Novel METTL3 inhibitors and their use in therapy

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to pharmaceutical compounds useful for the treatment and / or prevention in a mammal, pharmaceutical compositions comprising such compounds and their use as METTL3 inhibitors for the treatment of diseases such as cancer, autoimmune diseases, neurological diseases, infectious diseases and inflammatory diseases, and other diseases or conditions involving METTL3 activity. BACKGROUND

[0002] Particular chemical modifications of biomolecules are effective ways to modulate molecular function, and many downstream signaling pathways are affected by DNA and protein modifications. Many enzymes responsible for regulating protein and DNA modifications are current targets for cancer therapy. RNA epitranscriptomics (the study of RNA modifications) is a new frontier in this field. Although eukaryotic RNA modifications have been known since the 1970s, they were primarily identified on transfer RNAs and ribosomal RNAs, but only in the last decade have they been identified and characterized on mRNAs and various non-coding RNAs. Increasing evidence suggests that RNA modification pathways are also dysregulated in human cancers and can be ideal targets for cancer therapy (Barbieri & Kouzarides 2020).

[0003] N6-methyladenosine (m6A) is the most prevalent RNA modification in mammalian cells. m6A modification sites are evolutionarily conserved in the consensus motif DRACH (D = A, G or U; H = A, C or U), where A is converted to m6A, and usually occur in the coding sequence of mRNAs, the 3’ untranslated region (3’ UTR) proximal to the stop codon, and the 5’ untranslated region (5’ UTR). It is a potentially reversible and dynamic post-transcriptional modification of RNA molecules, regulated by methyltransferases (writers) and demethylases (erasers), and recognized by specific binding proteins (readers) (Li et al., 2022).

[0004] Increasing evidence suggests that m6A plays a crucial role in cancer and is also involved in a variety of physiological behaviors such as neural development, T cell homeostasis, glycolipid metabolism, and gametogenesis, and its disruption can lead to various diseases, including addiction, autoimmune diseases, metabolic diseases, and infertility (Yang et al., 2020).

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

[0006] METTL3 plays a crucial role in many biological processes, particularly in tumorigenesis and development. Typically, METTL3 acts as an oncogene in cancer. Therefore, it leads to altered mRNA translation and accelerates tumor progression, while downregulation of METTL3 results in tumor suppression. Consequently, METTL3 mRNA expression is significantly elevated in cancerous tissues compared to normal tissues. Therefore, it is associated with poor prognosis and is thus a potential novel diagnostic and prognostic biomarker in clinical cancer studies (Liu et al., 2020).

[0007] WO2020201773, WO2021111124, WO2022074379 and WO2022074391 describe METTL3 inhibitors and their use in the treatment of proliferative disorders (e.g., cancer), autoimmune diseases, neurological diseases, infectious and inflammatory diseases, and other diseases or conditions involving METTL3 activity.

[0008] WO2022254216 describes a combination therapy that includes a METTL3 inhibitor and further anticancer agents.

[0009] WO2022254218 describes a method for preparing inhibitory compounds.

[0010] WO2021079196, WO2021081211 and WO2022081739 describe the METTL3 modifier. Summary of the Invention

[0011] In a first aspect, the present invention relates to compounds of formula (I),

[0012]

[0013] Or its tautomers, stereoisomers, salts, solvates or N-oxides, wherein

[0014] A 1 Represents CR 1a Or N; A 2 Represents CR 2aOr N; A 3 Represents CR 3a Or N; A 4 Represents CR 4a Or N; A 5 Represents CR 5a Or N; A 6 Represents CR 6a Or N;

[0015] The condition is A 1 A 2 A 3 A 4 A 5 and A 6 No more than 3 characters represent N;

[0016] R 1a To R 6a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclic groups, C 3-4 Cycloalkyloxy or 3- to 5-membered heterocyclic alkyloxy, wherein the C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclic groups, C 3-4 Each of the cycloalkyloxy group or 3 to 5-membered heterocyclic oxy groups is optionally surrounded by one or more groups selected from cyano, hydroxyl, halogen, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2, -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl and OC 3-6 Substituents of cycloalkyl groups;

[0017] R 7a and R 7b Selected independently from:

[0018] (i)Hydrogen;

[0019] (ii)C 1-6 Alkyl group, optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C1-4 alkoxy, C 1-4 haloalkoxy, substituted by a substituent selected from the group consisting of cyano, hydroxy, halo, C

[0020] (iii) or R 7a and R 7b are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl group,

[0021] R 8a and R 8b are independently selected from the group consisting of:

[0022] (i) hydrogen,

[0023] (ii) C 1-6 alkyl, optionally substituted by one or more substituents selected from the group consisting of cyano, hydroxy, halo, C 1-2 alkoxy, C 1-2 haloalkoxy, substituted by a substituent selected from the group consisting of cyano, hydroxy, halo, C

[0024] (iii) a group of the formula -(CR c R d ) n -Z, wherein

[0025] n is 0, 1 or 2,

[0026] R c and R d are independently selected from the group consisting of:

[0027] o hydrogen

[0028] o C 1-6 alkyl, optionally substituted by one or more substituents selected from the group consisting of cyano, hydroxy, halo, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, and wherein C 3-6 cycloalkyl and -O-C 3-6 cycloalkyl are optionally substituted by one or more substituents selected from the group consisting of halo, cyano and hydroxy; and

[0029] o or R c and R d are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl group, optionally substituted by one or more substituents selected from the group consisting of cyano, hydroxy, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy;

[0030] and Z is selected from the group consisting of

[0031] o hydrogen, cyano, hydroxy,

[0032] o NR a R b or -S(O) 0-2 R a R b wherein R a and R b are H or C 1-2 alkyl, and

[0033] o C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, aryl, heterocyclyl, heteroaryl, bicyclic C 5-12 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b wherein R a and R b are H or C 1-2 alkyl;

[0034] iv) or R 8a and R 8b are linked together such that, together with the nitrogen atom to which they are attached, they form a monocyclic or bicyclic heterocyclyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b wherein R a and R b are independently H or C 1-4 alkyl;

[0035] X is selected from , , , or ;

[0036] The dashed lines represent points connected to Y, and the wavy lines represent points connected to the rest of the molecule;

[0037] R c and R d Independently selected from hydrogen, C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups;

[0038] R e and R f Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups;

[0039] R c R d and R e R f They can connect together, so that together with the carbon atoms they are attached to, they form C. 3-4 Cycloalkyl diester, optionally bonded by one or more radicals selected from halogen, methyl, cyano, hydroxyl, and C. 1-4 Substitution of alkoxy groups;

[0040] Y is selected from one of the following structures:

[0041] i)

[0042] in:

[0043] G1 is selected from CR h and N, where R h Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 5- or 6-membered heteroaryl, 3- to 4-membered heterocyclic and -OC 3-4 cycloalkyl;

[0044] G2 is selected from N and CR g , where R g Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, heterocyclyl, -O-(carbon-linked heterocyclyl), -(OCH2CH2) m -NR y R z , -(OCH2CH2) m -OCH3, NR y R z and -C(O)-NR y R z ;

[0045] wherein m is an integer from 1 to 6, and R y and R z are each independently hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 6-membered carbon-linked heterocyclyl, or R y and R z are linked together such that they form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclyl group;

[0046] wherein C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, heterocyclyl, and -O-(carbon-linked heterocyclyl) are optionally substituted with one or more substituents selected from hydroxyl, cyano, halogen, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, NR a R b or -S(O) 0-2 R a R b , wherein R a and R b are independently H or C 1-2 alkyl;

[0047] G3is N or CR i , wherein R i is selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from halogens, methyl groups, and methoxy groups;

[0048] G4 is selected from C and N;

[0049] G5 is selected from CR j and NR x ,in:

[0050] R j Selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, NH2 and C 1-4 Alkyl groups; and R x Selected from hydrogen and C 1-4 alkyl;

[0051] G7 represents N and NR. a or CR j ,

[0052] G8 is selected from C and N.

[0053] The condition is that no more than four of G1 to G8 are selected, with one, two, or three preferably being N or NR. a ;

[0054] ii) ,

[0055] Y2 is selected from CR k and N; where R k Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 3- to 4-membered heterocyclic groups and C 3-4 Cycloalkoxy;

[0056] Y3 is N or CR l , where R l Selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, methyl and methoxy;

[0057] Y4is C or N;

[0058] Y5is CR m or NR x wherein:

[0059] R m is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 3-6 cycloalkyl, NH2, C 1-4 alkoxy and optionally OH, C 1-4 alkoxy and C 3-6 cycloalkyl substituted C 1-4 alkyl;

[0060] R x is selected from the group consisting of hydrogen and C 1-4 alkyl;

[0061] Y6is CR m or N;

[0062] Y7is O, S, CR m or N;

[0063] Y8is C or N;

[0064] Y9is CR m or N;

[0065] with the proviso that not more than four of Y1to Y8are N;

[0066] iii)

[0067] X1is N or CR n , wherein R n is selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0068] X2is N or CR n ;

[0069] X3is N;

[0070] X4is N or C;

[0071] X5is selected from the group consisting of N, CR n and CR n R n1 , wherein:

[0072] R n and R n1independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

[0073] any one of X6and X7is independently CR n or N; or X6is CR n R n1 or NR x and X7is CR n R n1 , CR o R o1 or NR x wherein:

[0074] R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

[0075] R x is hydrogen or C 1-4 alkyl; and

[0076] R o and R o1 are independently selected from hydrogen, halogen, methoxy, and methyl;

[0077] X8is N, CR n or CR n R n1 wherein R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; and

[0078] X9is N or C;

[0079] provided that no more than four of X2to X9are N;

[0080] iv)

[0081] L1-L7are independently N or CR n wherein R n is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C1-4 Halogenated alkoxy groups,

[0082] The condition is that no more than three of L1 to L7 are N;

[0083] v)

[0084] E1 is either CR1 or N;

[0085] E2 is either CR2 or N;

[0086] E3 is either CR3 or N;

[0087] E4 is either CR4 or N.

[0088] E5 is either CR5 or N;

[0089] E6 is NR6 or CR 6a R 6b ;

[0090] Among them, R1, R2, R3, R4, R5, R 6a and R 6b Each is independently selected from hydrogen and NR. y1 R y2 Halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(C 1-4 Alkyl group 2, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 and C that is optionally replaced by OH 3-6 cycloalkyl, wherein R x1 and R x2 Independently selected from hydrogen and C 1-4 Alkyl (e.g., methyl), and wherein R y1 and R y2 Independently selected from hydrogen and C 3-6 cycloalkyl and optionally C 3-6 Cycloalkyl-substituted C 1-4 Alkyl (e.g., methyl), or R y1 and R y2 Together with the N carrying them, they form a 5- or 6-membered heteroaryl or heterocyclic group, which is optionally surrounded by OH, C 1-4 Alkoxy or C 1-4 Alkyl substitution, the C 1-4 Alkyl groups are optionally surrounded by OH or C 1-4Alkoxy substitution, wherein the heterocyclic group is a 4- to 7-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein each ring of the bicyclic heterocyclic group has 3 to 6 members; and

[0091] R6 is selected from hydrogen, NH2, halogen, cyano, and C. 1-4 alkyl;

[0092] or

[0093] R5 and R4 are linked together, forming a 5- or 6-membered heterocyclic group together with the atoms they are attached to.

[0094] Alternatively, R4 and R3 can be linked together to form a 5- or 6-membered heterocyclic group with the atoms they are attached to.

[0095] The 5- or 6-membered heterocyclic group is optionally surrounded by one or more groups selected from oxo, cyano, hydroxyl, halogen, C 1-2 Alkyl, C 3-6 cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, NR y1 R y2 Or –S(O) 0-2 R y1 R y2 Substituents of R, wherein R y1 and R y2 For H or C 1-2 alkyl;

[0096] The condition is that no more than three of E1 to E5 are N.

[0097] Preferably, in formula (I):

[0098] A 1 Represents CR 1a Or N; A 2 Represents CR 2a Or N; A 3 Represents CR 3a Or N; A 4 Represents CR 4a Or N; A 5 Represents CR 5a Or N; A 6 Represents CR 6a Or N;

[0099] The condition is A 1 A 2 A 3 A 4 A 5 and A 6 No more than 3 characters represent N;

[0100] R 1a to R 6a each independently represents hydrogen, hydroxyl, halogen, cyano and C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and O-C 3-6 cycloalkyl, which are optionally substituted by one or more substituents selected from cyano, hydroxyl, halogen, C

[0101] R 7a and R 7b are independently selected from:

[0102] (i) hydrogen;

[0103] (ii) C 1-6 alkyl, which is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy,

[0104] (iii) or R 7a and R 7b are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl,

[0105] R 8a and R 8b are independently

[0106] (i) hydrogen,

[0107] (ii) C 1-6 alkyl, which is optionally substituted by one or more substituents selected from cyano, hydroxyl, halogen, C 1-2 alkoxy, C 1-2 haloalkoxy,

[0108] (iii) formula -(CRc R d ) n -Z group, wherein

[0109] n is 0, 1 or 2,

[0110] R c and R d are independently selected from:

[0111] o hydrogen

[0112] o C 1-6 alkyl, optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, and wherein C 3-6 cycloalkyl and -O-C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano and hydroxy; and

[0113] o or R c and R d are linked together such that, together with the carbon atom to which they are attached, they form a 3- to 6-membered cycloalkanediyl or heterocyclyl group, optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy;

[0114] and Z is selected from

[0115] o hydrogen, cyano, hydroxy,

[0116] o NR a R b or -S(O) 0-2 R a R b wherein R a and R b are H or C 1-2 alkyl, and

[0117] o C 2-3 alkenyl, C 2-3 alkynyl, C 3-8 cycloalkyl, aryl, heterocyclyl, heteroaryl, bicyclic C 5-12 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 hydroxyalkyl, C1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b Substituents of R, wherein R a and R b For H or C 1-2 alkyl;

[0118] iv) or R 8a and R 8b The linkages allow them to form monocyclic or bicyclic heterocyclic groups together with the nitrogen atoms to which they are linked, optionally with one or more groups selected from halogens, cyano groups, hydroxyl groups, C6 groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b Substituents of R, wherein R a and R b Independently H or C 1-4 alkyl;

[0119] X is selected from , , , or ,in

[0120] Dashed lines represent points connected to Y, and wavy lines represent points connected to the rest of the molecule;

[0121] R c and R d Independently selected from hydrogen, C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups;

[0122] R e and R f Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups;

[0123] R c R d and R e R f may be linked together such that they, together with the carbon atom to which they are attached, form a C 3-4 cycloalkanediyl, which is optionally substituted with one or more substituents selected from halogen, methyl, cyano, hydroxyl, and C 1-4 alkoxy;

[0124] Y is selected from one of the following structures:

[0125] i)

[0126] wherein:

[0127] G1is selected from CR h and N, wherein R h is selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-4 cycloalkyl, 5- or 6-membered heteroaryl, 3- to 4-membered heterocyclyl, and -O-C 3-4 cycloalkyl;

[0128] G2is selected from N and CR g , wherein R g is selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, heterocyclyl, -O-(carbon-linked heterocyclyl), -(OCH2CH2) m -NR y R z , -(OCH2CH2) m -OCH3, NR y R z , and -C(O)-NR y R z ;

[0129] wherein m is an integer from 1 to 6, and R y and R z are each independently hydrogen, C 1-4alkyl, C 3-6 cycloalkyl, 3- to 6-membered carbon-linked heterocyclyl, or R y and R z are linked together such that they form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclyl group;

[0130] wherein C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, heterocyclyl, and -O-(carbon-linked heterocyclyl) are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, NR a R b or -S(O) 0-2 R a R b wherein R a and R b are independently H or C 1-2 alkyl;

[0131] G3is N or CR i wherein R i is selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl, and -O-C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl, and -O-C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, methyl, and methoxy;

[0132] G4is selected from C and N;

[0133] G5is selected from CR j and NR x wherein:

[0134] R j is selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, NH2, and C 1-4 alkoxy; and R x is selected from the group consisting of hydrogen and C 1-4 alkyl;

[0135] G7 is N, NR a or CR j ,

[0136] G8 is selected from C and N,

[0137] with the proviso that not more than four, preferably 1, 2 or 3 of G1to G8are N or NR a ;

[0138] ii) ,

[0139] Y2is selected from CR k and N; wherein R k is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-4 cycloalkyl, 3- to 4-membered heterocyclyl and C 3-4 cycloalkoxy;

[0140] Y3is N or CR l , wherein R l is selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl and -O-C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -O-C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from halogen, methyl and methoxy;

[0141] Y4is C or N;

[0142] Y5is CR m or NR x , wherein:

[0143] R m is selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 alkyl, NH2and C 1-4 alkoxy;

[0144] R x is selected from hydrogen and C 1-4 alkyl;

[0145] Y6is CR m or N;

[0146] Y7is O, S, CR m or N;

[0147] Y8is C or N;

[0148] Y9is CR m or N;

[0149] with the proviso that no more than four of Y1to Y8are N;

[0150] iii)

[0151] X1is N or CR n , wherein R n is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0152] X2is N or CR n ;

[0153] X3is N;

[0154] X4is N or C;

[0155] X5is selected from N, CR n and CR n R n1 , wherein:

[0156] R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0157] any of X6and X7is independently CR n or N; or X6is CR n R n1 or NR x and X7is CR n R n1 , CR o R o1 or NR x , wherein:

[0158] R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0159] Rx hydrogen or C 1-4 alkyl; and

[0160] R o and R o1 are independently selected from hydrogen, halogen, methoxy, and methyl;

[0161] X8is N, CR n or CR n R n1 wherein R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; and

[0162] X9is N or C;

[0163] with the proviso that no more than four of X2to X9are N;

[0164] iv)

[0165] L1-L7are independently N or CR n wherein R n is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy,

[0166] with the proviso that no more than three of L1to L7are N;

[0167] v)

[0168] E1is CR1or N;

[0169] E2is CR2or N;

[0170] E3is CR3or N;

[0171] E4is CR4or N,

[0172] E5is CR5or N;

[0173] E6is NR6or CR 6a R 6b ;

[0174] wherein R1, R2, R3, R4, R5, R 6a and R 6b are each independently selected from hydrogen, NR y1 R y2halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 haloalkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR x1 R x2 wherein R x1 and R x2 are independently selected from hydrogen and methyl, and wherein R y1 and R y2 are independently selected from hydrogen and methyl, or together with the N carrying them form a 5- or 6-membered heterocyclic group; and

[0175] R6is selected from hydrogen and C 1-4 alkyl;

[0176] or

[0177] R5and R4are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic group (such that a bicyclic system is actually formed which comprises one aromatic ring fused to one 5- or 6-membered heterocyclic group,

[0178] or R4and R3are linked together such that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic group (such that a bicyclic system is actually formed which comprises one aromatic ring fused to one 5- or 6-membered heterocyclic group,

[0179] wherein said 5- or 6-membered heterocyclic group is optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, NR y1 R y2 or -S(O) 0-2 R y1 R y2 wherein R y1 and R y2 are H or C 1-2 alkyl;

[0180] with the proviso that no more than three of E1to E5are N.

[0181] In another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable carrier.

[0182] In another aspect, the present application 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 medicament, in particular a medicament having METTL3 inhibitory activity.

[0183] In another aspect, the present application 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 disease, a neurological disease, an infectious disease or an inflammatory disease.

[0184] The present application also relates to the use of a compound of formula (I) as defined herein or a composition comprising a compound of formula (I) as described herein for the treatment or prevention of a cancer or an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease.

[0185] The present application also relates to the use of a compound of formula (I) as defined herein or a composition comprising a compound of formula (I) as described herein for the manufacture of a medicament intended for the treatment or prevention of a cancer or an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease.

[0186] The present application also relates to a method of treatment or prevention of a cancer or an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease, comprising administering to a person in need thereof an effective amount of a compound of formula (I) as defined herein or a composition comprising a compound of formula (I) as described herein.

[0187] It is understood that the present application encompasses only stable compounds. Those skilled in the art will recognize how to deduce the definition of a stable compound from the definition of a compound that would lead to an unstable compound.

[0188] Definitions

[0189] In the present specification, the term “ comprise ” and any variations thereof, such as “comprising” and “comprises”, are not intended to exclude other components or steps.

[0190] As used herein, the term “ hydrogen ” includes any isotope of hydrogen, such as deuterium.

[0191] As used herein, the term “ hydroxy ” means -OH, and the term “ cyano ” means -CN.

[0192] As used in the present application, the term “ halogen ” refers to a fluorine, bromine, chlorine or iodine atom, preferably a chlorine or fluorine atom.

[0193] As used in the present application, the term “ halo"Refers to the fluorine, bromine, chlorine or iodine portion, preferably the chlorine or fluorine portion.

[0194] As used in this invention, the term " C1- x alkyl "" refers to a straight-chain or branched monovalent saturated hydrocarbon chain containing 1 to x carbon atoms. Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms and include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0195] As used in this invention, the term " C1- x alkanediyl "" refers to a straight-chain or branched divalent saturated hydrocarbon chain containing 1 to x carbon atoms, including but not limited to mediyl, ethylenediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, etc.

[0196] As used in this invention, the term " C1- x haloalkyl "" refers to C1- as defined above, which is substituted with at least one halogen atom, and preferably with at least one fluorine atom. x Alkyl groups. Specifically, it can be a trifluoromethyl group.

[0197] As used in this invention, the term " C1- x hydroxyalkyl "" refers to a C1- group as defined above that has been substituted by a hydroxyl group. x Alkyl groups.

[0198] As used in this invention, the term " C2- x Alkenyl "" refers to a straight or branched monovalent unsaturated hydrocarbon chain containing 2 to x carbon atoms and at least one double bond, including but not limited to vinyl, propenyl, butenyl, etc.

[0199] As used in this invention, the term " C2- x alkynyl "" refers to a straight or branched monovalent unsaturated hydrocarbon chain containing 2 to x carbon atoms and at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, etc.

[0200] As used in this invention, the term " C1- x alkoxy "" refers to C1- as defined above, which is connected to the molecule through an oxygen atom. x Alkyl groups, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0201] As used in this invention, the term " C1- x haloalkoxy "" refers to C1- as defined above, which is substituted with at least one halogen atom, and preferably with at least one fluorine atom. x An alkoxy group. Specifically, it can be a trifluoromethoxy group.

[0202] As used in the present application, the term "C C x - y Cycloalkyl " or "C x to y-membered cycloalkyl " refers to a monovalent monocyclic hydrocarbon ring having x to y carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

[0203] As used in the present application, the term "C C x - y Cycloalkanediyl " or "C x to y-membered cycloalkanediyl " refers to a divalent monocyclic hydrocarbon ring having x to y carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

[0204] As used in the present application, the term "C Bicyclic C5- x Cycloalkyl " refers to a bicyclic hydrocarbon ring having 5 to x carbon atoms and comprising two linked rings. This includes spiro compounds, fused bicyclic compounds, and bridged bicyclic compounds.

