Search

JP-2026514449-A - Novel METTL3 inhibitors and their therapeutic use

JP2026514449AJP 2026514449 AJP2026514449 AJP 2026514449AJP-2026514449-A

Abstract

The present invention relates to formula (I): [Chemical formula 1] The present invention relates to a compound, or its tautomers, stereoisomers, salts, solvates, or N-oxides, wherein A1 to A6 , X, Y, R7a , R7b , R8a , and R8b are as defined in the claims. The present invention further relates to pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier, and their uses as agents, particularly 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.

Inventors

  • ムヴェレック，ロランス
  • プレヴェ，ユグ
  • シャンベル，フィリップ
  • ジョルジュ，ニコラ

Assignees

  • ノヴァリックス
  • アケミア

Dates

Publication Date
20260511
Application Date
20240329
Priority Date
20230330

Claims (15)

  1. Equation (I): A compound thereof, or its tautomers, stereoisomers, salts, solvates, or N-oxides, In the formula, A1 represents CR1a or N, A2 represents CR2a or N, A3 represents CR3a or N , A4 represents CR4a or N, A5 represents CR5a or N, and A6 represents CR6a or N; However, no more than three of A1 , A2 , A3 , A4 , A5 , and A6 may represent N; R1a to R6a each independently represent hydrogen, hydroxyl, halo, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, 3-5 membered heterocyclic group, C3-4 cycloalkyloxy, or 3-5 membered heterocyclic oxy. These C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, 3-5 membered heterocyclic group, C3-4 cycloalkyloxy, or 3-5 membered heterocyclic oxy are cyano, hydroxyl, halo, -C(O)NH2, -C(O)NH( C1-4 alkyl), -C(O) N ( C1-4 alkyl) 2 , -CO2H , -CO2 ( C1-4 alkyl), C1-4 alkoxy, C Optionally substituted with one or more substituents selected from 1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, and O- C3-6 cycloalkyl: R 7a and R 7b are independent of each other. (i) Hydrogen; (ii) Selected from C1-6 alkyl groups which are optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C1-4 alkoxy, and C1-4 haloalkoxy groups, (iii) or R7a and R7b bond together with the carbon atoms to which they bond to form a 3- to 6-membered cycloalkanediyl or heterocyclic group; R8a and R8b independently contain (i) hydrogen, (ii) C1-6 alkyl groups optionally substituted with one or more substituents selected from cyano, hydroxy, halo, C1-2 alkoxy, and C1-2 haloalkoxy groups. (iii) Equation (CR c R d ) n is the basis of Z, where n is 0, 1, or 2, R c and R d are independent of each other. hydrogen, A C1-6 alkyl group optionally substituted with one or more substituents selected from cyano, hydroxy, halo, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, and -O- C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O- C3-6 cycloalkyl groups are selected from C1-6 alkyl groups, which are optionally substituted with one or more substituents selected from halo, cyano, and hydroxy. Alternatively, R c and R d may bond together with the carbon atoms to which they are bonded to form a 3- to 6 - membered cycloalkanediyl or heterocyclic group which may be optionally substituted with one or more substituents selected from cyano, hydroxy, halo, C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, and C1-2 haloalkoxy. Z is, Hydrogen, cyano, hydroxy, NR a R b or -S(O) 0-2 R a R b , where R a and R b are H or C 1-2 alkyl, and selected from C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, aryl, heterocyclic, heteroaromatic , bicyclic C 5-12 cycloalkyl, each optionally substituted with one or more substituents selected from 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 ; (iv) or R 8a and R 8b are bonded together with the nitrogen atom to which they are bonded to form a monocyclic or bicyclic heterocyclic group optionally substituted with one or more substituents selected from H, cyano, hydroxy , C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-3 alkenyl, NR a R b , and -S(O) 0-2 R a R b , where R a and R b are independently H or C1-4 alkyl; X is, 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; Rc and Rd are independently selected from hydrogen and C1-4 alkyl, and the C1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, and