PLA2g15 inhibitors

Abstract

The current invention relates to PLA2G15 inhibitors represented by formula (I), and corresponding compositions and uses. Preferably, the inhibitors and compositions are for use in the treatment of lysosomal storage diseases, Alzheimer's disease and Parkinson's disease; in particular for use in the treatment of Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal dementia.

Description

[0001] PLA2G15 inhibitors

[0002] Field

[0003] The current invention relates to PLA2G15 inhibitors represented by formula (I), and corresponding compositions and uses. Preferably, the inhibitors and compositions are for use in the treatment of lysosomal storage diseases, HIV, Alzheimer’s disease and Parkinson’s disease; in particular for use in the treatment of Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal dementia.

[0004] Background of the invention

[0005] PLA2G15 proteins are phospholipase A2 group XV enzymes that occur naturally in humans. These proteins have been identified as clinically relevant, for example for their role in drug- induced phospholipidosis (Hinkovska-Galcheva, Vania, et al. "Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis." Journal of lipid research 62 (2021)). Nonetheless, few potent and / or selective PLA2G15 inhibitors have been identified to the best of our knowledge.

[0006] Hence, there is a continuing need in the art for novel potent and / or selective PLA2G15 inhibitors.

[0007] Description of the invention

[0008] Inhibitors

[0009] In an aspect, the invention provides a PLA2G15 inhibitor represented by formula (I), or a salt or solvate thereof: wherein X is CR6R7, O, NR6or a single bond; wherein RAcomprises a ring; wherein RBcomprises a ring, preferably an aliphatic ring, more preferably a cyclopropyl; wherein Rs, R1, R2, R3, R4, R5, R6, R7and R8are independently H, a C1-4 alkyl, a C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl and C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens; and wherein R1and R2, and / or R3and R4, and / or R5and R6may alternatively form =0.

[0010] In a second aspect, the invention provides a PLA2G15 inhibitor, or a salt or solvate thereof, as defined in the first aspect, for use as a medicament.

[0011] Inhibitors according to the first or the second aspect are referred to in the current application as (PLA2G15) inhibitors according to or of the invention. Wherever a(n) (PLA2G15) inhibitor is mentioned in this application, reference is made to an inhibitor according to the invention, unless explicitly mentioned otherwise.

[0012] Wherever embodiments and preferences are disclosed in this application, for example in relation to RA, RB, Rs, X, and R1-R6, explicit reference is made to both inhibitors according to the first and the second aspect of the invention. In other words, such embodiments and preferences relate to both the inhibitors and the inhibitors for use as a medicament. Relatedly, any embodiment aimed at inhibitors mentioned herein also discloses an embodiment for the inhibitors for use as a medicament. Likewise, such embodiments and preferences may be applied mutatis mutandis to related compositions, uses, therapeutic uses, etc. of the inhibitors according to the invention.

[0013] A halogen is F, Cl, Br, I, or At. Preferably, a halogen is F, Cl, Br, or I. More preferably, a halogen is F, Cl, or Br. Even more preferably, a halogen is F or Cl. Most preferably, a halogen is F.

[0014] A pseudohalogen is -CN, -CP, -NC, -OH, -SH, -SeH,-TeH, -OCN, -SCN, -NCS, -SeCN, - TeCN, -N3, -NO, or -NO2. Preferably, a pseudohalogen is -CN, -NC, -OH, -SH, -OCN, -SCN, - NCS, -N3, -NO, or -NO2.

[0015] A ring is an organic ring consisting of covalently bound ring atoms.

[0016] RING SYSTEM RA

[0017] In embodiments, RAcomprises a single ring system. A ring system comprised in a compound is a set of ring atoms, each comprised in the compound, that form a continuous covalent network of endocyclic bonds, not interrupted by any exocyclic bonds, wherein the addition to the set of any other ring atom comprised in the compound would break the continuous covalent network. A ring system can be a monocyclic or multicyclic ring, a group of annulated rings, a spiro compound, etc., but cannot be, for example, a ring substituted with two distinct rings (e.g., 2,2-dicyclopropylphenyl). Another example of a ring system is a cubyl. A moiety or a compound comprising a single ring system means that it contains one and only one ring system. In other words, all ring atoms comprised in such moieties or compounds are comprised in the ring system. Similar definitions can be made for moieties or compounds comprising a number of ring systems.

[0018] In embodiments, RAcomprises a three-, four-, five- or six-membered ring, preferably a five- or a six-membered ring. Preferably, RAcomprises a five-membered or a six-membered aromatic ring.

[0019] In embodiments, RAcomprises an aromatic ring. Preferably, RAcomprises a phenyl or a heteroaromatic ring, more preferably a phenyl or a six-membered heteroaromatic ring.

[0020] In embodiments, RAcomprises a phenyl, a pyridinyl, an oxazole, an isoxazole, a thiazole, an isothiazole, a pyrazole, an imidazole or a pyrrole. Preferably, the aromatic ring RAcomprises a phenyl, a pyridinyl, an oxazole or a isoxazole. More preferably, RAcomprises a phenyl of a pyridinyl. Most preferably, the aromatic ring mentioned in this embodiment is monocyclic and not annulated to another ring.

[0021] In embodiments, RAcomprises a single aromatic ring system.

[0022] In embodiments, RAcomprises a carbocyclic ring. A carbocyclic ring is a ring wherein each ring atom is a carbon atom. Preferably, RAcomprises a phenyl, a cyclopropyl, a cyclopentyl or a cyclohexyl.

[0023] In embodiments, RAcomprises an aliphatic ring. Preferably, RAcomprises a cyclopropyl, a cyclopentyl or a cyclohexyl.

[0024] In embodiments, RAcomprises a single aliphatic ring system.

[0025] In embodiments, RAcomprises a saturated or partially saturated ring. Preferably, RAcomprises a saturated or partially saturated aliphatic ring, more preferably a cyclopropyl, a cyclopentyl or a cyclohexyl.

[0026] In embodiments, RAcomprises a ring comprising a N, O or S ring atom. Preferably, RAcomprises 1 or 2 N, O or S ring atoms, more preferably 1 N, O or S ring atom.

[0027] In embodiments, RAcomprises a ring substituted with a C1-4 alkyl, a O-C1-4 alkyl, a S-C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, a S-C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl, O-C1-4 alkyl, S-C1-4 alkyl, C3-4 cycloalkyl, O-C3-4 cycloalkyl and S-C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens.

[0028] In embodiments, RAcomprises a ring substituted with one or more C1-4 alkyls, O-C1-4 alkyls, S-C1-4 alkyls, C3-4 cycloalkyls, O-C3-4 cycloalkyls, S-C3-4 cycloalkyls, or halogens. In embodiments, RAcomprises a ring substituted with one or more O-C1-3 alkyls, S-C1-3 alkyls, or halogens, preferably with one or more F atoms.

[0029] In embodiments, RAis attached to the thiazole ring depicted in formula (I) via a ring atom comprised in RA. Preferably, RAcomprises a single ring, of which a ring atom is attached to the thiazole ring.

[0030] In embodiments, the PLA2G15 inhibitor is represented by formula (II):

[0031] (II), wherein Y is C-RY2or N; and wherein RY1, RY2, RY3, RY4and RY5are independently H, a C1-4 alkyl, a O-C1-4 alkyl, a S-C1- 4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, a S-C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl, O-C1-4 alkyl, S-C1-4 alkyl, C3-4 cycloalkyl, O-C3-4 cycloalkyl and S-C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens.

[0032] In embodiments, Y is CH.

[0033] In embodiments, one, two or three of RY3, RY4and RY5are H. Preferably, Y is CH.

[0034] In embodiments, RY3is H, or RY4is H, or RY5is H, or RY3and RY4are H, or RY3and RY5are H, or RY4and RY5are H, or RY3and RY4and RY5are H.

[0035] In embodiments, RY3is H, or RY4is H, or RY5is H, or RY3and RY4are H, or RY3and RY5are H, or RY4and RY5are H, or RY3and RY4and RY5are H; and Y is CH.

[0036] In embodiments, RY3is H, or RY4is H, or RY5is H, or RY3and RY4are H, or RY3and RY5are H, or RY4and RY5are H, or RY3and RY4and RY5are H; and RY1is OCH3.

[0037] In embodiments, RY3is H, or RY4is H, or RY5is H, or RY3and RY4are H, or RY3and RY5are H, or RY4and RY5are H, or RY3and RY4and RY5are H; and Y is CH; and RY1is OCH3.

[0038] In embodiments, one, two or three of RY3, RY4and RY5are H or F. Preferably, Y is CH.

[0039] In embodiments, RY3is H or F, or RY4is H or F, or RY5is H or F, or RY3and RY4are H or F, or RY3and RY5are H or F, or RY4and RY5are H or F, or RY3and RY4and RY5are H or F. In embodiments, RY3is H or F, or RY4is H or F, or RY5is H or F, or RY3and RY4are H or F, or RY3and RY5are H or F, or RY4and RY5are H or F, or RY3and RY4and RY5are H or F; and Y is CH.

[0040] In embodiments, RY3is H or F, or RY4is H or F, or RY5is H or F, or RY3and RY4are H or F, or RY3and RY5are H or F, or RY4and RY5are H or F, or RY3and RY4and RY5are H or F; and RY1is OCH3.

[0041] In embodiments, RY3is H or F, or RY4is H or F, or RY5is H or F, or RY3and RY4are H or F, or RY3and RY5are H or F, or RY4and RY5are H or F, or RY3and RY4and RY5are H or F; and Y is CH; and RY1is OCH3.

[0042] In embodiments, RY1is a C1-4 alkyl, a O-C1-4 alkyl, a S-C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, or a S-C3-4 cycloalkyl. Preferably, Y is CH.

[0043] In embodiments, RY1is a C1-3 alkyl, a O-Ci-3alkyl, a S-Ci-3alkyl, a C3-4 cycloalkyl, a O-C3cycloalkyl, or a S-C3cycloalkyl. Preferably, Y is CH.

[0044] In embodiments, RY1is O-Ci-3alkyl or a S-Ci-3alkyl, preferably a O-Ci-3alkyl, most preferably an O-methyl. Preferably, Y is CH.

[0045] In embodiments, RY1is OCH3, OCFH2, OCF2H, or OCF3, preferably OCH3. Preferably, Y is CH.

[0046] In embodiments, RY1comprises a deuterium, preferably one, two or three deuteriums.

[0047] In embodiments, RY1is a C1-4 alkyl, a O-C1-4 alkyl, a S-C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, or a S-C3-4 cycloalkyl, wherein RY1comprises a deuterium. Preferably, Y is CH.

[0048] In embodiments, RY1is a C1-3 alkyl, a O-Ci-3alkyl, a S-Ci-3alkyl, a C3-4 cycloalkyl, a O-C3cycloalkyl, or a S-C3cycloalkyl, wherein RY1comprises a deuterium. Preferably, Y is CH.

[0049] In embodiments, RY1is O-Ci-3alkyl or a S-Ci-3alkyl, preferably a O-Ci-3alkyl, most preferably an O-methyl. Preferably, Y is CH. In embodiments, RY1is OCDF2, OCD2F, OCH3, OCF3, OCHF2, OCH2F, OCD3, OCHD2, OCH2D. Preferably, Y is CH.

[0050] RING SYSTEM RB

[0051] In embodiments, RBcomprises a single ring system.

[0052] In embodiments, RBcomprises a three-, four-, five- or six-membered ring, preferably a five- or a six-membered ring. Preferably, RBcomprises a five-membered or a six-membered aromatic ring. In embodiments, RBcomprises an aromatic ring. Preferably, RBcomprises a phenyl or a heteroaromatic ring, more preferably a phenyl or a six-membered heteroaromatic ring.

[0053] In embodiments, RBcomprises a phenyl, a pyridinyl, an oxazole, an isoxazole, a thiazole, an isothiazole, a pyrazole, an imidazole or a pyrrole. Preferably, the aromatic ring RBcomprises a phenyl, a pyridinyl, an oxazole or a isoxazole. More preferably, RBcomprises a phenyl of a pyridinyl. Most preferably, the aromatic ring mentioned in this embodiment is monocyclic and not annulated to another ring.

[0054] In embodiments, RBcomprises a single aromatic ring system.

[0055] In embodiments, RBcomprises a carbocyclic ring. Preferably, RBcomprises a phenyl, a cyclopropyl, a cyclopentyl or a cyclohexyl.

[0056] In embodiments, RBcomprises an aliphatic ring. Preferably, RBcomprises a cyclopropyl, a cyclopentyl or a cyclohexyl. More preferably, RBcomprises a cyclopropyl.

[0057] In embodiments, RBcomprises a single aliphatic ring system, preferably a cyclopropyl.

[0058] In embodiments, RBcomprises a saturated or partially saturated ring. Preferably, RBcomprises a saturated or partially saturated aliphatic ring, more preferably a cyclopropyl, a cyclopentyl or a cyclohexyl.

[0059] In embodiments, RBcomprises a ring comprising a N, O or S ring atom. Preferably, RBcomprises 1 or 2 N, O or S ring atoms, more preferably 1 N, O or S ring atom.

[0060] In embodiments, RBcomprises a cyclopropyl and / or a phenyl and / or a pyridinyl.

[0061] In embodiments, RBcomprises a ring substituted with a C1-4 alkyl, a O-C1-4 alkyl, a S-C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, a S-C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl, O-C1-4 alkyl, S-C1-4 alkyl, C3-4 cycloalkyl, O-C3-4 cycloalkyl and S-C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens.

[0062] In embodiments, RBcomprises a ring substituted with one or more halogens, preferably with one or more F atoms.

[0063] In embodiments, RBis attached to the amide carbonyl group depicted in formula (I) via a ring atom comprised in RB. Preferably, RBcomprises a single ring, of which a ring atom is attached to the thiazole ring.

[0064] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of a halogen, a pseudohalogen, a C1-4 alkyl and a C3-4 cycloalkyl, wherein each C1-4 alkyl and C3-4 cycloalkyl may be independently substituted with one or more of a halogen and a pseudohalogen. Preferably, the single ring system in this embodiment comprises 3 to 8 non-hydrogen ring atoms.

[0065] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of a halogen, a C1-4 alkyl and a C3-4 cycloalkyl, wherein each C1-4 alkyl and C3-4 cycloalkyl may be independently substituted with one or more halogens. Preferably, the single ring system in this embodiment comprises 3 to 8 non-hydrogen ring atoms.

[0066] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of a halogen, a C1-4 alkyl and a C3-4 cycloalkyl, wherein each C1-4 alkyl and C3-4 cycloalkyl may be independently substituted with one or more halogens, wherein each ring atom is carbon, nitrogen or oxygen. Preferably, the single ring system in this embodiment comprises 3 to 8 ring atoms.

[0067] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of a halogen, a C1-4 alkyl and a cyclopropyl, wherein each C1-4 alkyl and cyclopropyl may be independently substituted with one or more halogens, wherein each ring atom is carbon, nitrogen or oxygen. Preferably, the single ring system in this embodiment comprises 3 to 8 ring atoms.

[0068] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of fluorine, a C1-4 alkyl and a cyclopropyl, wherein each C1-4 alkyl and cyclopropyl may be independently substituted with one or more fluorine, wherein each ring atom is carbon, nitrogen or oxygen. Preferably, the single ring system in this embodiment comprises 3 to 8 ring atoms.

[0069] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of fluorine, a C1-3 alkyl and a cyclopropyl, wherein each C1-3 alkyl and cyclopropyl may be independently substituted with one or more fluorine, wherein each ring atom is carbon, nitrogen or oxygen. Preferably, the single ring system in this embodiment comprises 3 to 8 ring atoms. In the embodiments above, a single ring system may be substituted with one or more C3-4 cycloalkyls (or cyclopropyls). It is evident that this may result in an RBcomprising two or more ring systems, still covered by the embodiment.

[0070] In embodiments, RBcomprises or consists of a single ring system, wherein the single ring system may be substituted with one or more of fluorine and a C1-3 alkyl, wherein each C1-3 alkyl may be independently substituted with one or more fluorine, wherein each ring atom is carbon, nitrogen or oxygen. Preferably, the single ring system in this embodiment comprises 3 to 8 ring atoms.

[0071] In embodiments, RBis selected from: wherein n is 1 , 2, 3 or 4, preferably n is 1 or 2; wherein X1, X2, and X3are independently selected from CR6R7, O, N, NR6or a single bond; wherein RB1, RB2, RB3, RB4, RB5, RB6, RB7and RB8are independently selected from H, a halogen, a C1-4 alkyl, a 3 to 6-membered aromatic ring optionally substituted with a halogen, preferably a fluorine, a 3 to 4 membered aliphatic ring, -CHF2, -CH2F, -CF3, - CHF2, -CH2F.

[0072] In embodiments, RBis selected from:

[0073] In some embodiments, RBcomprises a group selected from:

[0074] In some preferable embodiments, RBcomprises a group selected from:

[0075]

[0076] In some embodiments, RBcomprises a group selected from:

[0077] In other embodiments, RBcomprises a group selected from:

[0078] THIAZOLE SUBSTITUTION RS

[0079] In embodiments, Rsis H, a C1-4 alkyl, a C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein C1-4 alkyl and C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens.

[0080] In embodiments, Rsis H, a C1-3 alkyl, a cyclopropyl, a halogen, or a pseudohalogen; preferably H, a C1-3 alkyl, a halogen, or a pseudohalogen; more preferably H, a C1-3 alkyl, or a halogen; even more preferably H or a halogen; even more preferably H or F; most preferably H. CENTRAL RING SUBSTITUTIONS R1-R6 X may be a single bond. This means that the ring comprising X and N, formally drawn as a six-membered ring, becomes a five-membered ring wherein the ring atom attached to R3and R4is directly attached to the ring atom attached to the thiazole ring.

[0081] In embodiments, X is CH2, O or NH. Preferably, X is CH2 or O. More preferably, X is CH2.

[0082] In embodiments, 1 , 2, 3 or 4 of R1, R2, R5and R6are H.

[0083] In embodiments, R1is H, or R2is H, or R5is H, or R6is H, or R1and R2are H, or R1and R5are H, or R1and R6are H, or R2and R5are H, or R2and R6are H, or R5and R6are H, or R1, R2and R3are H, or R1, R2and R6are H, or R1, R5and R6are H, or R2, R5and R6are H, or R1, R2, R5and R6are H. Preferably, X is CH2 or O. More preferably, X is CH2.

[0084] In embodiments, R3and R4are independently H or CH3. Preferably, R3is H and R4is H, or R3is CH3 and R4is H, or R3is H and R4is CH3, or R3is CH3 and R4is CH3. Preferably, X is CH2 or O. More preferably, X is CH2.

[0085] In embodiments, R1, R2, R5and R6are H and R3and R4are independently H or CH3. Preferably, R1, R2, R5and R6are H and R3is H and R4is H; or R1, R2, R5and R6are H and R3is CH3 and R4is H; or R1, R2, R5and R6are H and R3is H and R4is CH3; or R1, R2, R5and R6are H and R3is CH3 and R4is CH3. Preferably, X is CH2 or O. More preferably, X is CH2.

[0086] PREFERRED INHIBITORS

[0087] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H.

[0088] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and X is CH2or O, preferably CH2.

[0089] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and Y is CH.

[0090] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and X is CH2or O, preferably CH2, and Y is CH.

[0091] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and X is CH2, and Y is CH, and R3and R4are independently H or CH3.

[0092] In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and X is CH2, and Y is CH, and Y1is OMe. In embodiments, the PLA2G15 inhibitor is represented by formula (II), wherein Rs, R1, R2, R5, R6, RY4and RY5are H, and X is CH2, and Y is CH, and Y1is OMe, and R3and R4are independently H or CH3.

[0093] In embodiments, the PLA2G15 inhibitor is represented by formula (l-R) or by formula (l-L), preferably by formula (l-R):

[0094] In embodiments, the PLA2G15 is represented by any one of the following formulae:

[0095]

[0096] In embodiments, the PLA2G15 is represented by any one of the following formulae:

[0097]

[0098] 

[0099]

[0100] ISOMERY

[0101] Certain PLA2G15 inhibitors may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, stereoisomeric, tautomeric, (de)protonated, isotopomeric, isotopologues, isotopologic, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and p-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and h a Ifch air-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0102] Any reference to a compound or a class of compounds, either by a name or by a formula, is meant as a reference to the set of all isomers falling in that class, unless explicitly mentioned otherwise. This includes both the isomers mentioned above and all structural isomers, unless it is clear that they are explicitly excluded. For example, a C1-4 alkyl may refer to n-butyl and tert-butyl, together with all their isomers as mentioned above. A reference to n-butyl, on the other hand, only refers to n-butyl and its stereoisomers, isotopomers, isotopologues, etc., and not to tert-butyl.

[0103] If a compound or a class of compounds refers to multiple species, reference is made to both the isolated species and to any equimolar or non-equimolar mixture of the species. SALTS

[0104] A PLA2G15 inhibitor according to the invention may be present as a pharmaceutically acceptable salt.

[0105] Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1 -19.

[0106] For example, if a compound according to the invention is anionic, or has a functional group, which may be anionic (e.g., -COOH may be -COO ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+and K+, alkaline earth cations such as Ca2+and Mg2+, and other cations such as AP+as well as the ammonium ion (i.e., NH4+). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NHsR+, NH2R2+, NHRs+, NR4+), for example, where each R is independently linear or branched saturated Ci-isalkyl, Cs-scycloalkyl, Cs-acycloalkyl-Ci-ealkyl, and phenyl-Ci-ealkyl, wherein the phenyl group is optionally substituted. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[0107] If a PLA2G15 inhibitor is cationic, or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3+), then a salt may be formed with a suitable anion.

[0108] For example, if a PLA2G15 inhibitor contains a cationic group (e.g., -NMe2+), or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3+), then a salt may be formed with a suitable anion. In the case of a quaternary ammonium compound a counter-anion is generally always present in order to balance the positive charge. If, in addition to a cationic group (e.g., -NMe2+, -NH3+), the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt (also referred to as a zwitterion) may be formed.

[0109] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

[0110] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1 ,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0111] SOLVATES AND HYDRATES

[0112] A PLA2G15 inhibitor according to the invention may be present as a pharmaceutically acceptable solvate or hydrate.

