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WO2024200835A1 - Nouveaux inhibiteurs de mettl3 et leur utilisation en thérapie - Google Patents

Nouveaux inhibiteurs de mettl3 et leur utilisation en thérapie Download PDF

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Publication number
WO2024200835A1
WO2024200835A1 PCT/EP2024/058800 EP2024058800W WO2024200835A1 WO 2024200835 A1 WO2024200835 A1 WO 2024200835A1 EP 2024058800 W EP2024058800 W EP 2024058800W WO 2024200835 A1 WO2024200835 A1 WO 2024200835A1
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Prior art keywords
halo
hydrogen
mmol
hydroxy
cyano
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Inventor
Laurence Mevellec
Hugues PREVET
Philippe Schambel
Nicolas GEORGE
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Aqemia
Novalix SAS
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Aqemia
Novalix SAS
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Priority to AU2024244637A priority Critical patent/AU2024244637A1/en
Publication of WO2024200835A1 publication Critical patent/WO2024200835A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical compounds useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as METTL3 inhibitors, useful for treating diseases such as cancer, autoimmune, neurological, infectious and inflammatory diseases, as well as other diseases or conditions in which METTL3 activity is involved.
  • RNA epitranscriptomics the study of RNA modifications, is the new frontier of this arena. Despite being known since the 1970s, eukaryotic RNA modifications were mostly identified on transfer RNA and ribosomal RNA until the last decade, when they have been identified and characterized on mRNA and various non-coding RNAs. Increasing evidence suggests that RNA modification pathways are also misregulated in human cancers and may be ideal targets of cancer therapy (Barbieri & Kouzarides 2020).
  • m6A plays a crucial role in cancer and is also involved in a variety of physiological behaviors such as neurodevelopment, T cell homeostasis, glucolipid metabolism and gametogenesis, and its disruption leads to various diseases, including addiction, autoimmune disease, metabolic disease, and infertility (Yang et al. 2020).
  • methyltransferase complex (MTC) comprising numerous components.
  • MTC methyltransferase complex
  • METTL3 is an S-adenosyl methionine (SAM)-binding protein that catalyzes the transfer of methyl groups in SAM to adenine bases in RNA
  • SAM S-adenosyl methionine
  • METTL14 stabilizes the structure of MTC and identifies the consensus motif DRACH
  • WTAP Wilms tumor 1- associated protein promotes the recruitment of METTL3 and METTL14 (Wang et al. 2016, Ping et al. 2014).
  • METTL3 plays a crucial role in many biological processes, especially tumorigenesis and development.
  • METTL3 acts as an oncogene in cancer. Therefore, it causes alterations of mRNA translation and acceleration of tumor progression, and downregulating METTL3 results in tumor inhibition.
  • METTL3 mRNA expression is significantly elevated in cancers tissues compared to normal tissues. Thus, it is associated with poor prognosis, hence a potential novel diagnostic and prognostic biomarker in cancer clinics (Liu et al. 2020)
  • W02020201773, WO2021111124, WO2022074379, and WO2022074391 describe METTL3 inhibitors and their use in the treatment of proliferative disorders, such as cancer, autoimmune, neurological, infectious and inflammatory diseases, as well as other diseases or conditions in which METTL3 activity is implicated.
  • WO2022254216 describes the combination therapies comprising a METTL3 inhibitor and a further anticancer agent.
  • WO2022254218 describes the processes for the preparation of inhibitory compounds WO2021079196, W02021081211 and WO2022081739 describe METTL3 modulating agents.
  • the invention relates to a compound of Formula (I), or a tautomer, stereoisomer, salt, solvate or N-oxide thereof, wherein
  • 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; provided that no more than 3 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represents N;
  • R 1a to R 6a each independently represent hydrogen, hydroxy, halo, cyano and Ci.4 haloalkyl, Ci-4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3- 4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3- 4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(CI-4 alkyl), - C(O)N(CI-4 alkyl)2, -CO2H, -CO2(C
  • R 7a and R 7b are independently selected from: (i) hydrogen;
  • Ci-ealkyl which is optionally substituted by one more substituent selected from halo, cyano, hydroxy, Ci.4alkoxy, Ci.4haloalkoxy,
  • R 7a and R 7b are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,
  • R 8a and R 8b are independently
  • Ci-ealkyl optionally substituted by one more substituents selected from cyano, hydroxy, halo, Ci-2alkoxy, Ci aloalkoxy,
  • R c and R d are independently selected from: o Hydrogen o Ci-ealkyl which is optionally substituted by one more substituents selected from cyano, hydroxy, halo, Ci.4alkoxy, Ci.4haloalkoxy, Cs-ecycloalkyl, -O-C3- ecycloalkyl, and wherein Cs-ecycloalkyl and-O-Cs- ecycloalkyl are optionally substituted by one or more substituents selected from halo, cyano and hydroxy; and o or R c and R d are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl which is optionally substituted by one or more substituents selected from cyano, hydroxy, halo, Ci-2alkyl, Ci aloalkyl, Ci.2alkoxy, Ci aloalkoxy; and Z is selected from
  • X is selected from wherein the dotted line indicates the point of attachment to Y and the wavy line indicate the point of attachment to the rest of the molecule;
  • R c and R d are independently selected from hydrogen, Ci-4alkyl, wherein Ci-4alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano and Ci.4alkoxy;
  • R e and R f are independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, wherein Ci- 4alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano and Ci.4alkoxy;
  • R c R d and R e R f may be linked together such that, together with the carbon atom to which they are attached, they form a C ⁇ cycloalkanediyl optionally substituted by one or more substituents selected from the group consisting of halo, methyl, cyano, hydroxy and Ci- 4alkoxy;
  • Y is selected from one of the following structures: wherein:
  • Gi is selected from CR h and N, wherein R h is selected from hydrogen, hydroxy, halo, cyano, Ci-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C ⁇ cycloalkyl, a 5- or 6-membered heteroaryl, a 3- to 4- membered heterocyclyl and -O-C3-4cycloalkyl;
  • G2 is selected from N and CR 9 , wherein R 9 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, a 5- or 6-membered heteroaryl, Cs-ecycloalkyl, -O-Cs-ecycloalkyl, heterocyclyl, -O-(carbon- linked heterocyclyl), -(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 ; wherein m is an integer from 1 to 6 and R y and R z are each independently hydrogen, C1.4 alkyl, Cs-ecycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl,
  • G3 is N or CR', wherein R' is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci- 4haloalkyl, Ci.4haloalkoxy, Ci.4alkoxy, Cs-ecycloalkyl and -O-Cs-ecycloalkyl, wherein C3- ecycloalkyl and -O-Cs-ecycloalkyl are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
  • G4 is selected from C and N;
  • G5 is selected from CR j and NR X , wherein:
  • R j is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, NH2 and Ci.4alkoxy; and R x is selected from hydrogen and Ci-4alkyl;
  • G 7 is N, NR a or CR j ,
  • Gs is selected from C and N, with the proviso that no more than four, preferably 1 , 2 or 3, of G1 to Gs are N or NR a ;
  • Y2 is selected from CR k and N; wherein R k is selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C ⁇ cycloalkyl, a 3- to 4- membered heterocyclyl and C ⁇ cycloalkoxy;
  • Y3 is N or CR 1 wherein R 1 is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci- 4haloalkyl, Ci.4haloalkoxy, Ci.4alkoxy, Cs-ecycloalkyl and -O-Cs-ecycloalkyl, wherein C3- ecycloalkyl and -O-Cs-ecycloalkyl are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
  • Y4 is C or N
  • Y5 is CR m or NR X , wherein:
  • R m is selected from hydrogen, halo, hydroxy, cyano, Cs-ecycloalkyl, NH2, Ci.4alkoxy and Ci- 4alkyl optionally substituted with OH, Ci.4alkoxy and Cs-ecycloalkyl;
  • R x is selected from hydrogen and Ci-4alkyl
  • Y 6 is CR m or N
  • Y 7 is O, S, CR m or N;
  • Ys is C or N
  • Yg is CR m or N; with the proviso that no more than four of Y1 to Ys are N;
  • Xi is N or CR n wherein R n is selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;
  • X 2 is N or CR n ;
  • X 3 is N
  • X4 is N or C
  • X5 is selected from N, CR n and CR n R n1 wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X7 are independently CR n or N; or Xe is CR n R n1 or NR X and X7 is CR n R n1 , CR°R° 1 or NR X , wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;
  • R x is hydrogen or C1.4 alkyl
  • R° and R° 1 are independently selected from hydrogen, halo, methoxy and methyl;
  • Xs is N, CR n or CR n R n1 wherein R n and R n1 are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and
  • Xg is N or C; with the proviso that no more than four of X 2 to Xg are N;
  • L1-L7 are independently N or CR n wherein R n is selected from hydrogen, halo, cyano, C1.4 alkyl, Ci-4 haloalkyl, Ci.4alkoxy, and C1.4 haloalkoxy, with the proviso that no more than three L1 to L7 are N;
  • E1 is CR1 or N
  • E 2 is CR 2 or N
  • E3 is CR3 or N
  • E4 is CR4 or N
  • E5 is CR5 or N
  • E 6 is NR 6 or CReaReb wherein R1, R 2 , R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NR y iR y2 , halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH 2 OCH3, - CH2SO2CH3, -P(O)(Ci- 4 alkyl) 2 , -SO2CH3, -NHC(O)CH 3 , -C(O)NR X I R X2 , and Cs-ecycloalkyl optionally substituted by OH, wherein R xi and R X 2 are independently selected from hydrogen and Ci-4alkyl such as methyl, and wherein R yi and R y 2 are independently selected from hydrogen, Cs-ecycloalkyl and Ci-4alkyl, such as methyl, optionally substituted by C3- ecycloalkyl
  • Re is selected from hydrogen, NH2, halo, cyano, and Ci-4alkyl; or
  • R 4 and R3 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, or R 4 and R3 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, wherein the 5- or 6-membered heterocyclyl is optionally substituted by one or more substituents selected from oxo, cyano, hydroxy, halo, Ci-2alkyl, Cs-ecycloalkyl, Ci.2haloalkyl, Ci-2alkoxy, Ci.2haloalkoxy, NR y iR y 2 or -S(0)o-2R yi R y 2 wherein R yi and R y 2 are H orCi.2alkyl; with the proviso that no more than three of E1 to E5 are N.