[0205] As used in the present application, the term "C C x - y Cycloalkyloxy " refers to a C x - y cycloalkyl group as defined above linked to the molecule through an oxygen atom, including but not limited to cyclopropoxy or cyclobutyloxy.

[0206] As used in the present application, the term "C heterocyclyl " refers to a saturated or unsaturated, but non-aromatic, monocyclic or bicyclic ring containing at least one heteroatom (preferably 1, 2, 3 or 4 heteroatoms) in the ring, advantageously having 3 to 12 ring atoms. The bicyclic heterocyclyl group can be fused, bridged or a spiro compound. The spiro compound includes a monocyclic heterocyclyl group spiro-fused to a C 3-6 cycloalkyl group. Preferably, each ring of the heterocyclyl group comprises 3 to 6 ring atoms. The heteroatoms are preferably selected from O, N, P and S, more preferably the heteroatoms are selected from O, N and S. The S atom can be mono- or di-oxidized, i.e. the sulfur atom can be S, S(O) or SO2, preferably S. The phosphorus atom can be oxidized, i.e. the phosphorus atom can be P or P(O). The heterocyclyl group includes but is not limited to epoxide, aziridinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, dihydrooxazinyl, benzothiazinyl, benzothiazinonyl, indolinyl, isoindolinyl, 1,4-azaphosphorane-4-oxide, 3-aza-bicyclo[3.1.0]hexane.

[0207] The heterocyclyl group spiro-fused to a C 3-6 cycloalkyl group is to be understood as including spiro compounds of a heterocyclyl group fused to a C 3-6 cycloalkyl group.

[0208] As used in the present application, the term "C heterocyclyloxy"" refers to the heterocyclic group defined above that is connected to the molecule through an oxygen atom, including but not limited to oxobutyroxyl groups.

[0209] As used in this invention, the term " aryl "" refers to an aromatic hydrocarbon group containing one or more fused rings, and preferably contains 6 to 10 carbon atoms, such as a phenyl or naphthyl group. Advantageously, it is a phenyl group.

[0210] As used in this invention, the term " heteroaryl "Aromatic group" refers to an aromatic group comprising one or more (especially one or two) fused hydrocarbon rings, wherein one or more (especially one to four, advantageously one or two) carbon atoms are each replaced by a heteroatom selected from sulfur, oxygen and nitrogen (preferably oxygen and nitrogen). It can be furanyl, thiophene, pyrrole, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl or indoleyl.

[0211] As used in this invention, the term " N-protecting group "N-protecting group" refers to a group designed to protect the amino function (especially the primary amino function) from undesirable reactions during synthetic steps. Commonly used N-protecting groups are disclosed in "Greene's Protective Groups in Organic Synthesis", 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey. The amino function protected by the N-protecting group can be a carbamate, amide, sulfonamide, N-alkyl derivative, amino acetal derivative, N-benzyl derivative, imine derivative, enamine derivative, or N-heteroatom derivative. Specifically, the N-protecting group can be a formyl group; an aryl group (e.g., phenyl), optionally substituted with one or more methoxy groups (e.g., p-methoxyphenyl (PMP)); an aryl-(C1-C6)alkyl group, such as benzyl, with the aryl moiety optionally substituted with one or more methoxy groups (e.g., benzyl (Bn), p-methoxybenzyl (PMB), or 3,4-dimethoxybenzyl (DMPM)); a CO-R group; or a benzyl group. PG1 Examples include acetyl (Ac), neopentanoyl (Piv or Pv), benzoyl (Bz), or p-methoxybenzylcarbonyl (Moz); -CO2-RGP1, such as tert-butoxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz or Z), or 9-fluorenylmethoxycarbonyl (Fmoc); -SO2-R PG1such as phenylsulfonyl, toluenesulfonyl (Ts or Tos) or 2-nitrobenzenesulfonyl (also known as nosyl - Nos or Ns); and the like,

[0212] wherein R PG1 represents (C1-C6)alkyl optionally substituted by one or several halogen atoms (e.g. F or CI); (C2-C6)alkenyl (e.g. allyl); aryl (e.g. phenyl) optionally substituted by one or several groups selected from OMe (methoxy) and NO2(nitro); aryl-(C1-C6)alkyl (e.g. benzyl), the aryl moiety being optionally substituted by one or several methoxy groups; or a 9-fluorenylmethyl group.

[0213] In particular, it can be tert-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl.

[0214] The person skilled in the art is familiar with lewis acid and bronsted acid Examples of Lewis acids include aluminium chloride, zinc chloride, silver chloride. Examples of Bronsted acids include hydrochloric acid, trifluoroacetic acid, acetic acid. The person skilled in the art will select the appropriate Lewis acid or Bronsted acid according to the nature of the starting molecule and the desired result, and for this purpose can refer to "Greene's Protective Groups In Organic Synthesis", 4thEdition, 2007, John Wiley & Sons, Hoboken, New Jersey.

[0215] In the formula or , the plain circle represents an aromatic ring. Furthermore, the dotted line "— " represents the point of attachment to X.

[0216] In the formula , or , the dotted circle represents an aromatic or unsaturated ring. Furthermore, the dotted line "— " represents the point of attachment to X.

[0217] Furthermore, in the present application, Me represents methyl, Ph represents phenyl, Et represents ethyl, Ac represents acetyl, SEM represents 2-(trimethylsilyl)ethoxymethyl, and TMS represents trimethylsilyl. More generally, the abbreviations used refer to chemical groups having the meaning commonly known in the art.

[0218] For the purposes of the present application, the term "pharmaceutically acceptable" is intended to denote an agent that is useful in preparing a pharmaceutical composition, and that is generally safe and non-toxic for pharmaceutical use. pharmaceutically acceptable For the purposes of the present application, the term "pharmaceutically acceptable" is intended to denote an agent that is useful in preparing a pharmaceutical composition, and that is generally safe and non-toxic for pharmaceutical use. DETAILED DESCRIPTION

[0220] 1 - compound of formula (I)

[0221] A1 to A6

[0222] According to a specific embodiment, R 1a to R 6a each independently represents hydrogen, hydroxyl, halogen, cyano and C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C l-4 haloalkyl, C 3-6 cycloalkyl and O-C 3-6 cycloalkyl.

[0223] According to another specific embodiment, R 1a , R 2a , R 4a and R 5a each independently represents hydrogen, hydroxyl, halogen, cyano and C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, each of which C 1-4Alkyl), -C(O)N(C 1-4 Alkyl group 2, -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; and R 3a and R 6a Each can be represented independently as hydrogen, halogen, or cyano, with hydrogen being preferred.

[0224] According to another specific implementation plan, R 1a R 2a R 4a and R 5a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C 1-4 Alkoxy, the C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C 1-4 Each of the alkoxy groups is optionally substituted by one or more substituents selected from the following: cyano, hydroxyl, halogen, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl group 2, -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and R 3a and R 6a Each can be represented independently as hydrogen, halogen, or cyano, with hydrogen being preferred.

[0225] According to another specific implementation plan, R 1a R 2a and R 5a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C 1-4 Alkoxy; R 4a Representing hydrogen, hydroxyl, halogen, cyano, and C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C1-4 alkoxy, said C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -CO2H, -CO2(C 1-4 alkyl), C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl and C 1-4 haloalkyl; and R 3a and R 6a independently of one another represent hydrogen, halogen or cyano, preferably hydrogen.

[0226] advantageously, R 1a to R 6a each independently represent hydrogen, hydroxy, halogen, cyano and C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, all of which are optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and O-C 3-6 cycloalkyl.

[0227] preferably, R 1a represent hydrogen, hydroxy, halogen, cyano, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy or 3- to 5-membered heterocyclyloxy, all of which are optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl and -O-C 3-6cycloalkyl; preferably hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy or C 1-4 halogenalkoxy;

[0228] R 2a represents hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy or C 1-4 halogenalkoxy;

[0229] R 3a represents hydrogen, halogen or cyano;

[0230] R 4a represents hydrogen, halogen; cyano; C 1-4 alkyl optionally substituted by one or more -OH or C 1-4 alkyl; C 1-4 halogenalkyl optionally substituted by one or more -OH or C 1-4 alkoxy or -CONH2; C 1-4 alkyl; C 1-4 halogenalkyl; C 4a represents hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy or C 1-4 halogenalkoxy;

[0231] R 5a represents hydrogen, halogen, cyano, C 1-4 halogenalkyl, C 1-4 halogenalkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 3-4 cycloalkyl or 3- to 5-membered heterocyclyl, C 3-4 cycloalkyloxy, 3- to 5-membered heterocyclyloxy, all of which are optionally substituted by one or more substituents selected from the group consisting of cyano, hydroxy, C 1-4 alkoxy, halogen, C 1-4 halogenalkoxy, C 3-6 cycloalkyl or -O-C 3-6 cycloalkyl; preferably hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 halogenalkyl, C 1-4 alkoxy or C 1-4 halogenalkoxy; and

[0232] R 6a represents hydrogen, halogen or cyano.

[0233] R 1a to R 6a independently represent hydrogen, hydroxyl, halogen, cyano and C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 alkoxy, each of which C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 alkoxy, each of which C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl and C 1-4 haloalkyl; especially hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; and preferably:

[0234] R 1a represents hydrogen, hydroxyl, halogen, C 1-4 alkyl or C 1-4 alkoxy;

[0235] R 2a represents hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0236] R 3a represents hydrogen, halogen or cyano;

[0237] R 4a represents hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by one or more -OH or C 1-4 alkoxy, C 1-4 haloalkyl, optionally substituted by one or more -OH or C 1-4 alkoxy or -CONH2, C 1-4 alkoxy, or C 1-4 haloalkoxy;

[0238] R 5a represents hydrogen, hydroxyl, halogen, C 1-4 alkyl or C 1-4 alkoxy; and

[0239] R 6a represents hydrogen, halogen or cyano.

[0240] According to a specific embodiment, R 1a to R 6a independently represent hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; and preferably:

[0241] R 1a represents hydrogen, hydroxyl, halogen or C 1-4 alkoxy;

[0242] R 2a represents hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0243] R 3a represents hydrogen, halogen or cyano.

[0244] R 4a represents hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;

[0245] R 5a represents hydrogen, hydroxyl, halogen or C 1-4 alkoxy; and

[0246] R 6a represents hydrogen, halogen or cyano.

[0247] Preferably, not more than 2 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represent N. Preferably, 0, 1 or 2 of A 1 , A 2 , A 3 and A 4 represent N.

[0248] In particular, A 1represents CR 1a or N; A 2 represents CR 2a or N; A 3 represents CR 3a or N; A 4 represents CR 4a or N; A 5 represents CR 5a or N; A 6 represents CR 6a or N;

[0249] with the proviso that 0, 1 or 2 of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represent N; preferably with the proviso that 0, 1 or 2 of A 1 , A 2 , A 3 and A 4 represent N;

[0250] preferably R 1a through R 6a each independently represent hydrogen, hydroxyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 alkoxy; preferably R 2a , R 3a , R 4a and R 6a each represent H, and R 1a and R 5a each independently represent hydrogen, hydroxyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 alkoxy.

[0251] In particular embodiments, none of A 1 , A 2 , A 3 , A 4 , A 5 or A 6 represent N.

[0252] In particular embodiments, only one of A 1 , A 2 , A 3 , A 4 , A 5 and A 6 represents N; preferably A1 A 2 A 3 and A 4 Only one represents N.

[0253] In the specific implementation plan, A 1 A 2 A 3 A 4 A 5 and A 6 Two of them, preferred A 1 A 2 A 3 and A 4 The two in the text represent N. In this implementation, the following part is N:

[0254] o A1 and A3, or

[0255] o A2 and A3, or

[0256] o A2 and A4, or

[0257] o A2 and A6, or

[0258] o A3 and A4, or

[0259] o A3 and A6, or

[0260] o A4 and A6, or

[0261] o A4 and A5, or

[0262] o A5 and A6.

[0263] Advantageously, Selected from:

[0264] , , , , , , , , , , , , , ,

[0265] Especially R 1a To R 6a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C1-4 alkoxy, said C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halogen, -C(O)NH2, -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -CO2H, -CO2(C 1-4 alkyl), C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl and C 1-4 haloalkyl; especially hydrogen, hydroxy, halogen, cyano, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, optionally substituted with one or more -OH or C 1-4 alkyl, or C 1-4 alkoxy or -CONH2; preferably R 1-4 alkoxy; preferably R 1a to R 6a each independently represent hydrogen, hydroxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl or C 1-4 alkoxy; especially wherein R 2a , R 3a , R 4a and R 6a each represent H, and wherein R 1a and R 5a each independently represent hydrogen, hydroxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, optionally substituted with one or more -OH or C 1-4 alkyl, or C 1-4 alkoxy or -CONH2; preferably R 1-4 alkoxy, for example R 2a , R 3a , R 4a and R 6a each represent H, and wherein R 1a and R 5a each independently represent hydrogen, hydroxy, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C1-4 Alkyl or C 1-4 Alkyl group.

[0266] Advantageously, compounds of formula (I) are selected from compounds of the following formula:

[0267] , , , , or ,

[0268] Preferred , , or ,

[0269] Where R 1a To R 6a As defined above, and preferably independently representing hydrogen, hydroxyl, halogen, cyano, optionally surrounded by one or more -OH or C groups. 1-4 alkoxy-substituted C 1-4 Alkyl, C 1-4 Halogenated alkyl group, optionally with one or more -OH or C 1-4 alkoxy or -CONH2 substituted C 1-4 alkoxy, or C 1-4 Halogenated alkoxy groups; especially R 1a To R 6a Independently representing hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy; and advantageously, wherein:

[0270] R 1a Represents hydrogen, hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0271] R 2a Represents hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0272] R 4a Represents hydrogen, halogen, cyano, optionally surrounded by one or more -OH or C groups. 1-4 alkoxy-substituted C 1-4 Alkyl, C 1-4 Halogenated alkyl group, optionally with one or more -OH or C 1-4alkoxy or -CONH2 substituted C 1-4 alkoxy, or C 1-4 Halogenated alkoxy groups;

[0273] R 5a Represents hydrogen, hydroxyl, halogen, or C 1-4 Alkoxy;

[0274] R 3a and R 6a Represents hydrogen, halogen, or cyano;

[0275] In particular: R 1a Represents hydrogen, hydroxyl, halogen, or C 1-4 Alkoxy;

[0276] R 2a Represents hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0277] R 4a Represents hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0278] R 5a Represents hydrogen, hydroxyl, halogen, or C 1-4 Alkoxy;

[0279] R 6a Represents hydrogen, halogen, or cyano;

[0280] Even more preferably, R 1a Represents hydrogen, hydroxyl, or fluorine; and R 5a It represents hydrogen, hydroxyl, fluorine, or methoxy.

[0281] R 7a and R 7b

[0282] Advantageously, R 7a Let H be the number of 'R', and R be the number of 'R'. 7b It is hydrogen or optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group, especially those selected from hydroxyl and C, are... 1-4 alkoxy substituents of C 1-6 alkyl.

[0283] Preferably, R 7a Let H be the number of 'R', and R be the number of 'R'. 7bis hydrogen, or unsubstituted or substituted by one substituent selected from the group consisting of hydroxyl and C 1-4 alkoxy, one substituent of which is substituted by one substituent selected from the group consisting of hydroxyl and C 1-6 alkyl; preferably, R 7a and R 7b are each hydrogen.

[0284] R 8a and R 8b

[0285] advantageously, R 8a is H, and R 8b is of the formula -(CR c R d ) n a group of -Z, for example -(CHR d ) n -Z (for example -(CH2) n -Z), and especially -CHR d -Z or -Z, for example -CH2-Z or -Z,

[0286] or

[0287] R 8a and R 8b are linked such that, together with the nitrogen atom to which they are attached, they form a monocyclic or bicyclic heterocyclyl group, which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b , preferably selected from the group consisting of halogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 2-3 alkenyl, in particular the substituent(s) is / are selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl and C 2-3 alkenyl, and preferably from the group consisting of C 1-4 alkyl and C 2-3 alkenyl. Preferably, the monocyclic or bicyclic heterocyclyl group carries, in addition to R 8a and R 8band does not contain any heteroatoms other than nitrogen. Preferably, each ring of the monocyclic or bicyclic heterocyclyl group contains 4, 5, 6 or 7 ring atoms.

[0288] Preferably, R a and R b are independently H or C 1-4 alkyl.

[0289] Z can be C 3-8 cycloalkyl or bicyclic C 5-8 cycloalkyl, each of which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b substituted, for example, by one or more, particularly one or two, substituents selected from halo (e.g. fluorine), hydroxy, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 hydroxyalkyl, C 1-2 alkoxy and C 1-2 haloalkoxy.

[0290] In particular embodiments, Z is C 3-8 cycloalkyl or bicyclic C 5-8 cycloalkyl, each of which is optionally substituted by one or two substituents selected from C 1-2 alkyl, C 1-2 hydroxyalkyl, hydroxy and halo (e.g. fluorine).

[0291] X and Y

[0292] X is selected from , , , and ; preferably from , and ; even more preferably from , and .

[0293] Y is typically selected from one of the following structures:

[0294] i)

[0295] wherein:

[0296] G1is selected from CR h and N, wherein R h is selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0297] G2is CR g , wherein R g is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy,

[0298] G3is CR i , wherein R i is selected from the group consisting of hydrogen, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy,

[0299] G4is N;

[0300] G5is NH or CR j , wherein: R j is selected from the group consisting of hydrogen, C 1-4 alkyl, cyano, halogen, OH, NH2and C 1-4 alkoxy;

[0301] G7is CR j ,

[0302] G8is C,

[0303] ii)

[0304] Y2is CR k ; wherein R k is selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; preferably Y2is CH,

[0305] Y3is N or CR l , wherein R l is selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C1-4 haloalkyl, C 1-4 alkyl, cyano, halogen, OH, NH2and C

[0306] Y4is C or N;

[0307] Y5is CR m or N; x wherein:

[0308] R m is selected from hydrogen, C 1-4 alkyl, cyano, halogen, OH, NH2and C 1-4 alkyl, cyano, halogen, OH, NH2and C

[0309] R x is selected from hydrogen and C 1-4 alkyl;

[0310] Y5is CH or NH,

[0311] Y6is CR m or N; preferably Y6is CH,

[0312] Y7is CR m ; preferably Y7is CH,

[0313] Y8is C;

[0314] Y9is CR m or N; preferably Y2is CH or N,

[0315] with the proviso that not more than three of Y2to Y9are N;

[0316] iii)

[0317] X2is CR n ;

[0318] X4is N;

[0319] X5is selected from CR n and CR n R n1 wherein:

[0320] R n and R n1 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0321] any X6and X7are independently CR n ; or X6is CR n R n1and X7is CR n R n1 , CR o R o1 and NR x wherein:

[0322] R n and R n1 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

[0323] R x is hydrogen or C 1-4 alkyl; and

[0324] R o and R o1 are independently selected from the group consisting of hydrogen, halogen, methoxy and methyl;

[0325] X8is CR n or CR n R n1 wherein R n and R n1 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy; and

[0326] X9is C;

[0327] iv)

[0328] E1is N or CR1;

[0329] E2is N;

[0330] E3is N or CR3;

[0331] E4is CR4,

[0332] E5is N or CR5;

[0333] wherein R1, R2, R3, R4, R5, R 6a and R 6b are each independently selected from the group consisting of hydrogen, NR y1 R y2 , halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(C 1-4 Alkyl group 2, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 and C that is optionally replaced by OH 3-4 cycloalkyl, wherein R x1 and R x2 Independently selected from hydrogen and C 1-4 Alkyl (e.g., methyl), wherein R y1 and R y2 Independently selected from hydrogen and C 3-6 cycloalkyl and optionally C 3-6 Cycloalkyl-substituted C 1-4 Alkyl groups (e.g., methyl groups), or together with the N carrying them, form a 5-membered heteroaryl or heterocyclic group, which is optionally surrounded by OH, C 1-4 Alkoxy or C 1-4 Alkyl substitution, the C 1-4 Alkyl groups are optionally surrounded by OH or C 1-4 The heterocyclic group is alkoxy-substituted, and is a 4- to 7-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein each ring of the bicyclic heterocyclic group has 3 to 6 members.

[0334] Alternatively, R4 and R3 can be linked together to form a 5- or 6-membered heterocyclic group with the atoms to which they are attached, wherein the 5- or 6-membered heterocyclic group is optionally surrounded by one or more atoms selected from oxo, cyano, hydroxyl, halogen, C 1-2 Alkyl, C 3-6 cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, NR y1 R y2 Or –S(O) 0-2 R y1 R y2 Substituents of R, wherein R y1 and R y2 For H or C 1-2 alkyl.

[0335] Specifically, Y can be selected from the following structures:

[0336] , , , , or

[0337] Where R 1 R 2 and R 3As described above or below,

[0338] E7 is O or CH2,

[0339] R 3' independently represent H, or two R 3' together represent an oxo group (=0) or a C 3-5 cycloalkyl group, and

[0340] R 4' independently represent H, or two R 4' together represent an oxo group (=0) or a C 3-5 cycloalkyl group.

[0341] In some embodiments, Y is selected from the following structures:

[0342] wherein

[0343] E1 is CR1;

[0344] E2 is N;

[0345] E3 is CR3;

[0346] E4 is CR4,

[0347] E5 is CR5;

[0348] wherein R1, R2, R3, R4, R5, R 6a and R 6b are each independently selected from hydrogen, NH2, halogen, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 (wherein R x1 and R x2 are independently selected from hydrogen and methyl), and NR y1 R y2 wherein R y1 and R y2 form, together with the N carrying them, a 5- or 6-membered heterocyclyl group.