[0113] The term solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

[0114] PLA2G15

[0115] STRUCTURE OF PLA2G15

[0116] PLA2G15, which may also be called a PLA2G15 protein, a phospholipase A2 group XV (protein), a lysophospholipase 3 (protein) or LYPLA3, is a protein encoded by a PLA2G15 gene. Herein, all human variants and isoforms, and species homologues and their variants and isoforms are encompassed. In the context of this application, a PLA2G15 or a LYPLA3 refer to a PLA2G15 protein, unless explicitly mentioned otherwise.

[0117] All embodiments disclosed below relating to PLA2G15 proteins or genes may be applied accordingly to inhibitors and compositions according to the invention.

[0118] In embodiments, an PLA2G15 gene is located at open reading frame UNQ341 / PRO540. In this context, a PLA2G15 (protein) may also be called a UNQ341 / PRO540 (protein).

[0119] In embodiments, PLA2G15 is represented by an amino acid sequence having at least 75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%, 80.5%, 81 %, 81.5%, 82%,

[0120] 82.5%, 83%, 83.5%, 84%, 84.5%, 85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%,

[0121] 89.5%, 90%, 90.5%, 91 %, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%,

[0122] 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100% sequence identity with SEQ ID NO: 1 or 2, preferably with SEQ ID NO:1 .

[0123] In embodiments, PLA2G15 is represented by an amino acid sequence having at least 75%,

[0124] 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%, 80.5%, 81 %, 81.5%, 82%,

[0125] 82.5%, 83%, 83.5%, 84%, 84.5%, 85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%,

[0126] 89.5%, 90%, 90.5%, 91 %, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100% sequence similarity with SEQ ID NO: 1 or 2, preferably with SEQ ID NO:1 .

[0127] In embodiments, PLA2G15 comprises an amino acid sequence represented by SEQ ID NO: 1 or 2, preferably SEQ ID NO: 1 . In more specific aspects, PLA2G15 consists of an amino acid sequence represented by SEQ ID NO: 1 or 2, preferably SEQ ID NO: 1 .

[0128] In embodiments, PLA2G15 has a length from 322 up to 502 amino acids, or from 332 up to 492 amino acids, or from 342 up to 482 amino acids, or from 352 up to 472 amino acids, or from 362 up to 462 amino acids, or from 372 up to 452 amino acids, or from 382 up to 442 amino acids, or from 392 up to 432 amino acids, or from 402 up to 422 amino acids, or from 403 up to 421 amino acids, or from 404 up to 420 amino acids, or from 405 up to 419 amino acids, or from 406 up to 418 amino acids, or from 407 up to 417 amino acids, or from 408 up to 416 amino acids, or from 409 up to 415 amino acids, or from 410 up to 414 amino acids, or from 411 up to 413 amino acids, preferably wherein PLA2G15 is represented by an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 , more preferably wherein PLA2G15 is represented by an amino acid sequence comprising SEQ ID NO: 1 .

[0129] In embodiments, PLA2G15 has a length from 218 up to 418 amino acids, or from 228 up to 408 amino acids, or from 238 up to 398 amino acids, or from 248 up to 388 amino acids, or from 258 up to 378 amino acids, or from 268 up to 368 amino acids, or from 278 up to 358 amino acids, or from 288 up to 348 amino acids, or from 298 up to 338 amino acids, or from 308 up to 328 amino acids, or from 309 up to 327 amino acids, or from 310 up to 326 amino acids, or from 31 1 up to 325 amino acids, or from 312 up to 324 amino acids, or from 313 up to 323 amino acids, or from 314 up to 322 amino acids, or from 315 up to 321 amino acids, or from 316 up to 320 amino acids, or from 317 up to 319 amino acids, preferably wherein PLA2G15 is represented by an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2, more preferably wherein PLA2G15 is represented by an amino acid sequence comprising SEQ ID NO: 2.

[0130] In embodiments, PLA2G15 has a length of 412 amino acids, or 318 amino acids.

[0131] In embodiments, PLA2G15 is expressed in or is derived from a vertebrate, more preferably a mammal, even more preferably a rat, a mouse, a rabbit or a human, most preferably a human. In this context, PLA2G15 derived from a specific animal may be a recombinant protein expressed in a host organism.

[0132] ACTIVITY OF PLA2G15

[0133] An inhibitor according to the invention is able to inhibit (i.e. decrease) an activity of PLA2G15. In this context, an inhibitor according to the invention may also be called a compound able to inhibit an activity of PLA2G15. Herein, decreasing an activity may mean inhibiting an activity of PLA2G15 via direct or indirect contact between said inhibitor and PLA2G15.

[0134] In specific aspects, an inhibitor according to the invention is a competitive inhibitor of said PLA2G15 protein, wherein said inhibitor is able to specifically bind an active site of said PLA2G15 protein associated with said activity of said PLA2G15 protein.

[0135] In specific aspects, an inhibitor according to the invention is a non-competitive or allosteric inhibitor of said PLA2G15 protein, wherein said inhibitor is able to specifically bind a part of said PLA2G15 protein which is not an active site associated with said activity of said PLA2G15 protein. In this context, said binding site which is not an active site maybe called an allosteric site.

[0136] A skilled person in the art can test the inhibitory effect of the PLA2G15 inhibitors according to the invention on the PLA2G15 enzymatic activity with an inhibition assay, preferably the 4- nitrophenyl butyrate assay. In this 4-nitrophenyl butyrate assay, the compounds pNPA (paranitrophenyl acetate) and pNPB (para-nitrophenyl butyrate) are substrates that can be used to detect PLA2G15 enzyme activities. The PLA2G15 enzyme catalyzes the hydrolysis of ester bonds between an acyl moiety and p-nitrophenol (pNP): The release of 4-nitrophenolate anion (yellow at pH values above its pKa of 7.08 at 22 °C) is determined as a strong increase in absorbance at 405 nm.

[0137] In embodiments is provided an inhibitor according to the invention, wherein said inhibitor is able to decrease a catalytic activity of PLA2G15. In this context, PLA2G15 may be called an enzyme and a catalytic activity may be called a enzymatic activity. It is understood that a catalytic activity of a PLA2G15 protein or enzyme means that PLA2G15 increases the rate of a reaction, preferably by a factor of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, relative to the rate of a corresponding reaction performed in a corresponding environment (e.g. similar cellular conditions, pH, salt concentrations, enzyme concentrations, etc.) and under corresponding conditions (e.g. same temperature, etc.) wherein PLA2G15 is not present. Preferably, said rate increase of said reaction is defined under physiological conditions. In the context of this application, “a catalytic activity of PLA2G15, wherein said catalytic activity comprises a reaction”, “a reaction catalysed by PLA2G15” or similar phrases mean that the rate of said reaction is increased by PLA2G15, as explained above.

[0138] In embodiments, decreasing a catalytic activity means decreasing the rate of a reaction catalysed by PLA2G15, more preferably by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 , 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 , relative to the rate of a corresponding reaction performed in a corresponding environment (e.g. similar cellular conditions, pH, salt concentrations, PLA2G15 concentration, other enzyme concentrations, etc.) and under corresponding conditions (e.g. same temperature, etc.) wherein said inhibitor according to the invention is not present. Preferably, said rate decrease of said reaction is defined under physiological conditions. As explained above, decreasing the rate of a reaction catalysed by PLA2G15 may be the result of inhibiting a catalytic activity of PLA2G15 via direct or indirect contact between said inhibitor and PLA2G15. The rate of a reaction catalysed by PLA2G15 may be measured or assessed by any suitable methods well-known in the art.

[0139] In embodiments, the rate of a reaction catalysed by PLA2G15 is measured or defined at pH 4.5 and under otherwise physiological conditions. More preferably, said reaction takes place in an organelle, a cell fraction, a cell, a tissue, an organ or a subject, most preferably in a vertebrate, mammalian or human cell. Preferably, an organelle is a lysosome or an endosome. Preferably, an endosome is a late endosome.

[0140] Without being limited to any specific explanation, mechanism or hypothesis, an inhibitor as used in the invention is capable, in a suitable assay or model and / or upon administration to a subject, of decreasing in specific aspects a catalytic activity of PLA2G15 that originates from, is caused by or is linked to a catalytic triad comprised in PLA2G15, in particular a catalytic triad consisting of a histidine, a aspartic acid and a serine residue, and more in particular the catalytic triad that consists of His-359, Asp-327 and Ser-165.

[0141] In embodiments, a catalytic activity of PLA2G15 comprises the cleavage of a fatty acid residue from a compound, which may also be called a deacylase activity. More preferably, said compound is a lipid and said catalytic activity may be called a lipase activity. Even more preferably, said lipid is a phospholipid and said catalytic activity may be called a phospholipase activity. Most preferably, said phospholipase activity is a phospholipase A1 activity or a phospholipase A2 activity, preferably a phospholipase A2 activity.

[0142] In embodiments, a phospholipid in the aspects above is a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylglycerol, or a phosphatidylserine.

[0143] In embodiments, a phospholipid in the aspects above is an oxidized phospholipid, preferably wherein said oxidized phospholipid comprises short fatty acid chains (e.g. comprising less than 10 carbon atoms) and / or a free carboxyl or formyl group at the sn-2 position.

[0144] In embodiments, a phospholipid in the aspects above is not a phosphatidylinositol or a and sphingomyelin.

[0145] In embodiments, a catalytic activity of PLA2G15 comprises a transfer of a fatty acid residue from a donor compound to an acceptor compound, which may also be called a transacylase activity. A transacylase activity thus comprises a deacylase activity, to which the preferences above apply. In embodiments, a catalytic activity of PLA2G15 comprises a transacylase activity, wherein said acceptor compound is N-acetyl-sphingosine.

[0146] In embodiments, an activity of PLA2G15 comprises a catalytic activity during lipid metabolism. Herein, it is understood that lipid metabolism comprises lipid anabolism and lipid catabolism.

[0147] CLINICAL RELEVANCE OF PLA2G15

[0148] PLA2G15 inhibitors according to the invention and compositions according to the invention are particularly useful in the treatment of diseases characterized by disease characterized by lysosomal dysregulation. Lysosomal dysregulation or dysfunction is a hallmark of rare and common neurodegenerative diseases, metabolic disease and cancer, including neuronopathic lysosomal storage disorders as well as Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia (FTD) (1). Indeed, heterozygous carriers of well-known LSD causing mutations in genes like NPC1 , GRN or GBA carry increased risk of developing Alzheimer’s disease, Frontotemporal dementia or Parkinson’s disease, highlighting a mechanistic link between rare lysosomal storage diseases and more common neurodegenerative diseases (42, 10, 43). Therefore, counteracting lysosomal dysfunction is considered of potential therapeutic benefit not only to lysosomal storage diseases, but also more common neurodegenerative diseases like Alzheimer’s and Parkinson’s or frontotemporal dementia.

[0149] One of the characteristics of lysosomal dysregulation is that levels of bis(monoacylglycerol)- phosphate (BMP) are dysregulated. BMP is a lysosomal / late endosomal lipid that stimulates key lysosomal functions: it activates enzymatic activity mediating lipid degradation, controls cholesterol distribution to extra-lysosomal compartments and is involved in endosomal / lysosomal trafficking dynamics to allow cellular homeostasis (3). The central and limiting role of BMP in regulating lysosomal function is well understood in (glyco)-sphingolipid breakdown: here it plays a structural role as docking station for activating co-factors like GM2A, Saposin A-D or the heat shock protein HSP-70 in complex with lysosomal enzymes mediating degradation of (glyco)-sphingolipids (34, 37). Some of these BMP dependent enzymes are well known targets of genetic LSDs.

[0150] Dysregulation of BMPs may result in increased or decreased levels of BMP. Increased BMP levels have been linked to several well-studied lysosomal lipid storage diseases including NPC, GM1 Gangliosidosis [3], and Gaucher disease

[0045] . Increased BMP levels are also seen in an Alzheimer disease model carrying the APO4 risk allele (41), while in Batten CLN3 and CLN5 (14, 17) or FTD caused by granulin haploinsufficiency (10) BMP level is low. Neuronal ceroid lipofuscinosis variants caused by mutations in CLN5 shows a near absence of BMP, while mutations in CLN3 reduces BMP levels. Disorders caused by GRN mutations, including frontotemporal dementia and neuronal ceroid lipofuscinosis GRN also show decreased BMP abundance. It has been reported that treatments that raise BMP levels alleviate cellular symptoms.

[0151] Cellular treatments to increase BMP levels have been shown to correlate with reduced intracellular biogenesis of HIV viral particles and may therefore present novel therapeutic strategies in HIV treatment (47).

[0152] In Niemann Pick type C (NPC) disease, defects in lysosomal cholesterol trafficking are accompanied by accumulation of BMP, and further elevation of BMP levels is shown to lessen multiple cellular defects, including cholesterol accumulation and clearance of autophagic materials. The related disorders Niemann Pick type A and B disease are caused by accumulation of sphingomyelin due to mutations in the lysosomal enzyme acid sphingomyelinase (ASM) and also display enhanced levels of BMP. As BMP stimulates ASM activity, a further increase in BMP may be beneficial by enhancing hydrolysis of lysosomal sphingomyelin.

[0153] Increased levels of BMP in lysosomal storage disease are not merely considered a secondary storage phenotype but rather an active cellular response to increase BMP dependent lysosomal functions and counteract lysosomal pathology (17). Thus, limiting rather than increased or reduced levels of BMP are considered a pathological factor and restoring balanced BMP expression in lysosomes is considered an attractive therapeutic approach multiple human disorders. Indeed, therapeutic interventions leading to increased levels of BMP have been shown to correlate with therapeutic efficacy, including in preclinical models of NPC (21 , 22, 7) and Parkinson’s disease (36).

[0154] Therefore, increasing BMP levels in a wide class of diseases as outlined above is expected to have therapeutic impact.

[0155] We demonstrated that BMP and its precursor lysophosphatidylglycerol (LPG) are elevated in multiple tissues of mice that lack expression of Pla2g15 or after in vivo pharmacological inhibition of Pla2g15. Similarly, BMP and LPG levels are elevated in cell lines when the Pla2g15 gene is deleted or after inhibition with Pla2g15 specific inhibitors. Furthermore, we have shown mechanistically that PLA2G15 activity controls efficacy of the BMP biosynthetic pathway by hydrolyzing both the precursor LPG and the product BMP in vitro, consistent with our in vivo and cellular findings in genetic and pharmacological models.

[0156] Therapy

[0157] DISEASES

[0158] In aspects, the PLA2G15 inhibitors according to the invention and the compositions according to the invention are for use in the treatment of a disease characterized by lysosomal dysregulation. Below, preferred diseases characterized by lysosomal dysregulation, and other preferred features of the treatment are disclosed.

[0159] Said diseases include neuronopathic lysosomal storage disorders (LSD), Alzheimer’s disease, Parkinson’s disease, frontotemporal degeneration, neurodegenerative diseases, metabolic diseases, a kidney or a liver diseases and cancer.

[0160] In one embodiment, said disease is an LSD. LSDs are inherited diseases characterized by lysosomal dysfunction and neurodegeneration. The term LSDs defines a group of approximately 70 disorders, typically due to single gene defects: deficiency of specific enzymes that are normally required for the breakdown of lysosomal glycosaminoglycans (GAGs), glycosphingolipids or glycoproteins, which thus accumulate in the lysosomes of the cell. This accumulation disrupts the cell's normal functioning and gives rise to the clinical manifestations of LSDs.

[0161] Neurological impairment and neurodegenerative processes are associated to lysosomal dysfunction and represent a predominant feature in most LSDs. Neuropathology can occur in multiple brain regions (e.g., thalamus, cortex, hippocampus, and cerebellum) and involves unique temporal and spatial changes, which often entail early region-specific neurodegeneration and inflammation. As an example, Purkinje neurons degenerate in many of these diseases leading to cerebellar ataxia.

[0162] We demonstrated a reduction of the ganglioside GM3 and its degradation product lactosylceramide (LacCer) in brain of NPC1 / PLA2G15 dKO mice compared to NPC1 KO mice. Similarly, we showed a reduction of the gangliosides GM1 , GM2 and GM3 as well as its degradation products LacCer, Glucosylceramide (GlcCer) and Sphingosine in liver of NPC1 / PLA2G15 dKO mice compared to NPC1 KO mice. In addition, we detect a reduction in levels of Sphingomyelin (SM) and Sulfatide (SM4) in liver of NPC1 / PLA2G15 dKO mice compared to NPC1 KO mice. These findings indicate that PLA2G15 contributes to the accumulation of sphingomyelin and glycosphingolipids known to occur in primary or secondary sphingolipidoses. PLA2G15 inhibition can therefore be expected to have broad therapeutic benefit across this class of diseases.

[0163] In a specific embodiment, said disease is a sphingolipidosis. Sphingolipidosis is characterized by a disturbance of the sphingolipid metabolism.

[0164] Errors in sphingolipid metabolism represent a major class of lysosomal storage diseases (2). Mutations in key enzymes mediating lysosomal degradation of (glyco)-sphingolipids have been identified across the degradative pathway of this lipid class and give rise to so-call primary sphingolipidoses, including GM1 Gangliosidosis, Tay-Sachs disease (B variant), Sandhoff disease, GM2AP deficiency, Sialidosis, Fabry disease, Gaucher disease, Niemann-Pick Type A / B, Krabbe disease, Metachromatic Leukodystrophy, Farber disease (35). In addition, secondary sphingolipidoses like Niemann Pick type C disease and others occur where no mutations in the catabolic enzymes mediating (Glyco)sphingolipid degradation is detected, yet pathologic accumulation of so-called secondary storage lipids of the (Glyco)sphingolipid class is detected (44). Primary storage products like Cholesterol and Sphingomyelin in Niemann Pick type C and A / B, respectively, are thought to inhibit lysosomal activity by counteracting the stimulatory activity of BMP on the (glyco)-sphingolipid degradation pathway in the lysosome, as exemplified for ganglioside degradation by HexA (45). Therefore, restoring the balance between BMP expression in the late endosomal compartment and primary or secondary storage lipids like cholesterol or sphingomyelin is expected to have a positive therapeutic impact on a wide class of LSDs, including sphingolipidoses.

[0165] In a specific embodiment, said disease is a sphingolipidosis, including Niemann-Pick disease, type A an B, Niemann-Pick disease type C, Gaucher disease, Metachromatic leukodystrophy, Krabbe disease and Farber disease.

[0166] In a specific embodiment, said sphingolipidosis is a mucopolysaccharidosis (MPS), including, MPS I (Hurler syndrome, MPS II (Hunter syndrome) , MPS IIIA (Sanfilippo syndrome), MPS IIIB (Sanfilippo syndrome), MPS IIIC (Sanfilippo syndrome), MPS HID (Sanfilippo syndrome), MPS VI (Maroteaux-Lamy syndrome), MPS VII (Sly syndrome).

[0167] In a specific embodiment, said sphingolipidosis is a Mucolipidosis, including Mucolipidosis II (l-cell disease), Mucolipidosis III (pseudo-Hurler polydystrophy) and Mucolipidosis IV.

[0168] In a specific embodiment, said disease is glycoproteinosis, including galactosialidosis, mannosidosis, sialidosis.

[0169] In a specific embodiment, said sphingolipidosis is a Neuronal ceroid lipofuscinosis (NCL), including NCL 3 (Batten disease), NCL 10 and Hereditary spastic paraplegia (HSP).

[0170] In a specific embodiment, said disease is phospholipidosis.

[0171] In a specific embodiment, said disease is Alzheimer disease.

[0172] In a specific embodiment, said disease is Parkinson’s disease.

[0173] In preferred embodiments said condition is selected from neuronal ceroid lipofuscinosis (NCL), CLN3 Batten, CLN5 Batten, GRN , frontotemporal dementia and Niemann Pick disease, preferably of type C.

[0174] In specific embodiments, said condition is selected from the diseases mentioned in Table 1 .

[0175] In a preferred embodiment, said disease is Niemann Pick type C (NPC).

[0176] Niemann-Pick disease type C (NPC) is a rare autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. Classically, children with NPC disease demonstrate neurological dysfunction with cerebellar ataxia (an inability to coordinate balance, gait, extremity and eye movements), dysarthria (difficulty speaking), vertical gaze palsy (ability to move eyes in the vertical direction), motor impairment, dysphagia (trouble swallowing), psychotic episodes, and dementia (preferably progressive dementia). Affected individuals often experience progressive decline in intellectual function and about one-third have seizures. NPC is caused by mutations in the genes NPC1 or NPC2. NPC occurs at a frequency of 1 :100000 live births and is an autosomal recessive disorder. The gene products of NPC1 and NPC2 mediate redistribution of endocytic cholesterol from the late endosomal / lysosomal compartment to other cellular compartments like the endoplasmic reticulum and plasma membrane. Consequently, a hall mark of NPC disease is the cellular storage of cholesterol in the lysosomal compartment (38). While a small subset of early infantile cases will die within the first six months of birth from liver or respiratory failure, most patients will develop progressive and neurological complications and typically die between the ages of 10 to 25. The neurological symptoms typically present as cerebellar ataxia, dysarthria, dysphagia, and progressive dementia, and the majority of cases show a characteristic vertical supranuclear gaze palsy (VSGP) (38). In both human patients and preclinical models of NPC, progressive degeneration of the cerebellum and increased circulation of neurodegeneration biomarkers like Neurofilament light chain can be detected (Agrawal, Estibaliz Santiago-Mujica Helyon).

[0177] NPC disease is characterized by the secondary accumulation of (glyco)-sphingolipids and therefore considered a member of a group of diseases called shingolipidoses (35).

[0178] In specific embodiments, said LSD is characterized by progressive neurological symptoms tied to accumulation of lipid species. In specific embodiments, such condition is characterized by defects in lysosomal cholesterol trafficking. In specific embodiments, such condition is characterized by an increased level of cellular BMP. In other specific embodiments, said condition is characterized by a decreased level of cellular BMP. In preferred said cellular BMP level is elevated in the spleen, liver, brain, skin and / or plasma. In specific embodiments, said condition is characterized by cholesterol accumulation and lack of clearance of autophagic materials.

[0179] In specific embodiments, the treatment according to the invention results in the stabilization of cellular BMP levels. In other specific embodiments, the treatment according to the invention results in the increase of cellular BMP levels. In other specific embodiments, the treatment according to the invention results in enhancing hydrolysis of lysosomal sphingomyelin, glycosphingolipids and / or gangliosides. In preferred said cellular BMP level is elevated in the spleen, liver, brain, skin and / or plasma. In other specific embodiments, the treatment according to the invention results in the formation of free oleic acid from PG, LPG and BMP.

