; R ３ Het １ and Cy ２ Selected from the group consisting of; Het １ This is a monocyclic 4-7 member fully saturated heterocycline containing one N atom and each independently containing one or two additional heteroatoms selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ A monocyclic 4-7 member fully saturated heterocycline with a carbon bond that may form a monocyclic carbon bond; or a bicyclic 6-11 member fully saturated heterocycline with a carbon bond that contains one N atom and may each independently contain one or two additional heteroatoms selected from O, S and N, wherein the S atom is substituted with S(=O) or S(=O) ２ Represents a bicyclic C-bonded 6-11 member fully saturated heterocycline that may form a , and the heterocycline has R on one nitrogen. ６ and -C(=O)-R ８ The heterocyclyl may be substituted with substituents selected from the group consisting of the following, and the heterocyclyl may be substituted on one or two carbon atoms with a total of 1, 2, 3, or 4 substituents independently selected from the group consisting of oxo and -OH; R ６ and R ６ａ Het ４ ;Het ３ , Het ６ａ and Cy １ C may be substituted with one or two substituents independently selected from the group consisting of the above. １～６ alkyl; and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R ８ However, -O-C １～６ Represents alkyl; Het ３ , Het ３ａ , Het ５ and Het ５ａ Each of these independently represents a monocyclic 4-7 member fully saturated heterocycline containing one, two, or three heteroatoms independently selected from O, S, and N, and the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a C on one carbon atom. １～４ It may also be substituted with alkyl; Het ４ and Het ７ Each independently represents a monocyclic 5- or 6-membered aromatic ring with carbon bonds containing 1, 2, or 3 heteroatoms independently selected from O, S, and N, or a condensed bicyclic 9- or 10-membered aromatic ring with carbon bonds containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; the aromatic ring has a carbon atom on one nitrogen atom. １～４ Alkyl or -(C=O)-O-C １～４ It may be substituted with alkyl; the aromatic ring may have -OH, halo, C on one or two carbon atoms. １～４ Alkyl, -O-C １～４ Alkyl, -NR １１ａ R １１ｂ , C １～４ Alkyl-NR １１ａ R １１ｂ , -NH-C(=O)-C １～４ Alkyl, cyano, -COOH, -NH-C(=O)-O-C １～４ Alkyl, -NH-C(=O)-NR １０ａ R １０ｂ , -(C=O)-OC １～４ Alkyl, -NH-S (=O) ２ -C １～４ Alkyl, Het ８ａ , -C １～４ Alkyl-Het ８ａ , Het ８ｂ , Het ９ , and -C(=O)-NR １０ａ R １０ｂ They may be substituted with a total of one or two substituents independently selected from the group consisting of; Het ６ａ , Het ８ and Het ８ａ Each independently represents a monocyclic N-bonded 4- to 7-membered fully saturated heterocycline containing one N atom and possibly one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a halo, -OH, oxo, -NH-C(=O)-C on one or two carbon atoms; １～４ Alkyl, -NH-C(=O)-Cy ３ , -(C=O)-NR １０ａ R １０ｂ , -O-C ３～６ Cycloalkyl, -S (=O) ２ -C １～４ Alkyl, cyano, C １～４ Alkyl, -C １～４ Alkyl-OH and -O-C １～４ The heterocyclyl may be substituted on one or two carbon atoms with a total of one, two, three, or four substituents independently selected from the group consisting of alkyl groups; the heterocyclyl is -C(=O)-C １～４ Alkyl and -(C=O)-NR １０ａ R １０ｂ It may also be substituted on one nitrogen with a substituent selected from the group consisting of; Het ６ｂ and Het ８ｂ Each independently represents a bicyclic N-bonded 6- to 11-membered fully saturated heterocycline containing one N atom and possibly one or two additional heteroatoms independently selected from O, S, and N, wherein the S atom is substituted with S(=O) or S(=O). ２ The heterocyclyl may form a C on one or two carbon atoms. １～４ Alkyl, -OH, oxo, -(C=O)-NR １０ａ R １０ｂ , -NH-C(=O)-C １～４ Alkyl, -NH-C(=O)-Cy ３ , and -O-C １～４ The heterocyclyl may be substituted with a total of one or two substituents independently selected from the group consisting of alkyl groups, and the heterocyclyl is -C(=O)-C １～４ Alkyl, -C(=O)-Cy ３ , and C １～４ It may also be substituted on one nitrogen atom with a substituent selected from the group consisting of alkyl groups; Het ９ Each independently represents a monocyclic carbon-bonded 5 or 6-membered aromatic ring containing one, two, or three heteroatoms selected from O, S, and N; the aromatic ring has one or two carbon atoms on it. １～４ It may also be substituted with alkyl; Cy １ is -OH and C １～４ C may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups. ３～６ Represents a cycloalkyl group; Cy ２ is C ３～７ Represents cycloalkyl; the above C ３～７ Cycloalkyl, R ６ , Het ６ａ , Het ６ｂ , -NR ９ａ R ９ｂ , -OH, and C １～４ They may be substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl groups; Cy ３ is C ３～７ Represents cycloalkyl; the above C ３～７ The cycloalkyl group may be substituted with one, two, or three halo substituents; R ９ａ and R ９ｂ is hydrogen; C １～４ Alkyl; C ３～６ Cycloalkyl; -C(=O)-C １～４ Alkyl; -C(=O)-C ３～６ Cycloalkyl; Het ５ ;Het ７ ;-C １～４ Alkyl-R １６ ;-C(=O)-C １～４ Alkyl-Het ３ａ ;-C(=O)-R １４ ; and; halo, -OH and -O-C １～４ C substituted with one, two, or three substituents selected from the group consisting of alkyl groups １～４ Each is independently selected from the group consisting of alkyls; R １１ａ , R １１ｂ , R １３ａ , R １３ｂ , R １７ａ , and R １７ｂ is hydrogen and C １～４ Each is independently selected from the group consisting of alkyls; R １０ａ and R １０ｂ is hydrogen, C １～４ Alkyl and C ３～６ Each is independently selected from the group consisting of cycloalkyls; R １４ O-C １～４ Alkyl; -O-C １～４ C substituted with one, two, or three substituents selected from the group consisting of alkyl and halo ３～６ Cycloalkyl; or; -O-C １～４ Alkyl, -NR １３ａ R １３ｂ C substituted with one, two, or three substituents selected from the group consisting of and cyano １～４ Represents alkyl; R １６ is -C(=O)-NR １７ａ R １７ｂ or -S (=O) ２ -C １～４ The compound according to claim 1, representing an alkyl group.

4. Het is given by the following formula: 【Chemistry 4】 The compound according to claim 1, wherein the group is represented by .

5. The compound according to claim 1, wherein U represents N.

6. Y １ The compound according to claim 1, wherein -O- is represented.

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

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.

9. A process for preparing the pharmaceutical composition according to claim 8, comprising mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound according to any one of claims 1 to 7.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, for use as a pharmaceutical agent.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, for use in the prevention or treatment of cancer, myelodysplastic syndrome (MDS), and diabetes.

12. The pharmaceutical composition according to claim 11, wherein the cancer is selected from leukemia, myeloma, or solid tumor cancer selected from prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, and glioblastoma.

13. The pharmaceutical composition according to claim 12, wherein the leukemia is selected from acute leukemia, chronic leukemia, myeloid leukemia, myeloid leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T-cell prelymphoblastic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), MLL rearrangement leukemia, MLL-PTD leukemia, MLL amplification leukemia, MLL-positive leukemia, and leukemia exhibiting a HOX / MEIS1 gene expression signature.

14. The pharmaceutical composition according to claim 11, for use in the prevention or treatment of cancer.

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