[0349] Y can be selected from one of the following structures:

[0350] i) , preferably , , or ,

[0351] in particular, wherein

[0352] R h is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy, and is preferably H,

[0353] R g is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy, and is preferably H or C 1-4 alkoxy,

[0354] R i is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy, and is preferably H,

[0355] R j are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkyl and C 1-4 alkoxy, and is preferably H, and

[0356] R x is selected from the group consisting of hydrogen and C 1-4 alkyl, and is preferably H;

[0357] i) for example , , , preferably or ,

[0358] in particular, wherein

[0359] R k are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy, and is preferably H,

[0360] R m are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkyl and C 1-4 alkoxy, and is preferably H,

[0361] R x each independently selected from the group consisting of hydrogen and C 1-4 alkyl, and preferably H;

[0362] ii) , preferably

[0363] in particular wherein R n each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy, preferably H; and

[0364] iii)

[0365] wherein R1, R3, R4, R5 are advantageously each independently selected from the group consisting of hydrogen, NH2, NH-methyl (wherein methyl is optionally substituted by C 3-6 cycloalkyl), NH-C 3-6 cycloalkyl, halogen, cyano, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl, C 1-4 haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)Me 2、 -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 and C 3-4 cycloalkyl optionally substituted by OH (wherein R x1 and R x2 are independently selected from the group consisting of hydrogen and methyl), and NR y1 R y2 wherein R y1 and R y2 form together with the N carrying them a 5-membered heteroaryl or a 5- to 9-membered heterocyclyl, said 5-membered heteroaryl or 5- to 9-membered heterocyclyl being optionally substituted by OH, -CH2OCH3, or CH2OH,

[0366] or

[0367] or R4 and R3 are linked together such that they form together with the atoms to which they are attached a heterocyclyl,

[0368] wherein the heterocyclyl is optionally spiro-fused with C 3-6 cycloalkyl and / or is substituted by one or more selected from the group consisting of oxo, cyano, hydroxyl, halogen, C 1-2 alkyl, C 3-6 cycloalkyl, C1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, NR y1 R y2 or -S(O) 0- 2R y1 R y2 substituted with R y1 and R y2 are H or C 1-2 alkyl;

[0369] In particular, R1, R3, R4and R5are each independently selected from the group consisting of hydrogen, NR y1 R y2 , halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl and C 1-4 haloalkyl.

[0370] Y can also be selected from one of the following structures:

[0371] i) , or ,

[0372] In particular, wherein

[0373] R h , R g , R i and R j are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-4 alkoxy, and preferably H, and

[0374] R x is selected from the group consisting of hydrogen and C 1-4 alkyl, and preferably H;

[0375] ii) or ,

[0376] In particular, wherein

[0377] R k are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkoxy, and preferably H,

[0378] R m are each independently selected from the group consisting of hydrogen, halogen, hydroxyl and C 1-4 alkoxy, and preferably H,

[0379] R x is selected from the group consisting of hydrogen and C 1-4 alkyl, and preferably H;

[0380] iii)

[0381] In particular, wherein R4is selected from hydrogen, NR n each independently selected from hydrogen, halogen, C 1-4 C 1-4 alkyl, preferably H; and

[0382] iv)

[0383] In particular, wherein R4is selected from hydrogen, NR y1 R y2 , halogen, C 1-4 alkoxy, C 1-4 alkyl, and preferably NR y1 R y2 or C 1-4 alkoxy.

[0384] Preferably, Y is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0385] Advantageously, Y is selected from , , , , , , , , and .

[0386] In the specific implementation plan, XY is:

[0387] XY can also be , ¸ , , , , , , , .

[0388] In some embodiments, the compound of formula (I) is preferably... or R4a is usually methyl, methoxy or -CH2OH.

[0389] The compounds of formula (I) are specifically selected from compounds 1 to 145 as defined herein or in the claims, such as compounds 1 to 42, or tautomers, stereoisomers, salts, solvates or N-oxides thereof.

[0390] tautomers, stereoisomers, salts, solvates and N-oxides

[0391] The compounds of formula (I) described herein can exist in tautomer or stereoisomeric forms (i.e., diastereomeric or enantiomeric forms). This invention covers all such compounds, including cis and trans diastereomerics, E- and Z-stereomerics, R- and S-enantiomers, diastereomerics, d-isomers, l-isomers, racemic mixtures thereof, and other mixtures.

[0392] The term " tautomers "Tautomers" refers to structural isomers of compounds that readily tautomerize. For example, compounds containing an amide group (-C(=O)-NH-) and an imine group (-C(OH)=N-), respectively, are tautomers, such as the following structures:

[0393]

[0394] The term " stereoisomers "Refers to configurational stereoisomers, including geometric isomers and optical isomers." geometric isomers Also known as E / Z isomers or cis-trans isomers, they arise from the different positions of substituents on the C=C double bond, which can have either a Z or E configuration (also known as a cis or trans configuration). optical isomers This arises from the different spatial positions of the substituents or lone pairs on an atom (such as a carbon or sulfur atom) containing four different substituents (including possible lone pairs of electrons). Therefore, the atom represents a chiral or asymmetric center. Thus, optical isomers that are not mirror images of each other are designated as "diastereomers," and optical isomers that are mirror images that cannot be superimposed are designated as "enantiomers."

[0395] The compounds of the present invention may be in the form of a free base or a pharmaceutically acceptable acid addition salt thereof.

[0396] As used in this article, " pharmaceutically acceptable salt or solvate "" refers to a salt or solvation of a pharmaceutically acceptable compound as defined above, and which has the pharmacological activity of the corresponding compound.

[0397] The properties of salts can vary, provided they are pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds used in this method can be prepared from inorganic or organic acids. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic (heterocyclic and heteroaryl), carboxylic acids, and sulfonic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (dihydroxynaphthyl acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, hydroxybutyric acid, salicylic acid, galactobionic acid, and galacturonic acid. All these salts can be prepared by conventional methods from the corresponding compounds by, for example, reacting a suitable acid with any of the compounds of the present invention.

[0398] Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates, such as solvates formed during the final step of the preparation of the compounds of the present invention due to the presence of a solvent. As examples, solvates formed due to the presence of water (these solvates are also referred to as hydrates) or solvates formed due to the presence of ethanol may be mentioned.

[0399] The compounds of the application can also be in the form of N-oxides, i.e. the nitrogen atom of the compounds can be in oxidized form.

[0400] 2 - process for the preparation of a compound of formula (I)

[0401] The compounds of the application can be obtained by a process for the preparation of a compound of formula (I) as defined herein, which process comprises the successive steps of:

[0402] - subjecting an intermediate of formula (IIa) to a halogen-lithium exchange, typically using butyllithium in a polar aprotic solvent such as tetrahydrofuran:

[0403] (IIa)

[0404] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , X and Y are as defined herein, and are optionally in protected form,

[0405] then adding a ketone of formula R 7a R 7b -C=O, wherein R 7a and R 7b are as defined in any one of claims 1 to 10, and are optionally in protected form

[0406] to give an alcohol of formula (IIb):

[0407] (IIb)

[0408] - subjecting the above alcohol of formula (IIb) to a nucleophilic substitution with an azide ion precursor such as azidotrimethylsilane, in the presence of a Lewis acid such as boron trifluoride, and in particular boron trifluoride etherate,

[0409] to give an azide of formula (IIc):

[0410] (IIc)

[0411] - reducing the azide of formula (IIc) under Staudinger conditions, and in particular in the presence of water and a triarylphosphine such as triphenylphosphine, to obtain an amine of formula (IId)

[0412] (IId)

[0413] - functionalizing an amine of formula (lid) to obtain a compound of formula (I) as defined herein.

[0414] The final functionalization can for example involve:

[0415] • at least an alkylation step with a compound of formula R8a-Hal or R8b-Hal, wherein Hal represents a halogen, and preferably CI, Br or I, and R8a and R8b are as defined herein,

[0416] and / or at least one reductive amination step.

[0417] In particular embodiments, the compounds of the application can be obtained by a process for preparing a compound of formula (I) as defined herein, comprising the following successive steps:

[0418] - functionalizing an amine of formula (lid) to obtain a compound of formula (I) as defined herein. 8a R 8b -N-H, wherein R 8a and R 8b as defined in any one of claims 1 to 10 and optionally in protected form:

[0419] (II)

[0420] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , X and Y are as defined herein, and optionally in protected form;

[0421] and optionally deprotecting a group in protected form to obtain a compound of formula (I); and

[0422] - optionally salifying a compound of formula (I) to obtain a salt of a compound of formula (I).

[0423] Alternatively, the compounds of the application can be obtained by a process for preparing a compound of formula (I) as defined herein, comprising coupling an intermediate of formula (III) or (IV) with a reagent of formula Y-K", wherein Y is as defined in any one of claims 1 to 10 and optionally in protected form:

[0424] (III) (IV)

[0425] wherein A 1 , A 2 , A 3A 4 A 5 A 6 R 7a R 7b R 8a R 8b Rc, Rd, Re, and Rf are as defined in any one of claims 1 to 10, and optionally in the protected form.

[0426] Where K and K' are defined as follows:

[0427]

[0428] Those skilled in the art are familiar with the protecting groups and forms of protection mentioned above, as well as methods for protection and deprotection 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.

[0429] In which R 7b H is and X is In the implementation of the method, the method may include:

[0430] a) Reduce the nitrile in formula (II):

[0431] (II)

[0432] Where A 1 A 2 A 3 A 4 A 5 A 6 , R, R' and R 7a As defined in this article, and

[0433] R and R' are independently of C 1-2 Alkoxy substitution or not C 1-2 alkoxy-substituted C 1-4 Alkyl groups, or R and R' together, optionally formed by one to four Cs. 1-2 Alkoxy or C 1-2 Alkyl-substituted bridged C 1-2 Alkylene

[0434] To obtain the amine of formula (III):

[0435] (III)

[0436] Where A 1 A2 , A 3 , A 4 , A 5 , A 6 , R, R’ and R 7a as defined above with respect to formula (II), and PG is an N-protecting group,

[0437] b) deprotection of the acetal or ketal group (C(OR)(OR’)) of the amine of formula (III) using a Lewis acid or a Bronsted acid under acidic conditions to give the corresponding aldehyde or ketone of formula (IV):

[0438] (IV)

[0439] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a and PG are as defined above with respect to formula (III),

[0440] c) reductive amination of the aldehyde or ketone of formula (IV) with an amine of formula (V): 8a R 8b -N-H (V), wherein R 8a and R 8b are as defined herein,

[0441] (VI)

[0442] to give an intermediate of formula (VI), wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a and PG are as defined above with respect to formula (IV), and R 8a and R 8b are as defined above with respect to formula (V),

[0443] d) deprotection of the intermediate of formula (VI) to give an amine of formula (VII),

[0444] (VII)

[0445] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R7a , R 8a and R 8b as defined in relation to formula (VI),

[0446] e) performing a peptide coupling of the amine of formula (VII) with a carboxylic acid of formula (IX): Y-COOH, wherein Y is as defined herein,

[0447] or

[0448] a’) reducing the nitrile group of a compound of formula (II) as defined above to give an amine of formula (III’)

[0449] (III’)

[0450] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R’ and R 7a as defined above in relation to formula (II),

[0451] b’) performing a peptide coupling of the amine of formula (III’) with an aldehyde of formula (X): Y-COOH, wherein Y is as defined herein, to obtain an intermediate of formula (XI):

[0452] (XI)

[0453] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R’ and R 7a as defined above in relation to formula (III’), and Y is as defined in relation to formula (X),

[0454] 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 give the corresponding aldehyde or ketone of formula (XII):

[0455] (XII)

[0456] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a and Y are as defined above in relation to formula (XI),

[0457] d') subjecting the aldehyde or ketone of formula (XII) to a reductive amination with an amine of formula (V): R 8a R 8b -N-H (V), as defined above.

[0458] The peptide coupling is advantageously performed in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or propylphosphonic anhydride; optionally in combination with an additive or a base such as N-hydroxy-succinimide (NHS), N-hydroxy-benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HAt), N-hydroxysulfosuccinimide (sulfo-NHS), dimethylaminopyridine (DMAP), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM).

[0459] In embodiments wherein R 7b is H and X is The method can comprise, in embodiments wherein R

[0460] a") deprotecting the acetal or ketal group of the nitrile of formula (II) as defined above to give the corresponding aldehyde or ketone of formula (XIII):

[0461] (XIII)

[0462] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a are as defined above in relation to formula (II),

[0463] b") subjecting the aldehyde or ketone of formula (XIII) to a reductive amination with an amine of formula (V): R 8a R 8b -N-H (V), wherein R 8a and R 8bas defined herein to obtain an intermediate of formula (XIV):

[0464] (XIV)

[0465] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a are as defined above in relation to formula (II), and R 8a and R 8b are as defined herein,

[0466] c”) reducing the intermediate of formula (XIV) to obtain an intermediate of formula (XV) (alcohol):

[0467] (XV)

[0468] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 8a and R 8b are as defined above in relation to formula (XIV),

[0469] 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):

[0470] (XVI)

[0471] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 8a and R 8b are as defined above in relation to formula (XIV),

[0472] e”) subjecting the azide of formula (XVI) to a [3+2] cycloaddition reaction with an alkyne of formula (XVII) H-≡-Y (XVII), wherein Y is as defined herein,

[0473] or

[0474] a") reducing an intermediate of formula (II) as defined above to give an intermediate of formula (XVIII) (alcohol):

[0475] (XVIII)

[0476] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', R 7a as defined above in relation to formula (II), and

[0477] b") subjecting the intermediate of formula (XVIII) to an activation step followed by a nucleophilic substitution using sodium azide to give the corresponding azide of formula (XIX):

[0478] (XIX)

[0479] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R, R', R 7a as defined above in relation to formula (II),

[0480] c") subjecting the azide of formula (XIX) to a [3+2] cycloaddition with an alkyne of formula (XVII) as defined above to give an intermediate of formula (XX)

[0481] (XX)

[0482] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R and R' are as defined above in relation to formula (II), and Y is as defined herein,

[0483] d") deprotecting the acetal or ketal group of the intermediate of formula (XX) to give the corresponding intermediate of formula (XXI),

[0484] (XXI)

[0485] wherein A 1 , A 2 , A 3 , A 4, A 5 , A 6 , R, R', R 7a and Y are as defined above for formula (XX),

[0486] e'") reductive amination of the intermediate of formula (XXI) with an amine of formula (V) as defined above.

[0487] In embodiments wherein X is , the method can comprise,

[0488] a'") palladium coupling (e.g. Molander reaction) of the compound of formula (XXII) with a [(1,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)methyl]boron trifluoride derivative (e.g. potassium [(1,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)methyl]trifluoroborate),

[0489] (XXII)

[0490] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a and PG are as defined herein, and Hal represents a halogen atom, preferably CI or Br,

[0491] followed by a deprotection reaction, typically comprising the addition of ethylenediamine and an alcohol (e.g. propanol), to obtain a compound of formula (XXIII):

[0492] (XXIII)

[0493] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a and PG are as defined herein,

[0494] b'") peptide coupling of the compound of formula (XXIII) with a carboxylic acid of formula (IX): Y-COOH, wherein Y is as defined herein

[0495] to obtain a compound of formula (I) as described herein.

[0496] Typically, the palladium catalyst used in the palladium coupling of step a’’’’’) is Pd(dba)2.

[0497] In embodiments wherein R 8b is H, the method can comprise:

[0498] a’’’’’) reacting the compound of formula (XXIV) with 2-nitrobenzenesulfonyl chloride (o-nitrobenzenesulfonyl chloride),

[0499] (XXIV)

[0500] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , X and Y are as defined herein,

[0501] to give an o-nitrobenzenesulfonyl protected intermediate of formula (XXV):

[0502] (XXV)

[0503] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , X and Y are as defined herein, and Ns represents an o-nitrobenzenesulfonyl group,

[0504] b’’’’) subjecting the o-nitrobenzenesulfonyl protected intermediate of formula (XXV) to a Fukuyama-Mitsunobu reaction with an aldehyde of formula R 8a =O, wherein R 8a is as defined herein, to give an intermediate of formula (XXVI)

[0505] (XXVI)

[0506] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a , X and Y are as defined herein, and Ns represents an o-nitrobenzenesulfonyl group,

[0507] c’’’’’) deprotection of the o-nitrobenzenesulfonyl group in the presence of benzenethiol to give a compound of formula (XXVII)

[0508] (XXVII)

[0509] wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 7a , R 7b , R 8a , X and Y are as defined herein.

[0510] The reaction conditions of the o-nitrobenzenesulfonyl deprotection step c’’’’’) are known in the art.

[0511] 3 - pharmaceutical composition

[0512] The present application further relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and a pharmaceutically acceptable carrier.

[0513] The pharmaceutically acceptable carrier is selected from typical excipients known by the person skilled in the art according to the desired dosage form and mode of administration.

[0514] The pharmaceutical composition of the present application can be intended for 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 presented in unit form for administration, in admixture with conventional pharmaceutical carriers, to animals, preferably mammals including humans.

[0515] For oral administration, the pharmaceutical composition can be in solid or liquid (solution or suspension) form.

[0516] Solid compositions can be in the form of tablets, capsules, powders, granules, etc. In tablets, the active ingredient can be mixed with pharmaceutical vehicles (e.g. gelatine, starch, lactose, magnesium stearate, talc, gum arabic, etc.) before being compressed. The tablets can be further coated, in particular with sucrose or other suitable materials, or they can 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 flavouring or sweetening agents. In capsules, the active ingredient can be introduced in the form of, for example, the powders or granules mentioned above, in soft or hard capsules, or in the form of, for example, the liquid compositions mentioned below.

[0517] Liquid compositions (including gels) can contain the active ingredient in a solvent, for example water, as well as a sweetening agent, a taste enhancer or a suitable colourant. Liquid compositions can also be obtained by suspending or dissolving the powders or granules as mentioned above in a liquid (for example water, fruit juice, milk, etc.). For example, it can be a syrup or an elixir.

[0518] For sublingual (under the tongue) or buccal (between the gum and cheek) administration, the pharmaceutical composition can be in solid or liquid (solution or suspension) form.

[0519] The solid composition can in particular be in the form of tablets, gelatin capsules, powders or granules for oral administration as defined above. It can also be in the form of a film.

[0520] The liquid composition can be for oral administration as defined previously. It can be administered in the form of a spray or drops.

[0521] For rectal or vaginal administration, suppositories or ovules can be prepared with a binding agent (for example cocoa butter or polyethylene glycol) which melts at body temperature and is therefore liquid at the rectal or vaginal temperature.

[0522] For parenteral administration, the composition can be in the form of an aqueous suspension or solution, which can contain dispersing agents, wetting agents or suspending agents. The composition is advantageously sterile. It can be in the form of an isotonic solution.

[0523] The amount of the compound of the application that can be combined with the carrier materials to produce a single dose will vary depending upon the subject and the particular mode of administration, as is known in the art.

[0524] The pharmaceutical composition can further comprise another therapeutic compound, preferably another anticancer agent (or chemotherapeutic agent).

[0525] The compound according to the application or a pharmaceutical composition thereof can also have a therapeutic application in combination with an immunomodulator, for example an inhibitor of the PDI / PDLI immune checkpoint axis, for example an antibody (or peptide) that binds and / or inhibits the activity of PD-1 (such as Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab) or the activity of PD-L1 (such as Atezolizumab, Avelumab, Durvalumab). The compound according to the application or a pharmaceutical composition thereof can also be combined with radiotherapy or a chemotherapeutic agent as a standard of care. The compound can also be combined with a BCL2 inhibitor (such as Venetoclax).

[0526] The compound according to the application or a pharmaceutical composition thereof can also be combined with other agents (for example vaccines) that stimulate or enhance the immune response.

[0527] 4 - therapeutic use

[0528] The present application further relates to a compound or a pharmaceutical composition according to the application for use as a medicament, in particular a medicament having METTL3 inhibitory activity.

[0529] The medicament is particularly suitable for use in the treatment or prevention of cancer, or of an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease, typically cancer.

[0530] The compound or the pharmaceutical composition according to the application can be used as a medicament in a combination therapy with radiotherapy or an immunostimulant (e.g. a vaccine).

[0531] The present application further relates to a kit comprising:

[0532] - a composition according to the application;

[0533] - a second composition comprising at least another therapeutic compound, and

[0534] - preferably instructions for use of said kit,

[0535] said kit being particularly suitable for use as a combination product for simultaneous, separate and staggered use as a medicament, in particular a medicament having METTL3 inhibitory activity, in the treatment or prevention of cancer or of an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease, typically cancer.

[0536] The present application further relates to a method of preventing or treating a pathology associated with METTL3 oncogenic activity, comprising administering to a patient in need thereof an effective dose of a compound or a composition or a kit according to the application.

[0537] In particular, said pathology is cancer, or an autoimmune disease, a neurological disease, an infectious disease or an inflammatory disease, typically cancer.

[0538] The method can further comprise a combination with radiotherapy or an immunostimulant (e.g. a vaccine).

[0539] The “effective dose” of a compound according to the application varies as a function of various parameters, such as the route of administration and the body weight, age, sex, the progression and the sensitivity of the pathology to be treated of the subject or patient to be treated.

[0540] As used herein, “patient” or “subject” includes any mammal, and preferably is a human.

[0541] Exemplary autoimmune diseases are rheumatoid arthritis and Graves’ disease.

[0542] Examples of infectious diseases are viral infections (e.g. SARS-CoV-2, HIV, hepatitis virus), bacterial infections (e.g. Clostridium perfringens), bacterial infections (such as Clostridium perfringens), fungal infections (e.g. Fusarium infection) and parasitic infections (e.g. Toxoplasma).

[0543] Examples of neurological diseases are fragile X syndrome and Alzheimer’s disease.

[0544] Examples of inflammatory diseases are inflammatory bowel disease, Crohn’s disease and ulcerative colitis.

[0545] In some embodiments, the inhibition of METTL3 by the provided compounds can be used for the treatment or prevention, in particular the treatment, of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumor, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma and ovarian serous cystadenoma. More specifically, the cancer is lung cancer, melanoma, head and neck cancer, esophageal cancer, bladder cancer and urothelial cancer, liver cancer, kidney cancer, prostate cancer and hematopoietic cancer.

[0546] Examples of cancers that can be treated or prevented, particularly treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, 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, breast cancer, 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., adenocarcinoma of the cervix), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (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 adenocarcinoma), Ewing’s sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., squamous cell carcinoma of the head and neck), mouth cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., pharynx cancer, larynx cancer, nasopharynx cancer, oropharynx cancer), hematopoietic cancers (e.g., leukemias, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (B-cell CLL, T-cell CLL); lymphomas, e.g., Hodgkin’s lymphoma (HL) (B-cell HL, T-cell HL) and non-Hodgkin’s lymphoma (NHL) (B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt’s lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrom’s macroglobulinemia”), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL) (e.g., cutaneous T cell lymphoma (CTCL) (e.g., mycosis fungoides, 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 leukemiawlymphoma as described above;and multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocyte amyloidosis, kidney cancer (e.g., nephroblastoma aka Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (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, pulmonary neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM) aka myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillaty adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), 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 (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva). EMBODIMENT

[0547] All examples given below are for illustrative purposes only and should not be interpreted in any way as limiting the scope of the present application.

[0548] materials and methods

[0549] The following examples illustrate several methods for preparing the compounds of the present invention. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification, or could be synthesized by those skilled in the art using well-known methods.