[0180] In specific aspects, Niemann-Pick disease type C is caused by mutation in an NPC1 gene (chromosome location 18q11) or an NPC2 gene (chromosome location 14q24.3), preferably in an NPC1 gene. Niemann-Pick disease type C caused by mutation in an NPC1 gene or an NPC2 gene may be called Niemann-Pick disease type C1 (NPC1) or Niemann-Pick disease type C1 (NPC2), respectively.

[0181] Both the NPC1 gene and the NPC2 are involved in the efflux of lipids, particularly cholesterol, from late endosomes and lysosomes. The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. The NPC2 gene on the other hand encodes a protein that binds and transports cholesterol.

[0182] Niemann-Pick disease type C is biochemically, genetically and clinically distinct from Niemann-Pick disease types A or and B. In types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. Without being bound to this theory, in Niemann-Pick disease type C, the protein product (i.e. the NPC1 protein) of the NPC1 gene is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene (i.e. the NPC2 protein) more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.

[0183] Hence, in Niemann-Pick disease type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, leading to relative deficiency of this molecule in multiple membranes and for steroid synthesis.

[0184] The mutations in the NPC1 gene and / or the NPC2 gene comprised in a subject suffering from Niemann-Pick disease type C syndrome result in a decreased NPC1 protein and / or NPC2 protein expression level, respectively, and / or the expression of a defective decreased NPC1 protein and / or NPC2 protein, respectively.

[0185] In the context of this application, a normal NPC1 or NPC2 protein expression level is defined as the NPC1 or NPC2 protein expression level in a healthy subject. A decreased NPC1 or NPC2 protein expression level means a NPC1 or NPC2 protein expression level lower than a normal NPC1 or NPC2 protein expression level, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 .

[0186] In the context of this application, a defective NPC1 or NPC2 protein is an NPC1 or NPC2 protein whose cellular activity is decreased, preferably decreased by a factor equal to or lower than 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 relative to an NPC1 or NPC2 protein expressed in a healthy subject, or no longer comprises such cellular activity.

[0187] In specific aspects, an inhibitor of the invention is able to induce one or more of the following changes when said inhibitor is introduced in a subject suffering from Niemann-Pick disease type C:

[0188] — a restored or partially restored intralysosomal cholesterol concentration, preferably wherein the intralysosomal cholesterol concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal cholesterol concentration is decreased by a factor equal to or greater than 1 .5, 2, 2.5, 3, 3.5, 4,

[0189] 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0190] — a restored or partially restored endosomal, preferably late-endosomal cholesterol concentration, preferably wherein the endosomal, preferably the late-endosomal, cholesterol concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, cholesterol concentration is decreased by a factor equal to or greater than 1 .5, 2, 2.5, 3, 3.5, 4,

[0191] 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0192] — a restored or partially restored intralysosomal glycolipid concentration, preferably wherein the intralysosomal glycolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal glycolipid concentration is decreased by a factor equal to or greater than 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,

[0193] 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0194] — a restored or partially restored endosomal, preferably late-endosomal, glycolipid concentration, preferably wherein the endosomal, preferably the late-endosomal, glycolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late-endosomal, glycolipid concentration is decreased by a factor equal to or greater than 1 .5, 2, 2.5, 3, 3.5, 4,

[0195] 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0196] — a restored or partially restored intralysosomal glycosphingolipid concentration, preferably wherein the intralysosomal glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the intralysosomal glycosphingolipid concentration is decreased by a factor equal to or greater than

[0197] 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0198] — a restored or partially restored endosomal, preferably late-endosomal, glycosphingolipid concentration, preferably wherein the endosomal, preferably the late-endosomal, glycosphingolipid concentration is decreased after introduction of the inhibitor, more preferably wherein the endosomal, preferably the late- endosomal, glycosphingolipid concentration is decreased by a factor equal to or greater than 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; wherein a partially restored concentration means that the concentration is significantly closer to that in a corresponding healthy subject after introduction of said inhibitor, preferably by the factors described above, wherein a restored concentration means that the concentration is essentially the same as that in in a corresponding healthy subject.

[0199] In specific aspects, administration of an inhibitor according to the invention to a subject in need thereof results in one of the effects described above, particularly in a reduction of the intralysosomal cholesterol concentration and / or the intralysosomal glycosphingolipid concentration.

[0200] Niemann-Pick disease type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly).

[0201] Progressive neurological disease is the hallmark of Niemann-Pick type C disease. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).

[0202] Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, dementia (preferably progressive dementia), progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.

[0203] In specific aspects, an inhibitor of the invention is able to alleviate at least of the following symptoms when said inhibitor is introduced in a subject suffering from Niemann-Pick disease type C: splenomegaly, hepatomegaly, hepatosplenomegaly, cerebellar ataxia, dysarthria, dysphagia, tremorepilepsy, vertical supranuclear palsy, sleep inversion, gelastic cataplexy, dystonia, spasticity, hypotonia, ptosis, psychosis, dementia (preferably progressive dementia), progressive hearing loss, bipolar disorder, major and psychotic depression, hallucinations, delusions, mutism, and stupor. The alleviation of a symptom is generally acknowledged by the a skilled person (and in particular, by the treating physician) as an improvement.

[0204] In specific aspects, administration of an inhibitor according to the invention to a subject in need thereof results in the alleviation of at least of the following symptoms: cerebellar ataxia, dysarthria, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and dementia (preferably progressive dementia). TREATMENT OPTIONS

[0205] Wherever an inhibitor or a composition for use as a medicament is disclosed, a corresponding method for the manufacture or the production of a medicament comprising such an inhibitor or such a composition, a corresponding method of treatment comprising the administration of the inhibitor or composition to a subject in need thereof, and a corresponding use of such an inhibitor or such a composition as a medicament are also disclosed. In all these contexts, the inhibitor according to the invention and the composition according to the invention may be referred to as a medicament according to the invention.

[0206] A medicament according to the invention may be administered orally, nasally, buccally, sublingually, vaginally, parenterally, topically, systemically, intravenously, subcutaneously, intraperitoneally, intramuscularly, intrathecally, by inhalation or epidurally.

[0207] A medicament according to the invention, may be administered separately, sequentially or simultaneously in combination with another medicaments.

[0208] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time. The term "separate" therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes. The term "sequential" therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.

[0209] In the context of this application, the terms treating" or "treatment" refer to therapeutic treatment, wherein the object is to prevent, reduce, alleviate or slow down (lessen), respectively and as applicable, the targeted pathologic disorder or disease and / or its progression in a subject. In particular, said terms relate to a treatment which has the object of improving one or more symptoms and / or physiological parameters that are caused by, associated with and / or characteristic of the disease or disorder that is to be treated, and / or the object to preventing that such symptom(s) to arise and / or that such symptom(s) or physiological parameter(s) further deteriorate. Based on his general knowledge and the further disclosure herein, the skilled person (and in particular, the treating physician) will be able to suitably determine and measure said symptom(s) or physiological parameter(s), depending on the specific disease involved.

[0210] In the context of this application, the terms "prevention" or "preventing" of a disorder or disease refers to a compound that, in a statistical sample, reduces the occurrence of symptoms of a disorder or disease in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0211] A medicament according to the invention is administered to a subject in need thereof in an effective amount (i.e., amount that have desired therapeutic effect). Preferably, an effective amount refers to an amount of an inhibitor according to the invention comprised in said medicament. The dose and dosage regimen will depend upon the degree of the infection in the subject, the characteristics of the particular inhibitor according to the invention, e.g., its therapeutic index, the subject, and the subject's history. Certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the medicaments according to the invention can include a single treatment or a series of treatments.

[0212] The effective amount may be determined during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians. An effective amount of a peptide useful in the methods may be administered to a subject in need thereof by any of a number of well-known methods for administering pharmaceutical compounds.

[0213] Dosage, toxicity and therapeutic efficacy of a medicament according to the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Medicaments that exhibit high therapeutic indices are preferred.

[0214] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any medicament according to the invention, the therapeutically effective dose can be estimated initially from cell culture assays.

[0215] Compositions

[0216] In a further aspect, the invention provides a composition comprising an inhibitor according to the invention and a pharmaceutically acceptable excipient, preferably for use as a medicament, more preferably for use in the treatment of a disease characterized by lysosomal dysregulation. A related aspect pertains to a method of preparing such a composition. Such compositions are referred to in the current application as compositions according to or of the invention.

[0217] All specific embodiments disclosed above for an inhibitor according to the invention may be applied accordingly for an inhibitor according to the invention comprised in a composition according to the invention.

[0218] A composition according to the invention may be presented or formulated as capsules, tablets, powders, granules, solutions, suspensions in aqueous or non-aqueous liquids, edible, oil-in-water liquid emulsions, water-in-oil liquid emulsions, solution, syrups and elixirs, in microencapsulated form, liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles, transdermal patches, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, drops, sprays, aerosols, oils, lozenges, pastilles, mouth washes, suppositories, enemas, aqueous and non-aqueous sterile injection solutions, and so on. It will be appreciated that the compositions may include other agents conventional in the art having regard to the type of formulation.

[0219] Non-limiting examples of a pharmaceutically acceptable carrier comprised in a composition are saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds, besides an inhibitor according to the invention, can also be incorporated into the compositions.

[0220] A composition according to the invention formulated as solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0221] A composition according to the invention formulated as compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, a composition for parenteral administration must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0222] In a composition according to the invention prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerasol, and the like. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0223] A composition according to the invention formulated as oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the inhibitor according to the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.

[0224] Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0225] A composition according to the invention may be formulated for administration by inhalation, the inhibitor according to the invention can be delivered in the form of an aerosol spray from a pressurized container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0226] A composition according to the invention may be formulated for transmucosal ortransdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. In one aspect, transdermal administration may be performed by iontophoresis.

[0227] A composition according to the invention may comprise a carrier system such as a colloidal system. The colloidal system can be a liposome, a phospholipid bilayer vehicle. In one aspect, the inhibitor according to the invention is encapsulated in a liposome. An inhibitor according to the invention can also be loaded into a particle prepared from pharmaceutically acceptable ingredients including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.

[0228] Uses

[0229] In a further aspect, the invention provides the use of a PLA2G15 inhibitor according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15. Preferably, the binding of PLA2G15 results in in the inhibition of PLA2G15. The inhibition of PLA2G15 is described in more detail above.

[0230] All specific embodiments disclosed above for an inhibitor according to the invention and a composition according to the invention may be applied accordingly for the uses and therapeutic uses described below.

[0231] In embodiments, the use of a PLA2G15 inhibitor according to the invention or a composition according to the invention is for specifically binding and / or specifically inhibiting PLA2G15. Specifically means that the binding or inhibition stems from the amino acid sequence dependent molecular interaction between the inhibitor, or the inhibitor comprised in the composition, and PLA2G15. As such, the inhibitor or composition is not able to significantly bind or inhibit other enzymes that may share a similar function but a different amino acid structure.

[0232] In embodiments, the use of a PLA2G15 inhibitor according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15 comprises a PLA2G15 inhibitor which does not specifically bind and / or specifically inhibit other phospholipases than PLA2G15. In other words, whereas the inhibitor, or the inhibitor comprised in the composition, is able to specifically bind or inhibit PLA2G15, is not able to do so with other phospholipases. Other phospholipases include group I phospholipases (PLA2G1 B), group II phospholipases (PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F), group III phospholipases (PLA2G3), group IV phospholipases (PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F), group V phospholipases (PLA2G5), group VI phospholipases (PLA2G6), group VII phospholipases (PLA2G7), group X phospholipases (PLA2G10) and group XII phospholipases (PLA2G12A, PLA2G12B). Preferably, the PLA2G15 inhibitor or composition does not significantly bind or inhibit the phospholipases in this list. The inhibition of PLA2G15 can be expressed as the half maximal inhibitory concentration (IC50), as known to the skilled person. Lower IC50 values correspond with higher potencies to inhibit PLA2G15. IC50 can be determined using the protocol of Example 2.

[0233] In embodiments, the use of a PLA2G15 inhibitor according to the invention or a composition according to the invention for (specifically) inhibiting PLA2G15 comprises a PLA2G15 inhibitor having an IC50 for PLA2G15 of less than 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5,4, 3, 2, 1 , 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 pmol / L, preferably as measured by the 4-nitrophenyl butyrate activity assay as described herein.

[0234] In embodiments, the use of a PLA2G15 inhibitor according to the invention or a composition according to the invention for (specifically) inhibiting PLA2G15 comprises a PLA2G15 inhibitor having a ratio between its IC50 for PLA2G15 and its IC50 for other phospholipases, as provided above, equal to or higher than 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or 2 pmol / L.

[0235] In embodiments, the uses above are for use in vitro.

[0236] In embodiments, the uses above are for use in vivo.

[0237] In embodiments, (the use of) a PLA2G15 inhibitor according to the invention or a composition according to the invention does not induce an accumulation of phospholipids.

[0238] Definitions

[0239] All documents cited in the present specification are hereby incorporated by reference in their entirety. Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0240] Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is made to the standard handbooks, to the general background art referred to above and to the further references cited therein.

[0241] As used herein, the singular forms 'a', 'an', and 'the' include both singular and plural referents unless the context clearly dictates otherwise.

[0242] The terms 'comprising', 'comprises' and 'comprised of as used herein are synonymous with 'including', 'includes' or 'containing', 'contains', and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0243] Physiological conditions are defined in the context of this application as typical environmental conditions in a vertebrate, mammalian or human cell or tissue that is in homeostasis and is not subject to extraordinary external stress. Preferably, physiological conditions mean a temperature from 25°C up to 45°C, more preferably from 30°C up to 40°C.

[0244] A concentration is preferably a molar concentration, preferably a molar concentration per weight or per volume, most preferably measured under physiological conditions.

[0245] A subject is defined in the context of this application as a (living) organism, unless explicitly stated otherwise. A subject may be any organism, including invertebrates and vertebrates. Preferably, a subject is a vertebrate. More preferably, a vertebrate is a starfish or a mammal. Even more preferably, a mammal is a rat, a mouse, a rabbit or a human. Most preferably, a mammal is a human. In an alternative specific aspect, a subject is a non-human animal, more preferably a non-human vertebrate, most preferably a non-human mammal.

[0246] An organelle is preferably a lysosome or an endosome, more preferably a lysosome. An endosome is preferably a late endosome.

[0247] An increase of a parameter by a factor equal to or higher than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or higher than A*X.

[0248] An increase of a parameter by a factor equal to or lower than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or lower than A*X.

[0249] A decrease of a parameter by a factor equal to or lower than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or lower than A*X.

[0250] A decrease of a parameter by a factor equal to or higher than X is defined in the context of this application as a change of said parameter from its initial value A to a value equal to or higher than A*X.

[0251] Specifically named C1-4 alkyls and C1-4 alkylenes, such as methyl, ethyl, propyl, etc., may be unsubstituted (apart from their relevant attachment to the rest of the PLA2G15 inhibitor) or substituted with one or more of halogens or pseudohalogens. For example, methyl may refer to CH3, CH2OH, CHCI2, CF3, etc. In contrast, CH3 only refers to an unsubstituted methyl. Wherever a substitution with “n of A and B” or “n of A or B” is mentioned, a total of n substitutions independently selected from A and B is meant. In other words, n exocyclic hydrogen atoms are independently replaced by moieties selected from A and B.

[0252] A parameter that is essentially the same as in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or as in a corresponding healthy subject, preferably means that the value of said parameter cannot be distinguished by a skilled person from the value of a corresponding parameter in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject, and / or that the value of said parameter would be interpreted by a skilled person as measured in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject.

[0253] An alteration of a parameter which is significantly smaller after introduction of an inhibitor in a composition, organelle, cell fraction, cell, membrane, tissue, organ or subject preferably means that the absolute difference between the value of said parameter and the value of a corresponding parameter in a corresponding composition, organelle, cell fraction, cell, membrane, tissue or organ derived from a healthy subject or in a corresponding healthy subject is decreased by a factor equal to or lower than 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 after said introduction.

[0254] Any parameter referred to herein is preferably determined using the specific method, assay or methodology described herein. Where the present specification does not mention or describe a specific method, assay or methodology for determining said parameter, said parameter can be measured in a manner suitable per se, as will be clear to the skilled person based upon reading the present disclosure.

[0255] Each amino acid sequence described herein by virtue of its identity or similarity percentage (at least 60%) with a given amino acid sequence respectively has in a further specific aspect an identity or a similarity of at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identity or similarity with the given amino acid sequence respectively. In a specific aspect, sequence identity or similarity is determined by comparing the whole length of the sequences as identified herein. Unless otherwise indicated herein, identity or similarity with a given SEQ ID NO means identity or similarity based on the full length of said sequence ( / .e. over its whole length or as a whole).

[0256] Sequence identity is defined in the context of this application as a relationship between two or more amino acid (polypeptide or protein) sequences or two or more nucleic acid (polynucleotide) sequences, as determined by comparing the sequences. The identity between two amino acid sequences is preferably defined by assessing their identity within a whole SEQ ID NO as identified herein or part thereof. Part thereof may mean at least 50% of the length of the SEQ ID NO, or at least 60%, or at least 70%, or at least 80%, or at least 90%.

[0257] In the art, sequence identity also means the degree of sequence relatedness between amino acid sequences, as the case may be, as determined by the match between strings of such sequences. Sequence similarity between two amino acid sequences is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one polypeptide to the sequence of a second polypeptide. Sequence identity and similarity can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heine, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991 ; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48:1073 (1988).

[0258] Preferred methods to determine sequence identity are designed to give the largest match between the sequences tested. Methods to determine sequence identity and similarity are codified in publicly available computer programs. Preferred computer program methods to determine sequence identity and similarity between two sequences include e.g. the GCG program package (Devereux, J., et al., Nucleic Acids Research 12 (1): 387 (1984)), BestFit, FASTA, BLASTN, and BLASTP (Altschul, S. F. et al., J. Mol. Biol. 215:403-410 (1990)), EMBOSS Needle (Madeira, F., et al., Nucleic Acids Research 47(W1): W636-W641 (2019)). The BLAST program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990)). The EMOSS program is publicly available from EMBL-EBI. The well- known Smith Waterman algorithm may also be used to determine identity. The EMBOSS Needle program is the preferred program used.

[0259] Preferred parameters for polypeptide sequence comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol. 48 (3):443-453 (1970); Comparison matrix: BLOSUM62 from Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA. 89:10915-10919 (1992); Gap Open Penalty: 10; and Gap Extend Penalty: 0.5. A program useful with these parameters is publicly available as the EMBOSS Needle program from EMBL-EBI. The aforementioned parameters are the default parameters for a Global Pairwise Sequence alignment of proteins (along with no penalty for end gaps).

[0260] Preferred parameters for nucleic acid comparison include the following: Algorithm:

[0261] Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); Comparison matrix: DNAfull; Gap Open Penalty: 10; Gap Extend Penalty: 0.5. A program useful with these parameters is publicly available as the EMBOSS Needle program from EMBL-EBL The aforementioned parameters are the default parameters for a Global Pairwise Sequence alignment of nucleotide sequences (along with no penalty for end gaps).

[0262] Optionally, in determining the degree of amino acid (sequence) similarity, the skilled person may also take into account so-called "conservative" amino acid substitutions, as will be clear to the skilled person. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; a group of amino acids having acidic side chains is aspartate and glutamate; and a group of amino acids having sulphur- containing side chains is cysteine and methionine. Preferred conservative substitutions for each of the naturally occurring amino acids are as follows: Ala to Ser; Arg to Lys or Gin; Asn to Asp, His or Ser; Asp to Glu or Asn; Gin to Glu, Lys or Arg; Glu to Lys, Asp, Gin; His to Tyr or Asn; lie to Leu, Vai, or Met; Leu to He, Met or Vai; Lys to Arg, Gin or Glu; Met to Vai, Leu or lie; Phe to Trp or Tyr; Ser to Thr, Ala or Asn; Thr to Ser; Trp to Tyr or Phe; Tyr to His, Trp or Phe; and Vai to He, Leu or Met. Substitutional variants of the amino acid sequence disclosed herein are those in which at least one residue in the disclosed sequences has been removed and a different residue inserted in its place. Preferably, the amino acid change is conservative.

[0263] In an aspect of the invention, there is provided a PLA2G15 inhibitor for use as a medicament represented by formula (I), or a salt or solvate thereof:

[0264] (I), wherein X is CR6R7, O, NR6or a single bond; wherein RAcomprises a ring; wherein RBcomprises a ring, preferably an aliphatic ring, more preferably a cyclopropyl; wherein Rs, R1, R2, R3, R4, R5, R6, R7and R8are independently H, a C1-4 alkyl, a C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl and C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens; and wherein R1and R2, and / or R3and R4, and / or R5and R6may alternatively form =0.

[0265] In some embodiments, there is provided the PLA2G15 inhibitor, or a salt or solvate thereof, wherein RBcomprises an aliphatic ring, preferably a cyclopropyl.

[0266] In some embodiments, there is provided the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein RBcomprises a fivemembered or a six-membered aromatic ring.

[0267] In some embodiments, there is provided the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein RBcomprises a single aliphatic ring system.

[0268] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, represented by formula (II):

[0269] (II), wherein Y is C-RY2or N; and wherein RY1, RY2, RY3, RY4and RY5are independently H, a C1-4 alkyl, a O-C1-4 alkyl, a S- C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, a S-C3-4 cycloalkyl, a halogen, or a pseudohalogen, wherein each C1-4 alkyl, O-C1-4 alkyl, S-C1-4 alkyl, C3-4 cycloalkyl, O-C3-4 cycloalkyl and S-C3-4 cycloalkyl may be substituted with one or more halogens or pseudohalogens.

[0270] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein Y is CH, and RY4and RY5are H.

[0271] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein RY1is OCH3.

[0272] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein RY3is H. In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein Rsis H or F, preferably wherein Rsis H.

[0273] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein R1, R2, R5and R6are H.

[0274] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein R3and R4are independently H or CH3, preferably wherein R3and R4are H.

[0275] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, wherein X is CH2 or O, preferably wherein X is CH2.

[0276] In some embodiments, the PLA2G15 inhibitor for use according to the invention, or the PLA2G15 inhibitor according to the invention, represented by formula (l-R):

[0277] (l-R).

[0278] The PLA2G15 inhibitor according to the invention, represented by any one of formulae (1) to (56), preferably for use as a medicament.