  • 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; provided that no more than 3 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represents N;
  • R 1a to R 6a each independently represent hydrogen, hydroxy, halo, cyano and Ci.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3- 4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3- 4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1.4 alkoxy, Ci- 4 haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecyclo
  • R 7a and R 7b are independently selected from:
  • Ci-ealkyl which is optionally substituted by one more substituent selected from halo, cyano, hydroxy, Ci.4alkoxy, Ci.4haloalkoxy,
  • R 7a and R 7b are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,
  • R 8a and R 8b are independently
  • Ci-ealkyl optionally substituted by one more substituent selected from cyano, hydroxy, halo, Ci-2alkoxy, Ci aloalkoxy,
  • R c and R d are independently selected from: o Hydrogen o Ci-ealkyl which is optionally substituted by one more substituent selected from cyano, hydroxy, halo, Ci.4alkoxy, Ci.4haloalkoxy, Cs-ecycloalkyl, -O-C3- ecycloalkyl, and wherein Cs-ecycloalkyl and-O-Cs- ecycloalkyl are optionally substituted by one or more substituents selected from halo, cyano and hydroxy; and o or R c and R d are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl which is optionally substituted by one or more substituents selected from cyano, hydroxy, halo, Ci-2alkyl, Ci aloalkyl, Ci.2alkoxy, Ci aloalkoxy; and Z is selected from o
  • R c and R d are independently selected from hydrogen, Ci-4alkyl, wherein Ci-4alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano and Ci.4alkoxy;
  • R e and R f are independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, wherein Ci- 4alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano and Ci.4alkoxy;
  • R c R d and R e R f may be linked together such that, together with the carbon atom to which they are attached, they form a C ⁇ cycloalkanediyl optionally substituted by one or more substituents selected from the group consisting of halo, methyl, cyano, hydroxy and Ci- 4alkoxy;
  • Y is selected from one of the following structures: wherein:
  • Gi is selected from CR h and N, wherein R h is selected from hydrogen, hydroxy, halo, cyano, Ci-4alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C ⁇ cycloalkyl, a 5- or 6-membered heteroaryl, a 3- to 4- membered heterocyclyl and -O-C3-4cycloalkyl;
  • G2 is selected from N and CR 9 , wherein R 9 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, a 5- or 6-membered heteroaryl, Cs-ecycloalkyl, -O-Cs-ecycloalkyl, heterocyclyl, -O-(carbon- linked heterocyclyl), -(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 ; wherein m is an integer from 1 to 6 and R y and R z are each independently hydrogen, C1.4 alkyl, Cs-ecycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl,
  • G3 is N or CR', wherein R' is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci- 4haloalkyl, Ci.4haloalkoxy, Ci.4alkoxy, Cs-ecycloalkyl and -O-Cs-ecycloalkyl, wherein C3- ecycloalkyl and -O-Cs-ecycloalkyl are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
  • G4 is selected from C and N;
  • G5 is selected from CR j and NR X , wherein:
  • R j is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, NH2 and Ci.4alkoxy; and R x is selected from hydrogen and Ci-4alkyl; G 7 is N, NR a or CR j ,
  • Gs is selected from C and N, with the proviso that no more than four, preferably 1 , 2 or 3, of Gi to Gs are N or NR a ;
  • Y2 is selected from CR k and N; wherein R k is selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C ⁇ cycloalkyl, a 3- to 4- membered heterocyclyl and C ⁇ cycloalkoxy;
  • Y3 is N or CR 1 wherein R 1 is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci- 4haloalkyl, Ci.4haloalkoxy, Ci.4alkoxy, Cs-ecycloalkyl and -O-Cs-ecycloalkyl, wherein C3- ecycloalkyl and -O-Cs-scycloalkyl are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
  • Y4 is C or N
  • Y5 is CR m or NR X , wherein:
  • R m is selected from hydrogen, halo, hydroxy, cyano, Ci-4alkyl, NH2 and Ci.4alkoxy;
  • R x is selected from hydrogen and Ci-4alkyl
  • Y 6 is CR m or N
  • Y 7 is O, S, CR m or N;
  • Ys is C or N
  • Yg is CR m or N; with the proviso that no more than four of Y1 to Ys are N;
  • Xi is N or CR n wherein R n is selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;
  • X 2 is N or CR n ;
  • X 3 is N
  • X4 is N or C
  • X5 is selected from N, CR n and CR n R n1 wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X? are independently CR n or N; or Xe is CR n R n1 or NR X and X? is CR n R n1 , CR°R° 1 or NR X , wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;
  • R x is hydrogen or C1.4 alkyl
  • R° and R° 1 are independently selected from hydrogen, halo, methoxy and methyl;
  • Xs is N, CR n or CR n R n1 wherein R n and R n1 are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and
  • Xg is N or C; with the proviso that no more than four of X2 to Xg are N;
  • L1-L7 are independently N or CR n wherein R n is selected from hydrogen, halo, cyano, C1.4 alkyl, Ci-4 haloalkyl, Ci.4alkoxy, and C1.4 haloalkoxy, with the proviso that no more than three L1 to L7 are N;
  • E2 is CR2 or N
  • E3 is CR3 or N
  • E4 is CR4 or N
  • E5 is CR5 or N
  • E 6 is NR 6 or CReaReb wherein R1, R2, R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NR y iRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, - CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR X I R X 2, wherein R xi and R X 2 are independently selected from hydrogen and methyl, and wherein R yi and R y 2 are independently selected from hydrogen and methyl or, taken together with the N bearing them, form a 5- or 6-membered heterocyclic group; and
  • Re is selected from hydrogen and Ci-4alkyl
  • R4 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl (so that actually forms a bicyclic system comprising one aromatic ring fused with a 5- or 6-membered one heterocyclyl), or R4 and R3 are linked together such that, together with the atoms to which they are E 5 ' E4 --E 3 attached, they form a 5- or 6-membered heterocyclyl (so that actually forms a bicyclic system comprising one aromatic ring fused with a 5- or 6- membered one heterocyclyl), wherein the 5- or 6-membered heterocyclyl is optionally substituted by one or more substituents selected from cyano, hydroxy, halo, Ci-2alkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci- 2haloalkoxy, NR y iR y 2 or -S(0)o-2R yi R y 2 wherein R yi and R
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined herein, and a pharmaceutically acceptable carrier.
  • the invention relates to a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for use as a drug, in particular with an METTL3 inhibiting activity.
  • the invention relates to a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for use in the treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease.
  • the present invention also concerns 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 treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease.
  • the present invention also concerns 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 medicine intended to the treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease.
  • the present invention also concerns a method for treating or preventing a cancer, or an autoimmune, neurological, infectious or inflammatory disease comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein.
  • hydrogen includes any isotope of hydrogen such as deuterium.
  • hydroxy denotes -OH
  • cyano denotes -CN.
  • halogen refers to a fluorine, bromine, chlorine or iodine atom, preferably a chlorine or fluorine atom.
  • halo refers to a fluoro, bromo, chloro or iodo moiety, preferably a chloro or fluoro moiety.
  • Ci- X alkyl refers to a straight or branched monovalent saturated hydrocarbon chain containing from 1 to x carbon atoms.
  • a Ci- 6 alkyl contains 1 to 6 carbon atoms and includs, without being limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • Ci- X alkanediyl refers to a straight or branched divalent saturated hydrocarbon chain containing from 1 to x carbon atoms including, but not limited to, methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyle, and the like.
  • Ci- X haloalkyl refers to a Ci- X alkyl group as defined above substituted by at least one halogen atom, and preferably by at least one fluorine atom. It can be in particular a trifluoromethyl group.
  • Ci- X hydroxyalkyl refers to a Ci- X alkyl group as defined above substituted by one hydroxy group.
  • C2- X alkenyl refers to a straight or branched monovalent unsaturated hydrocarbon chain containing from 2 to x carbon atoms and comprising at least one double bond including, but not limited to, ethenyl, propenyl, butenyl and the like.
  • C2- X alkynyl refers to a straight or branched monovalent unsaturated hydrocarbon chain containing from 2 to x carbon atoms and comprising at least one triple bond including, but not limited to, ethynyl, propynyl, butynyl and the like.
  • Ci- X alkoxy refers to a Ci- X alkyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like.
  • Ci- X haloalkoxy refers to a Ci- X alkoxy group as defined above substituted by at least one halogen atom, and preferably by at least one fluorine atom. It can be in particular a trifluoromethoxy group.
  • C x-V cycloalkyl or “x- to y-membered cycloalkyl”, as used in the present invention, refers to a monovalent monocyclic hydrocarbon ring having x to y carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • C x-V cycloalkanediyl or “x- to y-membered cycloalkanediyl” as used in the present invention refers to a divalent monocyclic hydrocarbon ring having x to y carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • bicyclic Cs- X cycloalkyl refers to a bicyclic hydrocarbon ring having 5 to x carbon atoms and comprising two joined rings. This includes spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds.
  • C x-V cycloalkyloxy refers to a C x-y cycloalkyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, cyclopropoxy or cyclobutyloxy.
  • heterocyclyl refers to a saturated or unsaturated, but not aromatic, monocyclic or bicyclic ring, advantageously having 3 to 12 ring atoms, containing at least one heteroatom, preferably 1 , 2, 3 or 4 heteratoms, in the ring.
  • Bicyclic heterocyclyl may be fused, bridged or spirocyclic compounds.
  • Spirocyclic compounds include monocyclic heterocyclyls spiro-fused with a Cs-ecycloalkyl.
  • each ring of the heterocyclyl comprises 3 to 6 ring atoms.
  • the heteroatom is preferably selected from O, N, P and S, more preferably, the heteroatom is selected from O, N and S.
  • the S atom may be mono or dioxidized, i.e. the sulphur 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).
  • Heterocyclyls include, but are not limited to, epoxide, aziridinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, di hydrooxazinyl, benzothiazinyl, benzothiazinonyl, indolinyle, isoindolinyle, 1 ,4-azaphosphinane-4-oxide, 3-aza-bicyclo[3.1.0]hexane.
  • a heterocylclyl spiro-fused with a Cs-ecycloalkyl is understood as a spirocyclic compound comprising a heterocyclyl fused to a Cs-ecycloalkyl.
  • heterocyclyloxy refers to a heterocyclyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, oxetanoxy.
  • aryl refers to an aromatic hydrocarbon group comprising one or more fused rings and preferably comprising 6 to 10 carbon atoms, such as, for example, a phenyl or naphthyl group.
  • aryl refers to an aromatic hydrocarbon group comprising one or more fused rings and preferably comprising 6 to 10 carbon atoms, such as, for example, a phenyl or naphthyl group.
  • it will be a phenyl group.
  • heteroaryl refers to an aromatic group comprising one or several, notably one or two, fused hydrocarbon cycles in which one or several, notably one to four, advantageously one or two, carbon atoms each have been replaced with a heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom, preferably selected from an oxygen atom and a nitrogen atom.
  • It can be a furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyle, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or indyl.
  • N-protectinq group refers to groups intended to protect an amine function (notably a primary amine function) against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in “Greene’s Protective Groups In Organic Synthesis”, 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.
  • An amine function protected by a N-protecting group can be a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an amino acetal derivative, a N-benzyl derivative, an imine derivative, an enamine derivative or a N-heteroatom derivative.
  • N-protecting groups can be formyl; an aryl, such as a phenyl, optionally substituted with one or several methoxy groups such as p-methoxyphenyl (PMP); an aryl-(Ci-Ce)alkyl, such as a benzyl, the aryl moiety being optionally substituted with one or several methoxy groups, such as benzyl (Bn), p-methoxybenzyl (PMB) or 3,4- dimethoxybenzyl (DMPM); CO-RPGI such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz) or p-methoxybenzylcarbonyl (Moz); -CO2-RGP1 such as tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz or
  • it may be a t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl group.
  • Lewis and Bnansted acids examples include aluminium chloride, zinc chloride, silver chloride.
  • Bronsted acids include hydrochloric acid, trifluoroacetic acid, acetic acid.
  • the person of skill in the art will choose suitable Lewis or Bronsted acids depending on the nature of the starting molecule and desired result, and to this end may refer to “Greene’s Protective Groups In Organic Synthesis”, 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.
  • the plain circle denotes an aromatic ring.