C1-4 alkoxy; Re and R f are independently selected from hydrogen, halo, hydroxy, and C1-4 alkyl, and the C1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, and C1-4 alkoxy; R c R d and Re R f may bond together to form a C3-4 cycloalkanediyl, which, together with the carbon atoms to which they are bonded, may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl, cyano, hydroxy, and C1-4 alkoxy; Y is selected from one of the following structures i) to v): During the ceremony, G1 is selected from CR h and N, where R h is selected from hydrogen, hydroxy, halo, cyano, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-4 cycloalkyl, 5- or 6-membered heteroaromatic groups, 3- to 4-membered heterocyclic groups, and -O- C3-4 cycloalkyl; G2 is selected from N and CR g , where R g is selected from hydrogen, hydroxy, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-membered or 6-membered heteroaromatic group, C3-6 cycloalkyl, -O- C3-6 cycloalkyl, heterocyclic group, -O-(carbon-linked heterocyclic group), -( OCH2CH2 ) m - NRyRz , - ( OCH2CH2 ) m - OCH3 , NRyRz , and -C(O ) -NRyRz . In the formula, m is an integer from 1 to 6, and Ry and Rz are independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, or a 3-6 membered carbon-linked heterocyclic group, or Ry and Rz are bonded together with the nitrogen atom to which they are bonded to form a 3-6 membered heterocyclic group; Furthermore, any of the following are optionally substituted with one or more substituents selected from hydroxy , cyano, halo, C1-2 alkyl, C1-2 haloalkyl, C1-2 alkene, C2-4 alkynyl, phenyl, 5 -membered or 6-membered heteroaromatic group, C3-6 cycloalkyl, -O- C3-6 cycloalkyl, heterocyclic group, and -O- (carbon - linked heterocyclic group): R a R b , or -S(O) O-2 R a R b , where R a and R b are independently H or C1-2 alkyl; G3 is N or CRi , where Ri is selected from hydrogen, hydroxy, cyano, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkoxy, C3-6 cycloalkyl, and -O- C3-6 cycloalkyl, and C3-6 cycloalkyl and -O- C3-6 cycloalkyl are optionally substituted with one or more substituents selected from halo, methyl, and methoxy; G4 is selected from C and N; G 5 is selected from CR j and NR x , in the formula, Rj is selected from hydrogen, hydroxyl, cyano, halo, C1-4 alkyl, NH2 , and C1-4 alkoxy, and Rx is selected from hydrogen and C1-4 alkyl; G 7 is N, NR a , or CR j . G 8 is selected from C and N, However, four or fewer of G1 to G8 , preferably one, two, or three, are N or NRa ; Y2 is selected from CR k and N, and R k is selected from hydrogen, halo, C1-4 alkyl, cyano, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, and C3-4 cycloalkyl, 3-4 membered heterocyclic groups, and C3-4 cycloalkoxy; Y3 is N or CR1 , where R1 is selected from hydrogen, hydroxy, cyano, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkoxy, C3-6 cycloalkyl, and -O- C3-6 cycloalkyl, where C3-6 cycloalkyl and -O- C3-6 cycloalkyl are optionally substituted with one or more substituents selected from halo, methyl, and methoxy; Y4 is C or N, Y 5 is CR m or NR x , in the formula, R m is selected from hydrogen, halo, hydroxy, cyano, C3-6 cycloalkyl, NH2 , C1-4 alkoxy, and C1-4 alkyl which are optionally substituted with OH, C1-4 alkoxy, and C3-6 cycloalkyl; Rx is selected from hydrogen and C1-4 alkyl; Y 6 is CR m or N; Y7 is O, S, CR m , or N; Y 8 is C or N; Y 9 is CR m or N; However, four or fewer of Y1 to Y8 are N; X1 is N or CRn , and Rn is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, and C1-4 haloalkoxy; X² is N or CRn ; X 3 is N; X 4 is N or C; X5 is selected from N, CR n , and CR n R n1 , in the formula, R n and R n1 are independently selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; X6 and X7 are independently CR n or 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 ; R n and R n1 are independently selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R x is hydrogen or C1-4 alkyl; Ro and Ro1 are independently selected from hydrogen, halo, methoxy, and methyl; X8 is N, CR n , or CR n R n1 , where R n and R n1 are independently selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; X 