Novel mettl3 inhibitors and use thereof in therapy

Abstract

The invention relates to a compound of Formula (I), or a tautomer stereoisomer, salt, solvate or N-oxide thereof, wherein A1 to A6, X, Y, R7a, R7b, R8a and R8b are as defined in the claims. The invention further concerns a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, and uses thereof as a drug in particular with an METTL3 inhibiting activity, advantageously for use in the treatment or prevention of a cancer, or an autoimmune, neurological, infectious or inflammatory disease.

Description

[0001] NOVEL METTL3 INHIBITORS AND USE THEREOF IN THERAPY

[0002] FIELD OF THE INVENTION

[0003] 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.

[0004] BACKGROUND OF THE INVENTION

[0005] Specific chemical modifications of biological molecules are an efficient way of regulating molecular function, and many downstream signalling pathways are influenced by the modification of DNA and proteins. Many of the enzymes responsible for regulating protein and DNA modifications are targets of current cancer therapies. 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).

[0006] N6-methyladenosine (m6A) is the most prevalent RNA modification in mammalian cells. m6A modification sites are evolutionally conserved within a consensus motif DRACH (D = A, G or U; H = A, C, or U), in which A is converted to m6A and generally occurs in the coding sequence, 3' untranslated region (3' UTR) proximal to the stop codon, and 5' untranslated region (5' UTR) of mRNAs. It is a potentially reversible and dynamic post- transcriptional modification of RNA molecules that is regulated by methyltransferases (writers) and demethylases (erasers) and recognized by specific binding proteins (readers) (Li et al. 2022).

[0007] As increasing evidence suggests that 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).

[0008] The deposition of m6A is mainly catalyzed by a methyltransferase complex (MTC) comprising numerous components. As a core component of MTC, methyltransferase-like protein 3 (METTL3) is an S-adenosyl methionine (SAM)-binding protein that catalyzes the transfer of methyl groups in SAM to adenine bases in RNA, METTL14 stabilizes the structure of MTC and identifies the consensus motif DRACH, and Wilms tumor 1- associated protein (WTAP) promotes the recruitment of METTL3 and METTL14 (Wang et al. 2016, Ping et al. 2014).

[0009] METTL3 plays a crucial role in many biological processes, especially tumorigenesis and development. Generally, 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. Accordingly, 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)

[0010] 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.

[0011] WO2022254216 describes the combination therapies comprising a METTL3 inhibitor and a further anticancer agent.

[0012] WO2022254218 describes the processes for the preparation of inhibitory compounds WO2021079196, W02021081211 and WO2022081739 describe METTL3 modulating agents.

[0013] SUMMARY OF THE INVENTION

[0014] In a first aspect, the invention relates to a compound of Formula (I), or a tautomer, stereoisomer, salt, solvate or N-oxide thereof, wherein

[0015] A1represents CR1aor N; A2represents CR2aor N; A3represents CR3aor N; A4represents CR4aor N; A5represents CR5aor N; A6represents CR6aor N; provided that no more than 3 of A1, A2, A3, A4, A5and A6represents N;

[0016] R1ato R6aeach 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(Ci-4 alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecycloalkyl;

[0017] R7aand R7bare independently selected from: (i) hydrogen;

[0018] (ii) Ci-ealkyl which is optionally substituted by one more substituent selected from halo, cyano, hydroxy, Ci.4alkoxy, Ci.4haloalkoxy,

[0019] (iii) or R7aand R7bare linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,

[0020] R8aand R8bare independently

[0021] (i) hydrogen,

[0022] (ii) Ci-ealkyl optionally substituted by one more substituents selected from cyano, hydroxy, halo, Ci-2alkoxy, Ci aloalkoxy,

[0023] (iii) a group of formula -(CRcRd)n-Z with n is 0, 1 , or 2,

[0024] Rcand Rdare 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 Rcand Rdare 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 hydrogen, cyano, hydroxy, o NRaRbor -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl, and o C^alkenyl, C^alkynyl, Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, a bicyclic C5- i2cycloalkyl, each of which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci-2alkyl, Ci.2haloalkyl, Ci.2hydroxyalkyl, Ci- 2alkoxy, Ci.2haloalkoxy, C^alkenyl, NRaRband -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl; iv) or R8aand R8bare 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, NRaRband -S(0)o-2RaRbwherein Raand Rbare independently H or Ci-4alkyl;

[0025] 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;

[0026] Rcand Rdare 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;

[0027] Reand Rfare 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;

[0028] RcRdand ReRfmay 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;

[0029] Y is selected from one of the following structures: wherein:

[0030] Gi is selected from CRhand N, wherein Rhis 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;

[0031] G2 is selected from N and CR9, wherein R9is 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), -(OCH2CH2)m-NRyRz, -(OCH2CH2)m-OCH3, NRyRz, and -C(O)-NRyRz; wherein m is an integer from 1 to 6 and Ryand Rzare each independently hydrogen, C1.4 alkyl, Cs-ecycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, or Ryand Rzare linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6 membered heterocyclyl; wherein any of Ci-4alkyl, Ci.4alkoxy, C^alkenyl, C^alkynyl, phenyl, 5- or 6- membered heteroaryl, Cs-ecycloalkyl, -O-Cs-ecycloalkyl, heterocyclyl and -O- (carbon-linked heterocyclyl) is optionally substituted by one or more substituents selected from hydroxy, cyano, halo, Ci-2alkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci- 2haloalkoxy, NRaRbor -S(0)o-2RaRbwherein Raand Rbare independently H or Ci- 2alkyl;

[0032] 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;

[0033] G4 is selected from C and N;

[0034] G5 is selected from CRjand NRX, wherein:

[0035] Rjis selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, NH2 and Ci.4alkoxy; and Rxis selected from hydrogen and Ci-4alkyl;

[0036] G7is N, NRaor CRj,

[0037] 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 NRa;

[0038] Y2 is selected from CRkand N; wherein Rkis selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C^cycloalkyl, a 3- to 4- membered heterocyclyl and C^cycloalkoxy;

[0039] Y3 is N or CR1wherein R1is 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;

[0040] Y4 is C or N

[0041] Y5 is CRmor NRX, wherein:

[0042] Rmis selected from hydrogen, halo, hydroxy, cyano, Cs-ecycloalkyl, NH2, Ci.4alkoxy and Ci- 4alkyl optionally substituted with OH, Ci.4alkoxy and Cs-ecycloalkyl;

[0043] Rxis selected from hydrogen and Ci-4alkyl;

[0044] Y6is CRmor N;

[0045] Y7is O, S, CRmor N;

[0046] Ys is C or N;

[0047] Yg is CRmor N; with the proviso that no more than four of Y1 to Ys are N;

[0048] Xi is N or CRnwherein Rnis selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; X2is N or CRn;

[0049] X3is N;

[0050] X4 is N or C;

[0051] X5 is selected from N, CRnand CRnRn1wherein:

[0052] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X7 are independently CRnor N; or Xe is CRnRn1or NRXand X7 is CRnRn1, CR°R°1or NRX, wherein:

[0053] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;

[0054] Rxis hydrogen or C1.4 alkyl; and

[0055] R° and R°1are independently selected from hydrogen, halo, methoxy and methyl;

[0056] Xs is N, CRnor CRnRn1wherein Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and

[0057] Xg is N or C; with the proviso that no more than four of X2to Xg are N;

[0058] L1-L7 are independently N or CRnwherein Rnis 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;

[0059] E1 is CR1 or N;

[0060] E2is CR2or N;

[0061] E3 is CR3 or N;

[0062] E4 is CR4 or N,

[0063] E5 is CR5 or N;

[0064] E6is NR6or CReaReb wherein R1, R2, R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NRyiRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, - CH2SO2CH3, -P(O)(Ci-4alkyl)2, -SO2CH3, -NHC(O)CH3, -C(O)NRXI RX2, and Cs-ecycloalkyl optionally substituted by OH, wherein Rxiand RX2 are independently selected from hydrogen and Ci-4alkyl such as methyl, and wherein Ryiand Ry2 are independently selected from hydrogen, Cs-ecycloalkyl and Ci-4alkyl, such as methyl, optionally substituted by C3- ecycloalkyl, or, taken together with the N bearing them, Ryiand Ry2 form a 5- or 6- membered heteroaryl or a heterocyclyl , said 5- or 6-membered heteroaryl or a heterocyclyl being optionally substituted with OH, Ci.4alkoxy, or Ci-4alkyl optionally substituted with OH or Ci-4alkoxy, the heteocyclyl being a 4- to 7-member monocyclic heterocyclyl or a bicyclic heterocyclyl, each cycle of the bicyclic heterocyclyl having 3- to 6-members; and

[0065] Re is selected from hydrogen, NH2, halo, cyano, and Ci-4alkyl; or

[0066] Rs and R4are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, or R4and 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, NRyiRy2 or -S(0)o-2RyiRy2 wherein Ryiand Ry2 are H orCi.2alkyl; with the proviso that no more than three of E1 to E5 are N.

[0067] Preferably, in formula (I):

[0068] A1represents CR1aor N; A2represents CR2aor N; A3represents CR3aor N; A4represents CR4aor N; A5represents CR5aor N; A6represents CR6aor N; provided that no more than 3 of A1, A2, A3, A4, A5and A6represents N;

[0069] R1ato R6aeach 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-4haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecycloalkyl;

[0070] R7aand R7bare independently selected from:

[0071] (i) hydrogen;

[0072] (ii) Ci-ealkyl which is optionally substituted by one more substituent selected from halo, cyano, hydroxy, Ci.4alkoxy, Ci.4haloalkoxy,

[0073] (iii) or R7aand R7bare linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,

[0074] R8aand R8bare independently

[0075] (i) hydrogen, (ii) Ci-ealkyl optionally substituted by one more substituent selected from cyano, hydroxy, halo, Ci-2alkoxy, Ci aloalkoxy,

[0076] (iii) a group of formula -(CRcRd)n-Z with n is 0, 1 , or 2,

[0077] Rcand Rdare 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 Rcand Rdare 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 hydrogen, cyano, hydroxy, o NRaRbor -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl, and o C^alkenyl, C^alkynyl, Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, a bicyclic C5- i2cycloalkyl, each of which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci-2alkyl, Ci.2haloalkyl, Ci.2hydroxyalkyl, Ci- 2alkoxy, Ci.2haloalkoxy, C^alkenyl, NRaRband -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl; iv) or R8aand R8bare 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, NRaRband -S(0)o-2RaRbwherein Raand Rbare independently H or Ci-4alkyl; 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;

[0078] Rcand Rdare 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; Reand Rfare 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;

[0079] RcRdand ReRfmay 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;

[0080] Y is selected from one of the following structures: wherein:

[0081] Gi is selected from CRhand N, wherein Rhis 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;

[0082] G2 is selected from N and CR9, wherein R9is 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), -(OCH2CH2)m-NRyRz, -(OCH2CH2)m-OCH3, NRyRz, and -C(O)-NRyRz; wherein m is an integer from 1 to 6 and Ryand Rzare each independently hydrogen, C1.4 alkyl, Cs-ecycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, or Ryand Rzare linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6 membered heterocyclyl; wherein any of Ci-4alkyl, Ci.4alkoxy, C^alkenyl, C^alkynyl, phenyl, 5- or 6- membered heteroaryl, Cs-ecycloalkyl, -O-Cs-ecycloalkyl, heterocyclyl and -O- (carbon-linked heterocyclyl) is optionally substituted by one or more substituents selected from hydroxy, cyano, halo, Ci-2alkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci- 2haloalkoxy, NRaRbor -S(0)o-2RaRbwherein Raand Rbare independently H or Ci- 2alkyl;

[0083] 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;

[0084] G4 is selected from C and N;

[0085] G5 is selected from CRjand NRX, wherein:

[0086] Rjis selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, NH2 and Ci.4alkoxy; and Rxis selected from hydrogen and Ci-4alkyl; G7is N, NRaor CRj,

[0087] 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 NRa;

[0088] Y2 is selected from CRkand N; wherein Rkis selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C^cycloalkyl, a 3- to 4- membered heterocyclyl and C^cycloalkoxy;

[0089] Y3 is N or CR1wherein R1is 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;

[0090] Y4 is C or N

[0091] Y5 is CRmor NRX, wherein:

[0092] Rmis selected from hydrogen, halo, hydroxy, cyano, Ci-4alkyl, NH2 and Ci.4alkoxy;

[0093] Rxis selected from hydrogen and Ci-4alkyl;

[0094] Y6is CRmor N;

[0095] Y7is O, S, CRmor N;

[0096] Ys is C or N;

[0097] Yg is CRmor N; with the proviso that no more than four of Y1 to Ys are N;

[0098] Xi is N or CRnwherein Rnis selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;

[0099] X2is N or CRn;

[0100] X3is N;

[0101] X4 is N or C;

[0102] X5 is selected from N, CRnand CRnRn1wherein:

[0103] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X? are independently CRnor N; or Xe is CRnRn1or NRXand X? is CRnRn1, CR°R°1or NRX, wherein:

[0104] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;

[0105] Rxis hydrogen or C1.4 alkyl; and

[0106] R° and R°1are independently selected from hydrogen, halo, methoxy and methyl;

[0107] Xs is N, CRnor CRnRn1wherein Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and

[0108] Xg is N or C; with the proviso that no more than four of X2 to Xg are N;

[0109] L1-L7 are independently N or CRnwherein Rnis 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;

[0110] E2 is CR2 or N;

[0111] E3 is CR3 or N;

[0112] E4 is CR4 or N,

[0113] E5 is CR5 or N;

[0114] E6is NR6or CReaReb wherein R1, R2, R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NRyiRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, - CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NRXI RX2, wherein Rxiand RX2 are independently selected from hydrogen and methyl, and wherein Ryiand Ry2 are independently selected from hydrogen and methyl or, taken together with the N bearing them, form a 5- or 6-membered heterocyclic group; and

[0115] Re is selected from hydrogen and Ci-4alkyl; or

[0116] Rs and 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 E5'E4--E3attached, 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, NRyiRy2 or -S(0)o-2RyiRy2 wherein Ryiand Ry2 are H or Ci-2alkyl; with the proviso that no more than three of E1 to E5 are N.

[0117] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein, and a pharmaceutically acceptable carrier.

[0118] In another aspect, 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.

[0119] In another aspect, 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] It is understood that the present invention encompasses only stable compounds. The person of skill in the art knows how to segregate definitions which would lead to unstable compounds from definitions which would lead to stable compounds. DEFINITIONS

[0124] In the present specification, the word “comprise” and any variation thereof, such as “comprising” and “comprises”, is not intended to exclude other components or steps.

[0125] As used herein, the term “hydrogen” includes any isotope of hydrogen such as deuterium. As used herein, the term “hydroxy” denotes -OH, the term “cyano” denotes -CN.

[0126] The term “halogen”, as used in the present invention, refers to a fluorine, bromine, chlorine or iodine atom, preferably a chlorine or fluorine atom.

[0127] The term “halo”, as used in the present invention, refers to a fluoro, bromo, chloro or iodo moiety, preferably a chloro or fluoro moiety.

[0128] The term “Ci-Xalkyl”, as used in the present invention, refers to a straight or branched monovalent saturated hydrocarbon chain containing from 1 to x carbon atoms. Thus, 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.

[0129] The term “Ci-Xalkanediyl” as used in the present invention 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.

[0130] The term “Ci-Xhaloalkyl”, as used in the present invention, refers to a Ci-Xalkyl 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.

[0131] The term “Ci-Xhydroxyalkyl”, as used in the present invention, refers to a Ci-Xalkyl group as defined above substituted by one hydroxy group.

[0132] The term “C2-Xalkenyl”, as used in the present invention, 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.

[0133] The term “C2-Xalkynyl”, as used in the present invention, 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.

[0134] The term “Ci-Xalkoxy”, as used in the present invention, refers to a Ci-Xalkyl 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.

[0135] The term “Ci-Xhaloalkoxy”, as used in the present invention, refers to a Ci-Xalkoxy 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. The term “Cx-Vcycloalkyl” 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.

[0136] The term “Cx-Vcycloalkanediyl” 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.

[0137] The term “bicyclic Cs-Xcycloalkyl”, as used in the present invention, 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.

[0138] The term “Cx-Vcycloalkyloxy”, as used in the present invention, refers to a Cx-ycycloalkyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, cyclopropoxy or cyclobutyloxy.