[0279] Use of the PLA2G15 inhibitor as defined herein for specifically binding and / or inhibiting PLA2G15, preferably wherein the PLA2G15 inhibitor does not specifically bind and / or inhibit other phospholipases than PLA2G15.

[0280] The PLA2G15 inhibitor for use according to the invention, for use in the treatment of a disease characterized by lysosomal dysregulation, preferably wherein the disease is a lysosomal storage disease, HIV, Alzheimer’s disease or Parkinson’s disease, preferably more preferably wherein the lysosomal storage disease is Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal dementia. References

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[0327] Examples

[0328] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

[0329] Example 1: Synthesis of compounds

[0330] EXAMPLE 1.1: SYNTHESIS OF METHYL MORPHOLINE DERIVATIVES

[0331] HATU (341 mg, 0.896 mmol, 1.1 eq) was added to a solution of (2R,6R)-4-(tert- butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (200 mg, 0.815 mmol, 1 eq) and NH4CI (65 mg, 1 .215 mmol, 1 .5 eq) in DMF (5 mL). The mixture was stirred at r.t. for 2 min and DIPEA (348 mL, 2.032 mmol, 2.5 eq) was added. The solution was stirred at r.t. for 90 min, it was poured into brine (50 mL) and it was extracted with EtOAc (3x15 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated to give tert-butyl (2R,6R)-2- carbamoyl-6-methylmorpholine-4-carboxylate (185 mg, 93% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) δ 6.55 (s, 1 H), 5.49 (s, 1 H), 4.52-4.22 (m, 1 H), 4.02-3.91 (m, 2H), 3.72-3.47 (m, 1 H), 2.68 (t, J = 12.2 Hz, 1 H), 2.46 (t, J = 11.9 Hz, 1 H), 1.46 (s, 9H), 1.22 (d, J = 6.1 Hz, 3H); MS (ESI) m / z 231 [M + H]+.

[0332] A solution of tert-butyl (2R,6R)-2-carbamoyl-6-methylmorpholine-4-carboxylate (375 mg, 1 .535 mmol, 1 eq) in THF (5 mL) was added to a suspension of Lawesson's reagent (392 mg, 0.92 mmol, 0.6 eq) in THF (5 mL). The solution was stirred at r.t. for 5 h and H2O (20 mL) was added. The mixture was poured into NH4CI (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was flash chromatographed on SiO2 (0- 30% EtOAc / hexanes) to give tert-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4- carboxylate (270 mg, 68% yield) as a yellow solid.1H NMR (300 MHz, CDCI3) δ 8.02 (bs, 1 H), 7.50 (bs, 1 H), 4.66 (d, J = 13.8 Hz, 1 H), 4.26 (dd, J = 10.5, 3.1 Hz, 1 H), 4.06-3.88 (m, 1 H), 3.76-3.57 (m, 1 H), 2.59 (dd, J = 12.2 Hz, 1 H), 2.45 (dd, J = 12.1 Hz, 1 H), 1.24 (d, J = 6.2 Hz, 3H); MS (ESI) m / z 261 [M + H]+; SFC: RT 2.70 min

[0333] EXAMPLE 1.2: SYNTHESIS OF (1)

[0334] A solution of tert-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (88 mg, 0.338 mmol, 1 eq) and 2-methoxyphenacyl bromide (77 mg, 0.337 mmol, 1 eq) in EtOH (2 mL) was refluxed for 90 min and volatiles were concentrated off. The residue was dissolved in EtOH (6 mL), HCI (4M in dioxane, 845 mL, 3.38 mmol, 10 eq) was added and the solution was stirred at r.t. for 2 h. Volatiles were concentrated off and the residue was slurried with Et20 (2x5 mL) to give crude (2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine hydrochloride (140 mg, 127% yield) as a yellow solid. It was submitted to the next step without further purification, considering it was 82% pure w / w.1H NMR (300 MHz, DMSO-de) δ 9.73-9.39 (m, 2H), 8.17-8.08 (m, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.10-6.99 (m, 1 H), 5.32-5.22 (m, 1 H), 4.25-4.1 1 (m, 1 H), 3.92 (s, 3H), 3.50-3.29 (m, 2H), 3.19-3.06 (m, 1 H), 2.92- 2.77 (m, 1 H), 1 .25 (d, J = 6.3 Hz, 3H); MS (ESI) m / z free base 291 [M + H]+; SFC: RT 3.39 min

[0335] HATU (79 mg, 0.206 mmol, 1.1 eq) and DIPEA (128 mL, 0.747 mmol, 4 eq) were added to a solution of (2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine hydrochloride (75 mg, 82% w / w, 0.188 mmol, 1 eq) and bicyclo[2.1 .1]hexane-1-carboxylic acid (25 mg, 0.188 mmol, 1 eq) in DMF (2 mL), and the mixture was stirred at r.t. for 2 h. It was poured into H2O (10 mL) and it was extracted with EtOAc (2x10 mL). Combined organic layers were washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 50% to 70%] to give bicyclo[2.1 ,1]hexan-1-yl((2R,6R)-2-(4- (2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholino) methanone (53 mg, 71 % yield) as a white solid after lyophilization. 1 H NMR (300 MHz, CDCI3) δ 8.39-8.12 (m, 1 H), 7.94 (s, 1 H), 7.34- 121 (m, 1 H), 7.11 -6.95 (m, 2H), 4.89-4.73 (m, 1 H), 4.56 (d, J = 13.5 Hz, 1 H), 4.22 (d, J = 13.6 Hz, 1 H), 3.95 (s, 3H), 3.80 (s, 1 H), 3.16 (t, J = 12.0 Hz, 1 H), 2.62-2.38 (m, 2H), 2.04-1.86 (m, 4H), 1 .86-1 .75 (m, 2H), 1 .56-1 .41 (m, 2H), 1 .32 (d, J = 6.1 Hz, 3H); MS (ESI) m / z 399 [M + H]+; SFC: RT 3.81 min

[0336] EXAMPLE 1.3: SYNTHESIS OF (2)

[0337] Synthesis of compound 2

[0338] To the mixture of compound 1 (0.6 g, 2.63 mmol, 1 eq) in THF (6 mL) was added LAWESSON'S REAGENT (637.83 mg, 1.58 mmol, 0.6 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 :0 to 2:1 , TLC: Petroleum ether / Ethyl acetate = 1 :1) to give compound 2 (510 mg, 2.09 mmol, 79.41 % yield) as white solid.1H NMR: (400 MHz, DMSO-d6) δ = 9.44 (br s, 1 H), 9.22 (br s, 1 H), 3.87 - 3.86 (m, 1 H), 3.91 (br s, 1 H), 2.98 - 2.75 (m, 1 H), 2.63 - 2.54 (m, 2H), 1 .84 - 1 .74 (m, 1 H), 1.71 - 1 .61 (m, 2H), 1 .33 - 1 .24 (m, 1 H)

[0339] Synthesis of compound 4

[0340] The mixture of compound 2 (2.88 g, 11.79 mmol, 1 eq), compound 2A (2.59 g, 1 1.31 mmol, 0.96 eq) in EtOH (30 mL) was stirred at 90 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. To the residue was added DCM (20 mL), HCI (4 M, 6 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give compound 4 (3.4 g, crude, HCI salt) as white solid. 6.1 g compound 4 (crude, HCI salt) was dissolved with MeOH (200 mL), to the solution was added ion exchange resin (~50 g). The mixture was stirred at 25 °C for 1 h, filtered and the filtrate was concentrated. The residue was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10um); mobile phase: [0.1 %NH3H2O ETOH]; B%: 35%-35%, 5.6 min) to give compound 4 (4.9 g, 17.50 mmol, 78.72% yield, 98% purity, ee: 99%) as yellow solid. LCMS: RT = 0.449 min, m / z = 275.0 (M+H)+; SFC: RT = 1 .833 min.

[0341] Synthesis of (2)

[0342] To a solution of compound 4 (80 mg, 291.57μmol, 1 eq) and 1-(4-fluorophenyl) cyclopropanecarboxylic acid (52.53 mg, 291.57 μmol, 1 eq) in DMF (1 mL) was added DIEA (75.37 mg, 583.13 μmol, 101.57 μL, 2 eq), HOBt (47.28 mg, 349.88 μmol, 1.2 eq) and EDCI (67.07 mg, 349.88 μmol, 1 .2 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 56%-86%, 10 min), the eluent was concentrated and then freeze dried to give (2) (66.7 mg, 151 .26 μmol, 51 .88% yield, 99% purity) as white solid.1H NMR: (400 MHz, CDCI3) δ = 8.29 - 8.19 (m, 1 H), 7.85 - 7.77 (m, 1 H), 7.34 - 7.28 (m, 1 H), 121 - 7.12 (m, 2H), 7.11 - 7.05 (m, 1 H), 7.00 (br d, J = 7.9 Hz, 3H), 4.90 -3.96 (m, 6H), 3.23 - 2.85 (m, 2H), 2.75 - 2.47 (m, 1 H), 2.24 - 2.14 (m, 1 H), 1.92 - 1.68 (m, 3H), 1.45-1.43 (m, 1 H), 1.31 - 0.96 (m, 3H); LCMS: RT = 0.711 min, m / z = 437.4 (M+H)+.

[0343] EXAMPLE 1.4: SYNTHESIS OF (3)

[0344] 1 3 (3)

[0345] Synthesis of compound 3

[0346] A mixture of compound 2 (40 mg, 161.90 1 eq) anμdm coolm, pound 1 (42.15 mg, 161.90 pmol, 1 eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuum to give compound 3 (45 mg, 145.93 90.13% yiμemldo) l a, s white solid. LCMS: RT = 0.442 min, m / z = 309.0 (M+H)+.

[0347] Synthesis of (3)

[0348] To a solution of compound 3 (45 mg, 145.93 1 eq) aμnmdol c, ompound 4 (14.61 mg, 145.93 μmol 1, eq) in DMF (1 mL) was added HOBt (23.66 mg, 175.11 1.2 eq), EDCI μmol, (33.57 mg, 175.11 μ 1m.2ol, eq) and DIEA (75.44 mg, 583.71 101.67 μL, μ 4m eoql), . The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 55%- 85% B over 10 min) followed by lyophilization to give (3) (35.67 mg, 91.35 pmol, 62.60% yield, 100% purity) as off-white solid.1H NMR: (400 MHz, CD3OD) δ = 8.10 (s, 1 H), 7.90 (dd, J = 3.1 , 10.0 Hz, 1 H), 7.12 - 7.01 (m, 2H), 4.91 (br s, 1 H), 4.86 - 4.83 (m, 1 H), 4.38 (br d, J = 13.0 Hz, 1 H), 3.95 (s, 3H), 3.91 - 3.81 (m, 1 H), 3.22 - 2.61 (m, 2H), 1 .37 (s, 3H), 1 .33 (d, J = 6.1 Hz, 3H), 1.03 - 0.92 (m, 2H), 0.75 - 0.65 (m, 2H); LCMS: RT = 0.596 min, m / z = 391.2 (M+H)+; SFC: RT = 1.589 min.

[0349] EXAMPLE 1.5: SYNTHESIS OF (4)

[0350]

[0351] A deoxygenated solution of 2-bromo-4,5-difluoroanisole (250 mg, 1.121 mmol, 1 eq), butyl vinyl ether (1.5 mL, 11.591 mmol, 10.34 eq), dppp (93 mg, 0.225 mmol, 0.2 eq), Pd(OAc)2 (26 mg, 0.115 mmol, 0.1 eq) and EtaN (468 mL, 3.357 mmol, 3 eq) in DMF (4 mL) was reacted at 120 °C for 18 h in a sealed tube. The mixture was cooled down to r.t., it was poured into H2O (20 mL) and extracted with EtOAc (15 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated.

[0352] The residue was dissolved in THF (3 mL), HCI (10% aqueous solution, 5.00 mL) was added and the mixture was stirred at r.t. for 2 h. It was poured into H2O (20 mL) and it was extracted with EtOAc (3x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% EtOAc / hexanes) to give 1 -(4,5-difluoro-2-methoxyphenyl)ethan-1-one (165 mg, 79% yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 7.67 (t, J = 10.2 Hz, 1 H), 6.79 (dd, J = 11 .8, 6.1 Hz, 1 H), 3.90 (s, 3H), 2.59 (s, 3H); MS (El) mlz 186 [M]

[0353] Copper (II) bromide (780 mg, 3.492 mmol, 1.97 eq) was added to a solution of 1 -(4,5- difluoro-2-methoxyphenyl)ethan-1-one (330 mg, 1.772 mmol, 1 eq) in a mixture EtOAc (8 mL) and CHCb (8 mL) and the suspension was refluxed for 20 h. The reaction mixture was cooled down to r.t., filtered through a pad of celite, and product was eluted with EtOAc (60 mL). Organic layer was washed with NH4CI (saturated aqueous solution, 30 mL), dried over Na2SO4 (anhydrous), filtered and concentrated to give 2-bromo-1-(4,5-difluoro-2-methoxyphenyl)ethan- 1-one (456 mg, 97% yield) as a pale brown solid. It was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.75 (dd, J = 10.6, 9.2 Hz, 1 H), 6.82 (dd, J = 11.5, 6.1 Hz, 1 H), 4.54 (s, 2H), 3.94 (s, 3H).

[0354] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (160 mg, 0.649 mmol, 1 eq) and 2-bromo-1-(4,5-difluoro-2-methoxyphenyl)ethan-1-one (175 mg, 0.66 mmol, 1.02 eq) in EtOH (6 mL) was refluxed for 2 h. It was cooled down to r.t., HCI (4 M in dioxane, 1 .5 mL, 6 mmol, 9.24 eq) was added and the reaction was stirred at r.t. for 3 h. It was poured into NaHCOs (saturated aqueous solution, 40 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH / CH2Cl2 using NH3 as additive) to give (R)-2-(4-(4,5-difluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (127 mg, 63% yield) as a brown oil.1H NMR (300 MHz, CDCI3) δ 8.09 (dd, J = 11.9, 9.4 Hz, 1 H), 7.88 (s, 1 H), 6.79 (dd, J = 12.1 , 6.6 Hz, 1 H), 4.84 (dd, J = 9.8, 2.8 Hz, 1 H), 4.18-4.00 (m, 1 H), 3.91 (s, 3H), 3.79 (m, 1 H), 3.55-3.41 (m, 1 H), 3.08-2.87 (m, 3H); MS (ESI) m / z 313 [M + H]+; SFC: RT 3.07 min

[0355] HATU (80 mg, 0.21 mmol, 1.1 eq) and DIPEA (97 mL, 0.566 mmol, 2.97 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (20 mg, 0.189 mmol, 0.99 eq) and (R)-2- (4-(4,5-difluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (60 mg, 0.192 mmol, 1 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 60%] to give (R)-(2-(4-(4,5-difluoro-2- methoxyphenyl)thiazol-2-yl)morpholino)(1 -methylcyclopropyl)methanone (50 mg, 66% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.20-8.06 (m, 1 H), 7.93 (s, 1 H), 6.82 (m, 1 H), 4.88-4.69 (m, 2H), 4.37 (m, 1 H), 4.13 (m, 1 H), 3.93 (s, 3H), 3.76 (m, 1 H), 3.29-3.07 (m, 2H), 1.40 (s, 3H), 1.07-0.88 (m, 2H), 0.76-0.58 (m, 2H); MS (ESI) m / z 395 [M + H]+; SFC: RT 2.72 min

[0356] EXAMPLE 1.6: SYNTHESIS OF (5)

[0357] Synthesis of compound 4

[0358] To a mixture of compound 3 (2.5 g, 10.81 mmol, 1 eq) in THF (25 mL) was added CDI (2.10 g, 12.97 mmol, 1.2 eq). The mixture was stirred at 25 °C for 2 h. Then the mixture reaction poured into NHs'^O (13.53 g, 108.11 mmol, 14.87 mL, 28% purity, 10 eq) and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (30 mL) and the resulting mixture was extracted with ethyl acetate (10 mL*3), the combined organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 4 (2.9 g, crude) as white solid. LCMS: RT = 0.403 min, m / z = 175.1 (M + H - tBu)+.

[0359] Synthesis of compound 5

[0360] To a solution of compound 4 (2.9 g, 12.59 mmol, 1 eq) in THF (30 mL) was added LAWESSON'S REAGENT (3.06 g, 7.56 mmol, 0.6 eq). The reaction mixture was stirred at 5 °C for 4 h. LCMS showed compound 4 remained and then the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was directly purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1 , TLC (Petroleum ether : Ethyl acetate = 1 : 1 , Rf = 0.49) ) to give compound 5 (1 .64 g, 6.66 mmol, 52.86% yield) as pink solid. LCMS: RT = 0.463 min, m / z = 191.2 (M + H - tBu)+.

[0361] Synthesis of compound 7

[0362] A mixture of compound 5 (500 mg, 2.03 mmol, 1 eq) and compound 6 (464.97 mg, 2.03 mmol, 1 eq) in EtOH (5 mL) was stirred at 90 °C for 2 h. Then the reaction mixture was concentrated in vacuum to give a residue. A mixture of the residue in HCI / EtOAc (4 M, 5 mL, 9.85 eq) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give compound 7 (1 .05 g, crude, HCI) as yellow solid. LCMS: RT = 0.403 min, m / z = 277.1 (M+H)+.

[0363] Synthesis of (5)

[0364] A mixture of acid (20.16 mg, 159.84 1 eq), μ cmomolp, ound 7 (50 mg, 159.84 pmol, 1 eq, HCI), HOBt (25.92 mg, 191.81 1.2μ emq)o,l, EDCI (36.77 mg, 191.81 1.2 eq) and DIEAμmol, (51.65 mg, 399.60 μ 6m9o.6l,0 μL, 2.5 eq) in DMF (1 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 53%- 83% B over 10 min). (5) (38.29 mg, 98.59 61 .68% yield, 99%μmol, purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 8.31 - 8.17 (m, 1 H), 7.95 (s, 1 H), 7.31 (br t, J = 7.4 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 7.00 (br d, J = 8.2 Hz, 1 H), 5.05 - 4.43 (m, 2H), 4.29 - 4.05 (m, 2H), 3.95 (s, 3H), 3.81 - 3.63 (m, 1 H), 3.44 - 3.20 (m, 1 H), 3.05 - 2.88 (m, 1 H), 2.44 (br s, 1 H), 1 .90 (br s, 4H), 1 .81 (br s, 2H), 1 .54 - 1 .39 (m, 2H); LCMS: RT = 0.588 min, m / z = 385.1 (M+H)+.

[0365] EXAMPLE 1.7: SYNTHESIS OF (6) AND (52)

[0366] § Synthesis of compound 3

[0367] A mixture of compound 2 (130 mg, 532.02 1 eq)μ amnodl, compound 1 (131.44 mg, 532.02 μmo 1l, eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. The residue was added HCI / EtOAc (3 mL) and DCM (3 mL) and the mixture was stirred at 20 °C for 1 h. Compound 3 (230 mg, crude, HCI) was obtained as a yellow solid. LCMS: RT =0.460 min, m / z =293.0 (M+H)+.

[0368] Synthesis of compound (6)

[0369] A mixture of 1-(4 -fluorophenyl) cyclopropanecarboxylic acid (54.79 mg, 304.11 pmol, 1 eq), compound 3 (100 mg, 304.11 1 eμqm, HolC, I), DIEA (117.91 mg, 912.32 158.91 μL, 3 μmol, eq), HOBt (49.31 mg, 364.93 1.2μ emq)o al,nd EDCI (69.96 mg, 364.93 1.2 eq) in DMF μmol, (1 mL) was stirrred at 20 °C for 16 h. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 56%- 86%, 10 min). Compound (6) (19.48 mg, 41.14 13.53%μm yioell,d, 96% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.27 - 8.14 (m, 1 H), 7.72 (br s, 1 H), 7.26 - 7.10 (m, 2H), 7.00 (br t, J = 7.8 Hz, 2H), 6.82 - 6.68 (m, 2H), 4.84 - 4.45 (m, 1 H), 4.15 - 3.75 (m, 4H), 3.24 - 2.87 (m, 2H), 2.80 - 2.44 (m, 1 H), 2.27 - 2.1 1 (m, 1 H), 1 .94 - 1 .68 (m, 2H), 1 .53 - 0.92 (m, 5H); LCMS: RT =0.903 min, m / z =455.1 (M+H)+; SFC: RT =1 .629 min.

[0370] Synthesis of compound (52)

[0371] A mixture of 5-cyclopropylisoxazole-3-carboxylic acid (46.57 mg, 304.11 1 eq), μmol, compound 3 (100 mg, 304.11 1 eμqm, HolC, I), DIEA (117.91 mg, 912.33 158.91 μL, 3 μmol, eq), HOBt (49.31 mg, 364.93 1.2μ emq)o al,nd EDCI (69.96 mg, 364.93 1.2 eq) in DMF μmol, (1 mL) was stirrred at 20 °C for 16 h. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 51 %- 81 %, 10 min). Compound (52) (31.99 mg, 74.08 24.36%μ ymieoldl,, 99% purity) was obtained as a yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.35 - 8.04 (m, 1 H), 7.88 - 7.60 (m, 1 H), 6.90 - 6.60 (m, 2H), 6.31 - 6.03 (m, 1 H), 5.09 - 4.24 (m, 2H), 4.09 - 3.81 (m, 3H), 3.71 - 2.99 (m, 3H), 2.45 - 2.21 (m, 1 H), 2.16 - 1.86 (m, 3H), 1.83 - 1.73 (m, 1 H), 1.21 - 0.91 (m, 4H); LCMS: RT =0.857 min, m / z =428.1 (M+H)+; SFC: RT =1 .751 min.

[0372] EXAMPLE 1.8: SYNTHESIS OF (7)

[0373] 2'-Chloroacetophenone (1.500 g, 9.702 mmol, 1 eq) was dropwise added to a vigorously stirred solution of thiomethoxide (920 mg, 90% pure, 11.813 mmol, 1.22 eq) in DMF (20 mL). The reaction mixture was stirred at r.t. for 18 h and it was poured into brine (100 mL). It was extracted with EtOAc (2x50 mL) and combined organic layers were washed with NaOH (1 % aqueous solution, 60 mL), NaOCI (1 % aqueous solution, 60 mL) and brine (60 mL). It was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (5-15% EtOAc / hexanes), to give 1-(2-(methylthio)phenyl)ethan-1-one (1 .4 g, 87% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) δ 7.84 (d, J = 7.8 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.32 (m, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 2.61 (s, 3H), 2.45 (s, 3H).

