Novel METTL3 inhibitors and their therapeutic use

Abstract

The present invention relates to formula (I): [Formula 1] A compound of TIFF2026514449000425.tif27170, or its tautomers, stereoisomers, salts, solvates, or N-oxides, wherein A 1 ~A 6 X, Y, R 7a , R 7b , R 8a , and R 8b The claims are as defined. The present invention further relates to pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier, and their uses as agents, in particular as agents having METTL3 inhibitory activity, and advantageously for use in the treatment or prevention of cancer, or autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compounds useful for the treatment and / or prevention in mammals, pharmaceutical compositions comprising such compounds, and the use thereof as METTL3 inhibitors, which are useful for the treatment of cancer, autoimmune diseases, neurological diseases, infectious diseases, inflammatory diseases, and other diseases or conditions in which METTL3 activity is involved. [Background technology]

[0002] Specific chemical modifications of biomolecules are an efficient way to control molecular function, and many downstream signaling pathways are influenced by DNA and protein modifications. Many enzymes involved in regulating protein and DNA modifications are currently targets for cancer treatment. RNA epitranscriptomics, the study of RNA modifications, is a new frontier in this field. Although known since the 1970s, eukaryotic RNA modifications were identified primarily on transfer RNA and ribosomal RNA until about the last decade, and in this last decade, they have been identified and characterized on mRNA and various non-coding RNAs.

[0003] N6-methyladenosine (m6A) is the most common RNA modification in mammalian cells. The m6A modification site is evolutionarily conserved within the consensus motif DRACH (D=A, G, or U; H=A, C, or U), where A is converted to m6A, and m6A modifications generally occur in the coding region of mRNA, the 3′ untranslated region (3′UTR) near the stop codon, and the 5′ untranslated region (5′UTR). m6A is a potentially reversible and dynamic post-transcriptional modification of RNA molecules, regulated by methyltransferases (writer) and demethylases (eraser) and recognized by specific binding proteins (reader) (Li et al. 2022).

[0004] m6A plays a crucial role in cancer and is also involved in various physiological processes such as neurodevelopment, T cell homeostasis, glycolipid metabolism, and gamete formation. There is growing evidence suggesting that its disruption can lead to a range of diseases, including addiction, autoimmune diseases, metabolic disorders, and infertility (Yang et al. 2020).

[0005] The addition of m6A is primarily catalyzed by a methyltransferase complex (MTC) containing numerous components. As a core component of the MTC, methyltransferase-like protein 3 (METTL3) is an S-adenosylmethionine (SAM)-binding protein that catalyzes the transfer of methyl groups in SAM to adenine bases in RNA. METTL14 stabilizes the structure of the MTC and recognizes the consensus motif DRACH, while Wilms tumor 1-associated protein (WTAP) promotes the recruitment of METTL3 and METTL14 (Wang et al. 2016, Ping et al. 2014).

[0006] METTL3 plays a crucial role in many biological processes, particularly tumorigenesis and development. Generally, METTL3 acts as an oncogene in cancer. Therefore, METTL3 causes alterations in mRNA translation and accelerates tumor progression, while downregulation of METTL3 leads to tumor suppression. Consequently, METTL3 mRNA expression is significantly elevated in cancerous tissue compared to normal tissue. Thus, METTL3 is associated with poor prognosis and therefore represents a potential novel diagnostic and prognostic biomarker in cancer clinical practice (Liu et al. 2020).

[0007] WO2020201773, WO2021111124, WO2022074379, and WO2022074391 describe METTL3 inhibitors and their use in the treatment of proliferative disorders such as cancer, autoimmune diseases, neurological disorders, infections, and inflammatory diseases, as well as other diseases or conditions in which METTL3 activity is involved.

[0008] WO2022254216 describes a combination therapy comprising a METTL3 inhibitor and a further anti-cancer agent.

[0009] WO2022254218 describes a process for the manufacture of inhibitory compounds. WO2021079196, WO2021081211, and WO2022081739 describe METTL3 regulators. SUMMARY OF THE INVENTION

[0010] In a first aspect, the invention relates to a compound of formula (I):

Chemical formula

Chemical Formula

[0011] Preferably, in formula (I): A 1 CR 1a Or it represents N, A 2 CR 2a Or it represents N, A 3 CR 3a Or it represents N, A 4 CR 4a Or it represents N, A 5 CR 5a Or it represents N, A 6 CR 6a It also represents N, However, A 1 , A 2 , A 3 , A 4 , A 5 , and A6 No more than three of them represent N; R 1a ~R 6a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 Represents a cycloalkyloxy or a 3-5 membered heterocyclic oxy, and the C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 Cycloalkyloxy, or 3-5 membered heterocyclic oxy, is a type of cyano, hydroxy, halo, or C. 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, and OC 3-6 Optionally substituted with one or more substituents selected from cycloalkyl groups; R 7a and R 7b Independently, (i) Hydrogen; (ii) Halo, cyano, hydroxy, C 1-4 Alkoxy, and C 1-4 C optionally substituted with one or more substituents selected from haloalkoxys 1-6 Alkyl Select from, (iii) or R 7a and R 7b They bond together, forming a 3- to 6-membered cycloalkanediyl or heterocyclic group with the carbon atoms to which they bond; R 8a and R 8b Independently, (i) Hydrogen, (ii) Cyano, hydroxy, halo, C 1-2 Alkoxy, and C1-2 C optionally substituted with one or more substituents selected from haloalkoxys 1-6 Alkyl, (iii) Formula -(CR c R d ) n -Base of Z Selected from, n is 0, 1, or 2. R c and R d Independently, hydrogen, Cyano, hydroxy, halo, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, and -OC 3-6 C optionally substituted with one or more substituents selected from cycloalkyl groups 1-6 Alkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted with one or more substituents selected from halo, cyano, and hydroxyl groups. 1-6 Alkyl Selected from; and or R c and R d They bond together, and together with the carbon atoms they bond to, they form cyano, hydroxy, halo, and C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, and C 1-2 A 3-6 membered cycloalkanediyl or heterocyclic group is formed, optionally substituted with one or more substituents selected from haloalkoxys. Z is Hydrogen, cyano, hydroxy, R a and R b is H or C 1-2 NR is an alkyl group a R b or -S(O) 0-2 R a R b , and Each is a halo, cyano, hydroxy, and C. 1-2 Alkyl, C1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, C 2-3 Alkenil, NR a R b , and -S(O) 0-2 R a R b C is optionally substituted with one or more substituents selected from the following: 2-3 Alkenil, C 2-3 Alkinyl, C 3-8 Cycloalkyl, aryl, heterocyclic group, heteroaromatic group, bicyclic C 5-12 Cycloalkyl Selected from; iv) or R 8a and R 8b They bond together, and together with the nitrogen atom they bond to, they form halo, cyano, hydroxy, and C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 2-3 Alkenil, NR a R b , and -S(O) 0-2 R a R b A monocyclic or bicyclic heterocyclic group is formed which is optionally substituted with one or more substituents selected from R a and R b H or C 1-4 It is alkyl; X is [ka] Selected from, In the formula, the dotted line indicates the bond location to Y, and the wavy line indicates the bond location to the rest of the molecule; R c and R d Independently, hydrogen and C 1-4 Selected from alkyl groups, C 1-4 Alkyl includes halo, hydroxy, cyano, and C. 1-4Optionally substituted with one or more substituents selected from the group consisting of alkoxys; R e and R f These are independently hydrogen, halo, hydroxyl, and C. 1-4 Selected from alkyl groups, C 1-4 Alkyl includes halo, hydroxy, cyano, and C. 1-4 Optionally substituted with one or more substituents selected from the group consisting of alkoxys; R c R d and R e R f They bond together, and together with the carbon atoms to which they bond, they form halo, methylcyano, hydroxy, and C 1-4 C is optionally substituted with one or more substituents selected from the group consisting of alkoxys. 3-4 They may also form cycloalkanediyl; Y is selected from one of the following structures i) to v): [ka] During the ceremony, G1 is CR h and selected from N, R h These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Alkyl, C 2-4 Alkenil, C 2-4 Alkinyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl groups, 5- or 6-membered heteroaromatic groups, 3- to 4-membered heterocyclic groups, and -OC 3-4 Selected from cycloalkyl groups; G2 is N and CR g Selected from, here, R g These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenil, C 2-4Alkynyl, phenyl, 5-membered or 6-membered heteroaromatic group, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic group, -O- (carbon-linked heterocyclic group), -(OCH2CH2) m -NR y R z ,-(OCH2CH2) m -OCH3, NR y R z , and -C(O)-NR y R z Selected from, In the formula, m is an integer from 1 to 6, and R y and R z These are hydrogen and C, respectively, independently. 1-4 Alkyl, C 3-6 It is a cycloalkyl group, a 3-6 membered carbon-linked heterocyclic group, or R y and R z They bond together with the nitrogen atom to which they bond, forming a 3- to 6-membered heterocyclic group; Furthermore, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenil, C 2-4 Alkynyl, phenyl, 5-membered or 6-membered heteroaromatic group, C 3-6 Cycloalkyl, -OC 3-6 One of the cycloalkyl, heterocyclic, and -O- (carbon-linked heterocyclic) groups is hydroxy, cyano, halo, or C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, NR a R b , or -S(O) 0-2 R a R b Optionally substituted with one or more substituents selected from R a and R b H or C 1-2 It is alkyl; G3 is N or CR i And R i is hydrogen, hydroxyl, cyano, halo, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl, and -OC 3-6 Selected from cycloalkyl, C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted with one or more substituents selected from halo, methyl, and methoxy; G4 is selected from C and N; G5 is CR j and NR x Selected from, in the formula, R j These are hydrogen, hydroxyl, cyano, halo, and C. 1-4 Alkyl, NH2, and C 1-4 Selected from alkoxy, R x is hydrogen and C 1-4 Selected from alkyl groups; G7 is N, NR a , or CR j And, G8 is selected from C and N. However, four or fewer of G1 to G8, preferably one, two, or three, must be N or NR. a is; [ka] Y2 is CR k and selected from N, R k These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 3-4 Cycloalkyl groups, 3-4 membered heterocyclic groups, and C 3-4 Selected from cycloalkoxys; Y3 is N or CR l And here, R l These are hydrogen, hydroxyl, cyano, halo, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C3-6 Cycloalkyl, and -OC 3-6 Selected from cycloalkyl, where C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted with one or more substituents selected from halo, methyl, and methoxy; Y4 is either C or N. Y5 is CR m or NR x And in the formula, R m These are hydrogen, halo, hydroxy, cyano, and C. 1-4 Alkyl, NH2, and C 1-4 Selected from alkoxy; R x is hydrogen and C 1-4 Selected from alkyl groups; Y6 is CR m or N; Y7 is O, S, CR m , or N; Y8 is either C or N; Y9 is CR m or N; However, four or fewer of Y1 to Y8 are N; [ka] X1 is N or CR n And R n These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 Selected from haloalkoxys; X2 is N or CR n and; X3 is N; X4 is N or C; X5 is N, CR n , and CR n R n1 Selected from, in the formula, R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; X6 and X7 are independently CR n Or it is N; or X6 is CR n R n1 Or NR x And X7 is CR n R n1 CR o R o1 , or NR x and; R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; R x is hydrogen or C 1-4 It is alkyl; R o and R o1 These are independently selected from hydrogen, halo, methoxy, and methyl; X8 is N, CR n , or CR n R n1 And R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; X9 is either N or C; However, at least four of X2 to X9 are N; [ka] L1~L7 can be N or CR independently. n And R n These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C1-4 Selected from haloalkoxys, However, no more than three of L1 to L7 represent N; [ka] E1 is either CR1 or N; E2 is either CR2 or N; E3 is either CR3 or N; E4 is either CR4 or N. E5 is either CR5 or N; E6 is NR6 or CR 6a R 6b And, In the formula, R1, R2, R3, R4, R5, R 6a , and R 6b These are independently hydrogen and NR. y1 R y2 , Halo, Cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR x1 R x2 Selected from, here R x1 and R x2 R is independently selected from hydrogen and methyl, y1 and R y2 These independently form a 5-membered or 6-membered heterocyclic group with a nitrogen atom selected from hydrogen and methyl, or together with the nitrogen atom bearing them. R6 is hydrogen and C 1-4 Selected from alkyl groups; Alternatively, R5 and R4 bond together, forming a 5-membered or 6-membered heterocyclic group with the atom they bond to (therefore, [ka] However, in reality, it forms a bicyclic system in which one aromatic ring and one heterocyclic group with 5 or 6 members are fused together. Alternatively, R4 and R3 bond together with the atoms they bond to to form a 5-membered or 6-membered heterocyclic group (therefore, [ka] However, in reality, it forms a bicyclic system in which one aromatic ring and one heterocyclic group with 5 or 6 members are fused together. Here, the 5-membered or 6-membered heterocyclic group is cyano, hydroxy, halo, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, NR y1 R y2 , or -S(O) 0-2 R y1 R y2 Optionally substituted with one or more substituents selected from R y1 and R y2 is H or C 1-2 It is alkyl; However, no more than three of E1 to E5 represent N.

[0012] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable carrier.

[0013] In another aspect, the present invention relates to a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) described herein, for use as a drug, in particular a drug having METTL3 inhibitory activity.

[0014] In another aspect, the present invention relates to a composition comprising a compound of formula (I) as defined herein, or a compound of formula (I) described herein, for use in the treatment or prevention of cancer, autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases.

[0015] The present invention also relates to the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) described herein, for the treatment or prevention of cancer, autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases.

[0016] The present invention also relates to the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for the manufacture of a pharmaceutical product intended for the treatment or prevention of cancer, autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases.

[0017] The present invention also relates to a method for treating or preventing cancer, autoimmune diseases, neurological diseases, infections, or inflammatory diseases, comprising administering to a person in need an effective amount of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein.

[0018] It is understood that this invention encompasses only stable compounds. Those skilled in the art will be able to distinguish between definitions that result in unstable compounds and definitions that result in stable compounds.

[0019] definition In this specification, the term "comprise" and any variations thereof, such as "comprising" and "comprises," are not intended to exclude other components or processes.

[0020] As used herein, the term "hydrogen" includes any isotope of hydrogen, such as deuterium.

[0021] In this specification, the term "hydroxy" refers to -OH, and the term "cyano" refers to -CN.

[0022] In this invention, the term "halogen" refers to a fluorine, bromine, chlorine, or iodine atom, preferably a chlorine or fluorine atom.

[0023] In this invention, the term "halo" refers to a fluoro, bromo, chloro, or iodine group, preferably a chloro or fluoro group.

[0024] The term "C" used in this invention 1-x"Alkyl" refers to a monovalent saturated hydrocarbon chain, either linear or branched, containing 1 to x carbon atoms. Therefore, C 1-6 Alkyl compounds contain 1 to 6 carbon atoms and are not limited to these, but include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

[0025] The term "C" used in this invention 1-x "Alkanediyl" refers to, but is not limited to, a linear or branched divalent saturated hydrocarbon chain containing 1 to x carbon atoms, and includes methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, etc.

[0026] The term "C" used in this invention 1-x "Haloalkyl" is defined as C as described above. 1-x This refers to an alkyl group in which at least one halogen atom, preferably at least one fluorine atom, is substituted. A specific example may be a trifluoromethyl group.

[0027] The term "C" used in this invention 1-x "Hydroxyalkyl" is defined as C as defined above. 1-x This refers to a molecule in which an alkyl group is replaced by a single hydroxyl group.

[0028] The term "C" used in this invention 2-x "Alkenyl" refers to, but is not limited to, a linear or branched monounsaturated hydrocarbon chain containing 2 to x carbon atoms and having at least one double bond, including ethenyl, propenyl, and butenyl.

[0029] The term "C" used in this invention 2-x "Alkynyl" refers to a linear or branched monounsaturated hydrocarbon chain containing 2 to x carbon atoms and having at least one triple bond, and is not limited to, but includes ethynyl, propynyl, and butynyl.

[0030] The term "C" used in this invention 1-x "Alkoxy" is defined as C as described above. 1-x This refers to a group in which an alkyl group is bonded to a molecule via an oxygen atom, and is not limited to this group, but includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc.

[0031] The term "C" used in this invention 1-x "Haloalkoxy" is defined as C as described above. 1-x This refers to a group in which an alkoxy group is substituted with at least one halogen atom, preferably at least one fluorine atom. A specific example may be a trifluoromethoxy group.

[0032] "C" used in the present invention x-y The term "cycloalkyl" or "x-y member cycloalkyl" refers to, but is not limited to, a monovalent monocyclic hydrocarbon ring having x-y carbon atoms, including cyclopropyl, cyclopentyl, and cyclohexyl.

[0033] "C" used in the present invention x-y The term "cycloalkanediyl" or "x-y member cycloalkanediyl" refers to, but is not limited to, a divalent monocyclic hydrocarbon ring having x-y carbon atoms, and includes cyclopropyl, cyclopentyl, and cyclohexyl.

[0034] The "two-ring type C" used in the present invention 5-x The term "cycloalkyl" refers to a bicyclic hydrocarbon ring having 5 to x carbon atoms and containing two bonded rings. This includes spirocyclic compounds, condensed bicyclic compounds, and bridged bicyclic compounds.

[0035] "C" used in the present invention x-y The term "cycloalkyloxy" refers to the C defined above. x-yThis term refers to a group in which a cycloalkyl group is bonded to a molecule via an oxygen atom, and is not limited to such groups, but includes cyclopropoxy or cyclobutyloxy.

[0036] As used in this invention, the term "heterocyclic group" refers to a monocyclic or bicyclic ring that is saturated or unsaturated, but not aromatic, having 3 to 12 ring atoms and containing at least one heteroatom, preferably 1, 2, 3, or 4 heteroatoms in the ring. The bicyclic heterocyclic group may be a fused, bridging, or spirocyclic compound. Spirocyclic compounds include C 3-6 The material contains a monocyclic heterocyclic group spirocondensed with a cycloalkyl group. Preferably, each ring of the heterocyclic group contains 3 to 6 ring atoms. The heteroatoms are preferably selected from O, N, P, and S, and more preferably selected from O, N, and S. The S atom may be oxidized or dioxidized, i.e., the sulfur atom may be S, S(O), or SO2, preferably S. The phosphorus atom may be oxidized, i.e., the phosphorus atom may be P or P(O). Examples of heterocyclic groups, though not limited to them, include epoxides, azilidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydropyranyl, tetrahydropyridinyl, dihydrooxazinyl, benzothiadinyl, benzothiadinyl, indolyl, isoindolinyl, 1,4-azaphosfinan-4-oxide, and 3-aza-bicyclo[3.1.0]hexane.

[0037] C 3-6 The heterocyclic group formed by spirocondensation with a cycloalkyl group is C 3-6 It is understood as a spirocyclic compound containing a heterocyclic group fused with a cycloalkyl group.

[0038] The term "heterocyclic oxy" as used in this invention refers to a group in which the heterocyclic group defined above is bonded to a molecule via an oxygen atom, and includes, but is not limited to, oxetanoxy.

[0039] As used in this invention, the term "aryl" refers to an aromatic hydrocarbon group comprising one or more fused rings, preferably containing 6 to 10 carbon atoms, such as a phenyl or naphthyl group. Advantageously, it is a phenyl group.

[0040] As used in the present invention, the term “heteroaromatic group” refers to an aromatic group comprising one or more, particularly one or two, fused hydrocarbon rings, wherein one or more, particularly one to four, preferably one or two carbon atoms, are each substituted with heteroatoms selected from sulfur, oxygen, and nitrogen atoms. It may be furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl, or indyl.

[0041] As used in this invention, the term "N-protecting group" refers to a group intended to protect an amine functional group (particularly a primary amine functional group) from undesirable reactions in a synthetic procedure. Commonly used N-protecting groups are disclosed in "Greene's Protective Groups In Organic Synthesis," 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey. The amine functional group protected by the N-protecting group may be a carbamate, amide, sulfonamide, N-alkyl derivative, aminoacetal derivative, N-benzyl derivative, imine derivative, enamine derivative, or N-heteroatom derivative. In particular, the N-protecting group is an aryl such as formyl; phenyl, which can be optionally substituted with one or more methoxy groups such as p-methoxyphenyl (PMP); an aryl-(C1-C6)alkyl such as benzyl, in which the aryl group is optionally substituted with one or more methoxy groups such as benzyl (Bn), p-methoxybenzyl (PMB), or 3,4-dimethoxybenzyl (DMPM); or a CO-R such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz), or p-methoxybenzylcarbonyl (Moz). PG1 -CO2-R such as butyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz or Z), or 9-fluorenylmethyloxycarbonyl (Fmoc). PG1 -SO2-R such as phenylsulfonyl, tosyl (Ts or Tos), or 2-nitrobenzenesulfonyl (also called nosyl-Nos or Ns). PG1 It can be, Here, R PG1This represents a (C1-C6) alkyl group that can be optionally substituted with one or more halogen atoms such as F or Cl; a (C2-C6) alkenyl group such as allyl; an aryl group such as phenyl that can be optionally substituted with one or more groups selected from OMe (methoxy) or NO2 (nitro); an aryl-(C1-C6) alkyl group such as benzyl, in which the aryl group can be optionally substituted with one or more methoxy groups; or a 9-fluorenylmethyl group.

[0042] In particular, it can be a t-butyloxycarbonyl group, a benzyloxycarbonyl group, or a fluorenylmethyloxycarbonyl group.

[0043] Those skilled in the art are familiar with Lewis acids and Brønsted acids. Examples of Lewis acids include aluminum chloride, zinc chloride, and silver chloride. Examples of Brønsted acids include hydrochloric acid, trifluoroacetic acid, and acetic acid. Those skilled in the art can select an appropriate Lewis acid or Brønsted acid depending on the properties of the starting molecule and the desired result, and for this purpose, they can refer to "Greene's Protective Groups In Organic Synthesis," 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.

[0044] formula [ka] [ka] The white circles indicate aromatic rings. Also, the dotted lines... " [ka] The symbol " indicates the bonding position to X.

[0045] formula [ka] In this diagram, the dotted circle indicates an aromatic or unsaturated ring. " [ka] The symbol " indicates the bonding position to X.

[0046] In addition, in this invention, Me represents methyl, Ph represents phenyl, Et represents ethyl, Ac represents acetyl, SEM represents 2-(trimethylsilyl)ethoxymethyl, and TMS represents trimethylsilyl. More generally, the abbreviations used refer to chemical groups that have meanings commonly known in the art.

[0047] For the purposes of this invention, the term "pharmaceutically acceptable" means useful in the preparation of pharmaceutical compositions and generally safe and non-toxic in pharmaceutical use. [Modes for carrying out the invention]

[0048] 1. Compound of formula (I) A1~A6 According to a particular embodiment, R 1a ~R 6a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 Represents a cycloalkyloxy or a 3-5 membered heterocyclic oxy, and the C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl groups, 3-5 membered heterocyclic groups, C3-4 cycloalkyloxy groups, or 3-5 membered heterocyclic oxy groups are, respectively, cyano, hydroxy, halo, and C. 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C3-6 Cycloalkyl, and OC 3-6 It is optionally substituted with one or more substituents selected from cycloalkyl groups.

[0049] According to another specific embodiment, R 1a , R 2a , R 4a and R 5a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 Represents a cycloalkyloxy or a 3-5 membered heterocyclic oxy, Said C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 Cycloalkyloxy, or 3-5 membered heterocyclic oxy, are respectively cyano, hydroxy, and halo. -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2,-CO2H,-CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, and OC 3-6 Optionally substituted with one or more substituents selected from cycloalkyl groups; R 3a and R 6a Each of these independently represents hydrogen, halo, or cyano, and is preferably hydrogen.