  • the dotted circle denotes an aromatic or unsaturated ring.
  • the dotted line indicates the point of attachment to X.
  • Me stands for methyl
  • Ph stands for phenyl
  • Et stands for Ethyl
  • Ac stands for acetyl
  • SEM 2-(trimethylsilyl)ethoxymethyl
  • TMS trimethylsilyl
  • the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • R 1a to R 6a each independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3-4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3-4cycloalkyloxy, or a 3- to 5-membered heterocyclyloxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-e
  • R 1a , R 2a , R 4a and R 5a each independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, Ci- 4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3-4cycloalkyloxy, or a 3- to 5- membered heterocyclyloxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3 to 5 membered heterocyclyl, C3-4cycloalkyloxy, or a 3- to 5- membered heterocyclyloxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(CI-4 alkyl), -C(O)N(CI-4 alkyl)
  • R 1a , R 2a , R 4a and R 5a each independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, - C(O)NH 2 , -C(O)NH(CI.
  • R 3a and R 6a represent, independently of one another, hydrogen, halo, or cyano, preferably hydrogen.
  • R 1a , R 2a and R 5a each independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy;
  • R 4a represents hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, -C(O)NH 2 , -C(O)NH(CI- 4 alkyl), -C(O)N(Ci- 4 alkyl) 2 , -CO 2 H, -CO 2 (Ci- 4 alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl,
  • R 1a to R 6a each independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3- to 5 membered heterocyclyl, C3-4cycloalkyloxy, or 3- to 5-membered heterocyclyloxy which are all optionally substituted by one or more substituents selected from cyano, hydroxy, halo, Ci- 4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecycloalkyl.
  • R 1a represents hydrogen, hydroxy, halo, cyano, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy, C3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C3-4cycloalkyloxy, or 3- to 5-membered heterocyclyloxy, which are all optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1.4 alkoxy, C1.4 haloalkoxy, Cs-ecycloalkyl, and -O-Cs-ecycloalkyl; preferably hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci-4alkoxy, or C1.4 haloalkoxy;
  • R 2a represents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 3a represents hydrogen, halo, or cyano
  • R 4a represents hydrogen, halo; cyano; C1.4 alkyl optionally substituted by one or more -OH or Ci-4alkoxy; C1.4 haloalkyl; Ci.4alkoxy optionally substituted by one or more -OH or Ci- 4alkoxy or -CONH2; or C1.4 haloalkoxy; in particular R 4a represents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy
  • R 5a represents hydrogen, hydroxy, halo, cyano, Ci.4 haloalkyl, C1.4 haloalkoxy, Ci-4alkyl, Ci- 4 alkoxy, C3-4 cycloalkyl, or 3- to 5-membered heterocyclyl, C3-4cycloalkyloxy, 3- to 5- membered heterocyclyloxy, which are all optionally substituted by one or more substituents selected from cyano, hydroxy, Cual
  • R 6a represents hydrogen, halo, or cyano.
  • R 1a to R 6a represent independently hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(CI-4 alkyl), -C(O)N(CI-4 alkyl)2, -CO2H, -CO2(Ci-4 alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, and C1.4 haloalkyl; especially hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci- 4alkoxy, or C1.4 haloalkoxy; and preferably:
  • R 1a represents hydrogen, hydroxy, halo, C1.4 alkyl or C1.4 alkoxy
  • R 2a represents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 3a represents hydrogen, halo, or cyano
  • R 4a represents hydrogen, halo, cyano, C1.4 alkyl optionally substituted by one or more -OH or Ci-4alkoxy, C1.4 haloalkyl, Ci.4alkoxy optionally substituted by one or more -OH or Ci- 4alkoxy or -CONH2, or C1.4 haloalkoxy;
  • R 5a represents hydrogen, hydroxy, halo, C1.4 alkyl or C1.4 alkoxy
  • R 6a represents hydrogen, halo, or cyano.
  • R 1a to R 6a represent independently hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy; and preferably: R 1a represents hydrogen, hydroxy, halo, or C1.4 alkoxy;
  • R 2a represents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 3a represents hydrogen, halo, or cyano
  • R 4a represents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 5a represents hydrogen, hydroxy, halo, or C1.4 alkoxy
  • R 6a represents hydrogen, halo, or cyano.
  • no more than 2 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represent N.
  • 0, 1 or 2 of A 1 , A 2 , A 3 , and A 4 represent N.
  • 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; provided that 0, 1 or 2 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represent N; preferably provided that 0, 1 or 2 of A 1 , A 2 , A 3 , and A 4 represent N; preferably with R 1a to R 6a each independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy; preferably with R 2a , R 3a , R 4a and R 6a each representing H and with R 1a and R 5a each independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy.
  • none of A 1 , A 2 , A 3 , A 4 , A 5 or A 6 represents N.
  • 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.
  • 2 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 preferably 2 of A 1 , A 2 , A 3 , and A 4 , represent N.
  • the following moieties are N: o A1 and A3, or o A2 and A3, or o A2 and A4, or o A2 and A6, or o A3 and A4, or o A3and A6, or o A4 and A6, or o A4 and A5, or o A5 and A6.
  • R 1a to R 6a each independently representing hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy, each of said C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, -C(O)NH2, -C(O)NH(CI-4 alkyl), - C(O)N(Ci-4 alkyl)2, -CO2H, -CO2(Ci-4 alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, and C1.4 haloalkyl; especially hydrogen, hydroxy, halo, cyano, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl optionally substituted by one or more
  • the compound of formula (I) is selected from compounds of the following formulae: with R 1a to R 6a as defined previously and preferably representing independently hydrogen, hydroxy, halo, cyano, C1.4 alkyl optionally substituted by one or more -OH or Ci.4alkoxy, Ci- 4 haloalkyl, Ci.4alkoxy optionally substituted by one or more -OH or Ci.4alkoxy or -CONH2, or Ci-4 haloalkoxy; especially with R 1a to R 6a representing independently hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy or C1.4 haloalkoxy; and advantageously with:
  • R 1a representing hydrogen, hydroxy, halo, C1.4 alkyl, or C1.4 alkoxy
  • R 2a representing hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 4a representing hydrogen, halo, cyano, C1.4 alkyl optionally substituted by one or more - OH or Ci-4alkoxy, C1.4 haloalkyl, Ci.4alkoxy optionally substituted by one or more -OH or Ci- 4alkoxy or -CONH2, or C1.4 haloalkoxy;
  • R 5a representing hydrogen, hydroxy, halo, or C1.4 alkoxy
  • R 3a and R 6a representing hydrogen, halo, or cyano; notably with: R 1a representing hydrogen, hydroxy, halo, or C1.4 alkoxy;
  • R 2a representing hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 4a representing hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;
  • R 5a representing hydrogen, hydroxy, halo, or C1.4 alkoxy
  • R 6a representing hydrogen, halo, or cyano; even more preferably, R 1a represents hydrogen, hydroxy, or fluoro; and R 5a represents hydrogen, hydroxy, fluoro, or methoxy.
  • R 7a is H and R 7b is hydrogen, or Ci-ealkyl optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci.4alkoxy, and Ci.4haloalkoxy, in particular selected from hydroxy, and Ci.4alkoxy.
  • R 7a is H and R 7b is hydrogen, or Ci-ealkyl unsubstituted or substituted by one substituent selected from hydroxy and Ci-4alkoxy; preferably R 7a and R 7b are both a hydrogen.
  • R 8a is H and R 8b is a group of formula -(CR c R d ) n -Z, such as -(CHR d ) n -Z (e.g. -(CH2)n-Z), and in particular -CHR d -Z or -Z such as -CH2-Z or -Z, or
  • R 8a and R 8b are linked such that, together with the nitrogen atom to which they are attached, they form a mono- or bicyclic heterocyclyl, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci-4alkyl, Ci-4haloalkyl, Ci-4hydroxyalkyl, Ci-4alkoxy, Ci-4haloalkoxy, C ⁇ alkenyl, NR a R b and -S(0)o-2R a R b , preferably selected from halo, hydroxy, Ci-4alkyl, Ci-4haloalkyl, Ci-4hydroxyalkyl, Ci-4alkoxy, Ci-4haloalkoxy, and C2- salkenyl, in particular the substituent(s) is(are) selected from halo, Ci-4alkyl, Ci.4haloalkyl, and C ⁇ alkenyl, and preferably selected from Ci-4alkyl, and C ⁇ alkenyl.
  • the mono- or bicyclic heterocyclyl comprises no other heteroatom than the nitrogen atom bearing R 8a and R 8b .
  • each ring of the mono- or bicyclic heterocyclyl comprises 4, 5, 6 or 7 ring atoms.
  • R a and R b are independently H or Ci-4alkyl.
  • Z may be a Cs-scycloalkyl or a bicyclic Cs-scycloalkyl, each of which being optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci-2alkyl, Ci- 2haloalkyl, Ci.2hydroxyalkyl, Ci.2alkoxy, Ci.2haloalkoxy, C ⁇ alkenyl, NR a R b and -S(0)o- 2R a R b , such as one or more, in particular one or two, substituents selected from halo such as fluoro, hydroxy, Ci-2alkyl, Ci.2haloalkyl, Ci.2hydroxyalkyl, Ci.2alkoxy, and Ci.2haloalkoxy.
  • substituents selected from halo, cyano, hydroxy, Ci-2alkyl, Ci- 2haloalkyl, Ci.2hydroxyalkyl, Ci.2alkoxy, Ci.2haloalkoxy.
  • Z is a Cs-scycloalkyl or a bicyclic Cs-scycloalkyl, each of which being optionally substituted by one or two substituents selected from Ci-2alkyl, Ci- 2hydroxyalkyl, hydroxy, and halo such as fluoro.
  • X is selected from
  • Y is typically selected from one of the following structures: wherein:
  • G1 is selected from CR h and N, wherein R h is selected from hydrogen, halo, cyano, Ci- 4alkyl, C1.4 alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy;
  • G2 is CR 9 , wherein R 9 is selected from hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy,
  • G3 is CR', wherein R' is selected from hydrogen, cyano, halo, Ci-4alkyl, Ci.4haloalkyl, Ci- 4haloalkoxy, Ci.4alkoxy,
  • G4 is N; Gs is NH or CR j wherein: R j is selected from hydrogen, Ci-4alkyl, cyano, halo, OH NH2 and Ci-4alkoxy;
  • G7 is CR
  • Y2 is CR k ; wherein R k is selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci-
  • Ci.4haloalkoxy preferably Y2 is CH,
  • Y3 is N or CR 1 wherein R 1 is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci-
  • Ci.4haloalkoxy preferably Y3 is N or CH
  • Y4 is C or N
  • Y5 is CR m or NR X , wherein:
  • R m is selected from hydrogen, Ci-4alkyl, cyano, halo, OH, NH2 and Cualkoxy;
  • R x is selected from hydrogen and Ci-4alkyl; preferably Y5 is CH or NH,
  • Ye is CR m or N; preferably Ye is CH,
  • Y? is CR m ; preferably Y7 is CH,
  • Y 8 is C
  • Yg is CR m or N; preferably Y2 is CH or N, with the proviso that no more than three of Y2to Yg are N;
  • X 4 is N
  • X5 is selected from CR n and CR n R n1 wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X7 are independently CR n ; orXe is CR n R n1 and X7 is CR n R n1 , CR°R° 1 and NR X , wherein:
  • R n and R n1 are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;
  • R x is hydrogen or C1.4 alkyl
  • R° and R° 1 are independently selected from hydrogen, halo, methoxy and methyl;
  • X 8 is CR n or CR n R n1 wherein R n and R n1 are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and Xg is C; iv)
  • Ei is N or CRi
  • E3 is N or CR3
  • E4 is CR4
  • E5 is N or CR5; wherein R1, R 2 , R3, R4, Rs, Rea and Reb are in particular each independently selected from hydrogen, NR y iR y2 , halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, - CH 2 OCH 3 , -CH 2 SO 2 CH 3 , -P(O)(Ci.