[0374] HBr (5.1 M in AcOH, 2.7 mL, 13.77 mmol, 2.97 eq) was added to a solution of 1 -(2- (methylthio)phenyl)ethan-1-one (770 mg, 4.631 mmol, 1 eq) in CHCb (25 mL). The mixture was stirred at r.t. for 3 min and Br2 (250 mL, 4.849 mmol, 1 .05 eq) was dropwise added. The reaction was stirred at r.t. for 10 min and it was partitioned between CH2CI2 (40 mL) and brine (50 mL). The organic layer was washed with Na2S20s (saturated aqueous solution, 40 mL) and brine (40 mL). It was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude 2-bromo-1-(2- (methylthio)phenyl)ethan-1-one (1.13 g, quantitative yield) was obtained as a redish oil, which was immediately submitted to next step.

[0375] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq) and 2-bromo-1-(2-(methylthio)phenyl)ethan-1-one (500 mg, 2.039 mmol, 2.51 eq) in EtOH (15 mL) was refluxed for 3 h. It was cooled down to r.t., poured into NaHCOs (saturated aqueous solution, 100 mL) and it was extracted with CH2CI2 (2x30 mL). Combined organic layers were washed with brine (50 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH / CH2Cl2) to give (R)-2-(4- (2-(methylthio)phenyl)thiazol-2-yl)morpholine (150 mg, 63% yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 7.62 (d, J = 7.6 Hz, 1 H), 7.56 (s, 1 H), 7.36-7.15 (m, 3H), 4.89 (dd, J = 9.8, 2.9 Hz, 1 H), 4.06 (d, J = 11 .6 Hz, 1 H), 3.81 (t, J = 10.9 Hz, 1 H), 3.50 (m, 1 H), 2.98 (m, 3H),

[0376] 2.43 (s, 3H); MS (ESI) m / z 293 [M + H]+; SFC: RT 3.72 min

[0377] HATU (207 mg, 0.544 mmol, 1.1 eq) and DIPEA (254 mL, 1 .483 mmol, 2.99 eq) were added to a solution of bicyclo[2.1 .1]hexane-1 -carboxylic acid (66 mg, 0.497 mmol, 1 eq) and (R)-2-(4- (2-(methylthio)phenyl)thiazol-2-yl)morpholine (145 mg, 0.495 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-40% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2- (methylthio)phenyl)thiazol-2-yl)morpholino)methanone (104 mg, 52% yield) as a pale brown solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.75-7.54 (m, 2H), 7.32 (s, 1 H), 7.31- 7.14 (m, 2H), 5.10-4.73 (m, 1 H), 4.57-4.21 (m, 1 H), 4.13 (m, 1 H), 3.77 (m, 1 H), 3.28 (m, 1 H), 2.95 (m, 1 H), 2.45 (s, 3H), 2.41 (m, 2H), 1.98-1.73 (m, 6H), 1.47 (m, 2H); MS (ESI) mlz 401 [M + H]+; SFC: RT 3.77 min

[0378] EXAMPLE 1.9: SYNTHESIS OF (8)

[0379] A suspension of 1 -(2-methoxy-4-methylphenyl)ethanone (500 mg, 3.045 mmol, 1 eq) and copper (II) bromide (1.400 g, 6.268 mmol, 2.06 eq) in a mixture of EtOAc (14 mL) and CHCH (14 mL) was refluxed for 3 h. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(2-methoxy-4-methylphenyl)ethan-1-one (740 mg, quantitative yield) as a brown solid, which was submitted to next step without further purification. 1 H NMR (300 MHz, CDCI3) δ 7.75 (m, 1 H), 6.84 (d, J = 8.1 Hz, 1 H), 6.78 (s, 1 H), 4.58 (s, 2H), 3.93 (s, 3H), 2.39 (s, 3H).

[0380] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq) and 2-bromo-1-(2-methoxy-4-methylphenyl)ethan-1-one (250 mg, 1.028 mmol, 1.27 eq) in EtOH (8 mL) was refluxed for 45 min. It was cooled down to r.t., HCI (4 M in dioxane, 2.00 mL, 8 mmol, 9.85 eq) was added and the solution was stirred at r.t. for 18 h. It was poured into NaHCOs (saturated aqueous solution, 120 mL) and it was extracted with EtOAc (2x40 mL). Combined organic layers were washed with brine (50 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-10% MeOH / CH2Cl2), to give (R)-2-(4-(2-methoxy-4-methylphenyl)thiazol-2-yl)morpholine (156 mg, 66% yield) as an orange solid. 1 H NMR (300 MHz, CDCI3) δ 8.08 (d, J = 7.9 Hz, 1 H), 7.83 (s, 1 H), 6.85 (d, J = 7.9 Hz, 1 H), 6.79 (s, 1 H), 4.86 (dd, J = 9.7, 2.8 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.92 (s, 3H), 3.81 (td, J = 10.9, 3.2 Hz, 1 H), 3.49 (dd, J = 12.6, 2.8 Hz, 1 H), 3.09-2.88 (m, 3H), 2.38 (s, 3H); MS (ESI) m / z 291 [M + H]+; SFC: RT 3.31 min

[0381] HATU (130 mg, 0.341 mmol, 1 .2 eq) and DIPEA (146 mL, 0.852 mmol, 3 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (30 mg, 0.284 mmol, 1 eq) and (R)-2-(4- (2-methoxy-4-methylphenyl)thiazol-2-yl)morpholine (82 mg, 0.282 mmol, 0.99 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 18 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 60%] to give (R)-(2-(4-(2-methoxy-4- methylphenyl)thiazol-2-yl)morpholino)(1-methylcyclopropyl)methanone (76.93 mg, 73% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.15 (d, J = 7.7 Hz, 1 H), 7.90 (bs, 1 H), 6.89 (d, J = 8.0 Hz, 1 H), 6.82 (s, 1 H), 4.83 (t, J = 9.6 Hz, 2H), 4.36 (d, J = 13.5 Hz, 1 H), 4.20-4.06 (m, 1 H), 3.96 (s, 3H), 3.86-3.70 (m, 1 H), 3.19 (m, 2H), 2.41 (s, 3H), 1 .39 (s, 3H), 1 .09-0.94 (m, 2H), 0.74-0.61 (m, 2H); MS (ESI) m / z 373 [M + H]+; SFC: RT 3.10 min

[0382] EXAMPLE 1.10: SYNTHESIS OF (9)

[0383] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq) and bromo-1-(5-fluoro-2-methoxyphenyl)ethanone (250 mg, 1 .01 1 mmol, 1.25 eq) in EtOH (10 mL) was refluxed for 90 min. The reaction was cooled down to r.t., HCI (4 M in dioxane, 1.5 mL, 6 mmol, 7.39 eq) was added and it was reacted for 18 h. The mixture was poured into K2CO3 (saturated aqueous solution, 80 mL) and it was extracted with EtOAc (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH / CH2Ch) to give (R)-2-(4-(5-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (184 mg, 77% yield) as an amber oil.1H NMR (300 MHz, CDCI3) δ 8.96 (m, 2H), 6.94 (m, 2H), 4.86 (dd, J = 9.7, 2.8 Hz, 1 H), 4.18-4.01 (m, 1 H), 3.93 (s, 3H), 3.83 (td, J = 10.9, 3.4 Hz, 1 H), 3.51 (dd, J = 12.8, 2.8 Hz, 1 H), 2.98 (m, 3H); MS (ESI) m / z 295 [M + H]+; SFC: RT 4.16 min HATU (134 mg, 0.352 mmol, 1.1 eq) and DIPEA (165 mL, 0.963 mmol, 3 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (34 mg, 0.322 mmol, 1 eq) and ((R)-2-(4- (5-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (95 mg, 0.322 mmol, 1 eq) in DMF (5 mL), and the mixture was stirred at r.t. for 18 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 65%] to give (R)-(2-(4-(5-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholino)(1- methylcyclopropyl)methanone (94 mg, 77% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.07-7.94 (m, 2H), 7.07-6.85 (m, 2H), 4.89-4.73 (m,2H), 4.35 (d, J = 13.5 Hz, 1 H), 4.20-4.05 (m, 1 H), 3.94 (s, 3H), 3.83-3.66 (m, 1 H), 3.28-3.05 (m, 2H), 1.38 (s, 3H), 1 .09-0.89 (m, 2H), 0.75-0.57 (m, 2H); MS (ESI) mlz 377 [M + H]+; SFC: RT 3.12 min

[0384] EXAMPLE 1.11: SYNTHESIS OF (10)

[0385] A mixture of compound 1 (80 mg, 255.74 1 eq, HCμI)m, coolm, pound 2 (46.08 mg, 255.74 pmol, 1 eq), DIEA (82.63 mg, 639.36 111 .36μm pLo,l, 2.5 eq), HOBt (41 .47 mg, 306.89 pmol, 1.2 eq) and EDCI (58.83 mg, 306.89 1.2 eμqm) ionl, DMF (1 mL) was stirred as 20 °C for 16 h. The mixture was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (FA) -ACN]; gradient: 63%- 93% B over 9 min). (10) (54.72 mg, 124.79 pmol, 48.79% yield, 100% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 8.25 (br s, 1 H), 7.94 (s, 1 H), 7.38 - 7.28 (m, 2H), 7.25 - 7.17 (m, 1 H), 7.10 (br t, J = 7.3 Hz, 1 H), 7.06 - 6.96 (m, 3H), 5.04 - 4.00 (m, 3H), 3.96 (s, 3H), 3.94 - 2.88 (m, 4H), 1 .57 - 1 .34 (m, 2H), 1 .33 - 1 .08 (m, 2H); LCMS: RT = 0.624 min, m / z = 439.3 (M+H)+.

[0386] EXAMPLE 1.12: SYNTHESIS OF (11)

[0387] A solution of te / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (250 mg, 0.96 mmol, 1 eq) and 2-bromo-1-(2-fluorophenyl)ethanone (230 mg, 1.059 mmol, 1.1 eq) in EtOH (5 mL) was refluxed for 2 h and volatiles were concentrated off. The residue was dissolved in CH2CI2 (6 mL), TFA (1.1 mL, 14.364 mmol, 14.96 eq) was added and the mixture was stirred at r.t. for 18 h. It was poured into NaHCOs (saturated aqueous solution, 20 mL) and it was extracted with CH2CI2 (2x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH / CH2Cl2 using NH3 as additive) to give (2R,6R)-2-(4-(2- fluorophenyl)thiazol-2-yl)-6-methylmorpholine (120 mg, 45% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) δ 8.18 (t, J = 7.8 Hz, 1 H), 7.72 (d, J = 2.2 Hz, 1 H), 7.32-7.07 (m, 3H), 4.91 (dd, J = 10.3, 2.7 Hz, 1 H), 3.83 (m, 1 H), 3.54-3.43 (m, 1 H), 2.97 (m, 1 H), 2.89-2.75 (m, 1 H), 2.67- 2.54 (m, 1 H), 1 .26 (d, J = 6.2 Hz, 3H); MS (ESI) m / z 279 [M + H]+; SFC: RT 2.33 min

[0388] HATU (60 mg, 0.157 mmol, 1.1 eq) and DIPEA (73 mL, 0.426 mmol, 2.97 eq) were added to a solution of bicyclo[2.1 .1]hexane-1 -carboxylic acid (19 mg, 0.143 mmol, 1 eq) and (2R,6R)- 2-(4-(2-fluorophenyl)thiazol-2-yl)-6-methylmorpholine (40 mg, 0.143 mmol, 1 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was flash chromatographed on SiO2 (20-30% EtOAc / hexanes) to give bicyclo[2.1 .1]hexan-1-yl((2R,6R)-2-(4-(2- fluorophenyl)thiazol-2-yl)-6-methylmorpholino)methanone (51 mg, 92% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.17 (bs, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.36- 7.04 (m, 3H), 5.20-4.77 (m, 2H), 4.68-4.19 (m, 2H), 3.95-3.57 (m, 1 H), 3.29-2.74 (m, 1 H), 2.56- 2.17 (m, 2H), 2.00-1 .88 (m, 4H), 1 .85-1 .77 (m, 1 H), 1 .55-1 .42 (m, 2H), 1 .32 (d, J = 6.1 Hz, 3H); MS (ESI) m / z 387 [M + H]+; SFC: RT 3.19 min

[0389] EXAMPLE 1.13: SYNTHESIS OF (12) AND (55)

[0390] Synthesis of compound 3

[0391] A mixture of compound 1 (321.80 mg, 1 .30 mmol, 1 eq) and compound 2 (300 mg, 1.30 mmol, 1 eq) in EtOH (3 mL) was stirred at 90 °C for 2 h. To the reaction mixture was added HCI / EtOAc (4 M, 1 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (HCI) -ACN]; B%: 15%-45% , 8 min), the eluent was concentrated and then freeze dried. To give compound 3 (340 mg, 1.21 mmol, 92.84% yield, 99% purity) as white solid. LCMS: RT = 0.406 min, m / z = 279.1 (M+H)+; SFC: RT = 1.881 min.

[0392] Synthesis of (12)

[0393] To a solution of 1 -(4-fluorophenyl) cyclopropanecarboxylic acid (32.36 mg, 179.63 pmol, 1 eq) in DMF (1 mL) was added DIEA (46.43 mg, 359.26 62.58 μL,μ 2m eoql,), HOBT (29.13 mg, 215.56 μmo 1 l.2, eq), EDCI (41.32 mg, 215.56 1.2 eq) aμnmd o clo, mpound 3 (50 mg, 179.63 μmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; B%: 55%- 85%, 10 min), then eluent was concentrated and then freeze dried. To give (12) (42.97 mg, 96.57 μmol 5, 3.76% yield, 99% purity) as yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.19 - 8.06 (m, 1 H), 7.72 (d, J = 7.4 Hz, 1 H), 7.23 - 7.15 (m, 2H), 6.95 (dt, J = 2.3, 8.7 Hz, 2H), 6.81 - 6.67 (m, 2H), 4.03 - 3.94 (m, 1 H), 3.93 (s, 3H), 3.83 - 3.58 (m, 3H), 3.51 - 3.24 (m, 1 H), 2.40 - 2.15 (m, 2H), 1 .45 (br s, 2H), 1 .19 - 1 .08 (m, 2H); LCMS: RT = 0.627 min, m / z = 441 .2 (M+H)+; SFC: RT = 1.782 min.

[0394] Synthesis of (55)

[0395] To a solution of 6-fluoro-5-methyl-pyridine-3-carboxylic acid (27.87 mg, 179.63 pmol, 1 eq) in DMF (1 mL) was added DIEA (46.43 mg, 359.26 62.58 pLμ,m 2o el,q), HOBt (29.13 mg, 215.56 μmo 1l, .2 eq), EDCI (41 .32 mg, 215.56 1 .2 eq) anμdm cool,mpound 3 (50 mg, 179.63 pmol, 1 eq). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; B%: 55%-85%, 10 min), the eluent was concentrated and then freeze dried. To give (55) (41 .55 mg, 99.01 μm 5o5l,.12% yield, 99% purity) as yellow solid.1H NMR: (400 MHz, CDCI3 =) 8 δ.25 (s, 1 H), 8.24 - 8.10 (m, 1 H), 7.88 - 7.73 (m, 2H), 6.80 - 6.68 (m, 2H), 4.22 - 4.02 (m, 1 H), 3.95 (br s, 2H), 3.93 (s, 3H), 3.87 - 3.61 (m, 2H), 2.59 - 2.35 (m, 2H), 2.32 (d, J = 3.9 Hz, 3H); LCMS: RT = 0.579 min, m / z = 416.2 (M+H)+; SFC: RT = 1 .127 min.

[0396] EXAMPLE 1.14: SYNTHESIS OF (13)

[0397] Copper (II) bromide (600 mg, 2.686 mmol, 2 eq) was added to a solution of 1-[2- (difluoromethoxy)phenyl]ethan-1-one (250 mg, 1 .342 mmol, 1 eq) in a mixture of CHCh (10 mL) and EtOAc (10 mL). The suspension was warmed up to reflux and reacted for 5 h. It was filtered through a pad of Celite, eluting product with EtOAc (40 mL). Volatiles were concentrated off, to give crude 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (355 mg, 99% yield) as a pale amber oil, which was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.82 (m, 1 H), 7.57 (m, 1 H), 7.31 (m, 1 H), 7.18 (m, 1 H), 6.64 (t, J = 73 Hz, 1 H), 4.53 (s, 2H).

[0398] A solution of 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (270 mg, 74% by HPLC- MS, 0.753 mmol, 1.24 eq)) and (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (150 mg, 0.608 mmol, 1 eq) in EtOH (16 mL) was refluxed for 45 min. The mixture was cooled down to r.t. , HCI 4 M in dioxane (1 .5 mL, 6 mmol, 9.85 eq) was added and the solution was stirred at r.t. for 20 h. Volatiles were concentrated off and the residue was slurried with Et2<D (2x10 mL), to give crude (R)-2-(4-(2-(difluoromethoxy)phenyl)thiazol-2-yl)morpholine hydrochloride (300 mg, 141 % yield) as an orange solid, which was submitted next step without further purification, considering 71 % w / w.1H NMR (300 MHz, DMSO-d6) 6 9.36 (bs, 2H), 8.04 (m, 2H), 7.46-7.04 (m, 3H), 5.21 (m, 1 H), 4.21 -3.95 (m, 2H), 3.74 (m, 1 H), 3.40-3.07 (m, 4H). MS (ESI) m / z free base 313 [M + H]+; SFC: RT 2.92 min

[0399] HATU (120 mg, 0.315 mmol, 1.1 eq) and DIPEA (0.2 mL, 1 .168 mmol, 4.08 eq) were added to a solution of bicyclo[2.1 .1]hexane-1 -carboxylic acid (38 mg, 0.286 mmol, 1 eq) and (R)-2-(4- (2-(difluoromethoxy)phenyl)thiazol-2-yl)morpholine hydrochloride (160 mg, 71 % w / w, 0.325 mmol, 1 .14 eq) in DMF (6 mL) and the solution was stirred at r.t. for 3 h. The mixture was diluted with EtOAc (40 mL) and it was washed with H2O (20 mL) and brine (30 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was flash chromatographed on SiO2 (20-30% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4- (2-(difluoromethoxy)phenyl)thiazol-2-yl)morpholino)methanone (100 mg, 83% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.15 (s, 1 H), 7.86 (s, 1 H), 7.50-7.09 (m, 4H), 6.58 (t, J = 73 Hz, 1 H), 4.79-4.51 (m, 2H), 4.51 (m, 1 H), 4.25 (d, J = 12.7 Hz, 1 H), 4.14 (d, J = 11 .6 Hz, 1 H), 3.77 (m, 2H), 3.32 (m, 1 H), 2.98 (m, 1 H), 2.46 (d, J = 3.0 Hz, 1 H), 1 .89 (m, 5H), 1 .55 (m, 1 H). MS (ESI) m / z 421 [M + H]+; SFC: RT 3.77 min

[0400] EXAMPLE 1.15: SYNTHESIS OF (14)

[0401] Synthesis of compound 2

[0402] To a solution of compound 1 (710 mg, 2.89 mmol, 1 eq) in DMF (7 mL) was added NHa / MeOH (7 M, 496.24 μL, 1 .2 eq), HOBt (469.38 mg, 3.47 mmol, 1 .2 eq), EDCI (665.92 mg, 3.47 mmol, 1 .2 eq) and DIEA (1 .50 g, 11.58 mmol, 2.02 mL, 4 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the resulting mixture was washed with H2O (8 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 2 (265 mg, 1 .08 mmol, 37.47% yield) as yellow oil.

[0403] Synthesis of compound 3

[0404] To a solution of compound 2 (215 mg, 880.11 1 eq)μ imn o Tl,HF (2 mL) was added LAWESSON'S REAGENT (213.59 mg, 528.07 0.6 eqμ)m uondl,er 0 °C. The reaction mixture was stirred at 0 °C for 2 h. LCMS showed compound 2 remained and trace compound 3 detected. Then LAWESSON'S REAGENT (213.59 mg, 528.07 0.6 eq) waμsm aodld, ed, the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-TLC (Petroleum ether : Ethyl acetate = 1 : 1 , Rf = 0.61) to give compound 3 (160 mg, 614.55 pmol, 69.83% yield) as yellow solid. LCMS: RT = 0.511 min, m / z = 205.3 (M+H-tBu)+; SFC: RT= 1.012 min

[0405] Synthesis of compound 5

[0406] A mixture of compound 3 (50 mg, 192.05 1 eq) anμdm coolm, pound 4 (43.99 mg, 192.05 pmol, 1 eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. Then HCI / EtOAc (4 M, 1 mL, 20.83 eq) was added into the reaction mixture. The reaction mixture was concentrated in vacuum to give compound 5 (60 mg, crude, HCI) as yellow gum. LCMS: RT = 0.419 min, m / z = 291 .1 (M+H)+.

[0407] Synthesis of (14)

[0408] To a solution of compound 5 (60 mg, 183.58 1 eq, HCI)μ amnodl, compound 6 (26.90 mg, 220.29 μmo 3l,3.63 μL, 1.2 eq) in DMF (2 mL) was added HOBt (29.77 mg, 220.29 pmol, 1.2 eq), EDCI (42.23 mg, 220.29 1 .2μ emqo) l a, nd DIEA (71 .18 mg, 550.73 95.93 μL, 3 eq). μmol, The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (6 mL) and the resulting mixture was washed with H2O (2 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was triturated with DMF (3 mL) at 25 °C for 5 min. Then the resulting mixture was filtered to give filtrate and filter cake. The filtrated was discarded and filter cake was lyophilizated to give (14) (15.3 mg, 38.40 pmol, 20.92% yield, 99% purity) as white solid.1H NMR: (400 MHz, DMSO-d6) 6 = 8.30 - 7.73 (m, 2H), 7.49 (s, 5H), 7.39 - 6.89 (m, 3H), 5.01 (dd, J = 2.8, 10.6 Hz, 1 H), 4.98 - 4.42 (m, 1 H), 3.91 (br s, 4H), 3.68 - 3.37 (m, 1 H), 3.24 - 2.59 (m, 2H), 1 .34 - 1 .08 (m, 3H); LCMS: RT = 0.595 min, m / z = 395.1 (M+H)+.