[0139] The term “heterocyclyl”, as used in the present invention, 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. Preferably, 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.

[0140] A heterocylclyl spiro-fused with a Cs-ecycloalkyl is understood as a spirocyclic compound comprising a heterocyclyl fused to a Cs-ecycloalkyl.

[0141] The term “heterocyclyloxy”, as used in the present invention, refers to a heterocyclyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, oxetanoxy.

[0142] The term “aryl”, as used in the present invention, 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. Advantageously, it will be a phenyl group.

[0143] The term “heteroaryl”, as used in the present invention, 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.

[0144] The term “N-protectinq group”, as used in the present invention, 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. In particular, 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 Z) or 9-fluorenylmethyloxycarbonyl (Fmoc); -SO2-R PGI such as phenylsulfonyl, tosyl (Ts or Tos) or 2 nitrobenzenesulfonyl (also called nosyl - Nos or Ns); and the like, with R PGI representing a (Ci-Ce)alkyl optionally substituted with one or several halogen atoms such as F or Cl; a (C2-Ce)alkenyl such as an allyl; an aryl, such as a phenyl, optionally substituted with one or several groups chosen among OMe (methoxy) and NO2 (nitro); an aryl-(Ci-Ce)alkyl, such as a benzyl, the aryl moiety being optionally substituted with one or several methoxy groups; or a 9-fluorenylmethyl group.

[0145] In particular, it may be a t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl group.

[0146] The person of skill in the art is familiar with Lewis and Bnansted acids. Examples of Lewis acids include aluminium chloride, zinc chloride, silver chloride. Examples of 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. In formulae the plain circle denotes an aromatic ring. Also, the dotted line “ indicates the point of attachment to X. the dotted circle denotes an aromatic or unsaturated ring. Also, the dotted line indicates the point of attachment to X.

[0147] Also, in the present invention, Me stands for methyl, Ph stands for phenyl, Et stands for Ethyl, Ac stands for acetyl, SEM stands for 2-(trimethylsilyl)ethoxymethyl and TMS stands for trimethylsilyl. More generally, the abbreviations used refer to chemical groups having the meaning commonly known in the art.

[0148] For the purpose of the invention, 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.

[0149] DETAILED DESCRIPTION OF THE INVENTION

[0150] 1- Compounds of formula (I)

[0151] A1 to A6

[0152] According to a particular embodiment, R1ato R6aeach 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-ecycloalkyl.

[0153] According to another particular embodiment, R1a, R2a, R4aand R5aeach 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)2, - CO2H, -CO2(Ci-4 alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, Ci.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecycloalkyl; and R3aand R6arepresent, independently of one another, hydrogen, halo, or cyano, preferably hydrogen.

[0154] According to another particular embodiment, R1a, R2a, R4aand R5aeach 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)NH2, -C(O)NH(CI.4alkyl), -C(O)N(Ci-4alkyl)2, -CO2H, -CO2(Ci-4alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, and C1.4 haloalkyl; and R3aand R6arepresent, independently of one another, hydrogen, halo, or cyano, preferably hydrogen.

[0155] According to another particular embodiment, R1a, R2aand R5aeach independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy; R4arepresents 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-4alkyl), -C(O)N(Ci-4alkyl)2, -CO2H, -CO2(Ci-4alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, and C1.4 haloalkyl; and R3aand R6arepresent, independently of one another, hydrogen, halo, or cyano, preferably hydrogen.

[0156] Advantageously, R1ato R6aeach 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.

[0157] Preferably, R1arepresents 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;

[0158] R2arepresents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0159] R3arepresents hydrogen, halo, or cyano;

[0160] R4arepresents 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 R4arepresents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy R5arepresents 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, Cualkoxy, halo, Cuhaloalkoxy, Cs-ecycloalkyl, or -O-C3- ecycloalkyl; preferably hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy; and

[0161] R6arepresents hydrogen, halo, or cyano.

[0162] According to a particular embodiment, R1ato R6arepresent 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:

[0163] R1arepresents hydrogen, hydroxy, halo, C1.4 alkyl or C1.4 alkoxy;

[0164] R2arepresents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0165] R3arepresents hydrogen, halo, or cyano;

[0166] R4arepresents 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;

[0167] R5arepresents hydrogen, hydroxy, halo, C1.4 alkyl or C1.4 alkoxy; and

[0168] R6arepresents hydrogen, halo, or cyano.

[0169] According to a particular embodiment, R1ato R6arepresent independently hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy; and preferably: R1arepresents hydrogen, hydroxy, halo, or C1.4 alkoxy;

[0170] R2arepresents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0171] R3arepresents hydrogen, halo, or cyano;

[0172] R4arepresents hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0173] R5arepresents hydrogen, hydroxy, halo, or C1.4 alkoxy; and

[0174] R6arepresents hydrogen, halo, or cyano.

[0175] Preferably, no more than 2 of A1, A2, A3, A4, A5and A6represent N. Preferably, 0, 1 or 2 of A1, A2, A3, and A4represent N.

[0176] In particular, A1represents CR1aor N; A2represents CR2aor N; A3represents CR3aor N; A4represents CR4aor N; A5represents CR5aor N; A6represents CR6aor N; provided that 0, 1 or 2 of A1, A2, A3, A4, A5and A6represent N; preferably provided that 0, 1 or 2 of A1, A2, A3, and A4represent N; preferably with R1ato R6aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy; preferably with R2a, R3a, R4aand R6aeach representing H and with R1aand R5aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy.

[0177] In a particular embodiment, none of A1, A2, A3, A4, A5or A6represents N.

[0178] In a particular embodiment, only one of A1, A2, A3, A4, A5and A6, preferably only one of A1, A2, A3, and A4, represents N.

[0179] In a particular embodiment, 2 of A1, A2, A3, A4, A5and A6, preferably 2 of A1, A2, A3, and A4, represent N. In this embodiment, 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.

[0180] Advantageously, is selected from: in particular with R1ato R6aeach 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 -OH or Ci.4alkoxy, or C1.4 alkoxy optionally substituted by one or more -OH or Ci.4alkoxy or -CONH2; preferably R1ato R6aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy; in particular with R2a, R3a, R4aand R6aeach representing H and with R1aand R5aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl optionally substituted by one or more -OH or Ci.4alkoxy, or C1.4 alkoxy optionally substituted by one or more -OH or Ci.4alkoxy or -CONH2, such as R2a, R3a, R4aand R6aeach representing H and with R1aand R5aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl or C1.4 alkoxy.

[0181] Advantageously, the compound of formula (I) is selected from compounds of the following formulae: with R1ato R6aas 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 R1ato R6arepresenting independently hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy or C1.4 haloalkoxy; and advantageously with:

[0182] R1arepresenting hydrogen, hydroxy, halo, C1.4 alkyl, or C1.4 alkoxy;

[0183] R2arepresenting hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0184] R4arepresenting 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;

[0185] R5arepresenting hydrogen, hydroxy, halo, or C1.4 alkoxy;

[0186] R3aand R6arepresenting hydrogen, halo, or cyano; notably with: R1arepresenting hydrogen, hydroxy, halo, or C1.4 alkoxy;

[0187] R2arepresenting hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0188] R4arepresenting hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, or C1.4 haloalkoxy;

[0189] R5arepresenting hydrogen, hydroxy, halo, or C1.4 alkoxy;

[0190] R6arepresenting hydrogen, halo, or cyano; even more preferably, R1arepresents hydrogen, hydroxy, or fluoro; and R5arepresents hydrogen, hydroxy, fluoro, or methoxy.

[0191] R7aand R7b

[0192] Advantageously, R7ais H and R7bis 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.

[0193] Preferably, R7ais H and R7bis hydrogen, or Ci-ealkyl unsubstituted or substituted by one substituent selected from hydroxy and Ci-4alkoxy; preferably R7aand R7bare both a hydrogen.

[0194] R8aand R8b

[0195] Advantageously, R8ais H and R8bis a group of formula -(CRcRd)n-Z, such as -(CHRd)n-Z (e.g. -(CH2)n-Z), and in particular -CHRd-Z or -Z such as -CH2-Z or -Z, or

[0196] R8aand R8bare 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, NRaRband -S(0)o-2RaRb, 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. Preferably, the mono- or bicyclic heterocyclyl comprises no other heteroatom than the nitrogen atom bearing R8aand R8b. Preferably, each ring of the mono- or bicyclic heterocyclyl comprises 4, 5, 6 or 7 ring atoms.

[0197] Preferably, Raand Rbare independently H or Ci-4alkyl.

[0198] 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, NRaRband -S(0)o- 2RaRb, 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. In a particular embodiment, 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.

[0199] Xand Y

[0200] X is selected from

[0201] Y is typically selected from one of the following structures: wherein:

[0202] G1 is selected from CRhand N, wherein Rhis selected from hydrogen, halo, cyano, Ci- 4alkyl, C1.4 alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy;

[0203] G2 is CR9, wherein R9is selected from hydrogen, hydroxy, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy,

[0204] G3 is CR', wherein R' is selected from hydrogen, cyano, halo, Ci-4alkyl, Ci.4haloalkyl, Ci- 4haloalkoxy, Ci.4alkoxy,

[0205] G4 is N; Gs is NH or CRjwherein: Rjis selected from hydrogen, Ci-4alkyl, cyano, halo, OH NH2 and Ci-4alkoxy;

[0206] G7 is CR

[0207] Gs is C,

[0208] Y2 is CRk; wherein Rkis selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci-

[0209] 4haloalkyl, Ci.4haloalkoxy; preferably Y2 is CH,

[0210] Y3 is N or CR1wherein R1is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, Ci-

[0211] 4haloalkyl, Ci.4haloalkoxy, Ci.4alkoxy; preferably Y3 is N or CH,

[0212] Y4 is C or N

[0213] Y5 is CRmor NRX, wherein:

[0214] Rmis selected from hydrogen, Ci-4alkyl, cyano, halo, OH, NH2 and Cualkoxy;

[0215] Rxis selected from hydrogen and Ci-4alkyl; preferably Y5 is CH or NH,

[0216] Ye is CRmor N; preferably Ye is CH,

[0217] Y? is CRm; preferably Y7 is CH,

[0218] Y8is C;

[0219] Yg is CRmor N; preferably Y2 is CH or N, with the proviso that no more than three of Y2to Yg are N;

[0220] X4is N;

[0221] X5 is selected from CRnand CRnRn1wherein:

[0222] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy; either Xe and X7 are independently CRn; orXe is CRnRn1and X7 is CRnRn1, CR°R°1and NRX, wherein:

[0223] Rnand Rn1are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4haloalkyl, Ci-4alkoxy, and C1.4 haloalkoxy;

[0224] Rxis hydrogen or C1.4 alkyl; and

[0225] R° and R°1are independently selected from hydrogen, halo, methoxy and methyl;

[0226] X8is CRnor CRnRn1wherein Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; and Xg is C; iv)

[0227] Ei is N or CRi;

[0228] E2is N;

[0229] E3 is N or CR3;

[0230] E4 is CR4,

[0231] E5 is N or CR5; wherein R1, R2, R3, R4, Rs, Rea and Reb are in particular each independently selected from hydrogen, NRyiRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, - CH2OCH3, -CH2SO2CH3, -P(O)(Ci.4alkyl)2, -SO2CH3, -NHC(O)CH3, -C(O)NRXI RX2, and C3- 4cycloalkyl optionally substituted by OH, wherein Rxiand Rx2are independently selected from hydrogen and Ci-4alkyl (e.g. methyl), , wherein Ryiand Ry2are independently selected from hydrogen, Cs-ecycloalkyl and Ci-4alkyl (e.g. methyl) optionally substituted by C3- ecycloalkyl, or taken together with the N bearing them form a 5-membered heteroaryl or a heterocyclyl , said 5-membered heteroaryl or heterocyclyl being optionally substituted with OH, Ci-4alkoxy, or Ci-4alkyl optionally substituted with OH or Ci.4alkoxy, the heteocyclyl being a 4- to 7-member monocyclic heterocyclyl or a bicyclic heterocyclyl, each cycle of the bicyclic heterocyclyl having 3- to 6-members, or R4 and R3 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, the 5- or 6-membered heterocyclyl being optionally substituted by one or more substituents selected from oxo, cyano, hydroxy, halo, Ci-2alkyl, Cs-ecycloalkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci.2haloalkoxy, NRyiRy2or -S(0)o-2RyiRy2wherein Ryiand Ry2are H or Ci-2alkyl.

[0232] In particular, Y may be selected from the following structures: wherein R1, R2, and R3are as described above or below,

[0233] E? is O or CH2,

[0234] R3’ represents independently H or, taken together, the two R3’ substituents represent an oxo group (=0) or a Cs-scycloalkyl, and

[0235] R4’ represents independently H or, taken together, the two R4’ substituents represent an oxo group (=0) or a Cs-scycloalkyl. In some embodiments, Y is selected from the following structures:

[0236] Ei is CRi;

[0237] E2is N;

[0238] E3 is CR3;

[0239] E4 is CR4,

[0240] E5 is CR5; wherein R1, R2, R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NH2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, - CH2SO2CH3, -SO2CH3, -NHC(O)CH3, -C(O)NRXI RX2, wherein Rxiand Rx2are independently selected from hydrogen and methyl, and NRyiRy2, wherein Ryiand Ry2taken together with the N bearing them form a 5- or 6-membered heretocyclyl.

[0241] Y may be selected from one of the following structures: in particular with

[0242] Rhbeing selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci-4haloalkoxy, and preferably being H,

[0243] R9being selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci-4haloalkoxy, and preferably being H or C1.4 alkoxy,

[0244] R' being selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci- 4haloalkoxy, and preferably being H,

[0245] Rjbeing each independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, and Ci- 4alkoxy, and preferably being H, and

[0246] Rxbeing selected from hydrogen and Ci-4alkyl, and preferably being H; in particular with

[0247] Rkbeing each independently selected from hydrogen, halo, Ci-4alkyl, C1.4 alkoxy, Ci- 4haloalkyl, and Ci.4haloalkoxy, and preferably being H,

[0248] Rmbeing each independently selected from hydrogen, halo, hydroxy, Ci-4alkyl, and C1.4 alkoxy, and preferably being H,

[0249] Rxbeing each independently selected from hydrogen and Ci-4alkyl, and preferably being in particular with Rnbeing each independently selected from hydrogen, halo, C1.4 alkyl, Ci-

[0250] 4 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)NRXI RX2, and C^cycloalkyl optionally substituted by OH, wherein Rxiand RX2 are independently selected from hydrogen and methyl, and NRyiRy2, wherein Ryiand Ry2 taken together with the N bearing them form a 5-membered heteroaryl or a 5- to 9-membered heterocyclyl , said 5-membered heteroaryl or a 5- to 9- membered heterocyclyl being optionally substituted with OH, -CH2OCH3, or CH2OH, or or R4 and R3 are linked together such that, together with the atoms to which they are attached, they form a heterocyclyl, wherein the heterocyclyl is optionally spiro-fused with a Cs-ecycloalkyl and / or substituted by one or more substituents selected from oxo, cyano, hydroxy, halo, Ci-2alkyl, Cs-ecycloalkyl, Ci-2haloalkyl, Ci.2alkoxy, Ci.2haloalkoxy, NRyiRy2 or -S(0)o-2RyiRy2 wherein Ryiand Ry2 are H or Ci-2alkyl; in particular Ri, R3, R4, and R5 are each independently selected from hydrogen, NRyiRy2, halo, Ci-4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, and Ci.4haloalkyl.

[0251] Y may also be selected from one of the following structures: in particular with

[0252] Rh, R9, R', and Rjbeing each independently selected from hydrogen, halo, hydroxy, C1.4 alkoxy, and preferably being H, and

[0253] Rxbeing selected from hydrogen and Ci-4alkyl, and preferably being H; in particular with

[0254] Rkbeing each independently selected from hydrogen, halo, C1.4 alkoxy, and preferably being H,

[0255] Rmbeing each independently selected from hydrogen, halo, hydroxy, and C1.4 alkoxy, and preferably being H,

[0256] Rxbeing selected from hydrogen and Ci-4alkyl, and preferably being H; iii) in particular with Rnbeing each independently selected from hydrogen, halo, C1.4 Ci- 4alkoxy, preferably being H; and in particular with R4 being selected from hydrogen, NRyiRy2, halo, Ci.4alkoxy, Ci-4alkyl, and preferably being NRyiRy2 or Ci.4alkoxy.