9 is N or C; However, four or fewer of X2 to X9 are N; L1 to L7 are independently N or CRn , where Rn is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. However, no more than three of L1 to L7 represent N; E 1 is CR 1 or N; E 2 is CR 2 or N; E 3 is CR 3 or N; E 4 is CR 4 or N, E 5 is CR 5 or N; E 6 is NR 6 or CR 6a R 6b , In the formula, R1 , R2 , R3 , R4 , R5 , R6a , and R6b are each independently selected from hydrogen, NRy1 Ry2 , halo, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, -CH2OCH3 , -CH2SO2CH3 , -P ( O )( C1-4 alkyl) 2 , -SO2CH3 , -NHC (O) CH3 , -C (O) NRx1 Rx2 , and C3-6 cycloalkyls optionally substituted with OH, Rx1 and Rx2 are independently selected from hydrogen or C1-4 alkyls such as methyl, and Ry1 and Ry2 are independently selected from hydrogen, C A 5 -membered or 6-membered heteroaromatic or heterocyclic group is formed with a nitrogen atom, selected from a C1-4 alkyl group optionally substituted with a C3-6 cycloalkyl such as a 3-6 cycloalkyl or methyl group, and the 5-membered or 6-membered heteroaromatic or heterocyclic group is optionally substituted with an OH, a C1-4 alkoxy, or a C1-4 alkyl group optionally substituted with an OH or a C1-4 alkoxy, and the heterocyclic group is a 4- to 7-membered monocyclic or bicyclic heterocyclic group, and each ring of the bicyclic heterocyclic group has a 3- to 6-membered ring; R 6 is selected from hydrogen, NH₂ , halo, cyano, and C1-4 alkyl; Alternatively, R5 and R4 bond together to form a 5-membered or 6-membered heterocyclic group with the atom to which they bond. Alternatively, R4 and R3 bond together with the atom they bond to to form a 5-membered or 6-membered heterocyclic group. In the formula, the five-membered or six-membered heterocyclic group is optionally substituted with one or more substituents selected from oxo, cyano, hydroxy, halo, C1-2 alkyl, C3-6 cycloalkyl, C1-2 haloalkyl, C1-2 alkoxy, C1-2 haloalkoxy, NR y1 R y2 , or -S(O) 0-2 R y1 R y2 , where R y1 and R y2 are H or C1-2 alkyl; However, no more than three of E1 to E5 represent N. A compound, or its tautomers, stereoisomers, salts, solvates, or N-oxides.
  2. A1 represents CR1a or N; A2 represents CR2a or N; A3 represents CR3a or N; A4 represents CR4a or N; A5 represents CR5a or N; A6 represents CR6a or N; However, among A1 , A2 , A3 , A4 , A5 , and A6 , there are 0, 1, or 2 that represent N; R1a to R6a each independently represent hydrogen, hydroxyl, halo, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, or C1-4 alkoxy; preferably R2a , R3a , R4a , and R6a each represent hydrogen, and R1a and R5a each independently represent hydrogen, hydroxyl, halo, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, or C1-4 haloalkoxy. The compound according to claim 1.
  3. Selected from, In particular, R1a to R6a each independently represent hydrogen, hydroxyl, halo, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, or C1-4 alkoxy, and each of the C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, or C1-4 alkoxy is optionally substituted with one or more substituents selected from cyano, hydroxyl, halo, -C(O) NH2 , -C(O)NH( C1-4 alkyl), -C (O) N ( C1-4 alkyl) 2 , -CO2H, -CO2 (C1-4 alkyl), C1-4 alkoxy , C1-4 haloalkoxy, C1-4 alkyl, and C1-4 haloalkyl. The compound according to claim 1 or 2.
  4. The compound according to any one of claims 1 to 3 , wherein R 7a is H, and R 7b is hydrogen, or a C 1-6 alkyl, particularly selected from hydroxy and C 1-4 alkoxy, which is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C 1-4 alkoxy, and C 1-4 haloalkoxy, and preferably both R 7a and R 7b are hydrogen.
  5. R 8a is H, and R 8b is a group of the formula -(CR c R d ) n -Z, for example -(CHR d ) n -Z, particularly -CHR d -Z or -Z, where R d is preferably hydrogen. Alternatively, R 8a and R 8b may bond together, forming a monocyclic or bicyclic heterocyclic group that, along with the nitrogen atom to which they are bonded, is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-3 alkenyl, NR a R b , and -S(O) 0-2 R a R b , preferably one or more substituents selected from halo, hydroxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C2-3 alkenyl. The compound according to any one of claims 1 to 4.