[0409] EXAMPLE 1.16: SYNTHESIS OF (15)

[0410] A suspension of 1-(4-fluoro-2-methoxyphenyl)ethanone (760 mg, 4.293 mmol, 1 eq) and copper (II) bromide (2.100 g, 9.402 mmol, 2.08 eq) in a mixture of EtOAc (15 mL) and CHCH (15 mL) was refluxed for 90 min. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (1.2 g, 113% yield) as a beige solid. It was submitted to next step without purification, considering it was 88% pure (w / w).1H NMR (300 MHz, CDCI3) 6 7.88 (dd, J = 8.7, 6.8 Hz, 1 H), 6.82-6.62 (m, 2H), 4.55 (s, 2H), 3.95 (d, J = 7.0 Hz, 3H).

[0411] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq) and 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (290 mg, 88% pure w / w, 1 .032 mmol, 1 .27 eq) in EtOH (12 mL) was refluxed for 90 min. The mixture was cooled down to r.t., HCI (4 M in dioxane, 2.00 mL, 8 mmol, 9.85 eq) was added and it was reacted for 18 h. The reaction mixture was poured into K2CO3 (saturated aqueous solution, 80 mL) and it was extracted with EtOAc (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH / CH2Cl2) to give (R)-2-(4-(4-fluoro-2- methoxyphenyl)thiazol-2-yl)morpholine (105 mg, 44% yield) as a brown solid.1H NMR (300 MHz, CDCI3) δ 8.18 (t, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 6.73 (m, 2H), 4.85 (dd, J = 9.9, 2.8 Hz, 1 H), 4.05 (d, J = 11.6 Hz, 1 H), 3.93 (s, 3H), 3.88-3.74 (m, 1 H), 3.48 (d, J = 12.5 Hz, 1 H), 2.96 (m, 3H); MS (ESI) m / z 295 [M + H]+; SFC: RT 3.18 min

[0412] HATU (141 mg, 0.37 mmol, 1.1 eq) and DIPEA (172 mL, 1.004 mmol, 2.99 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (35 mg, 0.332 mmol, 0.99 eq) and (R)- 2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)morpholine (99 mg, 0.336 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 18 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 60%] to give (R)-(2-(4-(4-fluoro-2- methoxyphenyl)thiazol-2-yl)morpholino)(1 -methylcyclopropyl)methanone (104 mg, 82% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.25 (dd, J = 8.6, 7.1 Hz, 1 H), 7.89 (s, 1 H), 6.85-6.68 (m, 2H), 4.89-4.75 (m, 2H), 4.36 (d, J = 13.5 Hz, 1 H), 4.15 (dd, J = 11.4, 3.5 Hz, 1 H), 3.96 (s, 3H), 3.77 (td, J = 1 1.8, 2.8 Hz, 1 H), 3.23-3.15 (m, 3H), 1.39 (s, 3H), 1 .01 (m, 2H), 0.67 (m, 2H); MS (ESI) m / z 377 [M + H]+; SFC: RT 2.82 min

[0413] EXAMPLE 1.17: SYNTHESIS OF (16)

[0414] To a solution of compound 4 (60 mg, 218.67 1 eq) andμm 6-ofllu, oro-5-methyl-pyridine- 3 -carboxylic acid (33.92 mg, 218.67 1 eq)μ imno Dl,MF (1 mL) was added HOBt (35.46 mg, 262.41 μmo 1l, .2 eq) and EDCI (50.30 mg, 262.41 1 .2 eq) andμm DIoElA, (113.05 mg, 874.70 pmol, 152.36 μL, 4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-HPLC(column: UniSil 3 - 100 C18 Ultra (150*25 mm*3um); mobile phase: [water (FA) -ACN]; B%: 57%- 87%, 10 min) followed by lyophilization to give (16) (51.82 mg, 124.67 μmo 5l,7.01 % yield, 99% purity) as yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.34 - 8.04 (m, 2H), 7.83 (br s, 1 H), 7.76 - 7.56 (m, 1 H), 7.33 - 7.29 (m, 1 H), 7.05 (br t, J = 6.9 Hz, 1 H), 6.99 (br d, J = 8.2 Hz, 1 H), 5.04 - 4.30 (m, 1 H), 4.20-3.94 (m, 4H), 3.83 - 3.52 (m, 1 H), 3.38 - 3.16 (m, 2H), 2.43 - 2.16 (m, 4H), 2.11 - 1 .80 (m, 3H); LCMS: RT = 0.854 min, m / z =412.3 (M+H)+; SFC: RT =1.341 min.

[0415] EXAMPLE 1.18: SYNTHESIS OF (17)

[0416] Copper (II) bromide (446 mg, 1.998 mmol, 2 eq) was added to a solution of 1 -(2- (difluoromethyl)phenyl)ethan-1-one (170 mg, 0.999 mmol, 1 eq) in a mixture of CHCH (6 mL) and EtOAc (6mL) and the suspension was refluxed for 5 h. It was cooled down to r.t., filtered through a pad of Celite, eluting with EtOAc (60 mL). Volatiles were concentrated off to give crude 2-bromo-1-(2-(difluoromethyl)phenyl)ethan-1-one (204 mg, 82% yield) as a brown oil, which was submitted to the next step without purification.1H NMR (300 MHz, CDCI3) δ 7.86 (m, 2H), 7.70 (m, 1 H), 7.60 (m, 1 H), 7.29 (t, J = 55.6 Hz, 1 H), 4.46 (s, 2H).

[0417] A solution of 2-bromo-1-(2-(difluoromethyl)phenyl)ethan-1-one (86 mg, 0.345 mmol, 1 .2 eq) and te / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (75 mg, 0.288 mmol, 1 eq) in EtOH (8 mL) was refluxed for 2 h. It was cooled down to r.t., HCI (4 M in dioxane, 720 mL, 2.88 mmol, 10 eq) was added and the solution was stirred at r.t. for 2 h. It was poured into NaHCOs (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (1-5% MeOH / CH2Cl2 using NH3 as additive) to give (2R,6R)-2-(4-(2-(difluoromethyl)phenyl)thiazol-2-yl)-6-methylmorpholine (50 mg, 56% yield) as a brown oil. MS (ESI) mlz free base 311 [M + H]+; SFC: RT 2.56 min

[0418] HATU (63 mg, 0.165 mmol, 1.1 eq) and DIPEA (77 mL, 0.449 mmol, 2.99 eq) were added to a solution of bicyclo[2.1 .1]hexane-1 -carboxylic acid (20 mg, 0.15 mmol, 1 eq) and (2R,6R)- 2-(4-(2-(difluoromethyl)phenyl)thiazol-2-yl)-6-methylmorpholine (47 mg, 0.151 mmol, 1.01 eq) in DMF (4 mL), and the mixture was stirred at r.t. for 3 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20% EtOAc / hexanes) to give bicyclo[2.1 ,1]hexan-1-yl((2R,6R)-2-(4- (2-(difluoromethyl)phenyl)thiazol-2-yl)-6-methylmorpholino)methanone (53 mg, 84% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.82 (m, 1 H), 7.64 (m, 1 H), 7.58- 7.41 (m, 3H), 7.27 (t, J = 55.4 Hz, 1 H), 5.11 -4.71 (m, 1 H), 4.59 (m, 1 H), 4.29 (m, 1 H), 3.93-3.61 (m, 1 H), 3.20-2.76 (m,1 H), 2.59-2.35 (m, 2H), 1.95-1 .71 (m, 4H), 1.52-1.41 (m,1 H), 1 .33 (d, J = 6.2 Hz, 3H). MS (ESI) m / z 419 [M + H]+; SFC: RT 2.93 min

[0419] EXAMPLE 1.19: SYNTHESIS OF (18) AND (47)

[0420]

[0421] Synthesis of compound 4

[0422] A mixture of compound 1 (2.88 g, 11 .79 mmol, 1 eq), compound 2 (2.59 g, 11 .31 mmol, 0.96 eq) in EtOH (30 mL) was stirred at 90 °C for 2 h. The mixture was concentrated to give residue. To the residue was added DCM (20 mL), HCI (4 M, 6 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give compound 4 (3.4 g, crude, HCI salt) as white solid. 6.1 g compound 4 (crude, HCI salt) was dissolved with MeOH (200 mL), to the solution was added ion exchange resin (~50 g). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was concentrated to give residue. The residue was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10um); mobile phase: [0.1 %NH3H2O ETCH]; B%: 35%-35%, 5.6 min). The peak with RT (1.831 min) was collected to give compound 4 (4.9 g, 17.50 mmol, 78.72% yield, 98% purity, ee: 99%) as yellow solid. LCMS: RT = 0.449 min, m / z = 275.0 (M+H)+; SFC: RT = 1 .833 min

[0423] Synthesis of (18)

[0424] To a solution of compound 4 (50 mg, 182.23 1 eq) andμ 2m-o(4l,-fluorophenyl) acetic acid (28.09 mg, 182.23 μ 1 m eoq)l, in DMF (1 mL) was added DIEA (47.10 mg, 364.46 pmol, 63.48 μL, 2 eq), HOBt (29.55 mg, 218.67 1.2 eμqm) o aln, d EDCI (41.92 mg, 218.67 1.2 eq). μmol, The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 51 %-81 % , 10 min) to give (18) (37.8 mg, 89.32 49.02% yield,μ 9m7o%l, purity) as yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.28 - 8.22 (m, 1 H), 7.86 - 7.80 (m, 1 H), 7.36 - 7.29 (m, 1 H), 7.26 - 7.20 (m, 2H), 7.11 - 7.05 (m, 1 H), 7.05 - 6.97 (m, 3H), 4.49 - 4.15 (m, 1 H), 4.00 - 3.92 (m, 3H), 3.89 - 3.69 (m, 3H), 3.44 (dd, J = 10.0, 13.4 Hz, 1 H), 3.22 - 3.01 (m, 1 H), 2.95 - 2.86 (m, 1 H), 2.31 - 2.18 (m, 1 H), 1.97 - 1.80 (m, 2H), 1.79 - 1.69 (m, 1 H); LCMS: RT = 0.680 min, m / z = 411.4 (M+H)+.

[0425] Synthesis of (47)

[0426] To a solution of compound 4 (50 mg, 182.23 1 eq) andμm 2-o(l4,-fluorophenyl) propanoic acid (30.64 mg, 182.23 1 μ emq)ol i,n DMF (1 mL) was added DIEA (47.10 mg, 364.46 pmol, 63.48 μL, 2 eq), HOBt (29.55 mg, 218.67 1 .2 eq) μ amndol E, DCI (41 .92 mg, 218.67 pmol, 1 .2 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 54%-84%, 10 min) to give (47) (30.97 mg, 72.22 39.63% μ yimelodl,, 99% purity) as yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.30 - 8.19 (m, 1 H), 7.86 - 7.77 (m, 1 H), 7.36 - 7.27 (m, 2H), 7.26 - 7.14 (m, 1 H), 7.13 - 6.91 (m, 4H), 5.10 - 4.25 (m, 1 H), 4.18 - 3.99 (m, 1 H), 3.98 - 3.93 (m, 3H), 3.93 - 3.69 (m, 1 H), 3.45 - 2.50 (m, 3H), 2.38 - 2.04 (m, 1 H), 1 .98 - 1 .83 (m, 1 H), 1 .79 - 1 .52 (m, 2H), 1 .49 - 1 .40 (m, 3H); LCMS: RT = 0.712 min, m / z = 425.4 (M+H)+.

[0427] EXAMPLE 1.20: SYNTHESIS OF (19)

[0428] To a mixture of compound 1 (25 mg, 168.74 1 eq) andμ cmooml, pound 2 (25 mg, 168.74 pmol, 1 eq) in DMF (1 mL) was added HOBt (27.36 mg, 202.49 1 .2 eq), DIEA (8μ7m.2o3l, mg, 674.95 μmo 1l, 17.56 μL, 4 eq) and EDCI (38.82 mg, 202.49 1 .2 eq). The reμamctiooln, mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted ethyl acetate (6 mL) and washed with brine (3 mL*3), the organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 63%- 83% B over 10 min) followed by lyophilization to give (19) (16.71 mg, 41 .11 24.36% yield, 100%μmol, purity) as white solid.1H NMR: (400 MHz, CD3OD) δ = 8.16 (ddd, J = 1 .6, 3.9, 7.6 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.36 - 7.27 (m, 1 H), 7.10 (dd, J = 4.0, 8.1 Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 4.85 - 4.80 (m, 1 H), 4.40 - 4.35 (m, 2H), 4.35 - 4.29 (m, 2H), 4.16 - 3.98 (m, 6H), 3.96 (d, J = 3.9 Hz, 3H), 3.79 (dq, J = 3.2, 11 .6 Hz, 1 H), 3.46 - 3.34 (m, 1 H), 3.07 - 2.94 (m, 1 H); LCMS: RT = 0.628 min, m / z = 407.3 (M+H)+.

[0429] EXAMPLE 1.21: SYNTHESIS OF (20) 1-[2-(Difluoromethoxy)phenyl]ethan-1-one (750 mg, 4.028 mmol, 1 eq) was added to a suspension of copper (II) bromide (2.000 g, 8.954 mmol, 2.22 eq) in a mixture of CHCh (15 mL) and EtOAc (15 mL) and the mixture was refluxed for 4 h. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting product with EtOAc (80 mL). Organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na3SO4 (anhydrous), filtered and concentrated to give crude 2-bromo-1-(2- (difluoromethoxy)phenyl)ethan-1-one (1.05 g, 98% yield) as a colorless oil. It was submitted to next step without purification.1H NMR (300 MHz, CDCh) 5 7.82 (m, 1 H), 7.57 (m, 1 H), 7.31 (m, 1 H), 7.18 (m, 1 H), 6.64 (t, J = 73 Hz, 1 H), 4.53 (s, 2H).

[0430] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate 210 mg, 0.852 mmol, 1 eq) and 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (280 mg, 1.056 mmol, 1.24 eq) in EtOH (12 mL) was refluxed for 2 h. The mixture was cooled down to r.t., HCI (4 M in dioxane, 2.00 mL, 8 mmol, 9.38 eq) was added and it was reacted for 18 h. The mixture was poured into NaHCO3(saturated aqueous solution, 60 mL) and it was extracted with CH2CI2 (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH / CH2Cl2) to give (R)-2-(4-(2-(difluoromethoxy)phenyl)thiazol-2-yl)morpholine (215 mg, 81 % yield) as an amber oil.1H NMR (300 MHz, CDCI3) δ 8.17 (m, 1 H), 7.80 (s, 1 H), 7.37-7.26 (m, 2H), 7.17 (m, 1 H), 6.55 (t, J = 74.2 Hz, 1 H), 4.86 (dd, J = 9.7, 2.9 Hz, 1 H), 4.06 (d, J = 11.6 Hz, 1 H), 3.82 (td, J = 10.9, 3.2 Hz, 1 H), 3.48 (m, 1 H), 3.05-2.86 (m, 3H); MS (ESI) m / z 313 [M + H]+; SFC: RT 4.23 min

[0431] DIPEA (0.2 mL, 1.168 mmol, 3.65 eq) was added to a solution of (R)-2-(4-(2- (difluoromethoxy)phenyl)thiazol-2-yl)morpholine (100 mg, 0.32 mmol, 1 eq), 5- cyclopropylnicotinic acid (60 mg, 0.367 mmol, 1.15 eq) and HATU (135 mg, 0.355 mmol, 1.11 eq) in DMF (8 mL) and the reaction mixture was stirred at r.t. for 18 h. It was poured into brine (60 mL) and extracted with EtOAc (2x40 mL). Combined organic layers were washed with brine (30 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 15.5g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 65%] to give (R)-(5-cyclopropylpyridin-3-yl)(2-(4-(2- (difluoromethoxy)phenyl)thiazol-2-yl)morpholino)methanone (92 mg, 63% yield) as a beige solid after lyophilization.1H NMR (500 MHz, CDCI3) δ 8.52 (s, 2H), 8.14 (bs, 1 H), 7.85 (s, 1 H), 7.45 (s, 1 H), 7.32 (dt, J = 20.9, 7.8 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1 H), 6.54 (t, J = 74.2 Hz, 1 H), 4.89 (d, J = 9.4 Hz, 1 H), 4.16 (d, J = 11.8 Hz, 2H), 3.85 (t, J = 11.6 Hz, 2H), 3.42-3.33 (m, 2H), 1 .95 (m, 1 H), 1 .08 (d, J = 8.3 Hz, 2H), 0.80 (t, J = 4.7 Hz, 2H); MS (ESI) m / z 458 [M + H]+; SFC: RT 5.84 min

[0432] EXAMPLE 1.22: SYNTHESIS OF (21)

[0433] A solution of fe / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (180 mg, 0.691 mmol, 1 eq) and 2-methoxyphenacyl bromide (158 mg, 0.689 mmol, 1 eq) in EtOH (10 mL) was refluxed for 3 h. It was cooled down to r.t., HCI (4 M in dioxane, 1.8 mL, 7.2 mmol, 10.41 eq) was added and the solution was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (20 mL). Organic layer was washed with NaHCOs (saturated aqueous solution, 30 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (1-3% MeOH / CH2Cl2 using NH3 as additive) to give (2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (83 mg, 41 % yield) as a yellow solid.1H NMR (300 MHz, CDCI3) δ 8.20 (dd, J = 7.7, 1.8 Hz, 1 H), 7.89 (s, 1 H), 7.34-7.28 (m, 1 H), 7.10-6.91 (m, 2H), 4.90 (dd, J = 10.4, 2.6 Hz, 1 H), 3.94 (s, 3H), 3.90- 3.76 (m, 1 H), 3.53-3.39 (m, 1 H), 3.05-2.74 (m, 2H), 2.60 (dd, J = 12.6, 10.3 Hz, 1 H), 1.25 (d, J = 6.2 Hz, 3H); MS (ESI) m / z 291 [M + H]+; SFC: RT 3.13 min

[0434] HATU (93 mg, 0.244 mmol, 1.1 eq) and DIPEA (114 mL, 0.665 mmol, 3 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (23 mg, 0.218 mmol, 1 eq) and (2R,6R)- 2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (65 mg, 0.223 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (30% EtOAc / hexanes) to give ((2R,6R)-2-(4-(2- methoxyphenyl)thiazol-2-yl)-6-methylmorpholino)(1 -methylcyclopropyl) methanone (70 mg, 84% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.26 (d, J = 7.7 Hz, 1 H), 7.95 (s, 1 H), 7.35-7.27 (m, 1 H), 7.15-6.91 (m, 2H), 4.93-4.76 (m, 2H), 4.40 (d, J = 13.4 Hz, 1 H), 3.96 (s, 3H), 3.89-3.71 (m, 1 H), 3.17-2.96 (m, 1 H), 2.81 -2.59 (m, 1 H), 1.44-1.29 (m, 6H), 1 .04-0.86 (m, 2H), 0.76-0.58 (m, 2H); MS (ESI) m / z 373 [M + H]+; SFC: RT 2.62 min

[0435] EXAMPLE 1.23: SYNTHESIS OF (22) A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (150 mg, 0.608 mmol, 1 eq) and 2-methoxyphenacyl bromide (140 mg, 0.608 mmol, 1 eq) in EtOH (2 mL) was refluxed for 2 h. The reaction mixture was cooled down to r.t. , HCI (4 M in dioxane, 1 .52 mL, 6.08 mmol, 10 eq) was added and the mixture was stirred at r.t. for 2 h. Volatiles were concentrated off and the residue was slurried with Et2<D (10 mL) to give (R)-2-(4-(2-methoxyphenyl)thiazol-2- yl)morpholine (252 mg, > theoretical) as a yellow solid. It was submitted to the next reaction without further purification, considering it was 76% (w / w) pure.1H NMR (300 MHz, DMSO-de) 5 9.65 (bs, 1 H), 9.48 (bs, 1 H), 8.15 (s, 1 H), 8.11 (s, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.15 (d, J = 8.2 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 5.23 (d, J = 14.1 Hz, 1 H), 4.17 (d, J = 12.6 Hz, 1 H), 4.05 (t, J = 11.8 Hz, 1 H), 3.92 (s, 3H), 3.75 (d, J = 13.1 Hz, 1 H), 3.31 (d, J = 13.3 Hz, 1 H), 3.19 (t, J = 11 .7 Hz, 2H); MS (ESI) m / z free base 277 [M + H]+; SFC: RT 3.97 min

[0436] HATU (133.7 mg, 0.351 mmol, 1 .1 eq) and DIPEA (218 mL, 1 .273 mmol, 4 eq) were added to a suspension of (R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)morpholine hydrochloride (100 mg, 76% w / w, 0.319 mmol, 1 eq) and 6-fluoro-5-methylpyridine-3-carboxylic acid (53 mg, 0.341 mmol, 1.06 eq) in DMF (2 mL). The solution was stirred at r.t. for 2 h, it was poured into H2O (10 mL) and it was extracted with EtOAc (2x5 mL). Combined organic layers were washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 50% to 65%] to give (R)-(6-fluoro-5-methylpyridin-3-yl)(2-(4- (2-methoxyphenyl)thiazol-2-yl)morpholino)methanone (81 mg, 65% yield for the 2 steps) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.17 (s, 1 H), 8.07 (bs, 1 H), 7.94 (s, 1 H), 7.74 (d, J = 9.2 Hz, 1 H), 7.36-7.24 (m, 1 H), 7.09-6.94 (m, 2H), 4.87 (d, J = 9.5 Hz, 1 H), 4.69-4.03 (m, 2H), 3.94 (s, 3H), 3.90-3.76 (m, 1 H), 3.69 - 3.27 (m, 2H), 2.31 (s, 3H); MS (ESI) m / z 414 [M + H]+; SFC: RT 5.63 min

[0437] EXAMPLE 1.24: SYNTHESIS OF (23)

[0438] Synthesis of compound 2 To a solution of compound 1 (1 g, 5.95 mmol, 1 eq) in EtOAc (15 mL) was added CuBr2 (2.66 g, 11.89 mmol, 556.89 μL, 2 eq). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to room temperature, the mixture was filtered and the filter cake was collected, the cake was washed with EtOAc (5 mL). The filtrate phase was washed with H2O (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 : 0 to 5 : 1 , TLC : Petroleum ether / Ethyl acetate = 5 : 1 , RF = 0.37) . Compound 2 (1.2 g, 4.86 mmol, 81 .68% yield) was obtained as a colorless oil.1H NMR: (400 MHz, CDCI3) δ = 7.91 (dd, J = 6.9, 8.8 Hz, 1 H), 6.78 - 6.68 (m, 2H), 4.57 (s, 2H), 3.96 (s, 3H);

[0439] Synthesis of compound 4

[0440] A mixture of compound 3 (98.90 mg, 404.76 1 eq) and μ cmomolp, ound 2 (100 mg, 404.76 pmol, 1 eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. Compound 4 (50 mg, 171.02 42.25% yieldμ) m woals, obtained as a white solid. LCMS: RT =0.473 min, m / z =293.2 (M+H)+.