[0550] abbreviations

[0551] In the following text, "℃" represents degrees Celsius; "Å" represents angstroms; "aq." represents aqueous solution; "BiCl3" represents bismuth trichloride; "Boc" represents tert-butyloxycarbonyl; "Boc2O" represents ditert-butyl dicarbonate; "Celite" represents bismuth trichloride. ® " represents diatomaceous earth; "compound" represents compound; "CO" represents carbon monoxide; "CoCl2•6H2O" represents cobalt chloride hexahydrate; "Cs2CO3" represents cesium carbonate; "CuSO4" represents copper(II) sulfate; "DBU" represents 1,8-diazabicyclo[5.4.0]undec-7-ene; "DCM" represents dichloromethane; "DIAD" represents diisopropyl azodicarbonate; "DIBAL-H" represents diisobutylaluminum hydride; "DIPE" represents diatomaceous earth; "Cs2CO3" represents cesium carbonate; "Cs2CO3" represents copper(II) sulfate; "Cs2CO3" represents copper(II) sulfate; "DBU" represents 1,8-diazabicyclo[5.4.0]undec-7-ene; "DCM" represents dichloromethane; "DIAD" represents diisopropyl azodicarbonate; "DIBAL-H" represents diisobutylaluminum hydride; "DIPE" represents diisobutylaluminum hydride; "DIPE" represents diisobutylaluminum hydride; "DIPE" represents diisobutylaluminum hydride; "DIPE" represents diisobutylaluminum hydride; "Cs2CO3" represents cobalt chloride hexahydrate; "Cs2CO3" represents cobalt chloride hexahydrate; "Cs2CO3" represents cobalt chloride hexahydrate; "Cs2CO3" represents cobalt(II) sulfate; "Cs2CO3" represents cobalt(II) sulfate; "Cs2CO3" represents diisobutylaluminum hydride ... "A" represents N,N-diisopropylethylamine; "DMA" represents dimethylacetamide; "DMF" represents N,N-dimethylformamide; "DMSO" represents dimethyl sulfoxide; "DPPA" represents diphenylphosphine azide; "DPPF" represents 1,1′-ferrocene di-bis(diphenylphosphine); "EtOAc" represents ethyl acetate; "EtOH" represents ethanol; "h" represents hours; "HATU" represents 1-[bis(dimethylamino)methylene]-1H-1, 2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; "HCl" indicates hydrogen chloride; "HCO2NH4" indicates ammonium formate; "H2O" indicates water; "HPLC" indicates high performance liquid chromatography; "Int." indicates intermediate; "KOAc" indicates potassium acetate; "K2CO3" indicates potassium carbonate; "LC" indicates liquid chromatography; "LCMS" indicates liquid chromatography / mass spectrometry; "M" indicates mol / L; "MeCN" indicates acetonitrile; "MeOH" indicates methanol; "MgSO4" indicates magnesium sulfate; "min" indicates minutes; "mp" indicates melting point; "N2" indicates nitrogen; "Na2CO3" indicates sodium carbonate; "NaBH4" indicates sodium borohydride; "NaHB(OAc)3" indicates sodium triacetoxyborohydride; "NH4Cl" indicates ammonium chloride; "NaHCO3" indicates sodium bicarbonate; "NaOH" indicates sodium hydroxide; "NH4HCO3" indicates ammonium bicarbonate; "Ni" indicates nickel; n"BuLi" represents n-butyllithium; "NH3" represents ammonia; "NaOMe" represents sodium methoxide; "Pd(dppf)Cl2" represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; "Pd(dppf)Cl2•DCM" represents a complex of [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride and dichloromethane; "Pd(OAc)2" represents palladium(II) acetate; "PPh3" represents triphenylphosphine; "prep." indicates preparative; "quant." indicates quantitative; "rbf" indicates round-bottom flask; "rt" indicates room temperature; "s" indicates seconds; "SEM-Cl" represents 2-(trimethylsilyl)ethoxymethyl chloride; "TsOH" represents p-toluenesulfonic acid; t "AmOH" indicates tert-amyl alcohol; t "BuXPhosPd G3" indicates that it represents methanesulfonic acid [(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II); t "BuXPhos" represents 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl; "TEA" represents triethylamine; "TFA" represents trifluoroacetic acid; "TLC" represents thin-layer chromatography; "THF" represents tetrahydrofuran; "TMEDA" represents N,N,N′,N′-tetramethylethylenediamine; "TMS" represents trimethylsilyl; "XphosPd G3" represents methanesulfonic acid (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), and "Zn(CN)2" represents zinc cyanide.

[0552] preparation of intermediates

[0553] synthesis of intermediate 1 :

[0554] 6-Bromo-2-chloro-3-quinoline carbaldehyde (4 g, 14.8 mmol), triethyl orthoformate (4.38 g, 29.6 mmol, 4.92 mL), and TsOH monohydrate (56 mg, 0.3 mmol) were suspended in anhydrous EtOH (15 mL) at room temperature. The resulting reaction mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, and volatiles were removed under vacuum to give the crude product. The crude product was purified by silica gel chromatography with elution of heptane:EtOAc = 100:0–90:10 to give the intermediate. 1 (3.5g, yield 69%), it is a white solid.

[0555] synthesis of intermediate 2:

[0556] TMAF-4H2O (1.7 g, 10.3 mmol) was dissolved in t AmOH (50 mL). To this solution was added activated 3 A molecular sieves (7.5 g) and the slurry was stirred at room temperature for 24 h. The slurry was filtered and washed with t AmOH (3 x 4 mL). The filtrate and alcohol washes were combined and concentrated under reduced pressure to give intermediate 2 (2.8 g, 145% yield) as a viscous white solid. The material was used directly in the next step without further purification due to the presence of residual t AmOH, quant.

[0557] synthesis of intermediate 3:

[0558] Intermediate 1 (3.5 g, 10.3 mmol) and intermediate 2 (2.8 g, 15.4 mmol) were added under ambient atmospheric conditions. Anhydrous DMSO (51 mL) was added and the resulting reaction mixture was stirred at 80 °C for 24 h. The reaction mixture was cooled to room temperature 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 MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluting with heptane: [DCM / EtOAc 3 / 1] = 100:0-85:15 to give intermediate 3 (2.9 g, 87% yield) as a colourless oil.

[0559] synthesis of intermediate 4:

[0560] preparation of degassed aqueous solution: A round bottom flask was charged with water (22 mL) and fitted with a septum. The flask was placed in an ultrasonic bath filled with water, a vacuum was applied for 5 s and the vessel was backfilled with nitrogen. This cycle was repeated 5 times and the resulting degassed water was added to the rdb containing KOAc (110 mg, 1.12 mmol) via syringe under N2.

[0561] t BuXPhosPd G3 (142 mg, 0.18 mmol), t BuXPhos (76 mg, 0.18 mmol), potassium hexacyanoferrate(II) trihydrate (1.89 g, 4.47 mmol) and intermediate 3 ​(2.9 g, 8.93 mmol) was added to a Schlenk tube equipped with a magnetic stir bar. The vial was evacuated and backfilled three times with nitrogen. A solution of the above KOAc (110 mg, 1.12 mmol) in water (22 mL) and dioxane (22 mL) was added to the vial, and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature 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, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (eluting with heptane:EtOAc = 100:0-90:10) to give the intermediate. 4 (2g, 82% yield), it is a white solid.

[0562] synthesis of intermediate 5:

[0563] To the intermediate 4 A solution of Boc2O (500 mg, 1.82 mmol) and Boc2O (1.19 g, 5.47 mmol) in EtOAc (17 mL) and EtOH (17 mL) was added to a slurry of ragnetin in H2O (500 mg). The reaction mixture was stirred at room temperature for 12 h at 4 bar under H2 atmosphere. Boc2O (398 mg, 1.82 mmol) was added, followed by a slurry of ragnetin in H2O (500 mg), and the reaction mixture was stirred at room temperature for 24 h at 4 bar under H2 atmosphere. The reaction mixture was filtered through a celite® pad and washed with EtOAc. The filtrate was concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography (eluting with heptane:EtOAc = 100:0-75:25) to give the intermediate. 5 (497 mg, 72% yield), it is a colorless oil.

[0564] synthesis of intermediate 6:

[0565] intermediate 5 BiCl3 (83 mg, 0.26 mmol) was added to a solution of 500 mg (1.32 mmol) in MeCN (5.5 mL) and water (0.13 mL), and the mixture was stirred at 55 °C for 1 h. After the reaction was complete, the volatiles were removed under vacuum to obtain the intermediate. 6 (405 mg, quantitative yield), which is a pale yellow solid that can be used in the next step without further purification.

[0566] synthesis of intermediate 7:

[0567] A mixture of intermediate 6 (837 mg, 2.75 mmol), 4,4-dimethylpiperidine hydrochloride (494 mg, 3.3 mmol) and TEA (835 mg, 8.25 mmol, 1.15 mL) in DCM (28 mL) was stirred at rt for 10 min (until complete dissolution) before NaBH(OAc)3(1.17 g, 5.50 mmol) was added immediately. The reaction mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure. The residue was partitioned between saturated aqueous NaHC03solution and EtOAc. The organic layer was washed once more with saturated aqueous NaHC03solution. The organic layer was dried over MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluting with heptane:EtOAc = 100:0-50:50 to give intermediate 7 (537 mg, 49% yield) as a white solid.

[0568] synthesis of intermediate 8 (HCI salt):

[0569] To a solution of intermediate 7 (180 mg, 0.45 mmol) in 1,4-dioxane (1 mL) was added HC1 (4 M in dioxane) (177 mg, 4.48 mmol, 1.12 mL) (solution precipitate) and the resulting suspension was stirred at rt for 4 h. The volatiles were removed under reduced pressure to give intermediate 8 (154 mg, 92% yield) as a yellow solid which was used in the next step without further purification.

[0570] synthesis of intermediate 9:

[0571] a) synthesis of intermediate 10:

[0572] To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (500 mg, 2.52 mmol) in DMF (5 mL) was added Cs2C03(4.53 g, 13.9 mmol) and SEM-Cl (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 eluting with heptane:EtOAc = 100:0-80:20 to give intermediate10 (281 mg, 34% yield) as a colorless oil.

[0573] b) synthesis of intermediate 11:

[0574] Intermediate 10 (267 mg, 0.81 mmol), Pd(PPh3)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 under CO atmosphere (10 bar) overnight. The mixture was cooled to room temperature and the precipitated solid was removed by filtration. The filtrate was concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluting with heptane:EtOAc = 100:0-60:40 to give intermediate 11 (232 mg, 93% yield) as a yellow solid.

[0575] c) synthesis of intermediate 9:

[0576] Intermediate 11 (232 mg, 0.75 mmol) in MeOH (5.4 mL) was treated with 1 M aqueous NaOH solution (1.36 mL, 1.36 mmol). The resulting solution was stirred at room temperature for 2 h. The pH was adjusted to 3 with 1 M aqueous HC1 solution. The solid was collected by filtration to give intermediate 9 (218 mg, quantitative yield) as a yellow solid.

[0577] synthesis of intermediate 13:

[0578] To a solution of intermediate 4 (0.91 g, 3.33 mmol) in EtOAc (33 mL) and EtOH (33 mL) was added a slurry of Raney-Ni in H2O (1 g). The reaction mixture was stirred at room temperature under hydrogen atmosphere at 4 bar for 24 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under vacuum to give intermediate 13 (837 mg, 90% yield) as a colorless oil which was used in the next step without further purification.

[0579] Alternatively, intermediate 13 was prepared as described below to reduce the amount of dimer side compounds.

[0580] A solution of intermediate 4 (710 mg, 2.59 mmol) in EtOH (11.8 mL) was stirred at 0 °C. CoCl2.6H2O (924 mg, 3.88 mmol) was added at 0 °C, followed by NaBH4(490 mg, 12.9 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, then poured into a saturated aqueous Na2C03solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to give intermediate 13 (703 mg, quantitative yield) as a yellow oil which was used in the next step without further purification.

[0581] synthesis of intermediate 14:

[0582] To a solution of intermediate 13 (735 mg, 2.64 mmol), 4-oxo-4H-pyrido[l,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 room temperature for 20 h. Water was added and the residue was extracted with EtOAc three times. The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography eluting with heptane: (EtOAc / MeOH 3 / 1) = 100:0-60:40 to give intermediate 14 (725 mg, 30% yield) as a light yellow solid.

[0583] synthesis of intermediate 15:

[0584] A solution of intermediate 14 (360 mg, 0.8 mmol) in acetonitrile (4 mL) and water (0.08 mL) was treated with BiCl3(50.4 mg, 0.16 mmol) and stirred at 55 °C for 1 h (until starting material was consumed). Upon completion of the reaction (monitored by TLC), the volatiles were removed under vacuum to give intermediate 15 (310 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification.

[0585] synthesis of intermediate 16:

[0586] At room temperature, 6-bromo-2-chloro-7-methoxyquinoline-3-carbaldehyde (7.6 g, 25.2 mmol), triethyl 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. The volatiles were removed under vacuum to give crude material. The crude product was purified by silica gel chromatography eluting with heptane:EtOAc = 100:0-85:15 to give intermediate 21 (7.8 g, 86% yield) as a white solid.

[0587] synthesis of intermediate 17:

[0588] 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.

[0589] synthesis of intermediate 18:

[0590] 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.

[0591] synthesis of intermediate 19:

[0592] To a solution of intermediate 18 (781 mg, 2.57 mmol) in EtOH (11.7 mL) was added CoCl2-6H2O (916 mg, 3.85 mmol) at 0 °C (the solution turned blue), followed by NaBH4(515 mg, 13.6 mmol) (the solution turned black). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and the filtrate was poured into a saturated aqueous Na2C03solution and the residue was extracted twice with EtOAc (purple aqueous phase). The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum to give intermediate 19(579 mg, 73%) as a colorless oil which was used in the next step without further purification.

[0593] synthesis of intermediate 20:

[0594] 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.

[0595] The following intermediates were prepared by analogous procedures:

[0596]

[0597] synthesis of intermediate 22:

[0598] 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.

[0599] The following intermediates were prepared by analogous procedures:

[0600]

[0601] synthesis of intermediate 24:

[0602] 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 room temperature for 10 min (troublesome reaction mixture) before sodium triacetoxyborohydride (219 mg, 1.03 mmol) was added immediately. The reaction was stirred at room temperature for 3 h. After completion of the reaction, the residual solvent was evaporated under reduced pressure. The mixture was then dissolved with saturated aqueous NaHC03solution and extracted with EtOAc twice. The organic layer was washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluted with heptane:EtOAc = 100:0-85:15) to give intermediate 24 (146 mg, 34% yield) as a white powder.

[0603] synthesis of intermediate 25:

[0604] 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 light yellow solid.

[0605] synthesis of intermediate 26:

[0606] Intermediate 26 was prepared according to the procedure described for intermediate 4 starting from intermediate 25 (60 mg, 0.16 mmol) to give intermediate 26 (28 mg, 54% yield) as a light yellow solid.

[0607] synthesis of intermediate 27:

[0608] To intermediate 26A solution of 10 mg (30.5 µmol) and Boc₂O (20 mg, 0.092 mmol) in EtOAc (0.28 mL) and EtOH (0.28 mL) was added to a slurry of Ramane nickel in H₂O (10 mg). The reaction mixture was stirred overnight at room temperature at 5 bar under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad and washed with EtOAc. The filtrate was concentrated under vacuum to give the intermediate. 27 (13 mg, quantitative yield).

[0609] synthesis of intermediate 28 (HCI salt):

[0610] To the intermediate 27 A solution of 13 mg (30.6 µmol) in dioxane (100 µL) was added to dioxane with 4 M HCl (100 µL, 0.4 mmol) (precipitation), and the resulting reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure to give an intermediate as an HCl salt. 28 (12.4 mg, quantitative yield), which is a light-colored solid that can be used in the next step without further purification.

[0611] synthesis of intermediate 29:

[0612] intermediate 29 The intermediate was prepared starting from 6-bromo-2-chloro-7-fluoroquinoline-3-carboxaldehyde (720 mg, 2.5 mmol) and 4,4-dimethylpiperidine hydrochloride (448 mg, 2.99 mmol) according to the steps described for intermediate 24 to obtain the intermediate. 29 (575 mg, 60% yield), it is a white solid.

[0613] synthesis of intermediate 30:

[0614] intermediate 30 According to the intermediate 3 The steps described start from the intermediate 29 (570 mg, 1.48 mmol) and intermediates 2 Preparation began with (536 mg, 2.96 mmol) to obtain the intermediate. 30 (342 mg, 63% yield), it is a white solid.

[0615] synthesis of intermediate 31:

[0616] intermediate31 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 light yellow solid.

[0617] synthesis of intermediate 32:

[0618] Intermediate 32 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.

[0619] synthesis of intermediate 33:

[0620] Intermediate 33 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 intermediate 33 (5.3 g, 79% yield) as a white solid.

[0621] synthesis of intermediate 34:

[0622] Intermediate 34 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 light yellow solid.

[0623] synthesis of intermediate 35:

[0624] To a solution of intermediate 34To a solution of intermediate (500 mg, 1.42 mmol) in THF (15 mL) 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 warmed to room temperature and stirred for 30 min. 10% aqueous 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 MgS04, filtered and evaporated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (eluted with heptane:EtOAc = 100:0-50:50) to give intermediate 35 (362 mg, 85% yield) as a light yellow solid.

[0625] synthesis of intermediate 36:

[0626] NaBH4(55 mg, 1.45 mmol) was added to a solution of intermediate 35 (362 mg, 1.21 mmol) in MeOH (10 mL) and the mixture was stirred at room temperature 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 MgS04, filtered 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.

[0627] synthesis of intermediate 37:

[0628] 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) was added dropwise diphenylphosphoryl azide (273 mg, 0.99 mmol, 0.21 mL) under N2and the reaction mixture was stirred at room temperature for 2 hours. The reaction was carefully quenched with water. Then EtOAc was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography (eluted with heptane:EtOAc = 90:10-70:30) to give intermediate 37 (169 mg, 52% yield) as a colorless oil.

[0629] synthesis of intermediate 38:

[0630] Intermediate 38 According to the procedure described for Intermediate 35 from Intermediate 3 (485 mg, 1.48 mmol) to give Intermediate 38 (342 mg, 83% yield) as a white solid.

[0631] synthesis of intermediate 39:

[0632] Intermediate 39 According to the procedure described for Intermediate 36 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.

[0633] synthesis of intermediate 40:

[0634] 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), PPh3(166 mg, 0.63 mmol) and diphenylphosphoryl azide (174 mg, 0.63 mmol, 0.14 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography (heptane:EtOAc = 100:0-50:50 elution) to give the product which was further purified by reverse phase chromatography (elution with MeCN / 0.2% NH4HCO3 in water (pH = 7.9) = 60:40-80:20) to give Intermediate 40 (50 mg, 55% yield) as a colorless oil.

[0635] synthesis of intermediate 41:

[0636] Intermediate 40A solution of intermediate (193 mg, 0.63 mmol), 8-ethynylimidazo[l,5- a]pyridine (108 mg, 0.76 mmol), sodium ascorbate (151 mg, 0.76 mmol) and CuSO4(20.2 mg, 0.13 mmol) in DMF (6.9 mL) / water (1.5 mL) was stirred at room temperature for 3 h. The mixture was diluted with water and DCM. The organic layer was separated and then concentrated under vacuum to give crude material. The crude product was purified by silica gel column chromatography eluting with heptane: (EtOAc / MeOH 1 / 1) = 100:0-60:40 to give intermediate 41 (196 mg, 69% yield) as a yellow solid.

[0637] synthesis of intermediate 42:

[0638] A solution of 8-chloroimidazo[l,5-a]pyrazine (262 mg, 1.706 mmol) in DMF (1.41 mL) was placed under N2atmosphere. Pd(PPh3)2Cl2(71.9 mg, 0.10 mmol) and Cul (19.5 mg, 0.10 mmol) were then added and the mixture was purged under N2for 5 minutes. TEA (309 mg, 3.05 mmol, 0.42 mL) and trimethylsilyl acetylene (335 mg, 3.41 mmol, 0.49 mL) were added and the reaction mixture was heated at 90 °C for 1 h. The mixture was cooled to room temperature, diluted with EtOAc and filtered through a Celite pad. The filtrate was evaporated to dryness to give crude material. The crude product was purified by silica gel chromatography eluting with heptane:EtOAc = 70:30-0:100 to give intermediate 42 (95 mg, 26% yield) as a yellow oil.

[0639] synthesis of intermediate 43:

[0640] 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 stirred at room temperature for 0.5 h. The reaction mixture was filtered and the filtrate was partitioned between DCM and a solution of NH4CI. Extraction was performed. The organic layer was dried over a chromabond filter and evaporated under vacuum to give intermediate 43 (50 mg, quantitative yield) as a yellow solid which was used in the next step without further purification.

[0641] synthesis of intermediate 44:

[0642] Intermediate 44 According to the procedure described for Intermediate 41 40 and Intermediate 43 to give Intermediate 44 (30 mg, 23% yield) as a yellow solid.

[0643] synthesis of intermediate 45:

[0644] Intermediate 41 A solution of Intermediate (100 mg, 0.22 mmol) in MeCN (2.2 mL) and water (0.022 mL) was treated with BiCl3(14 mg, 0.045 mmol) and stirred at 55 °C for 1 h. Then BiCl3(30 mg, 0.095 mmol) was added and the reaction mixture was stirred at 55 °C for another 1 h. After the reaction was completed (monitored by TLC), the volatiles were removed under vacuum to give Intermediate (80 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification. 45

[0645] The following intermediates were prepared by similar procedures:

[0646]

[0647] synthesis of intermediate 47:

[0648] Intermediate (100 mg, 0.22 mmol) in MeCN (2.2 mL) and water (0.022 mL) was treated with BiCl3(14 mg, 0.045 mmol) and stirred at 55 °C for 1 h. Then BiCl3(30 mg, 0.095 mmol) was added and the reaction mixture was stirred at 55 °C for another 1 h. After the reaction was completed (monitored by TLC), the volatiles were removed under vacuum to give Intermediate (80 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification. 18 ​​To a solution of intermediate (600 mg, 1.97 mmol) in DCM (9.9 mL) was added DIBAL-H (2.37 mL, 2.37 mmol) dropwise and the reaction mixture was slowly warmed to -15 °C (with the 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 another 1 h. After 1 h, DIBAL-H (2.37 mL, 2.37 mmol) was added until complete conversion. The reaction mixture was cooled to -40 °C and quenched by the addition of a Rochelle salt solution. The resulting emulsion was warmed to room temperature and stirred vigorously for 1 h. DCM was added and the residue was extracted with DCM twice. The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum to give the crude material. The crude product was purified by silica gel column chromatography (heptane:EtOAc = 100:0-85:25 elution) to give intermediate 47 (306 mg, 51% yield) as a yellow solid.

[0649] synthesis of intermediate 48:

[0650] 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.

[0651] synthesis of intermediate 49:

[0652] 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 colorless oil.

[0653] synthesis of intermediate 50:

[0654] Intermediate 50 was prepared according to the procedure described for intermediate 41 starting from intermediate 49 and 8-ethynylimidazo[l,5-a]pyridine to give intermediate 50 (153 mg, 64% yield) as a brown oil.