[0050] According to another specific embodiment, R 1a , R 2a , R 4a and R 5aThese are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Represents an alkoxy, and the C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Each of the alkoxys is cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl), -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl and C 1-4 Optionally substituted with one or more substituents selected from haloalkyl groups; R 3a and R 6a Each of these independently represents hydrogen, halo, or cyano, and is preferably hydrogen.

[0051] According to another specific embodiment, R 1a , R 2a and R 5a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 R represents alkoxy. 4a These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Represents an alkoxy, and the C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Each of the alkoxys is cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2,-CO2H,-CO2(C1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl and C 1-4 Optionally substituted with one or more substituents selected from haloalkyl groups; R 3a and R 6a Each of these independently represents hydrogen, halo, or cyano, and is preferably hydrogen.

[0052] To have an advantage, R 1a ~R 6a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 These represent cycloalkyl, 3-5 membered heterocyclic groups, C3-4 cycloalkyloxy, or 3-5 membered heterocyclic oxy groups, all of which are cyano, hydroxy, halo, and C. 1-4 Alkoxy, C l-4 Haloalkoxy, C 1-4 Alkyl, C l-4 Haloalkyl, C 3-6 Cycloalkyl, and OC 3-6 It may be substituted with one or more substituents selected from cycloalkyl groups. Preferably, R 1a These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 These represent cycloalkyloxy or 3- to 5-membered heterocyclic oxy groups, all of which are cyano, hydroxy, halo, and C. 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, and -OC 3-6 It is optionally substituted with one or more substituents selected from cycloalkyl groups.

[0053] Preferably, R 1a These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 3-5 membered heterocyclic group, C 3-4 These represent cycloalkyloxy or 3- to 5-membered heterocyclic oxy groups, all of which are cyano, hydroxy, halo, and C. 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, and -OC 3-6 It may be optionally substituted with one or more substituents selected from cycloalkyl groups; more preferably, hydrogen, hydroxyl, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is a haloalkoxy; R 2a These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Represents a haloalkoxy; R 3a represents hydrogen, halo, or cyano; R 4a is hydrogen, halo; cyano; one or more -OH or C 1-4 C arbitrarily substituted with alkoxy 1-4 Alkyl; C 1-4 Haloalkyl; 1 or more -OH, C 1-4 C optionally substituted with alkoxy or -CONH2 1-4 Alkoxy; or C 1-4 Represents haloalkoxy; especially R 4a These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Represents a haloalkoxy; R5a These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, or 3-5 membered heterocyclic group, C 3-4 Cycloalkyloxy represents a 3- to 5-membered heterocyclic oxy group, and these all have the prefixes cyano, hydroxy, and C. l-4 Alkoxy, Halo, C l-4 Haloalkoxy, C 3-6 Cycloalkyl, or -OC 3-6 Optionally substituted with one or more substituents selected from cycloalkyl groups; preferably hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Represents a haloalkoxy; R 6a represents hydrogen, halo, or cyano.

[0054] According to a particular embodiment, R 1a ~R 6a These are independently hydrogen, hydroxyl, halo, cyano, and C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Represents an alkoxy, and the C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 The alkoxys are cyano, hydroxy, halo, -C(O)NH2, and -C(O)NH(C) respectively. 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2,-CO2H,-CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl and C 1-4 Optionally substituted with one or more substituents selected from haloalkyl groups; in particular, hydrogen, hydroxyl, halo, cyano, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Represents haloalkoxy, Preferably, R 1a is hydrogen, hydroxyl, halo, C 1-4 Alkyl, or C 1-4 Represents alkoxy; R 2a These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Represents a haloalkoxy; R 3a represents hydrogen, halo, or cyano; R 4a These are hydrogen, halo, cyano, 1-tera-OH, or C 1-4 C arbitrarily substituted with alkoxy 1-4 Alkyl, C 1-4 Haloalkyl, one or more -OH or C 1-4 C optionally substituted with alkoxy or -CONH2 1-4 Alkoxy, or C 1-4 Represents a haloalkoxy; R 5a is hydrogen, hydroxyl, halo, C 1-4 Alkyl, or C 1-4 Represents alkoxy; R 6a represents hydrogen, halo, or cyano.

[0055] According to a particular embodiment, R 1a ~R 6a These are independently hydrogen, hydroxyl, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 Represents a haloalkoxy, preferably, R 1a is hydrogen, hydroxyl, halo, or C 1-4 Represents alkoxy; R 2a These are hydrogen, halo, cyano, and C. 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 3a represents hydrogen, halo, or cyano; R 4a represents hydrogen, halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; R 5a represents hydrogen, hydroxy, halo, or C 1-4 alkoxy; R 6a represents hydrogen, halo, or cyano.

[0056] Preferably, among A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , the number of those representing N is two or less. Preferably, among A 1 , A 2 , A 3 , and A 4 , the number of those representing N is 0, 1, or 2.

[0057] In particular, A 1 represents CR 1a or N, A 2 represents CR 2a or N, A 3 represents CR 3a or N, A 4 represents CR 4a or N, A 5 represents CR 5a or N, A 6 represents CR 6a or N; A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 , the number of those representing N is 0, 1, or 2, and preferably, A1 、A 2 、A 3 、and A 4 provided that the number of those representing N is 0, 1 or 2; Preferably, R 1a ~ R 6a are each independently hydrogen, hydroxy, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy; preferably R 2a 、R 3a 、R 4a and R 6a each represent hydrogen, and R 1a and R 5a are each independently hydrogen, hydroxy, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, or C 1-4 haloalkoxy.

[0058] In certain embodiments, none of A 1 、A 2 、A 3 、A 4 、A 5 or A 6 represents N.

[0059] In certain embodiments, only one of A 1 、A 2 、A 3 、A 4 、A 5 and A 6 preferably only one of A 1 、A 2 、A 3 、and A 4 represents N.

[0060] In certain embodiments, two of A 1 、A 2 、A 3 、A 4 、A 5 and A 6 represent N, preferably A1 , A 2 , A 3 , and A 4 Two of these represent N. In this embodiment, the following part is N: · A1 and A3, or · A2 and A3, or A2 and A4, or · A2 and A6, or A3 and A4, or A3 and A6, or A4 and A6, or A4 and A5, or A5 and A6.

[0061] To have an advantage, [ka] The following: [ka] Selected from, In particular, R 1a ~R 6a Each of these independently produces hydrogen, hydroxyl, halo, cyano, and C. 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 These represent alkoxys, and these C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Alkoxy includes cyano, hydroxy, halo, -C(O)NH2, and -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2,-CO2H,-CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl and C 1-4 Optionally substituted with one or more substituents selected from haloalkyl groups; in particular, hydrogen, hydroxyl, halo, cyano, C 1-4Haloalkyl, C 1-4 Haloalkoxy, one or more -OH or C 1-4 Alkyl optionally substituted with C 1-4 Alkyl, or one or more -OH, C 1-4 Alkoxy, or C optionally substituted with -CONH2 1-4 Is alkoxy; preferably, R 1a ~R 6a Each independently represents hydrogen, hydroxy, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkyl, or C 1-4 Represents alkoxy; in particular, R 2a R 3a R 4a And R 6a Each represents H, and R 1a And R 5a Each independently represents hydrogen, hydroxy, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, one or more -OH or C 1-4 Alkyl optionally substituted with C 1-4 Alkyl, or one or more -OH, C 1-4 Alkoxy, or C optionally substituted with -CONH2 1-4 Represents alkoxy.

[0062] Advantageously, the compound of formula (I) is a compound selected from the following formula:

Chemical formula

[0063] R 7a and R 7b To have an advantage, R 7a H is R 7b is hydrogen, or halo, cyano, hydroxy, C 1-4 Alkoxy, and C 1-4 C, optionally substituted with one or more substituents selected from haloalkoxys 1-6 Represents alkyl, and especially hydroxy, and C 1-4 Selected from alkoxy. Preferably, R 7a H is R 7b is hydrogen, or unsubstituted C 1-6 Alkyl or hydroxy and C 1-4 C substituted with one substituent selected from alkoxy 1-6 Represents alkyl; preferably, R 7a and R 7b Both are hydrogen.

[0064] R 8a and R 8b To have an advantage, R 8a H is R 8b is, formula - (CR c R d ) n -Z, for example -(CHR d ) n -Z(Example:-(CH2) n -Z) is the basis, and especially -CHR d-Z or -Z, for example, -CH2-Z or -Z, or R 8a and R 8b They bond together, and together with the nitrogen atom to which they bond, they form halo, cyano, hydroxy, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 2-3 Alkenil, NR a R b and -S(O) 0-2 R a R b Forming a monocyclic or bicyclic heterocyclic group which is optionally substituted with one or more substituents selected from, Preferably, the substituents are halo, hydroxy, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 2-3 Selected from Alkenil, In particular, one or more of the substituents are halo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-3 Alkenyl is selected, preferably C 1-4 Alkyl and C 2-3 Selected from alkenyls. Preferably, a monocyclic or bicyclic heterocyclic group is R 8a and R 8b It does not contain heteroatoms other than nitrogen atoms. Preferably, each ring in a monocyclic or bicyclic heterocyclic group contains 4, 5, 6, or 7 ring atoms.

[0065] Preferably, R a and R b H or C 1-4 It is alkyl.

[0066] Z is C 3-8 Cycloalkyl or bicyclic C 5-8They may also be cycloalkyl, and these are all halo, cyano, hydroxy, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, C 2-3 Alkenil, NR a R b , and -S(O) 0-2 R a R b Optionally substituted with one or more substituents selected from, for example, fluoro, halo, hydroxy, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, and C 1-2 It is optionally substituted by one or more substituents selected from haloalkoxys, particularly one or two substituents. In certain embodiments, Z is C 3-8 Cycloalkyl or bicyclic C 5-8 It is a cycloalkyl group, and each of them is C 1-2 Alkyl, C 1-2 It is optionally substituted with one or two substituents selected from halos such as hydroxyalkyl, hydroxy, and fluoro.

[0067] X and Y X is [ka] Selected from, preferably, [ka] Selected from, and more preferably, [ka] Selected from.

[0068] Y is typically selected from one of the following structures i) to iv): [ka] During the ceremony, G1 is CR h and selected from N, R h is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Selected from haloalkoxys; G2 is CR g And R g These are hydrogen, hydroxyl, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys, G3 is CR i And R i is hydrogen, cyano, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy and C 1-4 Selected from alkoxy, G4 is N; G5 is NH or CR j And R j is hydrogen, C 1-4 Alkyl, cyano, halo, OH, NH2, and C 1-4 Selected from alkoxy; G7 is CR j And, G8 is C, [ka] Y2 is CR k And; R k is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Selected from haloalkoxys; preferably Y2 is CH, Y3 is N or CR l And R l These are hydrogen, hydroxyl, cyano, halo, and C. 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Selected from alkoxys, preferably Y3 is N or CH. Y4 is either C or N. Y5 is CR m or NR x And here, R m is hydrogen, C 1-4 Alkyl, cyano, halo, OH, NH2 and C l-4 Selected from alkoxy, R x is hydrogen and C 1-4 Selected from alkyl groups; Preferably, Y5 is CH or NH. Y6 is CR m or N; preferably Y6 is CH, Y7 is CR m Preferably, Y7 is CH. Y8 is C; Y9 is CR m or N; preferably Y2 is CH or N, However, there are no more than 3 of Y2 to Y9 that are N; [ka] X2 is CR n and; X4 is N; X5 is CR n and CR n R n1 Selected from, in the formula, R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; X6 and X7 are independently CR n Is it; or is X6 CR n R n1 And X7 is CRn R n1 CR o R o1 , and NR x And here, R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; R x is hydrogen or C 1-4 Selected from alkyl groups; R o and R o1 These are independently selected from hydrogen, halo, methoxy, and methyl; X8 is CR n or CR n1 And here, R n and R n1 These are independently hydrogen, halo, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys; X9 is C; [ka] E1 is either N or CR1; E2 is N; E3 is either N or CR3; E4 is CR4; E5 is either N or CR5; In the formula, R1, R2, R3, R4, R5, R 6a , and R 6b In particular, hydrogen and NR are used independently of each other. y1 R y2 , Halo, Cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(C) 1-4Alkyl)2,-SO2CH3,-NHC(O)CH3,-C(O)NR x1 R x2 , and C optionally substituted with OH 3-4 Selected from cycloalkyl groups, Here, R x1 and R x2 Independently, hydrogen and C 1-4 Selected from alkyl groups (e.g., methyl), R y1 and R y2 Independently, hydrogen and C 3-6 Cycloalkyl, or C 3-6 C optionally substituted with cycloalkyl groups 1-4 Selected from alkyl (e.g., methyl), or R y1 and R y2 These may form a 5-membered heteroaromatic group or heterocyclic group with the N that holds them, and the 5-membered heteroaromatic group or heterocyclic group may be OH, C 1-4 Alkoxy, or OH or C 1-4 C arbitrarily substituted with alkoxy 1-4 The heterocyclic group is optionally substituted with alkyl, and is either a monocyclic heterocyclic group with 4 to 7 members, or a bicyclic heterocyclic group with 3 to 6 members in each ring. Alternatively, R4 and R3 bond together with the atom they bond to to form a 5-membered or 6-membered heterocyclic group, and this 5-membered or 6-membered heterocyclic group is oxo, cyano, hydroxy, halo, or C. 1-2 Alkyl, C 1-2 Cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, NR y1 R y2 or -S(O) 0-2 R y1 R y2 (In the formula, R y1 and R y2 is H or C 1-2 It is optionally substituted with one or more substituents selected from alkyl groups.

[0069] In particular, Y has the following structure: [ka] You may choose from the following: In the formula, R 1 , R 2 , and R 3 This is as described above or below, E7 is either O or CH2. R 3 They can represent H independently, or together as two R's. 3’ The substituent is an oxo group (=O) or C 3-5 Represents cycloalkyl, R 4’ They can represent H independently, or together as two R's. 4’ The substituent is an oxo group (=O) or C 3-5 This represents a cycloalkyl group.

[0070] In some embodiments, Y has the following structure: [ka] Selected from, E1 is CR1; E2 is N; E3 is CR3; E4 is CR4; E5 is CR5; In the formula, R1, R2, R3, R4, R5, R 6a , and R 6b These are, independently, hydrogen, NH2, halo, cyano, and C. 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 Selected from, here, R x1 and R x2 This includes hydrogen and methyl, as well as NR y1 R y2 Selected independently from, R y1 and R y2These, together with the N atoms that carry them, form a 5-membered or 6-membered heterocyclic group.

[0071] Y can be selected from one of the following structures i) to iv): [ka] especially, R h is hydrogen, halo, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Selected from haloalkoxys, preferably H, R g is hydrogen, halo, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Selected from haloalkoxys, preferably H or C 1-4 It is an alkoxy, R i is hydrogen, halo, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Selected from haloalkoxys, preferably H, R j These are, independently, hydrogen, halo, hydroxyl, and C. 1-4 Alkyl and C 1-4 Selected from alkoxys, preferably H, and R x is hydrogen and C 1-4 Selected from alkyl groups, preferably H; [ka] especially, R k These are, independently, hydrogen, halo, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4Selected from haloalkoxys, preferably H, R m These are, independently, hydrogen, halo, hydroxyl, and C. 1-4 Alkyl and C 1-4 Selected from alkoxy, preferably H, R x These are hydrogen and C, respectively, independently. 1-4 Selected from alkyl groups, preferably H; [ka] In particular, R n These are, independently, hydrogen, halo, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 Selected from haloalkoxys, preferably H; [ka] R1, R3, R4, and R5 are advantageously selected independently from hydrogen, NH2, and NH-methyl, respectively, wherein the methyl is C 3-6 Cycloalkyl, NH-C 3-6 Cycloalkyl, halo, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)Me2, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 , and C optionally substituted with OH 3-4 It is optionally substituted with a cycloalkyl group, where R x1 and R x2 These are independently hydrogen and methyl and NR y1 R y2 Selected independently from, R y1 and R y2Together with the N supporting them, they form a 5-membered heteroaromatic group or a 5- to 9-membered heterocyclic group, and the 5-membered heteroaromatic group or 5- to 9-membered heterocyclic group may be optionally substituted with OH, -CH2OCH3, or -CH2OH, or R4 and R3 bond together to form a heterocyclic group with the atom to which they bond, and this heterocyclic group is C 3-6 It is spirocondensed with cycloalkyl groups and / or oxo, cyano, hydroxy, halo, C 1-2 Alkyl, C 3-6 Cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, NR y1 R y2 , or -S(O) 0-2 R y1 R y2 Substituted with one or more substituents selected from R y1 and R y2 is H or C 1-2 It is alkyl; In particular, R1, R3, R4, and R5 are each independently hydrogen, NR y1 R y2 Hello, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkyl and C 1-4 Selected from haloalkyl groups.

[0072] Y can also be selected from one of the following structures i) to iv): [ka] especially R h , R g , R i , and R j These are, independently, hydrogen, halo, hydroxyl, and C. 1-4 Selected from alkoxy, preferably H, R x is hydrogen and C 1-4 Selected from alkyl groups, preferably H; [ka] especially R k These are, independently, hydrogen, halo, and C. 1-4 Selected from alkoxy, preferably H, R m These are independently hydrogen, halo, hydroxyl, and C. 1-4 Selected from alkoxy, preferably H, R x is hydrogen and C 1-4 Selected from alkyl groups, preferably H; [ka] In particular, R n These are, independently, hydrogen, halo, and C. 1-4 C 1-4 Selected from alkoxys, preferably H; [ka] In particular, R4 is hydrogen, NR y1 R y2 Hello, C 1-4 Alkoxy, and C 1-4 Selected from alkyl groups, preferably NR y1 R y2 or C 1-4 It is an alkoxy.

[0073] Preferably, Y is [ka] Selected from.

[0074] To the advantage of Y, [ka] Selected from.

[0075] In a particular embodiment, XY is [ka] That is the case.

[0076] XY also [ka] But that's fine.

[0077] In some embodiments, the compound of formula (I) is preferably, [ka] In the formula, R4a is typically methyl, methoxy, or -CH2OH.

[0078] The compound of formula (I) is, in particular, selected from compounds Co.1 to Co.145 as defined herein or in the claims, for example, a compound selected from compounds Co.1 to Co.42, or a tautomer, stereoisomer, salt, solvate, or N-oxide thereof.

[0079] Tautomers, stereoisomers, salts, solvates, and n-oxides The compounds of formula (I) described herein may exist in tautomer or stereoisomer forms, i.e., diastereomer or enantiomer forms. The present invention encompasses all such compounds and includes cis-diastereomers and trans-diastereomers, E- and Z-stereomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, racemic mixtures thereof, and other mixtures thereof.

[0080] In this invention, the term "tautomer" refers to structural isomers of chemical compounds that readily interconvert. As an example, compounds containing an amide group (-C(=O)-NH-) and an imido acid group (-C(OH)=N-), respectively, are tautomers with the following structures. [ka]

[0081] The term "stereoisomer" as used in this invention refers to stereoisomers of stereoconfiguration and includes geometric isomers and optical isomers. Geometric isomers, also called E / Z isomers or cis-trans isomers, are due to differences in the position of substituents on a double C=C bond, which can have a Z configuration or an E configuration, also called a cis or trans configuration. Optical isomers are due to differences in the spatial arrangement of substituents or lone pairs on an atom (such as a carbon atom or a sulfur atom) containing four different substituents (which may include lone pairs). Therefore, this atom represents a chiral center or a chiral center. Optical isomers that are not mirror images of each other are called "diastereomers," and optical isomers that are mirror images of each other but cannot be superimposed are called "enantiomers."

[0082] The compounds of the present invention may be in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt.

[0083] As used herein, the term "pharmaceutically acceptable salt or solvate" means a salt or solvate of a pharmaceutically acceptable compound as defined above, which has the pharmacological activity of the corresponding compound.

[0084] The type of salt is not particularly limited, as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds used in this method can be prepared from inorganic or organic acids. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from compounds classified as aliphatic, alicyclic, aromatic, aromatic aliphatic (alaliphatic), heterocyclic (heterocyclic and heteroaromatic groups), carboxylic acids, and sulfonic acids. Examples of organic acids include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, emonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid. All of these salts can be prepared by conventional means from the corresponding compounds, for example, by reacting a suitable acid with one of the compounds of the present invention.

[0085] Acceptable solvates for therapeutic use of the compounds of the present invention include conventional solvates, such as those formed in the presence of a solvent during the final step of preparation of the compounds of the present invention. Examples include solvates formed in the presence of water (these solvates are also called hydrates) or solvates formed in the presence of ethanol.

[0086] The compounds of the present invention may also be in the form of N-oxides, that is, in a form in which the nitrogen atom of the compound is oxidized.

[0087] 2. Method for preparing the compound of formula (I) The compounds of the present invention are obtained by a process for producing a compound represented by formula (I) as defined herein, comprising the following sequence of steps: -Formula (IIa): [ka] A process of replacing an intermediate halogen-lithium, represented by A 1 , A 2 , A 3 , A 4 , A 5 , A 6 X and Y are as defined herein and may optionally be in a protective form, and this exchange is typically carried out using butyllithium in a polar aprotic solvent such as tetrahydrofuran. Next, R, which is defined in any of claims 1 to 10 and may optionally be a form of protection 7a and R 7b Saddle type R 7a R 7b Adding a -C=O ketone, equation (IIb): [ka] The process of obtaining the alcohol represented by, -By subjecting the alcohol of formula (IIb) above to nucleophilic substitution with an azide ion precursor, we obtain formula (IIc): [ka] A step to obtain an azide, wherein the azide ion precursor is, for example, trimethylsilyl azide, and the step is carried out in the presence of a Lewis acid, such as boron trifluoride, particularly boron trifluoride etherate. - Under Staudinger conditions, particularly in the presence of water and triarylphosphines such as triphenylphosphine, the azide of formula (IIc) is reduced to formula (IId): [ka] The process of obtaining the amine, - A step of obtaining a compound of formula (I) as defined herein by functionalization of an amine of formula (IId).

[0088] The final functionalization may include, for example: At a minimum, an alkylation step using a compound of formula R8a-Hal or R8b-Hal, where Hal represents a halogen, preferably Cl, Br, or I, and R8a and R8b are as defined herein. and / or at least one reductive amination step.

[0089] In certain embodiments, the compounds of the present invention can be obtained by a process for preparing a compound of formula (I) as defined herein, comprising the following sequence of steps: -Formula (II): [ka] The intermediate represented by is defined in any of claims 1 to 10 and may optionally be in a protected form R 8a and R 8b Saddle type R 8a R 8b A step of reductive amination with an amine using an amine of -NH, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a X and Y are as defined herein and may optionally be in the form of protection. Optionally, a step of deprotecting a group in a protected form in order to obtain a compound of formula (I); and Optionally, a step of chlorinating the compound of formula (I) to obtain a salt of the compound of formula (I).

[0090] Alternatively, the present invention relates to a step for preparing a compound of formula (I) as defined herein, wherein the compound is of formula (III) or (IV): [ka] The intermediate can be obtained by a coupling step with a reagent of formula Y-K'', where Y is as defined in any of claims 1 to 10, and may optionally be in a protected form. Here, A 1 , A 2 , A 3 , A 5 , A 6 , R 7a , R 7b , R 8a , R 8b Rc, Rd, Re, and Rf are as defined in any of claims 1 to 10, and are optionally forms of protection. K and K' are defined as follows: [Table 1]

[0091] Those skilled in the art are familiar with the above-mentioned protecting groups and forms of protection, as well as methods of protection and deprotection using such groups, and can refer to the textbook "Greene's Protective Groups In Organic Synthesis," 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.