[0257]

[0258] 10 In a particular embodiment, X-Y is:

[0259] In some embodiments, 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.

[0260] Tautomers, stereoisomers, salts, solvates and N-oxides

[0261] 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.

[0262] The term “tautomer” used in this invention refers to structural isomers of chemical compounds that readily interconvert. As an example, compounds comprising respectively an amide group (-C(=O)-NH-) and an imidic acid group (-C(OH)=N-) are tautomers such as in the following structures:

[0263] The term “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”.

[0264] The compounds of the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof.

[0265] As used herein, 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.

[0266] The nature of the salt may vary, provided that it is pharmaceutically acceptable. 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. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate 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, salicylic, galactaric and galacturonic acid. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid with any of the compounds of the invention.

[0267] 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. As an example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or ethanol.

[0268] 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.

[0269] 2 - Methods for preparing the compounds of formula (I)

[0270] 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:

[0271] - subjecting an intermediate of formula (Ila): with A1, A2, A3, A4, A5, A6, X and Y as defined herein, and optionally in a protected form, to a halogen-lithium exchange, typically using butyllithium in a polar non protic solvent such as tetrahydrofuran, followed by addition of a ketone of formula R7aR7b-C=O, with R7aand R7bas defined in any of claims 1 to 10 and optionally in a protected form to obtain the alcohol of formula (lib):

[0272] - Subjecting the alcohol of formula (lib) above to a nucleophilic substitution with an azide ion precursor, such as trimethylsilylazide in the presence of a Lewis acid such as boron trifluoride and in particular boron trifluoride etherate, to obtain the azide of formula (lie),

[0273] - Reducing the azide of formula (He) under Staudinger conditions, and in particular in the presence of water and a triarylphosphine such as triphenylphosphine, to obtain the amine of formula (lid)

[0274] - Functionalization of the amine of formula (lid) to obtain the compound of formula (I) as defined herein.

[0275] The final functionalization may for instance involve:

[0276] • at least an alkylation step with a compound of formula R8a-Hal or R8b-Hal, wherein Hal represents a halogen and preferably Cl, Br or I, and R8a and R8b are as defined herein, and / or at least one reductive amination step.

[0277] In a particular embodiment, 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:

[0278] - subjecting an intermediate of formula (II): with A1, A2, A3, A4, A5, A6, R7a, X and Y as defined herein, and optionally in a protected form, to a reductive amination with an amine of formula R8aR8b-N-H, with R8aand R8bas defined in any of claims 1 to 10 and optionally in a protected form; and optionally deprotecting the groups that are in a protected form in order to obtain a compound of formula (I); and

[0279] - optionally salifying the compound of formula (I) in order to obtain a salt of a compound of formula (I). Alternatively, 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:

[0280] The person of skill in the art is familiar with protecting groups and protected forms as mentioned above, as well as methods for protecting and deprotecting using such groups, and may refer to the textbook “Greene’s Protective Groups In Organic Synthesis”, 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey.

[0281] H

[0282] In embodiments wherein R7bis H and X is o , the process may comprise: a) Reducing the nitrile of formula (II): with A1, A2, A3, A4, A5, A6, R, R’ and R7aas defined herein, and

[0283] 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 A1, A2, A3, A4, A5, A6, R, R’ and R7aas 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 A1, A2, A3, A4, A5, A6, R7aand PG as defined above in connection with formula (III), c) Subjecting the aldehyde or ketone of formula (IV) to a reductive amination with an amine of formula (V): R8aR8b-N-H (V), with R8aand R8bas defined herein, to obtain an intermediate of formula (VI), with A1, A2, A3, A4, A5, A6, R7a, and PG as defined above in connection with formula (IV) and R8aand R8bas defined in connection with formula (V), d) Deprotecting the intermediate of formula (VI), to obtain an amine of formula (VII), with A1, A2, A3, A4, A5, A6, R7a, R8aand R8bas defined in connection with formula (VI), e) Subjecting the amine of formula (VII) to a peptide coupling with a carboxylic acid of formula (IX): Y-COOH, with Y as defined herein, a') Reducing the nitrile group of a compound of formula (II) as defined above to obtain an amine of formula (III’) with A1, A2, A3, A4, A5, A6, R, R’ and R7aas defined above in connection with formula (II), b') Subjecting the amine of formula (III’) to a peptide coupling with an aldehyde of formula (X): Y-COOH, with Y as defined herein, to obtain an intermediate of formula

[0284] (XI): with A1, A2, A3, A4, A5, A6, R, R’ and R7aas defined above in connection with formula (III’), and Y as defined in connection with formula (X), c') Deprotecting the acetal or ketal group (C(OR)(OR’)) of the intermediate of formula (XI) under acidic conditions using a Lewis acid or a Bronsted acid, to obtain the corresponding aldehyde or ketone of formula (XII): with A1, A2, A3, A4, A5, A6, R7aand Y as defined above in connection with formula (XI), d') Subjecting the aldehyde or ketone of formula (XII) to a reductive amination with an amine of formula (V): R8aR8b-N-H (V), as defined above.

[0285] 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 hexafluorophosphate (PyBOP) or propylphosphonic anhydride; optionally associated with an additive or a base, such as N- hydroxy-succinimide (NHS), N-hydroxy-benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4- oxo-1 ,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HAt), N- hydroxysylfosuccinimide (sulfo NHS), dimethylaminopyridine (DMAP), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM).

[0286] In embodiments wherein R7bis H and X is , 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 A1, A2, A3, A4, A5, A6, R7aas 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): R8aR8b-N-H (V), with R8aand R8bas defined herein, to obtain an intermediate of formula (XIV): with A1, A2, A3, A4, A5, A6, R7aas defined above in connection with formula (II) and R8aand R8bas defined herein, c") Reducing the intermediate of formula (XIV) to obtain an intermediate (alcohol) of formula (XV): with A1, A2, A3, A4, A5, A6, R7a, R8aand R8bas defined above in connection with formula (XIV), d") Subjecting the intermediate of formula (XV) to an activation step followed by a nucleophilic substitution using sodium azide, to obtain the corresponding azide of formula (XVI): with A1, A2, A3, A4, A5, A6, R7a, R8aand R8bas defined above in connection with formula (XIV), e") Subjecting the azide of formula (XVI) to a [3+2] cycloaddition with an alkyne of formula (XVII): H-H-Y (XVII) with Y as defined herein, or a'") Reducing the intermediate of formula (II) as defined above to obtain an intermediate

[0287] (alcohol) of formula (XVIII): with A1, A2, A3, A4, A5, A6, R, R’, R7aas defined above in connection with formula (II), and b'") Subjecting the intermediate of formula (XVIII) to an activation step followed by a nucleophilic substitution using sodium azide, to obtain the corresponding azide of formula (XIX): with A1, A2, A3, A4, A5, A6, R, R’, R7aas defined above in connection with formula (II), c’") Subjecting the azide of formula (XIX) to a [3+2] cycloaddition with an alkyne of formula (XVII) as defined above, to obtain an intermediate of formula (XX) with A1, A2, A3, A4, A5, A6, R7a, R and R’ as defined above in connection with formula (II), and Y as defined herein, d'") Deprotecting the acetal or ketal group of the intermediate of formula (XX), to obtain the corresponding intermediate of formula (XXI), with A1, A2, A3, A4, A5, A6, R, R’, R7a, and Y as defined above in connection with formula (XX), e'") Subjecting the intermediate of formula (XXI) to a reductive amination with an amine of formula (V) as defined above.

[0288] In embodiments wherein X is o , the process may comprise, a””) subjecting the compound of formula (XXII) with A1, A2, A3, A4, A5, A6, 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 A1, A2, A3, A4, A5, A6, R?a, R?b, Rsa and PG as defined herein, b””) Subjecting the compound of formula (XXIII) to a peptide coupling with a carboxylic acid of formula (IX): Y-COOH, with Y as defined herein to obtain a compound of formula (I) as described herein.

[0289] Typically, the palladium catalyst used in the palladium coupling of step a””) is Pd(dba)2.

[0290] In embodiments wherein R8bis H, the process may comprise: a’””) Reacting a compound of formula (XXIV) with A1, A2, A3, A4, A5, A6, 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 A1, A2, A3, A4, A5, A6, R?a, R?b, X and Y as defined herein, and Ns representing a nosyl group, b””) subjecting the nosyl-protected intermediate of formula (XXV) to a Fukuyama- Mitsunobu reaction with an aldehyde of formula R8a=O with R8aas defined herein, to obtain an intermediate of formula (XXVI) with A1, A2, A3, A4, A5, A6, R?a, R?b, Rsa, X and Y as defined herein, and Ns representing a nosyl group, c’””) deprotecting the nosyl group in the presence of thiophenol to obtain a compound of formula (XXVII) with A1, A2, A3, A4, A5, A6, R?a, R?b, Rsa, X and Y as defined herein.

[0291] The reaction conditions of the nosyl deprotecting step c’””) are known in the art.

[0292] 3 - Pharmaceutical Composition

[0293] The present invention further concerns a pharmaceutical composition comprising a compound of formula (I) as defined above, and a pharmaceutically acceptable carrier.

[0294] 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.

[0295] The pharmaceutical 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. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals, preferably mammals including humans.

[0296] For oral administration, the pharmaceutical composition can be in a solid or liquid (solution or suspension) form.

[0297] A solid composition can be in the form of tablets, capsules, powders, granules and the like. In tablets, 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. In powders or granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with flavor correctors or sweeteners. In capsules, 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.

[0298] A liquid composition (including a gel) 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. For sublingual (under the tongue) or buccal (between the gums and the cheek) administration, the pharmaceutical composition can be in a solid or liquid (solution or suspension) form.

[0299] 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.

[0300] A liquid composition can be as defined previously for oral administration. It can be administered in the form of a spray or drops.

[0301] For rectal or vaginal administration, suppositories or ovules can be prepared with binders which melt at rectal or vaginal temperature, for example cocoa butter or polyethylene glycols.

[0302] For parenteral administration, 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.

[0303] 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.

[0304] The pharmaceutical composition may further comprise another therapeutic compound, preferably another anticancer agent (or chemotherapeutic agents).

[0305] 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).

[0306] 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.

[0307] 4 - Therapeutic Use

[0308] 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.

[0309] 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.

[0310] The invention further relates to a kit comprising:

[0311] - a composition according to the invention;

[0312] - a second composition comprising at least another therapeutic compound, and

[0313] - preferably instructions 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.

[0314] 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.

[0315] In particular, said pathology is a cancer, or an autoimmune, neurological, infectious or inflammatory disease, typically a cancer.

[0316] The method may further comprise combination with radiotherapy, or with immune- stimulating agents such as vaccines.

[0317] 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.

[0318] As used herein, "patient" or “subject” includes any mammal, and is preferably a human being.

[0319] Exemplary autoimmune diseases are rheumatoid arthritis and Grave's disease.

[0320] Examples of 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).

[0321] Examples of neurological diseases are Fragile X syndrome and Alzheimer disease.

[0322] Examples of inflammatory disease are inflammatory bowel disease, Crohn's disease and ulcerative colitis.

[0323] In some embodiments, 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.

[0324] Examples of 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 adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g-, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g. , uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, 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) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e-g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) B-cell CLL, T- cell CLL); lymphoma such as Hodgkin lymphoma (HL) B-cell HL, T-cell HL) and non-HOdgkin lymphoma (NHL) B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa- associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macro globulinemia"), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g-, cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma), a mixture of one or more leukemiw'lymphoma as described above; and multiple myeloma (MM)), heavy Chain disease (e.g. , alpha Chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous lung cancer (SLC), adenocarcinoma of the lung, Lewis hmg carcinoma, lung neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillaty adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e-g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (P TC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g. , Paget' s disease of the vulva). EXAMPLES

[0325] All the examples below are given purely for illustrative purposes, and should not be construed as limiting the scope of the invention in any way.

[0326] Materials and Methods

[0327] Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.

[0328] Abbreviations

[0329] Hereinafter, “°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-diisopropylethylamine; “DMA” means dimethylacetamide; “DMF” means N,N- dimethyl formamide; “DMSO” means dimethyl sulfoxide; “DPPA” means diphenyl phosphoryl azide; “DPPF” means 1 ,1 ' -ferrocenediyl-bis(diphenylphosphine); “EtOAc ” means ethylacetate; “EtOH” means ethanol; “h” means hours; “HATU” means 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; “HCI” means hydrogen chloride; “HCO2NH4” means ammonium formate; “H2O” means water; “HPLC” means high-performance liquid chromatography; “I nt.” Means Intermediate; “KOAc” means potassium acetate; “K2CO3” means potassium carbonate; “LC” means liquid chromatography; “LCMS” means Liquid Chromatography / Mass spectrometry; “M” means mol / L; “MeCN” means acetonitrile; “MeOH” means methanol; “MgSC ” means magnesium sulfate; “min” means minute(s); “m.p.” means melting point; “N2” means nitrogen; “Na2CO3” means sodium carbonate; “NaBH4” means sodium borohydride; “NaHB(OAc)3” means sodium triacetoxyborohydride; “NH4CI” means ammonium chloride; “NaHCOs” means sodium bicarbonate; ”NaOH” means sodium hydroxide; “NH4HCO3” means ammonium bicarbonate; “Ni” means nickel; “nBuLi” means n-utyllithium, “NH3” means ammoniac; “NaOMe” means sodium methoxide; “Pd(dppf)Cl2” means [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; “Pd(dppf)Cl2’DCM” means [1 ,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane; “Pd(OAc)2” means palladium^ I) acetate; “PPhs” means triphenylphosphine; “prep.” means preparative; “quant.” means quantitative; “rbf” means round bottom flask; “rt” means room temperature; “s” means second(s); “SEM-CI” means 2-(trimethylsilyl)ethoxymethyl chloride; “TsOH” means p-toluenesulfonic acid; “'AmOH” means terf-amyl alcohol; “BuXPhosPd G3” means [(2-di-tert-butylphosphino-2',4',6'- tri isopropyl- 1 , 1 '-biphenyl)-2-(2'-amino-1 , 1 -biphenyl)] palladium^ I) methanesulfonate; “'BuXPhos” means 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; “TEA” means triethylamine; “TFA” means trifluoroacetic acid; “TLC” means thin layer chromatography; “THF” means tetra hydrofuran; “TMEDA” means N,N,N',N'-tetramethylethylenediamine; “TMS” means trimethylsilyl; “XPhosPd G3” means (2-dicyclohexylphosphino-2',4',6'- tri isopropyl- 1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(l I) methanesulfonate and “Zn(CN)2” means zinc cyanide.

[0330] Preparation of Intermediates

[0331] Synthesis of intermediate 1 : OEt 6-bromo-2-chloro-3-quinolinecarboxaldehyde (4 g, 14.8 mmol), ethyl orthoformate (4.38 g, 29.6 mmol, 4.92 mL) and TsOH monohydrate (56 mg, 0.3 mmol) were suspended at rt in dry EtOH (15 mL). The resulting reaction mixture was refluxed for 24 h. The reaction mixture was cooled down to rt and volatiles were removed under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-90:10 to give intermediate 1 (3.5 g, 69% yield) as a white solid.

[0332] Synthesis of intermediate 2: TMAF.'AITIOH

[0333] 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.

[0334] Synthesis of intermediate 3

[0335] Intermediate 1 (3.5 g, 10.3 mmol) and intermediate 2 (2.8 g, 15.4 mmol) were added under ambient atmospheric conditions. Dry DMSO (51 mL) was added and the resulting reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was cooled down to rt and the residue was partitioned between EtOAc and brine. The aqueous layer was further extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered off and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : [DCM / EtOAc 3 / 1] = 100:0-85:15 to give intermediate 3 (2.9 g, 87% yield) as a colourless oil. Synthesis of intermediate

[0336] Preparation of degassed aqueous solution: 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).

[0337] 'BuXPhosPd G3 (142 mg, 0.18 mmol), 'BuXPhos (76 mg, 0.18 mmol), potassium hexacyanoferrate(ll) trihydrate (1.89 g, 4.47 mmol) and intermediate 3 (2.9 g, 8.93 mmol) were added to a Schlenk tube equipped with a magnetic stir bar. The vial was evacuated and backfilled with nitrogen three times. The above mentioned solution of KOAc (110 mg, 1.12 mmol) in water (22 mL) and dioxane (22 mL) were added to the vial and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled down to rt and diluted with EtOAc. The residue was washed once with brine (the aqueous layer turned dark blue). The aqueous layer was further extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered off and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-90:10 to give intermediate 4 (2 g, 82% yield) as a white solid.