  • R xi and R x2 are independently selected from hydrogen and Ci-4alkyl (e.g. methyl), , wherein R yi and R y2 are independently selected from hydrogen, Cs-ecycloalkyl and Ci-4alkyl (e.g.
  • Y may be selected from the following structures: wherein R 1 , R 2 , and R 3 are as described above or below,
  • E? is O or CH 2 ,
  • Y is selected from the following structures:
  • Ei is CRi
  • E3 is CR3
  • E4 is CR4
  • E5 is CR5; wherein R1, R 2 , R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NH 2 , halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH 2 OCH3, - CH 2 SO 2 CH 3 , -SO 2 CH 3 , -NHC(O)CH 3 , -C(O)NR X I RX2, wherein R xi and R x2 are independently selected from hydrogen and methyl, and NR y iR y2 , wherein R yi and R y2 taken together with the N bearing them form a 5- or 6-membered heretocyclyl.
  • Y may be selected from one of the following structures: in particular with
  • R h being selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci-4haloalkoxy, and preferably being H,
  • R 9 being selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci-4haloalkoxy, and preferably being H or C1.4 alkoxy,
  • R' being selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci- 4haloalkoxy, and preferably being H,
  • R j being each independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, and Ci- 4alkoxy, and preferably being H, and
  • R x being selected from hydrogen and Ci-4alkyl, and preferably being H; in particular with
  • R k being each independently selected from hydrogen, halo, Ci-4alkyl, C1.4 alkoxy, Ci- 4haloalkyl, and Ci.4haloalkoxy, and preferably being H,
  • R m being each independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, and C1.4 alkoxy, and preferably being H,
  • R x being each independently selected from hydrogen and Ci-4alkyl, and preferably being in particular with R n being each independently selected from hydrogen, halo, C1.4 alkyl, Ci-
  • haloalkyl, Ci.4alkoxy, and C1.4 haloalkoxy preferably being H; and with Ri, R3, R4, Rs, are advantageously each independently selected from hydrogen, NH2, NH-methyl with the methyl being optionally substituted by Cs-ecycloalkyl, NH-Cs-ecycloalkyl, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, -CH2SO2CH3, - P(O)Me2, -SO2CH3, -NHC(O)CH3, -C(O)NR X I R X 2, and C ⁇ cycloalkyl optionally substituted by OH, wherein R xi and R X 2 are independently selected from hydrogen and methyl, and NR y iRy2, wherein R yi and R y 2 taken together with the N bearing them form a 5-membered heteroaryl
  • Y may also be selected from one of the following structures: in particular with
  • R h , R 9 , R', and R j being each independently selected from hydrogen, halo, hydroxy, C1.4 alkoxy, and preferably being H, and
  • R x being selected from hydrogen and Ci-4alkyl, and preferably being H; in particular with
  • R k being each independently selected from hydrogen, halo, C1.4 alkoxy, and preferably being H,
  • R m being each independently selected from hydrogen, halo, hydroxy, and C1.4 alkoxy, and preferably being H,
  • R x being selected from hydrogen and Ci-4alkyl, and preferably being H; iii) in particular with R n being each independently selected from hydrogen, halo, C1.4 Ci- 4alkoxy, preferably being H; and in particular with R4 being selected from hydrogen, NR y iR y 2, halo, Ci.4alkoxy, Ci-4alkyl, and preferably being NR y iR y 2 or Ci.4alkoxy.
  • X-Y is:
  • the compound of formula (I) is preferably methoxy or -CH2OH.
  • the compound of formula (I) is in particular selected from compounds Co.1 to Co.145, such as compounds Co.1 to Co.42, as defined herein or in the claims, or a tautomer, stereoisomer, salt, solvate or N-oxide thereof.
  • the compounds of formula (I) as described herein may exist in tautomeric form or steroisomeric form, i.e. in diastereomeric or enantiomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-diastereomers, E- and Z- stereomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, racemic mixtures thereof and other mixtures thereof.
  • tautomer used in this invention refers to structural isomers of chemical compounds that readily interconvert.
  • stereoisomers used in this invention refers to configurational stereoisomers and includes geometric isomers and optical isomers.
  • the “geometric isomers”, also called E/Z isomers or cis-trans isomers, result from the different position of substituents on a double C C bond which can have a Z or E configuration, also called cis or trans configuration.
  • the “optical isomers” result from the different position in space of substituents or lone pair of electrons on an atom (such as a carbon or sulphur atom) comprising four different substituents (including potentially a lone pair of electron). This atom thus represents a chiral or asymmetric center.
  • Optical isomers which are not mirror images of one another are thus designated as “diastereoisomers” and optical isomers which are non-superimposable mirror images are designated as “enantiomers”.
  • the compounds of the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof.
  • a “pharmaceutically acceptable salt or solvate” designates a salt or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • Suitable pharmaceutically acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic (heterocyclyl and heteraryl), carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2- hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric,
  • Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents.
  • solvates due to the presence of water these solvates are also called hydrates) or ethanol.
  • the compounds of the present invention may also be in the form of N-oxides, i.e. a nitrogen atom of said compounds may be in an oxidized form.
  • the compounds of the invention may be obtained by a process for preparing a compound of formula (I) as defined herein, comprising the following successive steps:
  • the final functionalization may for instance involve:
  • the compounds of the invention may be obtained by a process for preparing a compound of formula (I) as defined herein, comprising the following successive steps:
  • the compounds of the invention may be obtained by a process for preparing a compound of formula (I) as defined herein, comprising subjecting an intermediate of formula (III) or (IV): d in any one of claims 1 to 10 and optionally in a protected form, to a coupling with a reagent of formula Y-K”, with Y as defined in any of claims 1 to 10 and optionally in a protected form, wherein K, K’ are as defined below:
  • the process may comprise: a) Reducing the nitrile of formula (II): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R’ and R 7a as defined herein, and
  • R and R’ being independently a Ci-4alkyl substituted or not by a Ci.2alkoxy, or taken together forming a bridge Ci.2alkylenyl optionally substituted by one to four Ci.2alkoxy or Ci-2alkyl, to obtain an amine of formula (III): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R’ and R 7a as defined above in connection with formula (II), and PG being a N-protecting group, b) Deprotecting the acetal or ketal group (C(OR)(OR’)) of the amine of formula (III) under acidic conditions using a Lewis acid or a Bronsted acid, to obtain the corresponding aldehyde or ketone of formula (IV): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a and PG as defined above in connection with formula (III), c) Subjecting the aldehy
  • the peptide coupling will be advantageously carried out in the presence of a coupling agent, such as diisopropylcarbodiimide (DIG), dicyclohexylcarbodiimide (DCC), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (GDI), hexafluorophosphate 2 (1 H benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium (HBTLI), tetrafluoroborate 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium (TBTLI), hexafluorophosphate O (7-azobenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium (HATLI), (benzotriazol-l-yloxy)tripyrrolodinophosphonium
  • the process may comprise: a") Deprotecting the acetal or ketal group of the nitrile of formula (II) as defined above, to obtain the corresponding aldehyde or ketone of formula (XIII): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a as defined above in connection with formula (II), b") Subjecting the aldehyde or ketone of formula (XIII) to a reductive amination with an amine of formula (V): R 8a R 8b -N-H (V), with R 8a and R 8b as defined herein, to obtain an intermediate of formula (XIV): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a as defined above in connection with formula (II) and R 8a and R 8b as defined herein, c") Reducing the intermediate of formula (XIV): with A 1 , A 2 , A 3 ,
  • the process may comprise, a””) subjecting the compound of formula (XXII) with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R? a , R?b, Rsa and PG as defined herein, and Hal representing a halogen atom, preferably Cl or Br, to a palladium coupling (such as Molander reaction) with a [(1 ,3-dioxo-2,3-dihydro-1 H- isoindol-2-yl)methyl]trifluoroboron derivative such as potassium [(1 ,3-dioxo-2,3-dihydro- 1 H-isoindol-2-yl)methyl]trifluoroboranide, followed by a deprotection reaction, typically including addition of ethylenediamine and an alcohol such as propanol, to obtain the compound of formula (XXIII): with A 1 , A 2 , A 3
  • the palladium catalyst used in the palladium coupling of step a” is Pd(dba)2.
  • the process may comprise: a’””) Reacting a compound of formula (XXIV) with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R? a , R?b, X and Y as defined herein, with a 2-nitrobenzenesulfonyl chloride (nosyl chloride) to obtain a nosyl-protected intermediate of formula (XXV): with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R?
  • the present invention further concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined above, and a pharmaceutically acceptable carrier.
  • Said pharmaceutically acceptable carrier is selected, according to the dosage form and mode of administration desired, from the typical excipients known to persons skilled in the art.
  • compositions of the invention can be intended to enteral (e.g. oral, sublingual, buccal, rectal, vaginal, etc.), parenteral (e.g. subcutaneous, intramuscular, intravenous, intraocular, intraperitoneal, intracranial, intrathecal, etc.) or topical (e.g. transdermal) administration, preferably oral or intravenous administration.
  • enteral e.g. oral, sublingual, buccal, rectal, vaginal, etc.
  • parenteral e.g. subcutaneous, intramuscular, intravenous, intraocular, intraperitoneal, intracranial, intrathecal, etc.
  • topical e.g. transdermal
  • the active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals, preferably mammals including humans.
  • the pharmaceutical composition can be in a solid or liquid (solution or suspension) form.
  • a solid composition can be in the form of tablets, capsules, powders, granules and the like.
  • the active ingredient can be mixed with pharmaceutical vehicle(s) such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like before being compressed.
  • the tablets may be further coated, notably with sucrose or with other suitable materials, or they may be treated in such a way that they have a sustained or delayed activity.
  • the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with flavor correctors or sweeteners.
  • the active ingredient can be introduced into soft or hard capsules in the form of a powder or granules such as mentioned previously or in the form of a liquid composition such as mentioned below.
  • a liquid composition can contain the active ingredient together with a sweetener, a taste enhancer or a suitable coloring agent in a solvent such as water.
  • the liquid composition can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It can be for example a syrup or an elixir.
  • the pharmaceutical composition can be in a solid or liquid (solution or suspension) form.
  • a solid composition can be notably in the form of tablets, gelatin capsules, powders or granules as defined above for oral administration. It can be also in the form of a film.
  • a liquid composition can be as defined previously for oral administration. It can be administered in the form of a spray or drops.
  • suppositories or ovules can be prepared with binders which melt at rectal or vaginal temperature, for example cocoa butter or polyethylene glycols.
  • the composition can be in the form of an aqueous suspension or solution which may contain dispersing agents, wetting agents or suspending agents.