[0441] Synthesis of compound (23)

[0442] A mixture of compound 4 (50 mg, 171.02 1 eq) μ ,m boeln,zoic acid (20.88 mg, 171 .02 pmol, 26.11 μL, 1 eq), DIEA (66.31 mg, 513.05 89.36 μL,μ 3m eoql),, HOBt (27.73 mg, 205.22 pmol, 1.2 eq) and EDCI (39.34 mg, 205.22 1.2 eq)μ imn o Dl,MF (1 mL) was stirred at 20 °C for 16 h. The reaction mixture was purified by reversed-phase HPLC (column : Phenomenex luna C18 150*25 mm* 10um;mobile phase : [water (FA) -ACN] ;B% : 51 %- 81 %, 10 min) , the eluent was concentrated and then freeze dried. Compound (23) (32.15 mg, 24.97 pmol, 14.60% yield, 99% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.36 - 8.04 (m, 1 H), 7.80-7.74 (m, 1 H), 7.42 (br s, 5H), 6.84 - 6.66 (m, 2H), 5.08 - 4.44 (m, 1 H), 4.12 - 3.76 (m, 4H), 3.51 - 2.92 (m, 3H), 2.46 - 2.27 (m, 1 H), 2.11 - 1 .67 (m, 3H); LCMS: RT =0.654 min, m / z =397.1 (M+H)+. SFC: RT =2.090 min

[0443] EXAMPLE 1.25: SYNTHESIS OF (24)

[0444] NH4CI (70 mg, 1 .308 mmol, 3.23 eq) and DIPEA (210 mL, 1 .226 mmol, 3.03 eq) were added to a solution of (R)-4-(te / Y-butoxycarbonyl)-6,6-dimethylmorpholine-2-carboxylic acid (105 mg, 0.404 mmol, 1 eq) and HATU (170 mg, 0.447 mmol, 1.1 eq) in DMF (4 mL). The reaction mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (2x10 mL). Combined organic layers were washed with citric acid (10% aqueous solution, 10 mL) and brine (2x10 mL), dried over Na3SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (3% MeOH / CH2Cl2) to give tert-buty I (R)- 6-carbamoyl-2,2-dimethylmorpholine-4-carboxylate (115 mg, > theoretical) as a white solid.1H NMR (300 MHz, CDCI3) δ 6.53 (bs, 1 H), 5.43 (bs, 1 H), 5.47-5.41 (m, 1 H), 4.48-4.27 (m, 1 H), 4.19 (dd, J = 11.2, 3.4 Hz, 1 H), 3.90-3.72 (m, 1 H), 2.71-2.53 (m, 2H), 1 .47 (s, 9H), 1.26 (s, 3H), 1.23 (s, 3H).

[0445] Lawesson's reagent (110 mg, 0.258 mmol, 0.61 eq) was added to a solution of fe / Y-butyl (R)-6-carbamoyl-2,2-dimethylmorpholine-4-carboxylate (1 10 mg, 0.425 mmol, 1 eq) in THF (25 mL) and the reaction mixture was stirred at r.t. for 2 h. It was poured into H2O (20 mL), extracted with EtOAc (2x20 mL) and washed with NH4CI (saturated aqueous solution, 60 mL). Organic layer was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20% EtOAc / hexanes) to give fe / Y-butyl (R)-6- carbamothioyl-2,2-dimethylmorpholine-4-carboxylate (118 mg, quantitative yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 8.09-7.96 (m, 1 H), 7.57-7.43 (m, 1 H), 4.82-4.61 (m, 1 H), 4.57-4.45 (m, 1 H), 3.89-3.76 (m, 1 H), 2.67-2.47 (m, 2H), 1 .48 (s, 9H), 1 .27 (s, 3H), 1 .22 (s, 3H); MS (ESI) mlz 273 [M - H]_; SFC: RT 2.94 min

[0446] A solution of 2-methoxyphenacyl bromide (96 mg, 0.419 mmol, 1 eq) and fe / Y-butyl (R)-6- carbamothioyl-2,2-dimethylmorpholine-4-carboxylate (115 mg, 0.419 mmol, 1 eq) in EtOH (10 mL) was refluxed for 2 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (3 mL), TFA (641 mL, 8.37 mmol, 20 eq) was added and the solution was stirred at r.t. for 15 min. Volatiles were concentrated off and the residue was coevaporated with CH2CI2 (2x4 mL) and slurried with Et20 (2x2 mL) to give (R)-6-(4-(2- methoxyphenyl)thiazol-2-yl)-2,2-dimethylmorpholine trifluoroacetic salt (100 mg, 57% yield) as a white solid.1H NMR (300 MHz, CDCI3) δ 10.21 (bs, 1 H), 9.61 (bs, 1 H), 8.21 (d, J = 7.4 Hz, 1 H), 7.94 (s, 1 H), 7.29 (m, 1 H), 7.10-6.94 (m, 2H), 5.45 (dd, J = 10.6, 2.5 Hz, 1 H), 4.04 (d, J = 12.7 Hz, 1 H), 3.94 (s, 3H), 3.34 (m, 1 H), 3.11 (m, 1 H), 2.96 (m, 1 H), 1 .72 (s, 6H); MS (ESI) m / z 305 [M + H]+free base; SFC: RT 3.45 min

[0447] HATU (107 mg, 0.281 mmol, 1.15 eq) and DIPEA (132 mL, 0.771 mmol, 3.16 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (27 mg, 0.269 mmol, 1.11 eq) and (R)-6-(4-(2-methoxyphenyl)thiazol-2-yl)-2,2-dimethylmorpholine trifluoroacetic salt (102 mg, 0.243 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 55%] to give (R)-(6-(4-(2-methoxyphenyl)thiazol-2- yl)-2,2-dimethylmorpholino)(1 -methylcyclopropyl)methanone (88 mg, 93% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.25 (dd, J = 7.7, 1.8 Hz, 1 H), 7.93 (s, 1 H), 7.35-7.27 (m, 1 H), 7.12-6.95 (m, 2H), 5.14 (dd, J = 10.9, 3.1 Hz, 1 H), 4.81 (d, J = 13.3 Hz, 1 H), 4.25 (d, J = 13.1 Hz, 1 H), 3.95 (s, 3H), 3.01 (t, J = 12.1 Hz, 1 H), 2.77 (d, J = 13.1 Hz, 1 H), 1 .41 (s, 3H), 1 .39 (s, 3H), 1 .33 (s, 3H), 1.10-0.91 (m, 2H), 0.73-0.59 (m, 2H); MS (ESI) m / z 387 [M + H]+; SFC: RT 2.81 min

[0448] EXAMPLE 1.26: SYNTHESIS OF (25)

[0449] Synthesis of compound 3

[0450] A mixture of compound 1 (500 mg, 2.31 mmol, 1 eq), compound 2 (298.21 mg, 3.47 mmol, 1 .5 eq), Pd(dppf)CI2(169.35 mg, 231 .45 0.1 eq), μ CmsFol (,703.15 mg, 4.63 mmol, 170.88 μL, 2 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether / Ethyl acetate = 1 : 0 to 1 : 1 , TLC: Petroleum ether: Ethyl acetate = 5: 1 , Rf = 0.53) to give compound 3 (500 mg, crude) as white solid.1H NMR: (400 MHz, CDCh) 6 = 8.99 (br s, 1 H), 8.59 (br s, 1 H), 7.87 (s, 1 H), 3.93 (s, 3H), 1 .98 - 1.91 (m, 1 H), 1.10 - 1.04 (m, 2H), 0.80 - 0.75 (m, 2H)

[0451] Synthesis of compound 4

[0452] A mixture of compound 3 (300 mg, 1 .69 mmol, 1 eq), UOH H2O (213.13 mg, 5.08 mmol, 3 eq) in MeOH (2.5 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. The pH of the reaction mixture was adjusted about to 7 with 1 M HCI aqueous solution. EtOAc (40 mL) and water (40 mL) were added and layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). Combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound 4 (200 mg, crude) as white solid.

[0453] Synthesis of (25)

[0454] A mixture of compound 4 (60 mg, 367.71 1 eq), μ cmomolp, ound 5 (101.62 mg, 367.71 pmol, 1 eq), DIEA (190.09 mg, 1 .47 mmol, 256.19 μL, 4 eq), HOBt (59.62 mg, 441 .25 pmol, 1 .2 eq) and EDCI (84.59 mg, 441 .25 1 .2 eμqm)o iln, DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient: 43%- 73% B over 10 min) to give (25) (42.72 mg, 100.34 27.29% yield, μmol, 99% purity) as white solid.1H NMR: (400 MHz, CDCI3) δ = 8.50 (br s, 2H), 8.38 - 8.01 (m, 1 H), 7.95 (br s, 1 H), 7.47 - 7.41 (m, 1 H), 7.31 (br t, J = 7.5 Hz, 1 H), 7.11 - 6.96 (m, 2H), 5.26 - 4.44 (m, 2H), 4.42 - 4.00 (m, 2H), 3.95 (s, 3H), 3.90 - 3.70 (m, 1 H), 3.58 - 3.12 (m, 2H), 2.00 - 1.90 (m, 1 H), 1 .14 - 1 .03 (m, 2H), 0.86 - 0.75 (m, 2H); LCMS: RT = 0.505 min, m / z = 422.2 (M+H)+; SFC: RT = 1.641 min.

[0455] EXAMPLE 1.27: SYNTHESIS OF (26)

[0456] Copper (II) bromide (600 mg, 2.686 mmol, 2 eq) was added to a solution of 1 -[2- (difluoromethoxy)phenyl]ethan-1-one (250 mg, 1 .342 mmol, 1 eq) in a mixture of CHCb (10 mL) and EtOAc (10 mL) and the suspension was refluxed for 5 h. It was cooled down to r.t. and filtered through a pad of Celite, eluting product with EtOAc (40 mL). Volatiles were concentrated off, to give crude 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (355 mg, 99% yield) as an amber oil, which was submitted to next step without purification.1H NMR (300 MHz, CDCb) 5 7.82 (m, 1 H), 7.57 (m, 1 H), 7.31 (m, 1 H), 7.18 (m, 1 H), 6.64 (t, J = 73 Hz, 1 H), 4.53 (s, 2H).

[0457] A solution of fe / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (150 mg, 0.576 mmol, 1 eq) and 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (230 mg, 0.867 mmol, 1 .51 eq) in EtOH (10 mL) was refluxed for 1 h. It was cooled down to r.t., HCI (4 M in dioxane, 1.4 mL, 5.60 mmol, 9.72 eq) was added and the mixture was stirred at r.t. for 2 h. It was poured into K2CO3 (saturated aqueous solution, 60 mL) and it was extracted with EtOAc (2x40 mL). Combined organic layers were washed with K2CO3 (saturated aqueous solution, 30 mL) and brine (40 mL). It was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH / CH2Cb) to give (2R,6R)- 2-(4-(2-(difluoromethoxy)phenyl)thiazol-2-yl)-6-methylmorpholine (115 mg, 61 % yield) as a beige solid. MS (ESI) m / z 327 [M + H]+

[0458] HATU (119 mg, 0.312 mmol, 1.1 eq) and DIPEA (146 mL, 0.852 mmol, 3 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (30 mg, 0.284 mmol, 1 eq) and (2R,6R)- 2-(4-(2-(difluoromethoxy)phenyl)thiazol-2-yl)-6-methylmorpholine (111 mg, 0.34 mmol, 1.19 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-30% EtOAc / hexanes) to give ((2R,6R)-2-(4-(2- (difluoromethoxy)phenyl)thiazol-2-yl)-6-methylmorpholino) (l -methylcyclopropyl)methanone (104 mg, 89% yield) as a white solid.1H NMR (300 MHz, CDCI3) δ 8.18 (m, 1 H), 7.84 (s, 1 H), 7.44-7.28 (m, 2H), 7.19 (m, 1 H), 6.58 (t, J = 74.4 Hz, 1 H), 4.95-4.75 (m, 2H), 4.40 (d, J = 13.3 Hz, 1 H), 3.90-3.70 (m, 1 H), 3.14-2.95 (m, 1 H), 2.69 (m, 1 H), 1.45-1.29 (m, 6H), 1.02 (m, 2H), 0.67 (m, 2H); MS (ESI) m / z 409 [M + H]+; SFC: RT 1 .71 min

[0459] EXAMPLE 1.28: SYNTHESIS OF (27)

[0460] A mixture of compound 1 (50 mg, 182.23 μmol, 1 eq), 1-(3-fluorophenyl) cyclopropanecarboxylic acid (32.83 mg, 182.23 1 eq), HOBtμ (m29ol.5, 5 mg, 218.67 pmol, 1 .2 eq), EDCI (41.92 mg, 218.67 1.2μ emqo)l a, nd DIEA (47.10 mg, 364.46 63.48 μL, 2 eq) μmol, in DMF (1 mL) was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Unisil 3 - 100 C18 Ultra 150*50 mm*3 um;mobile phase : [water (FA) -ACN] ;B% : 61 %- 91 %, 7 min) to give (27) (44.54 mg, 101.01 55.43% yield, μmol, 99% purity) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.19 - 8.03 (m, 1 H), 8.01 - 7.89 (m, 1 H), 7.41 - 7.26 (m, 2H), 7.12 (br d, J = 8.3 Hz, 1 H), 7.08 - 6.91 (m, 4H), 4.55 - 4.27 (m, 1 H), 3.90-3.78 (m, 4H), 3.17-3.02 (m, 3H), 2.14 - 2.06 (m, 1 H), 1.81 - 1.71 (m, 1 H), 1.51 - 1.01 (m, 6H); LCMS: RT = 0.678 min, m / z = 437.2 (M+H)+; SFC: RT = 1 .833 min.

[0461] EXAMPLE 1.29: SYNTHESIS OF (28)

[0462] 6 (28)

[0463] Synthesis of compound 3

[0464] To the mixture of compound 1 (300 mg, 1 .95 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (537.98 mg, 3.89 mmol, 2 eq) and compound 2 (311.27 mg, 1.95 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. To the mixture was added K2CO3 (200 mg). The mixture was stirred at 40 °C for 4 h. To the mixture was added compound 2 (250 mg, 1.56 mmol, 8.03e- 1 eq), K2CO3 (500 mg). The mixture was stirred at 40 °C for 16 h. To the mixture was added compound 2 (100 mg, 625.28 3.2μ1m e-o1l, eq), K2CO3 (100 mg). The mixture was stirred at 80 °C for 4 h. The mixture was diluted with H2O (20 mL) and the resulting mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 2: 1 , TLC: Petroleum ether: Ethyl acetate = 20: 1 , RF = 0.28). Compound 3 (84 mg, 351 .96 18.08% yield, 78%μ pmuorlit,y) was obtained as a yellow oil.1H NMR: (400 MHz, CDCI3) δ = 7.47 - 7.40 (m, 1 H), 7.20 (s, 1 H), 7.18 (s, 1 H), 5.83 (s, 1 H), 5.70 (s, 1 H), 2.63 (s, 3H).

[0465] Synthesis of compound 4

[0466] To the mixture of compound 3 (84 mg, 451.24 1 eq) in EtμOmHol (,0.4 mL) and DCM (1.5 mL) was added PyBrs (144.31 mg, 451 .24 1 eq). Tμhmeo ml, ixture was stirred at 40 °C for 2 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 2: 1 , TLC: Petroleum ether: EtOAc = 10: 1 , Rf = 0.43). Compound 4 (61 mg, 230.14 51μ .0m0o%l, yield) was obtained as a yellow oil.1H NMR: (400 MHz, CDCI3) δ = 7.54 (dd, J = 3.0, 8.6 Hz, 1 H), 7.26 - 7.20 (m, 2H), 5.89 - 5.87 (s, 1 H), 5.73 (s, 1 H), 4.55 (s, 2H).

[0467] Synthesis of compound 6

[0468] To the mixture of compound 4 (30 mg, 113.19 1 eq) iμnm EotOl, H (1 mL) was added compound 5 (27.88 mg, 113.19 1 eμqm)o. l T, he mixture was stirred at 80 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. To the residue was added HCI / dioxane (1 mL) and DCM (2 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated at reduced pressure to give compound 6 (54 mg, crude, HCI) as a yellow oil.LCMS: RT = 0.418 min, m / z = 313.0 (M+H)+.

[0469] Synthesis of compound (28)

[0470] To the mixture of compound 6 (54 mg, 154.82 1 eq, HCI) μ inm DoMl, F (1 .5 mL) was added HOBt (25.10 mg, 185.78 1μ.2m eoql,) and EDCI (35.61 mg, 185.78 1.2 eq) and DIμEmAol, (60.03 mg, 464.46 8μ0m.9o0l, μL, 3 eq) and compound 7 (15.50 mg, 154.82 1 eq). The μmol, mixture was stirred at 25 °C for 16 h. The mixture was diluted with H2O (15 mL) and extracted with Ethyl acetate (15 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 48%- 78% B over 10 min). Compound (28) (5.66 mg, 14.06 9.08% yield, 98%μmol, purity) was obtained as a brown gum.1H NMR: (400 MHz, CDCI3) δ = 8.00 - 7.93 (m, 2H), 7.20 (dd, J = 4.5, 9.0 Hz, 1 H), 7.07 - 6.98 (m, 1 H), 5.85 (s, 1 H), 5.72 (s, 1 H), 4.91 - 4.75 (m, 2H), 4.37 (br d, J = 12.8 Hz, 1 H), 4.15 (dd, J = 2.8, 1 1.4 Hz, 1 H), 3.77 (dt, J = 2.6, 1 1.7 Hz, 1 H), 3.18-3.05 (m, 2H), 1 .39 (s, 3H), 1 .08 - 0.93 (m, 2H), 0.68 (s, 2H); LCMS: RT = 0.548 min, m / z = 395.0 (M+H)+.

[0471] EXAMPLE 1.30: SYNTHESIS OF (29)

[0472] Synthesis of compound 2

[0473] To a solution of compound 1 (1 g, 3.86 mmol, 1 eq) in THF (10 mL) was added CDI (1.25 g, 7.71 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Then the mixture reaction poured into NH3°H2O (4.83 g, 38.57 mmol, 5.30 mL, 28% purity, 10 eq) and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (50 mL) and the resulting mixture extracted with ethyl acetate (20 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 2 (1 .1 g, crude) as white solid.1H NMR: (400 MHz, CDCI3) δ = 11.12 - 10.66 (m, 2H), 4.72 - 4.42 (m, 1 H), 4.40 - 4.24 (m, 1 H), 4.09 - 3.75 (m, 1 H), 2.97 - 2.63 (m, 2H), 1 .63 (s, 9H), 1 .42 (s, 3H), 1 .38 (s, 3H).

[0474] Synthesis of compound 3

[0475] To a solution of compound 2 (500 mg, 1.94 mmol, 1 eq) in THF (1 mL) was added LAWESSON'S REAGENT (469.74 mg, 1.16 mmol, 0.6 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was filtered to give filtrate and filter cake. The filter cake was discarded and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 1 : 1) to give compound 3 (350 mg, 1 .28 mmol, 65.90% yield) as white solid. LCMS: RT = 0.502 min, m / z = 219.0 (M+H-tBu)+; SFC: RT=1.152 min

[0476] Synthesis of compound 5 A mixture of compound 3 (100 mg, 364.46 1 eq) andμ cmooml,pound 4 (83.49 mg, 364.46 pmol, 1 eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuum to give a residue. Then a mixture of the residue in HCI / dioxane (4 M, 1 mL, 10.98 eq) was stirred at 25°C for 1 h. The reaction mixture was concentrated in vacuum to give compound 5 (100 mg, 293.37 80.4μ9m%ol y, ield, HCI) as white solid. LCMS: RT = 0.422 min, m / z = 305.1 (M+H)+.

[0477] Synthesis of (29)

[0478] To a mixture of compound 5 (100 mg, 293.37 1 eq, HCμmI) o aln, d compound 6 (35.83 mg, 293.37 μm 4o4l,.78 μL, 1 eq) in DMF (1 mL) was added HOBt (47.57 mg, 352.04 pmol, 1 .2 eq), EDCI (67.49 mg, 352.04 1 .2μ emq)o al,nd DIEA (151 .66 mg, 1.17 mmol, 204.40 μL, 4 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted ethyl acetate (6 mL) and the resulting mixture was washed with H2O (3 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was triturated with DMF (3 mL), filtered to give filtrate and filter cake. The filtrate was discarded, the filter cake was triturated with MeOH (3 mL), filtered to give filtrate and filter cake. The filtrate was discarded, the filter cake was followed by lyophilization to give (29) (53.64 mg, 128.68 43.86% yield, μmol, 98% purity) as white solid.1H NMR: (400 MHz, DMSO-d6) 6 = 8.28 - 7.81 (m, 2H), 7.66 - 7.21 (m, 6H), 7.19 - 6.89 (m, 2H), 5.19 (dd, J = 2.9, 10.8 Hz, 1 H), 5.01 - 4.24 (m, 1 H), 3.91 (br s, 3H), 3.51 - 3.32 (m, 1 H), 3.29 - 3.07 (m, 1 H), 3.01 - 2.76 (m, 1 H), 1 .52 - 1 .02 (m, 6H); LCMS: RT = 0.637 min, m / z = 409.2 (M+H)+.

[0479] EXAMPLE 1.31: SYNTHESIS OF (30)

[0480] Copper (II) bromide (446 mg, 1.998 mmol, 2 eq) was added to a solution of 1 -(2- (difluoromethyl)phenyl)ethan-1-one (170 mg, 0.999 mmol, 1 eq) in a mixture of CHCH (6 mL) and EtOAc (6mL) and the suspension was warmed up to reflux. It was reacted for 5 h, cooled down to r.t., and filtered through a pad of Celite, eluting with EtOAc (60 mL). Volatiles were concentrated off to give crude 2-bromo-1-(2-(difluoromethyl)phenyl)ethan-1-one (204 mg, 82% yield) as a brown oil, which was submitted to the next step without purification.1H NMR (300 MHz, CDCI3) 6 7.86 (m, 2H), 7.70 (m, 1 H), 7.60 (m, 1 H), 7.29 (t, J = 55.6 Hz, 1 H), 4.46 (s, 2H).