  6. The compound according to any one of claims 1 to 5, wherein Z is a C3-8 cycloalkyl or a bicyclic C5-8 cycloalkyl, which is optionally substituted with one or more substituents selected from halo, cyano, hydroxy , C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, C1-2 haloalkoxy, C2-3 alkenyl, NR a R b , and -S(O) 0-2 R a R b , for example, optionally substituted with one or more substituents selected from halo, hydroxy , C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, and C1-2 haloalkoxy such as fluoro, particularly one or two substituents.
  7. X is, Selected from, preferably A compound selected from any one of claims 1 to 6.
  8. Y is selected from one of the following structures i) to v): especially, R h is selected from hydrogen, halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, and is preferably H. R g is selected from hydrogen, halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, preferably H or C1-4 alkoxy. Ri is selected from hydrogen, halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, and is particularly hydrogen or C1-4 alkoxy, preferably H. R j is selected from hydrogen, halo, hydroxy, C1-4 alkyl, and C1-4 alkoxy, preferably H, and R x is selected from hydrogen and C1-4 alkyl, preferably H; especially, R k is selected from hydrogen, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, and is preferably H. R m is selected from hydrogen, halo, hydroxy, C3-6 cycloalkyl, C1-4 alkoxy, and C1-4 alkyl optionally substituted with OH, C1-4 alkoxy, and C3-6 cycloalkyl, for example, selected from hydrogen, halo, hydroxy, C1-4 alkyl, and C1-4 alkoxy , preferably selected from H, C3-6 cycloalkyl, or C1-4 alkyl optionally substituted with OH, C1-4 alkoxy, and C3-6 cycloalkyl, particularly selected from H. Rx is selected from hydrogen and C1-4 alkyl, preferably H; In particular, R n is selected from hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, preferably H; In the formula, R1 , R3 , R4 , and R5 are preferably each independently selected from hydrogen, NRy1 Ry2 , halo, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, -CH2OCH3 , -CH2SO2CH3 , -P (O)( C1-4 alkyl) 2 , -SO2CH3 , -NHC (O) CH3 , -C (O) NRx1 Rx2 , and C3-6 cycloalkyl which are optionally substituted with OH. Here, R x1 and R x2 are independently selected from hydrogen and C1-4 alkyl, R y1 and R y2 are independently selected from hydrogen, C3-6 cycloalkyl, and C1-4 alkyl optionally substituted with C3-6 cycloalkyl, or R y1 and R y2 , together with the N that holds them, may form a 5-membered or 6-membered heteroaromatic group or heterocyclic group, the 5-membered or 6-membered heteroaromatic group or heterocyclic group may be optionally substituted with OH, C1-4 alkoxy, or C1-4 alkyl optionally substituted with OH or C1-4 alkoxy, the heterocyclic group may be a 4-7 membered monocyclic heterocyclic group, or a bicyclic heterocyclic group where each ring has 3-6 members. Alternatively, R4 and R3 are bonded together with the atoms to which they are bonded to form a five-membered or six-membered heterocyclic group, the five-membered or six-membered heterocyclic group is optionally spirocondensed with a C3-6 cycloalkyl group and/or optionally substituted with one or more substituents selected from oxo, cyano, hydroxy, halo, C1-2 alkyl, C1-2 cycloalkyl, C1-2 haloalkyl, C1-2 alkoxy, C1-2 haloalkoxy, NR y1 R y2 , or -S(O) 0-2 R y1 R y2 (wherein R y1 and R y2 are H or C1-2 alkyl), E7 is either O or CH2 . R3 independently represents H, or together, the two R3 ' substituents represent an oxo group (=O) or a C3-5 cycloalkyl group. R 4' independently represents H, or together, the two R 4' substituents represent an oxo group (=O) or a C 3-5 cycloalkyl group; In particular, R1 , R3 , R4 , and R5 are independently hydrogen, NRy1 , Ry2 , halo, cyano, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkyl, and C1-4 haloalkyl, respectively. The compound according to any one of claims 1 to 7.
  9. Y is, 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.