  • the composition is advantageously sterile. It can be in the form of an isotonic solution.
  • the amount of the compound of the invention that may be combined with the carrier materials to produce a single dosage of the composition will vary depending upon the subject and the particular mode of administration, as known in the art.
  • the pharmaceutical composition may further comprise another therapeutic compound, preferably another anticancer agent (or chemotherapeutic agents).
  • another therapeutic compound preferably another anticancer agent (or chemotherapeutic agents).
  • the compounds according to the present invention or pharmaceutical compositions thereof may also have therapeutic applications in combination with immune modulatory agents, such as inhibitors of the PDI/PDLI immune checkpoint axis, for example antibodies (or peptides) that bind to and/or inhibit the activity of PD-I (like Nivolumab, Pembrolizumab, Cemiplimab, Dostartimab) or the activity of PD-LI (like Atezolizumab, Avelumab, Durvalumab).
  • the compounds according to the present invention or pharmaceutical compositions thereof may also be combined with radiotherapy or chemotherapeutic agents as standard of care.
  • the compounds may also be combined with BCL2 inhibitors (like Venetoclax).
  • the compounds according to the present invention or pharmaceutical compositions thereof may also be combined with other agents that stimulate or enhance the immune response, such as vaccines.
  • the invention further concerns a compound or a pharmaceutical composition of the invention, for use as a drug, in particular with an METTL3 inhibiting activity.
  • the drug is in particular useful in the treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease, typically a cancer.
  • the compounds or pharmaceutical compositions of the invention may be used as drug in a combination therapy with radiotherapy, or with immune-stimulating agents such as vaccines.
  • the invention further relates to a kit comprising:
  • kits for using said kit, as a combination product for simultaneous, separate and staggered use as drug, in particular with an METTL3 inhibiting activity, in particular useful in the treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease, typically a cancer.
  • the present invention further relates to a method for preventing or treating a pathology associated with METTL3 oncogenic activity, comprising administering to a patient in need thereof an effective dose of the compound or the composition or the kit of the invention.
  • said pathology is a cancer, or an autoimmune, neurological, infectious or inflammatory disease, typically a cancer.
  • the method may further comprise combination with radiotherapy, or with immune- stimulating agents such as vaccines.
  • the “effective dose” of a compound of the invention varies as a function of numerous parameters such as, for example, the route of administration and the weight, the age, the sex, the advancement of the pathology to be treated and the sensitivity of the subject or patient to be treated.
  • patient or “subject” includes any mammal, and is preferably a human being.
  • Exemplary autoimmune diseases are rheumatoid arthritis and Grave's disease.
  • infectious diseases are viral (such as SARS-CoV-2, HIV, hepatitis virus), bacterial (for example Clostridium perfringens), bacterial (such as Clostridium perfringens), fungal (such as fusarium infection) and parasitic infections (for instance Toxoplasma gondii).
  • viral such as SARS-CoV-2, HIV, hepatitis virus
  • bacterial for example Clostridium perfringens
  • bacterial such as Clostridium perfringens
  • fungal such as fusarium infection
  • parasitic infections for instance Toxoplasma gondii).
  • neurological diseases are Fragile X syndrome and Alzheimer disease.
  • inflammatory disease examples include inflammatory bowel disease, Crohn's disease and ulcerative colitis.
  • the inhibition of METTL3 by a provided compound may be useful in treating or preventing, in particular treating, the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma. More specifically, the cancer is lung cancer, melanoma, head and neck cancer, oesophageal cancer, bladder and urothelial cancer, liver cancer, kidney cancer, prostate cancer and hematopoietic cancer.
  • cancers which may be treated or prevented, in particular treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangio sarcoma, lymphangioendothelio sarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e- g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g-, cervical adenocarcinom
  • uterine cancer uterine sarcoma
  • esophageal cancer e.g., adenocarcinoma of the esophagus, Barrett' s adenocarinoma
  • eye cancer e.g., intraocular melanoma, retinoblastoma
  • familiar hypereosinophilia gall bladder cancer
  • gastric cancer e.g., stomach adenocarcinoma
  • gastrointestinal stromal tumor GIST
  • head and neck cancer e.g., head and neck squamous cell carcinoma
  • oral cancer e.g., oral squamous cell carcinoma (OSCC)
  • throat cancer e-g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
  • hematopoietic cancers e.g., leukemia such as acute lymphocytic leukemia (ALL)
  • ALL acute lymphoc
  • alpha Chain disease gamma chain disease, mu chain disease
  • hemangioblastoma inflammatory myofibroblastic tumors
  • immunocytic amyloidosis kidney cancer (e.g., nephroblastoma a.k.a.
  • MMD myeloproliferative disorder
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma ovarian cancer
  • cystadenocarcinoma ovarian embryonal carcinoma, ovarian adenocarcinoma
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer e.g., Paget' s disease
  • °C means degrees Celsius; “A” means Angstrom; “aq.” means aqueous; “BiC ” means bismuth trichloride; “Boc” means terf-butoxycarbonyl; “BOC2O” means di-tert- butyl dicarbonate; “Celite®” means diatomaceous earth; “Co.” means compound; “CO” means carbon monoxide; “CoCh’S ⁇ O” means cobalt(ll) chloride hexahydrate; “CS2CO3” means cesium carbonate; “CuSO4” means copper(ll) sulfate; “DBU” means 1 ,8- diazabicyclo[5.4.0]undec-7-ene; “DCM” means dichloromethane; “DIAD” means diisopropyl azodicarboxylate; “DIBAL-H” means diisobutylaluminum hydride; “DI PEA” means N,N-diisopropy
  • TMAF*4H2O (1.7 g, 10.3 mmol) was dissolved in 'AmOH (50 mL). To this solution was added activated 3 molecular sieves (7.5 g) and the slurry was stirred at rt for 24 h. The slurry was filtered and washed with 'AmOH (3 x 4 mL). The filtrate and alcohol washes were combined and concentrated under reduced pressure to give the intermediate 2 (2.8 g, 145% yield) as a sticky white solid. Material was used directly in the next step without further purification with greater than quantitative yield due to the presence of residual 'AmOH.
  • a rbf was filled with water (22 mL) and fitted with a septum. The flask was placed into a water-filled sonication bath, vacuum was applied for 5 s, and the vessel was refilled with nitrogen gas. The cycle was repeated 5 times and the resulting degassed water was added under N2 via a syringe to a rdb containing KOAc (110 mg, 1.12 mmol).
  • intermediate 13 was prepared as described below to reduce the amount of dimer side compound.
  • Intermediate 17 was prepared according to the procedure described for intermediate 3 starting from intermediate 16 (1.45 g, 3.87 mmol) and intermediate 2 (1 g, 5.81 mmol) to give intermediate 44 (1 .4 g, 97% yield) as a white solid.
  • Intermediate 18 was prepared according to the procedure described for intermediate 4 starting from intermediate 17 (1.35 g, 3.77 mmol) to give intermediate 18 (840 mg, 73% yield) as a white solid.
  • Intermediate 20 was prepared according to the procedure described for intermediate 14 starting from intermediate 19 (289 mg, 0.94 mmol) to give intermediate 20 (354 mg, 79% yield) as a white solid.
  • Intermediate 22 was prepared according to the procedure described for intermediate 15 starting from intermediate 20 (100 mg, 0.208 mmol) to give intermediate 22 (85 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification.
  • Intermediate 25 was prepared according to the procedure described for intermediate 3 starting from intermediate 24 (146 mg, 0.37 mmol) to give intermediate 25 (82 mg, 59% yield) as a pale yellow solid.
  • Intermediate 26 was prepared according to the procedure described for intermediate 4 starting from intermediate 25 (60 mg, 0.16 mmol) to give the intermediate 26 (28 mg, 54% yield) as a pale yellow solid.
  • Intermediate 30 was prepared according to the procedure described for intermediate 3 starting from intermediate 29 (570 mg, 1 .48 mmol) and intermediate 2 (536 mg, 2.96 mmol) to give intermediate 30 (342 mg, 63% yield) as a white solid.
  • Intermediate 32 was prepared according to the procedure described for intermediate 19 starting from intermediate 31 (150 mg, 0.48 mmol) to give intermediate 32 (76 mg, 50% yield) as a yellow sticky solid which was used in the next step without further purification.
  • Intermediate 33 was prepared according to the procedure described for intermediate 24 starting from 6-bromo-2-chloro-3-formylquinoline (5 g, 18.5 mmol) and 4,4- dimethylpiperidine hydrochloride (3.32 g, 22.2 mmol) to give the intermediate 33 (5.3 g, 79% yield) as a white solid.
  • Intermediate 34 was prepared according to the procedure described for intermediate 3 starting from intermediate 33 (6.5 g, 17.7 mmol) and intermediate 2 (7.92 g, 43.9 mmol) to give intermediate 34 (4.4 g, 72% yield) as a pale yellow solid.
  • Intermediate 38 was prepared according to the procedure described for intermediate 35 starting from intermediate 3 (485 mg, 1.48 mmol) to give intermediate 38 (342 mg, 83% yield) as a white solid.
  • Intermediate 39 was prepared according to the procedure described for intermediate 36 starting from intermediate 38 (363 mg, 1.31 mmol) to give intermediate 39 (340 mg, 90% yield) as a white solid which was used in the next step without further purification.
  • Intermediate 44 was prepared according to the procedure described for intermediate 41 starting from intermediate 40 and intermediate 43 to give intermediate 44 (30 mg, 23% yield) as a yellow solid.
  • Intermediate 48 was prepared according to the procedure described for intermediate 36 starting from intermediate 47 (306 mg, 1 mmol) to give intermediate 48 (265 mg, 86% yield) as a colorless oil.
  • Intermediate 50 was prepared according to the procedure described for intermediate 41 starting from intermediate 49 and 8-ethynylimidazo[1 ,5-a]pyridine to give intermediate 50 (153 mg, 64% yield) as a brown oil. Synthesis of intermediate 51
  • Intermediate 51 was prepared according to the procedure described for intermediate 45 starting from intermediate 50 to give intermediate 51 (114 mg, quantitative yield) as a beige
  • Intermediate 53 was prepared according to the procedure described for intermediate 4 starting from intermediate 52 (235 mg, 0.71 mmol) to give intermediate 53 (131 mg, 66% yield) as a white solid.
  • Intermediate 55 was prepared according to the procedure described for intermediate 52 starting from intermediate 1 (1.89 g, 5.49 mmol) to give intermediate 55 (344 mg, 20% yield) as a white solid.
  • Intermediate 56 was prepared according to the procedure described for intermediate 4 starting from intermediate 55 (271 mg, 0.87 mmol) to give intermediate 56 (188 mg, 84% yield) as a white solid.
  • Intermediate 58 was prepared according to the procedure described for intermediate 14 starting from intermediate 57 (194 mg, 0.75 mmol) and 4-oxopyrido[1,2-a]pyrimidine-2- carboxylic acid (142 mg, 0.75 mmol) to give intermediate 58 (86 mg, 27% yield) as a white solid.
  • intermediate 58 (86 mg, 0.2 mmol) in chloroform (0.4 mL) was added TFA (273 mg, 2.39 mmol, 0.18 mL) at room temperature and the resulting mixture was stirred for 15 hours. Then the reaction mixture was quenched with water and was extracted three times with EtOAc. The combined organic layer was washed twice with brine, dried over MgSC , filtered off and the solvent was concentrated under reduced pressure to intermediate 59 (71 mg, quantitative yield) as a yellow oil which was used in the next step without further purification.