[0092] R 7b H is and X is [ka] In an embodiment in which this is the case, the process may include the following: a) Nitrile of formula (II): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a This is defined herein as follows: R and R' are independent of C1-2 C that is substituted with or not substituted with alkoxy 1-4 Alkyl or combined with 1 to 4 C 1-2 Alkoxy or C 1-2 Crosslinked C, optionally substituted with alkyl groups. 1-2 (Forms alkylenyl) Reducing this, we get equation (III): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a (As defined above in relation to formula (II), PG is an N-protecting group), The process of obtaining the amine, b) Using a Lewis acid or Brønsted acid, deprotect the acetal or ketal group (C(OR)(OR')) of the amine of formula (III) under acidic conditions to obtain formula (IV): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7a , and PG are as defined above in relation to formula (III). A process to obtain the corresponding aldehyde or ketone, c) An aldehyde or ketone of formula (IV), formula (V):R 8a R 8b When subjected to reductive amination with an amine represented by -NH, formula (VI): [ka] (In the formula, R 8a and R 8b (This is defined herein.) The process of obtaining an intermediate (in the formula: A1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , and PG are defined with respect to formula (IV) above, and R 8a and R 8b (This is as defined with respect to equation (V) above), d) Deprotecting the intermediate of equation (VI), we obtain equation (VII): [ka] (In the formula: A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 8a , and R 8b (This is as defined with respect to equation (VI) above.) The process of obtaining the amine, e) A step of subjecting the amine of formula (VII) to a peptide coupling with the carboxylic acid of formula (IX):Y-COOH (wherein Y is as defined herein), or a') By ​​reducing the nitrile group of the compound of formula (II) as defined above, we obtain formula (III'): [ka] The process of obtaining the amine (wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a (This is as defined with respect to equation (II) above), b') The amine of formula (III') is peptide-coupled with the aldehyde of formula (X):Y-COOH (wherein Y is as defined herein) to form formula (XI): [ka] The process of obtaining an intermediate (in the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a (where is defined as in equation (III) above, and Y is defined as in equation (X) above), c') Using a Lewis acid or Brønsted acid, the acetal or ketal group (C(OR)(OR')) of the intermediate of formula (XI) is deprotected under acidic conditions to obtain formula (XII): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , and Y are as defined with respect to equation (XI) above. The process of obtaining the corresponding aldehyde or ketone represented by: d') The aldehyde or ketone of formula (XI) is given by formula (V):R as defined above. 8a R 8b -A step of reductive amination of NH(V) with an amine,

[0093] Peptide coupling is advantageously carried out in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), hexafluorophosphate 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (TBTU), tetrafluoroborate 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium (TBTU), and hexafluorophosphate O(7-azobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium (HAT). The peptide coupling is, for example, U), (benzotriazole-1-yloxy)tripyrolodinophosphonium hexafluorophosphate (PyBOP), or propylphosphonic anhydride; the peptide coupling is optionally carried out in the presence of an additive or base, such as N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazole (HOOBt), 1-hydroxy-7-azabenzotriazole (HAt), N-hydroxysylphosuccinimide (sulfoNHS), dimethylaminopyridine (DMAP), diisopropylethylamine (DIEA), or N-methylmorpholine (NMM).

[0094] R 7b H is and X is [ka] In this embodiment, the process may include the following: a'') Deprotect the acetal or ketal group of the nitrile of formula (II) defined above to obtain formula (XIII): [ka] (In the formula, A 1 , A 2 , A 3 , A4 , A 5 , A 6 , and R 7a (This is as defined above with respect to equation (II).) A process to obtain the corresponding aldehyde or ketone, b'') An aldehyde or ketone of formula (XIII) as defined herein by R 8a and R 8b Formula (V):R 8a R 8b -NH(V) is subjected to reductive amination with an amine, resulting in formula (XIV): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and R 7a As defined above with respect to equation (II), R 8a and R 8b (This is defined as described herein.) The process of obtaining an intermediate, c'') Reducing the intermediate of equation (XIV), we get equation (XV): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 8a , and R 8b (This is as defined above with respect to equation (XIV)). The process of obtaining an intermediate, d'') The intermediate of formula (XV) is subjected to the activation step, followed by nucleophilic substitution with sodium azide, resulting in formula (XVI): [ka] (In the formula, A 1 , A 2, A 3 , A 4 , A 5 , A 6 , R 7a , R 8a , and R 8b (This is as defined above with respect to equation (XIV)). The process of obtaining the corresponding azid, e'') A step of subjecting an azide of formula (XVI) to a [3+2] cycloaddition with an alkyne of formula (XVII): H-≡-Y(XVII) (where Y is as defined herein), or Reducing the intermediate of equation (II) defined above, we get equation (XVIII): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a The process of obtaining an intermediate (alcohol) of formula (II) as defined above, The intermediate b''')(XVIII) is subjected to an activation step, followed by nucleophilic substitution with sodium azide to obtain formula (XIX): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a (This is as defined above with respect to equation (II).) The process of obtaining the corresponding azid, c''') The azide of formula (XIX) is subjected to a [3+2] cycloaddition with the alkyne of formula (XVII) defined above, and formula (XX): [ka] (In the formula, A 1, A 2 , A 3 , A 4 , A 5 , A 6 , R, R', and R 7a (wherein Y is as defined above with respect to formula (II), and Y is as defined herein.) The process of obtaining an intermediate, d''') Deprotect the acetal or ketal group of the intermediate of formula (XX) to obtain formula (XXI): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', R 7a , and Y are as defined above with respect to equation (XX). The process of obtaining the corresponding intermediate, The step of subjecting the intermediate of formula (XXI) to reductive amination with the amine of formula (V) defined above.

[0095] X [ka] In an embodiment in which this is the case, the process may include the following: a'''') Equation (XXII): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a , and PG are as defined herein, and Hal represents a halogen atom, preferably Cl or Br. A step of subjecting the compound to a palladium coupling reaction (e.g., a Morander reaction), wherein the palladium coupling reaction includes a reaction with a [(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)methyl]trifluoroboron derivative such as potassium [(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)methyl]trifluoroboronide, Next, a deprotection reaction is carried out, typically involving the addition of ethylenediamine and an alcohol such as propanol, resulting in formula (XXIII): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a (and PG are as defined herein) A step to obtain a compound represented by, b'''') A step of obtaining a compound of formula (I) as described herein by subjecting a compound of formula (XXIII) to a peptide coupling with a carboxylic acid of formula (IX): Y-COOH (wherein Y is as defined herein).

[0096] Typically, the palladium catalyst used in the palladium coupling of step a''') is Pd(dba)2.

[0097] R 8b In embodiments where is H, the process may include the following: a''''') formula (XXIV): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R7b (X and Y are as defined herein) The compound is reacted with 2-nitrobenzenesulfonyl chloride (nosilchloride) to produce formula (XXV): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b X and Y are as defined herein, and Ns represents a nosyl group. The process of obtaining a nosyl-protected intermediate, b''''') Nosyl-protected intermediate of formula (XXV), formula R 8a =O(in the formula, R 8a The Fukuyama-Mitsunobu reaction with an aldehyde (as defined herein) is performed using formula (XXVI): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b X and Y are as defined herein, and Ns represents a nosyl group. The process of obtaining an intermediate, c''''') Deprotecting the nosyl group in the presence of thiophenol, formula (XXVII): [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a(X and Y are as defined herein) The process of obtaining the compound.

[0098] The reaction conditions for the nosyl deprotection step c'''''') are known in the art.

[0099] 3. Pharmaceutical Compositions The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and a pharmaceutically acceptable carrier.

[0100] The pharmaceutically acceptable carrier is selected from typical excipients known to those skilled in the art, depending on the desired dosage form and route of administration.

[0101] The pharmaceutical composition of the present invention can be administered enterally (e.g., orally, sublingually, cheek, rectally, vaginally, etc.), parenterally (e.g., subcutaneously, intramuscularly, intravenously, intraocularly, intraperitoneally, intracranially, intrathecally, etc.), or topically (e.g., transdermally), preferably by oral or intravenous administration. The active ingredient can be administered to animals, preferably mammals including humans, in the form of a dosage unit mixed with a conventional pharmaceutical carrier.

[0102] For oral administration, the pharmaceutical composition may be in solid or liquid form (solution or suspension).

[0103] Solid compositions can be in the form of tablets, capsules, powders, granules, etc. In the case of tablets, the active ingredient may be mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, or gum arabic before being compressed into tablets. Tablets may be further coated with sucrose or other suitable materials, or they may be treated in a manner that provides sustained-release or delayed-release properties. In the case of powders or granules, the active ingredient may be mixed or granulated with a dispersant, wetting agent, or suspending agent, and a flavoring agent or sweetener. In the case of capsules, the active ingredient may be introduced into soft capsules or hard capsules in the form of powders or granules as described above, or in the form of liquid compositions as described later.

[0104] Liquid compositions (including gels) can contain active ingredients in a solvent such as water, together with sweeteners, flavor enhancers, or suitable colorants. Alternatively, liquid compositions may be obtained by suspending or dissolving powders or granules in a liquid such as water, juice, or milk, as described above. Liquid compositions can be, for example, syrups or elixirs.

[0105] For sublingual administration (when applied under the tongue) or buccal administration (when applied between the gums and cheek), the pharmaceutical composition may be in solid or liquid form (solution or suspension).

[0106] The solid composition may be in the form of tablets, gelatin capsules, powders, or granules as defined above, particularly for oral administration. It may also be in the form of a film.

[0107] The liquid composition may be as previously defined for oral administration. The liquid composition may be administered in the form of a spray or drops.

[0108] For rectal or vaginal administration, suppositories or oval formulations can be prepared using a base that melts at rectal or vaginal temperature, such as cocoa butter or polyethylene glycol.

[0109] For parenteral administration, the composition may be in the form of an aqueous suspension or aqueous solution that may contain a dispersant, wetting agent, or suspending agent. The composition is preferably sterile. It may be in the form of an isotonic solution.

[0110] The amount of the compound used in the preparation of a single-dose composition by combining the compound of the present invention with a carrier material varies depending on the subject (test subject) and the route of administration, and this is well known to those skilled in the art.

[0111] The pharmaceutical composition of the present invention may further contain another therapeutic compound, preferably another anticancer agent (or chemotherapeutic agent).

[0112] The compounds or pharmaceutical compositions of the present invention may also have therapeutic applications in combination with immunomodulators, such as inhibitors of the PD1 / PDL1 immune checkpoint axis, including antibodies (or peptides) that inhibit and / or the activity of PD-1 (e.g., nivolumab, pembrolizumab, cemiplimab, dostarlimab) or PD-L1 (e.g., atezolizumab, avelumab, durvalumab). The compounds or pharmaceutical compositions of the present invention may also be used in combination with radiotherapy or chemotherapy agents as standard treatment. The compounds may also be used in combination with BCL2 inhibitors (e.g., venetoclax).

[0113] The compounds or pharmaceutical compositions according to the present invention can also be combined with other agents that stimulate or enhance the immune response, such as vaccines.

[0114] 4-Therapeutic uses The present invention further relates to the use of the compounds or pharmaceutical compositions of the present invention as pharmaceuticals, particularly as pharmaceuticals having METTL3 inhibitory activity.

[0115] This drug is particularly useful in treating or preventing cancer, or autoimmune diseases, neurological disorders, infections, or inflammatory diseases, and is typically useful in treating cancer.

[0116] The compound or pharmaceutical composition of the present invention can be used as a drug in combination therapy with radiotherapy or in combination therapy with immunostimulants such as vaccines.

[0117] The present invention further, - Composition of the present invention; - A second composition comprising at least another therapeutic compound; and - Preferably instructions for using the kit. Regarding kits that include, The aforementioned kit is a combination product of drugs used simultaneously, individually, and with time delays, and is particularly useful as a drug with METTL3 inhibitory activity, especially in the treatment or prevention of cancer, or autoimmune diseases, neurological diseases, infections, or inflammatory diseases, and is typically useful in the treatment of cancer.

[0118] The present invention further relates to a method for preventing or treating a condition associated with the oncogenic activity of METTL3, comprising the step of administering an effective amount of the compound, composition, or kit of the present invention to a patient in need of such treatment.

[0119] In particular, the aforementioned conditions include cancer, autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases, and are typically cancer.

[0120] This method may further include combination therapy with radiotherapy or immunostimulants such as vaccines.

[0121] The "effective amount" of the compound of the present invention varies as a function of numerous parameters, such as the route of administration, body weight, age, sex, the progression of the disease being treated, and the sensitivity of the subject or patient being treated.

[0122] In this specification, "patient" or "subject" includes any mammal, preferably human.

[0123] Examples of autoimmune diseases include rheumatoid arthritis and Graves' disease.

[0124] Examples of infectious diseases include viral infections (e.g., SARS-CoV-2, HIV, hepatitis viruses), bacterial infections (e.g., Clostridium perfringens), fungal infections (e.g., Fusarium infection), and parasitic infections (e.g., Toxoplasma gondii).

[0125] Examples of neurological disorders include fragile X syndrome and Alzheimer's disease.

[0126] Examples of inflammatory diseases include inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0127] In some embodiments, inhibition of METTL3 by the compounds of the present invention may be useful in the treatment or prevention, particularly in the treatment, of the following, but not limited, cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic malignancies, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumor, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma. More specifically, the cancers are lung cancer, melanoma, head and neck cancer, esophageal cancer, bladder cancer, and urothelial carcinoma, liver cancer, kidney cancer, prostate cancer, and hematopoietic malignancies.

[0128] Examples of cancers that can be treated or prevented, particularly those that can be treated, include, but are not limited to, the following: Acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, intralymphatic sarcoma, angiosarcoma), appendiceal cancer, benign monoclonal ganmovopathy, biliary tract cancer (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., mammary gland cancer, papillary carcinoma, medullary mammary carcinoma), brain tumor (e.g., meningioma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, rectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endosarcoma ( Examples: Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer [e.g., oral squamous cell carcinoma (OSCC)], pharyngeal cancer [e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer]), hematopoietic malignancies (e.g., leukemia [e.g., acute lymphoblastic leukemia (ALL)]). )(e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (B-cell CLL, T-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) B-cell NHL (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)) )), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., MALT lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenström macroglobulinemia), immunoblastic large cell lymphoma, pilocytic cell leukemia (HCL), precursor B-lymphoblastic lymphoma, primary central nervous system (CNS) lymphoma;and T-cell NHL (precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma)), mixed forms of the above leukemia / lymphomas; multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, μ-chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocellular amyloidosis, renal cell carcinoma (e.g., nephrocyte Froblastoma (Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., primary lung cancer, non-small cell lung cancer (NSCLC), squamous cell lung cancer, lung adenocarcinoma, Lewis's lung cancer, pulmonary neuroendocrine neoplasms (typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), large cell neuroendocrine carcinoma)), leiomyosarcoma (LMS), systemic mastocytosis, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative neoplasms (MPD) (e.g., polycythemia (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), chronic bone marrow Leukemia luteum (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannomatosis), neuroendocrine tumors (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian germ cell tumors, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pineal gland tumor, undifferentiated neuroectodermal tumor (PNET), prostate Adenocarcinoma (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratosinosarcoma (KA), malignant melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial sarcoma, testicular cancer (e.g., seminomas, testicular germ cell tumor), thyroid cancer (e.g., papillary carcinoma [papillary thyroid carcinoma (PTC)], medullary thyroid carcinoma), urethral cancer, vaginal cancer, vulvar cancer (e.g., Paget's disease of the vulva). [Examples]

[0129] The following examples are provided purely for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

[0130] Materials and methods Several methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise specified, all starting materials were obtained from commercially available sources and used without further purification. Those skilled in the art may also synthesize these starting materials using well-known methods.

[0131] In this specification, "℃" means degrees Celsius; "A" means angstrom; "aq." means aqueous solution; "BiCl3" means bismuth trichloride; "Boc" means tert-butoxycarbonyl; "Boc2O" means di-tert-butyldicarbonate; "Celite(R)" means diatomaceous earth; "Co." means compound; "CO" means carbon monoxide; "CoCl2·6H2O" means cobalt(II) chloride hexahydrate; "Cs2CO3" means cesium carbonate; "CuSO4" means copper(II) sulfate; "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene; "DCM" means dichloromethane; "DIAD" means diisopropyl azodicarboxylate; "DIBAL-H" means diisobutylaluminum hydride; "DIPEA" means N,N-diisopropylethylamine; "DMA" means dimethylacetamide; "DMF" means N,N-dimethylformamide; "DMSO" means dimethyl sulfoxide "Side" means; "DPPA" means diphenylphosphoryl azide; "DPPF" means 1,1'-ferrocenediylbis(diphenylphosphine); "SiO" means ethyl acetate; "EtOH" means ethanol; "h" means time; "HATU" means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate; "HCl" means hydrogen chloride; "HCO2NH4" means ammonium formate "H2O" means water; "HPLC" means high-performance liquid chromatography; "Int." means intermediate; "KOAc" means potassium acetate; "K2CO3" means potassium carbonate; "LC" means liquid chromatography; "LCMS" means liquid chromatography-mass spectrometry; "M" means mol / L; "MeCN" means acetonitrile; "MeOH" means methanol; "MgSO4" means magnesium sulfate; "min" means minute; "mp" means" represents the melting point; "N2" represents nitrogen; "Na2CO3" represents sodium carbonate; "NaBH4" represents sodium borohydride; "NaHB(OAc)3" represents sodium triacetoxybrohydride; "NH4Cl" represents ammonium chloride; "NaHCO3" represents sodium bicarbonate; "NaOH" represents sodium hydroxide; "NH4HCO3" represents ammonium bicarbonate; "Ni" represents nickel; "." n "BuLi" means n-butyllithium; "NH3" means ammonia; "NaOMe" means sodium methoxide; "Pd(dppf)Cl2" means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; "Pd(dppf)Cl2·DCM" means the dichloromethane adduct of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; "Pd(OAc)2" means palladium(II) acetate; "PPh3" means triphenylphosphine; "prep." means for preparation; "quant." means quantitative determination; "rbf" means round-bottom flask; "rt" means room temperature; "s" means seconds; "SEM-Cl" means 2-(trimethylsilyl)ethoxymethyl chloride; "TsOH" means p-toluenesulfonic acid; t "AmOH" means tert-amyl alcohol; t "BuXPhosPd G3" means [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; t"BuXPhos" means 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; "TEA" means triethylamine; "TFA" means trifluoroacetic acid; "TLC" means thin-layer chromatography; "THF" means tetrahydrofuran; "TMEDA" means N,N,N',N'-tetramethylethylenediamine; "TMS" means trimethylsilyl; "XPhosPd G3" means (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; and "Zn(CN)2" means zinc cyanide.

[0132] Preparation of intermediates Synthesis of Intermediate 1: [ka] 6-Bromo-2-chloro-3-quinoline carboxaldehyde (4 g, 14.8 mmol), ethyl orthoformate (4.38 g, 29.6 mmol, 4.92 mL), and p-toluenesulfonic acid monohydrate (56 mg, 0.3 mmol) were suspended in dry ethanol (15 mL) at room temperature. The resulting reaction mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, and volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane / ethyl acetate = 100:0 to 90:10) to obtain intermediate 1 (3.5 g, yield 69%) as a white solid.

[0133] Synthesis of intermediate 2: TMAF t AmOH TMAF·4H2O (1.7g, 10.3 mmol) t It was dissolved in AmOH (50 mL). Activated 3 Å molecular sieves (7.5 g) were added to this solution, and the resulting slurry was stirred at room temperature for 24 hours. The slurry was filtered, tThe mixture was washed with AmOH (4 mL x 3). The filtrate and washing solution were combined and concentrated under reduced pressure to obtain intermediate 2 (2.8 g, yield 145%) as a white, viscous solid. This material is residual. t Due to the presence of AmOH, the yield exceeded the quantitative threshold, so it was used directly in the next process without further purification.

[0134] Synthesis of intermediate 3: [ka] Intermediate 1 (3.5 g, 10.3 mmol) and intermediate 2 (2.8 g, 15.4 mmol) were added under ambient air. Dry DMSO (51 mL) was added, and the resulting reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was cooled to room temperature, and the residue was partitioned between ethyl acetate and saline. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:[DCM / ethyl acetate=3 / 1]=100:0~85:15) to obtain intermediate 3 (2.9 g, yield 87%) as a colorless oil.

[0135] Synthesis of intermediate 4: [ka] Preparation of degassed aqueous solution: A rbf containing water (22 mL) was sealed with a septum. The rbf was placed in an ultrasonic bath filled with water, the pressure was reduced for 5 seconds, and then nitrogen gas was refilled. This procedure was repeated 5 times. The resulting degassed water was added to an rbf containing KOAc (110 mg, 1.12 mmol) using a syringe under an N2 atmosphere.

[0136] t BuXPhosPd G3 (142mg, 0.18mmol), tBuXPhos (76 mg, 0.18 mmol), potassium hexacyanoferrate(II) trihydrate (1.89 g, 4.47 mmol), and intermediate 3 (2.9 g, 8.93 mmol) were added to a Schlenk tube equipped with a magnetic stirrer. The vial was evacuated and purged with nitrogen three times. The above-mentioned KOAc (110 mg, 1.12 mmol) was dissolved in water (22 mL) and dioxane (22 mL) and added to the vial. The resulting reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The residue was washed once with saline solution (the aqueous layer turned dark blue). The aqueous layer was further extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by silica gel chromatography (elution with heptane:ethyl acetate = 100:0 to 90:10) to obtain intermediate 4 (2.0 g, yield 82%) as a white solid.

[0137] Synthesis of intermediate 5: [ka] Intermediate 4 (500 mg, 1.82 mmol) and Boc2O (1.19 g, 5.47 mmol) were dissolved in SiO (17 mL) and EtOH (17 mL), to which Raney nickel H2O slurry (500 mg) was added. The reaction mixture was stirred at 4 bar under a hydrogen (H2O) atmosphere at room temperature for 12 hours. Next, Boc2O (398 mg, 1.82 mmol) was added, followed by Raney nickel H2O slurry (500 mg), and the reaction mixture was stirred at 4 bar under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through a Celite(R) pad and washed with SiO. The filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel chromatography (elution at heptane:SiO = 100:0 to 75:25) to obtain intermediate 5 (497 mg, yield 72%) as a colorless oil.

[0138] Synthesis of intermediate 6: [ka] Intermediate 5 (500 mg, 1.32 mmol) was dissolved in MeCN (5.5 mL) and water (0.13 mL). BiCl3 (83 mg, 0.26 mmol) was added to the solution and the mixture was stirred at 55°C for 1 hour. After the reaction was complete, volatile components were removed under reduced pressure to obtain intermediate 6 (405 mg, quantitative yield) as a pale yellow solid. This intermediate 6 was used in the next step without further purification.

[0139] Synthesis of intermediate 7: [ka] Intermediate 6 (837 mg, 2.75 mmol), 4,4-dimethylpiperidine hydrochloride (494 mg, 3.3 mmol), and TEA (835 mg, 8.25 mmol, 1.15 mL) were mixed in DCM (28 mL) and stirred at room temperature for 10 minutes (until completely dissolved). Then, NaBH(OAc)3 (1.17 g, 5.50 mmol) was added all at once. The reaction mixture was stirred at room temperature for 16 hours. After removing volatile components under reduced pressure, the residue was partitioned between saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer was further washed once with saturated aqueous NaHCO3 solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel chromatography (elution at heptane:ethyl acetate = 100:0 to 50:50) to obtain intermediate 7 (537 mg, yield 49%) as a white solid.

[0140] Synthesis of intermediate 8 (HCl salt): [ka] Intermediate 7 (180 mg, 0.45 mmol) was dissolved in 1,4-dioxane (1 mL), and HCl (4 M in dioxane) (177 mg, 4.48 mmol, 1.12 mL) was added to the solution (this solution precipitated). The resulting suspension was stirred at room temperature for 4 hours. Volatile components were removed under reduced pressure to obtain intermediate 8 (154 mg, yield 92%) as a yellow solid. This intermediate was used in the next step without further purification.