[0655] synthesis of intermediate 51:

[0656] Intermediate 51 According to the procedure described for Intermediate 45 was prepared starting from Intermediate 50 to give Intermediate 51 (114 mg, quantitative yield) as a beige solid.

[0657] synthesis of intermediate 52:

[0658] Intermediate 33 (500 mg, 1.36 mmol) in dry THF (27.2 mL) was degassed by N2 bubbling for few minutes. 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 sequentially. The mixture was stirred at room temperature for 3 h. The residue was dissolved in brine and extracted with EtOAc. The organic phase was separated, dried over MgSO4 and evaporated to give the crude material. The crude product was purified by silica gel chromatography eluting with DCM:MeOH = 100:0 to 96:4 to give Intermediate 52 (255 mg, 56% yield) as a white solid.

[0659] synthesis of intermediate 53:

[0660] Intermediate 53 According to the procedure described for Intermediate 4 was prepared starting from Intermediate 52 (235 mg, 0.71 mmol) to give Intermediate 53 (131 mg, 66% yield) as a white solid.

[0661] synthesis of intermediate 54:

[0662] To a mixture of Intermediate 53 (110 mg, 0.39 mmol) in 7 M NH3 / MeOH To a solution of intermediate (1 mL) was added a slurry of Raney nickel in H2O (120 mg) dissolved in 7 M NH3 / MeOH (3 mL). The resulting suspension was evacuated and backfilled with N2, then stirred under an atmosphere of H2 at 4 bar at room temperature overnight. The catalyst was removed by filtration over celite and washed with MeOH. The filtrate was concentrated under reduced pressure to give intermediate 54 (64 mg, 57% yield) as a colourless oil which was used in the next step without further purification.

[0663] synthesis of intermediate 55:

[0664] 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.

[0665] synthesis of intermediate 56:

[0666] 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.

[0667] synthesis of intermediate 57:

[0668] 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

[0669] synthesis of intermediate 58:

[0670] 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 intermediate58 (86 mg,27% yield) as a white solid.

[0671] synthesis of intermediate 59:

[0672] 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) and the resulting mixture was stirred for 15 h. The reaction mixture was then quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine twice, dried over MgS04, filtered and the solvent was concentrated under reduced pressure to give intermediate 59 (71 mg, quantitative yield) as a yellow oil which was used in the next step without further purification.

[0673] synthesis of intermediate 60:

[0674] 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) and 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 to room temperature and the solvent was evaporated under reduced pressure. Water was added and the residue was extracted with DCM, dried over MgS04, filtered to give the crude product. The crude product was purified by silica gel column chromatography (eluted with DCM:MeOH = 100:0-96:4) to give intermediate 60 (180 mg, 52% yield) as a white solid.

[0675] synthesis of intermediate 61:

[0676] 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.

[0677] synthesis of intermediate 62:

[0678] Intermediate 62 was prepared according to the procedure described for intermediate 5 starting from intermediate 61(70 mg, 0.23 mmol) starting from the preparation of intermediate 62 (50 mg, 53% yield) as a white solid.

[0679] synthesis of intermediate 63 (HCI salt):

[0680] 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 room temperature for 4 h. Then to the reaction mixture was added TFA (69 mg, 0.61 mmol, 45 µL) and it was stirred for 16 h. The mixture was concentrated with 4 M HC1 / dioxane (repeated three times) to give intermediate 63 (50 mg, quantitative yield) as a white solid.

[0681] synthesis of intermediate 64:

[0682] Intermediate 64 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.

[0683] synthesis of intermediate 65:

[0684] Intermediate 65 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.

[0685] synthesis of intermediate 66:

[0686] Intermediate 66 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.

[0687] synthesis of intermediate 67:

[0688] At room temperature, Desmartin oxidant (1.85 g, 4.37 mmol) was added to a solution of (6-bromopyrin-3-yl)methanol (870 mg, 3.64 mmol) in DCM (8.7 mL). The reaction mixture was then stirred at 40 °C for 16 h. The mixture was filtered through a Celite® pad and washed with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by silica gel chromatography (eluting with heptane:EtOAc = 100:0-50:50) to give the intermediate. 67 (673 mg, 78% yield), it is a yellow solid.

[0689] synthesis of intermediate 68:

[0690] intermediate 68 According to the intermediate 7 The steps described start from the intermediate 67 Preparations were started with 4,4-dimethylpiperidine hydrochloride (670 mg, 2.83 mmol) and 4,4-dimethylpiperidine hydrochloride (634 mg, 4.24 mmol) to obtain the intermediate. 68 (390 mg, 41% yield), it is a yellow oily substance.

[0691] synthesis of intermediate 69:

[0692] At room temperature and under N2, potassium hexacyanoferrate(II) trihydrate (179 mg, 0.42 mmol), t BuXPhos (36 mg, 0.085 mmol), KOAc (41.6 mg, 0.42 mmol), and XphosPd G3 (71.7 mg, 0.085 mmol) were added to the intermediate. 68 A solution of (283 mg, 0.85 mmol) in dioxane (3.6 mL) / water (3.8 mL) was prepared. The reaction mixture was then degassed by bubbling with N2 for 15 min and heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and then added to cold water. The aqueous phase was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by silica gel chromatography (eluting with heptane:EtOAc = 100:0-50:50) to give the intermediate. 69(130 mg, 55% yield) as a yellow solid.

[0693] synthesis of intermediate 70:

[0694] Intermediate 70 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.

[0695] synthesis of intermediate 72:

[0696] To a solution of intermediate 15 (110 mg, 0.29 mmol) in DCM (2.8 mL) was added 3 M methylmagnesium chloride in THF (0.12 mL, 0.35 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 1 h and was allowed to warm to room temperature for 17 h. Saturated aqueous NH4CI and DCM were added, the organic layer was dried over Na2S04, filtered and concentrated to give crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0 to 92:8 to give intermediate 72 (74 mg, 65% yield) as a yellow solid.

[0697] The following intermediates were prepared by similar procedures:

[0698]

[0699] synthesis of intermediate 74:

[0700] To a solution of intermediate 72 (60 mg, 0.15 mmol) in DCM (1 mL) was added TEA (46.4 mg, 0.46 mmol, 0.064 mL) and methanesulfonyl chloride (70 mg, 0.61 mmol, 0.047 mL) at 0 °C under argon. The reaction mixture was stirred at room temperature for 18 h. Water and DCM were added and the aqueous layer was extracted with DCM, dried over Na2S04, filtered and concentrated to give crude material. The crude material was purified by silica gel column chromatography eluting with DCM:MeOH = 100:0 to 95:5 to give intermediate 74 (42 mg, 67% yield) as a yellow solid.

[0701] The following intermediates were prepared by analogous procedures:

[0702]

[0703] synthesis of intermediate 76:

[0704] 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) under Ar and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated to dryness under reduced pressure, then the residue was dissolved in EtOAc and washed with saturated NaHC03solution, brine, then dried over Na2S04, filtered and concentrated to give crude material. The crude product was purified by silica gel column chromatography (c-Hex:EtOAc = 95:5-0:100 eluting) to give intermediate 76 (1.4 g, 40% yield) as a yellow solid.

[0705] The following intermediates were prepared by analogous procedures:

[0706]

[0707] synthesis of intermediate 79:

[0708] To a stirred solution of intermediate 76 (1.43 g, 5.44 mmol) and potassium vinyltrifluoroborate (0.73 g, 5.44 mmol) in PrOH (59.3 mL) at room temperature was added PdCl2(dppf).CH2Cl2(0.089 g, 0.109 mmol) and TEA (0.55 g, 5.44 mmol, 0.76 mL). 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 H20 was added. The residue was extracted with Et20. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give crude product. The crude material was purified by silica gel chromatography (eluting with c-Hex:EtOAc = 95:5-40:60) to give intermediate 77 (870 mg, 76% yield) as a pale yellow solid.

[0709] The following intermediates were prepared by analogous procedures:

[0710]

[0711] synthesis of intermediate 83:

[0712] 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 room temperature. The resulting mixture was stirred for 10 min, then sodium periodate (1.77 g, 8.28 mmol) was added at room temperature. The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was diluted with water. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to dryness to give intermediate 83 (748 mg, 85% yield) as a brown solid which was used in the next step without further purification.

[0713] The following intermediates were prepared by analogous procedures:

[0714]

[0715] synthesis of intermediate 86:

[0716] 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.

[0717] The following intermediates were prepared by analogous procedures:

[0718]

[0719] synthesis of intermediate 88:

[0720] 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.

[0721] The following intermediates were prepared by analogous procedures:

[0722]

[0723] synthesis of intermediate 89a:

[0724] Intermediate 89a According to the procedure described for Intermediate 7 starting from Intermediate 85 (570 mg, 2.2 mmol) and 1-cyclobutylmethylamine hydrochloride to give Intermediate 89a (423 mg, 59% yield) as a yellow solid.

[0725] synthesis of intermediate 90a:

[0726] To a solution of Intermediate 89a (423 mg, 1.28 mmol) in MeCN (8.7 mL) was added Boc20 (335 mg, 1.54 mmol) dropwise. The reaction mixture was stirred at 80 °C for 1 h. The reaction solution was allowed to cool 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 saturated aqueous NaHC03, dried over MgS04, filtered and concentrated under reduced pressure to give Intermediate 90a (542 mg, 98% yield) as a yellow oil.

[0727] synthesis of intermediate 91:

[0728] 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 N2and stirred at 80 °C overnight. The reaction mixture was filtered through a filter pad. The filtrate was concentrated under reduced pressure to give crude material. The crude material was purified by silica gel chromatography eluting with heptane:EtOAc = 100:0-70:30 to give Intermediate 91 (448 mg, 66% yield) as a yellow solid.

[0729] synthesis of intermediate 92:

[0730] To a solution of Intermediate 91To a solution of intermediate (300 mg, 1.17 mmol) in DCM (6 mL) was added dropwise 1.2 M DIBAL 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 dropwise MeOH and EtOAc. The solution was concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-90:10 to give intermediate 92 (87 mg, 32% yield) as a yellow oil.

[0731] The following intermediate was prepared by a similar procedure:

[0732]

[0733] synthesis of intermediate 94:

[0734] 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.

[0735] The following intermediate was prepared by a similar procedure:

[0736]

[0737] synthesis of intermediate 96:

[0738] PPh3(200 mg, 0.76 mmol) was added to a solution of intermediate 94 (97 mg, 0.38 mmol) in H20 (0.25 mL) and THF (1.2 mL). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give the crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-80:20 to give intermediate 96 (50 mg, 57% yield) as a white solid.

[0739] The following intermediate was prepared by a similar procedure:

[0740]

[0741] synthesis of intermediate 98:

[0742] 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 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 dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel chromatography eluting with heptane:EtOAc = 100:0-70:30 to give intermediate 98 (330 mg, 47% yield) as a brown oil.

[0743] The following intermediates were prepared by similar procedures:

[0744]

[0745] synthesis of intermediate 100:

[0746] A microwave vial was charged with 6-bromo-3-(diethoxymethyl)-8-fluoroquinoline (430 mg, 1.31 mmol), potassium [(1,3-dioxo-2,3-dihydro-1H-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), Na2CO3 (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) was added followed by PrOH (6.5 mL) and the resulting reaction mixture was stirred at reflux for 24 h. The reaction mixture was cooled to room temperature, EtOAc and saturated aqueous K2CO3 were added. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give the crude material. The crude material was purified by silica gel column chromatography eluting with DCM:MeOH = 100:0-92:8 to give intermediate 100(303 mg, 83%) as a light brown oil.

[0747] The following intermediates were prepared by analogous procedures:

[0748]

[0749] synthesis of intermediate 108:

[0750] DIPEA (642 mg, 4.96 mmol, 0.86 mL) and a solution of T3P in EtOAc (1.3 g, 1.99 mmol, 1.19 mL) were added to a stirred solution of intermediate 88 (310 mg, 0.99 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (189 mg, 0.99 mmol) in DMF (3.3 mL) at room temperature for 16 h. The reaction mixture was diluted with H2O and extracted with CHCI3 / iPrOH (3 / 1). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-92:8 to give intermediate 108 (120 mg, 26% yield) as a light brown oil.

[0751] The following intermediates were prepared by analogous procedures:

[0752]

[0753]

[0754] synthesis of intermediate 123:

[0755] A stirred solution of 4-oxo-4H-pyrido[l,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) was stirred at 0 °C for 15 min. POCl3(2.25 g, 14.7 mmol, 1.37 mL) was added to the mixture at 0 °C and the mixture was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was carefully quenched and basified with 10% aq. K2CO3solution. The precipitate was filtered, washed with H2O several times and with DCM once, then dried to give intermediate 123(1.1 g, 67% yield) as a grey solid.

[0756] synthesis of intermediate 124:

[0757] Intermediate 124 According to the procedure described for intermediate 15 starting from intermediate 108 (79 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification. 124 The following intermediates were prepared by analogous procedures:

[0758]

[0759]

[0760]

[0761] synthesis of intermediate 136:

[0762] 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), N-Boc-aminomethylpotassium trifluoroborate (1.28 g, 5.42 mmol) and Na2CO3(1.72 g, 16.3 mmol) in dioxane (15.8 mL) and H2O (7.9 mL) at room temperature. 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 give crude material. The crude material was purified by silica gel chromatography eluting with c-Hex:EtOAc = 100:0 to 10:90 to give intermediate 136 (395 mg, 35% yield) as a yellow solid.

[0763] The following intermediates were prepared by analogous procedures:

[0764]

[0765] Synthesis of intermediate 140:

[0766] The reaction was carried out under anhydrous conditions and the glassware was flame dried and anhydrous THF was dried over 4A molecular sieves. To intermediate 137 ​An argon purged solution of intermediate (1.9 g, 6.31 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (102 mg, 0.38 mmol) and bis(pinacolato)diboron (1.76 g, 6.94 mmol) in THF (15.5 mL) was added (1,5-cyclooctadiene)(methoxy)iridium(I) 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 room temperature, diluted with EtOAc and concentrated to dryness to give intermediate 140 (2.6 g, quantitative yield) as a brown foam which was used in the next step without further purification.

[0767] The following intermediate was prepared by a similar procedure:

[0768]

[0769] Synthesis of intermediate 142:

[0770] To a solution of intermediate 140 (3.9 g, 6.3 mmol) in DMF (72 mL) was added 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 room temperature, diluted with saturated NaHC03and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to dryness to give the crude product. The crude material was purified by silica gel chromatography eluting with c-Hex:EtOAc = 70:30 to 20:80 to give intermediate 142 (728 mg, 37% yield) as a yellow solid.

[0771] Synthesis of intermediate 143:

[0772] Intermediate 143 was prepared according to the procedure described for intermediate 54 starting from intermediate 136 (508 mg, 1.62 mmol) to give intermediate 143 (485 mg, 94% yield) as a green foam.

[0773] The following intermediate was prepared by a similar procedure:

[0774]

[0775] Synthesis of intermediate 145:

[0776] Intermediate 145 According to the procedure described for Intermediate 108 starting from Intermediate 143 (485 mg, 1.53 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (291 mg, 1.53 mmol) to afford Intermediate 145 (400 mg, 53% yield) as a brown solid.

[0777] The following intermediates were prepared by analogous procedures:

[0778]

[0779] Synthesis of intermediate 147:

[0780] Intermediate 147 According to the procedure described for Compound 7 starting from Intermediate 145 (490 mg, 0.82 mmol) to afford Intermediate 147 (221 mg, 70% yield) as a brown solid.

[0781] The following intermediates were prepared by analogous procedures:

[0782]

[0783] Synthesis of intermediate 150:

[0784] 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 2-nitrobenzenesulfonyl chloride (144 mg, 0.65 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with saturated NaHC03and extracted with DCM. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to dryness to afford crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-96:4 to afford Intermediate 150 ( 298 mg, 88% yield) as an orange solid.

[0785] The following intermediates were prepared by analogous procedures:

[0786]

[0787] Synthesis of intermediate 153:

[0788] The reaction was carried out under anhydrous conditions. To a solution of intermediate 150 (150 mg, 0.26 mmol) and (3-fluorobicyclo[l. l. l]pentan-l-yl)methanol (96 mg, 0.54 mmol) in THF (0.75 mL) was added a solution of 2-(tributyl-λ 5 phosphonitrile)acetonitrile (378 mg, 1.57 mmol, 0.41 mL) in THF (3.5 mL). The resulting reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was concentrated to dryness to give crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-90:10 to give intermediate 153 (17 mg, 10% yield) as a brown gum.

[0789] The following intermediates were prepared by analogous procedures:

[0790]

[0791] Synthesis of intermediate 158:

[0792] 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% aqueous solution) was added and the aqueous phase was extracted twice with DCM. The combined organic layers were dried over MgS04, filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude material was purified by silica gel column chromatography eluting with heptane:EtOAc = 100:0-60:40 to give intermediate 158 (241 mg, 29% yield) as a yellow oil.

[0793] Synthesis of intermediate 159:

[0794] Intermediate 159 According to the procedure for intermediate 8The steps described above from intermediate 158 (228 mg, 0.64 mmol) to give intermediate 159 (182 mg, 97% yield) as a white solid.

[0795] Synthesis of intermediate 160:

[0796] Intermediate 160 According to the procedure described above for intermediate 108 The steps described above from intermediate 159 (182 mg, 0.62 mmol) and 4-oxo-4H-pyrido[l,2- a]pyrimidine-2-carboxylic acid (119 mg, 0.62 mmol) to give intermediate 160 (120 mg, 45% yield) as a yellow solid.

[0797] Synthesis of intermediate 161:

[0798] Intermediate 161 According to the procedure described above for intermediate 7 The steps described above from intermediate 83 (182 mg, 0.62 mmol) to give intermediate 161 (105 mg, 59% yield) as an orange oil.

[0799] Synthesis of intermediate 162:

[0800] Intermediate 162 According to the procedure described above for intermediate 54 The steps described above from intermediate 161 (100 mg, 0.34 mmol) to give intermediate 162 (100 mg, 99% yield) as a brown viscous oil.

[0801] Synthesis of intermediate 163:

[0802] Intermediate 163 According to the procedure described above for intermediate 83 The steps described above from intermediate 112 (40 mg, 0.1 mmol) to give intermediate 163 (40 mg, quantitative yield) as a brown solid.

[0803] Synthesis of intermediate 165:

[0804] 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 room temperature for 4 h. The reaction mixture was quenched with water and neutralized to pH 7 with saturated aqueous NaHC03solution. The resulting mixture was extracted twice with a mixture of CHC13 / IPA (3 / 1). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to give intermediate 165 (211 mg) as a light yellow solid which was used in the next step without further purification.

[0805] Synthesis of intermediate 166:

[0806] To a solution of intermediate 165 (180 mg, 0.39 mmol) in acetonitrile (0.96 mL) was added TEA (137 mg, 1.35 mmol, 0.19 mL) and TMSCN (134 mg, 1.35 mmol, 0.18 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum to give the crude product. The crude material was purified by silica gel chromatography eluting with heptane:EtOAc = 80:20 to 60:40 to give intermediate 166 (128 mg, 70% yield) as a light yellow solid.

[0807] Synthesis of intermediate 167:

[0808] 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 light yellow solid which was used in the next step without further purification.

[0809] Synthesis of intermediate 168:

[0810] To a solution of methyl 3-(diethoxymethyl)-8-methoxyquinoline-6-carboxylate (805 mg, 2.52 mmol) in DCM (18.9 mL) was added dropwise 1.2 M DIBAL / toluene (25.25 mL, 6.3 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was cooled to 0 °C and quenched by the addition of EtOAc, dropwise MeOH and water. Celite was added and the reaction mixture was directly purified by silica gel chromatography (eluting with DCM:MeOH = 100:0-92:8) to give the intermediate (634 mg, 86% yield) as a brown oil.

[0811] Synthesis of intermediate 169:

[0812] Intermediate 169 According to the procedure described for Intermediate 37 starting from Intermediate 168 (610 mg, 2.1 mmol) to give the intermediate (391 mg, 59% yield) as a brown oil. 169

[0813] Synthesis of intermediate 170:

[0814] Intermediate 170 According to the procedure described for Intermediate 41 starting from Intermediate 169 (180 mg, 0.57 mmol) and 8-ethynylimidazo[l,5-a]pyridine to give the intermediate (139 mg, 53% yield) as a yellow solid. 170

[0815] Synthesis of intermediate 171:

[0816] Intermediate 171 According to the procedure described for Intermediate 15 starting from Intermediate 170 (150 mg, 0.33 mmol) to give the intermediate (125 mg, quantitative yield) as a light yellow solid which was used in the next step without further purification. 171

[0817] Synthesis of intermediate 172:

[0818] ​​​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 to room temperature, 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 with DCM 3 times. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product. The crude material was triturated in Et20 and the solid was filtered and dried under reduced pressure to give intermediate 172 (1.35 g, 64% yield) as a yellow solid.

[0819] Synthesis of intermediate 173:

[0820] 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.

[0821] Synthesis of intermediate 174:

[0822] 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.

[0823] Synthesis of intermediate 175:

[0824] Intermediate 175 was prepared according to the procedure described for intermediate 7 starting from intermediate 174 (475 mg, 2.1 mmol) and 1-cyclobutylmethylamine hydrochloride (301 mg, 2.48 mmol) to give intermediate 175 (576 mg, 93% yield) as a white solid.

[0825] Synthesis of intermediate 176:

[0826] Intermediate 176 According to the procedure described for Intermediate 90a was prepared starting from Intermediate 175 (100 mg, 0.33 mmol) to give Intermediate 176 (116 mg, 87% yield) as a white solid.

[0827] Synthesis of intermediate 177:

[0828] H2O (7.42 mL) was added to a solution of Intermediate 176 (602 mg, 1.507 mmol) in THF (7.42 mL), then LiOH (565 mg, 7.53 mmol) was added and the mixture was stirred at room temperature for 1 h. Upon completion, water was added and the layers were extracted. The basic aqueous layer was washed with EtOAc several times. The basic aqueous layer was then acidified with acetic acid until pH 4-5 was reached. The acidic aqueous layer was then extracted with EtOAc three times. The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to give Intermediate 177 (384 mg, 69% yield) as a light brown solid.

[0829] Synthesis of intermediate 178:

[0830] 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) was added ethyl chloroformate (244 mg, 2.25 mmol, 0.21 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. NaBH4(102 mg, 2.7 mmol) was added followed by water (0.86 mL). The mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 1 h. The crude was cooled to 0 °C, then 1 N aqueous HC1 was added slowly. After stirring for 10 min, EtOAc and 10% aqueous K2C03were added. The aqueous layer was separated and extracted with EtOAc again. The combined organic layers were dried over MgS04, filtered, and evaporated in vacuum to give the crude material. The crude material was purified by silica gel column chromatography (eluted with DCM:MeOH = 100:0-80:20) to give Intermediate 178 (166 mg, 52% yield) as a light yellow oil.