[0338] Synthesis of intermediate 5:

[0339] To a solution of intermediate 4 (500 mg, 1.82 mmol) and BOC2O (1.19 g, 5.47 mmol) in EtOAc (17 mL) and EtOH (17 mL) was added Ni Raney slurry in H2O (500 mg). The reaction mixture was stirred at rt for 12 h at 4 bars under H2 atmosphere. BOC2O (398 mg, 1.82 mmol) followed by Ni Raney slurry in H2O (500 mg) were added and the reaction mixture was stirred at rt for 24 h at 4 bars under H2 atmosphere. The reaction mixture was filtered through a pad of celite® and washed with EtOAc. The filtrate was concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-75:25 to give intermediate 5 (497 mg, 72% yield) as a colourless oil.

[0340] Synthesis of intermediate 6:

[0341] To a solution of intermediate 5 (500 mg, 1.32 mmol) in MeCN (5.5 mL) and water (0.13 mL) was added BiCh (83 mg, 0.26 mmol) and stirred at 55 °C for 1 h. After completion of the reaction, volatiles were removed under vacuum to intermediate 6 (405 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification.

[0342] Synthesis of intermediate 7: A mixture of intermediate 6 (837 mg, 2.75 mmol), 4,4-dimethylpipendine hydrochloride (494 mg, 3.3 mmol) and TEA (835 mg, 8.25 mmol, 1.15 mL) in DCM (28 mL) was stirred at rt for 10 min (until complete dissolution), then NaBH(OAc)s (1.17 g, 5.50 mmol) was added at once. The reaction mixture was stirred at rt for 16 h. Volatiles were removed under reduced pressure. The residue was partitioned between a saturated aqueous NaHCCh solution and EtOAc. The organic layer was washed once more with a saturated aqueous NaHCOs solution. The organic layer was dried over MgSO4, filtered off and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-50:50 to give intermediate 7 (537 mg, 49% yield) as a white solid.

[0343] Synthesis of intermediate 8 (HCI salt):

[0344] To a solution of intermediate 7 (180 mg, 0.45 mmol) in 1 ,4-dioxane (1 mL) was added HCI

[0345] (4 M in dioxane) (177 mg, 4.48 mmol, 1.12 mL) (the solution precipitate) and the resulting suspension was stirred at rt for 4 h. Volatiles were removed under reduced pressure to afford intermediate 8 (154 mg, 92% yield) as a yellow solid which was used in the next step without further purification.

[0346] Synthesis of intermediate 9

[0347] SEM a) Synthesis of intermediate 10:

[0348] To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.52 mmol) in DMF (5 mL) were added CS2CO3 (4.53 g, 13.9 mmol) and SEM-CI (2.32 g, 13.9 mmol, 2.47 mL). The reaction mixture was stirred at rt for 64 h. The solution was concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-80:20 to give intermediate 10 (281 mg, 34% yield) as a colourless oil. b) Synthesis of intermediate 11

[0349] A solution of intermediate 10 (267 mg, 0.81 mmol), Pd(PPhs)2Cl2 (114 mg, 0.16 mmol), DIPEA (315 mg, 2.44 mmol, 0.43 mL) in MeOH (2.7 mL) was heated at 100 °C overnight under an atmosphere of CO (10 bars). The mixture was allowed to cool to rt and the precipitated solid removed by filtration. The filtrate was concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-60:40 to give intermediate 11 (232 mg, 93% yield) as a yellow solid. c) Synthesis of intermediate 9:

[0350] A solution of intermediate 11 (232 mg, 0.75 mmol) in MeOH (5.4 mL) was treated with an aqueous solution of NaOH 1 M (1.36 mL, 1.36 mmol). The resulting solution was stirred for 2 h at rt. The pH value was adjusted to 3 with an aqueous HCI 1 M solution. The solids were collected by filtration to afford intermediate 9 (218 mg, quantitative yield) as a yellow solid.

[0351] Synthesis of intermediate 13: OEt

[0352] To a solution of intermediate 4 (0.91 g, 3.33 mmol) in EtOAc (33 mL) and EtOH (33 mL) was added Ni Raney slurry in H2O (1 g). The reaction mixture was stirred at rt for 24 h at 4 bars under hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under vacuum to afford intermediate 13 (837 mg, 90% yield) as a colourless oil which was used in the next step without further purification.

[0353] Alternatively, intermediate 13 was prepared as described below to reduce the amount of dimer side compound.

[0354] A solution of intermediate 4 (710 mg, 2.59 mmol) in EtOH (11.8 mL) was stirred at 0 °C. COCI2.6H2O (924 mg, 3.88 mmol) was added at 0 °C, followed by NaBH4 (490 mg, 12.9 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was filtered then poured into a sat. aq. Na2COs solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to intermediate 13 (703 mg, quantitative yield) as a yellow oil which was used in the next step without further purification.

[0355] Synthesis of intermediate 14:

[0356] To a solution of intermediate 13 (735 mg, 2.64 mmol), 4-Oxo-4 / 7-pyrido[1 ,2-a]pyrimidine- 2-carboxylic acid (502 mg, 2.64 mmol) and HATU (2 g, 5.28 mmol) in DMF (6.6 mL) was added DIPEA (683 mg, 5.28 mmol, 0.92 mL). The resulting solution was stirred at rt for 20 h. Water was added and the residue was extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered off and concentrated under vacuum to afford crude product. The crude product was purified by silica gel chromatography eluted with Heptane : (EtOAc / MeOH 3 / 1) = 100:0-60:40 to give intermediate 14 (725 mg, 30% yield) as a light yellow solid.

[0357] Synthesis of intermediate 15: A solution of intermediate 14 (360 mg, 0.8 mmol) was dissolved in acetonitrile (4 mL) and water (0.08 mL) and treated with BiCh (50.4 mg, 0.16 mmol) and stirred at 55 °C for 1 h (until consumption of starting material). After completion of the reaction (monitored by TLC), volatiles were removed under vacuum to afford intermediate 15 (310 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification.

[0358] Synthesis of intermediate 16: OEt

[0359] At rt, 6-bromo-2-chloro-7-methoxyquinoline-3-carbaldehyde (7.6 g, 25.2 mmol), ethyl orthoformate (11.2 g, 75.6 mmol, 12.6 mL) and TsOH monohydrate (96 mg, 0.504 mmol, 0.09 mL) were dissolved in EtOH (25 mL). The reaction mixture was refluxed for 22 h. Volatiles were removed under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane : EtOAc = 100:0-85:15 to give intermediate 21 (7.8 g, 86% yield) as a white solid.

[0360] Synthesis of intermediate 17: OEt

[0361] 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.

[0362] Synthesis of intermediate 18: OEt

[0363] 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.

[0364] Synthesis of intermediate 19: OEt

[0365] To a solution of intermediate 18 (781 mg, 2.57 mmol) in EtOH (11.7 mL) was added COCI2.6H2O (916 mg, 3.85 mmol) (solution turned blue) followed by NaBH4 (515 mg, 13.6 mmol) at 0 °C (solution turned black). The resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was filtered off and the filtrate was poured into a saturated aqueous Na2COs solution, and the residue was extracted twice with EtOAc (purple aqueous phase). The organic layers were combined, dried over MgSO4, filtered off and concentrated under vacuum to afford intermediate 19 (579 mg, 73%) as a colourless oil which was used in the next step without further purification. Synthesis of intermediate 20:

[0366] 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.

[0367] The following intermediate was prepared via an analogous procedure:

[0368] 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.

[0369] The following intermediate was prepared via an analogous procedure:

[0370] CI^. N^^ .OMe

[0371] Synthesis of intermediate 24: N QC Br

[0372] A mixture of 6-bromo-2-chloro-7-methoxyquinoline-3-carbaldehyde (155 mg, 0.52 mmol), 4,4-dimethylpiperidine hydrochloride (85 mg, 0.57 mmol) and TEA (157 mg, 1.55 mmol, 0.22 mL) in DCM (4.7 mL) was stirred at rt for 10 min (trouble reaction mixture), then sodium triacetoxyborohydride (219 mg, 1.03 mmol) was added at once. The reaction was stirred at room temperature for 3 h. After completion of the reaction, residuals solvents were evaporated under reduced pressure. Then the mixture was dissolved with an aqueous saturated solution of NaHCCh and extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSC , filtered off, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 100:0-85:15 to give the intermediate 24 (146 mg, 34% yield) as a white powder. Synthesis of intermediate 25: N XJG Br

[0373] 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.

[0374] Synthesis of intermediate 26:

[0375] 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.

[0376] Synthesis of intermediate 27:

[0377] To a solution of intermediate 26 (10 mg, 30.5 pmol) and BOC2O (20 mg, 0.092 mmol) in EtOAc (0.28 mL) and EtOH (0.28 mL) was added Ni Raney slurry in H2O (10 mg). The reaction mixture was stirred at rt overnight at 5 bars under hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under vacuum to afford the intermediate 27 (13 mg, quantitative yield).

[0378] Synthesis of intermediate 28 (HCI salt):

[0379] To a solution of intermediate 27 (13 mg, 30.6 pmol) in dioxane (100 pL) was added HCI 4 M in dioxane (100 pL, 0.4 mmol) (the solution precipitate) and the resulting reaction mixture was stirred at rt overnight. Volatiles were removed under reduced pressure to afford the intermediate 28 as a HCI salt (12.4 mg, quantitative yield) as a pale solid which was used in the next step without further purification.

[0380] Synthesis of intermediate 29: N CX Br

[0381] Intermediate 29 was prepared according to the procedure described for intermediate 24 starting from 6-bromo-2-chloro-7-fluoroquinoline-3-carbaldehyde (720 mg, 2.5 mmol) and

[0382] 4,4-dimethylpiperidine hydrochloride (448 mg, 2.99 mmol) to give the intermediate 29 (575 mg, 60% yield) as a white solid.

[0383] Synthesis of intermediate 30: N X Br

[0384] 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.

[0385] Synthesis of intermediate 31 : Intermediate 31 was prepared according to the procedure described for intermediate 4 starting from intermediate 30 (253 mg, 0.69 mmol) to give intermediate 31 (171 mg, 79% yield) as a pale yellow solid.

[0386] Synthesis of intermediate 32:

[0387] 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.

[0388] Synthesis of intermediate 33:

[0389] 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.

[0390] Synthesis of intermediate 34: N XJ L Br

[0391] 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.

[0392] Synthesis of intermediate 35:

[0393] To a solution of intermediate 34 (500 mg, 1.42 mmol) in THF (15 mL) at -78 °C under N2 was added nBuLi (0.98 mL, 1.57 mmol) (solution turned red / brown). The solution was stirred at -78 °C for 1 h then DMF (208 mg, 2.85 mmol, 0.22 mL) was added. The solution was stirred at -78 °C for 10 min then allowed to warm to rt and stirred for 30 min. A 10% aqueous solution of NH4CI was slowly added to the crude followed by EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered off and evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluted with Heptane:EtOAc = 100:0- 50:50 to give the intermediate 35 (362 mg, 85% yield) as a pale yellow solid.

[0394] Synthesis of intermediate 36:

[0395] NaBH4 (55 mg, 1.45 mmol) was added to a solution intermediate 35 (362 mg, 1.21 mmol) in MeOH (10 mL) and the mixture was stirred at rt for 30 min. DCM and water were added to the crude. The aqueous layer was separated and extracted twice with DCM. The combined organic layers were dried over MgSC , filtered off and evaporated in vacuo to give intermediate 36 (351 mg, 96% yield) as a yellow solid which was used in the next step without further purification. Synthesis of intermediate 37:

[0396] To a stirred solution of intermediate 36 (300 mg, 0.99 mmol) and DBU (151 mg, 0.99 mmol, 0.15 mL) in DMF (5.8 mL) under N2 at 0 °C was added dropwise diphenylphosphoryl azide

[0397] (273 mg, 0.99 mmol, 0.21 mL) and the reaction mixture was stirred at rt for 2 hours. Reaction was quenched carefully with water. Then EtOAc was added, and the mixture was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered off and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 90:10- 70:30 to give the intermediate 37 (169 mg, 52% yield) as a colourless oil.

[0398] Synthesis of intermediate 38: OEt

[0399] 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.

[0400] Synthesis of intermediate 39: OEt

[0401] 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.

[0402] Synthesis of intermediate 40: OEt

[0403] To a mixture of intermediate 39 (84 mg, 0.3 mmol) in THF (3.5 mL) was added DIAD (128 mg, 0.63 mmol, 0.13 mL), PPhs (166 mg, 0.63 mmol) and diphenylphosphoryl azide (174 mg, 0.63 mmol, 0.14 mL). The reaction mixture was stirred at rtfor 1 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered off and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 100:0-50:50 to give the product which was further purified by reverse phase chromatography eluted with MeCN / aq.NH4HCO3 0.2% (pH=7.9) = 60:40-80:20 to give intermediate 40 (50 mg, 55% yield) as a colourless oil.

[0404] A solution of intermediate 40 (193 mg, 0.63 mmol), 8-ethynylimidazo[1 ,5-a]pyridine (108 mg, 0.76 mmol), sodium ascorbate (151 mg, 0.76 mmol) and CuSC (20.2 mg, 0.13 mmol) in DMF (6.9 mL) / water (1.5 mL) was stirred at rt for 3 h. The mixture was diluted in water and DCM. The organic layer was separated and then concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane:(EtOAc / MeOH 1 / 1) = 100:0-60:40 to afford intermediate 41 (196 mg, 69% yield) as a yellow solid.

[0405] N-

[0406] TMS— ^— / / J

[0407] Synthesis of intermediate 42: N

[0408] A solution of 8-chloroimidazo[1 ,5-a]pyrazine (262 mg, 1.706 mmol) in DMF (1.41 mL) was put under N2 atmosphere. Then Pd(PPh3)2Cl2 (71.9 mg, 0.10 mmol) and Cui (19.5 mg, 0.10 mmol) were added and the mixture was purged under N2 for 5 minutes. TEA (309 mg, 3.05 mmol, 0.42 mL) and trimethylsilylacetylene (335 mg, 3.41 mmol, 0.49 mL) were added the reaction mixture was heated at 90 °C for 1 h. The mixture was cooled down to rt, diluted with EtOAc and filtered through a pad of Celite. The filtrate was evaporated to dryness to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 70:30-0:100 to afford intermediate 42 (95 mg, 26% yield) as a yellow oil.

[0409] Synthesis of intermediate 43:

[0410] K2CO3 (4.8 mg, 0.035 mmol) was added to a solution of intermediate 42 (75 mg, 0.35 mmol) in MeOH (1.6 mL), and it was stirred at rt for 0.5 h. The reaction mixture was filtered off, and the filtrate was partitioned between DCM and a solution of NH4CI. An extraction was done. The organic layers were dried over a chromabond filter and evaporated under vacuum to afford intermediate 43 (50 mg, quantitative yield) as a yellow solid which was used in the next step without further purification.

[0411] 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.

[0412] A solution of intermediate 41 (100 mg, 0.22 mmol) was dissolved in MeCN (2.2 mL) and water (0.022 mL) and treated with BiCh (14 mg, 0.045 mmol) and stirred at 55 °C for 1 h. Then, BiCh (30 mg, 0.095 mmol) was added and the reaction mixture was stirred at 55 °C for 1 more hour. After completion of the reaction (monitored by TLC), volatiles were removed under vacuum to afford intermediate 45 (80 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification.

[0413] The following intermediate was prepared via an analogous procedure:

[0414] Synthesis of intermediate 47: OEt

[0415] To a solution of intermediate 18 (600 mg, 1.97 mmol) in DCM (9.9 mL) at - 78 °C was added dropwise DIBAL-H (2.37 mL, 2.37 mmol) and the reaction mixture was slowly warmed up to -15 °C (flask just above the dry ice / acetone bath) and stirred for 1 h. After 1 h, DIBAL-H (2.37 mL, 2.37 mmol) was added and the reaction mixture was stirred at -15 °C for 1 more hour. After 1 h, DIBAL-H (2.37 mL, 2.37 mmol) was added until complete conversion. The reaction mixture was cooled down to - 40 °C and quenched by addition of Rochelle salt solution. The resulting emulsion was warmed up to rt and stirred vigorously for 1 h. DCM was added and the residue was extracted twice with DCM. The organic layers were combined, dried over MgSC , filtered off and concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane:EtOAc = 100:0-85:25 to afford intermediate 47 (306 mg, 51% yield) as a yellow solid.