[0141] Synthesis of intermediate 9: [ka]

[0142] a) Synthesis of intermediate 10: [ka] 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.52 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (4.53 g, 13.9 mmol) and SEM-Cl (2.32 g, 13.9 mmol, 2.47 mL) were added to the solution. The reaction mixture was stirred at room temperature for 64 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution with heptane:ethyl acetate = 100:0 to 80:20) to obtain intermediate 10 (281 mg, yield 34%) as a colorless oil.

[0143] b) Synthesis of intermediate 11: [ka] A solution of intermediate 10 (267 mg, 0.81 mmol), Pd(PPh3)2Cl2 (114 mg, 0.16 mmol), and DIPEA (315 mg, 2.44 mmol, 0.43 mL) dissolved in MeOH (2.7 mL) was heated overnight at 100°C under a carbon monoxide (10 bar) atmosphere. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel chromatography (elution at heptane:ethyl acetate = 100:0 to 60:40) to obtain intermediate 11 (232 mg, yield 93%) as a yellow solid.

[0144] c) Synthesis of intermediate 9: Intermediate 11 (232 mg, 0.75 mmol) was dissolved in MeOH (5.4 mL), and 1 M sodium hydroxide aqueous solution (1.36 mL, 1.36 mmol) was added to the solution. The resulting solution was stirred at room temperature for 2 hours. The pH was adjusted to 3 with 1 M hydrochloric acid aqueous solution. The precipitated solid was collected by filtration, and intermediate 9 (218 mg, quantitative yield) was obtained as a yellow solid.

[0145] Synthesis of intermediate 13: [ka] Intermediate 4 (0.91 g, 3.33 mmol) was dissolved in SiO2 (33 mL) and EtOH (33 mL), to which Raney nickel H2O slurry (1 g) was added. The reaction mixture was stirred at 4 bar under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered through a Celite pad and washed with SiO2. The filtrate was concentrated under reduced pressure to obtain intermediate 13 (837 mg, 90% yield) as a colorless oil. This intermediate was used directly in the next step without further purification.

[0146] Alternatively, to reduce the amount of dimeric by-products, intermediate 13 was prepared by the method described below.

[0147] Intermediate 4 (710 mg, 2.59 mmol) was dissolved in EtOH (11.8 mL) and the solution was stirred at 0°C. Cobalt chloride hexahydrate (924 mg, 3.88 mmol) was added at 0°C, followed by NaBH4 (490 mg, 12.9 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, then poured into saturated sodium carbonate aqueous solution, and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 13 (703 mg, quantitative yield) as a yellow oily substance. This intermediate was used directly in the next step without further purification.

[0148] Synthesis of intermediate 14: [ka] Intermediate 13 (735 mg, 2.64 mmol), 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (502 mg, 2.64 mmol), and HATU (2 g, 5.28 mmol) were dissolved in DMF (6.6 mL) to which DIPEA (683 mg, 5.28 mmol, 0.92 mL) was added. The resulting solution was stirred at room temperature for 20 hours. Water was added, and the residue was extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:(siRNA / MeOH=3 / 1)=100:0 to 60:40) to obtain intermediate 14 (725 mg, yield 30%) as a pale yellow solid.

[0149] Synthesis of intermediate 15: [ka] Intermediate 14 (360 mg, 0.8 mmol) was dissolved in acetonitrile (4 mL) and water (0.08 mL). Bismuth chloride (50.4 mg, 0.16 mmol) was added to the solution and the mixture was stirred at 55°C for 1 hour (until the starting material was consumed). After confirming the completion of the reaction by TLC, volatile components were removed under reduced pressure to obtain intermediate 15 (310 mg, quantitative yield) as a pale yellow solid. This intermediate was used directly in the next step without further purification.

[0150] Synthesis of intermediate 16: [ka] At room temperature, 6-bromo-2-chloro-7-methoxyquinoline-3-carbaldehyde (7.6 g, 25.2 mmol), ethyl orthoformate (11.2 g, 75.6 mmol, 12.6 mL), and p-toluenesulfonic acid monohydrate (96 mg, 0.504 mmol, 0.09 mL) were dissolved in ethanol (25 mL). The resulting reaction mixture was heated under reflux for 22 hours. After the reaction, volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:ethyl acetate = 100:0 to 85:15) to obtain intermediate 21 (7.8 g, yield 86%) as a white solid.

[0151] Synthesis of intermediate 17: [ka] Intermediate 17 was prepared using intermediate 16 (1.45 g, 3.87 mmol) and intermediate 2 (1 g, 5.81 mmol) as starting materials, following the same procedure as the preparation method for intermediate 3, to obtain intermediate 44 (1.4 g, yield 97%) as a white solid.

[0152] Synthesis of intermediate 18: [ka] Intermediate 18 was prepared using intermediate 17 (1.35 g, 3.77 mmol) as the starting material, following the same procedure as the preparation method for intermediate 4, to obtain intermediate 18 (840 mg, yield 73%) as a white solid.

[0153] Synthesis of intermediate 19: [ka] Intermediate 18 (781 mg, 2.57 mmol) was dissolved in EtOH (11.7 mL), and CoCl2·6H2O (916 mg, 3.85 mmol) was added (the solution turned blue). Then, NaBH4 (515 mg, 13.6 mmol) was added at 0°C (the solution turned black). The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was poured into a saturated aqueous Na2CO3 solution. The residue was extracted twice with ELISA (the layers turned purple). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 19 (579 mg, yield 73%) as a colorless oil. This intermediate was used in the next step without further purification.

[0154] Synthesis of intermediate 20: [ka] Intermediate 20 was prepared using intermediate 19 (289 mg, 0.94 mmol) as the starting material, following the same procedure as the preparation method for intermediate 14, to obtain intermediate 20 (354 mg, yield 79%) as a white solid.

[0155] The following intermediates were prepared using the same procedure. [Table 2]

[0156] Synthesis of intermediate 22: [ka] Intermediate 22 was prepared starting from intermediate 20 (100 mg, 0.208 mmol) following the same procedure as the preparation of intermediate 15, yielding intermediate 22 (85 mg, yield: quantitative) as a pale yellow solid. This intermediate was used directly in the next step without further purification.

[0157] The following intermediates were prepared using a similar procedure. [Table 3]

[0158] Synthesis of intermediate 24: [ka] 6-Bromo-2-chloro-7-methoxyquinoline-3-carbaldehyde (155 mg, 0.52 mmol), 4,4-dimethylpiperidine hydrochloride (85 mg, 0.57 mmol), and TEA (157 mg, 1.55 mmol, 0.22 mL) were mixed in DCM (4.7 mL), and the mixture (heterogeneous reaction mixture) was stirred at room temperature for 10 minutes. Then, sodium triacetoxyburohydride (219 mg, 1.03 mmol) was added all at once. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the residual solvent was removed under reduced pressure. The mixture was dissolved in saturated aqueous NaHCO3 and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by silica gel chromatography (elution with heptane:ethyl acetate = 100:0 to 85:15) to obtain intermediate 24 (146 mg, yield 34%) as a white powder.

[0159] Synthesis of intermediate 25: [ka] Intermediate 25 was prepared starting from intermediate 24 (146 mg, 0.37 mmol) and following the same procedure as the preparation method for intermediate 3 described above, yielding intermediate 25 (82 mg, yield 59%) as a pale yellow solid.

[0160] Synthesis of intermediate 26: [ka] Intermediate 26 was prepared starting from intermediate 25 (60 mg, 0.16 mmol) following the same procedure as the preparation method for intermediate 4 described above, yielding intermediate 26 (28 mg, yield 54%) as a pale yellow solid.

[0161] Synthesis of intermediate 27: [ka] Intermediate 26 (10 mg, 30.5 μmol) and Boc2O (20 mg, 0.092 mmol) were dissolved in ethyl acetate (0.28 mL) and ethanol (0.28 mL). To these solutions, Raney nickel H2O slurry (10 mg) was added. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere at 5 bar. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain intermediate 27 (13 mg, quantitative).

[0162] Synthesis of intermediate 28 (HCl salt): [ka] To a solution of dioxane (100 μL) containing intermediate 27 (13 mg, 30.6 μmol), 4 M HCl (100 μL, 0.4 mmol) was added to the dioxane (the solution precipitated). The resulting reaction mixture was stirred overnight at room temperature. Volatile components were removed under reduced pressure to obtain the HCl salt of intermediate 28 (12.4 mg, quantitative yield) as a pale solid. This solid was used in the next step without purification.

[0163] Synthesis of intermediate 29: [ka] Following the procedure described for intermediate 24, intermediate 29 (575 mg, 60% yield) was obtained as a white solid using 6-bromo-2-chloro-7-fluoroquinoline-3-carbaldehyde (720 mg, 2.5 mmol) and 4,4-dimethylpiperidine hydrochloride (448 mg, 2.99 mmol) as starting materials.

[0164] Synthesis of intermediate 30: [ka] Following the procedure described for intermediate 3, intermediate 30 (342 mg, 63% yield) was obtained as a white solid using intermediate 29 (570 mg, 1.48 mmol) and intermediate 2 (536 mg, 2.96 mmol) as starting materials.

[0165] Synthesis of intermediate 31: [ka] Following the procedure described for intermediate 4, intermediate 31 (171 mg, 79% yield) was obtained as a pale yellow solid using intermediate 30 (253 mg, 0.69 mmol) as the starting material.

[0166] Synthesis of intermediate 32: [ka] Following the procedure described for intermediate 19, intermediate 32 (76 mg, 50% yield) was obtained as a yellow viscous solid using intermediate 31 (150 mg, 0.48 mmol) as the starting material. This solid was used in the next step without purification.

[0167] Synthesis of intermediate 33: [ka] Following the procedure described for intermediate 24, intermediate 33 (5.3 g, 79% yield) was obtained as a white solid using 6-bromo-2-chloro-3-formylquinoline (5 g, 18.5 mmol) and 4,4-dimethylpiperidine hydrochloride (3.32 g, 22.2 mmol) as starting materials.

[0168] Synthesis of intermediate 34: [ka] Following the procedure described for intermediate 3, intermediate 34 (4.4 g, 72% yield) was obtained as a pale yellow solid using intermediate 33 (6.5 g, 17.7 mmol) and intermediate 2 (7.92 g, 43.9 mmol) as starting materials.

[0169] Synthesis of intermediate 35: [ka] Under an N2 atmosphere, at -78°C, intermediate 34 (500 mg, 1.42 mmol) was dissolved in THF (15 mL) and nBuLi (0.98 mL, 1.57 mmol) was added (the solution turned reddish-brown). The solution was stirred at -78°C for 1 hour, and then DMF (208 mg, 2.85 mmol, 0.22 mL) was added. The solution was stirred at -78°C for 10 minutes, then raised to room temperature and stirred for 30 minutes. A 10% aqueous ammonium chloride solution was gradually added to the crude product, followed by the addition of RINKAN. The aqueous layer was separated and extracted twice with RINKAN. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:RINKAN = 100:0 to 50:50) to obtain intermediate 35 (362 mg, 85% yield) as a pale yellow solid.

[0170] Synthesis of intermediate 36: [ka] NaBH4 (55 mg, 1.45 mmol) was added to a solution of MeOH (10 mL) containing intermediate 35 (362 mg, 1.21 mmol), and the mixture was stirred at room temperature for 30 minutes. DCM and water were added to the crude product. The aqueous layer was separated and extracted twice with DCM. The resulting organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 36 (351 mg, 96% yield) as a yellow solid. This solid was used in the next step without purification.

[0171] Synthesis of intermediate 37: [ka] Under an N2 atmosphere, at 0°C, intermediate 36 (300 mg, 0.99 mmol) and DBU (151 mg, 0.99 mmol, 0.15 mL) were mixed in DMF (5.8 mL) under stirring. Diphenyl phosphoryl azide (273 mg, 0.99 mmol, 0.21 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with water. Depositphotos was then added, and the mixture was extracted twice with Depositphotos. The resulting organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluting with heptane: Depositphotos = 90:10 to 70:30) to obtain intermediate 37 (169 mg, 52% yield) as a colorless oil.

[0172] Synthesis of intermediate 38: [ka] Following the procedure described for intermediate 35, intermediate 38 (342 mg, 83% yield) was obtained as a white solid using intermediate 3 (485 mg, 1.48 mmol) as the starting material.

[0173] Synthesis of intermediate 39: [ka] Following the procedure described for intermediate 36, intermediate 39 (340 mg, 90% yield) was obtained as a white solid using intermediate 38 (363 mg, 1.31 mmol) as the starting material. This solid was used in the next step without purification.

[0174] Synthesis of intermediate 40: [ka] A mixture containing intermediate 39 (84 mg, 0.3 mmol) in THF (3.5 mL) was to which DIAD (128 mg, 0.63 mmol, 0.13 mL), PPh3 (166 mg, 0.63 mmol), and diphenylphosphoryl azide (174 mg, 0.63 mmol, 0.14 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:ethyl = 100:0 to 50:50) and further purified by reverse-phase chromatography (elution at MeCN / aqueous NH4HCO3 0.2% (pH=7.9) = 60:40 to 80:20) to obtain intermediate 40 (50 mg, 55% yield) as a colorless oil.

[0175] Synthesis of intermediate 41: [ka] A solution of intermediate 40 (193 mg, 0.63 mmol), 8-ethynylimidazo[1,5-a]pyridine (108 mg, 0.76 mmol), sodium ascorbate (151 mg, 0.76 mmol), and CuSO4 (20.2 mg, 0.13 mmol) in DMF (6.9 mL) / water (1.5 mL) was stirred at room temperature for 3 hours. The mixture was diluted with water and DCM. The organic layer was separated and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:(siRNA / MeOH=1 / 1)=100:0 to 60:40) to obtain intermediate 41 (196 mg, 69% yield) as a yellow solid.

[0176] Synthesis of intermediate 42: [ka] A solution of 8-chloroimidazo[1,5-a]pyrazine (262 mg, 1.706 mmol) in DMF (1.41 mL) was placed under an N2 atmosphere. Pd(PPh3)2Cl2 (71.9 mg, 0.10 mmol) and CuI (19.5 mg, 0.10 mmol) were added, and the mixture was purged under an N2 atmosphere for 5 minutes. TEA (309 mg, 3.05 mmol, 0.42 mL) and trimethylsilylacetylene (335 mg, 3.41 mmol, 0.49 mL) were added, and the reaction mixture was heated at 90°C for 1 hour. The mixture was cooled to room temperature, diluted with SiO, and filtered through a Celite pad. The filtrate was dried under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution with heptane: siRNA = 70:30 to 0:100) to obtain intermediate 42 (95 mg, 26% yield) as a yellow oily substance.

[0177] Synthesis of intermediate 43: [ka] K2CO3 (4.8 mg, 0.035 mmol) was added to a solution of MeOH (1.6 mL) containing intermediate 42 (75 mg, 0.35 mmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered, and the filtrate was partitioned between DCM and NH4Cl aqueous solution for extraction. The organic layer was dried using a Chromabond filter and concentrated under reduced pressure to obtain intermediate 43 (50 mg, quantitative yield) as a yellow solid. This solid was used in the next step without purification.

[0178] Synthesis of intermediate 44: [ka] Following the procedure described for intermediate 41, intermediate 44 (30 mg, 23% yield) was obtained as a yellow solid using intermediates 40 and 43 as starting materials.

[0179] Synthesis of intermediate 45: [ka] Intermediate 41 (100 mg, 0.22 mmol) was dissolved in MeCN (2.2 mL) and water (0.022 mL). BiCl3 (14 mg, 0.045 mmol) was added to the solution and the mixture was stirred at 55°C for 1 hour. Subsequently, BiCl3 (30 mg, 0.095 mmol) was added, and the reaction mixture was stirred at 55°C for another 1 hour. After confirming the completion of the reaction by TLC, volatile components were removed under reduced pressure to obtain intermediate 45 (80 mg, quantitative yield) as a pale yellow solid. This solid was used in the next step without purification.

[0180] The following intermediates were prepared using the same procedure. [Table 4]

[0181] Synthesis of intermediate 47: [ka] To a solution of intermediate 18 (600 mg, 1.97 mmol) in DCM (9.9 mL) at -78°C, DIBAL-H (2.37 mL, 2.37 mmol) was added dropwise. The reaction mixture was gradually heated to -15°C (the flask was placed above a dry ice / acetone bath) and stirred for 1 hour. After 1 hour, DIBAL-H (2.37 mL, 2.37 mmol) was added, and the reaction mixture was stirred at -15°C for another 1 hour. After 1 hour, DIBAL-H (2.37 mL, 2.37 mmol) was added to allow the reaction to proceed completely. The reaction mixture was cooled to -40°C and quenched by adding Rochelle salt solution. The resulting emulsion was heated to room temperature and vigorously stirred for 1 hour. DCM was added, and the residue was extracted twice with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution with heptane: siRNA = 100:0 to 85:25) to obtain intermediate 47 (306 mg, 51% yield) as a yellow solid.

[0182] Synthesis of intermediate 48: [ka] Following the procedure described for intermediate 36, intermediate 48 (265 mg, 86% yield) was obtained as a colorless oily substance using intermediate 47 (306 mg, 1 mmol) as the starting material.

[0183] Synthesis of intermediate 49: [ka] Following the procedure described for intermediate 37, intermediate 49 (186 mg, 65% yield) was obtained as a colorless oily substance using intermediate 48 (265 mg, 0.86 mmol) as the starting material.

[0184] Synthesis of intermediate 50: [ka] Following the procedure described for intermediate 41, intermediate 50 (153 mg, 64% yield) was obtained as a brown oily substance using intermediate 49 and 8-ethynylimidazo[1,5-a]pyridine as starting materials.

[0185] Synthesis of intermediate 51: [ka] Following the procedure described for intermediate 45, intermediate 51 (114 mg, quantitative yield) was obtained as a beige solid using intermediate 50 as the starting material.

[0186] Synthesis of intermediate 52: [ka] A mixture of anhydrous THF (27.2 mL) containing intermediate 33 (500 mg, 1.36 mmol) was degassed by bubbling N2 for several minutes. Subsequently, Pd(dppf)Cl2·DCM (222 mg, 0.27 mmol), TMEDA (269 mg, 2.31 mmol, 0.35 mL), and finally NaBH4 (87.5 mg, 2.31 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. The residue was suspended in saline and extracted with siRNA. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 96:4) to obtain intermediate 52 (255 mg, 56% yield) as a white solid.

[0187] Synthesis of intermediate 53: [ka] Following the procedure described for intermediate 4, intermediate 53 (131 mg, 66% yield) was obtained as a white solid using intermediate 52 (235 mg, 0.71 mmol) as the starting material.

[0188] Synthesis of intermediate 54: [ka] To a solution of 7MNH3 / MeOH (1 mL) containing intermediate 53 (110 mg, 0.39 mmol), 7MNH3 / MeOH (3 mL) containing Raney nickel H2O slurry (120 mg) was added. The resulting suspension was replaced under reduced pressure, backfilled with N2, and stirred overnight at room temperature under a 4 bar H2 atmosphere. The catalyst was filtered off with Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain intermediate 54 (64 mg, 57% yield) as a colorless oil. This oil was used in the next step without purification.

[0189] Synthesis of intermediate 55: [ka] Following the procedure described for intermediate 52, intermediate 55 (344 mg, 20% yield) was obtained as a white solid using intermediate 1 (1.89 g, 5.49 mmol) as the starting material.

[0190] Synthesis of intermediate 56: [ka] Following the procedure described for intermediate 4, intermediate 56 (188 mg, 84% yield) was obtained as a white solid using intermediate 55 (271 mg, 0.87 mmol) as the starting material.

[0191] Synthesis of intermediate 57: [ka] Following the procedure described for intermediate 54, intermediate 57 (175 mg, quantitative yield) was obtained as a white solid using intermediate 56 (175 mg, 0.69 mmol) as the starting material.

[0192] Synthesis of intermediate 58: [ka] Following the procedure described for intermediate 14, intermediate 57 (194 mg, 0.75 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (142 mg, 0.75 mmol) were used as starting materials to obtain intermediate 58 (86 mg, 27% yield) as a white solid.

[0193] Synthesis of intermediate 59: [ka] To a solution of chloroform (0.4 mL) containing intermediate 58 (86 mg, 0.2 mmol), TFA (273 mg, 2.39 mmol, 0.18 mL) was added at room temperature, and the resulting mixture was stirred for 15 hours. The reaction mixture was quenched with water and extracted three times with toluene. The combined organic layers were washed twice with brine, dried over magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain intermediate 59 (71 mg, quantitative yield) as a yellow oil. This oil was used in the next step without purification.

[0194] Synthesis of intermediate 60: [ka] To a solution of MeOH (3.9 mL) containing intermediate 33 (350 mg, 0.95 mmol), NaOMe (1.2 g, 6.66 mmol, 1.24 mL) was added, and the reaction mixture was stirred at 60°C for 6 hours. After confirming completion of the reaction by TLC, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water was added, the residue was extracted with DCM, dried over magnesium sulfate, and filtered to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 96:4) to obtain intermediate 60 (180 mg, 52% yield) as a white solid.

[0195] Synthesis of intermediate 61: [ka] Following the procedure described for intermediate 4, intermediate 61 (70 mg, 46% yield) was obtained as a white solid using intermediate 60 (180 mg, 0.5 mmol) as the starting material.

[0196] Synthesis of intermediate 62: [ka] Following the procedure described for intermediate 5, intermediate 62 (50 mg, 53% yield) was obtained as a white solid using intermediate 61 (70 mg, 0.23 mmol) as the starting material.

[0197] Synthesis of intermediate 63 (HCl salt): [ka] To a solution of DCM (0.44 mL) containing intermediate 62 (50 mg, 0.12 mmol), TFA (165 mg, 1.45 mmol, 0.1 mL) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. Subsequently, TFA (69 mg, 0.61 mmol, 45 μL) was added to the reaction mixture and stirred for 16 hours. The mixture was concentrated three times with 4 M HCl in dioxane to obtain intermediate 63 (50 mg, quantitative yield) as a white solid.

[0198] Synthesis of intermediate 64: [ka] Following the procedure described for intermediate 7, intermediate 64 (134 mg, 77% yield) was obtained as a white solid using 3-bromoquinoline-6-carbaldehyde (124 mg, 0.53 mmol) and 4,4-dimethylpiperidine hydrochloride (80 mg, 0.54 mmol) as starting materials.

[0199] Synthesis of intermediate 65: [ka] Following the procedure described for intermediate 4, intermediate 65 (139 mg, 42% yield) was obtained as a white solid using intermediate 64 (399 mg, 1.2 mmol) as the starting material.

[0200] Synthesis of intermediate 66: [ka] Following the procedure described for intermediate 54, intermediate 66 (7 mg, 12% yield) was obtained as a white solid using intermediate 65 (58 mg, 0.21 mmol) as the starting material.

[0201] Synthesis of intermediate 67: [ka] Dess Martinperiodinane (1.85 g, 4.37 mmol) was added at room temperature to a solution of (6-bromosinnolin-3-yl)methanol (870 mg, 3.64 mmol) in DCM (8.7 mL). The reaction mixture was then stirred at 40 °C for 16 hours. The mixture was filtered through a Celite® pad and washed with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane: siRNA = 100:0 to 50:50) to obtain intermediate 67 (673 mg, 78% yield) as a yellow solid.

[0202] Synthesis of intermediate 68: [ka] Following the procedure described for intermediate 7, intermediate 68 (390 mg, 41% yield) was obtained as a yellow oily substance using intermediate 67 (670 mg, 2.83 mmol) and 4,4-dimethylpiperidine hydrochloride (634 mg, 4.24 mmol) as starting materials.