  • Intermediate 61 was prepared according to the procedure described for intermediate 4 starting from intermediate 60 (180 mg, 0.5 mmol) to give intermediate 61 (70 mg, 46% yield) as a white solid.
  • Intermediate 62 was prepared according to the procedure described for intermediate 5 starting from intermediate 61 (70 mg, 0.23 mmol) to give intermediate 62 (50 mg, 53% yield) as a white solid.
  • Intermediate 64 was prepared according to the procedure described for intermediate 7 starting from 3-bromo-quinoline-6-carbaldehyde (124 mg, 0.53 mmol) and 4,4- dimethylpiperidine hydrochloride (80 mg, 0.54 mmol) to give intermediate 64 (134 mg, 77% yield) as a white solid.
  • Intermediate 65 was prepared according to the procedure described for intermediate 4 starting from intermediate 64 (399 mg, 1.2 mmol) to give intermediate 65 (139 mg, 42% yield) as a white solid.
  • Intermediate 66 was prepared according to the procedure described for intermediate 54 starting from intermediate 65 (58 mg, 0.21 mmol) to give intermediate 66 (7 mg, 12% yield) as a white solid.
  • Intermediate 68 was prepared according to the procedure described for intermediate 7 starting from intermediate 67 (670 mg, 2.83 mmol) and 4,4-dimethylpiperidine hydrochloride (634 mg, 4.24 mmol) to give intermediate 68 (390 mg, 41 % yield) as a yellow oil.
  • Intermediate 70 was prepared according to the procedure described for intermediate 19 starting from intermediate 69 (81 mg, 0.29 mmol) to give intermediate 70 (66 mg, 80% yield) as a yellow oil.
  • Intermediate 86 was prepared according to the procedure described for intermediate 1 starting from intermediate 83 (748 mg, 3.52 mmol) to give intermediate 86 (670 mg, 66% yield) as a yellow solid.
  • Intermediate 88 was prepared according to the procedure described for intermediate 54 starting from intermediate 86 (430 mg, 1.5 mmol) to give intermediate 88 (435 mg, quantitative yield) as a brown oil.
  • Intermediate 89a was prepared according to the procedure described for intermediate 7 starting from intermediate 85 (570 mg, 2.2 mmol) and 1-cyclobutylmethanamine hydrochloride to give intermediate 89a (423 mg, 59% yield) as a yellow solid.
  • intermediate 89a (423 mg, 1.28 mmol) in MeCN (8.7 mL) was added BOC2O (335 mg, 1.54 mmol) dropwise.
  • the reaction mixture was stirred at 80 °C for 1 h.
  • the reaction solution was allowed to cool down to room temperature.
  • Water and DCM were added and the layers were separated.
  • the aqueous layer was extracted twice with DCM.
  • the combined organic layers were washed with a saturated aqueous NaHCOs solution, dried over MgSC , filtered off and concentrated under reduced pressure to afford intermediate 90a (542 mg, 98% yield) as a yellow oil.
  • Intermediate 94 was prepared according to the procedure described for intermediate 37 starting from intermediate 92 to give intermediate 94 (78 mg, 39% yield) as a white solid.
  • the following intermediate was prepared via an analogous procedure:
  • a microwave vial was charged with 6-bromo-3-(diethoxymethyl)-8-fluoroquinoline (430 mg, 1.31 mmol), potassium [(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)methyl]trifluoroboranuide (525 mg, 1.97 mmol), Pd(OAc)2 (14.7 mg, 0.066 mmol), SPhos (64.6 mg, 0.16 mmol), Na2CC>3 (625 mg, 5.9 mmol) in dioxane (6 mL)/H2O (3 mL). The tube was sealed and heated at 100 °C overnight.
  • Intermediate 124 was prepared according to the procedure described for intermediate 15 starting from intermediate 108 (95 mg, 0.205 mmol) to give intermediate 124 (79 mg, quantitative yield) as a pale yellow solid which was used in the next step without further purification.
  • Pd(dba)2 (104 mg, 0.18 mmol) and SPhos (180 mg, 0.43 mmol) were added to a degassed suspension of 3-bromo-7-methoxyquinoline-6-carbonitrile (1.12 g, 3.61 mmol), potassium N-Boc-aminomethyltrifluoroborate (1.28 g, 5.42 mmol) and Na2COs (1.72 g, 16.3 mmol in dioxane (15.8 mL) and H2O (7.9 mL) at rt. The resulting mixture was stirred at 100 °C for 20 h. The reaction mixture was diluted with H2O and extracted with EtOAc.
  • intermediate 143 was prepared according to the procedure described for intermediate 54 starting from intermediate 136 (508 mg, 1.62 mmol) to give intermediate 143 (485 mg, 94% yield) as a green foam.
  • Intermediate 145 was prepared according to the procedure described for intermediate 108 starting from intermediate 143 (485 mg, 1.53 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (291 mg, 1.53 mmol) to give intermediate 145 (400 mg, 53% yield) as a brown solid.
  • Intermediate 147 was prepared according to the procedure described for Co. 7 starting from intermediate 145 (490 mg, 0.82 mmol) to give intermediate 147 (221 mg, 70% yield) as a brown solid.
  • Intermediate 159 was prepared according to the procedure described for intermediate 8 starting from intermediate 158 (228 mg, 0.64 mmol) to give intermediate 159 (182 mg, 97% yield) as a white solid.
  • Intermediate 160 was prepared according to the procedure described for intermediate 108 starting from intermediate 159 (182 mg, 0.62 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (119 mg, 0.62 mmol) to give intermediate 160 (120 mg, 45% yield) as a yellow solid. Synthesis of intermediate 161
  • Intermediate 161 was prepared according to the procedure described for intermediate 7 starting from intermediate 83 (182 mg, 0.62 mmol) to give intermediate 161 (105 mg, 59% yield) as an orange oil.
  • Intermediate 162 was prepared according to the procedure described for intermediate 54 starting from intermediate 161 (100 mg, 0.34 mmol) to give intermediate 162 (100 mg, 99% yield) as a brown sticky oil.
  • Intermediate 163 was prepared according to the procedure described for intermediate 83 starting from intermediate 112 (40 mg, 0.1 mmol) to give intermediate 163 (40 mg, quantitative yield) as a brown solid.
  • Intermediate 167 was prepared according to the procedure described for intermediate 15 starting from intermediate 166 (110 mg, 0.23 mmol) to give intermediate 167 (66 mg, 71% yield) as a pale yellow solid which was used in the next step without further purification.
  • Intermediate 169 was prepared according to the procedure described for intermediate 37 starting from intermediate 168 (610 mg, 2.1 mmol) to give intermediate 169 (391 mg, 59% yield) as a brown oil.
  • Intermediate 170 was prepared according to the procedure described for intermediate 41 starting from intermediate 169 (180 mg, 0.57 mmol) and 8-ethynylimidazo[1 ,5-a]pyridine to give intermediate 170 (139 mg, 53% yield) as a yellow solid. Synthesis of intermediate 171
  • Intermediate 171 was prepared according to the procedure described for intermediate 15 starting from intermediate 170 (150 mg, 0.33 mmol) to give intermediate 171 (125 mg, quantitative yield) as a pale yellow solid which was used in the next step without further purification.
  • Intermediate 172 was prepared according to the procedure described for intermediate 79 starting from intermediate 172 (1.9 g, 6.65 mmol) to give intermediate 173 (772 mg, 51% yield) as a beige solid.
  • Intermediate 174 was prepared according to the procedure described for intermediate 83 starting from intermediate 173 (670 mg, 2.94 mmol) to give intermediate 174 (477 mg, 71% yield) as a brown solid which was used in the next step without further purification.
  • Intermediate 175 was prepared according to the procedure described for intermediate 7 starting from intermediate 174 (475 mg, 2.1 mmol) and 1-cyclobutylmethanamine hydrochloride (301 mg, 2.48 mmol) to give intermediate 175 (576 mg, 93% yield) as a white solid.
  • Intermediate 176 was prepared according to the procedure described for intermediate 90a starting from intermediate 175 (100 mg, 0.33 mmol) to give intermediate 176 (116 mg, 87% yield) as a white solid.
  • Intermediate 179 was prepared according to the procedure described for intermediate 37 starting from intermediate 178 (130 mg, 0.36 mmol) to give intermediate 179 (102 mg, 73% yield) as a white solid.
  • Intermediate 180 was prepared according to the procedure described for intermediate 96 starting from intermediate 179 (100 mg, 0.26 mmol) to give intermediate 180 (50 mg, 54% yield) as a white solid.
  • Intermediate 181 was prepared according to the procedure described for intermediate 108 starting from intermediate 180 (50 mg, 0.14 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (27 mg, 0.14 mmol) to give intermediate 181 (35 mg, 47% yield) as a white solid.
  • Intermediate 183 was prepared according to the procedure described for intermediate 79 starting from intermediate 182 (3.4 g, 12.5 mmol) to give intermediate 183 (2.6 g, 95% yield) as a white solid.
  • Intermediate 184 was prepared according to the procedure described for intermediate 83 starting from intermediate 183 (2.6 g, 11.8 mmol) to give intermediate 184 (2.6 g, quantitative yield) as a brown solid.
  • Intermediate 185 was prepared according to the procedure described for intermediate 7 starting from intermediate 184 (2.6 g, 11.8 mmol) and cyclobutylmethanamine hydrochloride (1.4 g, 11.8 mmol) to give intermediate 185 (2.3 g, 67% yield) as a brown solid.
  • Intermediate 186 was prepared according to the procedure described for intermediate 90a starting from intermediate 185 (735 mg, 2.5 mmol) to give intermediate 186 (990 mg, quantitative yield) as a colourless oil.
  • Intermediate 187 was prepared according to the procedure described for intermediate 100 starting from intermediate 186 (1.2 g, 2.9 mmol) to give intermediate 187 (611 mg, 54% yield) as a white solid.
  • Intermediate 188 was prepared according to the procedure described for intermediate 108 starting from intermediate 187 (150 mg, 0.39 mmol) and 5-(3-azabicyclo[3.1.0]hexan-3- yl)nicotinic acid (79.5 mg, 0.39 mmol) to give intermediate 188 (150 mg, 67% yield) as a yellow solid.
  • Intermediate 202 was prepared according to the procedure described for intermediate 1 starting from intermediate 184 (638 mg, 2.73 mmol) to give intermediate 202 (504 mg, 62% yield) as a pale brown oil.
  • Intermediate 203 was prepared according to the procedure described for intermediate 100 starting from intermediate 202 (615 mg, 1.71 mmol) to give intermediate 203 (408 mg, 82% yield) as a yellow oil. Synthesis of intermediate 204:
  • Intermediate 204 was prepared according to the procedure described for intermediate 108 starting from intermediate 203 (385 mg, 1.33 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (252 mg, 1.33 mmol) to give intermediate 204 (406 mg, 66% yield) as a yellow solid.