[0416] Synthesis of intermediate 48:

[0417] 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.

[0418] Synthesis of intermediate 49:

[0419] Intermediate 49 was prepared according to the procedure described for intermediate 37 starting from intermediate 48 (265 mg, 0.86 mmol) to give intermediate 49 (186 mg, 65% yield) as a colourless oil. Synthesis of intermediate 50:

[0420] 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

[0421] 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

[0422] A mixture of intermediate 33 (500 mg, 1.36 mmol) in anhydrous THF anhydrous (27.2 mL) was degassed by bubbling N2 for few minutes. Then, Pd(dppf)Cl2’DCM (222 mg, 0.27 mmol), TMEDA (269 mg, 2.31 mmol, 0.35 mL) and finally NaBH4 (87.5 mg, 2.31 mmol) were introduced in sequence. The mixture was stirred at room temperature for 3 h. The residue was taken up in brine and extracted with EtOAc. The organic phase was separated, dried over MgSC and evaporated to give the crude material. The crude product was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-96:4 to afford intermediate 52 (255 mg, 56% yield) as a white solid.

[0423] Synthesis of intermediate 53:

[0424] 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.

[0425] Synthesis of intermediate 54:

[0426] To a solution of intermediate 53 (110 mg, 0.39 mmol) in NH3 in MeOH 7 M (1 mL) was added Ni Raney slurry in H2O (120 mg) in NH3 in MeOH 7 M (3 mL). The resulting suspension was evacuated and backfilled with N2 before being stirred under H2 atmosphere at 4 bars at rt overnight. The catalyst was removed by filtration under celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford intermediate 54 (64 mg, 57% yield) as a colourless oil which was used in the next step without further purification. Synthesis of intermediate 55:

[0427] 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.

[0428] Synthesis of intermediate 56: OEt

[0429] 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.

[0430] Synthesis of intermediate 57: OEt

[0431] Intermediate 57 was prepared according to the procedure described for intermediate 54 starting from intermediate 56 (175 mg, 0.69 mmol) to give intermediate 57 (175 mg, quantitative yield) as a white solid

[0432] Synthesis of intermediate 58:

[0433] 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.

[0434] Synthesis of intermediate 59:

[0435] To a solution of 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.

[0436] I Synthesis of intermediate 60: UNJ Br To a solution of intermediate 33 (350 mg, 0.95 mmol) in MeOH (3.9 mL), was added NaOMe (1.2 g, 6.66 mmol, 1 .24 mL), then the reaction mixture was stirred at 60 °C for 6 h. After completion of the reaction (monitored by TLC), the reaction mixture was allowed to cool down to rt and solvent was evaporated under reduced pressure. Water was added and the residue was extracted with DCM, dried over MgSC , filtered off to afford the crude product. The crude product was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-96:4 to afford intermediate 60 (180 mg, 52% yield) as a white solid.

[0437] Synthesis of intermediate 61 :

[0438] 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.

[0439] H

[0440] Synthesis of intermediate 62: Boc

[0441] 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.

[0442] Synthesis of intermediate 63 (HCI salt):

[0443] To a solution of intermediate 62 (50 mg, 0.12 mmol) in DCM (0.44 mL) was added TFA (165 mg, 1.45 mmol, 0.1 mL) and the resulting reaction mixture was stirred at rt for 4 h. Then TFA (69 mg, 0.61 mmol, 45 pL) was added to the reaction mixture and it was stirred for 16 h. The mixture was concentrated with HCI 4 M in dioxane (repeated three times) to afford intermediate 63 (50 mg, quantitative yield) as a white solid.

[0444] Synthesis of intermediate 64:

[0445] 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.

[0446] Synthesis of intermediate 65:

[0447] 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.

[0448] Synthesis of intermediate 66: 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.

[0449] Synthesis of intermediate 67:

[0450] Dess-Martin periodinane (1.85 g, 4.37 mmol) was added to a solution of (6-bromocinnolin- 3-yl)methanol (870 mg, 3.64 mmol) in DCM (8.7 mL) at rt. Then the reaction mixture was stirred at 40 °C for 16 h. The mixture was filtrated through a pad of Celite® and washed with DCM. The combined organic layers were dried over MgSC , filtered off and concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane: EtOAc = 100:0-50:50 to afford intermediate 67 (673 mg, 78% yield) as a yellow solid.

[0451] Synthesis of intermediate 68:

[0452] 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.

[0453] Synthesis of intermediate 69:

[0454] Potassium hexacyanoferrate(ll) trihydrate (179 mg, 0.42 mmol), iBuXPhos (36 mg, 0.085 mmol), KOAc (41.6 mg, 0.42 mmol) and XPhosPd G3 (71.7 mg, 0.085 mmol) were added to a solution of intermediate 68 (283 mg, 0.85 mmol) in dioxane (3.6 mL) / water (3.8 mL) under N2 at rt. Then the reaction mixture was degassed by bubbling N2 for 15 minutes and heated at 100 °C for 1 h. The reaction mixture was cooled down to rt and then added to cold water. The aqueous phase was extracted with EtOAc and the combined organic layer was washed with brine, dried with MgSO4, filtered off and concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with Heptane:EtOAc = 100:0-50:50 to afford intermediate 69 (130 mg, 55% yield) as a yellow solid.

[0455] Synthesis of intermediate 70:

[0456] 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.

[0457] Synthesis of intermediate 72: llnder argon atmsophere, Methylmagnesium chloride 3 M in THF (0.12 mL, 0.35 mmol) was added to intermediate 15 (110 mg, 0.29 mmol) in DCM (2.8 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h and warmed up to rt for 17 h. Aqueous NH4CI sat. and DCM was added, the organic layer was dried over Na2SO4, filtered, and concentrated to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-92:8 to afford intermediate 72 (74 mg, 65% yield) as a yellow solid.

[0458] To a solution of intermediate 72 (60 mg, 0.15 mmol) in DCM (1 mL) under argon atmosphere were added TEA (46.4 mg, 0.46 mmol, 0.064 mL) and mesyl chloride (70 mg, 0.61 mmol, 0.047 mL) at 0 °C. The reaction mixture was stirred at rt for 18 h. Water and DCM were added, and the aqueous layer was extracted with DCM, dried over Na2SO4, filtered, and concentrated to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-95:5 to afford intermediate 74 (42 mg, 67% yield) as a yellow solid.

[0459] The following intermediate was prepared via an analogous procedure:

[0460] To a solution of 4-amino-3-methoxybenzonitrile (2 g, 13.5 mmol) in AcOH (19.6 mL) was added 2,2,3-tribromopropanal (4.4 g, 14.9 mmol, 1.71 mL) and the reaction mixture was stirred at 100 °C for 3 hours under Ar. The reaction mixture was concentrated to dryness under reduced pressure then the residue was dissolved in EtOAc, and washed with a saturated solution of NaHCCh, with brine, then dried over Na2SO4, filtered, and concentrated to afford the crude material. The crude product was purified by silica gel chromatography eluted with c-Hex: EtOAc = 95:5-0:100 to afford intermediate 76 (1.4 g, 40% yield) as a yellow solid.

[0461] The following intermediates were prepared via an analogous procedure:

[0462] To a purged solution of intermediate 76 (1.43 g, 5.44 mmol) and potassium vinyltrifluoroborate (0.73 g, 5.44 mmol) in PrOH (59.3 mL) was added PdCl2(dppf).CH2Cl2

[0463] (0.089 g, 0.109 mmol) and TEA (0.55 g, 5.44 mmol, 0.76 mL) at rt. The resulting mixture was then purged with Ar and stirred at 100 °C for 6 h. The reaction mixture was allowed to cool to room temperature and H2O was added. The residue was extracted with Et20. The combined organics layers were dried over Na2SCU, filtered, and concentrated in reduced pressure to afford the crude product. The crude material was purified by silica gel chromatography eluted with c-Hex:EtOAc = 95:5-40:60 to afford intermediate 77 (870 mg, 76% yield) as a pale yellow solid.

[0464] The following intermediates were prepared via an analogous procedure:

[0465] OMe

[0466] Synthesis of intermediate 83: Potassium osmate (VI) dihydrate (167 mg, 0.41 mmol) was added to a solution of intermediate 76 (870 mg, 4.14 mmol) in THF (50.6 mL) and H2O (18.4 mL) at rt. The resulting mixture was stirred 10 minutes before addition of sodium periodate (1.77 g, 8.28 mmol) at rt. Then the reaction mixture was stirred at rt for 18h.The reaction mixture was diluted with H2O. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford intermediate 83 (748 mg, 85% yield) as a brown solid which was used in the next step without further purification.

[0467] The following intermediates were prepared via an analogous procedure: Synthesis of intermediate 86:

[0468] 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.

[0469] The following intermediate was prepared via an analogous procedure:

[0470] OMe Synthesis of intermediate 88: OEt

[0471] 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.

[0472] The following intermediates were prepared via an analogous procedure:

[0473] H N

[0474] Synthesis of intermediate 89a: CO2Et

[0475] 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.

[0476] Synthesis of intermediate 90a: CO2Et

[0477] To a solution of 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.

[0478] Synthesis of intermediate 9

[0479] A mixture of intermediate 81 (650 mg, 2.6 mmol), tributyl(methoxymethyl)stannane (1.32 g, 3.94 mmol), XPhos Pd G2 (206 mg, 0.26 mmol) and dioxane (15 mL) was purged with N2 and stirred at 80 °C overnight. The reaction mixture was filtered through a filter pad. The filtrate was concentrated under reduced pressure to afford the crude material. The crude material was purified by silica gel chromatography eluted with Heptane: EtOAc = 100:0- 70:30 to afford intermediate 91 (448 mg, 66% yield) as a yellow solid.

[0480] Synthesis of intermediate 92:

[0481] To a solution of intermediate 91 (300 mg, 1.17 mmol) in DCM (6 mL) at -78 °C was added dropwise DIBAL 1.2 M in toluene (2.43 mL, 2.92 mmol). The reaction mixture was stirred at - 78 °C for 1 h. The reaction solution was quenched with drops of MeOH and EtOAc. The solution was concentrated under reduced pressure to the crude product. The crude material was purified by silica gel chromatography eluted with DCM: MeOH = 100:0-90:10 to afford intermediate 92 (87 mg, 32% yield) as a yellow oil. The following intermediate was prepared via an analogous procedure:

[0482] Synthesis of intermediate 94:

[0483] 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:

[0484] PPhs (200 mg, 0.76 mmol) was added to a solution of intermediate 94 (97 mg, 0.38 mmol) in H2O (0.25 mL) and THF (1.2 mL). The resulting mixture was stirred at rt overnight. The reaction solution was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered off and concentrated under reduced pressure to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-80:20 to afford intermediate 96 (50 mg, 57% yield) as a white solid.

[0485] The following intermediate was prepared via an analogous procedure: Synthesis of intermediate 98: A mixture of 6-bromo-3-(diethoxymethyl)quinolin-8-ol (600 mg, 1.84 mmol), K2CO3 (305 mg, 2.21 mmol) and 1-bromo-2-methoxyethane (511 mg, 3.68 mmol, 0.35 mL) in DMF (15 mL) was stirred at 70 °C for 3 h. After cooling down to rt, water and DCM were added and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSC , filtered off and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel chromatography eluted with Heptane: EtOAc = 100:0-70:30 to afford intermediate 98 (330 mg, 47% yield) as a brown oil.

[0486] The following intermediate was prepared via an analogous procedure:

[0487] F

[0488] Synthesis of intermediate 100: OEt

[0489] 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. Then, ethylenediamine (551 mg, 9.17 mmol, 0.61 mL) followed by PrOH (6.5 mL) were added and the resulting reaction mixture was stirred for 24 h at reflux. The reaction mixture was cooled down to rt, EtOAc and a saturated aqueous K2CO3 solution were added. The aqueous layer was further extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered off and concentrated under vacuum to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-92:8 to afford intermediate 100 (303 mg, 83%) as a light brown oil.

[0490] The following intermediates were prepared via an analogous procedure:

[0491] OMe O

[0492] Synthesis of intermediate 108: OEt o

[0493] DI PEA (642 mg, 4.96 mmol, 0.86 mL) and T3P in EtOAc (1.3 g, 1.99 mmol, 1.19 mL) were added to a stirring solution of intermediate 88 (310 mg, 0.99 mmol) and 4-oxo-4 / 7- pyrido[1 ,2-a]pyrimidine-2-carboxylic acid (189 mg, 0.99 mmol) in DMF (3.3 mL) at rt for 16 h. The reaction mixture was diluted with H2O and extracted with CHC / iPrOH (3 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-92:8 to afford intermediate 108 (120 mg, 26% yield) as a light brown oil. The following intermediates were prepared via an analogous procedure:

[0494]

[0495] 4-Oxo-4 / 7-pyrido[1 ,2-a]pyrimidine-2-carboxylic acid (698 mg, 3.67 mmol), (6-bromo-2- methoxyquinolin-3-yl)methanamine (980 mg, 3.67 mmol) and pyridine (4.4 g, 55 mmol, 4.45 mL) in DCM (37 mL) were stirred at 0 °C for 15 min. POC (2.25 g, 14.7 mmol, 1.37 mL) was added to the mixture at 0 °C and the mixture was warm up to rt and stirred for 48 h. The reaction mixture was carefully quenched and basified with a 10% aqueous solution of K2CO3. A precipitate was filtered, washed many times with H2O and once with DCM then dried to give intermediate 123 (1.1 g, 67% yield) as a grey solid.

[0496] Synthesis of intermediate 124:

[0497] 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.

[0498] The following intermediates were prepared via an analogous procedure:

[0499] Synthesis of intermediate 136: BochN A r A n Ax CN

[0500] 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. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude material. The crude material was purified by silica gel chromatography eluted with c-Hex:EtOAc = 100:0-10:90 to afford intermediate 136 (395 mg, 35% yield) as a yellow solid.

[0501] The following intermediates were prepared via an analogous procedure:

[0502] The reaction was performed under anhydrous conditions and the glassware was flame- dried and anhydrous THF was dried over molecular sieves. To an argon purged solution of intermediate 137 (1.9 g, 6.31 mmol), 4,4'-Di-tert-butyl-2,2'-dipyridyl (102 mg, 0.38 mmol) and bis(pinacolato)diboron (1.76 g, 6.94 mmol) in THF (15.5 mL) was added at rt (1 ,5- Cyclooctadiene)(methoxy)iridium(l) dimer (130 mg, 0.19 mmol). The reaction mixture was purged with Argon, then heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to rt, diluted with EtOAc and concentrated to dryness to afford intermediate 140 (2.6 g, quantitative yield) as a brown foam used without further purification in the next step.

[0503] The following intermediate was prepared via an analogous procedure:

[0504] To a solution of intermediate 140 (3.9 g, 6.3 mmol) in DMF (72 mL) was added at rt KCN (820 mg, 12.6 mmol), Cu(OTf)2 (4.6 g, 12.6 mmol), pyridine (7.5 g, 94.4 mmol, 7.64 mL) and KF (440 mg, 7.55 mmol). The reaction mixture was heated at 100 °C and stirred for 18 hours. The reaction mixture was cooled to rt, diluted with sat. NaHCCh and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to dryness to afford the crude product. The crude material was purified by silica gel chromatography eluted with c-Hex:EtOAc = 70:30-20:80 to afford intermediate 142 (728 mg, 37% yield) as a yellow solid. hN. ii i ,NH2

[0505] Synthesis of intermediate 143: Bocv v v vIntermediate 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.

[0506] The following intermediate was prepared via an analogous procedure:

[0507] 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.

[0508] The following intermediate was prepared via an analogous procedure:

[0509] Synthesis of intermediate 147: o

[0510] 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.

[0511] The following intermediates were prepared via an analogous procedure:

[0512] To a suspension of intermediate 147 (230 mg, 0.59 mmol) and TEA (131 mg, 1.3 mmol, 0.18 mL) in DCM (2.2 mL) was added at 0 °C 2-nitrobenzenesulfonyl chloride (144 mg,

[0513] 0.65 mmol). The reaction mixture was warmed to rt and stirred for 18 h. The reaction mixture was diluted with saturated NaHCCh and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-96:4 to afford intermediate 150 (298 mg, 88% yield) as an orange solid. The following intermediates were prepared via an analogous procedure:

[0514] The reaction was performed under anhydrous conditions. To a solution of intermediate 150 (150 mg, 0.26 mmol) and (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (96 mg, 0.54 mmol) in THF (0.75 mL) was added 2-(tributyl-A5-phosphanylidene)acetonitrile (378 mg, 1.57 mmol, 0.41 mL) in THF (3.5 mL) at rt. The resulting reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was concentrated to dryness to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-90:10 to afford intermediate 153 (17 mg, 10% yield) as a brown gum.