[0203] Synthesis of intermediate 69: [ka] Potassium hexacyanoferrate(II) trihydrate (179 mg, 0.42 mmol), t BuXPhos (36 mg, 0.085 mmol), KOAc (41.6 mg, 0.42 mmol), and XPhosPd G3 (71.7 mg, 0.085 mmol) were added to a solution of dioxane (3.6 mL) / water (3.8 mL) containing intermediate 68 (283 mg, 0.85 mmol) at room temperature under an N2 atmosphere. Subsequently, the reaction mixture was degassed by bubbling with N2 for 15 minutes and heated at 100°C for 1 hour. The reaction mixture was cooled to room temperature and added to cold water. The aqueous layer was extracted with Â, the organic layers were washed together with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane:Â = 100:0 to 50:50) to obtain intermediate 69 (130 mg, 55% yield) as a yellow solid.

[0204] Synthesis of intermediate 70: [ka] Following the procedure described for intermediate 19, intermediate 70 (66 mg, 80% yield) was obtained as a yellow oily substance using intermediate 69 (81 mg, 0.29 mmol) as the starting material.

[0205] Synthesis of intermediate 72: [ka] Under an argon atmosphere, at -78°C, a solution of intermediate 15 (110 mg, 0.29 mmol) in DCM (2.8 mL) was mixed with 3 M methylmagnesium chloride in THF (0.12 mL, 0.35 mmol). The mixture was stirred at -78°C for 1 hour and then heated to room temperature over 17 hours. Saturated aqueous NH4Cl solution and DCM were added, and the organic layer was dried over sodium sulfate. After filtration, the mixture was concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 92:8) to obtain intermediate 72 (74 mg, 65% yield) as a yellow solid.

[0206] The following intermediates were prepared using the same procedure. [Table 5]

[0207] Synthesis of intermediate 74: [ka] Under an argon atmosphere at 0°C, TEA (46.4 mg, 0.46 mmol, 0.064 mL) and mesylchloride (70 mg, 0.61 mmol, 0.047 mL) were added to a solution of DCM (1 mL) containing intermediate 72 (60 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water and DCM were added, and the aqueous layer was extracted with DCM. The mixture was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 95:5) to obtain intermediate 74 (42 mg, 67% yield) as a yellow solid.

[0208] The following intermediates were prepared using the same procedure. [Table 6]

[0209] Synthesis of intermediate 76: [ka] To a solution of 4-amino-3-methoxybenzonitrile (2 g, 13.5 mmol) in AcOH (19.6 mL), 2,2,3-tribromopropanal (4.4 g, 14.9 mmol, 1.71 mL) was added, and the reaction mixture was stirred at 100 °C for 3 hours under an Ar atmosphere. The reaction mixture was dried under reduced pressure, the residue was dissolved in siRNA, washed with saturated aqueous NaHCO3 solution and brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (elution at c-Hex:siRNA = 95:5~0:100) to obtain intermediate 76 (1.4 g, 40% yield) as a yellow solid.

[0210] The following intermediates were prepared using the same procedure. [Table 7]

[0211] Synthesis of intermediate 79: [ka] To a solution purged with PrOH (59.3 mL) containing intermediate 76 (1.43 g, 5.44 mmol) and potassium vinyl trifluoroborate (0.73 g, 5.44 mmol), PdCl2 (dppf)·CH2Cl2 (0.089 g, 0.109 mmol) and TEA (0.55 g, 5.44 mmol, 0.76 mL) were added at room temperature. The resulting mixture was purged with Ar and stirred at 100°C for 6 hours. The reaction mixture was cooled to room temperature and H2O was added. The residue was extracted with Et2O, the organic layers were combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at c-Hex: siRNA = 95:5 to 40:60) to obtain intermediate 77 (870 mg, 76% yield) as a pale yellow solid.

[0212] The following intermediates were prepared using the same procedure. [Table 8]

[0213] Synthesis of intermediate 83: [ka] To a solution of THF (50.6 mL) and H2O (18.4 mL) containing intermediate 76 (870 mg, 4.14 mmol), potassium osmium(VI) dihydrate (167 mg, 0.41 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, and then sodium periodate (1.77 g, 8.28 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O, the aqueous layer was extracted with DCM, the organic layers were washed together with brine, dried over sodium sulfate, filtered, and dried to dryness to obtain intermediate 83 (748 mg, 85% yield) as a brown solid. This solid was used in the next step without purification.

[0214] The following intermediates were prepared using the same procedure. [Table 9]

[0215] Synthesis of intermediate 86: [ka] Following the procedure described for intermediate 1, intermediate 86 (670 mg, 66% yield) was obtained as a yellow solid using intermediate 83 (748 mg, 3.52 mmol) as the starting material.

[0216] The following intermediates were prepared using the same procedure. [Table 10]

[0217] Synthesis of intermediate 88: [ka] Following the procedure described for intermediate 54, intermediate 86 (430 mg, 1.5 mmol) was used as the starting material to obtain intermediate 88 (435 mg, quantitative yield) as a brown oily substance.

[0218] The following intermediates were prepared using the same procedure. [Table 11]

[0219] Synthesis of intermediate 89a: [ka] Following the procedure described for intermediate 7, intermediate 89a (423 mg, 59% yield) was obtained as a yellow solid using intermediate 85 (570 mg, 2.2 mmol) and 1-cyclobutylmethanamine hydrochloride as starting materials.

[0220] Synthesis of intermediate 90a: [ka] To a solution of MeCN (8.7 mL) containing intermediate 89a (423 mg, 1.28 mmol), Boc2O (335 mg, 1.54 mmol) was added dropwise. The reaction mixture was stirred at 80°C for 1 hour. After the reaction solution was cooled to room temperature, water and DCM were added and the layers were separated. The aqueous layer was extracted twice with DCM, and the organic layers were washed together with saturated NaHCO3 aqueous solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 90a (542 mg, 98% yield) as a yellow oily substance.

[0221] Synthesis of intermediate 91: [ka] A mixture of intermediate 81 (650 mg, 2.6 mmol), tributyl(methoxymethyl) stannane (1.32 g, 3.94 mmol), XPhos Pd G2 (206 mg, 0.26 mmol), and dioxane (15 mL) was purged with N2 and stirred overnight at 80°C. The reaction mixture was filtered through a filter pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane: siRNA = 100:0 to 70:30) to obtain intermediate 91 (448 mg, 66% yield) as a yellow solid.

[0222] Synthesis of intermediate 92: [ka] To a solution of DCM (6 mL) containing intermediate 91 (300 mg, 1.17 mmol) at -78°C, 1.2 M DIBAL (2.43 mL, 2.92 mmol) in toluene was added dropwise. The reaction mixture was stirred at -78°C for 1 hour. The reaction solution was quenched by the dropwise addition of MeOH and siRNA. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 90:10) to obtain intermediate 92 (87 mg, 32% yield) as a yellow oily substance.

[0223] The following intermediates were prepared using the same procedure. [Table 12]

[0224] Synthesis of intermediate 94: [ka] Following the procedure described for intermediate 37, intermediate 94 (78 mg, 39% yield) was obtained as a white solid using intermediate 92 as the starting material.

[0225] The following intermediates were prepared using the same procedure. [Table 13]

[0226] Synthesis of intermediate 96: [ka] To a solution of H2O (0.25 mL) and THF (1.2 mL) containing intermediate 94 (97 mg, 0.38 mmol), PPh3 (200 mg, 0.76 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction solution was diluted with RINKAN and water and separated into layers. The aqueous layer was extracted twice with RINKAN, and the organic layers were combined and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 80:20) to obtain intermediate 96 (50 mg, 57% yield) as a white solid.

[0227] The following intermediates were prepared using the same procedure. [Table 14]

[0228] Synthesis of intermediate 98: [ka] A mixture of 6-bromo-3-(diethoxymethyl)quinoline-8-ol (600 mg, 1.84 mmol), K2CO3 (305 mg, 2.21 mmol), and 1-bromo-2-methoxyethane (511 mg, 3.68 mmol, 0.35 mL) in DMF (15 mL) was stirred at 70°C for 3 hours. After cooling to room temperature, water and DCM were added and the layers were separated. The aqueous layer was extracted twice with DCM, and the organic layers were combined and dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane: siRNA = 100:0 to 70:30) to obtain intermediate 98 (330 mg, 47% yield) as a brown oily substance.

[0229] The following intermediates were prepared using the same procedure. [Table 15]

[0230] Synthesis of intermediate 100: [ka] Dioxane (6 mL) / H2O (3 mL) containing 6-bromo-3-(diethoxymethyl)-8-fluoroquinoline (430 mg, 1.31 mmol), potassium [(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)methyl]trifluoroboranoid (525 mg, 1.97 mmol), Pd(OAc)2 (14.7 mg, 0.066 mmol), SPhos (64.6 mg, 0.16 mmol), and Na2CO3 (625 mg, 5.9 mmol) was placed in a microwave vial. The tube was sealed and heated overnight at 100°C. Subsequently, ethylenediamine (551 mg, 9.17 mmol, 0.61 mL) and PrOH (6.5 mL) were added sequentially, and the resulting reaction mixture was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature, and toluene and saturated K2CO3 aqueous solution were added. The aqueous layer was further extracted with toluene, and the organic layers were dried over magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 92:8) to obtain intermediate 100 (303 mg, 83% yield) as a light brown oily substance.

[0231] The following intermediates were prepared using the same procedure. [Table 16]

[0232] Synthesis of intermediate 108: [ka] DIPEA (642 mg, 4.96 mmol, 0.86 mL) and T3P in siRNA (1.3 g, 1.99 mmol, 1.19 mL) were added to a solution of intermediate 88 (310 mg, 0.99 mmol), which was stirred at room temperature for 16 hours, and DMF (3.3 mL) containing 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (189 mg, 0.99 mmol). The reaction mixture was diluted with H2O and extracted with CHCl3 / iPrOH (3 / 1). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography with elution at DCM:MeOH = 100:0 to 92:8 to obtain intermediate 108 (120 mg, 26% yield) as a light brown oil.

[0233] The following intermediates were prepared using the same procedure. [Table 17] TIFF2026514449000177.tif206170

[0234] Synthesis of intermediate 123: [ka] 37 mL of DCM containing 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (698 mg, 3.67 mmol), (6-bromo-2-methoxyquinoline-3-yl)methaneamine (980 mg, 3.67 mmol), and pyridine (4.4 g, 55 mmol, 4.45 mL) was stirred at 0°C for 15 minutes. POCl3 (2.25 g, 14.7 mmol, 1.37 mL) was added to the mixture at 0°C, and the mixture was heated to room temperature and stirred for 48 hours. The reaction mixture was carefully quenched and made basic with 10% K2CO3 aqueous solution. The resulting precipitate was filtered, washed multiple times with H2O, washed once with DCM, and dried to obtain intermediate 123 (1.1 g, 67% yield) as a gray solid.

[0235] Synthesis of intermediate 124: [ka] Following the procedure described for intermediate 15, intermediate 124 (79 mg, quantitative yield) was obtained as a pale yellow solid using intermediate 108 (95 mg, 0.205 mmol) as the starting material. This solid was used in the next step without purification.

[0236] The following intermediates were prepared using the same procedure. [Table 18] TIFF2026514449000181.tif135170

[0237] Synthesis of intermediate 136: [ka] To a degassed suspension (dioxane (15.8 mL) and H2O (7.9 mL)) containing 3-bromo-7-methoxyquinoline-6-carbonitrile (1.12 g, 3.61 mmol), N-Boc-aminomethyltrifluoroborate potassium (1.28 g, 5.42 mmol), and Na2CO3 (1.72 g, 16.3 mmol), Pd(dba)2 (104 mg, 0.18 mmol) and SPhos (180 mg, 0.43 mmol) were added at room temperature. The resulting mixture was stirred at 100°C for 20 hours. The reaction mixture was diluted with H2O and extracted with RINKAN. The organic layers were washed together with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by silica gel chromatography (elution at c-Hex: siRNA = 100:0-10:90) to obtain intermediate 136 (395 mg, 35% yield) as a yellow solid.

[0238] The following intermediates were prepared using the same procedure. [Table 19]

[0239] Synthesis of intermediate 140: [ka] The reaction was carried out under anhydrous conditions, glassware was flame-dried, and anhydrous THF was dried on molecular sieves. To a solution of Ar-purged THF (15.5 mL) containing intermediate 137 (1.9 g, 6.31 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (102 mg, 0.38 mmol), and bis(pinacolate)diborone (1.76 g, 6.94 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (130 mg, 0.19 mmol) was added at room temperature. The resulting reaction mixture was purged with Ar and heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with ELISA, and concentrated to dryness to obtain intermediate 140 (2.6 g, quantitative yield) as a brown foam. This foam was used in the next step without purification.

[0240] The following intermediates were prepared using the same procedure. [Table 20]

[0241] Synthesis of intermediate 142: [ka] To a solution of intermediate 140 (3.9 g, 6.3 mmol) in DMF (72 mL), KCN (820 mg, 12.6 mmol), Cu(OTf)2 (4.6 g, 12.6 mmol), pyridine (7.5 g, 94.4 mmol, 7.64 mL), and KF (440 mg, 7.55 mmol) were added at room temperature. The resulting reaction mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3 aqueous solution and siRNA. The aqueous layer was extracted with siRNA. The organic layers were washed together with brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by silica gel chromatography (elution at c-Hex:siRNA = 70:30~20:80) to obtain intermediate 142 (728 mg, 37% yield) as a yellow solid.

[0242] Synthesis of intermediate 143: [ka] Following the procedure described for intermediate 54, intermediate 143 (485 mg, 94% yield) was obtained as a green foam using intermediate 136 (508 mg, 1.62 mmol) as the starting material.

[0243] The following intermediates were prepared using the same procedure. [Table 21]

[0244] Synthesis of intermediate 145: [ka] Following the procedure described for intermediate 108, intermediate 145 (400 mg, 53% yield) was obtained as a brown solid using intermediate 143 (485 mg, 1.53 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (291 mg, 1.53 mmol) as starting materials.

[0245] The following intermediates were prepared using the same procedure. [Table 22]

[0246] Synthesis of intermediate 147: [ka] Following the procedure described for Co.7, intermediate 147 (221 mg, 70% yield) was obtained as a brown solid using intermediate 145 (490 mg, 0.82 mmol) as the starting material.

[0247] The following intermediates were prepared using the same procedure. [Table 23]

[0248] Synthesis of intermediate 150: [ka] To a suspension of intermediate 147 (230 mg, 0.59 mmol) and TEA (131 mg, 1.3 mmol, 0.18 mL) in DCM (2.2 mL), 2-nitrobenzenesulfonyl chloride (144 mg, 0.65 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 18 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layers were washed together with brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 96:4) to obtain intermediate 150 (298 mg, 88% yield) as an orange solid.

[0249] The following intermediates were prepared using the same procedure. [Table 24]

[0250] Synthesis of intermediate 153: [ka] The reaction was carried out under anhydrous conditions. In a solution of THF (0.75 mL) containing intermediate 150 (150 mg, 0.26 mmol) and (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (96 mg, 0.54 mmol), 2-(tributyl-λ) in THF (3.5 mL) was added at room temperature. 5 Phosphanylidene acetonitrile (378 mg, 1.57 mmol, 0.41 mL) was added. The resulting reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was concentrated until dry to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 90:10) to obtain intermediate 153 (17 mg, 10% yield) as a brown gum-like substance.

[0251] The following intermediates were prepared using the same procedure. [Table 25]

[0252] Synthesis of intermediate 158: [ka] A solution of H2O (10.6 mL) containing CuBr2 (1.6 g, 6.96 mmol) was added dropwise to a solution of MeOH (10.6 mL) containing intermediate 141 (933 mg, 2.32 mmol). The resulting reaction mixture was heated at 80°C for 3 hours. NH4OH (15% aqueous solution) was added, and the aqueous layer was extracted twice by DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at heptane: siRNA = 100:0 to 60:40) to obtain intermediate 158 (241 mg, 29% yield) as a yellow oily substance.

[0253] Synthesis of intermediate 159: [ka] Following the procedure described for intermediate 8, intermediate 159 (182 mg, 97% yield) was obtained as a white solid using intermediate 158 (228 mg, 0.64 mmol) as the starting material.

[0254] Synthesis of intermediate 160: [ka] Following the procedure described for intermediate 108, intermediate 160 (120 mg, 45% yield) was obtained as a yellow solid using intermediate 159 (182 mg, 0.62 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (119 mg, 0.62 mmol) as starting materials.

[0255] Synthesis of intermediate 161: [ka] Following the procedure described for intermediate 7, intermediate 161 (105 mg, 59% yield) was obtained as an orange oily substance using intermediate 83 (182 mg, 0.62 mmol) as the starting material.

[0256] Synthesis of intermediate 162: [ka] Following the procedure described for intermediate 54, intermediate 162 (100 mg, 99% yield) was obtained as a brown viscous oily substance using intermediate 161 (100 mg, 0.34 mmol) as the starting material.

[0257] Synthesis of intermediate 163: [ka] Following the procedure described for intermediate 83, intermediate 163 (40 mg, quantitative yield) was obtained as a brown solid using intermediate 112 (40 mg, 0.1 mmol) as the starting material.

[0258] Synthesis of intermediate 165: [ka] To a solution of DCM (2.1 mL) containing intermediate 121 (310 mg, 0.69 mmol), m-CPBA (254 mg, 1.032 mmol, 0.45 mL) was added in several portions at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and neutralized to pH 7 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted twice with a CHCl3 / IPA(3 / 1) mixed solvent. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 165 (211 mg) as a pale yellow solid. This solid was used in the next step without purification.

[0259] Synthesis of intermediate 166: [ka] To a solution of intermediate 165 (180 mg, 0.39 mmol) in acetonitrile (0.96 mL), TEA (137 mg, 1.35 mmol, 0.19 mL) and TMSCN (134 mg, 1.35 mmol, 0.18 mL) were added under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (elution at heptane: Â180:20~60:40) yielded intermediate 166 (128 mg, 70% yield) as a pale yellow solid.

[0260] Synthesis of intermediate 167: [ka] Following the procedure described for intermediate 15, intermediate 167 (66 mg, 71% yield) was obtained as a pale yellow solid, starting from intermediate 166 (110 mg, 0.23 mmol). This solid was used in the next step without purification.

[0261] Synthesis of intermediate 168: [ka] To a solution of DCM (18.9 mL) containing methyl 3-(diethoxymethyl)-8-methoxyquinoline-6-carboxylate (805 mg, 2.52 mmol) at -78°C, 1.2 M DIBAL (25.25 mL, 6.3 mmol) in toluene was added dropwise. The reaction mixture was stirred at -78°C for 1 hour, then heated to 0°C, and quenched with toluene, a few drops of MeOH, and water. Celite was added, and the reaction mixture was purified directly by silica gel chromatography (eluting at DCM:MeOH = 100:0 to 92:8) to obtain the intermediate (634 mg, 86% yield) as a brown oily substance.

[0262] Synthesis of intermediate 169: [ka] Following the procedure described for intermediate 37, intermediate 169 (391 mg, 59% yield) was obtained as a brown oily substance, starting from intermediate 168 (610 mg, 2.1 mmol).

[0263] Synthesis of intermediate 170: [ka] Following the procedure described for intermediate 41, intermediate 170 (139 mg, 53% yield) was obtained as a yellow solid, starting from intermediate 169 (180 mg, 0.57 mmol) and 8-ethinylimidazo[1,5-a]pyridine.

[0264] Synthesis of intermediate 171: [ka] Following the procedure described for intermediate 15, intermediate 171 (125 mg, quantitative yield) was obtained as a pale yellow solid, starting from intermediate 170 (150 mg, 0.33 mmol). This solid was used in the next step without purification.

[0265] Synthesis of intermediate 172: [ka] A mixture of 2-amino-5-bromopyridine-3-carbaldehyde (1.5 g, 7.46 mmol), ethyl propiolate (0.88 g, 8.95 mmol, 0.907 mL), and L-proline (0.43 g, 3.73 mmol, 0.32 mL) in EtOH (75 mL) was heated at 80°C and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and water, and after separating the layers, the aqueous layer was extracted three times with DCM. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was ground in Et2O, the resulting solid was filtered, and dried under reduced pressure to obtain intermediate 172 (1.35 g, 64% yield) as a yellow solid.

[0266] Synthesis of intermediate 173: [ka] Following the procedure described for intermediate 79, intermediate 173 (772 mg, 51% yield) was obtained as a beige solid, starting from intermediate 172 (1.9 g, 6.65 mmol).

[0267] Synthesis of intermediate 174: [ka] Following the procedure described for intermediate 83, intermediate 174 (477 mg, 71% yield) was obtained as a brown solid, starting from intermediate 173 (670 mg, 2.94 mmol). This solid was used in the next step without purification.

[0268] Synthesis of intermediate 175: [ka] Following the procedure described for intermediate 7, intermediate 175 (576 mg, 93% yield) was obtained as a white solid, starting from intermediate 174 (475 mg, 2.1 mmol) and 1-cyclobutylmethanamine hydrochloride (301 mg, 2.48 mmol).

[0269] Synthesis of intermediate 176: [ka] Following the procedure described for intermediate 90a, intermediate 176 (116 mg, 87% yield) was obtained as a white solid, starting from intermediate 175 (100 mg, 0.33 mmol).

[0270] Synthesis of intermediate 177: [ka] To a solution of THF (7.42 mL) containing intermediate 176 (602 mg, 1.507 mmol), H2O (7.42 mL) was added, followed by the addition of LiOH (565 mg, 7.53 mmol). The mixture was stirred at room temperature for 1 hour. After completion, water was added to separate the layers, and the basic aqueous layer was washed several times with SiO2. Subsequently, the basic aqueous layer was acidified with acetic acid to a pH of 4-5, and the acidic aqueous layer was extracted three times with SiO2. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 177 (384 mg, 69% yield) as a light brown solid.

[0271] Synthesis of intermediate 178: [ka] Under an N2 atmosphere at 0°C, ethyl chloroformate (244 mg, 2.25 mmol, 0.21 mL) was added to a mixture of intermediate 177 (334 mg, 0.9 mmol) and TEA (227 mg, 2.25 mmol, 0.31 mL) in THF (5.6 mL). The mixture was stirred at 0°C for 30 minutes, after which NaBH4 (102 mg, 2.7 mmol) and water (0.86 mL) were added sequentially. The mixture was stirred at 0°C for 10 minutes, then heated to room temperature and stirred for 1 hour. The crude product was cooled to 0°C, and 1N HCl aqueous solution was gradually added. After stirring for 10 minutes, pharmaceutically acceptable HCl and 10% K2CO3 aqueous solution were added. The aqueous layer was separated and re-extracted with RINKAN. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 80:20) to obtain intermediate 178 (166 mg, 52% yield) as a pale yellow oily substance.

[0272] Synthesis of intermediate 179: [ka] Following the procedure described for intermediate 37, intermediate 179 (102 mg, 73% yield) was obtained as a white solid, starting from intermediate 178 (130 mg, 0.36 mmol).

[0273] Synthesis of intermediate 180: [ka] Following the procedure described for intermediate 96, intermediate 180 (50 mg, 54% yield) was obtained as a white solid, starting from intermediate 179 (100 mg, 0.26 mmol).

[0274] Synthesis of intermediate 181: [ka] Following the procedure described for intermediate 108, intermediate 181 (35 mg, 47% yield) was obtained as a white solid, starting with intermediate 180 (50 mg, 0.14 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (27 mg, 0.14 mmol).

[0275] Synthesis of intermediate 182: [ka] To a solution of MeOH (181 mL) containing Ar-purged 6-bromo-1,3-dichloroisoquinoline (5 g, 18.1 mmol), NaOMe (23.5 g, 108 mmol, 24.8 mL) was added at room temperature. The reaction mixture was stirred at 65 °C for 16 hours. The mixture was cooled to room temperature and diluted with toluene and H₂O. The resulting solid was filtered, washed with toluene, and dried under reduced pressure to obtain intermediate 182 (4.9 g, quantitative yield) as a white solid.