[0831] Synthesis of intermediate 179:

[0832] Intermediate 179 According to the procedure described for Intermediate 37 from Intermediate 178 (130 mg, 0.36 mmol) to give Intermediate 179 (102 mg, 73% yield) as a white solid.

[0833] Synthesis of intermediate 180:

[0834] Intermediate 180 According to the procedure described for Intermediate 96 from Intermediate 179 (100 mg, 0.26 mmol) to give Intermediate 180 (50 mg, 54% yield) as a white solid.

[0835] Synthesis of intermediate 181:

[0836] Intermediate 181 According to the procedure described for Intermediate 108 from Intermediate 180 (50 mg, 0.14 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (27 mg, 0.14 mmol) to give Intermediate 181 (35 mg, 47% yield) as a white solid.

[0837] Synthesis of intermediate 182:

[0838] To a solution of 6-bromo-l,3-dichloroisoquinoline (5 g, 18.1 mmol) in MeOH (181 mL) purged with argon was added NaOMe (23.5 g, 108 mmol, 24.8 mL) at room temperature. The reaction mixture was stirred at 65 °C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc and H2O. The solid was filtered off, washed with ethyl acetate, and dried under vacuum to give Intermediate 182 (4.9 g, quantitative yield) as a white solid.

[0839] Synthesis of intermediate 183:

[0840] Intermediate 183 According to the procedure described for Intermediate 79 from Intermediate182 (3.4 g, 12.5 mmol) starting from the preparation of intermediate 183 (2.6 g, 95% yield) as a white solid.

[0841] Synthesis of intermediate 184:

[0842] Intermediate 184 According to the procedure described for intermediate 83 starting from intermediate 183 (2.6 g, 11.8 mmol) starting from the preparation of intermediate 184 (2.6 g, quantitative yield) as a brown solid.

[0843] Synthesis of intermediate 185:

[0844] Intermediate 185 According to the procedure described for intermediate 7 starting from intermediate 184 (2.6 g, 11.8 mmol) and cyclobutylmethylamine hydrochloride (1.4 g, 11.8 mmol) to give intermediate 185 (2.3 g, 67% yield) as a brown solid 。

[0845] Synthesis of intermediate 186:

[0846] Intermediate 186 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 colorless oil.

[0847] Synthesis of intermediate 187:

[0848] Intermediate 187 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.

[0849] Synthesis of intermediate 188:

[0850] Intermediate188 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 afford intermediate 188 (150 mg, 67% yield) as a yellow solid.

[0851] The following intermediate was prepared by an analogous procedure:

[0852]

[0853] Synthesis of intermediate 198:

[0854] 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 t The solution was evacuated and backfilled with Ar three times, then Pd2(dba)3(3.93 mg, 3.8 µmol) was added and the vial was evacuated and backfilled with Ar three times, then heated at 100 °C for 3 h. The reaction mixture was cooled to room temperature and the volatiles were removed under vacuum to afford crude material. The crude material was purified by normal phase chromatography eluting with DCM:MeOH = 100:0-85:15 to afford intermediate 198 (46 mg, 64% yield) as an orange solid.

[0855] The following intermediate was prepared by an analogous procedure:

[0856]

[0857] Synthesis of intermediate 202:

[0858] Intermediate 202 According to the procedure described for intermediate 1 starting from intermediate 184 (638 mg, 2.73 mmol) to afford intermediate 202 (504 mg, 62% yield) as a light brown oil.

[0859] Synthesis of intermediate 203:

[0860] Intermediate 203 According to the procedure described for Intermediate 100 from Intermediate 202 (615 mg, 1.71 mmol) to give Intermediate 203 (408 mg, 82% yield) as a yellow oil.

[0861] Synthesis of intermediate 204:

[0862] Intermediate 204 According to the procedure described for Intermediate 108 from Intermediate 203 (385 mg, 1.33 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (252 mg, 1.33 mmol) to give Intermediate 204 (406 mg, 66% yield) as a yellow solid.

[0863] Synthesis of intermediate 205:

[0864] Intermediate 205 According to the procedure described for Intermediate 15 from Intermediate 204 (178 mg, 0.38 mmol) to give Intermediate 205 (149 mg, quantitative yield) as a light yellow solid.

[0865] Synthesis of intermediate 206 (HBr salt):

[0866] Intermediate 185 (350 mg, 1.2 mmol) in HBr / H2O (6.52 g, 80.6 mmol, 4.4 mL) was stirred at 50 °C for 5 h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to give Intermediate 206 (420 mg, 98% yield) as a brown solid which was used in the next step without further purification.

[0867] Synthesis of intermediate 207:

[0868] Intermediate 207 According to the procedure described for Intermediate 90a from Intermediate 206(420 mg, 1.17 mmol) was prepared starting from intermediate 207 (320 mg, 72% yield) as a light brown solid.

[0869] Synthesis of intermediate 208:

[0870] Intermediate 207 (305 mg, 0.81 mmol), 2-bromopropane (109 mg, 0.89 mmol, 84 µL) and K2CO3 (168 mg, 1.21 mmol) in DMF (5.3 mL) was stirred at 70 °C for 3 h. The reaction mixture was cooled to rt and diluted with H2O. The residue was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with cy-Hex:EtOAc = 100:0-80:20 to give intermediate 208 (252 mg, 74% yield) as a colorless oil.

[0871] The following intermediates were prepared by analogous procedures:

[0872]

[0873] Synthesis of intermediate 213:

[0874] To a solution of intermediate 207 (269 mg, 0.71 mmol), Ag2CO3 (394 mg, 1.43 mmol) in CHCl3 (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. The volatiles were removed under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with cy-Hex:EtOAc = 100:0-60:40 to give intermediate 213 (205 mg, 73% yield) as a brown solid.

[0875] Synthesis of intermediate 214:

[0876] Intermediate 207(375 mg, 1 mmol) and Na2C03(116 mg, 1.1 mmol) were added to a vial. Then, MeCN (2.5 mL) was added at room temperature and the resulting mixture was heated at 60 °C for 10 min, then (bromodifluoromethyl)trimethylsilane (243 mg, 1.19 mmol, 0.19 mL) was added. The resulting reaction mixture was stirred at 60 °C overnight. Brine was added and the residue was extracted with DCM twice. The organic layers were combined, dried over MgS04, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by normal phase chromatography eluting with heptane:EtOAc = 100:0-90:10 to give intermediate 214 (240 mg, 57%) as a white solid.

[0877] Synthesis of intermediate 215:

[0878] 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.

[0879] The following intermediate was prepared by an analogous procedure:

[0880]

[0881] Synthesis of intermediate 221:

[0882] Intermediate 221 was prepared according to the procedure described for intermediate 108 starting from intermediate 215 (145 mg, 0.35 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (66.7 mg, 0.35 mmol) to give intermediate 221 (120 mg, 58% yield) as a colorless oil.

[0883] The following intermediate was prepared by an analogous procedure:

[0884]

[0885] Synthesis of intermediate 227:

[0886] Intermediate 227 was prepared according to the procedure described for intermediate4 The procedure described for Intermediate 212 (407 mg, 0.88 mmol) to give Intermediate 227 (282 mg, 71% yield) as a yellow solid.

[0887] Synthesis of intermediate 228:

[0888] Intermediate 228 The procedure described for Intermediate 54 The procedure described for Intermediate 227 (282 mg, 0.62 mmol) to give Intermediate 228 (218 mg, 79% yield) as a yellow oil.

[0889] Synthesis of intermediate 229:

[0890] Intermediate 229 The procedure described for Intermediate 108 The procedure described for Intermediate 228 (303 mg, 0.49 mmol) and 4-oxo-4H-pyrido[l,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.

[0891] Synthesis of intermediate 230:

[0892] 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 crude material. The crude product was purified by normal phase chromatography eluting with DCM:methanol = 100:0-95:5 to give Intermediate 230 (112 mg, 82%) as a white solid.

[0893] Synthesis of intermediate 231:

[0894] Intermediate 231 The procedure described for Intermediate 206 The procedure described for Intermediate 184 (2.85 g, 10.7 mmol) to give Intermediate231 (1.12 g, 51% yield) as a brown solid.

[0895] Synthesis of intermediate 232:

[0896] Intermediate 232 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.

[0897] Synthesis of intermediate 233:

[0898] Intermediate 233 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.

[0899] Synthesis of intermediate 234:

[0900] Intermediate 234 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.

[0901] Synthesis of intermediate 235:

[0902] Intermediate 235 According to the procedure described for Intermediate 108 starting from Intermediate 234 (205 mg, 0.47 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (90 mg, 0.47 mmol) to give Intermediate 235 (163 mg, 57% yield) as a light brown solid.

[0903] Synthesis of intermediate 323:

[0904] Intermediate 323 According to the procedure described for Intermediate 15 Starting from Intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol), the procedure described for Intermediate 235 (572 mg, 79% yield) as a white solid. 323

[0905] Synthesis of intermediate 236:

[0906] Intermediate 236 According to the procedure described for Intermediate 79 Starting from Intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol), the procedure described for Intermediate 236 (572 mg, 79% yield) as a white solid.

[0907] Synthesis of intermediate 237:

[0908] Intermediate 237 According to the procedure described for Intermediate 83 Starting from Intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol), the procedure described for Intermediate 236 (592 mg, 3.12 mmol), the procedure described for Intermediate 237 (598 mg, quantitative yield) as a brown solid.

[0909] Synthesis of intermediate 238:

[0910] Intermediate 238 According to the procedure described for Intermediate 1 Starting from Intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol), the procedure described for Intermediate 237 (800 mg, 3.8 mmol), the procedure described for Intermediate 238 (645 mg, 64% yield) as a yellow oil.

[0911] Synthesis of intermediate 239:

[0912] Intermediate 239 According to the procedure described for Intermediate 4 Starting from Intermediate 3-chloro-6-bromoisoquinoline (930 mg, 3.84 mmol), the procedure described for Intermediate 238 (278 mg, 1.05 mmol), the procedure described for Intermediate 239 (90 mg, 34% yield) as a yellow solid.

[0913] Synthesis of intermediate 240: ​

[0914] Intermediate 240 According to the procedure described for Intermediate 19 from Intermediate 239 (190 mg, 0.74 mmol) to give Intermediate 240 (193 mg, quantitative yield) as a brown oil.

[0915] Synthesis of intermediate 241:

[0916] Intermediate 241 According to the procedure described for Intermediate 108 from Intermediate 240 (140 mg, 0.43 mmol) and 4-oxo-4H-pyrido[l,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.

[0917] Synthesis of intermediate 324:

[0918] Intermediate 324 According to the procedure described for Intermediate 15 from Intermediate 241 (60 mg, 0.14 mmol) to give Intermediate 324 (49 mg, quantitative yield) as a light yellow solid.

[0919] Synthesis of intermediate 242:

[0920] Intermediate 242 According to the procedure described for Intermediate 7 from Intermediate 237 (2.45 g, 12.8 mmol) and cyclobutylmethylamine hydrochloride (1.87 g, 15.3 mmol) to give Intermediate 242 (2.54 g, 76% yield) as a dark purple oil.

[0921] Synthesis of intermediate 243:

[0922] Intermediate 243 According to the procedure described for Intermediate 90a from Intermediate 242 (2.38 g, 9.13 mmol) to give Intermediate 243(3.01 g, 91% yield) as a brown oil.

[0923] Synthesis of intermediate 244:

[0924] 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 MeNO2(3.26 g, 53.4 mmol, 2.91 mL). The resulting reaction mixture was stirred at room temperature for 5 d. NH4Cl was added and the residue was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with cy-Hex:EtOAc = 100:0-88:12 to give intermediate 244 (231 mg, 23% yield) as a colorless oil.

[0925] Synthesis of intermediate 245:

[0926] 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.

[0927] Synthesis of intermediate 246:

[0928] Intermediate 246 was prepared according to the procedure described for intermediate 108 starting from intermediate 245 (70 mg, 0.19 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (36 mg, 0.19 mmol) to give intermediate 246 (51 mg, 50% yield) as a yellow foam.

[0929] The following intermediates were prepared by analogous procedures:

[0930]

[0931] Synthesis of intermediate 247a:

[0932] To a solution of methyl 4-bromo-2-formylbenzoate (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 room temperature for 18 h. Water was added and the residue was extracted with DCM twice. The organic layers were combined, dried over MgS04, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by normal phase chromatography eluting with heptane:EtOAc = 85:15-65:35 to give intermediate 247a (37.5 g, 68% yield) as a white solid.

[0933] Synthesis of intermediate 248 (TFA salt):

[0934] 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.

[0935] Synthesis of intermediate 249:

[0936] Intermediate 248 A mixture of intermediate 249 (11.8 g, 74% yield) as a white solid.

[0937] Synthesis of intermediate 250:

[0938] 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.

[0939] Synthesis of intermediate 251:

[0940] To a mixture of intermediate 250 (9 g, 35 mmol) in toluene (250 mL) was added POCl3(21.5 g, 140 mmol, 13 mL) and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to room temperature and the volatiles were removed under vacuum. The residue was diluted with a mixture of CHCl3 / IPA (3 / 1) and washed with 30% aqueous NaOH solution. The organic layers were combined, dried over MgSO4 ， filtered and concentrated under vacuum to yield intermediate 251 (8.62 g, 89% yield) as a light yellow solid.

[0941] Synthesis of intermediate 252:

[0942] Intermediate 252 was prepared according to the procedure described for intermediate 83 starting from intermediate 251 (6.3 g, 22.7 mmol) to yield intermediate 252 (6 g, 95% yield) as a light brown solid.

[0943] Synthesis of intermediate 253:

[0944] Intermediate 253 was prepared according to the procedure described for intermediate 7 starting from intermediate 252 (6 g, 21.6 mmol) and cyclobutylmethylamine hydrochloride (3.15 g, 25.9 mmol) to yield intermediate 253 (6.29 g, 84% yield) as a brown solid.

[0945] Synthesis of intermediate 254:

[0946] Intermediate 254 was prepared according to the procedure described for intermediate 90a starting from intermediate 253 (5.8 g, 16.7 mmol) to yield intermediate 254 (7.39 g, quantitative yield) as a colorless oil.

[0947] Synthesis of intermediate 255:

[0948] A suspension of NaBH4(2.39 g, 63.3 mmol) and CaCl2(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 room temperature for 1.5 h. The reaction was quenched with water and saturated aqueous NH4Cl solution. The residue was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to yield intermediate 255 (4.7 g, quantitative yield) as a brown oil.

[0949] Synthesis of intermediate 256:

[0950] Intermediate 256 was prepared according to the procedure described for intermediate 37 starting from intermediate 255 (455 mg, 1.16 mmol) to yield intermediate 256 (406 mg, 84% yield) as a colorless oil.

[0951] Synthesis of intermediate 257:

[0952] Intermediate 257 was prepared according to the procedure described for intermediate 96 starting from intermediate 256 (386 mg, 0.96 mmol) to yield intermediate 257 (341 mg, 94% yield) as a colorless oil.

[0953] Synthesis of intermediate 258:

[0954] Intermediate 258 was prepared according to the procedure described for intermediate 108 starting from intermediate 258 (281 mg, 0.72 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (166 mg, 0.87 mmol) to yield intermediate 258 (371 mg, 92% yield) as a light yellow solid.

[0955] Synthesis of intermediate 259:

[0956] Intermediate 258 (116 mg, 0.21 mmol), tributyl(methoxymethyl)stannane (138 mg, 0.41 mmol), Pd(PPh3)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 to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by normal phase chromatography eluting with DCM:EtOAc = 60:40-30:70 to give intermediate 259 (83 mg, 70% yield) as a yellow solid.

[0957] Synthesis of intermediate 260:

[0958] Intermediate 258 (200 mg, 0.36 mmol), vinylpotassium trifluoroborate (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) and H2O (0.8 mL) was degassed with N2and stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and water was added. The residue was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by normal phase chromatography eluting with DCM:iPrOH = 100:0-95:5 to give intermediate 260 (102 mg, 52%) as a light brown solid.

[0959] Synthesis of intermediate 261:

[0960] 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 µmol). The reaction mixture was stirred at room temperature for 5 min and NMO (20.3 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. DCM and saturated aqueous NH4Cl were added. The residue was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by normal phase chromatography eluting with DCM:iPrOH = 100:0-89:11 to give intermediate 261(61 mg,60%) as a light brown solid.

[0961] Synthesis of intermediate 262:

[0962] Intermediate 258 (297 mg, 0.53 mmol), trifluoro[2-(oxan-2-yloxy)ethyl]borate (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 N2and stirred at 100 °C overnight. DCM and H2O were added. The residue was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with DCM:MeOH = 100:0-90:10 to give intermediate 262 (65 mg,19%) as a light orange oil.

[0963] Synthesis of intermediate 263:

[0964] 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. Trimethyl cyclo- trioxane (2.91 g, 23.2 mmol, 3.27 mL) was added under N2and 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, and concentrated under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with heptane:EtOAc = 100:0-50:50 to give intermediate 263 (913 mg, 31%) as a white solid.

[0965] Synthesis of intermediate 264:

[0966] Intermediate 263To a solution of intermediate (695 mg, 2.72 mmol) in dioxane (10 mL) was added Se02(393 mg, 3.54 mmol) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to rt and filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to give intermediate 264 (730 mg, quantitative yield) as a light brown solid.

[0967] Synthesis of intermediate 265:

[0968] 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 colorless oil.

[0969] Synthesis of intermediate 266:

[0970] 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 sat. aq. NaHC03solution and the residue was extracted with DCM twice. The combined organic layers were dried over MgS04, filtered and concentrated under vacuum to give crude material. The crude product was purified by normal phase chromatography eluting with DCM:MeOH = 100:0 to 99:1 to give intermediate 266 (509 mg, 61%) as a yellow oil.

[0971] Synthesis of intermediate 267:

[0972] 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.

[0973] Synthesis of intermediate 268:

[0974] Intermediate 268 was prepared according to the procedure described for intermediate7 The procedure described for intermediate 267 starting from intermediate 268 (216 mg, 40% yield) as a red oil.

[0975] Synthesis of intermediate 269:

[0976] Intermediate 269 The procedure described for intermediate 90a starting from intermediate 268 (200 mg, 0.47 mmol) to yield intermediate 269 (200 mg, 81% yield) as a colorless oil.

[0977] Synthesis of intermediate 270:

[0978] Intermediate 270 The procedure described for intermediate 255 starting from intermediate 269 (180 mg, 0.34 mmol) to yield intermediate 270 (158 mg, 98% yield) as a colorless oil.

[0979] Synthesis of intermediate 271:

[0980] Intermediate 271 The procedure described for intermediate 37 starting from intermediate 270 (470 mg, 1 mmol) to yield intermediate 271 (494 mg, quantitative yield) as a colorless oil.

[0981] Synthesis of intermediate 272:

[0982] Intermediate 272 The procedure described for intermediate 96 starting from intermediate 271 (540 mg, 1.09 mmol) to yield intermediate 272 (326 mg, 64% yield) as a yellowish oil.

[0983] Synthesis of intermediate 273:

[0984] Intermediate 273 According to the procedure described for Intermediate 108 Starting from Intermediate 272 (200 mg, 0.43 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (89 mg, 0.43 mmol) to give Intermediate 273 (190 mg, 70% yield) as a brown oil.

[0985] The following intermediates were prepared by analogous procedures:

[0986]

[0987] Synthesis of intermediate 275:

[0988] Intermediate 275 According to the procedure described for Intermediate 247a Starting from 5-bromo-3-formylpyridine carboxylic acid methyl ester (3.8 g, 15.9 mmol) to give Intermediate 275 (3.18 g, 52% yield) as a white solid.

[0989] The following intermediates were prepared by analogous procedures:

[0990]

[0991] Synthesis of intermediate 276a (TFA salt):

[0992] Intermediate 276a 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.

[0993] The following intermediates were prepared by analogous procedures:

[0994]

[0995] Synthesis of intermediate 279:

[0996] Intermediate 279 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.

[0997] The following intermediates were prepared by analogous procedures:

[0998]

[0999] Synthesis of intermediate 282:

[1000] 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 light brown solid.

[1001] The following intermediates were prepared by analogous procedures:

[1002]

[1003] Synthesis of intermediate 284:

[1004] 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 light brown solid.

[1005] Synthesis of intermediate 285:

[1006] 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.

[1007] Synthesis of intermediate 286:

[1008] Intermediate 286 was prepared according to the procedure described for Intermediate 7 starting from Intermediate 285 (340 mg, 1.38 mmol) and cyclobutylmethylamine hydrochloride (202 mg, 1.66 mmol) to give Intermediate 286(254 mg, 58% yield) as a light yellow oil.

[1009] Synthesis of intermediate 287:

[1010] Intermediate 287 According to the procedure described for Intermediate 90a from Intermediate 286 (244 mg, 0.77 mmol) to give Intermediate 287 (312 mg, 97% yield) as a brown oil.

[1011] Synthesis of intermediate 288:

[1012] Intermediate 288 According to the procedure described for Intermediate 255 from Intermediate 287 (280 mg, 0.67 mmol) to give Intermediate 288 (234 mg, 90% yield) as a colorless oil.

[1013] Synthesis of intermediate 289:

[1014] Intermediate 289 According to the procedure described for Intermediate 37 from Intermediate 288 (234 mg, 0.60 mmol) to give Intermediate 289 (246 mg, quantitative yield) as a colorless oil.

[1015] Synthesis of intermediate 290:

[1016] Intermediate 290 According to the procedure described for Intermediate 96 from Intermediate 289 (245 mg, 0.59 mmol) to give Intermediate 290 (207 mg, 90% yield) as a light yellow oil.

[1017] Synthesis of intermediate 291:

[1018] Intermediate 291 According to the procedure described for Intermediate 108 from Intermediate 290(105 mg, 0.27 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (52 mg, 0.27 mmol) starting from the preparation of intermediate 291 (106 mg, 70% yield) as a white solid.

[1019] The following intermediate was prepared by an analogous procedure:

[1020]

[1021] Synthesis of intermediate 293:

[1022] Intermediate 293 According to the procedure described for intermediate 263 starting from the preparation of intermediate 283 (1.75 g, 5.96 mmol) to give intermediate 293 (651 mg, 40% yield) as a white solid.

[1023] Synthesis of intermediate 294:

[1024] Intermediate 294 According to the procedure described for intermediate 83 starting from the preparation of intermediate 293 (650 mg, 2.38 mmol) to give intermediate 294 (597 mg, 91% yield) as a grey solid.

[1025] Synthesis of intermediate 295:

[1026] Intermediate 295 According to the procedure described for intermediate 7 starting from the preparation of intermediate 294 (597 mg, 2.17 mmol) and cyclobutylmethylamine hydrochloride (316 mg, 2.6 mmol) to give intermediate 295 (610 mg, 82% yield) as a yellow oil.