[0515]

[0516] To a solution of intermediate 141 (933 mg, 2.32 mmol) in MeOH (10.6 mL) was added dropwise a solution of CuBr2 (1.6 g, 6.96 mmol) in H2O (10.6 mL). The reaction mixture was heated to 80 °C for 3 h. NH4OH (15% aq. sol.) was added and the aqueous phase was extracted twice with DCM. The combined organic layers were dried over MgSC , filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel chromatography eluted with Heptane: EtOAc =

[0517] 100:0-60:40 to afford intermediate 158 (241 mg, 29% yield) as a yellow oil.

[0518] Synthesis of intermediate 159: F

[0519] 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.

[0520] Synthesis of intermediate 160:

[0521] 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

[0522] 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.

[0523] OMe

[0524] Synthesis of intermediate 162:

[0525] 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.

[0526] Synthesis of intermediate 163:

[0527] 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.

[0528] Synthesis of intermediate 165:

[0529] To a solution of intermediate 121 (310 mg, 0.69 mmol) in DCM (2.1 mL) was added m- CPBA (254 mg, 1.032 mmol, 0.45 mL) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred at rt for 4 h. The reaction mixture was quenched with water and neutralized to pH 7 with a saturated aqueous NaHCCh solution. The resulting mixture was extracted twice with a mixture of CHCh / IPA (3 / 1). The organic layers were combined, dried over MgSC , filtered and concentrated under reduced pressure to afford intermediate 165 (211 mg) as a pale yellow solid which was used in the next step without further purification.

[0530] Synthesis of intermediate 166:

[0531] To a solution of intermediate 165 (180 mg, 0.39 mmol) in acetonitrile (0.96 mL) under a nitrogen atmosphere at 0 °C was added TEA (137 mg, 1.35 mmol, 0.19 mL) and TMSCN (134 mg, 1.35 mmol, 0.18 mL). The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under vacuum to afford the crude product. The crude material was purified by silica gel chromatography eluted with Heptane: EtOAc = 80:20-60:40 to afford intermediate 166 (128 mg, 70% yield) as a pale yellow solid. Synthesis of intermediate 167:

[0532] 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.

[0533] Synthesis of intermediate 168:

[0534] To a solution of methyl 3-(diethoxymethyl)-8-methoxyquinoline-6-carboxylate (805 mg, 2.52 mmol) in DCM (18.9 mL) at -78 °C was added dropwise DIBAL 1.2 M in toluene (25.25 mL, 6.3 mmol). The reaction mixture was stirred at - 78 °C for 1 h. The reaction mixture was cooled down to 0 °C and quenched by addition of EtOAc, drops of MeOH, and water. Celite was added and the reaction mixture was directly purified by silica gel chromatography eluted with DCM:MeOH = 100:0-92:8 to afford intermediate (634 mg, 86% yield) as a brown oil.

[0535] Synthesis of intermediate 169:

[0536] 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.

[0537] Synthesis of intermediate 170:

[0538] 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

[0539] 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.

[0540] Synthesis of intermediate 172: A mixture of 2-amino-5-bromopyridine-3-carbaldehyde (1.5 g, 7.46 mmol), ethyl propiolate (0.88 g, 8.95 mmol, 0.907 mL), and L-proline (0.43 g, 3.73 mmol, 0.32 mL) in EtOH (75 mL) was heated at 80°C and stirred at this temperature overnight. After cooling down to rt, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and water. The layers were separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over Na2SO4, filtered off and concentrated under reduced pressure to afford the crude product. The crude material was triturated in Et20 and the solid was filtered, dried under reduced pressure to afford intermediate 172 (1 .35 g, 64% yield) as a yellow solid.

[0541] Synthesis of intermediate 173:

[0542] 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.

[0543] Synthesis of intermediate 174:

[0544] 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.

[0545] Synthesis of intermediate 175:

[0546] 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.

[0547] Synthesis of intermediate 176:

[0548] 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.

[0549] Synthesis of intermediate 177:

[0550] H2O (7.42 mL) was added to a solution of intermediate 176 (602 mg, 1.507 mmol) in THF (7.42 mL), and then LiOH (565 mg, 7.53 mmol) was added and the mixture was stirred at rt for 1 h. After completion, water was added and the layers were extracted. The basic aqueous layer was washed with EtOAc several times. Then the basic aqueous layer was acidified with acetic acid until reach pH 4~5. Then the acidic aqueous layer was extracted with EtOAc three times. The combined organic layer were dried over MgSO4, filtered off and concentrated under reduced pressure to afford intermediate 177 (384 mg, 69% yield) as a light brown solid. r'A

[0551] Synthesis of intermediate 178:

[0552] To a mixture of intermediate 177 (334 mg, 0.9 mmol) and TEA (227 mg, 2.25 mmol, 0.31 mL) in THF (5.6 mL) at 0 °C under N2 was added ethyl chloroformate (244 mg, 2.25 mmol, 0.21 mL). The mixture was stirred at 0 °C for 30 min. NaBH4 (102 mg, 2.7 mmol) followed by water (0.86 mL) were added. NaBH4 (102 mg, 2.7 mmol) followed by water (0.86 mL) were added. The mixture was stirred for 10 min at 0 °C then allowed to warm to rt and stirred for 1 h. The crude was cooled to 0 °C then a 1 N aqueous solution of HCI was slowly added. After 10 min of stirring, EtOAc and a 10% aqueous solution of K2CO3 were added. The aqueous layer was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO4, filtered off and evaporated in vacuo to give the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-80:20 to afford intermediate 178 (166 mg, 52% yield) as a pale yellow oil.

[0553] Synthesis of intermediate 179:

[0554] 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.

[0555] Synthesis of intermediate 180:

[0556] 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.

[0557] Synthesis of intermediate 181

[0558] 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.

[0559] OMe

[0560] Synthesis of intermediate 182:

[0561] To an argon purged solution of 6-bromo-1 ,3-dichloroisoquinoline (5 g, 18.1 mmol) in MeOH (181 mL) was added NaOMe (23.5 g, 108 mmol, 24.8 mL) at rt. The reaction mixture was stirred at 65 °C for 16 h. The mixture was cooled down to rt, diluted with EtOAc and H2O. The solid was filtered off, washed with EtOAc and dried under vacuum to afford intermediate 182 (4.9 g, quantitative yield) as a white solid.

[0562] OMe

[0563] Synthesis of intermediate 183:

[0564] 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.

[0565] OMe

[0566] Synthesis of intermediate 184:

[0567] 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.

[0568] OMe

[0569] Synthesis of intermediate 185:

[0570] 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.

[0571] OMe

[0572] Synthesis of intermediate 186:

[0573] 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.

[0574] OMe

[0575] Synthesis of intermediate 187:

[0576] 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.

[0577] Synthesis of intermediate 188:

[0578] 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.

[0579] The following intermediates were prepared via an analogous procedure:

[0580] A solution of intermediate 197 (100 mg, 0.13 mmol), 2-azabicyclo[3.1.0]hexane hydrochloride 15.1 mg, 0.13 mmol), XPhos (5.42 mg, 0.011 mmol) and CS2CO3 (165 mg, 0.51 mmol) in 'Bu-OH (2 mL) was evacuated and backfilled with Ar three times, then Pd2(dba)s (3.93 mg, 3.8 pmol) was added and the vial was evacuated and backfilled with Ar three times before being heated at 100 °C for 3 h. The reaction mixture was cooled down to rt and volatiles were removed under vacuum to afford the crude material. The crude material was purified by normal phase chromatography eluted with DCM:MeOH = 100:0- 85:15 to afford intermediate 198 (46 mg, 64% yield) as an orange solid.

[0581] The following intermediates were prepared via an analogous procedure:

[0582] 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.

[0583] Synthesis of intermediate 203:

[0584] 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:

[0585] 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.

[0586] Synthesis of intermediate 205:

[0587] 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

[0588] Synthesis of intermediate 206 (HBr salt):

[0589] A suspension of intermediate 185 (350 mg, 1.2 mmol) in HBr in H2O (6.52 g, 80.6 mmol, 4.4 mL) was stirred at 50 °C for 5 h. The reaction mixture was cooled down to rt and volatiles were removed under reduced pressure to afford intermediate 206 (420 mg, 98% yield) as a brown solid which was used in the next step without further purification.

[0590] Synthesis of intermediate 207:

[0591] 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.

[0592] Synthesis of intermediate 208:

[0593] A suspension of intermediate 207 (305 mg, 0.81 mmol), 2-bromopropane (109 mg, 0.89 mmol, 84 pL) and K2CO3 (168 mg, 1.21 mmol) in DMF (5.3 mL) was stirred at 70 °C for 3 h. The reaction mixture was cooled down to rt and diluted with H2O. The residue was extracted twice with EtOAc. The organic layers were combined, dried over MgSCU, filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with Heptane:EtOAc = 100:0-80:20 to afford intermediate 208 (252 mg, 74% yield) as a colourless oil.

[0594] The following intermediates were prepared via an analogous procedure:

[0595] To a solution of intermediate 207 (269 mg, 0.71 mmol), Ag2COs (394 mg, 1.43 mmol) in CHC (3.6 mL) was added CD3I (310 mg, 2.14 mmol, 0.13 mL) at rt. The resulting mixture was stirred at 65 °C overnight. Volatiles were removed under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with cy-

[0596] Hex:EtOAc = 100:0-60:40 to afford intermediate 213 (205 mg, 73% yield) as a brown solid..

[0597] Synthesis of intermediate 214:

[0598] Intermediate 207 (375 mg, 1 mmol) and Na2COs (116 mg, 1.1 mmol) were added into a vial under air. Then, MeCN (2.5 mL) was added at rt and the resulting was heated at 60 °C for

[0599] 10 min before adding (bromodifluoromethyl)trimethylsilane (243 mg, 1.19 mmol, 0.19 mL). The resulting reaction mixture was stirred at 60 °C overnight. Brine was added and the residue was extracted twice with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with Heptane: EtOAc = 100:0-

[0600] 90:10 to afford intermediate 214 (240 mg, 57%) as a white solid.

[0601] Synthesis of intermediate 215:

[0602] 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.

[0603] The following intermediates were prepared via an analogous procedure:

[0604] Synthesis of intermediate 221 : o

[0605] 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.

[0606] The following intermediates were prepared via an analogous procedure:

[0607] Intermediate 227 was prepared according to the procedure described for intermediate 4 starting from intermediate 212 (407 mg, 0.88 mmol) to give intermediate 227 (282 mg, 71% yield) as a yellow solid. r"\ Boc

[0608] Synthesis of intermediate 228:

[0609] 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.

[0610] Synthesis of intermediate 229:

[0611] 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.

[0612] O CONH20 Boc nA H A^

[0613] Synthesis of intermediate 230: 0

[0614] To a solution of intermediate 229 (180 mg, 0.23 mmol) in MeOH (0.8 mL) was added NH3 (7 M in MeOH) (0.84 mL, 5.9 mmol). The reaction mixture was stirred at 50 °C overnight. The volatiles were removed under vacuum to give the crude material. The crude product was purified by normal phase chromatography eluted with DCM:MeOH = 100:0-95:5 to afford intermediate 230 (112 mg, 82%) as a white solid. o

[0615] Synthesis of intermediate 231 :

[0616] 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.

[0617] 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.

[0618] 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.

[0619] 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.

[0620] 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.

[0621] 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.

[0622] Intermediate 236 was prepared according to the procedure described for intermediate 79 starting from intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol) to give intermediate 236 (572 mg, 79% yield) as a white solid. Synthesis of intermediate 237:

[0623] 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.

[0624] Synthesis of intermediate 238: OEt

[0625] 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.

[0626] 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.

[0627] 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.

[0628] Synthesis of intermediate 241

[0629] 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.

[0630] Synthesis of intermediate 324:

[0631] 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.

[0632] Synthesis of intermediate 242:

[0633] 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.

[0634] Synthesis of intermediate 243:

[0635] 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.

[0636] Synthesis of intermediate 244:

[0637] To a solution of intermediate 243 (964 mg, 2.67 mmol) in DMSO (14.5 mL) was added DBU (3.33 g, 21.9 mmol, 3.27 mL) followed by MeNC>2 (3.26 g, 53.4 mmol, 2.91 mL). The resulting reaction mixture was stirred at rt for 5 d. NH4CI was added and the residue was extracted twice with EtOAc. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with cy-Hex:EtOAc = 100:0-88:12 to afford intermediate 244 (231 mg, 23% yield) as a colourless oil.

[0638] Boc

[0639] Synthesis of intermediate 245: N NH2

[0640] 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.

[0641] Synthesis of intermediate 246:

[0642] 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.

[0643] The following intermediates were prepared via an analogous procedure:

[0644] To a solution of methyl 4-bromo-2-formyl benzoate (34.8 g, 143 mmol) in DCM (287 mL) was added DBU (21.8 g, 143 mmol, 21.4 mmol) and methyl 2-{[(tert- butoxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (42.6 g, 143 mmol) at 0 °C. The reaction mixture was stirred at rt for 18 h. Water was added and the residue was extracted twice with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with Heptane: EtOAc = 85:15-65:35 to afford intermediate 247a (37.5 g, 68% yield) as a white solid.

[0645] Synthesis of intermediate 248 (TFA salt)

[0646] 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

[0647] Synthesis of intermediate 249:

[0648] A mixture of intermediate 248 (20.4 g, 51.5 mmol) and CS2CO3 (33.6 g, 103 mmol) was flushed with N2. Then dry PrOH (340 mL) was added and the reaction mixture was stirred at 60 °C for 30 min. Water was added and the solid was filtered off and dried under vacuum to afford intermediate 249 (11.8 g, 74% yield) as a white solid.

[0649] 0

[0650] Synthesis of intermediate 250:

[0651] 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.

[0652] Synthesis of intermediate 251

[0653] To a mixture of intermediate 250 (9 g, 35 mmol) in toluene (250 mL) was added POCh (21.5 g, 140 mmol, 13 mL) and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled down to rt and volatiles were removed under vacuum. The residue was diluted with a mix CHCh / IPA (3 / 1) and washed with a 30% aqueous NaOH solution. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford intermediate 251 (8.62 g, 89% yield) as a pale yellow solid.

[0654] Synthesis of intermediate 252:

[0655] 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. ci

[0656] Synthesis of intermediate 253: CO2Pr

[0657] 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. ci

[0658] Synthesis of intermediate 254:

[0659] Intermediate 254 was prepared according to the procedure described for intermediate 90a starting from intermediate 253 (5.8 g, 16.7 mmol) to give intermediate 254 (7.39 g, quantitative yield) as a colourless oil. ci

[0660] Synthesis of intermediate 255: OH

[0661] A suspension of NaBH4 (2.39 g, 63.3 mmol) and CaCh (4.21 g, 38 mmol) in THF (75 mL) and EtOH (75 mL) was stirred at -10 °C for 20 min. A solution of intermediate 254 (5.4 g, 12.7 mmol) in THF (35 mL) and EtOH (35 mL) was added dropwise. The reaction mixture was stirred at rt for 1.5 h. The reaction was quenched with water and a saturated aqueous NH4CI solution. The residue was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered off, and concentrated under vacuum to afford intermediate 255 (4.7 g, quantitative yield) as a brown oil.

[0662] Cl

[0663] Synthesis of intermediate 256:

[0664] 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.

[0665] Cl

[0666] Synthesis of intermediate 257: 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.

[0667] Synthesis of intermediate 258:

[0668] 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.

[0669] Synthesis of intermediate 259:

[0670] A mixture of intermediate 258 (116 mg, 0.21 mmol), tributyl(methoxymethyl)stannane (138 mg, 0.41 mmol) Pd(PPhs)4 (23.9 mg, 0.021 mmol) in DMF (1.7 mL) was degassed and stirred at 100 °C overnight. The reaction mixture was cooled down to rt and filtrated and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by normal phase chromatography eluted with DCM:EtOAc = 60:40- 30:70 to give intermediate 259 (83 mg, 70% yield) as a yellow solid.