[0276] Synthesis of intermediate 183: [ka] Following the procedure described for intermediate 79, intermediate 183 (2.6 g, 95% yield) was obtained as a white solid, starting from intermediate 182 (3.4 g, 12.5 mmol).

[0277] Synthesis of intermediate 184: [ka] Following the procedure described for intermediate 83, intermediate 184 (2.6 g, quantitative yield) was obtained as a brown solid, starting from intermediate 183 (2.6 g, 11.8 mmol).

[0278] Synthesis of intermediate 185: [ka] Following the procedure described for intermediate 7, intermediate 185 (2.3 g, 67% yield) was obtained as a brown solid, starting with intermediate 184 (2.6 g, 11.8 mmol) and cyclobutylmethanamine hydrochloride (1.4 g, 11.8 mmol).

[0279] Synthesis of intermediate 186: [ka] Following the procedure described for intermediate 90a, intermediate 186 (990 mg, quantitative yield) was obtained as a colorless oily substance, starting from intermediate 185 (735 mg, 2.5 mmol).

[0280] Synthesis of intermediate 187: [ka] Following the procedure described for intermediate 100, intermediate 187 (611 mg, 54% yield) was obtained as a white solid, starting from intermediate 186 (1.2 g, 2.9 mmol).

[0281] Synthesis of intermediate 188: [ka] Following the procedure described for intermediate 108, intermediate 188 (150 mg, 67% yield) was obtained as a yellow solid, starting with intermediate 187 (150 mg, 0.39 mmol) and 5-(3-azabicyclo[3.1.0]hexane-3-yl)nicotinic acid (79.5 mg, 0.39 mmol).

[0282] The following intermediates were prepared using the same procedure. [Table 26]

[0283] Synthesis of intermediate 198: [ka] It contains intermediate 197 (100 mg, 0.13 mmol), 2-azabicyclo[3.1.0]hexane hydrochloride (15.1 mg, 0.13 mmol), XPhos (5.42 mg, 0.011 mmol), and Cs2CO3 (165 mg, 0.51 mmol). t A 2 mL solution of Bu-OH was subjected to three vacuum substitutions with Ar, followed by the addition of Pd2(dba)3 (3.93 mg, 3.8 μmol). The mixture was then subjected to three more vacuum substitutions with Ar and heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:MeOH = 100:0 to 85:15) to obtain intermediate 198 (46 mg, 64% yield) as an orange solid.

[0284] The following intermediates were prepared using the same procedure. [Table 27]

[0285] Synthesis of intermediate 202: [ka] Following the procedure described for intermediate 1, intermediate 202 (504 mg, 62% yield) was obtained as a light brown oily substance, starting from intermediate 184 (638 mg, 2.73 mmol).

[0286] Synthesis of intermediate 203: [ka] Following the procedure described for intermediate 100, intermediate 203 (408 mg, 82% yield) was obtained as a yellow oily substance, starting from intermediate 202 (615 mg, 1.71 mmol).

[0287] Synthesis of intermediate 204: [ka] Following the procedure described for intermediate 108, intermediate 204 (406 mg, 66% yield) was obtained as a yellow solid, starting with intermediate 203 (385 mg, 1.33 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (252 mg, 1.33 mmol).

[0288] Synthesis of intermediate 205: [ka] Following the procedure described for intermediate 15, intermediate 205 (149 mg, quantitative yield) was obtained as a pale yellow solid, starting from intermediate 204 (178 mg, 0.38 mmol).

[0289] Synthesis of intermediate 206 (HBr salt): [ka] A suspension of HBr (6.52 g, 80.6 mmol, 4.4 mL) in H2O containing intermediate 185 (350 mg, 1.2 mmol) was stirred at 50°C for 5 hours. The reaction mixture was cooled to room temperature, and volatile components were removed under reduced pressure to obtain intermediate 206 (420 mg, 98% yield) as a brown solid. This solid was used in the next step without purification.

[0290] Synthesis of intermediate 207: [ka] Following the procedure described for intermediate 90a, intermediate 207 (320 mg, 72% yield) was obtained as a light brown solid, starting from intermediate 206 (420 mg, 1.17 mmol).

[0291] Synthesis of intermediate 208: [ka] A suspension of intermediate 207 (305 mg, 0.81 mmol), 2-bromopropane (109 mg, 0.89 mmol, 84 μL), and K2CO3 (168 mg, 1.21 mmol) in DMF (5.3 mL) was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The residue was extracted twice with siRNA. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase chromatography (eluting at heptane:siRNA = 100:0 to 80:20) to obtain intermediate 208 (252 mg, 74% yield) as a colorless oil.

[0292] The following intermediates were prepared using the same procedure. [Table 28]

[0293] Synthesis of intermediate 213: [ka] To a solution of intermediate 207 (269 mg, 0.71 mmol) and Ag2CO3 (394 mg, 1.43 mmol) in CHCl3 (3.6 mL), CD3I (310 mg, 2.14 mmol, 0.13 mL) was added at room temperature. The resulting mixture was stirred overnight at 65 °C. Volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution with cyclohexane: siRNA = 100:0 to 80:20) to obtain intermediate 208 (252 mg, 74% yield) as a colorless oil.

[0294] Synthesis of intermediate 214: [ka] Intermediate 207 (375 mg, 1 mmol) and Na2CO3 (116 mg, 1.1 mmol) were added to a vial under air. Then, MeCN (2.5 mL) was added at room temperature, and the resulting mixture was heated at 60°C for 10 minutes, after which (bromodifluoromethyl)trimethylsilane (243 mg, 1.19 mmol, 0.19 mL) was added. The resulting reaction mixture was stirred overnight at 60°C. Saline solution was added, and the residue was extracted twice with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (eluting with heptane: siRNA = 100:0 to 90:10) to obtain intermediate 214 (240 mg, 57%) as a white solid.

[0295] Synthesis of intermediate 215: [ka] Following the procedure described for intermediate 100, intermediate 215 (145 mg, 59% yield) was obtained as a yellow oily substance, starting from intermediate 208 (250 mg, 0.6 mmol).

[0296] The following intermediates were prepared using the same procedure. [Table 29]

[0297] Synthesis of intermediate 221: [ka] Following the procedure described for intermediate 108, intermediate 221 (120 mg, 58% yield) was obtained as a colorless oily substance, starting with intermediate 215 (145 mg, 0.35 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (66.7 mg, 0.35 mmol).

[0298] The following intermediates were prepared using the same procedure. [Table 30]

[0299] Synthesis of intermediate 227: [ka] Following the procedure described for intermediate 4, intermediate 227 (282 mg, 71% yield) was obtained as a yellow solid, starting from intermediate 212 (407 mg, 0.88 mmol).

[0300] Synthesis of intermediate 228: [ka] Following the procedure described for intermediate 54, intermediate 228 (218 mg, 79% yield) was obtained as a yellow oily substance, starting from intermediate 227 (282 mg, 0.62 mmol).

[0301] Synthesis of intermediate 229: [ka] Following the procedure described for intermediate 108, intermediate 229 (151 mg, 50% yield) was obtained as a light brown solid, starting with intermediate 228 (303 mg, 0.49 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (93.5 mg, 0.49 mmol).

[0302] Synthesis of intermediate 230: [ka] Intermediate 229 (180 mg, 0.23 mmol) was dissolved in MeOH (0.8 mL), and NH3 (7 M, MeOH) (0.84 mL, 5.9 mmol) was added to the solution. The reaction mixture was stirred overnight at 50°C. Volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:MeOH = 100:0 to 95:5) to obtain intermediate 230 (112 mg, 82%) as a white solid.

[0303] Synthesis of intermediate 231: [ka] Following the procedure described for intermediate 206, intermediate 231 (1.12 g, 51% yield) was obtained as a brown solid, starting from intermediate 184 (2.85 g, 10.7 mmol).

[0304] Synthesis of intermediate 232: [ka] Following the procedure described for intermediate 1, intermediate 232 (1.1 g, 37% yield) was obtained as a white solid, starting from intermediate 231 (2.21 g, 10.7 mmol).

[0305] Synthesis of intermediate 233: [ka] Following the procedure described for intermediate 208, intermediate 233 (386 mg, 31% yield) was obtained as a yellow oily substance, starting from intermediate 232 (800 mg, 2.84 mmol) and 2-bromo-tert-butyldimethylsilane (1.36 g, 5.68 mmol, 1.12 mL).

[0306] Synthesis of intermediate 234: [ka] Following the procedure described for intermediate 100, intermediate 234 (208 mg, 24% yield) was obtained as a yellow oily substance, starting from intermediate 233 (870 mg, 1.98 mmol).

[0307] Synthesis of intermediate 235: [ka] Following the procedure described for intermediate 108, intermediate 235 (163 mg, 57% yield) was obtained as a light brown solid, starting with intermediate 234 (205 mg, 0.47 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (90 mg, 0.47 mmol).

[0308] Synthesis of intermediate 323: [ka] Following the procedure described for intermediate 15, intermediate 323 (120 mg, quantitative yield) was obtained as a pale yellow solid, starting from intermediate 235 (175 mg, 0.29 mmol).

[0309] Synthesis of intermediate 236: [ka] Following the procedure described for intermediate 79, intermediate 236 (572 mg, 79% yield) was obtained as a white solid, starting with 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol).

[0310] Synthesis of intermediate 237: [ka] Following the procedure described for intermediate 83, intermediate 237 (598 mg, quantitative yield) was obtained as a brown solid, starting from intermediate 236 (592 mg, 3.12 mmol).

[0311] Synthesis of intermediate 238: [ka] Following the procedure described for intermediate 1, intermediate 238 (645 mg, 64% yield) was obtained as a yellow oily substance, starting from intermediate 237 (800 mg, 3.8 mmol).

[0312] Synthesis of intermediate 239: [ka] Following the procedure described for intermediate 4, intermediate 239 (90 mg, 34% yield) was obtained as a yellow solid, starting from intermediate 238 (278 mg, 1.05 mmol).

[0313] Synthesis of intermediate 240: [ka] Following the procedure described for intermediate 19, intermediate 240 (193 mg, quantitative yield) was obtained as a brown oily substance, starting from intermediate 239 (190 mg, 0.74 mmol).

[0314] Synthesis of intermediate 241: [ka] Following the procedure described for intermediate 108, intermediate 241 (60 mg, 32% yield) was obtained as a light brown solid, starting with intermediate 240 (140 mg, 0.43 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (81.8 mg, 0.43 mmol).

[0315] Synthesis of intermediate 324: [ka] Following the procedure described for intermediate 15, intermediate 324 (49 mg, quantitative yield) was obtained as a pale yellow solid, starting from intermediate 241 (60 mg, 0.14 mmol).

[0316] Synthesis of intermediate 242: [ka] Following the procedure described for intermediate 7, intermediate 242 (2.54 g, 76% yield) was obtained as a dark purple oily substance, starting from intermediate 237 (2.45 g, 12.8 mmol) and cyclobutylmethanamine hydrochloride (1.87 g, 15.3 mmol).

[0317] Synthesis of intermediate 243: [ka] Following the procedure described for intermediate 90a, intermediate 243 (3.01 g, 91% yield) was obtained as a brown oily substance, starting from intermediate 242 (2.38 g, 9.13 mmol).

[0318] Synthesis of intermediate 244: [ka] Intermediate 243 (964 mg, 2.67 mmol) was dissolved in DMSO (14.5 mL), to which DBU (3.33 g, 21.9 mmol, 3.27 mL) was added, followed by MeNO2 (3.26 g, 53.4 mmol, 2.91 mL). The resulting reaction mixture was stirred at room temperature for 5 days. NH4Cl was added, and the residue was extracted twice with HCl. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase chromatography (elution at cyclohexane:HCl = 100:0 to 88:12) to obtain intermediate 244 (231 mg, 23% yield) as a colorless oil.

[0319] Synthesis of intermediate 245: [ka] Following the procedure described for intermediate 100, intermediate 245 (186 mg, 72% yield) was obtained as a yellow oily substance, starting from intermediate 244 (262 mg, 0.7 mmol).

[0320] Synthesis of intermediate 246: [ka] Following the procedure described for intermediate 108, intermediate 246 (51 mg, 50% yield) was obtained as a yellow foamy substance, starting with intermediate 245 (70 mg, 0.19 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (36 mg, 0.19 mmol).

[0321] The following intermediates were prepared using the same procedure. [Table 31]

[0322] Synthesis of intermediate 247a: [ka] To a solution of methyl 4-bromo-2-formyl methyl benzoate (34.8 g, 143 mmol) dissolved in DCM (287 mL), DBU (21.8 g, 143 mmol, 21.4 mmol) and methyl 2-{[(tert-butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (42.6 g, 143 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 18 hours. Water was added, and the residue was extracted twice with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase chromatography (eluting with heptane: siRNA = 85:15 to 65:35) to obtain intermediate 247a (37.5 g, 68% yield) as a white solid.

[0323] Synthesis of intermediate 248 (TFA salt): [ka] Following the procedure described for intermediate 63, intermediate 248 (34.4 g, 98% yield) was obtained as a white solid, starting from intermediate 247a (33.9 g, 88.7 mmol).

[0324] Synthesis of intermediate 249: [ka] A mixture of intermediate 248 (20.4 g, 51.5 mmol) and Cs2CO3 (33.6 g, 103 mmol) was purged with N2. Subsequently, dry PrOH (340 mL) was added, and the reaction mixture was stirred at 60°C for 30 minutes. Water was added, the solid was filtered and recovered, and dried under reduced pressure to obtain intermediate 249 (11.8 g, 74% yield) as a white solid.

[0325] Synthesis of intermediate 250: [ka] Following the procedure described for intermediate 79, intermediate 250 (7.4 g, 65% yield) was obtained as a beige solid, starting from intermediate 249 (13.7 g, 44.3 mmol).

[0326] Synthesis of intermediate 251: [ka] Intermediate 250 (9 g, 35 mmol) was mixed with toluene (250 mL), and POCl3 (21.5 g, 140 mmol, 13 mL) was added to the mixture. The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was cooled to room temperature, and volatile components were removed under reduced pressure. The residue was diluted with a CHCl3 / IPA (3 / 1) mixture and washed with a 30% aqueous sodium hydroxide solution. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 251 (8.62 g, 89% yield) as a pale yellow solid.

[0327] Synthesis of intermediate 252: [ka] Following the procedure described for intermediate 83, intermediate 252 (6g, 95% yield) was obtained as a light brown solid, starting from intermediate 251 (6.3g, 22.7 mmol).

[0328] Synthesis of intermediate 253: [ka] Following the procedure described for intermediate 7, intermediate 253 (6.29 g, 84% yield) was obtained as a brown solid, starting with intermediate 252 (6 g, 21.6 mmol) and cyclobutylmethanamine hydrochloride (3.15 g, 25.9 mmol).

[0329] Synthesis of intermediate 254: [ka] Following the procedure described for intermediate 90a, intermediate 254 (7.39 g, quantitative yield) was obtained as a colorless oily substance, starting from intermediate 253 (5.8 g, 16.7 mmol).

[0330] Synthesis of intermediate 255: [ka] A mixture of NaBH4 (2.39 g, 63.3 mmol) and CaCl2 (4.21 g, 38 mmol) suspended in THF (75 mL) and EtOH (75 mL) was stirred at -10°C for 20 minutes. A solution of intermediate 254 (5.4 g, 12.7 mmol) dissolved in THF (35 mL) and EtOH (35 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. Water and saturated NH4Cl aqueous solution were added to the reaction mixture and quenched. The residue was extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 255 (4.7 g, quantitative yield) as a brown oily substance.

[0331] Synthesis of intermediate 256: [ka] Following the procedure described for intermediate 37, intermediate 256 (406 mg, 84% yield) was obtained as a colorless oily substance, starting from intermediate 255 (455 mg, 1.16 mmol).

[0332] Synthesis of intermediate 257: [ka] Following the procedure described for intermediate 96, intermediate 257 (341 mg, 94% yield) was obtained as a colorless oily substance, starting from intermediate 256 (386 mg, 0.96 mmol).

[0333] Synthesis of intermediate 258: [ka] Following the procedure described for intermediate 108, intermediate 258 (371 mg, 92% yield) was obtained as a pale yellow solid, starting with intermediate 258 (281 mg, 0.72 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (166 mg, 0.87 mmol).

[0334] Synthesis of intermediate 259: [ka] Intermediate 258 (116 mg, 0.21 mmol), tributyl(methoxymethyl) stannane (138 mg, 0.41 mmol), and Pd(PPh3)4 (23.9 mg, 0.021 mmol) were mixed in DMF (1.7 mL), degassed, and stirred overnight at 100°C. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (DCM: siRNA = 60:40 to 30:70 elution) to obtain intermediate 259 (83 mg, 70% yield) as a yellow solid.

[0335] Synthesis of intermediate 260: [ka] Intermediate 258 (200 mg, 0.36 mmol), potassium vinyl trifluoroborate (95.3 mg, 0.71 mmol), Cs2CO3 (348 mg, 1.07 mmol), and PdCl2 (dppf).DCM (29.1 mg, 0.036 mmol) were mixed with dioxane (2.4 mL) and H2O (0.8 mL). The mixture was degassed with N2 and stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature and water was added. The residue was extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:iPrOH = 100:0 to 95:5) to obtain intermediate 260 (102 mg, 52%) as a light brown solid.

[0336] Synthesis of intermediate 261: [ka] Intermediate 260 (96 mg, 0.17 mmol) was dissolved in H2O (0.34 mL) and THF (1.4 mL) and mixed under stirring. Potassium osmium(VI) dihydrate (3.49 mg, 8.7 μmol) was added to the mixture. The reaction mixture was stirred at room temperature for 5 minutes, and NMO (20.3 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. DCM and saturated NH4Cl aqueous solution were added, and the residue was extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:iPrOH = 100:0 to 89:11) to obtain intermediate 261 (61 mg, 60%) as a light brown solid.

[0337] Synthesis of intermediate 262: [ka] Intermediate 258 (297 mg, 0.53 mmol), trifluoro[2-(oxan-2-yloxy)ethyl]boranoid (208 mg, 1.06 mmol), Cs2CO3 (516 mg, 1.59 mmol), and catCXium (38.5 mg, 0.053 mmol) were mixed with dioxane (3.6 mL) and H2O (1.2 mL). The mixture was degassed with N2 and stirred overnight at 100°C. DCM and H2O were added, and the residue was extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:MeOH = 100:0 to 90:10) to obtain intermediate 262 (65 mg, 19%) as a pale orange oily substance.

[0338] Synthesis of intermediate 263: [ka] Intermediate 251 (3.2 g, 11.6 mmol), Cs2CO3 (5.67 g, 17.4 mmol), and PdCl2(dppf).DCM (0.76 g, 0.93 mmol) were mixed with dioxane (31.4 mL) and purged with N2. Under an N2 atmosphere, trimethylboroxine (2.91 g, 23.2 mmol, 3.27 mL) was added, and the reaction mixture was stirred overnight at 100 °C. Depositphotos and H2 O were added, and the residue was extracted with Depositphotos. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at heptane: Depositphotos = 100:0 to 50:50) to obtain intermediate 263 (913 mg, 31%) as a white solid.

[0339] Synthesis of intermediate 264: [ka] Intermediate 263 (695 mg, 2.72 mmol) was dissolved in dioxane (10 mL), and SeO2 (393 mg, 3.54 mmol) was added to the solution. The mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain intermediate 264 (730 mg, quantitative yield) as a light brown solid.

[0340] Synthesis of intermediate 265: [ka] Following the procedure described for intermediate 36, intermediate 265 (660 mg, 85% yield) was obtained as a colorless oily substance, starting from intermediate 264 (770 mg, 2.86 mmol).

[0341] Synthesis of intermediate 266: [ka] A mixture of intermediate 265 (640 mg, 2.36 mmol), DHP (298 mg, 3.54 mmol, 0.32 mL), and PTSA monohydrate (13.3 mg, 0.07 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with saturated NaHCO3 aqueous solution, and the residue was extracted twice with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase chromatography (elution at DCM:MeOH = 100:0 to 99:1) to obtain intermediate 266 (509 mg, 61%) as a yellow oily substance.

[0342] Synthesis of intermediate 267: [ka] Following the procedure described for intermediate 83, intermediate 267 (453 mg, 72% yield) was obtained as a gray solid, starting from intermediate 266 (455 mg, 1.28 mmol).

[0343] Synthesis of intermediate 268: [ka] Following the procedure described for intermediate 7, intermediate 268 (216 mg, 40% yield) was obtained as a red oily substance, starting from intermediate 267 (450 mg, 1.26 mmol) and cyclobutylmethanamine hydrochloride (184 mg, 1.51 mmol).

[0344] Synthesis of intermediate 269: [ka] Following the procedure described for intermediate 90a, intermediate 269 (200 mg, 81% yield) was obtained as a colorless oily substance, starting from intermediate 268 (200 mg, 0.47 mmol).

[0345] Synthesis of intermediate 270: [ka] Following the procedure described for intermediate 255, intermediate 270 (158 mg, 98% yield) was obtained as a colorless oily substance, starting from intermediate 269 (180 mg, 0.34 mmol).

[0346] Synthesis of intermediate 271: [ka] Following the procedure described for intermediate 37, intermediate 271 (494 mg, quantitative yield) was obtained as a colorless oily substance, starting from intermediate 270 (470 mg, 1 mmol).

[0347] Synthesis of intermediate 272: [ka] Following the procedure described for intermediate 96, intermediate 272 (326 mg, 64% yield) was obtained as a pale yellow oily substance, starting from intermediate 271 (540 mg, 1.09 mmol).

[0348] Synthesis of intermediate 273: [ka] Following the procedure described for intermediate 108, intermediate 273 (190 mg, 70% yield) was obtained as a brown oily substance, starting with intermediate 272 (200 mg, 0.43 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (89 mg, 0.43 mmol).

[0349] The following intermediates were prepared using the same procedure. [Table 32]

[0350] Synthesis of intermediate 275: [ka] Following the procedure described for intermediate 247a, intermediate 275 (3.18 g, 52% yield) was obtained as a white solid, starting with methyl 5-bromo-3-formyl picolinate (3.8 g, 15.9 mmol).

[0351] The following intermediates were prepared using the same procedure. [Table 33]

[0352] Synthesis of intermediate 276a (TFA salt): [ka] Following the procedure described for intermediate 63, intermediate 276a (3.61 g, 98% yield) was obtained as a white solid, starting from intermediate 275 (3.6 g, 9.31 mmol).

[0353] The following intermediates were prepared using the same procedure. [Table 34]

[0354] Synthesis of intermediate 279: [ka] Following the procedure described for intermediate 79, intermediate 279 (1 g, 53% yield) was obtained as an orange solid, starting from intermediate 276a (3.3 g, 8.3 mmol).

[0355] The following intermediates were prepared using the same procedure. [Table 35]

[0356] Synthesis of intermediate 282: [ka] Following the procedure described for intermediate 251, intermediate 282 (542 mg, 48% yield) was obtained as a light brown solid, starting from intermediate 279 (1.1 g, 4.56 mmol).

[0357] The following intermediates were prepared using the same procedure. [Table 36]

[0358] Synthesis of intermediate 284: [ka] Following the procedure described for intermediate 182, intermediate 284 (192 mg, 48% yield) was obtained as a light brown solid, starting from intermediate 282 (408 mg, 1.64 mmol).

[0359] Synthesis of intermediate 285: [ka] Following the procedure described for intermediate 83, intermediate 285 (340 mg, 94% yield) was obtained as a gray solid, starting from intermediate 284 (359 mg, 1.47 mmol).

[0360] Synthesis of intermediate 286: [ka] Following the procedure described for intermediate 7, intermediate 286 (254 mg, 58% yield) was obtained as a pale yellow oily substance, starting from intermediate 285 (340 mg, 1.38 mmol) and cyclobutylmethanamine hydrochloride (202 mg, 1.66 mmol).