  • Intermediate 205 was prepared according to the procedure described for intermediate 15 starting from intermediate 204 (178 mg, 0.38 mmol) to give intermediate 205 (149 mg, quantitative yield) as a pale yellow solid. o
  • Intermediate 207 was prepared according to the procedure described for intermediate 90a starting from intermediate 206 (420 mg, 1.17 mmol) to give intermediate 207 (320 mg, 72% yield) as a light brown solid.
  • Intermediate 215 was prepared according to the procedure described for intermediate 100 starting from intermediate 208 (250 mg, 0.6 mmol) to give intermediate 215 (145 mg, 59% yield) as a yellow oil.
  • Intermediate 221 was prepared according to the procedure described for intermediate 108 starting from intermediate 215 (145 mg, 0.35 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (66.7 mg, 0.35 mmol) to give intermediate 221 (120 mg, 58% yield) as a colourless oil.
  • Intermediate 228 was prepared according to the procedure described for intermediate 54 starting from intermediate 227 (282 mg, 0.62 mmol) to give intermediate 228 (218 mg, 79% yield) as a yellow oil.
  • Intermediate 229 was prepared according to the procedure described for intermediate 108 starting from intermediate 228 (303 mg, 0.49 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (93.5 mg, 0.49 mmol) to give intermediate 229 (151 mg, 50% yield) as a light brown solid.
  • Intermediate 231 was prepared according to the procedure described for intermediate 206 starting from intermediate 184 (2.85 g, 10.7 mmol) to give intermediate 231 (1.12 g, 51% yield) as a brown solid.
  • Intermediate 232 was prepared according to the procedure described for intermediate 1 starting from intermediate 231 (2.21 g, 10.7 mmol) to give intermediate 232 (1.1 g, 37% yield) as a white solid.
  • Intermediate 233 was prepared according to the procedure described for intermediate 208 starting from intermediate 232 (800 mg, 2.84 mmol) and 2-bromo-tert-butyldimethylsilane (1.36 g, 5.68 mmol, 1.12 mL) to give intermediate 233 (386 mg, 31% yield) as a yellow oil.
  • Intermediate 234 was prepared according to the procedure described for intermediate 100 starting from intermediate 233 (870 mg, 1.98 mmol) to give intermediate 234 (208 mg, 24% yield) as a yellow oil.
  • Intermediate 235 was prepared according to the procedure described for intermediate 108 starting from intermediate 234 (205 mg, 0.47 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (90 mg, 0.47 mmol) to give intermediate 235 (163 mg, 57% yield) as a light brown solid.
  • Intermediate 323 was prepared according to the procedure described for intermediate 15 starting from intermediate 235 (175 mg, 0.29 mmol) to give intermediate 323 (120 mg, quantitative yield) as a pale yellow solid.
  • Intermediate 237 was prepared according to the procedure described for intermediate 83 starting from intermediate 236 (592 mg, 3.12 mmol) to give intermediate 237 (598 mg, quantitative yield) as a brown solid.
  • Intermediate 238 was prepared according to the procedure described for intermediate 1 starting from intermediate 237 (800 mg, 3.8 mmol) to give intermediate 238 (645 mg, 64% yield) as a yellow oil.
  • Intermediate 239 was prepared according to the procedure described for intermediate 4 starting from intermediate 238 (278 mg, 1.05 mmol) to give intermediate 239 (90 mg, 34% yield) as a yellow solid.
  • Intermediate 240 was prepared according to the procedure described for intermediate 19 starting from intermediate 239 (190 mg, 0.74 mmol) to give intermediate 240 (193 mg, quantitative yield) as a brown oil.
  • Intermediate 241 was prepared according to the procedure described for intermediate 108 starting from intermediate 240 (140 mg, 0.43 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (81.8 mg, 0.43 mmol) to give intermediate 241 (60 mg, 32% yield) as a light brown solid.
  • Intermediate 324 was prepared according to the procedure described for intermediate 15 starting from intermediate 241 (60 mg, 0.14 mmol) to give intermediate 324 (49 mg, quantitative yield) as a pale yellow solid.
  • Intermediate 242 was prepared according to the procedure described for intermediate 7 starting from intermediate 237 (2.45 g, 12.8 mmol) and cyclobutylmethanamine hydrochloride (1.87 g, 15.3 mmol) to give intermediate 242 (2.54 g, 76% yield) as a dark purple oil.
  • Intermediate 243 was prepared according to the procedure described for intermediate 90a starting from intermediate 242 (2.38 g, 9.13 mmol) to give intermediate 243 (3.01 g, 91 % yield) as a brown oil.
  • Intermediate 245 was prepared according to the procedure described for intermediate 100 starting from intermediate 244 (262 mg, 0.7 mmol) to give intermediate 245 (186 mg, 72% yield) as a yellow oil.
  • Intermediate 246 was prepared according to the procedure described for intermediate 108 starting from intermediate 245 (70 mg, 0.19 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (36 mg, 0.19 mmol) to give intermediate 246 (51 mg, 50% yield) as a yellow foam.
  • Intermediate 248 was prepared according to the procedure described for intermediate 63 starting from intermediate 247a (33.9 g, 88.7 mmol) to give intermediate 248 (34.4 g, 98% yield) as a white solid. o
  • Intermediate 250 was prepared according to the procedure described for intermediate 79 starting from intermediate 249 (13.7 g, 44.3 mmol) to give intermediate 250 (7.4 g, 65% yield) as a beige solid.
  • Intermediate 252 was prepared according to the procedure described for intermediate 83 starting from intermediate 251 (6.3 g, 22.7 mmol) to give intermediate 252 (6 g, 95% yield) as a pale brown solid.
  • Intermediate 253 was prepared according to the procedure described for intermediate 7 starting from intermediate 252 (6 g, 21.6 mmol) and cyclobutylmethanamine hydrochloride (3.15 g, 25.9 mmol) to give intermediate 253 (6.29 g, 84% yield) as a brown solid.
  • Intermediate 256 was prepared according to the procedure described for intermediate 37 starting from intermediate 255 (455 mg, 1.16 mmol) to give intermediate 256 (406 mg, 84% yield) as a colourless oil.
  • Intermediate 257 was prepared according to the procedure described for intermediate 96 starting from intermediate 256 (386 mg, 0.96 mmol) to give intermediate 257 (341 mg, 94% yield) as a colourless oil.
  • Intermediate 258 was prepared according to the procedure described for intermediate 108 starting from intermediate 258 (281 mg, 0.72 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (166 mg, 0.87 mmol) to give intermediate 258 (371 mg, 92% yield) as a pale yellow solid.
  • Intermediate 265 was prepared according to the procedure described for intermediate 36 starting from intermediate 264 (770 mg, 2.86 mmol) to give intermediate 265 (660 mg, 85% yield) as a colourless oil.
  • Intermediate 267 was prepared according to the procedure described for intermediate 83 starting from intermediate 266 (455 mg, 1.28 mmol) to give intermediate 267 (453 mg, 72% yield) as a grey solid.
  • Intermediate 268 was prepared according to the procedure described for intermediate 7 starting from intermediate 267 (450 mg, 1.26 mmol) and cyclobutylmethanamine hydrochloride (184 mg, 1.51 mmol) to give intermediate 268 (216 mg, 40% yield) as a red oil.
  • Intermediate 269 was prepared according to the procedure described for intermediate 90a starting from intermediate 268 (200 mg, 0.47 mmol) to give intermediate 269 (200 mg, 81% yield) as a colourless oil.
  • Intermediate 271 was prepared according to the procedure described for intermediate 37 starting from intermediate 270 (470 mg, 1 mmol) to give intermediate 271 (494 mg, quantitative yield) as a colourless oil.
  • Intermediate 272 was prepared according to the procedure described for intermediate 96 starting from intermediate 271 (540 mg, 1.09 mmol) to give intermediate 272 (326 mg, 64% yield) as a pale yellow oil.
  • Intermediate 273 was prepared according to the procedure described for intermediate 108 starting from intermediate 272 (200 mg, 0.43 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (89 mg, 0.43 mmol) to give intermediate 273 (190 mg, 70% yield) as a brown oil.
  • Intermediate 275 was prepared according to the procedure described for intermediate 247a starting from methyl 5-bromo-3-formylpicolinate (3.8 g, 15.9 mmol) to give intermediate 275 (3.18 g, 52% yield) as a white solid.
  • Intermediate 276a was prepared according to the procedure described for intermediate 63 starting from intermediate 275 (3.6 g, 9.31 mmol) to give intermediate 276a (3.61 g, 98% yield) as a white solid.
  • the following intermediates were prepared via an analogous procedure: o
  • Intermediate 279 was prepared according to the procedure described for intermediate 79 starting from intermediate 276a (3.3 g, 8.3 mmol) to give intermediate 279 (1 g, 53% yield) as an orange solid.
  • the following intermediates were prepared via an analogous procedure: ci
  • Intermediate 282 was prepared according to the procedure described for intermediate 251 starting from intermediate 279 (1.1 g, 4.56 mmol) to give intermediate 282 (542 mg, 48% yield) as a pale brown solid.
  • the following intermediate was prepared via an analogous procedure:
  • Intermediate 284 was prepared according to the procedure described for intermediate 182 starting from intermediate 282 (408 mg, 1.64 mmol) to give intermediate 284 (192 mg, 48% yield) as a pale brown solid.
  • Intermediate 285 was prepared according to the procedure described for intermediate 83 starting from intermediate 284 (359 mg, 1 .47 mmol) to give intermediate 285 (340 mg, 94% yield) as a grey solid.
  • Intermediate 286 was prepared according to the procedure described for intermediate 7 starting from intermediate 285 (340 mg, 1.38 mmol) and cyclobutylmethanamine hydrochloride (202 mg, 1.66 mmol) to give intermediate 286 (254 mg, 58% yield) as a pale yellow oil.
  • Intermediate 287 was prepared according to the procedure described for intermediate 90a starting from intermediate 286 (244 mg, 0.77 mmol) to give intermediate 287 (312 mg, 97% yield) as a brown oil.
  • Intermediate 288 was prepared according to the procedure described for intermediate 255 starting from intermediate 287 (280 mg, 0.67 mmol) to give intermediate 288 (234 mg, 90% yield) as a colourless oil.
  • Intermediate 290 was prepared according to the procedure described for intermediate 96 starting from intermediate 289 (245 mg, 0.59 mmol) to give intermediate 290 (207 mg, 90% yield) as a pale yellow oil.
  • Intermediate 291 was prepared according to the procedure described for intermediate 108 starting from intermediate 290 (105 mg, 0.27 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (52 mg, 0.27 mmol) to give intermediate 291 (106 mg, 70% yield) as a white solid.
  • Intermediate 293 was prepared according to the procedure described for intermediate 263 starting from intermediate 283 (1.75 g, 5.96 mmol) to give intermediate 293 (651 mg, 40% yield) as a white solid.
  • Intermediate 294 was prepared according to the procedure described for intermediate 83 starting from intermediate 293 (650 mg, 2.38 mmol) to give intermediate 294 (597 mg, 91% yield) as a grey solid.
  • Intermediate 295 was prepared according to the procedure described for intermediate 7 starting from intermediate 294 (597 mg, 2.17 mmol) and cyclobutylmethanamme hydrochloride (316 mg, 2.6 mmol) to give intermediate 295 (610 mg, 82% yield) as a yellow oil.
  • Intermediate 296 was prepared according to the procedure described for intermediate 90a starting from intermediate 295 (610 mg, 1.77 mmol) to give intermediate 296 (711 mg, 90% yield) as a colourless oil.