[0671] Synthesis of intermediate 260: o

[0672] A mixture of intermediate 258 (200 mg, 0.36 mmol) potassium vinyltrifluoroborate (95.3 mg, 0.71 mmol), CS2CO3 (348 mg, 1.07 mmol), PdCl2(dppf).DCM (29.1 mg, 0.036 mmol) in dioxane (2.4 mL) an H2O (0.8 mL) was degassed with N2 and stirred at 100 °C for 4 h. The reaction mixture was cooled down to rt and water was added. The residue was extracted with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with DCM:iPrOH = 100:0-95:5 to give intermediate 260 (102 mg, 52%) as a pale brown solid.

[0673] Synthesis of intermediate 261

[0674] To a stirred solution of intermediate 260 (96 mg, 0.17 mmol) in H2O (0.34 mL) and THF (1.4 mL) was added potassium osmate (VI) dihydrate (3.49 mg, 8.7 pmol). The reaction mixture was stirred at rt for 5 min and NMO (20.3 mg, 0.17 mmol) was added. The reaction mixture was stirred at rt for 2 h. DCM and a saturated aqueous NH4CI solution were added. The residue was extracted with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with DCM:iPrOH = 100:0-

[0675] 89:11 to give intermediate 261 (61 mg, 60%) as a pale brown solid. i^OTHP 0 H Boc Hl I H Xn

[0676] Synthesis of intermediate 262: o

[0677] A mixture of intermediate 258 (297 mg, 0.53 mmol), trifluoro[2-(oxan-2- yloxy)ethyl]boranuide (208 mg, 1.06 mmol), CS2CO3 (516 mg, 1.59 mmol), catCXium (38.5 mg, 0.053 mmol) in dioxane (3.6 mL) and H2O (1.2 mL) was degassed with N2 and stirred at 100 °C overnight. DCM and H2O were added. The residue was extracted with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with DCM:MeOH = 100:0-90:10 to give intermediate 262 (65 mg, 19%) as a light orange oil.

[0678] Synthesis of intermediate 263:

[0679] A mixture of intermediate 251 (3.2 g, 11.6 mmol), CS2CO3 (5.67 g, 17.4 mmol), PdCl2(dppf).DCM (0.76 g, 0.93 mmol) in dioxane (31.4 mL) was purged with N2. Trimethylboroxine (2.91 g, 23.2 mmol, 3.27 mL) was added under N2 and the reaction mixture was stirred at 100 °C overnight. EtOAc and H2O were added. The residue was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with Heptane:EtOAc = 100:0-50:50 to give intermediate 263 (913 mg, 31%) as a white solid.

[0680] Synthesis of intermediate 264:

[0681] To a solution of intermediate 263 (695 mg, 2.72 mmol) in dioxane (10 mL) was added SeO2 (393 mg, 3.54 mmol) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled down to rt and filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to afford intermediate 264 (730 mg, quantitative yield) as pale brown solid.

[0682] Synthesis of intermediate 265: 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.

[0683] Synthesis of intermediate 266:

[0684] A mixture of intermediate 265 (640 mg, 2.36 mmol), DHP (298 mg, 3.54 mmol, 0.32 mL) and PTSA monohydrate (13.3 mg, 0.07 mmol) was stirred at rt overnight. The reaction mixture was quenched with a saturated aqueous NaHCCh solution, and the residue was extracted twice with DCM. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with DCM:MeOH = 100:0-99:1 to give intermediate 266 (509 mg, 61%) as a yellow oil.

[0685] Synthesis of intermediate 267:

[0686] 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.

[0687] Synthesis of intermediate 268:

[0688] 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.

[0689] Synthesis of intermediate 269:

[0690] 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.

[0691] Synthesis of intermediate 270:

[0692] Intermediate 270 was prepared according to the procedure described for intermediate 255 starting from intermediate 269 (180 mg, 0.34 mmol) to give intermediate 270 (158 mg, 98% yield) as a colourless oil. Synthesis of intermediate 271

[0693] 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.

[0694] Synthesis of intermediate 272:

[0695] 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.

[0696] Synthesis of intermediate 273:

[0697] 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.

[0698] The following intermediate was prepared via an analogous procedure: o Synthesis of intermediate 275:BrXX co2Me

[0699] 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.

[0700] The following intermediates were prepared via an analogous procedure:

[0701] 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

[0702] Synthesis of intermediate 279: co2Me

[0703] 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

[0704] Synthesis of intermediate 282: co2Me

[0705] 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:

[0706] OMe

[0707] Synthesis of intermediate 284: CO2M6

[0708] 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.

[0709] OMe

[0710] Synthesis of intermediate 285:

[0711] 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.

[0712] OMe

[0713] Synthesis of intermediate 286:

[0714] 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.

[0715] Synthesis of intermediate 287:

[0716] 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.

[0717] OMe

[0718] Synthesis of intermediate 288: OH

[0719] 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.

[0720] OMe

[0721] Synthesis of intermediate 289: Intermediate 289 was prepared according to the procedure described for intermediate 37 starting from intermediate 288 (234 mg, 0.60 mmol) to give intermediate 289 (246 mg, quantitative yield) as a colourless oil.

[0722] OMe

[0723] Synthesis of intermediate 290:

[0724] 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.

[0725] Synthesis of intermediate 291 :

[0726] 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.

[0727] 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.

[0728] Synthesis of intermediate 294:

[0729] 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.

[0730] Synthesis of intermediate 295: CO2Pr

[0731] 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.

[0732] Synthesis of intermediate 296:

[0733] 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.

[0734] Synthesis of intermediate 297:

[0735] 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.

[0736] Synthesis of intermediate 298:

[0737] 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.

[0738] Synthesis of intermediate 299:

[0739] 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.

[0740] Synthesis of intermediate 300:

[0741] 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.

[0742] The following intermediate was prepared via an analogous procedure: Synthesis of intermediate 302:

[0743] 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.

[0744] Synthesis of intermediate 303:

[0745] 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.

[0746] F OMe

[0747] Synthesis of intermediate 304:

[0748] 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.

[0749] F OMe

[0750] Synthesis of intermediate 305:

[0751] 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.

[0752] F OMe

[0753] Synthesis of intermediate 306:

[0754] 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.

[0755] F OMe

[0756] Synthesis of intermediate 307: N3

[0757] 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.

[0758] Synthesis of intermediate 309:

[0759] 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.

[0760] Synthesis of intermediate 310:

[0761] 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. ci

[0762] Synthesis of intermediate 311 :

[0763] 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.

[0764] Synthesis of intermediate 312:

[0765] 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.

[0766] 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. ci

[0767] O Y AAl A

[0768] Synthesis of intermediate 314: ci

[0769] To a solution of intermediate 313 (393 mg, 1.33 mmol) in THF (14.8 mL) at -78 °C was added nBuLi (2.5 M in THF, 0.64 mL, 1.6 mmol) dropwise under N2 atmosphere. The resulting solution was stirred at -78 °C for 30 min and then DMF (0.39 mL) was added and the reaction was stirred at rt for 1 h. A 10% aqueous NH4CI solution was added and the residue was extracted twice with EtOAc. The organic layers were combined, dried over MgSC , filtered off, and concentrated under vacuum to afford the crude material. The crude product was purified by normal phase chromatography eluted with Heptane: EtOAc = 100:0- 90:10 to give intermediate 314 (102 mg, 31 %) as a white solid. ci

[0770] Synthesis of intermediate 315:

[0771] 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. ci

[0772] Synthesis of intermediate 316:

[0773] 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.

[0774] OMe

[0775] Synthesis of intermediate 317:

[0776] 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.

[0777] OMe

[0778] Synthesis of intermediate 318: NH2

[0779] 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.

[0780] Synthesis of intermediate 319:

[0781] 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.

[0782] Preparation of final compounds o

[0783] Synthesis of Co. 1 : o

[0784] To a solution of intermediate 8 (126 mg, 0.37 mmol), 4-Oxo-4 / 7-pyrido[1 ,2-a]pyrimidine-2- carboxylic acid (85.1 mg, 0.45 mmol) and HATLI (284 mg, 0.75 mmol) in DMF (1.9 mL) was added DIPEA (193 mg, 1.49 mmol, 0.26 mL). The resulting solution was stirred at rt for 16 h. Water was added and the residue was extracted three times with EtOAc. The organic layers were combined, dried over MgSC , filtered off and concentrated under vacuum to afford the crude product. The crude product was purified by silica gel chromatography NH2 eluted with Heptane : [EtOAc / MeOH 3 / 1] = 100:0-20:80 to give intermediate impure material which was further purified by reverse phase column chromatography eluted with MeCN / aq.NH4HCO30.2% (pH = 7.9) = 50:50-75:25 to afford Co. 1 (45 mg, 25% yield) as a white solid.

[0785] The following compounds were prepared via an analogous procedure: Synthesis of Co. a) Synthesis of intermediate 12:

[0786] Intermediate 12 was prepared following the protocol described for the synthesis of Co. 1 , starting with intermediates 8 and 9 and affording intermediate 12 (84 mg, 78% yield) as a red oil. b) Step 5 - Synthesis of Co. 7:

[0787] To a solution of intermediate 12 (80 mg, 0.14 mmol) in DCM (0.15 mL) was added TFA (431 mg, 3.78 mmol, 0.28 mL). The resulting reaction mixture was stirred at rt for 2 h. Solvents were removed under vacuum to afford the crude product. The crude product was purified by reverse phase column chromatography eluted with MeCN / aq. NH4HCO3 0.2% (pH = 7.9) = 35:65-55:45 to afford Co. 7 (3 mg, 5% yield) as a white solid.

[0788] Synthesis of Co. 8

[0789] A mixture of intermediate 15 (86 mg, 0.23 mmol), 1-{3-fluorobicyclo[1.1.1]pentan-1- yljmethanamine hydrochloride (41.6 mg, 0.27 mmol) and TEA (69.4 mg, 0.69 mmol, 0.095 mL) in DCM (2.3 mL) was stirred at rt for 10 min (until complete dissolution), then sodium triacetoxyborohydride (96.9 mg, 0.46 mmol) was added at once. The reaction mixture was stirred at rt for 16 h. Volatiles were removed under reduced pressure. The residue was partitioned between a saturated aqueous NaHCCh solution and EtOAc. The organic layer was washed once more with a saturated aqueous NaHCCh solution. The organic layer was dried over MgSC , filtered off and concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with DCM : MeOH = 100:0-95:5 to give the product which which was further purified by reverse phase column chromatography eluted with MeCN / aq HCO2NH4 0.6 g / L (pH = 3.5) = 10:90-50:50 to afford Co. 8 (27 mg, 25% yield) as a white solid.

[0790] The following compounds were prepared via an analogous procedure:

[0791]

[0792] A mixture of intermediate 324 (5 mg, 0.014 mmol), 1-cyclobutylmethanamine hydrochloride (2 mg, 0.017 mmol) and TEA (4.24 mg, 0.042 mmol, 5.82 pL) in 1, 1 ,1 , 3,3,3- hexafluoroisopropanol (235 pL) was stirred at rt for 1 h, then NaBH4 (8.13 mg, 0.21 mmol) was added with a few drops of MeOH and stirred for 5 min at rt. MeOH was added and the volatiles were removed under reduced pressure to afford the crude material. . The crude product was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-98:2 to give Co. 143 (3 mg, 49% yield) as a white solid.

[0793] The following compound was prepared via an analogous procedure:

[0794] a) Synthesis of intermediate 7

[0795] Intermediate 71 was prepared following the protocol described for the synthesis of Co. 8, starting with intermediate 15 and ((rac-trans)-2-(((tert- butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanamine and affording intermediate 71 (151 mg, 76% yield) as a yellow oil. b) Synthesis of Co. 56 and Co. 57:

[0796] To a solution of intermediate 71 (206 mg, 0.29 mmol) in THF (0.58 mL) was added TBAF (1.44 mL, 1.44 mmol). The resulting reaction mixture was stirred at rt for 1 h. Volatiles were removed under vacuum and the crude product was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-98:2. Both enantiomers were separated by SFC eluted with CO21 (MeOH + DCM [50 / 50] + 0,3%iPrNH2) = 65 / 35 to give Co. 56 (24 mg, 17% yield) as a light beige solid and Co. 57 (29 mg, 21% yield) as a light beige solid.

[0797] 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.

[0798] The following compounds were prepared via an analogous procedure:

[0799]

[0800] 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

[0801] (17 mg, 37 pmol) to give Co. 28 (4 mg, 11% yield) as a white solid. The following compound was prepared via an analogous procedure:

[0802] Synthesis of Co. 60 and Co. 61 To a solution of intermediate 74 (143 mg, 0.35 mmol) and 1-{3-fluorobicyclo[1.1.1]pentan- 1-yl}methanamine hydrochloride (63.3 mg, 0.42 mmol) in acetonitrile (2.9 mL) was added TEA (0.15 mL, 1.044 mmol, 105 mg) and the reaction mixture was stirred at 80 °C for 36 h. Volatiles were removed under reduced pressure. The residue was partitioned between a saturated aqueous NaHCCh solution and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered off and concentrated under vacuum to afford the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-95:5 to afford the compound (80 mg, 47% yield) as a racemic mixture. 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. .

[0803] 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.

[0804] A solution of intermediate 37 (50 mg, 0.15 mmol), 8-ethynylimidazo[1 ,5-a]pyridine (52 mg, 0.18 mmol), sodium ascorbate (36 mg, 0.18 mmol) and CuSC (4.9 mg, 0.03 mmol) in DMF (1.65 mL) / water (0.37 mL) was stirred at rt for 4 h. The mixture was diluted in water and DCM. The organic layer was separated and then concentrated under vacuum to afford the crude material. The crude product was purified by silica gel chromatography eluted with DCM: MeOH = 100:0-98:2 to give Co. 31 (56 mg, 78% yield) as a white solid.

[0805] The following compounds were prepared via an analogous procedure:

[0806]

[0807] 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.

[0808] 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:

[0809] 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.

[0810] Synthesis of Co. 40:

[0811] 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.

[0812] Synthesis of Co. 41

[0813] 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.

[0814] Synthesis of Co. 42:

[0815] 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.

[0816] Synthesis of Co. 89:

[0817] To a solution of intermediate 153 (17 mg, 0.025 mmol) in MeCN (0.16 mL) were added thiophenol (5.57 mg, 0.051 mmol, 5.2 pL) and CS2CO3 (16.5 mg, 0.051 mmol) at rt. The reaction mixture was stirred at rt for 18 hours. The reaction mixture was diluted with saturated H2O and extracted with a mixture of CHC / IPA (3 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford the crude product. The crude material was purified by C18 silica gel chromatography eluted with Water+0.1 F formic acid:MeCN = 85:15-70:30 to afford (1.7 mg, 13% yield) as a white solid.

[0818] The following compounds were prepared via an analogous procedure:

[0819] To a vial was added potassium (bromomethyl)trifluoroboranuide (1 g, 4.98 mmol) followed by THF (2.5 mL), tert-butanol (1.25 mL) and 1-cyclobutylmethanamine (509 mg, 5.98 mmol). The vial was sealed and was place in a drysin at rt and stirred at 80 °C for 2 h. The volatiles were removed under vacuum. The crude solid was dried before being dissolved in a solution of hot MeCN and the solution was filtered to give intermediate 164 (536 mg, 64% yield) as a white solid. b) Synthesis of Co. 94:

[0820] To a mixture of intermediate 1223 (100 mg, 0.23 mmol), intermediate 164 (87.7 mg, 0.27 mmol), CS2CO3 (222 mg, 0.68 mmol) in dioxane (0.95 mL) and H2O (0.095 mL) was added Di-|j-iodobis(tri-t-butylphosphino)dipalladium(l) (9.92 mg, 0.011 mmol) at rt. The reaction mixture was purged with N2, then heated to 100 °C for 15 h. Water added and the residue was extracted twice with EtOAc and once with CHC / IPA (3 / 1). Organic phases were combined, dried with MgSO4, filtered and evaporated to give the crude material. The crude material was purified by silica gel chromatography eluted with DCM:MeOH = 100:0-85:15 to afford Co. 94 (17 mg, 16% yield) as a pale yellow solid.

[0821] The following compound was prepared via an analogous procedure:

[0822]

[0823] 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.