[0361] Synthesis of intermediate 287: [ka] Following the procedure described for intermediate 90a, intermediate 287 (312 mg, 97% yield) was obtained as a brown oily substance, starting from intermediate 286 (244 mg, 0.77 mmol).

[0362] Synthesis of intermediate 288: [ka] Following the procedure described for intermediate 255, intermediate 288 (234 mg, 90% yield) was obtained as a colorless oily substance, starting from intermediate 287 (280 mg, 0.67 mmol).

[0363] Synthesis of intermediate 289: [ka] Following the procedure described for intermediate 37, intermediate 289 (246 mg, quantitative yield) was obtained as a colorless oily substance, starting from intermediate 288 (234 mg, 0.60 mmol).

[0364] Synthesis of intermediate 290: [ka] Following the procedure described for intermediate 96, intermediate 290 (207 mg, 90% yield) was obtained as a pale yellow oily substance, starting from intermediate 289 (245 mg, 0.59 mmol).

[0365] Synthesis of intermediate 291: [ka] Following the procedure described for intermediate 108, intermediate 291 (106 mg, 70% yield) was obtained as a white solid, starting with intermediate 290 (105 mg, 0.27 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (52 mg, 0.27 mmol).

[0366] The following intermediates were prepared using the same procedure. [Table 37]

[0367] Synthesis of intermediate 293: [ka] Following the procedure described for intermediate 263, intermediate 293 (651 mg, 40% yield) was obtained as a white solid, starting from intermediate 283 (1.75 g, 5.96 mmol).

[0368] Synthesis of intermediate 294: [ka] Following the procedure described for intermediate 83, intermediate 294 (597 mg, 91% yield) was obtained as a gray solid, starting from intermediate 293 (650 mg, 2.38 mmol).

[0369] Synthesis of intermediate 295: [ka] Following the procedure described for intermediate 7, intermediate 295 (610 mg, 82% yield) was obtained as a yellow oily substance, starting from intermediate 294 (597 mg, 2.17 mmol) and cyclobutylmethanamine hydrochloride (316 mg, 2.6 mmol).

[0370] Synthesis of intermediate 296: [ka] Following the procedure described for intermediate 90a, intermediate 296 (711 mg, 90% yield) was obtained as a colorless oily substance, starting from intermediate 295 (610 mg, 1.77 mmol).

[0371] Synthesis of intermediate 297: [ka] Following the procedure described for intermediate 255, intermediate 297 (399 mg, 91% yield) was obtained as a colorless oily substance, starting from intermediate 296 (500 mg, 1.12 mmol).

[0372] Synthesis of intermediate 298: [ka] Following the procedure described for intermediate 37, intermediate 298 (348 mg, 82% yield) was obtained as a colorless oily substance, starting from intermediate 297 (399 mg, 1 mmol).

[0373] Synthesis of intermediate 299: [ka] Following the procedure described for intermediate 96, intermediate 299 (302 mg, 75% yield) was obtained as a colorless oily substance, starting from intermediate 298 (429 mg, 1 mmol).

[0374] Synthesis of intermediate 300: [ka] Following the procedure described for intermediate 108, intermediate 300 (174 mg, 86% yield) was obtained as a pale yellow solid, starting with intermediate 299 (140 mg, 0.36 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (68.7 mg, 0.36 mmol).

[0375] The following intermediates were prepared using the same procedure. [Table 38]

[0376] Synthesis of intermediate 302: [ka] Following the procedure described for intermediate 213, intermediate 302 (153 mg, 73% yield) was obtained as a white solid, starting from intermediate 281 (200 mg, 0.73 mmol).

[0377] Synthesis of intermediate 303: [ka] Following the procedure described for intermediate 83, intermediate 303 (108 mg, 70% yield) was obtained as a yellow solid, starting from intermediate 302 (174 mg, 0.53 mmol).

[0378] Synthesis of intermediate 304: [ka] Following the procedure described for intermediate 7, intermediate 304 (34 mg, 26% yield) was obtained as a brown oily substance, starting from intermediate 303 (136 mg, 0.36 mmol) and cyclobutylmethanamine hydrochloride (48.7 mg, 0.40 mmol).

[0379] Synthesis of intermediate 305: [ka] Following the procedure described for intermediate 90a, intermediate 305 (74 mg, 84% yield) was obtained as a brown oily substance, starting from intermediate 304 (68.5 mg, 0.19 mmol).

[0380] Synthesis of intermediate 306: [ka] Following the procedure described for intermediate 168, intermediate 306 (38 mg, quantitative yield) was obtained as a white solid, starting from intermediate 305 (44 mg, 0.096 mmol).

[0381] Synthesis of intermediate 307: [ka] Following the procedure described for intermediate 37, intermediate 307 (57 mg, 93% yield) was obtained as a yellow oily substance, starting from intermediate 306 (58 mg, 0.14 mmol).

[0382] Synthesis of intermediate 308: [ka] Following the procedure described for intermediate 96, intermediate 308 (39 mg, 24% yield) was obtained as a colorless oily substance, starting from intermediate 307 (170 mg, 0.4 mmol).

[0383] Synthesis of intermediate 309: [ka] Following the procedure described for intermediate 108, intermediate 309 (29 mg, 45% yield) was obtained as a yellow oily substance, starting from intermediate 308 (46 mg, 0.11 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (21.7 mg, 0.11 mmol).

[0384] Synthesis of intermediate 310: [ka] Following the procedure described for intermediate 165, intermediate 310 (158 mg, 59% yield) was obtained as a pink solid, starting with 6-bromo-7-fluoroisoquinoline (250 mg, 1.1 mmol).

[0385] Synthesis of intermediate 311: [ka] Following the procedure described for intermediate 251, intermediate 311 (297 mg, 55% yield) was obtained as a pink solid, starting from intermediate 310 (500 mg, 2.1 mmol).

[0386] Synthesis of intermediate 312: [ka] Following the procedure described for intermediate 165, intermediate 312 (1.3 g, 33% yield) was obtained as a white solid, starting from intermediate 311 (3.84 g, 14.7 mmol).

[0387] Synthesis of intermediate 313: [ka] Following the procedure described for intermediate 251, intermediate 313 (700 mg, 49% yield) was obtained as a white solid, starting from intermediate 312 (1.3 g, 4.8 mmol).

[0388] Synthesis of intermediate 314: [ka] Intermediate 313 (393 mg, 1.33 mmol) at -78°C was dissolved in THF (14.8 mL) and nBuLi (2.5 M in THF, 0.64 mL, 1.6 mmol) was added dropwise under an N2 atmosphere. The resulting solution was stirred at -78°C for 30 minutes, DMF (0.39 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. 10% NH4Cl aqueous solution was added, and the residue was extracted twice with RINKAN. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase chromatography (eluting at heptane:RINKAN = 100:0 to 90:10) to obtain intermediate 314 (102 mg, 31%) as a white solid.

[0389] Synthesis of intermediate 315: [ka] Following the procedure described for intermediate 7, intermediate 315 (96 mg, 73% yield) was obtained as a colorless oily substance, starting from intermediate 314 (102 mg, 0.42 mmol) and cyclobutylmethanamine hydrochloride (50.8 mg, 0.42 mmol).

[0390] Synthesis of intermediate 316: [ka] Following the procedure described for intermediate 90a, intermediate 316 (118 mg, 75% yield) was obtained as a light brown oily substance, starting from intermediate 315 (119 mg, 0.38 mmol).

[0391] Synthesis of intermediate 317: [ka] Following the procedure described for intermediate 182, intermediate 317 (98 mg, 70% yield) was obtained as a colorless oily substance, starting from intermediate 316 (142 mg, 0.34 mmol).

[0392] Synthesis of intermediate 318: [ka] Following the procedure described for intermediate 100, intermediate 318 (63 mg, 68% yield) was obtained as a light brown oily substance, starting from intermediate 317 (94 mg, 0.23 mmol).

[0393] Synthesis of intermediate 319: [ka] Following the procedure described for intermediate 108, intermediate 319 (56 mg, 62% yield) was obtained as a white solid, starting with intermediate 318 (63 mg, 0.16 mmol) and 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (29.7 mg, 0.16 mmol).

[0394] Preparation of the final compound Synthesis of compound 1 (Co.1): [ka] Intermediate 8 (126 mg, 0.37 mmol), 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid (85.1 mg, 0.45 mmol), and HATU (284 mg, 0.75 mmol) were dissolved in DMF (1.9 mL), to which DIPEA (193 mg, 1.49 mmol, 0.26 mL) was added. The resulting solution was stirred at room temperature for 16 hours. Water was added, and the residue was extracted three times with RINKAN. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (NH2, heptane: [siRNA / MeOH=3 / 1] = 100:0 to 20:80) to obtain an intermediate unpurified product. This was further purified by reverse-phase column chromatography (MeCN / aqueous NH4HCO3 0.2% (pH=7.9) = 50:50 to 75:25) to obtain Co.1 (45 mg, 25% yield) as a white solid.

[0395] The following compounds were prepared using the same procedure. [Table 39]

[0396] Synthesis of compound 7 (Co.7): [ka]

[0397] a) Synthesis of intermediate 12: [ka] Following the procedure described in the synthesis of Co.1, intermediate 12 (84 mg, 78% yield) was obtained as a red oily substance, starting from intermediates 8 and 9.

[0398] b) Step 5 - Synthesis of compound 7 (Co.7): Intermediate 12 (80 mg, 0.14 mmol) was dissolved in DCM (0.15 mL), and TFA (431 mg, 3.78 mmol, 0.28 mL) was added to the solution. The resulting reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / aqueous NH4HCO3 0.2% (pH=7.9) = 35:65~55:45 elution) to obtain Co.7 (3 mg, 5% yield) as a white solid.

[0399] Synthesis of compound 8 (Co.8): [ka] Intermediate 15 (86 mg, 0.23 mmol), 1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methaneamine hydrochloride (41.6 mg, 0.27 mmol), and TEA (69.4 mg, 0.69 mmol, 0.095 mL) were mixed in DCM (2.3 mL) and stirred at room temperature for 10 minutes (until completely dissolved). Then, sodium triacetoxyborohydride (96.9 mg, 0.46 mmol) was added all at once. The reaction mixture was stirred at room temperature for 16 hours. Volatile components were removed under reduced pressure. The residue was partitioned into two phases: saturated NaHCO3 aqueous solution and siRNA. The organic layer was washed once more with saturated NaHCO3 aqueous solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 95:5) to obtain the product, which was further purified by reversed-phase column chromatography (elution at MeCN / aqueous HCO2NH4 0.6 g / L (pH=3.5) = 10:90 to 50:50) to obtain Co.8 (27 mg, 25% yield) as a white solid.

[0400] The following compounds were prepared using the same procedure. [Table 40] TIFF2026514449000345.tif255170TIFF2026514449000346.tif255168TIFF20265144490 00347.tif253170TIFF2026514449000348.tif247170TIFF2026514449000349.tif190170

[0401] Synthesis of compound 143 (Co.143): [ka] A mixture of intermediate 324 (5 mg, 0.014 mmol), 1-cyclobutylmethanamine hydrochloride (2 mg, 0.017 mmol), and TEA (4.24 mg, 0.042 mmol, 5.82 μL) was stirred in 1,1,1,3,3,3-hexafluoroisopropanol (235 μL) at room temperature for 1 hour. Subsequently, NaBH4 (8.13 mg, 0.21 mmol) was added along with a few drops of MeOH, and the mixture was stirred at room temperature for 5 minutes. After adding MeOH, volatile components were removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 98:2) to obtain Co.143 (3 mg, 49% yield) as a white solid.

[0402] The following compounds were prepared using the same procedure. [Table 41]

[0403] Synthesis of compound 56 (Co.56) and compound 57 (Co.57): [ka]

[0404] a) Synthesis of intermediate 71: [ka] Starting from intermediate 15 and ((rac-trans)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methaneamine, intermediate 71 (151 mg, 76% yield) was obtained as a yellow oily substance according to the procedure described for the synthesis of Co. 8.

[0405] b) Synthesis of compound 56 (Co.56) and compound 57 (Co.57): Intermediate 71 (206 mg, 0.29 mmol) was dissolved in THF (0.58 mL), and TBAF (1.44 mL, 1.44 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for 1 hour. Volatile components were removed under reduced pressure, and the crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 98:2). Both enantiomers were eluted at CO2 / (MeOH + DCM[50 / 50] + 0.3% iPrNH2) = 65 / 35 and separated by SFC to obtain Co.56 (24 mg, 17% yield) as a pale beige solid and Co.57 (29 mg, 21% yield) as a pale beige solid.

[0406] Synthesis of compound 24 (Co.24): [ka] Starting with intermediate 22 (84 mg, 0.207 mmol) and 1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methaneamine hydrochloride (26.1 mg, 0.17 mmol), Co.24 (11 mg, 13% yield) was obtained as a white solid according to the procedure described for Co.8.

[0407] The following compounds were prepared using the same procedure. [Table 42]

[0408] Synthesis of compound 28 (Co.28): [ka] Starting with intermediate 28 (12.4 mg, 30.7 μmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (17 mg, 37 μmol), Co.28 (4 mg, 11% yield) was obtained as a white solid according to the procedure described for Co.8.

[0409] The following compounds were prepared using the same procedure. [Table 43]

[0410] Synthesis of compound 60 (Co.60) and compound 61 (Co.61): [ka] Intermediate 74 (143 mg, 0.35 mmol) and 1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methaneamine hydrochloride (63.3 mg, 0.42 mmol) were dissolved in acetonitrile (2.9 mL). TEA (0.15 mL, 1.044 mmol, 105 mg) was added to the solution, and the reaction mixture was stirred at 80°C for 36 hours. Volatile components were removed under reduced pressure, and the residue was partitioned between saturated NaHCO3 aqueous solution and RINKAN. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 95:5) to obtain the compound (80 mg, 47% yield) as a racemic mixture. This racemic product was eluted with CO2 / (MeOH+0.3%iPrNH2)=55 / 45 and purified by chiral SFC to obtain Co.60 (25 mg, 31% yield) as a white solid and Co.61 (25 mg, 31% yield) as a white solid.

[0411] The following compounds were prepared using the same procedure. [Table 44]

[0412] Synthesis of compound 30 (Co.30): [ka] Starting with intermediate 32 (76 mg, 0.24 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (50 mg, 0.26 mmol), Co.30 (22 mg, 19% yield) was obtained as a white solid according to the procedure described for Co.8.

[0413] Synthesis of compound 31 (Co.31): [ka] Intermediate 37 (50 mg, 0.15 mmol), 8-ethynylimidazo[1,5-a]pyridine (52 mg, 0.18 mmol), sodium ascorbate (36 mg, 0.18 mmol), and CuSO4 (4.9 mg, 0.03 mmol) were stirred in DMF (1.65 mL) / water (0.37 mL) at room temperature for 4 hours. The mixture was diluted with water and DCM, the organic layer was separated, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 98:2) to obtain Co.31 (56 mg, 78% yield) as a white solid.

[0414] The following compounds were prepared using the same procedure. [Table 45]

[0415] Synthesis of compound 35 (Co.35): [ka] Starting with intermediate 45 (100 mg, 0.27 mmol) and 1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methaneamine hydrochloride (49 mg, 0.32 mmol), Co.35 (21 mg, 17% yield) was obtained as a white solid according to the procedure described for Co.8.

[0416] The following compounds were prepared using the same procedure. [Table 46]

[0417] Synthesis of compound 38 (Co.38): [ka] Starting from intermediate 54 (64 mg, 0.23 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (42.9 mg, 0.23 mmol), Co.38 (30 mg, 29% yield) was obtained as a white solid according to the procedure described for Co.1.

[0418] Synthesis of compound 39 (Co.39): [ka] Starting with intermediate 59 (71 mg, 0.2 mmol) and cyclohexanemethylamine (25 mg, 3.11 mmol, 28.4 μL), the final compound Co.39 (14 mg, 8% yield) was obtained as a white solid according to the procedure described for Co.8.

[0419] Synthesis of compound 40 (Co.40): [ka] Starting with intermediate 63 (50 mg, 0.12 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (33 mg, 0.17 mmol), the final compound Co.40 (3 mg, 5% yield) was obtained as a white solid according to the procedure described for Co.1.

[0420] Synthesis of compound 41 (Co.41): [ka] Starting with intermediate 66 (6 mg, 0.03 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (7 mg, 0.03 mmol), Co.41 (3 mg, 28% yield) was obtained as a white solid according to the procedure described for Co.1.

[0421] Synthesis of compound 42 (Co.42): [ka] Starting with intermediate 70 (66 mg, 0.23 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (48.5 mg, 0.26 mmol), the final compound Co.42 (8 mg, 7% yield) was obtained as a white solid according to the procedure described for final compound 1.

[0422] Synthesis of compound 89 (Co.89): [ka] To a solution of intermediate 153 (17 mg, 0.025 mmol) dissolved in MeCN (0.16 mL), thiophenol (5.57 mg, 0.051 mmol, 5.2 μL) and Cs2CO3 (16.5 mg, 0.051 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated water and extracted with a mixed solvent of CHCl3 / IPA (3 / 1). The organic layers were washed together with brine, dried over sodium sulfate, filtered, and dried to dryness to obtain the crude product. The crude product was purified by C18 silica gel chromatography (eluting with water + 0.1% formic acid:MeCN = 85:15~70:30) to obtain a white solid (1.7 mg, 13% yield).

[0423] The following compounds were prepared using the same procedure. [Table 47]

[0424] Synthesis of compound 94 (Co.94): [ka]

[0425] a) Synthesis of intermediate 164: [ka] Potassium (bromomethyl)trifluoroboranoid (1 g, 4.98 mmol) was added to the vial, followed by THF (2.5 mL), tert-butanol (1.25 mL), and 1-cyclobutylmethanamine (509 mg, 5.98 mmol). The vial was sealed tightly and placed in a dry cell at room temperature, then stirred at 80°C for 2 hours. Volatile components were removed under reduced pressure. After drying the crude solid, it was dissolved in warm MeCN solution, and the solution was filtered to obtain intermediate 164 (536 mg, 64% yield) as a white solid.

[0426] b) Synthesis of compound 94 (Co.94): A mixture of intermediates 1223 (100 mg, 0.23 mmol), 164 (87.7 mg, 0.27 mmol), and Cs2CO3 (222 mg, 0.68 mmol) was added to dioxane (0.95 mL) and water (0.095 mL), and Di-μ-iodobis(tri-t-butylphosphino)dipalladium(I) (9.92 mg, 0.011 mmol) was added at room temperature. The reaction mixture was purged with N2 and heated at 100°C for 15 hours. Water was added, and the residue was extracted twice with siRNA and once with CHCl3 / IPA(3 / 1). The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated to obtain the crude product. The crude product was purified by silica gel chromatography (elution at DCM:MeOH = 100:0 to 85:15) to obtain Co.94 (17 mg, 16% yield) as a pale yellow solid.

[0427] The following compounds were prepared using the same procedure. [Table 48]

[0428] Synthesis of compound 96 (Co.96): [ka] Starting with intermediate 113 (200 mg, 0.36 mmol), the final compound Co.96 (147 mg, 90% yield) was obtained as a white solid following the procedure described for intermediate 8.

[0429] The following compounds were prepared using the same procedure. [Table 49]

[0430] Synthesis of compound 100 (Co.100): [ka] Intermediate 188 (150 mg, 0.26 mmol) was dissolved in DCM (0.84 mL), and TFA (449 mg, 3.94 mmol, 0.29 mL) was added to the solution. The resulting reaction mixture was stirred at room temperature for 1 hour. DCM and saturated Na2CO3 aqueous solution were added, the organic layer was washed twice with saturated Na2CO3 aqueous solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain Co.100 (115 mg, 93% yield) as a white solid.

[0431] The following compounds were prepared using the same procedure. [Table 50] TIFF2026514449000379.tif249170TIFF2026514449000380.tif237170TIFF2026514449000381.tif211170

[0432] Synthesis of compound 137 (Co.137): [ka] Starting with intermediate 261 (50 mg, 0.085 mmol), the final compound Co.137 (15 mg, 36% yield) was obtained as a white solid following the procedure described for intermediate 8.

[0433] The following compounds were prepared using the same procedure. [Table 51]

[0434] LCMS (Liquid Chromatography / Mass Spectrometry) LCMS general procedure High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array (DAD), or UV detector, and the column specified for each method. Additional detectors were included as needed (see the table below for each method).

[0435] The effluent from the column was introduced into a mass spectrometer (MS) equipped with an atmospheric pressure ionization source. Setting adjustment parameters such as scanning range and duel time to obtain ions identifiable for determining the nominal monoisotopic molecular weight (MW) of the compound is within the knowledge of those skilled in the art. Data acquisition was performed using appropriate software.

[0436] The compound's experimental retention time (R t ) and ions are described. Unless otherwise specified in the data table, the reported molecular ions are [M+H] + (protonated molecule) and / or [MH] - This corresponds to a (deprotonated molecule). If the compound is not directly ionized, the type of adduct is specified (e.g., [M+NH4]). + [M + HCOO] - (etc.). For molecules with multiple isotopic patterns, such as Br and Cl, the reported values ​​are based on the lowest isotopic mass. All results are subject to the experimental errors generally associated with the method of use.

[0437] Hereafter, "MSD" stands for Mass Selective Detector, and "DAD" stands for Diode Array Detector.

[0438] [Table 52]

[0439] [Table 53] TIFF2026514449000386.tif221170TIFF2026514449000387.tif221170TIFF2026514449000388.tif231170

[0440] NMR Several NMR measurements were performed using a Bruker Avance 500 spectrometer fitted with a Bruker 5mm BBFO probe head with a z-axis gradient, with 500 MHz for protons and fluorine ( 19 For F), the test was conducted at 471 MHz. The chemical shift (δ) is shown in parts per million (ppm), and the J value is expressed in Hz.

[0441] [Table 54]

[0442] Pharmacology Department MTase Glo assay The methyltransferase activity of METTL3 was measured by Promega's (V7602) MTase Glo TM The bioluminescence was measured using a bioluminescence assay kit.

[0443] The enzyme used was a recombinant METTL3 / METTL14 complex containing full-length human METTL3 (accession number NP_062826.2, untagged) and full-length human METTL14 protein with a FLAG tag at the N-terminus (accession number NP_066012.1), expressed in Sf9 cells from Actif Motif. The synthetic RNA substrate 5'UACACUCGAUCUGGACUAAAG.CUGCUC 3' was purchased from Horizon Discovery. The enzymatic reaction was performed in duplicate in an Optiplate 96 half-area (Perkin Elmer 6002290) with a final volume of 10 μL, under conditions including 20 mM Tris-HCl (pH 7.5), 0.01% Triton X-100, and 2 mM MgCl2. The experiment was also performed again independently in duplicate.

[0444] METTL3 / 14 solution (RNA substrate (10 μM) and MTaseGlo to convert the resulting SAH to ADP) TM The reagents were pre-incubated at room temperature for 10 minutes under various concentrations of the compound (final concentrations of the compound ranged from 5 μM to 0.25 nM with 1% DMSO remaining). Then, SAM (final concentration 0.6 μM) was added and the enzymatic reaction was incubated at room temperature for 60 minutes. MTaseGlo was used to convert ADP to ATP. TM The detection solution was added, and the resulting reaction mixture was incubated at room temperature for a further 60 minutes.

[0445] Luminescence signals were measured using a plate-reading luminometer (SpectraMax i3X) and correlated with SAH concentration. Inhibition rates were obtained by normalizing to a control well without inhibition (DMSO only). IC 50 The values ​​were calculated by measuring enzyme activity against a dilution series of inhibitor concentrations (10 levels of concentration, 3-fold dilution) using a 4-parameter nonlinear regression analysis.