[1027] Synthesis of intermediate 296:

[1028] Intermediate 296 According to the procedure described for intermediate 90a starting from the preparation of intermediate 295 (610 mg, 1.77 mmol) to give intermediate 296(711 mg, 90% yield) as a colorless oil.

[1029] Synthesis of intermediate 297:

[1030] Intermediate 297 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 colorless oil.

[1031] Synthesis of intermediate 298:

[1032] Intermediate 298 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 colorless oil.

[1033] Synthesis of intermediate 299:

[1034] Intermediate 299 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 colorless oil.

[1035] Synthesis of intermediate 300:

[1036] Intermediate 300 According to the procedure described for Intermediate 108 starting from Intermediate 299 (140 mg, 0.36 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (68.7 mg, 0.36 mmol) to give Intermediate 300 (174 mg, 86% yield) as a light yellow solid.

[1037] The following intermediates were prepared by analogous procedures:

[1038]

[1039] Synthesis of intermediate 302:

[1040] Intermediate 302 According to the procedure described for Intermediate 213 from Intermediate 281 (200 mg, 0.73 mmol) to give Intermediate 302 (153 mg, 73% yield) as a white solid.

[1041] Synthesis of intermediate 303:

[1042] Intermediate 303 According to the procedure described for Intermediate 83 from Intermediate 302 (174 mg, 0.53 mmol) to give Intermediate 303 (108 mg, 70% yield) as a yellow solid.

[1043] Synthesis of intermediate 304:

[1044] Intermediate 304 According to the procedure described for Intermediate 7 from Intermediate 303 (136 mg, 0.36 mmol) and cyclobutylmethylamine hydrochloride (48.7 mg, 0.40 mmol) to give Intermediate 304 (34 mg, 26% yield) as a brown oil.

[1045] Synthesis of intermediate 305:

[1046] Intermediate 305 According to the procedure described for Intermediate 90a from Intermediate 304 (68.5 mg, 0.19 mmol) to give Intermediate 305 (74 mg, 84% yield) as a brown oil.

[1047] Synthesis of intermediate 306:

[1048] Intermediate 306 According to the procedure described for Intermediate 168 from Intermediate 305 (44 mg, 0.096 mmol) to give Intermediate 306 (38 mg, quantitative yield) as a white solid.

[1049] Synthesis of intermediate 307:

[1050] Intermediate 307 According to the procedure described for Intermediate 37 from Intermediate 306 (58 mg, 0.14 mmol) to give Intermediate 307 (57 mg, 93% yield) as a yellow oil.

[1051] Synthesis of intermediate 308:

[1052] Intermediate 308 According to the procedure described for Intermediate 96 from Intermediate 307 (170 mg, 0.4 mmol) to give Intermediate 308 (39 mg, 24% yield) as a colorless oil.

[1053] Synthesis of intermediate 309:

[1054] Intermediate 309 According to the procedure described for Intermediate 108 from Intermediate 308 (46 mg, 0.11 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (21.7 mg, 0.11 mmol) to give Intermediate 309 (29 mg, 45% yield) as a yellow oil.

[1055] Synthesis of intermediate 310:

[1056] Intermediate 310 According to the procedure described for Intermediate 165 from 6-bromo-7-fluoroisoquinoline (250 mg, 1.1 mmol) to give Intermediate 310 (158 mg, 59% yield) as a light pink solid.

[1057] Synthesis of intermediate 311:

[1058] Intermediate 311 According to the procedure described for Intermediate 251 from Intermediate 310(500 mg, 2.1 mmol) starting from the preparation of the intermediate 311 (297 mg, 55% yield) as a light pink solid.

[1059] Synthesis of intermediate 312:

[1060] Intermediate 312 According to the procedure described for the intermediate 165 starting from the preparation of the intermediate 311 (3.84 g, 14.7 mmol) to yield the intermediate 312 (1.3 g, 33% yield) as a white solid.

[1061] Synthesis of intermediate 313:

[1062] Intermediate 313 According to the procedure described for the intermediate 251 starting from the preparation of the intermediate 312 (1.3 g, 4.8 mmol) to yield the intermediate 313 (700 mg, 49% yield) as a white solid.

[1063] Synthesis of intermediate 314:

[1064] To a solution of the intermediate 313 (393 mg, 1.33 mmol) in THF (14.8 mL) was added dropwise nBuLi (2.5 M in THF, 0.64 mL, 1.6 mmol) under N2atmosphere at -78 °C. The resulting solution was stirred at -78 °C for 30 min, then DMF (0.39 mL) was added and the reaction was stirred at room temperature for 1 h. 10% aqueous NH4CI solution was added and the residue was extracted twice with EtOAc. The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum to yield the crude product. The crude product was purified by normal phase chromatography (elution with heptane:EtOAc = 100:0-90:10) to yield the intermediate 314 (102 mg, 31%) as a white solid.

[1065] Synthesis of intermediate 315:

[1066] Intermediate 315 According to the procedure described for the intermediate 7 starting from the preparation of the intermediate 314(102 mg, 0.42 mmol) and cyclobutylmethanamine hydrochloride (50.8 mg, 0.42 mmol) starting from intermediate 315 (96 mg, 73% yield) as a colorless oil.

[1067] Synthesis of intermediate 316:

[1068] Intermediate 316 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.

[1069] Synthesis of intermediate 317:

[1070] Intermediate 317 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 colorless oil.

[1071] Synthesis of intermediate 318:

[1072] Intermediate 318 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.

[1073] Synthesis of intermediate 319:

[1074] Intermediate 319 According to the procedure described for intermediate 108 starting from intermediate 318 (63 mg, 0.16 mmol) and 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (29.7 mg, 0.16 mmol) to give intermediate 319 (56 mg, 62% yield) as a white solid.

[1075] Preparation of the final compound

[1076] Synthesis of Compound 1:

[1077] To a solution of intermediate 8 (126 mg, 0.37 mmol), 4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxylic acid (85.1 mg, 0.45 mmol) and HATU (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 room temperature for 16 h. Water was added and the residue was extracted with EtOAc three times. The organic layers were combined, dried over MgS04, filtered and concentrated under vacuum to give the crude product. The crude product was purified by NH2silica gel chromatography eluting with heptane: [EtOAc / MeOH 3 / 1] = 100:0-20:80 to give an intermediate impure material which was further purified by reverse phase column chromatography eluting with MeCN / 0.2% NH4HCO3 in water (pH = 7.9) = 50:50-75:25 to give compound 1 (45 mg, 25% yield) as a white solid. Scoupa_2886_1

[1078] The following compounds were prepared by analogous procedures:

[1079]

[1080] Synthesis of compound 7:

[1081] a) Synthesis of intermediate 12:

[1082] Intermediate 12 Following the procedure described for the synthesis of Compound 1 starting from intermediate 8 and 9 and gave intermediate 12 (84 mg, 78% yield) as a red oil.

[1083] b) Synthesis of compound 7 in step 5:

[1084] To a solution of intermediate 12TFA (431 mg, 3.78 mmol, 0.28 mL) was added to a solution of (80 mg, 0.14 mmol) in DCM (0.15 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum to give the crude product. The crude product was purified by reversed-phase column chromatography (eluting with MeCN / 0.2% NH4HCO3 aqueous solution (pH = 7.9) = 35:65-55:45) to give compound 7 (3 mg, 5% yield) as a white solid.

[1085] Synthesis of compound 8:

[1086] intermediate 15 A mixture of 1-{3-fluorobicyclo[1.1.1]pent-1-yl}methylamine hydrochloride (86 mg, 0.23 mmol), TEA (69.4 mg, 0.69 mmol, 0.095 mL), and sodium triacetoxyborohydride (96.9 mg, 0.46 mmol) in DCM (2.3 mL) was stirred at room temperature for 10 min (until completely dissolved), and then sodium triacetoxyborohydride (96.9 mg, 0.46 mmol) was immediately added. The reaction mixture was stirred at room temperature for 16 h. Volatile substances were removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was washed again with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give the crude material. The crude product was purified by silica gel chromatography (eluting with DCM:MeOH = 100:0-95:5) to obtain the product, which was further purified by reversed-phase column chromatography (eluting with MeCN / aq HCO2NH4 0.6 g / L (pH = 3.5) = 10:90-50:50) to obtain compound 8 (27 mg, 25% yield), which was a white solid.

[1087] The following compounds were prepared using similar steps:

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094] Synthesis of compound 143:

[1095] A mixture of intermediate 324 (5 mg, 0.014 mmol), 1-cyclobutylmethanamine hydrochloride (2 mg, 0.017 mmol) and TEA (4.24 mg, 0.042 mmol, 5.82 µL) in 1,1,1,3,3,3-hexafluoroisopropanol (235 µL) was stirred at rt for 1 h, then NaBH4(8.13 mg, 0.21 mmol) and few drops of MeOH were added and stirred at rt for 5 min. MeOH was added and volatiles were removed under reduced pressure to give crude material. The crude product was purified by silica gel chromatography eluting with DCM:MeOH = 100:0 to 98:2 to give compound 143 (3 mg, 49% yield) as a white solid.

[1096] The following compounds were prepared by analogous procedures:

[1097]

[1098] Synthesis of compounds 56 and 57:

[1099] a) Synthesis of intermediate 71:

[1100] Intermediate 71 Following the procedure described for the synthesis of Compound 8 starting from intermediate 15 and ((rac-trans)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanamine to give intermediate 71 (151 mg, 76% yield) as a yellow oil.

[1101] b) Synthesis of compounds 56 and 57:

[1102] 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 eluting with DCM:MeOH = 100:0 to 98:2. The two enantiomers were separated by SFC (eluting with CO2 / (MeOH + DCM [50 / 50] + 0,3% iPrNH2) = 65 / 35) to give Compound 56(24 mg, 17% yield) as a light beige solid, and Compound 57 (29 mg, 21% yield) as a light beige solid.

[1103] Synthesis of compound 24:

[1104] Compound 24 was prepared according to the procedure described for Compound 8, starting from intermediate 22 (84 mg, 0.207 mmol) and 1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methanamine hydrochloride (26.1 mg, 0.17 mmol) to give Compound 24 (11 mg, 13% yield) as a white solid.

[1105] The following compounds were prepared by analogous procedures:

[1106]

[1107] Synthesis of compound 28:

[1108] Compound 28 was prepared according to the procedure described for Compound 8, starting from intermediate 28 (12.4 mg, 30.7 µmol) and 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (17 mg, 37 µmol) to give Compound 28 (4 mg, 11% yield) as a white solid.

[1109] The following compounds were prepared by analogous procedures:

[1110]

[1111] Synthesis of compounds 60 and 61:

[1112] To intermediate 74(143 mg, 0.35 mmol) and l-{3-fluorobicyclo[l.l.l]pentan-l-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. The volatiles were removed under reduced pressure. The residue was partitioned between saturated aqueous NaHC03and EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under vacuum to give crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-95:5 to give compound (80 mg, 47% yield) as a racemic mixture. The racemic material was purified by chiral SFC (eluting with C02 / (MeOH + 0.3% i PrNH2) 55 / 45) to give compound 60 (25 mg, 31% yield) as a white solid and compound 61 (25 mg, 31% yield) as a white solid.

[1113] The following compounds were prepared by analogous procedures:

[1114]

[1115] Synthesis of compound 30:

[1116] Compound 30 was prepared according to the procedure described for compound 8 starting from intermediate 32 (76 mg, 0.24 mmol) and 4-oxopyrido[l,2-a]pyrimidine-2-carboxylic acid (50 mg, 0.26 mmol) to give compound 30 (22 mg, 19% yield) as a white solid.

[1117] Synthesis of compound 31:

[1118] Intermediate 37A solution of compound 31 (100 mg, 0.23 mmol), 8-ethynylimidazo[l,5- a]pyridine (52 mg, 0.23 mmol), sodium ascorbate (36 mg, 0.23 mmol) and CuS04(4.9 mg, 0.03 mmol) in DMF (1.65 mL) / water (0.37 mL) was stirred at room temperature for 4 h. The mixture was diluted with water and DCM. The organic layer was separated and then concentrated under vacuum to give crude material. The crude product was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-98:2 to give compound 32 (56 mg, 78% yield) as a white solid.

[1119] The following compounds were prepared by analogous procedures:

[1120]

[1121] Synthesis of compound 35:

[1122] Compound 35 was prepared according to the procedure described for compound 8 starting from intermediate 45 (100 mg, 0.27 mmol) and l-{3-fluorobicyclo[l. l. l]pentan-l-yl}methanamine hydrochloride (49 mg, 0.32 mmol) to give compound 35 (21 mg, 17% yield) as a white solid.

[1123] The following compounds were prepared by analogous procedures:

[1124]

[1125] Synthesis of compound 38:

[1126] Compound 38 was prepared according to the procedure described for compound 1 starting from intermediate 54 (64 mg, 0.23 mmol) and 4-oxopyrido[l,2-a]pyrimidine-2-carboxylic acid (42.9 mg, 0.23 mmol) to give compound 38 (30 mg, 29% yield) as a white solid

[1127] Synthesis of compound 39:

[1128] Compound 39 was prepared according to the procedure described for compound 8 starting from intermediate 59(71 mg, 0.2 mmol) and cyclohexanemethylamine (25 mg, 3.11 mmol, 28.4 µL) starting from the preparation to obtain the final compound 39 (14 mg, 8% yield) as a white solid.

[1129] Synthesis of compound 40:

[1130] Compound 40 was prepared according to the procedure described for compound 1 from intermediate 63 (50 mg, 0.12 mmol) and 4-oxo-pyrido[l,2-a]pyrimidine-2-carboxylic acid (33 mg, 0.17 mmol) starting from the preparation to obtain the final compound, compound 40 (3 mg, 5% yield) as a white solid.

[1131] Synthesis of compound 41:

[1132] Compound 41 was prepared according to the procedure described for compound 1 from intermediate 66 (6 mg, 0.03 mmol) and 4-oxo-pyrido[l,2-a]pyrimidine-2-carboxylic acid (7 mg, 0.03 mmol) starting from the preparation to obtain compound 41 (3 mg, 28% yield) as a white solid.

[1133] Synthesis of compound 42:

[1134] Compound 42 was prepared according to the procedure described for final compound 1 from intermediate 70 (66 mg, 0.23 mmol) and 4-oxo-pyrido[l,2-a]pyrimidine-2-carboxylic acid (48.5 mg, 0.26 mmol) starting from the preparation to obtain the final compound, compound 42 (8 mg, 7% yield) as a white solid.

[1135] Synthesis of compound 89:

[1136] To intermediate 153To a solution of intermediate (17 mg, 0.025 mmol) in MeCN (0.16 mL) were added thiophenol (5.57 mg, 0.051 mmol, 5.2 μί) and Cs2C03(16.5 mg, 0.051 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated H20 and extracted with a mixture of CHCI3 / IPA (3 / 1). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to dryness to give the crude product. The crude material was purified by C18 silica gel chromatography eluting with water + 0.1 F formic acid: MeCN = 85:15 to 70:30 to give (1.7 mg, 13% yield) as a white solid.

[1137] The following compounds were prepared by analogous procedures:

[1138]

[1139] Synthesis of compound 94:

[1140] a) Synthesis of intermediate 164:

[1141] To a vial was added potassium (bromomethyl)trifluoroborate (1 g, 4.98 mmol) followed by THF (2.5 mL), t-butanol (1.25 mL) and 1-cyclobutylmethanamine (509 mg, 5.98 mmol). The vial was sealed and placed in a drysin at room temperature and stirred at 80 °C for 2 h. The volatiles were removed under vacuum. The crude solid was dried and then dissolved in hot MeCN solution and the solution was filtered to give intermediate 164 (536 mg, 64% yield) as a white solid.

[1142] Synthesis of compound 94:

[1143] To a solution of intermediate 122 3 (100 mg, 0.23 mmol) and intermediate 164A mixture of compound 87 (87.7 mg, 0.27 mmol), Cs2C03(222 mg, 0.68 mmol) in dioxane (0.95 mL) and H20 (0.095 mL) was added di-µ-iodobis(tri-tert-butylphosphine)palladium(II) (9.92 mg, 0.011 mmol). The reaction mixture was purged with N2and then heated to 100 °C for 15 h. Water was added and the residue was extracted twice with EtOAc and once with CHCl3 / IPA (3 / 1). The organic phases were combined, dried over MgS04, filtered and evaporated to give the crude material. The crude material was purified by silica gel chromatography eluting with DCM:MeOH = 100:0-85:15 to give compound 94 (17 mg, 16% yield) as a light yellow solid.

[1144] The following compounds were prepared by analogous procedures:

[1145]

[1146] Synthesis of compound 96:

[1147] Compound 96 was prepared according to the procedure described for intermediate 8 starting from intermediate 113 (200 mg, 0.36 mmol) to give the final compound, compound 96 (147 mg, 90% yield) as a white solid.

[1148] The following compounds were prepared by analogous procedures:

[1149]

[1150] Synthesis of Compound 100:

[1151] 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 room temperature for 1 h. DCM and saturated aqueous Na2C03solution were added. The organic layer was washed twice with saturated aqueous Na2C03solution, dried over MgS04, filtered and concentrated under reduced pressure to give compound 100 (115 mg, 93% yield) as a white solid.

[1152] The following compounds were prepared by analogous procedures:

[1153]

[1154]

[1155]

[1156]

[1157]

[1158] Synthesis of compound 137:

[1159] Compound 137 was prepared according to the procedure described for intermediate 8 starting from intermediate 261 (50 mg, 0.085 mmol) to give the final compound, Compound 137 (15 mg, 36% yield), as a white solid.

[1160] The following compounds were prepared by analogous procedures:

[1161]

[1162] LCMS (Liquid chromatography / mass spectrometry)

[1163] LCMS General Steps

[1164] High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array detector (DAD) or a UV detector and the columns specified in the respective methods. Additional detectors can be included if necessary (see table of methods below).

[1165] The flow from the column was introduced into a mass spectrometer (MS) configured with an atmospheric pressure ion source. The tuning parameters (e.g. scan range, dwell time...) were set so as to obtain ions allowing the identification of the nominal monoisotopic molecular weight (MW) of the compounds within the skill of the person. Data acquisition was performed using appropriate software.

[1166] Compounds are described by their experimental retention time (R t ) and ions. If not differently specified in the data table, the molecular ion reported corresponds to [M+H] + (protonated molecule) and / or [M-H] - (deprotonated molecule). In case the compound cannot be ionized directly, the type of adduct is specified (i.e. [M+NH4] + , [M+HCOO] -The reported values are obtained for the lowest isotope mass. All results are obtained under experimental uncertainties, which are usually related to the method used.

[1167] In the following, "MSD" means mass selective detector, "DAD" means diode array detector.

[1168] Table: LCMS method codes (flow in mL / min; column temperature (T) in °C; run time in min).

[1169]

[1170] Table: Retention time (R t )(min), [M+H] + Peak (protonated molecule), LC / MS method

[1171] Compound numbering [R t ]]> [[M+H] + ]]> LCMS method 1 3.13 474.3 1 2 2.92 446.3 1 3 2.92 446.3 1 4 2.81 446.3 1 5 2.98 437.3 1 6 2.90 492.3 1 7 3.06 447.3 1 8 2.66 476.2 1 9 3.02 474.3 1 10 2.37 476.2 1 11 3.09 472.3 1 12 3.53 474.2 1 13 2.67 446.2 1 14 2.61 482.2 1 15 2.54 446.3 1 16 3.00 460.3 1 17 2.23 432.3 1 18 2.63 458.2 1 19 2.40 446.2 1 20 5.60 462.5 2 21 5.94 476.4 2 22 6.57 460.4 2 23 9.13 472.4 3 24 2.73 506.2 1 25 2.80 478.3 1 26 2.79 488.2 1 27 2.71 488.2 1 28 3.10 504.3 1 29 2.86 476.3 1 30 3.24 492.3 1 31 3.11 470.3 1 32 3.14 470.3 1 33 3.23 461.3 1 34 3.20 500.3 1 35 2.85 472.3 1 36 2.75 473.3 1 37 2.71 502.2 1 38 2.57 456.3 1 39 1.07 456.3 1 40 2.11 472.3 1 41 2.41 456.3 1 42 2.44 457.3 1 43 1.25 460.4 1 44 1.24 460.4 1 45 6.57 472.6 2 46 6.09 458.6 2 47 3.21 474.3 1 48 5.94 476.5 2 49 6.27 460.6 2 50 5.65 462.6 2 51 2.99 490.2 1 52 2.95 490.2 1 53 2.95 490.2 1 54 3.46 488.4 1 55 6.89 500.7 2 56 2.27 476.2 1 57 2.28 476.2 1 58 6.66 502.6 2 59 2.67 476.4 1 60 2.81 490.2 1 61 2.81 490.2 1 62 6.68 490.5 2 63 6.69 520.5 2 64 3.78 470.5 2 65 3.79 470.5 2 66 3.76 484.4 2 67 5.80 458.5 2 68 3.74 460.5 2 69 2.60 506.4 1 70 2.37 476.4 1 71 2.81 457.2 1 72 2.48 427.2 1 73 2.40 476.2 1 74 2.22 446.5 1 75 2.64 472.3 1 76 2.46 442.4 1 77 2.45 532.4 1 78 2.35 518.3 1 79 3.58 442.5 3 80 3.87 494.4 3 81 3.92 464.4 3 82 5.74 476.6 2 83 5.74 446.6 2 84 5.58 458.5 2 85 2.49 476.4 1 86 2.29 446.4 1 87 2.87 472.3 1 88 2.48 502.5 1 89 5.75 488.5 2 90 5.88 458.4 2 91 6.20 446.4 2 92 5.56 488.4 2 93 5.62 458.3 2 94 2.72 458.3 1 95 2.48 446.3 1 96 2.42 460.3 1 97 2.96 471.3 1 98 3.20 484.5 3 99 1.99 429.3 2 100 3.03 472.4 1 101 3.16 486.4 1 102 4.33 444.5 3 103 4.09 430.6 3 104 2.56 476.4 1 105 4.25 444.6 2 106 2.53 421.4 1 107 4.43 449.2 2 108 3.96 473.4 2 109 4.01 472.5 2 110 3.53 522.5 2 111 3.94 516.5 2 112 3.85 476.5 2 113 3.02 460.4 1 114 2.54 490.4 1 115 3.12 486.2 1 116 2.93 472.2 1 117 5.52 502.6 2 119 4.27 461.5 2 120 3.09 494.4 1 121 3.80 501.4 2 122 3.33 442.5 2 123 3.40 428.5 2 124 3.30 456.5 2 125 2.90 457.3 1 126 2.86 462.3 1 127 2.42 472.4 1 128 2.20 472.4 1 129 2.16 458.2 1 130 2.53 472.3 1 131 2.40 459.3 1 132 2.65 473.3 1 133 2.79 460.2 1 134 3.05 474.5 1 135 4.33 476.5 2 136 3.10 476.4 1 137 2.04 488.3 1 138 3.54 416.5 2 139 1.94 462.5 1 140 4.41 458.5 2 141 6.68 488.6 2 142 3.91 488.7 2 143 3.59 428.4 2 144 3.56 458.5 2 145 3.55 444.6 2

[1172] NMR

[1173] Some NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a Bruker 5 mm BBFO probe with z-gradient and operated at 500 MHz for protons and at 471 MHz for fluorine. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.