[0824] To a solution of intermediate 188 (150 mg, 0.26 mmol) in DCM (0.84 mL) was added TFA (449 mg, 3.94 mmol, 0.29 mL). The resulting reaction mixture was stirred at rt for 1 h. DCM and a saturated aqueous Na2COs solution was added. The organic layer was washed with a saturated aqueous Na2COs solution twice, dried over MgSO4, filtered off and concentrated under reduced pressure to afford Co. 100 (115 mg, 93% yield) as a white solid.

[0825] The following compounds were prepared via an analogous procedure: Synthesis of Co. 137:

[0826] 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.

[0827] The following compound was prepared via an analogous procedure:

[0828] LCMS (Liquid Chromatography / Mass spectrometry)

[0829] LCMS General procedure

[0830] The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0831] Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

[0832] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “MSD” means Mass Selective Detector, “DAD” Diode Array Detector.

[0833] Table: LCMS Method codes (Flow expressed in mL / min; column temperature (T) in °C;

[0834] Run time in minutes).

[0835] Table: Retention time (Rt) in min., [M+H]+peak (protonated molecule), LC / MS method

[0836] NMR

[0837] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 471 MHz for fluor. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.

[0838] Table :1H NMR and19F NMR results

[0839] PHARMACOLOGICAL PART

[0840] MTase Gio assay

[0841] The methyltransferase activity of METTL3 was measured with a bioluminescent assay using the MTase-Glo™ Methyltransferase Assay kit from Promega (V7602).

[0842] 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.G.A.C.U.A.A.A.G.C.U.G.C.U.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 MTaseGlo™ 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). 0.6pM final concentration of SAM was then added and the enzymatic reaction was incubated for 60 min at room temperature. MTaseGlo™ detection solution to convert ADP to ATP was added and the resulting reaction mixture was allowed to incubate for another 60 min at room temperature.

[0843] 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.

[0844] Proliferation assays

[0845] 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. Cells were incubated at 37°C in the presence of 5% CO2 and humidified atmosphere. 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.

[0846] Table : Biochemical and proliferative data

[0847] ND : Not Determined

[0848] REFERENCES

[0849] Reference herein to a patent, patent application, publication or any other document which is cited herein as prior art, and in particular the documents listed below, is not to be taken as an admission that that patent, patent application, publication or matter was known or that its teaching was part of the common general knowledge at the priority date.

[0850] (1) Barbieri I &. Kouzarides T (2020) Role of RNA modifications in cancer. Nat Rev Cancer. 20(6): 303-322;

[0851] (2) Li W, Hao Y, Zhang X, Xu S, Pang D (2022) Targeting RNA N6-methyladenosine modification: a precise weapon in overcoming tumor immune escape. Mol Cancer. 21 (1 ): 176;

[0852] (3) Liu S, Zhuo L, Wang J, Zhang Q, Li Q, Li G, Yan L, Jin T, Pan T, Sui X, Lv Q, Xie T (2020) METTL3 plays multiple functions in biological processes. Am J Cancer Res. 10(6): 1631 -1646;

[0853] (4) Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24(2): 177-89;

[0854] (5) Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P (2016) Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 534:575-8;

[0855] (6) Yang C, Hu Y, Zhou B, Bao Y, Li Z, Gong C, Yang H, Wang S, Xiao Y (2020) The role of m6A modification in physiology and disease. Cell Death Dis. 11 (11):960;

[0856] (7) WG2020201773;

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[0861] (12) WO2022254218;

[0862] (13) WO2021079196;

[0863] (14) WG2021081211 ;

[0864] (15) WO2022081739.

Claims

CLAIMS1 . A compound of Formulaor a tautomer stereoisomer, salt, solvate or N-oxide thereof, wherein■ A1represents CR1aor N; A2represents CR2aor N; A3represents CR3aor N; A4represents CR4aor N; A5represents CR5aor N; A6represents CR6aor N; provided that no more than 3 of A1, A2, A3, A4, A5and A6represents N; “ R1ato R6aeach independently represent hydrogen, hydroxy, halo, cyano and C1.4 haloalkyl, C1.4 haloalkoxy, Ci-4alkyl, Ci.4alkoxy, 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, Ci- 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-4alkyl), -C(O)N(CI-4alkyl)2, -CO2H, -CO2(Ci-4alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, C1.4 haloalkyl, C3-6 cycloalkyl, and O-Cs-ecycloalkyl;■ R7aand R7bare independently selected from:(i) hydrogen;(ii) Ci-ealkyl which is optionally substituted by one more substituent selected from halo, cyano, hydroxy, Ci.4alkoxy, Ci.4haloalkoxy,(iii) or R7aand R7bare linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,R8aand R8bare independently(i) hydrogen, (ii) Ci-ealkyl optionally substituted by one more substituents selected from cyano, hydroxy, halo, Ci.2alkoxy, Ci.2haloalkoxy,(iii) a group of formula -(CRcRd)n-Z with n is 0, 1 , or 2,Rcand Rdare 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-Cs-ecycloalkyl, and wherein Cs-ecycloalkyl and-O-Cs- ecycloalkyl are optionally substituted by one or more substituents selected from halo, cyano and hydroxy; ando or Rcand Rdare 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-2haloalkyl, Ci.2alkoxy, Ci.2haloalkoxy; and Z is selected from o hydrogen, cyano, hydroxy, o NRaRbor -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl, and o C^alkenyl, C^alkynyl, Cs-scycloalkyl, aryl, heterocyclyl, heteroaryl, a bicyclic C5- i2cycloalkyl, each of which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, Ci-2alkyl, Ci aloalkyl, Ci.2hydroxyalkyl, Ci.2alkoxy, Ci- 2haloalkoxy, C^alkenyl, NRaRband -S(0)o-2RaRbwherein Raand Rbare H or Ci-2alkyl; iv) or R8aand R8bare 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, NRaRband -S(0)o-2RaRbwherein Raand Rbare independently H or Ci-4alkyl;X is selected fromwherein 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;Rcand Rdare 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;Reand Rfare 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;RcRdand ReRfmay 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 CRhand N, wherein Rhis 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 CR9, wherein R9is 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), -(OCH2CH2)m-NRyRz, -(OCH2CH2)m-OCH3, NRyRz, and -C(O)-NRyRz; wherein m is an integer from 1 to 6 and Ryand Rzare each independently hydrogen, C1.4 alkyl, Cs-ecycloalkyl, a 3- to 6- membered carbon-linked heterocyclyl, or Ryand Rzare linked together such that, together with the nitrogen atom to which they are attached, they form a 3- to 6 membered heterocyclyl; wherein any of Ci-4alkyl, Ci.4alkoxy, C^alkenyl, C^alkynyl, phenyl, 5- or 6- membered heteroaryl, Cs-ecycloalkyl, -O-Cs-ecycloalkyl, heterocyclyl and -O-(carbon-linked heterocyclyl) is optionally substituted by one or more substituents selected from hydroxy, cyano, halo, Ci-2alkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci.2haloalkoxy, NRaRbor -S(0)o-2RaRbwherein Raand Rbare independently H or Ci-2alkyl;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 Cs-ecycloalkyl and -O-C3- 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 CRjand NRX, wherein:Rjis selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, NH2 and Ci.4alkoxy; and Rxis selected from hydrogen and Ci-4alkyl;G7is N, NRaor CRj,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 NRa;Y2 is selected from CRkand N; wherein Rkis selected from hydrogen, halo, cyano, Ci-4alkyl, Ci.4alkoxy, Ci.4haloalkyl, Ci.4haloalkoxy, C3-4cycloalkyl, a 3- to 4- membered heterocyclyl and C3-4cycloalkoxy;Y3 is N or CR1wherein R1is selected from hydrogen, hydroxy, cyano, halo, Ci-4alkyl, C haloalkyl, 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 NYs is CRmor NRX, wherein:Rmis selected from hydrogen, halo, hydroxy, cyano, Cs-ecycloalkyl, NH2, Ci.4alkoxy and Ci-4alkyl optionally substituted with OH, Ci.4alkoxy and Cs-ecycloalkyl;Rxis selected from hydrogen and Ci-4alkyl;Y6is CRmor N;Y7is O, S, CRmor N;Ys is C or N;Yg is CRmor N; with the proviso that no more than four of Y1 to Ys are N;Xi is N or CRnwherein Rnis selected from hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci- 4alkoxy, and C1.4 haloalkoxy;X2is N or CRn;X3is N;X4 is N or C;X5 is selected from N, CRnand CRnRn1wherein:Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci- 4alkoxy, and C1.4 haloalkoxy; either Xs and X7are independently CRnor N; or Xs is CRnRn1or NRXand X7is CRnRn1, CR°R°1or NRX, wherein:Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci- 4alkoxy, and C1.4 haloalkoxy;Rxis hydrogen or C1.4 alkyl; andR° and R°1are independently selected from hydrogen, halo, methoxy and methyl;Xs is N, CRnor CRnRn1wherein Rnand Rn1are independently selected from hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, and Ci- 4 haloalkoxy; andXg is N or C; with the proviso that no more than four of X2to Xg are N;LI-L7are independently N or CRnwherein Rnis selected from hydrogen, halo, cyano, C1.4 alkyl, C1.4 haloalkyl, Ci.4alkoxy, and C1.4 haloalkoxy,with the proviso that no more than three L1 to L7 are N;Ei is CRi or N;E2 is CR2 or N;E3 is CR3 or N;E4 is CR4 or N,E5 is CR5 or N;E6is NR6or CReaReb wherein R1, R2, R3, R4, Rs, Rea and Reb are each independently selected from hydrogen, NRyiRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, - CH2SO2CH3, -P(O)(Ci-4alkyl)2, -SO2CH3, -NHC(O)CH3, -C(0)NRXI RX2, and Cs-ecycloalkyl optionally substituted by OH, wherein Rxiand RX2 are independently selected from hydrogen and Ci-4alkyl such as methyl, and wherein Ryiand Ry2 are independently selected from hydrogen, C3- ecycloalkyl and Ci-4alkyl, such as methyl, optionally substituted by Cs-ecycloalkyl, or, taken together with the N bearing them, Ryiand Ry2 form a 5- or 6-membered heteroaryl or a heterocyclyl , said 5- or 6-membered heteroaryl or a heterocyclyl being optionally substituted with OH, Ci-4alkoxy, or Ci-4alkyl optionally substituted with OH or Ci.4alkoxy, the heteocyclyl being a 4- to 7-member monocyclic heterocyclyl or a bicyclic heterocyclyl, each cycle of the bicyclic heterocyclyl having 3- to 6-members; andRe is selected from hydrogen, NH2, halo, cyano, and Ci-4alkyl; orRs and R4 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, or R4 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, NRyiRy2 or -S(0)o-2RyiRy2 wherein Ryiand Ry2 are H or Ci-2alkyl; with the proviso that no more than three of E1 to E5 are N.

2. The compound of claim 1 , wherein A1represents CR1aor N; A2represents CR2aor N; A3represents CR3aor N; A4represents CR4aor N; A5represents CR5aor N; A6represents CR6aor N; provided that 0, 1 or 2 of A1, A2, A3, A4, A5and A6represent N; in particular with R1ato R6aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, C1.4 alkoxy; preferably with R2a, R3a, R4aand R6aeach representing H and with R1aand R5aeach independently representing hydrogen, hydroxy, halo, C1.4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, or C1.4 alkoxy.

3. The compound of claim 1 or 2, whereinselected selected from:in particular with R1ato R6aeach independently representing hydrogen, hydroxy, halo, cyano andCi-4 haloalkyl, C1.4 haloalkoxy, C1.4 alkyl, 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-4alkyl), -C(O)N(Ci-4alkyl)2, -CO2H, -CO2(Ci-4alkyl), C1.4 alkoxy, C1.4 haloalkoxy, C1.4 alkyl, and C1.4 haloalkyl.

4. The compound of any one of claims 1 to 3, wherein R7ais H and R7bis 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; preferably R7aand R7bare both a hydrogen.

5. The compound of any one of claims 1 to 4, whereinR8ais H and R8bis a group of formula -(CRcRd)n-Z, such as -(CHRd)n-Z, and in particular -CHRd- Z or -Z, with Rdpreferably being hydrogen, orR8aand R8bare 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, C2.3alkenyl, NRaRband -S(0)o-2RaRb, preferably selected from halo, hydroxy, Ci- 4alkyl, Ci-4haloalkyl, Ci.4hydroxyalkyl, Ci.4alkoxy, Ci.4haloalkoxy, and C2.3alkenyl.

6. The compound of any one of claims 1 to 5, wherein Z is a Cs-scycloalkyl or a bicyclic C5- 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, C2.salkenyl, NRaRband -S(0)o-2RaRb, 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.

7. The compound of any one of claims 1 to 6, wherein X is selectedand8. The compound of any one of claims 1 to 7, wherein Y is selected from one of the following structures:in particular withRhbeing selected from hydrogen, halo, hydroxy, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci- 4haloalkoxy, and preferably being H,R9being 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, in particular hydrogen or C1.4 alkoxy, and preferably being H,Rjis selected from hydrogen, halo, hydroxy, Ci-4alkyl, and Ci.4alkoxy, and preferably being H, andin particular withRkbeing selected from hydrogen, halo, Ci-4alkyl, C1.4 alkoxy, Ci.4haloalkyl, and Ci.4haloalkoxy, and preferably being H,Rmbeing selected from hydrogen, halo, hydroxy, Cs-ecycloalkyl, C1.4 alkoxy, and Ci-4alkyl optionally substituted by OH, Ci.4alkoxy and Cs-ecycloalkyl, such as hydrogen, halo, hydroxy, Ci- 4alkyl, and C1.4 alkoxy, and preferably being H, Cs-ecycloalkyl, or Ci.4alkyl optionally substituted by OH, Ci-4alkoxy and Cs-ecycloalkyl, especially H,Rxbeing selected from hydrogen and Ci-4alkyl, and preferably being H;in particular with Rnbeing selected from hydrogen, halo, C1.4 alkyl, Ci.4 haloalkyl, Ci.4alkoxy, andC1.4 haloalkoxy, preferably being H; andwherein R1, R3, R4, Rs, are preferably each independently selected from hydrogen, NRyiRy2, halo, cyano, Ci.4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, Ci.4haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(Ci. 4alkyl)2, -SO2CH3, -NHC(O)CH3, -C(O)NRXI RX2, and Cs-ecycloalkyl optionally substituted by OH, wherein Rxiand RX2 are independently selected from hydrogen and Ci-4alkyl, and wherein Ryiand Ry2 are independently selected from hydrogen, Cs-ecycloalkyl and Ci-4alkyl optionally substituted by Cs-ecycloalkyl, or, taken together with the N bearing them, Ryiand Ry2 form a 5- or 6-membered heteroaryl or a heterocyclyl, said 5- or 6-membered heteroaryl or a heterocyclyl being optionally substituted with OH, Ci.4alkoxy, or Ci-4alkyl optionally substituted with OH or Ci- 4alkoxy, the heteocyclyl being a 4- to 7-member monocyclic heterocyclyl or a bicyclic heterocyclyl, each cycle of the bicyclic heterocyclyl having 3- to 6-members,R4 and R3 are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl, the 5- or 6-membered heterocyclyl being optionally spirofused with a Cs-ecycloalkyl and / or substituted by one or more substituents selected from oxo, cyano, hydroxy, halo, Ci-2alkyl, Cs-ecycloalkyl, Ci.2haloalkyl, Ci.2alkoxy, Ci.2haloalkoxy, NRyiRy2 or -S(0)o-2RyiRy2wherein Ryiand Ry2 are H or Ci-2alkylE? is O or CH2,R3’ represents independently H or, taken together, the two R3’ substituents represent an oxo group (=0) or a Cs-scycloalkyl, andR4’ represents independently H or, taken together, the two R4’ substituents represent an oxo group (=0) or a Cs-scycloalkyl; in particular with Ri, R3, R4, and R5 being each independently selected from hydrogen, NRyiRy2, halo, Ci-4alkoxy, Ci.4haloalkoxy, Ci-4alkyl, and Ci.4haloalkyl.

10. The compound of any one of claims 1 to 9, wherein the compound of formula (I) is selected from:and the salts thereof.

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

12. The pharmaceutical composition of claim 11 , further comprising another anticancer agent.

13. A compound of any one of claims 1 to 10 or a composition of claim 11 or 12, for use as a drug, in particular with an METTL3 inhibiting activity.

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

15. The compound or composition for use of claims 13 or 14, in a combination therapy with radiotherapy, or with immuno-stimulating agents such as vaccines.

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