[0446] Cell proliferation assay MOLM-13 cells and Kasumi-1 cells were seeded in quadruple rows in 27 μL of suspension in 384-well plates (Greiner 781080) at concentrations of 1200 cells / well and 10000 cells / well, respectively. RPMI 1640 medium containing 10% fetal bovine serum, 2 mM glutamine, and 0.2% Pen / Strep was used as the culture medium. Cells were treated by adding 3 μL of intermediate compound / medium concentration solution. This resulted in final compound concentrations ranging from 50 μM to 2.54 nM with residual 0.5% DMSO. Intermediate (10-fold) compound / medium dilution plates were prepared by taking 5 μL of compound solution from the initial compound dilution plate (concentration range of 10 mM to 508 nM in 100% DMSO) and mixing it with 95 μL of medium. Cells were incubated at 37°C under a 5% CO2 and humidified atmosphere. Luminescence signaling was measured on day 5 using the CellTiter-Glo® luminescent cell viability assay (30 μL / well; Promega, G7572), and relative cell proliferation rates were calculated compared to control wells with and without cells treated with 0.5% DMSO alone.

[0447] [Table 55] TIFF2026514449000391.tif220170TIFF2026514449000392.tif220170TIFF2026514449000393.tif214170TIFF2026514449000394.tif50170

[0448] reference No reference herein to patents, patent applications, publications, or other documents, in particular to the documents listed below, should be construed as an indication that such patents, patent applications, publications, or matters were publicly known on the priority date, or that the teachings thereof were part of the well-known art. (1) Barbieri I &. Kouzarides T (2020) Role of RNA modifications in cancer. Nat Rev Cancer. 20(6):303-322; (2) Li W, Hao Y, Zhang X, Xu S, Pang D (2022) Targeting RNA N6-methyladenosine modification: a precise weapon in overcoming tumor immune escape. Mol Cancer. 21(1):176; (3) Liu S, Zhuo L, Wang J, Zhang Q, Li Q, Li G, Yan L, Jin T, Pan T, Sui X, Lv Q, Xie T (2020) METTL3 plays multiple functions in biological processes. Am J Cancer Res. 10(6):1631-1646; (4) Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24(2):177-89; (5) Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P (2016) Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 534:575-8; (6) Yang C, Hu Y, Zhou B, Bao Y, Li Z, Gong C, Yang H, Wang S, Xiao Y (2020) The role of m6A modification in physiology and disease. Cell Death Dis. 11(11):960; (7) WO2020201773; (8) WO2021111124; (9) WO2022074379; (10) WO2022074391; (11) WO2022254216; (12) WO2022254218; (13) WO2021079196; (14) WO2021081211; (15) WO2022081739.

Claims

1. Equation (I): 【Chemistry 1】 A compound thereof, or its tautomers, stereoisomers, salts, solvates, or N-oxides, wherein, A １ represents CR １ａ or N, and A ２ represents CR ２ａ or N, and A ３ represents CR ３ａ or N, and A ４ represents CR ４ａ or N, and A ５ represents CR ５ａ or N, and A ６ represents CR ６ａ or N; However, A １ A ２ A ３ A ４ A ５ , and A ６ No more than three of them represent N; R １ａ ~R ６ａ These are independently hydrogen, hydroxyl, halo, cyano, and C. １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Alkoxy, C ３－４ Cycloalkyl, 3-5 membered heterocyclic group, C ３－４ This represents a cycloalkyloxy or a 3- to 5-membered heterocyclic oxy, and these C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Alkoxy, C ３－４ Cycloalkyl, 3-5 membered heterocyclic group, C ３－４ Cycloalkyloxy, or 3- to 5-membered heterocyclic oxy, is defined as cyano, hydroxy, halo, -C(O)NH ２ , -C(O)NH(C １－４ Alkyl), -C(O)N(C １－４ Alkyl) ２ , -CO ２ H, -CO ２ (C １－４ Alkyl), C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, and O-C ３－６ Optionally substituted with one or more substituents selected from cycloalkyl groups: R ７ａ and R ７ｂ Independently, (i) Hydrogen; (ii) Halo, cyano, hydroxy, C １－４ Alkoxy and C １－４ C optionally substituted with one or more substituents selected from haloalkoxys １－６ Alkyl Select from, (iii) or R ７ａ and R ７ｂ They bond together with the carbon atoms to which they bond, forming a 3- to 6-membered cycloalkanediyl or heterocyclic group; R ８ａ and R ８ｂ Independently (i) Hydrogen, (ii) Cyano, Hydroxy, Halo, C １－２ Alkoxy and C １－２ C optionally substituted with one or more substituents selected from haloalkoxys １－６ Alkyl, (iii) Formula (CR ｃ R ｄ ) ｎ - is the basis of Z n is 0, 1, or 2, R ｃ and R ｄ Independently, hydrogen, Cyano, hydroxy, halo, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－６ Cycloalkyl and -O-C ３－６ C optionally substituted with one or more substituents selected from cycloalkyl groups １－６ Alkyl, C ３－６ Cycloalkyl and -O-C ３－６ The cycloalkyl group is optionally substituted with one or more substituents selected from halo, cyano, and hydroxyl groups. １－６ Alkyl Select from, Or, R ｃ and R ｄ They bond together, and together with the carbon atoms they bond to, they form cyano, hydroxy, halo, C １－２ Alkyl, C １－２ Haloalkyl, C １－２ Alkoxy, and C １－２ A 3- to 6-membered cycloalkanediyl or heterocyclic group is formed, optionally substituted with one or more substituents selected from haloalkoxys. Z is, Hydrogen, cyano, hydroxy, R ａ and R ｂ is H or C １－２ NR is alkyl ａ R ｂ or -S(O) ０－２ R ａ R ｂ , and each being halo, cyano, hydroxy, C １－２ alkyl, C １－２ haloalkyl, C １－２ hydroxyalkyl, C １－２ alkoxy, C １－２ haloalkoxy, C ２－３ alkenyl, NR ａ R ｂ , and -S(O) ０－２ R ａ R ｂ optionally substituted with one or more substituents selected from C ２－３ alkenyl, C ２－３ alkynyl, C ３－８ cycloalkyl, aryl, heterocyclic group, heteroaromatic group, bicyclic C ５－１２ cycloalkyl Selected from; (iv) or R ８ａ and R ８ｂ They bond together, and together with the nitrogen atom they bond to, they form halo, cyano, hydroxy, and C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ２－３ Alkenil, NR ａ R ｂ , and -S(O) ０－２ R ａ R ｂ A monocyclic or bicyclic heterocyclic group is formed which is optionally substituted with one or more substituents selected from R ａ and R ｂ H or C １－４ It is alkyl; X is, 【Chemistry 2】 Selected from, In the formula, the dotted line indicates the bond location to Y, and the wavy line indicates the bond location to the rest of the molecule; R ｃ and R ｄ These are independently hydrogen and C １－４ Selected from alkyl groups, C １－４ Alkyls include halo, hydroxy, cyano, and C. １－４ Optionally substituted with one or more substituents selected from the group consisting of alkoxys; R ｅ and R ｆ These are independently hydrogen, halo, hydroxyl, and C. １－４ Selected from alkyl groups, C １－４ Alkyls include halo, hydroxy, cyano, and C. １－４ Optionally substituted with one or more substituents selected from the group consisting of alkoxys; R ｃ R ｄ and R ｅ R ｆ They bond together, and together with the carbon atoms to which they bond, they form halo, methyl, cyano, hydroxy, and C １－４ C is optionally substituted with one or more substituents selected from the group consisting of alkoxys. ３－４ They may also form cycloalkanediyl; Y is selected from one of the following structures i) to v): 【Transformation 3】 During the ceremony, G １ CR ｈ And selected from N, where R ｈ are hydrogen, hydroxyl, halo, cyano, C １－４ Alkyl, C ２－４ Alkenil, C ２－４ Alkinyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－４ Cycloalkyl groups, 5- or 6-membered heteroaromatic groups, 3- to 4-membered heterocyclic groups, and -O-C ３－４ Selected from cycloalkyl; G ２ N and CR ｇ Selected from, here, R ｇ are hydrogen, hydroxyl, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ２－４ Alkenil, C ２－４ Alkynyl, phenyl, 5-membered or 6-membered heteroaromatic group, C ３－６ Cycloalkyl, -O-C ３－６ Cycloalkyl, heterocyclic group, -O- (carbon-linked heterocyclic group), -(OCH ２ CH ２ ) ｍ -NR ｙ R ｚ ,-(OCH ２ CH ２ ) ｍ - OCH ３ , NR ｙ R ｚ , and -C(O)-NR ｙ R ｚ Selected from, In the formula, m is an integer from 1 to 6, and R ｙ and R ｚ These are, independently, hydrogen and C. １－４ Alkyl, C ３－６ It is a cycloalkyl group, a 3-6 membered carbon linked heterocyclic group, or R ｙ and R ｚ They bond together with the nitrogen atom to which they bond, forming a 3- to 6-membered heterocyclic group; Furthermore, C １－４ Alkyl, C １－４ Alkoxy, C ２－４ Alkenil, C ２－４ Alkynyl, phenyl, 5-membered or 6-membered heteroaromatic group, C ３－６ Cycloalkyl, -O-C ３－６ One of the cycloalkyl, heterocyclic, and -O- (carbon-linked heterocyclic) groups is hydroxy, cyano, halo, or C. １－２ Alkyl, C １－２ Haloalkyl, C １－２ Alkoxy, C １－２ Haloalkoxy, NR ａ R ｂ , or -S(O) ０－２ R ａ R ｂ Optionally substituted with one or more substituents selected from R ａ and R ｂ H or C １－２ It is alkyl; G ３ is N or CR ｉ And R ｉ is hydrogen, hydroxyl, cyano, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkoxy, C ３－６ Cycloalkyl and -O-C ３－６ Selected from cycloalkyl, C ３－６ Cycloalkyl and -O-C ３－６ The cycloalkyl group is optionally substituted with one or more substituents selected from halo, methyl, and methoxy; G ４ is selected from C and N; G ５ CR ｊ and NR ｘ Selected from, in the formula, R ｊ is hydrogen, hydroxyl, cyano, halo, C １－４ Alkyl, NH ２ , and C １－４ Selected from alkoxy, R ｘ is hydrogen and C １－４ Selected from alkyl groups; G ７ N, NR ａ , or CR ｊ And, G ８ is selected from C and N, However, G １ ~G ８ Four or fewer of these, preferably one, two, or three, are N or NR. ａ It is; 【Chemistry 4】 Y ２ CR ｋ and selected from N, R ｋ is hydrogen, halo, C １－４ Alkyl, cyano, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy and C ３－４ Cycloalkyl groups, 3-4 membered heterocyclic groups, and C ３－４ Selected from cycloalkoxys; Y ３ is N or CR ｌ And here, R ｌ is hydrogen, hydroxyl, cyano, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkoxy, C ３－６ Cycloalkyl and -O-C ３－６ Selected from cycloalkyl, where C ３－６ Cycloalkyl and -O-C ３－６ The cycloalkyl group is optionally substituted with one or more substituents selected from halo, methyl, and methoxy; Y ４ is C or N, Y ５ CR ｍ Or NR ｘ And in the formula, R ｍ is hydrogen, halo, hydroxy, cyano, C ３－６ Cycloalkyl, NH ２ , C １－４ Alkoxy, and OH, C １－４ Alkoxy and C ３－６ C is optionally substituted with a cycloalkyl group. １－４ Selected from alkyl groups; R ｘ is hydrogen and C １－４ Selected from alkyl groups; Y ６ CR ｍ or N; Y ７ O, S, CR ｍ , or N; Y ８ is C or N; Y ９ CR ｍ or N; However, Y １ ~Y ８ N is defined as four or fewer of these; 【Transformation 5】 X １ is N or CR ｎ And R ｎ These are hydrogen, halo, cyano, and C. １－４ Alkyl, C １－４ Haloalkyl and C １－４ Selected from haloalkoxys; X ２ is N or CR ｎ And; X ３ is N; X ４ is N or C; X ５ N, CR ｎ , and CR ｎ R ｎ１ Selected from, in the formula, R ｎ and R ｎ１ These are independently hydrogen, halo, cyano, and C. １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ Selected from haloalkoxys; X ６ and X ７ CR ｎ or N; or X ６ CR ｎ R ｎ１ Or NR ｘ X ７ CR ｎ R ｎ１ CR ｏ R ｏ１ , or NR ｘ And; R ｎ and R ｎ１ These are independently hydrogen, halo, cyano, and C. １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ Selected from haloalkoxys; R ｘ is hydrogen or C １－４ It is alkyl; R ｏ and R ｏ１ These are independently selected from hydrogen, halo, methoxy, and methyl; X ８ N, CR ｎ , or CR ｎ R ｎ１ And R ｎ and R ｎ１ These are independently hydrogen, halo, cyano, and C. １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ Selected from haloalkoxys; X ９ is N or C; However, X ２ ~X ９ N is defined as four or fewer of these; 【Transformation 6】 L １ ~L ７ Independently, N or CR ｎ And R ｎ These are hydrogen, halo, cyano, and C. １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ Selected from haloalkoxys, However, L １ ~L ７ The number of elements representing N may not exceed three; 【Transformation 7】 E １ CR １ or N; E ２ CR ２ or N; E ３ CR ３ or N; E ４ CR ４ or N, E ５ CR ５ or N; E ６ NR ６ or CR ６ａ R ６ｂ And, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ａ , and R ６ｂ These are independently of hydrogen and NR ｙ１ R ｙ２ , Halo, Cyano, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Haloalkyl, -CH ２ OCH ３ ien-CH ２ SO ２ CH ３ , -P(O)(C １－４ Alkyl) ２ , -SO ２ CH ３ , -NHC(O)CH ３ , -C(O)NR ｘ１ R ｘ２ , and C which is optionally substituted with OH ３－６ Selected from cycloalkyl, R ｘ１ and R ｘ２ These are independently hydrogen or methyl C １－４ Selected from alkyl groups, R ｙ１ and R ｙ２ These are independently hydrogen and C ３－６ C such as cycloalkyl or methyl ３－６ C is optionally substituted with a cycloalkyl group. １－４ Selected from alkyl groups, or together with the nitrogen atoms bearing them, they form a five-membered or six-membered heteroaromatic or heterocyclic group, wherein the five-membered or six-membered heteroaromatic or heterocyclic group is OH, C １－４ Alkoxy, or OH or C １－４ C arbitrarily substituted with alkoxy １－４ The heterocyclic group is optionally substituted with alkyl, and the heterocyclic group is a 4- to 7-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, where each ring of the bicyclic heterocyclic group has a 3- to 6-membered ring; R ６ is hydrogen, NH ２ , halo, cyano, and C １－４ Selected from alkyl groups; or R ５ and R ４ These atoms bond together, forming a five-membered or six-membered heterocyclic group with the atoms to which they bond. or R ４ and R ３ They bond together, and together with the atoms they bond to, they form a five-membered or six-membered heterocyclic group. In the formula, the five-membered or six-membered heterocyclic group is oxo, cyano, hydroxy, halo, or C. １－２ Alkyl, C ３－６ Cycloalkyl, C １－２ Haloalkyl, C １－２ Alkoxy, C １－２ Haloalkoxy, NR ｙ１ R ｙ２ , or -S(O) ０－２ R ｙ１ R ｙ２ Optionally substituted with one or more substituents selected from R ｙ１ and R ｙ２ is H or C １－２ It is alkyl; However, E １ ~E ５ The number of items representing N may not exceed three. A compound, or its tautomers, stereoisomers, salts, solvates, or N-oxides.

2. A １ CR １ａ Or it represents N; A ２ CR ２ａ Or it represents N; A ３ CR ３ａ Or it represents N; A ４ CR ４ａ Or it represents N; A ５ CR ５ａ Or it represents N; A ６ CR ６ａ It also represents N; However, A １ A ２ A ３ A ４ A ５ , and A ６ Among these, there are 0, 1, or 2 that represent N; R １ａ ~R ６ａ These are independently hydrogen, hydroxyl, halo, and C. １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Represents an alkoxy; preferably R ２ａ , R ３ａ , R ４ａ , and R ６ａ Each of these represents hydrogen, and R １ａ and R ５ａ Each of these independently produces hydrogen, hydroxyl, halo, and C. １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, or C １－４ Represents haloalkoxy, The compound according to claim 1. 【Request Item 3】 【Transformation 8】 Selected from, In particular, R １ａ ~R ６ａ Each of these independently produces hydrogen, hydroxyl, halo, cyano, and C. １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, or C １－４ Represents an alkoxy, and the C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkyl, or C １－４ The alkoxys are cyano, hydroxy, halo, and -C(O)NH, respectively. ２ , -C(O)NH(C １－４ Alkyl), -C(O)N(C １－４ Alkyl) ２ , -CO ２ H, -CO ２ (C １－４ Alkyl), C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Alkyl and C １－４ Optionally substituted with one or more substituents selected from haloalkyl groups, The compound according to claim 1 or 2.

4. R ７ａ H is R ７ｂ is hydrogen, or halo, cyano, hydroxy, C １－４ Alkoxy and C １－４ C, optionally substituted with one or more substituents selected from haloalkoxys １－６ Alkyl, especially hydroxy and C １－４ Selected from alkoxys, preferably R ７ａ and R ７ｂ The compound according to any one of claims 1 to 3, wherein both are hydrogen.

5. R ８ａ H is R ８ｂ is, formula - (CR ｃ R ｄ ) ｎ -Z, for example- (CHR ｄ ) ｎ -Z is the basis, and especially -CHR ｄ -Z or -Z, R ｄ Preferably hydrogen, or R ８ａ and R ８ｂ They bond together, and together with the nitrogen atom to which they bond, they form halo, cyano, hydroxy, and C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ２－３ Alkenil, NR ａ R ｂ , and -S(O) ０－２ R ａ R ｂ One or more substituents selected from, preferably halo, hydroxy, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy and C ２－３ A monocyclic or bicyclic heterocyclic group is formed by optionally substituting one or more substituents selected from alkenyls. The compound according to any one of claims 1 to 4.

6. Z is C ３－８ Cycloalkyl or bicyclic C ５－８ These are cycloalkyls, and all of them are halo, cyano, hydroxy, and C. １－２ Alkyl, C １－２ Haloalkyl, C １－２ Hydroxyalkyl, C １－２ Alkoxy, C １－２ Haloalkoxy, C ２－３ Alkenil, NR ａ R ｂ , and -S(O) ０－２ R ａ R ｂ Optionally substituted with one or more substituents selected from, for example, fluoro, halo, hydroxy, C １－２ Alkyl, C １－２ Haloalkyl, C １－２ Hydroxyalkyl, C １－２ Alkoxy and C １－２ The compound according to any one of claims 1 to 5, optionally substituted with one or more substituents selected from haloalkoxys, particularly one or two substituents.

7. X is, 【Chemistry 9】 Selected from, preferably 【Chemistry 10】 A compound selected from any one of claims 1 to 6.

8. Y is selected from one of the following structures i) to v): 【Chemistry 11】 especially, R ｈ is hydrogen, halo, hydroxyl, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl and C １－４ Selected from haloalkoxys, preferably H, R ｇ is hydrogen, halo, hydroxyl, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl and C １－４ Selected from haloalkoxys, preferably H or C １－４ It is an alkoxy, R ｉ is hydrogen, halo, hydroxyl, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl and C １－４ Selected from haloalkoxys, particularly hydrogen or C １－４ It is an alkoxy, preferably H, R ｊ is hydrogen, halo, hydroxyl, C １－４ Alkyl and C １－４ Selected from alkoxys, preferably H, and R ｘ is hydrogen and C １－４ Selected from alkyl groups, preferably H; 【Chemistry 12】 especially, R ｋ is hydrogen, halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl and C １－４ Selected from haloalkoxys, preferably H, R ｍ is hydrogen, halo, hydroxyl, C ３－６ Cycloalkyl, C １－４ Alkoxy, as well as OH, C １－４ Alkoxy and C ３－６ C is optionally substituted with a cycloalkyl group. １－４ Selected from alkyl groups, for example, hydrogen, halo, hydroxyl, C １－４ Alkyl and C １－４ Selected from alkoxys, preferably H, C ３－６ Cycloalkyl, or OH, C １－４ Alkoxy and C ３－６ C is optionally substituted with a cycloalkyl group. １－４ Selected from alkyl groups, and especially selected from H, R ｘ is hydrogen and C １－４ Selected from alkyl groups, preferably H; 【Chemistry 13】 In particular, R ｎ is hydrogen, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and C １－４ Selected from haloalkoxys, preferably H; 【Chemistry 14】 In the formula, R １ , R ３ , R ４ , R ５ Preferably, each is independently hydrogen, NR ｙ１ R ｙ２ , Halo, Cyano, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Alkyl, C １－４ Haloalkyl, -CH ２ OCH ３ ien-CH ２ SO ２ CH ３ , -P(O)(C １－４ Alkyl) ２ , -SO ２ CH ３ , -NHC(O)CH ３ , -C(O)NR ｘ１ R ｘ２ , and C which is optionally substituted with OH ３－６ Selected from cycloalkyl groups, Here, R ｘ１ and R ｘ２ Independently, hydrogen and C １－４ Selected from alkyl groups, R ｙ１ and R ｙ２ These are independently hydrogen and C ３－６ Cycloalkyl, and C ３－６ C is optionally substituted with a cycloalkyl group. １－４ Selected from alkyl groups, or R ｙ１ and R ｙ２ These may form a five-membered or six-membered heteroaromatic group or heterocyclic group together with N which holds them, and the five-membered or six-membered heteroaromatic group or heterocyclic group may be OH, C １－４ Alkoxy, or OH or C １－４ C arbitrarily substituted with alkoxy １－４ The alkyl group is optionally substituted, and the heterocyclic group is a monocyclic heterocyclic group with 4 to 7 members, or a bicyclic heterocyclic group in which each ring has 3 to 6 members. or R ４ and R ３ These atoms bond together, forming a five-membered or six-membered heterocyclic group with the atoms they bond to, and the five-membered or six-membered heterocyclic group optionally contains C ３－６ It is spirocondensed with a cycloalkyl group, and / or oxo, cyano, hydroxy, halo, C １－２ Alkyl, C １－２ Cycloalkyl, C １－２ Haloalkyl, C １－２ Alkoxy, C １－２ Haloalkoxy, NR ｙ１ R ｙ２ , or -S(O) ０－２ R ｙ１ R ｙ２ (In the formula, R ｙ１ and R ｙ２ is H or C １－２ Optionally substituted with one or more substituents selected from alkyl groups, E ７ is O or CH ２ And, R ３ These independently represent H, or together represent two R's. ３’ The substituent is an oxo group (=O) or C ３－５ Represents cycloalkyl, R ４’ These independently represent H, or together represent two R's. ４’ The substituent is an oxo group (=O) or C ３－５ Represents a cycloalkyl group; In particular, R １ , R ３ , R ４ , R ５ These are independently of hydrogen and NR ｙ１ R ｙ２ , Halo, Cyano, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Alkyl and C １－４ It is a haloalkyl, The compound according to any one of claims 1 to 7.

9. Y is, 【Chemistry 15】 A compound selected from any one of claims 1 to 8.

10. The compound of formula (I) is as follows: A compound according to any one of claims 1 to 9, selected from, and salts thereof.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, further comprising other anticancer agents.

13. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or 12, for use as a pharmaceutical agent, particularly for use as a pharmaceutical agent having METTL3 inhibitory activity.

14. A compound according to any one of claims 1 to 10 or a composition according to claim 11 or 12 for use in the treatment or prevention of cancer, or autoimmune diseases, neurological diseases, infectious diseases, or inflammatory diseases.

15. A compound or composition for the use of claim 13 or 14 in combination therapy with radiotherapy or combination therapy with an immunostimulant such as a vaccine.

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