Description

This invention relates to pharmaceutical compounds useful for the treatment and/or prevention in mammals, pharmaceutical compositions containing such compounds, and their use as METTL3 inhibitors, which are useful for the treatment of cancer, autoimmune diseases, neurological diseases, infectious diseases, inflammatory diseases, and other diseases or conditions involving METTL3 activity. 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 in cancer treatment. RNA epitranscriptomics, the study of RNA modifications, represents a new frontier in this field. Although known since the 1970s, eukaryotic RNA modifications were primarily identified on transfer RNA and ribosomal RNA until about the last decade. In this last decade, however, they have been identified and characterized on mRNA and various non-coding RNAs. 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, the 3' untranslated region (3'UTR) near the stop codon, and the 5' untranslated region (5'UTR) of mRNA. m6A is a potentially reversible and dynamic post-transcriptional modification of RNA molecules, regulated by methyltransferases (writers) and demethylases (erasers) and recognized by specific binding proteins (readers) (Li et al. 2022). 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. Increasing evidence suggests that its disruption can lead to various diseases, including addiction, autoimmune diseases, metabolic disorders, and infertility (Yang et al. 2020). 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. Wilms tumor 1-associated protein (WTAP) promotes the recruitment of METTL3 and METTL14 (Wang et al. 2016, Ping et al. 2014). 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. Therefore, METTL3 is associated with poor prognosis and thus represents a potential novel diagnostic and prognostic biomarker in cancer clinical practice (Liu et al. 2020). 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. WO2022254216 describes combination therapies including METTL3 inhibitors and additional anticancer agents. WO2022254218 describes the manufacturing process of the inhibitory compound. WO2021079196, WO2021081211, and WO2022081739 describe METTL3 modifiers. In the first aspect, the present invention relates to formula (I): With respect to the compound, or its tautomers, stereoisomers, salts, solvates, or N-oxides, In the formula, A1 represents CR1a or N, A2 represents CR2a or N, A3 represents CR3a or N , A4 represents CR4a or N, A5 represents CR5a or N, and A6 represents CR6a or N; However, no more than three of A1 , A2 , A3 , A4 , A5 , and A6 may represent N; R1a to R6a each independently represent hydrogen, hydroxyl, halo, cyano, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, 3-5 membered heterocyclic group, C3-4 cycloalkyloxy, or 3-5 membered heterocyclic oxy. These C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, 3-5 membered heterocyclic group, C3-4 cycloalkyloxy, or 3-5 membered heterocyclic oxy are cyano, hydroxyl, halo, -C(O)NH2, -C(O)NH( C1-4 alkyl), -C(O) N ( C1-4 alkyl) 2 , -CO2H , -CO2 ( C1-4 alkyl), C1-4 alkoxy, C Optionally substituted with one or more substituents selected from 1-4 haloalkoxy, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, and O- C3-6 cycloalkyl: R 7a and R 7b are independent of each other. (i) Hydrogen; (ii) Selected from C1-6 alkyl groups which are optionally substituted with one or more substituents selected from halo, cyano,