[1174] Table: 1 H NMR and 19 F NMR results

[1175]

[1176]

[1177] Pharmacology section

[1178] MTase Glo assay

[1179] Methyltransferase activity of METTL3 was measured using a bioluminescence assay with the MTase-Glo™ Methyltransferase Assay Kit from Promega (V7602).

[1180] The enzyme used was a recombinant METTL3 / METTL14 complex expressed in Sf9 cells purchased from Actif Motif, comprising a full-length human METTL3 protein (accession number NP_062826.2) without tag and a full-length human METTL14 protein (accession number NP_066012.1) with a N-terminal FLAG tag. 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. The enzymatic reaction was performed in Optiplate 96 half-area (Perkin Elmer 6002290) using 10 mΐ of a final volume containing 20 mM Tris-HCl pH 7.5, 0.01% Triton X-100 and 2 mM MgCh, in duplicate. The experiment was also performed independently in duplicate.

[1181] METTL3 / 14 solution containing the RNA substrate (10 pM) and MTaseGlo™ reagent for the conversion of the produced SAH into ADP at a final concentration of 20 nM were pre-incubated with different concentrations of compounds for 10 min at room temperature (final compound concentration range from 5 pM to 0.25 nM, final DMSO residue of 1%). Then 0.6 pM final concentration of SAM was added and the enzymatic reaction was incubated for 60 min at room temperature. The MTaseGlo™ detection solution for the conversion of ADP into ATP was added and the resulting reaction mixture was incubated for additional 60 min at room temperature.

[1182] The luminescence signal was measured with a plate reading luminometer (SpectraMax i3X) and correlated with the SAH concentration. The percentage of inhibition was obtained by normalizing to the non-inhibited control well (DMSO only). IC 50 Values were calculated using a four-parameter non-linear regression analysis by measuring the enzyme activity within a dilution series of the inhibitor concentration (10 different concentrations, third dilution).

[1183] Proliferation assay

[1184] MOLM-13 and Kasumi-1 cells were plated at 1200 and 10000 cells / well, respectively, in 384-well plates (Greiner 781080) in a volume of 27 mΐ in RPMI 1640 medium containing 10% fetal bovine serum, 2 mM glutamine and 0.2% penicillin / streptomycin, in quadruplicate. Cells were treated by adding 3 mΐ of compound / medium intermediate concentrations resulting in a final concentration range of 50 mM to 2.54 nM with a final residual DMSO of 0.5%. The compound / medium intermediate concentration 10X dilution plates were prepared by mixing 5 mΐ of compound in 100% DMSO from the initial compound dilution plates (concentration range 10 mM to 508 nM in 100% DMSO) with 95 mΐ of medium. Cells were incubated at 37°C in the presence of 5% CO2 and a humidified atmosphere. Luminescent signal was measured on day 5 using CellTiter-Glo® Luminescent Cell Viability Assay (30 mΐ / well; Promega, G7572) to calculate the relative cell proliferation compared to cell control wells treated with 0.5% DMSO only and cell free control wells.

[1185] Table: Biochemical and proliferation data

[1186] Compound numbering METTL3 IC 50 (nM) MOLM-13 IC 50 (µM)]]> Kasumi-1 IC 50 (µM)]]> 1 40 13.5 19 2 172 6.8 9.5 3 63 10.8 14.6 4 162 10 16.7 5 176 23 24.3 6 103 12.2 15.1 7 49 12.5 12.3 8 25 4.6 6.9 9 430 ND ND 10 191 19 19.1 11 74 15 17.2 12 154 >42 >46 13 302 ND ND 14 307 ND ND 15 81 7.6 4.7 16 152 24.4 32.8 17 521 ND ND 18 29 9.5 5.4 19 121 10.7 8.8 20 236 ND ND 21 237 ND ND 22 267 ND ND 23 256 ND ND 24 <10 3.6 2.2 25 12 2.8 3.6 26 <10 4.2 0.3 27 16 5.3 0.72 28 21 7.2 5.1 29 23 7.6 6.1 30 53 23.7 25.9 31 29 5.9 9.9 32 261 7.2 13.6 33 756 ND ND 34 38 18.8 20 35 28 ND ND 36 69 ND ND 37 19 2.2 2.3 38 71 12.8 9.1 39 674 ND ND 40 126 26.6 26.8 41 93 34.2 36.4 42 270 32.8 29.4 43 157 ND ND 44 105 ND ND 45 63 7.4 7.3 46 362 ND ND 47 31 8.0 10.4 48 111 8.5 7.3 49 139 ND ND 50 230 ND ND 51 62 13.1 13.8 52 137 17.8 21.3 53 75 11 20.5 54 101 25.8 >39 55 166 18.6 15.4 56 1350 ND ND 57 282 ND ND 58 25 16.1 10.3 59 64 11.8 3.6 60 157 20.4 20.6 61 635 ND ND 62 286 ND ND 63 114 15.1 7.5 64 47 22.1 10 65 31 7.9 4.5 66 28 7.1 8.1 67 90 15.1 9.4 68 44 6.9 20 69 48 7.5 9.3 70 164 ND ND 71 20 11.9 10.2 72 80 8.0 7.6 73 42 7.4 14 74 151 ND ND 75 13 7.5 4.5 76 49 7.3 4.4 77 36 5.2 7.2 78 40 9 19;1 79 90 13.9 8.5 80 34 11.6 16.6 81 122 ND ND 82 32 7.7 9.3 83 106 13.1 12.2 84 75 32.9 14.4 85 36 19.9 15.6 86 119 32.4 10.2 87 51 11.9 6.6 88 27 5.7 5.7 89 22 4.9 3.7 90 54 3.8 4.8 91 310 ND ND 92 95 11.6 18.8 93 800 ND ND 94 121 7.3 12.3 95 92 6.6 5 96 75 ND ND 97 277 ND ND 98 11 2 1.9 99 409 ND ND 100 11 0.89 1.4 101 17 1.7 3.2 102 11 1.5 1.1 103 40 4 3 104 36 5.3 4.3 105 57 2.5 2.9 106 89 ND ND 107 73 ND ND 108 193 ND ND 109 10 2.1 1.9 110 97 ND ND 111 14 1.9 2 112 13 3.1 2.3 113 10 ND ND 114 12 ND ND 115 67 ND ND 116 30 ND ND 117 42 3.9 3 119 18 ND ND 120 77 ND ND 121 33 ND ND 122 53 9.6 3.3 123 <10 1.0 0.75 124 <10 0.56 0.63 125 22 ND ND 126 46 ND ND 127 58 ND ND 128 56 ND ND 129 18 4.1 2.5 130 <10 ND ND 131 43 ND ND 132 <10 ND ND 133 30 5.1 2.1 134 <10 ND ND 135 89 ND ND 136 16 2.9 2.5 137 18 ND ND 138 143 ND ND 139 151 ND ND 140 21 1.1 1.4 141 <10 1.2 1.9 142 55 6.6 3.1 143 86 30.3 7.9 144 21 5.9 10.4 145 119 ND ND

[1187] ND: not determined

[1188] References

[1189] The mention of patents, patent applications, publications, or other documents herein to

[1190] (1) Barbieri I &. Kouzarides T (2020) Role of RNA modifications in cancer. Nat Rev Cancer. 20(6):303-322;

[1191] (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;

[1192] (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;

[1193] (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;

[1194] (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;

[1195] (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;

[1196] (7) WO2020201773;

[1197] (8) WO2021111124;

[1198] (9) WO2022074379;

[1199] (10) WO2022074391;

[1200] (11) WO2022254216;

[1201] (12) WO2022254218;

[1202] (13) WO2021079196;

[1203] (14) WO2021081211;

[1204] (15) WO2022081739.

Claims

1. Compound of formula (I), Or its tautomers, stereoisomers, salts, solvates or N-oxides, wherein A 1 Represents CR 1a Or N; A 2 Represents CR 2a Or N; A 3 Represents CR 3a Or N; A 4 Represents CR 4a Or N; A 5 Represents CR 5a Or N; A 6 Represents CR 6a Or N; The condition is A 1 A 2 A 3 A 4 A 5 and A 6 No more than 3 characters represent N; R 1a To R 6a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclic groups, C 3-4 Cycloalkyloxy or 3- to 5-membered heterocyclic alkyloxy, wherein the C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 cycloalkyl, 3- to 5-membered heterocyclic groups, C 3-4 Each of the cycloalkyloxy group or the 3- to 5-membered heterocyclic alkyloxy group is optionally substituted by one or more substituents selected from the following: cyano, hydroxyl, halogen, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2, -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl and OC 3-6 cycloalkyl; R 7a and R 7b Selected independently from: (i)Hydrogen; (ii)C 1-6 Alkyl groups, optionally composed of one or more radicals selected from halogens, cyano groups, hydroxyl groups, C6 groups, and C7 groups. 1-4 Alkoxy, C 1-4 Substitution of haloalkoxy groups, (iii) or R 7a and R 7b Together with the carbon atoms they are attached to, they form 3 to 6-membered cycloalkane diols or heterocyclic groups. R 8a and R 8b Independently (i)Hydrogen, (ii)C 1-6 Alkyl groups, optionally composed of one or more radicals selected from cyano, hydroxyl, halogen, C 1-2 Alkoxy, C 1-2 Substitution of haloalkoxy groups, (iii) Equation - (CR) c R d ) n -Z groups, in which n is 0, 1, or 2. R c and R d Selected independently from: o hydrogen o C 1-6 Alkyl groups, optionally composed of one or more radicals selected from cyano, hydroxyl, halogen, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl substituents are used for substitution, and where C... 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from halogen, cyano and hydroxyl groups; o or R c and R d Together with the carbon atoms to which they are attached, they form 3 to 6-membered cycloalkanediyl or heterocyclic groups, which are optionally connected by one or more groups selected from cyano, hydroxyl, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Substituents of haloalkoxy groups; And Z is selected from o Hydrogen, cyano group, hydroxyl group; o NR a R b or -S(O) 0-2 R a R b , where R a and R b For H or C 1-2 Alkyl groups, and o C 2-3 alkenyl, C 2-3 alkynyl group, C 3-8 Cycloalkyl, aryl, heterocyclic, heteroaryl, bicyclic C 5-12 Cycloalkyl groups, each optionally radicalized by one or more groups selected from halogen, cyano, hydroxyl, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b Substituents of R, wherein R a and R b For H or C 1-2 alkyl; iv) or R 8a and R 8b Together with the nitrogen atoms to which they are attached, they form monocyclic or bicyclic heterocyclic groups, which are optionally connected by one or more elements selected from halogen, cyano, hydroxyl, C, and hydroxyl groups. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b Substituents of R, wherein R a and R b Independently H or C 1-4 alkyl; X is selected from , , , or ; The dashed lines represent points connected to Y, and the wavy lines represent points connected to the rest of the molecule; R c and R d Independently selected from hydrogen and C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups; R e and R f Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, wherein C 1-4 Alkyl groups are optionally surrounded by one or more groups selected from halogens, hydroxyl groups, cyano groups, and C. 1-4 Substitution of alkoxy groups; R c R d and R e R f They can connect together, so that together with the carbon atoms they are attached to, they form C. 3-4 Cycloalkyldiyl, the C 3-4 The cycloalkane diene is optionally surrounded by one or more radicals selected from halogen, methyl, cyano, hydroxyl, and C. 1-4 Substitution of alkoxy groups; Y is selected from one of the following structures: i) in: G1 is selected from CR h and N, where R h Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 5- or 6-membered heteroaryl, 3- to 4-membered heterocyclic and -OC 3-4 cycloalkyl; G2 is selected from N and CR g , where R g Selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6-membered heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl groups, heterocyclic groups, -O- (carbon-linked heterocyclic groups), -(OCH2CH2) m -NR y R z -(OCH2CH2) m -OCH3, NR y R z and -C(O)-NR y R z ; Where m is an integer from 1 to 6, and R y and R z Each independently is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups linked to 3 to 6 carbons, or R y and R z Together with the nitrogen atoms they are attached to, they form 3 to 6-membered heterocyclic groups; Where C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6-membered heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Any one of cycloalkyl, heterocyclic, and -O- (carbon-linked heterocyclic) groups may optionally be selected from one or more groups selected from hydroxyl, cyano, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, NR a R b or -S(O) 0-2 R a R b Substituents of R, wherein R a and R b Independently H or C 1-2 alkyl; G3 is N or CR i , where R i Selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from halogens, methyl groups, and methoxy groups; G4 is selected from C and N; G5 is selected from CR j and NR x ,in: R j Selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, NH2 and C 1-4 Alkoxy; and R x Selected from hydrogen and C 1-4 alkyl; G7 represents N and NR. a or CR j , G8 is selected from C and N. The condition is that no more than four of G1 to G8 are selected, with one, two, or three preferably being N or NR. a ; ii) , Y2 is selected from CR k and N; where R k Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, 3- to 4-membered heterocyclic groups and C 3-4 Cycloalkoxy; Y3 is N or CR l , where R l Selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group is optionally substituted by one or more substituents selected from halogens, methyl groups, and methoxy groups; Y4 is either C or N; Y5 is CR m or NR x ,in: R m Selected from hydrogen, halogen, hydroxyl, cyano, C 3-6 cycloalkyl, NH2, C 1-4 Alkyl groups and optionally OH, C 1-4 Alkoxy and C 3-6 Cycloalkyl-substituted C 1-4 alkyl; R x Selected from hydrogen and C 1-4 alkyl; Y6 is CR m Or N; Y7 represents O, S, and CR. m Or N; Y8 is either C or N; Y9 is CR m Or N; The condition is that no more than four of Y1 to Y8 are N; iii) X1 is N or CR n , where R n Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; X2 is N or CR n ; X3 is N; X4 is either N or C; X5 is selected from N and CR. n and CR n R n1 ;in: R n and R n1 Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; Any X6 and X7 are independently CR n Or N; or X6 is CR n R n1 or NR x And X7 is CR n R n1 CR o R o1 or NR x ,in: R n and R n1 Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; R x It is hydrogen or C 1-4 Alkyl; and R o and R o1 Independently selected from hydrogen, halogen, methoxy, and methyl; X8 represents N and CR. n or CR n R n1 , where R n and R n1 Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; and X9 is either N or C; The condition is that no more than four of X2 to X9 are N; iv) L1-L7 are independently N or CR n , where R n Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups, The condition is that no more than three of L1 to L7 are N; v) E1 is either CR1 or N; E2 is either CR2 or N; E3 is either CR3 or N; E4 is either CR4 or N. E5 is either CR5 or N; E6 is NR6 or CR 6a R 6b ; Among them, R1, R2, R3, R4, R5, R 6a and R 6b Each is independently selected from hydrogen and NR. y1 R y2 Halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(C 1-4 Alkyl group 2, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 and C that is optionally replaced by OH 3-6 cycloalkyl, wherein R x1 and R x2 Independently selected from hydrogen and C 1-4 Alkyl (e.g., methyl), and wherein R y1 and R y2 Independently selected from hydrogen and C 3-6 cycloalkyl groups and optionally C 3-6 Cycloalkyl-substituted C 1-4 Alkyl, such as methyl, or, R y1 and R y2 Together with the N carrying them, they form a 5- or 6-membered heteroaryl or heterocyclic group, which is optionally surrounded by OH, C 1-4 Alkoxy or C 1-4 Alkyl substitution, the C 1-4 Alkyl groups are optionally surrounded by OH or C 1-4 Alkoxy substitution, wherein the heterocyclic group is a 4- to 7-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein each ring of the bicyclic heterocyclic group has 3 to 6 members; and R6 is selected from hydrogen, NH2, halogen, cyano, and C. 1-4 alkyl; or R5 and R4, together with the atoms they are attached to, form 5- or 6-membered heterocyclic groups. Alternatively, R4 and R3 can be linked with the atoms they are attached to to form 5- or 6-membered heterocyclic groups. The 5- or 6-membered heterocyclic group is optionally surrounded by one or more groups selected from oxo, cyano, hydroxyl, halogen, C 1-2 Alkyl, C 3-6 cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, NR y1 R y2 or -S(O) 0-2 R y1 R y2 Substituents of R, wherein R y1 and R y2 For H or C 1-2 alkyl; The condition is that no more than three of E1 to E5 are N.

2. The compound of claim 1, wherein A 1 Represents CR 1a Or N; A 2 Represents CR 2a Or N; A 3 Represents CR 3a Or N; A 4 Represents CR 4a Or N; A 5 Represents CR 5a Or N; A 6 Represents CR 6a Or N; The condition is A 1 A 2 A 3 A 4 A 5 and A 6 The 0, 1, or 2 in the text represent N; Especially R 1a To R 6a Each independently represents hydrogen, hydroxyl, halogen, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy; preferably wherein R 2a R 3a R 4a and R 6a Each represents H, and R is one of them. 1a and R 5a Each independently represents hydrogen, hydroxyl, halogen, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C 1-4 Alkyl group.

3. The compound according to claim 1 or 2, wherein Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 Especially R 1a To R 6a Each independently represents hydrogen, hydroxyl, halogen, cyano, and C. 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Alkoxy, the C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl or C 1-4 Each of the alkoxy groups is optionally surrounded by one or more groups selected from cyano, hydroxyl, halogen, -C(O)NH2, -C(O)NH(C 1-4 Alkyl), -C(O)N(C 1-4 Alkyl)2, -CO2H, -CO2(C 1-4 Alkyl), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl and C 1-4 Substitution of alkyl halogens.

4. The compound according to any one of claims 1 to 3, wherein R 7a For H and R 7b C is hydrogen or optionally substituted with one or more substituents selected from the following 1-6 Alkyl groups: halogen, cyano, hydroxyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups, especially those selected from hydroxyl and C 1-4 Alkoxy; preferably, R 7a and R 7b Both are hydrogen.

5. The compound according to any one of claims 1 to 4, wherein R 8a Let H be the number of 'R', and R be the number of 'R'. 8b For the formula - (CR) c R d ) n -Z groups, such as -(CHR) d ) n -Z, and especially -CHR d -Z or -Z, where R d Hydrogen is preferred. or R 8a and R 8b Together with the nitrogen atoms to which they are attached, they form monocyclic or bicyclic heterocyclic groups, which are optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b Preferably, the substituents are selected from halogens, hydroxyl groups, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 2-3 Alkenyl group.

6. The compound according to any one of claims 1 to 5, wherein Z is C 3-8 cycloalkyl or bicyclic C 5-8 Cycloalkyl groups, wherein each is optionally radically selected from one or more groups selected from halogen, cyano, hydroxyl, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 2-3 alkenyl, NR a R b and -S(O) 0-2 R a R b The substituents are replaced, for example by one or more, especially one or two, selected from halogens such as fluorine, hydroxyl, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Hydroxyalkyl, C 1-2 Alkoxy and C 1-2 Substituents of haloalkoxy groups.

7. The compound of any one of claims 1 to 6, wherein X is selected from... , and Preferably selected from , and .

8. The compound of any one of claims 1 to 7, wherein Y is selected from one of the following structures: i) or Preferred , or , Especially among them R h Selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group, and preferably H, R g Selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups, and preferably H or C. 1-4 Alkoxy R i Selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups, especially hydrogen or C 1-4 Alkyl group, and preferably H, R j Selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl and C 1-4 Alkyl group, and preferably H, and R x Selected from hydrogen and C 1-4 Alkyl group, and preferably H; ii) ,For example , , , Preferred or , Especially among them R k Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group, and preferably H, R m Selected from hydrogen, halogen, hydroxyl, C 3-6 cycloalkyl, C 1-4 Alkyl groups and optionally OH, C 1-4 Alkoxy and C 3-6 Cycloalkyl-substituted C 1-4 Alkyl groups, such as hydrogen, halogens, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkyl groups, and preferably H or C. 3-6 Cycloalkyl groups or optionally OH, C 1-4 Alkoxy and C 3-6 Cycloalkyl-substituted C 1-4 Alkyl groups, especially H, R x Selected from hydrogen and C 1-4 Alkyl group, and preferably H; iii) Preferred , Especially R n Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy groups, preferably H; and v) , , , , , or , R1, R3, R4, and R5 are preferably each independently selected from hydrogen and NR. y1 R y2 Halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OCH3, -CH2SO2CH3, -P(O)(C 1-4 Alkyl group 2, -SO2CH3, -NHC(O)CH3, -C(O)NR x1 R x2 and C that is optionally replaced by OH 3-6 cycloalkyl, wherein R x1 and R x2 Independently selected from hydrogen and C 1-4 Alkyl group, wherein R y1 and R y2 Independently selected from hydrogen and C 3-6 cycloalkyl groups and optionally C 3-6 Cycloalkyl-substituted C 1-4 Alkyl, or R y1 and R y2 Together with the N carrying them, they form a 5- or 6-membered heteroaryl or heterocyclic group, which is optionally surrounded by OH, C 1-4 Alkyl groups or optionally OH or C 1-4 alkoxy-substituted C 1-4 Alkyl substitution, wherein the heterocyclic group is a 4- to 7-membered monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein each ring of the bicyclic heterocyclic group has 3 to 6 members. or R4 and R3, together with the atoms they are attached to, form a 5- or 6-membered heterocyclic group, which optionally connects to C. 3-6 Cycloalkyl spiropolymers and / or are fused together with one or more groups selected from oxo, cyano, hydroxyl, halogen, C 1-2 Alkyl, C 3-6 cycloalkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, NR y1 R y2 or -S(O) 0-2 R y1 R y2 Substituents of R, wherein R y1 and R y2 For H or C 1-2 alkyl, E7 is either O or CH2. R 3’ Independently representing H, or two Rs 3’ Substituents together represent oxo groups (=O) or C. 3-5 cycloalkyl, and R 4’ Independently representing H, or two Rs 4’ Substituents together represent oxo groups (=O) or C. 3-5 cycloalkyl; In particular, R1, R3, R4, and R5 are each independently selected from hydrogen and NR. y1 R y2 Halogen, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

9. The compound of any one of claims 1 to 8, wherein Y is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

10. The compound of any one of claims 1 to 9, wherein the compound of formula (I) is selected from: And its salt.

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, used as a medicament, particularly a medicament having METTL3 inhibitory activity.

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

15. A compound or composition for use in claim 13 or 14, wherein it is used in combination therapy with radiotherapy or with an immunostimulant such as a vaccine.

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