  • Intermediate 297 was prepared according to the procedure described for intermediate 255 starting from intermediate 296 (500 mg, 1.12 mmol) to give intermediate 297 (399 mg, 91% yield) as a colourless oil.
  • Intermediate 298 was prepared according to the procedure described for intermediate 37 starting from intermediate 297 (399 mg, 1 mmol) to give intermediate 298 (348 mg, 82% yield) as a colourless oil.
  • Intermediate 299 was prepared according to the procedure described for intermediate 96 starting from intermediate 298 (429 mg, 1 mmol) to give intermediate 299 (302 mg, 75% yield) as a colourless oil.
  • Intermediate 300 was prepared according to the procedure described for intermediate 108 starting from intermediate 299 (140 mg, 0.36 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (68.7 mg, 0.36 mmol) to give intermediate 300 (174 mg, 86% yield) as a pale yellow solid.
  • Intermediate 302 was prepared according to the procedure described for intermediate 213 starting from intermediate 281 (200 mg, 0.73 mmol) to give intermediate 302 (153 mg, 73% yield) as a white solid.
  • Intermediate 303 was prepared according to the procedure described for intermediate 83 starting from intermediate 302 (174 mg, 0.53 mmol) to give intermediate 303 (108 mg, 70% yield) as a yellow solid.
  • Intermediate 304 was prepared according to the procedure described for intermediate 7 starting from intermediate 303 (136 mg, 0.36 mmol) and cyclobutylmethanamine hydrochloride (48.7 mg, 0.40 mmol) to give intermediate 304 (34 mg, 26% yield) as a brown oil.
  • Intermediate 305 was prepared according to the procedure described for intermediate 90a starting from intermediate 304 (68.5 mg, 0.19 mmol) to give intermediate 305 (74 mg, 84% yield) as a brown oil.
  • Intermediate 306 was prepared according to the procedure described for intermediate 168 starting from intermediate 305 (44 mg, 0.096 mmol) to give intermediate 306 (38 mg, quantitative yield) as a white solid.
  • Intermediate 307 was prepared according to the procedure described for intermediate 37 starting from intermediate 306 (58 mg, 0.14 mmol) to give intermediate 307 (57 mg, 93% yield) as a yellow oil.
  • Intermediate 308 was prepared according to the procedure described for intermediate 96 starting from intermediate 307 (170 mg, 0.4 mmol) to give intermediate 308 (39 mg, 24% yield) as a colourless oil.
  • Intermediate 309 was prepared according to the procedure described for intermediate 108 starting from intermediate 308 (46 mg, 0.11 mmol) and 4-oxo-4/7-pyrido[1,2-a]pyrimidine- 2-carboxylic acid (21.7 mg, 0.11 mmol) to give intermediate 309 (29 mg, 45% yield) as a yellow oil.
  • Intermediate 310 was prepared according to the procedure described for intermediate 165 starting from 6-bromo-7-fluoroisoquinoline (250 mg, 1.1 mmol) to give intermediate 310 (158 mg, 59% yield) as a pinkish solid.
  • Intermediate 311 was prepared according to the procedure described for intermediate 251 starting from intermediate 310 (500 mg, 2.1 mmol) to give intermediate 311 (297 mg, 55% yield) as a pinkish solid.
  • Intermediate 312 was prepared according to the procedure described for intermediate 165 starting from intermediate 311 (3.84 g, 14.7 mmol) to give intermediate 312 (1.3 g, 33% yield) as a white solid.
  • Intermediate 313 was prepared according to the procedure described for intermediate 251 starting from intermediate 312 (1.3 g, 4.8 mmol) to give intermediate 313 (700 mg, 49% yield) as a white solid.
  • Intermediate 315 was prepared according to the procedure described for intermediate 7 starting from intermediate 314 (102 mg, 0.42 mmol) and cyclobutylmethanamine hydrochloride (50.8 mg, 0.42 mmol) to give intermediate 315 (96 mg, 73% yield) as a colourless oil.
  • Intermediate 316 was prepared according to the procedure described for intermediate 90a starting from intermediate 315 (119 mg, 0.38 mmol) to give intermediate 316 (118 mg, 75% yield) as a light brown oil.
  • Intermediate 317 was prepared according to the procedure described for intermediate 182 starting from intermediate 316 (142 mg, 0.34 mmol) to give intermediate 317 (98 mg, 70% yield) as a colourless oil.
  • Intermediate 318 was prepared according to the procedure described for intermediate 100 starting from intermediate 317 (94 mg, 0.23 mmol) to give intermediate 318 (63 mg, 68% yield) as a light brown oil.
  • Intermediate 319 was prepared according to the procedure described for intermediate 108 starting from intermediate 318 (63 mg, 0.16 mmol) and 4-oxo-4/7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (29.7 mg, 0.16 mmol) to give intermediate 319 (56 mg, 62% yield) as a white solid.
  • Co. 24 was prepared according to the procedure described for Co. 8 starting from intermediate 22 (84 mg, 0.207 mmol) and 1- ⁇ 3-fluorobicyclo[1.1.1]pentan-1- yljmethanamine hydrochloride (26.1 mg, 0.17 mmol) to give Co. 24 (11 mg, 13% yield) as a white solid.
  • Co. 28 was prepared according to the procedure described for Co. 8 starting from intermediate 28 (12.4 mg, 30.7 pmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid
  • the racemic material was purified by chiral SFC eluted with CO2 1 (MeOH + 0.3%'PrNH2) 55/45 to afford Co. 60 (25 mg, 31% yield) as a white solid and Co. 61 (25 mg, 31 % yield) as a white solid. .
  • Co. 30 was prepared according to the procedure described for Co. 8 starting from intermediate 32 (76 mg, 0.24 mmol) and 4-oxopyrido[1 ,2-a]pyrimidine-2-carboxylic acid (50 mg, 0.26 mmol) to give Co. 30 (22 mg, 19% yield) as a white solid.
  • Co. 35 was prepared according to the procedure described for Co. 8 starting from intermediate 45 (100 mg, 0.27 mmol) and 1- ⁇ 3-fluorobicyclo[1.1.1]pentan-1- yljmethanamine hydrochloride (49 mg, 0.32 mmol) to give Co. 35 (21 mg, 17% yield) as a white solid.
  • Co. 38 was prepared according to the procedure described for Co. 1 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) to give Co. 38 (30 mg, 29% yield) as a white solid Synthesis of Co. 39:
  • Co. 39 was prepared according to the procedure described for Co. 8 starting from intermediate 59 (71 mg, 0.2 mmol) and cyclohexanemethylamine (25 mg, 3.11 mmol, 28.4 pL) to give final Co. 39 (14 mg, 8% yield) as a white solid.
  • Co. 40 was prepared according to the procedure described for Co. 1 from intermediate 63 (50 mg, 0.12 mmol) and 4-oxopyrido[1 ,2-a]pyrimidine-2-carboxylic acid (33 mg, 0.17 mmol) to give final compound Co. 40 (3 mg, 5% yield) as a white solid.
  • Co. 41 was prepared according to the procedure described for Co. 1 starting from intermediate 66 (6 mg, 0.03 mmol) and 4-oxopyrido[1 ,2-a]pyrimidine-2-carboxylic acid (7 mg, 0.03 mmol) to give Co. 41 (3 mg, 28% yield) as a white solid.
  • Co. 42 was prepared according to the procedure described for final compound 1 starting from intermediate 70 (66 mg, 0.23 mmol) and 4-oxopyrido[1 ,2-a]pyrimidine-2-carboxylic acid (48.5 mg, 0.26 mmol) to give final compound Co. 42 (8 mg, 7% yield) as a white solid.
  • Co.96 was prepared according to the procedure described for intermediate 8 starting from intermediate 113 (200 mg, 0.36 mmol) to give final compound Co. 96 (147 mg, 90% yield) as a white solid.
  • Co.137 was prepared according to the procedure described for intermediate 8 starting from intermediate 261 (50 mg, 0.085 mmol) to give final compound Co. 137 (15 mg, 36% yield) as a white solid.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • methyltransferase activity of METTL3 was measured with a bioluminescent assay using the MTase-GloTM Methyltransferase Assay kit from Promega (V7602).
  • the enzyme used was the recombinant METTL3/METTL14 complex that includes full-length human METTL3 (accession number NP_062826.2) without a tag and full length human METTL14 protein (accession number NP_066012.1) with an N-terminal FLAG-Tag expressed in Sf9 cells purchased from Actif Motif.
  • the synthetic RNA substrate 5' U.A.C.A.C.U.C.G.A.U.C.U.G.A.C.U.A.A.A.G.C.U.G.C.U.C.C 3' was purchased from Horizon discovery.
  • Enzymatic reactions were performed in Optiplate 96 half area (Perkin Elmer 6002290) using a final volume of 10pl containing 20 mM Tris-HCI pH 7.5, 0.01 % Triton X-100, 2mM MgCI2 in duplicate. Experiments were also independently duplicated. A 20nM final concentration of METTL3/14 solution containing RNA substrate (10pM) and MTaseGloTM reagent to convert resulting SAH to ADP, was pre-incubated with various compound concentration for 10 min at room temperature (final compound concentration ranging from 5pM to 0.25nM with 1 % DMSO final residual).
  • the luminescence signal was measured with a plate-reading luminometer (SpectraMax i3X) and correlated to SAH concentration. Percentage of inhibition were obtained by normalizing to control wells without inhibition (DMSO only). IC50 values were calculated by measuring enzyme activity over a dilution series of inhibitor concentrations (10 different concentrations, third dilution) using a four-parameter nonlinear regression analysis.
  • MOLM-13 and Kasumi-1 cells were plated in suspension at 1200 and 10000 cells/well respectively in a volume of 27pl in a 384-well plate (Greiner 781080) in quadruplet, in RPMI 1640 media containing 10% fetal bovine serum, 2mM Glutamine and 0.2% Pen/Strep. Cells were treated by adding 3pl of compound/media intermediate concentration resulting in a final concentration ranging from 50pM to 2.54nM with 0.5% DMSO final residual.
  • the compound/media intermediate 10X dilution plate was prepared by mixing 5pl of compound from initial compound dilution plate in 100% DMSO (concentration ranging from 10mM to 508nM in 100% DMSO) with 95pl of media.
  • Luminescence signals were measured on day 5 using CellTiter-Glo® Luminescent Cell Viability Assay (30pl/well; Promega, G7572) to calculate the relative cell proliferation compared to the control wells with cells treated only with 0.5% DMSO and to the control wells without cells.

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Abstract

L'invention concerne un composé de formule (I), ou un stéréoisomère, un sel, un solvate ou un N-oxyde de celui-ci, où A1 à A6, X, Y, R7a, R7b, R8a et R8b sont tels que définis dans les revendications. L'invention concerne en outre une composition pharmaceutique le comprenant et un véhicule pharmaceutiquement acceptable, et ses utilisations en tant que médicament en particulier à activité inhibitrice de METTL3, avantageusement pour une utilisation dans le traitement ou la prévention d'un cancer, ou d'une maladie auto-immune, neurologique, infectieuse ou inflammatoire.
PCT/EP2024/058800 2023-03-30 2024-03-29 Nouveaux inhibiteurs de mettl3 et leur utilisation en thérapie Pending WO2024200835A1 (fr)

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