[0481] A solution of 2-bromo-1-(2-(difluoromethyl)phenyl)ethan-1-one (100 mg, 0.401 mmol, 1 eq) and (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (99 mg, 0.401 mmol, 1 eq) in EtOH (4 mL) was refluxed for 1 h. The reaction was cooled down to r.t., HCI (4 M in dioxane, 4.0 mL, 16.0 mmol, 10 eq) was added and the mixture was stirred at r.t. for 45 min. Volatiles were concentrated off and the residue was slurried with Et20 (2x4 mL), to give crude (R)-2-(4-(2- (difluoromethyl)phenyl)thiazol-2-yl)morpholine hydrochloride (125 mg, 94% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) 6 9.47-9.13 (m, 2H), 8.08 (s, 1 H), 7.73 (m, 2H), 7.60 (m, 2H), 7.24 (t, J = 54 Hz, 1 H), 5.22 (m, 1 H), 4.19-3.94 (m, 2H), 3.92-3.58 (m, 1 H), 3.18 (m, 2H); MS (ESI) m / z free base 297 [M + H]+; SFC: RT 2.96 min

[0482] HATU (110 mg, 0.289 mmol, 1.1 eq) and DIPEA (180 mL, 1 .051 mmol, 4 eq) were added to a solution of bicyclo[2.1.1 ]hexane-1 -carboxylic acid (35 mg, 0.263 mmol, 1 eq) and (R)-2-(4-(2- (difluoromethyl)phenyl)thiazol-2-yl)morpholine hydrochloride (112 mg, 0.289 mmol, 1.1 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (10 mL) and it was extracted with EtOAc (2x5 mL). Combined organic layers were washed with brine (3x5 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (10-30% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2- (4-(2-(difluoromethyl)phenyl)thiazol-2-yl)morpholino)methanone (79 mg, 74% yield) as a pale yellow solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.81 (d, J = 7.1 Hz, 1 H), 7.64 (d, J = 6.8 Hz, 1 H), 7.58 -7.40 (m, 3H), 7.17 (t, J = 55.4 Hz, 1 H), 5.05-4.66 (m, 2H), 4.52 (d, J = 13.4 Hz, 1 H), 4.29 (d, J = 13.3 Hz, 1 H), 4.12 (d, J = 11.6 Hz, 1 H), 3.91 -3.53 (m, 2H), 3.47-3.13 (m, 1 H), 3.10-2.82 (m, 1 H), 2.43 (s, 1 H), 1.97-1.73 (m, 5H), 1.52-1.40 (m, 1 H); MS (ESI) m / z 405 [M + H]+; SFC: RT 3.95 min

[0483] EXAMPLE 1.32: SYNTHESIS OF (31)

[0484] A solution of 2-bromo-1-(2-fluorophenyl)ethan-1-one (300 mg, 1 .382 mmol, 1.36 eq) and (R)-fe / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (250 mg, 1.014 mmol, 1 eq) in EtOH (10 mL) was refluxed for 2.5 h. The mixture was cooled down to r.t. , HCI (4 M in dioxane, 2.00 mL, 8 mmol, 7.88 eq) was added and it was reacted for 18 h. The reaction mixture was poured into NaHCOs (saturated aqueous solution, 60 mL) and it was extracted with CH2CI2 (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH / CH2Cl2) to give (R)-2-(4-(2-fluorophenyl)thiazol-2-yl)morpholine (240 mg, 89% yield) as an off-white solid.1H NMR (300 MHz, CDCI3) δ 8.18 (m, 1 H), 7.73 (s, 1 H), 7.32-7.07 (m, 3H), 4.86 (dd, J = 9.7, 2.7 Hz, 1 H), 4.06 (m, 1 H), 3.82 (td, J = 10.9, 3.1 Hz, 1 H), 3.49 (m, 1 H), 2.96 (m, 3H); MS (ESI) m / z 265 [M + H]+; SFC: RT 4.37 min

[0485] HATU (1 18 mg, 0.31 mmol, 1.1 eq) and DIPEA (145 mL, 0.847 mmol, 3 eq) were added to a solution of bicyclo[2.1.1 ]hexane-1 -carboxylic acid (37 mg, 0.278 mmol, 1 eq) and (R)-2-(4-(2- fluorophenyl)thiazol-2-yl)morpholine (75 mg, 0.283 mmol, 1 eq) in DMF (3 mL), and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), it was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20- 30% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2-fluorophenyl)thiazol-2- yl)morpholino)methanone (87 mg, 82% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.29-8.09 (m, 1 H), 7.77 (d, J = 2.1 Hz, 1 H), 7.37-7.28 (m, 1 H), 7.25-7.07 (m, 2H), 5.05-4.43 (m, 2H), 4.30-3.96 (m, 2H), 3.76 (s, 1 H), 3.47-3.14 (m, 1 H), 3.09-2.84 (m, 1 H), 2.45 (s, 1 H), 2.03-1.87 (m, 4H), 1.85-1.79 (m, 2H), 1 .55-1.40 (m, 2H); MS (ESI) m / z 373 [M + H]+; SFC: RT 3.63 min

[0486] EXAMPLE 1.33: SYNTHESIS OF (32)

[0487] To a solution of compound 4 (60 mg, 218.67 1 eq) anμdm 3o-lf,luorobenzoic acid (30.64 mg, 218.67 μm 1ol e, q) in DMF (1 mL) was added HOBt (35.46 mg, 262.41 1.2 eq) and μmol, EDCI (50.30 mg, 262.41 1μ.2m eoql,) and DIEA (113.05 mg, 874.70 152.36 μL, 4 eqμ)m. ol, The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep- HPLC(column: Unisil 3 - 100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 53%- 83%, 7 min) followed by lyophilization to give (32) (48.23 mg, 120.43 pmol, 55.07% yield, 99% purity) as yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.39 - 8.05 (m, 1 H), 7.83 (br s, 1 H), 7.46 - 7.27 (m, 2H), 7.20 (br d, J = 7.1 Hz, 1 H), 7.17 - 7.08 (m, 2H), 7.06 (br d, J = 7.3 Hz, 1 H), 6.99 (br d, J = 8.1 Hz, 1 H), 5.03 - 4.48 (m, 1 H), 4.17 - 3.85 (m, 4H), 3.52 - 3.03 (m, 3H), 2.34 (br d, J = 11 .5 Hz, 1 H), 2.06 - 1 .94 (m, 2H), 1 .82 (br s, 1 H); LCMS: RT = 0.647 min, m / z =397.1 (M+H)+.

[0488] EXAMPLE 1.34: SYNTHESIS OF (33)

[0489] Synthesis of compound 4

[0490] A mixture of compound 2 (178.12 mg, 777.57 0.95 eq)μ amnodl, compound 1 (200 mg, 818.49 μmol 1, eq) in EtOH (2 mL) was stirred at 90 °C for 2h. The mixture was concentrated and to the residue was added HCI / EtOAc (1 mL). The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated at reduced pressure to give compound 4 (250 mg, 804.27 pmol, 98.26% yield, HCI) as a white solid. LCMS: RT =0.443 min, m / z =275.2 (M+H)+.

[0491] Synthesis of (33)

[0492] To the mixture of compound 6 (19.64 mg, 160.85 24.55 μL, 1μ emq)ol i,n ACN (1 mL) was added TCFH (54.16 mg, 193.02 1.μ2m eoql), , 1 -METHYLIMIDAZOLE (46.22 mg, 562.99 pmol, 44.88 μL, 3.5 eq). The mixture was stirred at 20 °C for 30 min. Then to the mixture was added compound 4 (50 mg, 160.85 1 eq,μ HmCoI)l,, the mixture was stirred 20 °C for 15.5 h. The mixture was concentrated. The residue was purified by reversed-phase HPLC (column : Unisil 3 - 100 C18 Ultra 150*50 mm*3 um;mobile phase : [water (FA) -ACN] ;B% : 55%- 85%, 7 min) , the eluent was concentrated and then freeze dried. Compound (33) (20.39 mg, 51.72 pmol, 32.15% yield, 96% purity) was obtained as an off white solid.1H NMR: (400 MHz, DMSO- d6) 6 = 8.09-7.92 (m, 2H), 7.46 - 7.37 (m, 5H) , 7.35 - 7.29 (m, 1 H) , 7.13-7.03 (m, 2H), 4.47 - 4.19 (m, 1 H) , 3.92 (s, 3H) , 3.37 - 3.29 (m, 2H) , 3.21 - 3.06 (m, 2H), 2.30 - 2.22 (m, 1 H) , 1 .99 - 1 .57 (m, 3H); LCMS: RT =0.895 min, m / z =379.3 (M+H)+.

[0493] EXAMPLE 1.35: SYNTHESIS OF (34)

[0494] Synthesis of compound 3

[0495] A mixture of compound 2 (80 mg, 327.40 1 eq) andμm cooml, pound 1 (80.89 mg, 327.40 pmol, 1 eq) in EtOH (1 mL) was stirred at 90 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. The residue was added HCI / EtOAc (3 mL) and DCM (3 mL) and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated at reduced pressure to give compound 3 (170 mg, crude, HCI) as a black brown oil. LCMS: RT =0.473 min, m / z =293.0 (M+H)+.

[0496] Synthesis of compound (34)

[0497] A mixture of 4-fluorobenzoic acid (47.92 mg, 342.03 1 eq), comμpmoouln, d 3 (100 mg, 342.03 μmol 1, eq), DIEA (132.62 mg, 1.03 mmol, 178.73 μL, 3 eq), HOBt (55.46 mg, 410.44 pmol, 1.2 eq) and EDCI (78.68 mg, 410.44 1.2 eq)μ imn o Dl,MF (1 mL) was stirred at 20 °C for 16 h. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 63%- 83%, 9 min). Compound (34) (19.62 mg, 46.86 13.70%μm yioell,d, 99% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.35 - 7.95 (m, 1 H), 7.82 - 7.65 (m, 1 H), 7.52 - 7.36 (m, 2H), 7.10 (br t, J = 8.3 Hz, 2H), 6.87 - 6.64 (m, 2H), 5.16 - 4.30 (m, 1 H), 4.25-3.75 (m, 4H), 3.55 - 3.00 (m, 3H), 2.43 - 2.25 (m, 1 H), 2.08 - 1 .67 (m, 3H); LCMS: RT =0.657 min, m / z =415.1 (M+H)+; SFC: RT =1.564 min

[0498] EXAMPLE 1.36: SYNTHESIS OF (35)

[0499] A suspension of 1 -(m-tolyl)ethan-1-one (500 mg, 3.726 mmol, 1 eq) and copper (II) bromide (1.750 g, 7.835 mmol, 2.1 eq) in a mixture of EtOAc (15 mL) and CHCb (15 mL) was refluxed for 3.5 h. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (80 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 40 mL) and brine (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(m-tolyl)ethan-1-one (790 mg, 99% yield) as a colorless oil. It was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.47-7.29 (m, 2H), 4.45 (s, 2H), 2.43 (s, 3H).

[0500] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (200 mg, 0.811 mmol, 1 eq)) and 2-bromo-1-(m-tolyl)ethan-1-one (250 mg, 1.173 mmol, 1.45 eq) in EtOH (12 mL) was refluxed for 25 min. The mixture was cooled down to r.t., HCI (4 M in dioxane, 2.00 mL, 8 mmol, 9.85 eq) was added and it was reacted for 18 h. The reaction mixture was poured into NaHCOs (saturated aqueous solution, 60 mL) and it was extracted with CH2CI2 (2x25 mL). Combined organic layers were washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-8% MeOH / CH2Cb) to give (R)-2-(4-(m-tolyl)thiazol-2-yl)morpholine (91 mg, 43% yield) as a colorless oil.1H NMR (300 MHz, CDCI3) δ 7.71 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.43 (s, 1 H), 7.30 (m, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 4.90 (dd, J = 9.7, 2.7 Hz, 1 H), 4.07 (d, J = 11.6 Hz, 1 H), 3.85 (m, 1 H), 3.52 (dd, J = 11 .8, 9.3 Hz, 1 H), 3.10-2.92 (m, 3H), 2.40 (s, 3H); MS (ESI) m / z 261 [M + H]+; SFC: RT 3.52 min

[0501] HATU (141 mg, 0.37 mmol, 1 .1 eq) and DIPEA (173 mL, 1 .01 mmol, 3 eq) were added to a solution of bicyclo[2.1 .1]hexane-1-carboxylic acid (44 mg, 0.331 mmol, 1 eq) and (R)-2-(4-(m- tolyl)thiazol-2-yl)morpholine (88 mg, 0.338 mmol, 1 eq) in DMF (3 mL), and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 45% to 65%] to give (R)- bicyclo[2.1 .1]hexan-1-yl(2-(4-(m-tolyl)thiazol-2-yl)morpholino)methanone (90 mg, 72% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.46 (s, 1 H), 7.31 (t, J = 7.7 Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 5.09-4.35 (m, 2H), 4.29-3.95 (m, 2H), 3.88-3.59 (m, 1 H), 3.44-3.19 (m, 1 H), 3.12-2.88 (m, 1 H), 2.50-2.34 (m, 4H), 1 .99-1 .76 (m, 6H), 1 .57-1 .35 (m, 2H); MS (ESI) m / z 369 [M + H]+; SFC: RT 4.21 min

[0502] EXAMPLE 1.37: SYNTHESIS OF (36)

[0503] CDI (1 .808 g, 1 1.15 mmol, 1 .2 eq) was added to a solution of (R)-1-(tert- butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.000 g, 9.291 mmol, 1 eq) in THF (20 mL) and the reaction mixture was stirred at r.t. for 1 h. Extra CDI (300 mg, 1 .85 mmol, 0.2 eq) was added and the mixture was stirred at r.t. for 30 min. NH4OH (13.3 M in H2O, 7.00 mL, 93.1 mmol, 10.02 eq) was added and the solution was stirred at r.t. for 30 min. It was diluted with H2O (25 mL) and it was extracted with EtOAc (4x20 mL). Combined organic layers were washed with citric acid (5% aqueous solution, 3x20 mL) and brine (3x20 mL). It was dried over Na2SO4 (anhydrous), filtered, and concentrated to give fe / Y-butyl (R)-3-carbamoylpyrrolidine-1- carboxylate (2.1 g, > theoretical) as a beige solid, which was submitted to next step without purification. 1 H NMR (300 MHz, CDCI3) δ 5.57 (bs, 2H), 3.59 (bs, 1 H), 3.58-3.44 (m, 2H), 3.40- 3.28 (m, 1 H), 2.97-2.85 (m, 1 H), 2.16-2.08 (m, 2H), 1.45 (s, 9H). Lawesson's (2.400 g, 5.637 mmol, 0.6 eq) was added to a solution of te / Y-butyl (R)-3- carbamoylpyrrolidine-1 -carboxylate (crude from previous step, 9.291 mmol) in THF (25 mL) and the reaction mixture was stirred at r.t. for 3 h. Extra Lawesson's reagent (2.400 g, 5.637 mmol, 0.6 eq) was added and it was stirred at r.t. for 1 h. It was poured into H2O (150 mL) and extracted with EtOAc (2x30 mL). Combined organic layers were washed with NH4CI (saturated aqueous solution, 60 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes) to give te / Y-butyl (R)-3- carbamothioylpyrrolidine-1-carboxylate (1 g, 47% yield) as a pale yellow solid.1H NMR (300 MHz, CDCI3) δ 7.56 (bs, 1 H), 7.10 (bs, 1 H), 3.76-3.67 (m, 1 H), 3.65-3.53 (m, 2H), 3.43-3.18 (m, 2H), 2.26-2.15 (m, 2H), 1 .45 (s, 9H); MS (ESI) mlz 229 [M - H]-; SFC: RT 2.11 min

[0504] A suspension of 1-(4-fluoro-2-methoxyphenyl)ethanone (760 mg, 4.293 mmol, 1 eq) and copper (II) bromide (2.100 g, 9.402 mmol, 2.08 eq) in a mixture of EtOAc (15 mL) and CHCH (15 mL) was refluxed for 90 min. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (1.2 g, 113% yield) as a beige solid. It was submitted to next step without purification, considering it was 88% pure (w / w). 1 H NMR (300 MHz, CDCI3) δ 7.88 (dd, J = 8.7, 6.8 Hz, 1 H), 6.82-6.62 (m, 2H), 4.55 (s, 2H), 3.95 (s, 3H).

[0505] A solution of te / Y-butyl (R)-3-carbamothioylpyrrolidine-1-carboxylate (155 mg, 0.672 mmol, 1 eq) and 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (166 mg, 88% w / w, 0.591 mmol, 0.88 eq) in EtOH (10 mL) was refluxed for 30 min. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (3 mL) and TFA (1 .00 mL, 13.058 mmol, 19.41 eq) was added. The reaction mixture was stirred at r.t. for 15 min, concentrated, and coevaporated with CH2CI2 (8 mL). Crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes then 5% MeOH / CH2Cb with NH3 as additive) to give (R)-4-(4-fluoro-2- methoxyphenyl)-2-(pyrrolidin-3-yl)thiazole TFA salt (180 mg, 71 % yield) as a white solid.1H NMR (300 MHz, CDCI3) δ 10.14 (bs, 1 H), 9.53 (bs, 1 H), 8.21 (t, J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 6.81-6.66 (m, 2H), 3.98 (d, J = 6.9 Hz, 1 H), 3.93 (s, 3H), 3.77 (m, 2H), 3.57 (m, 2H), 2.55 (m, 1 H), 2.35 (m, 1 H); MS (ESI) m / z 279 [M + H]+free base; SFC: RT 4.87 min

[0506] HATU (140 mg, 0.368 mmol, 1.21 eq) and DIPEA (156 mL, 0.911 mmol, 2.99 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (31 mg, 0.309 mmol, 1.04 eq) and (R)-4-(4-fluoro-2-methoxyphenyl)-2-(pyrrolidin-3-yl)thiazole TFA salt (120 mg, 0.305 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 55%] to give (R)-(3-(4-(4-fluoro-2- methoxyphenyl)thiazol-2-yl)pyrrohdm-1-yl)(1-methylcyclopropyl)methanone (53 mg, 48% yield) as a pale yellow solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.19 (dd, J = 8.6, 7.0 Hz, 1 H), 7.75 (s, 1 H), 6.82-6.64 (m, 2H), 4.20-3.51 (m, 8H), 2.52-2.22 (m, 2H), 1.34 (s, 3H), 1 .06-0.85 (m, 2H), 0.66-0.50 (m, 2H); MS (ESI) m / z 361 [M + H]+; SFC: RT 5.30 min

[0507] EXAMPLE 1.38: SYNTHESIS OF (37)

[0508] Error! Reference source not found.

[0509] CDI (1 .599 g, 9.861 mmol, 1 .2 eq) was added to a solution of (R)-4-(fert- butoxycarbonyl)morpholine-2-carboxylic acid (2.0 g, 8.216 mmol, 1 eq) in THF (20 mL). The reaction mixture was stirred at r.t. for 2 h. NH4OH (13.3 M, 6.178 mL, 82.46 mmol, 10 eq) was added and the solution was at r.t. for 1 h. It was poured into H2O (40 mL) and it was extracted with EtOAc (4x20 mL). Combined organic layers were washed with citric acid (5% aqueous solution, 40 mL) and brine (40 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give (R)-te / Y-butyl-2-carbamoylmorpholine-4-carboxylate (1.76 g, 93% yield) as a white solid. It was submitted to next step without purification.1H NMR (300 MHz, CDCh) 5 6.51 (bs, 1 H), 5.62 (bs, 1 H), 4.32 (d, J = 13.6 Hz, 1 H), 4.00-3.85 (m, 3H), 3.58 (td, J = 11 .6, 2.8 Hz, 1 H), 3.03-2.61 (m, 2H), 1.47 (s, 9H); MS (ESI) mlz 231 [M + H]+.

[0510] (R)-te / Y-Butyl-2-carbamoylmorpholine-4-carboxylate (500 mg, 2.171 mmol, 1 eq) was added to a suspension of Lawesson's reagent (555 mg, 1.302 mmol, 0.6 eq) in THF (5 mL). The reaction mixture was stirred at r.t. for 2 h. H2O (10 mL) was added, the mixture was poured into NH4CI (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-40% EtOAc / hexanes), to give (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (490 mg, 92% yield) as a white solid.1H NMR (300 MHz, CDCI3) 6 7.97 (bs, 1 H), 7.53 (bs, 1 H), 4.66 (d, J = 13.8 Hz, 1 H), 4.20 (dd, J = 10.5, 3.1 Hz, 1 H), 4.03-3.90 (m, 2H), 3.61 (td, J = 11.7, 2.8 Hz, 1 H), 2.88 (t, J = 12.2 Hz, 1 H), 2.68 (t, J = 12.1 Hz, 1 H), 1.48 (s, 9H); MS (ESI) mlz 246 [M + H]+;SFC: RT 3.04 min

[0511] Iodomethane-d3 (1.350 g, 9.313 mmol, 1 .33 eq) was added to a suspension of 2'- hydroxyacetophenone (1.000 g, 6.977 mmol, 1 eq) and CS2CO3 (4.000 g, 12.276 mmol, 1.76 eq) in CH3CN (20 mL). The suspension was stirred at r.t. for 3 h. It was diluted with EtOAc (80 mL) and it was washed with brine (3x30 mL). Organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 1 -(2-(methoxy-d3)phenyl)ethan-1-one (1.07 g, quantitative yield) as a pale yellow-colored oil, which was submitted next step without purification.1H NMR (300 MHz, CDCI3) δ 7.72 (dd, J = 7.7, 1 .8 Hz, 1 H), 7.50-7.39 (m, 1 H), 6.97 (td, J = 8.3, 3.1 Hz, 2H), 2.60 (s, 3H).

[0512] A suspension of 1-(2-(methoxy-d3)phenyl)ethan-1-one (500 mg, 3.263 mmol, 1 eq) and copper (II) bromide (1.500 g, 6.715 mmol, 2.06 eq) in a mixture of EtOAc (14 mL) and CHCH (14 mL) was refluxed for 3 h. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 2-bromo-1-(2-(methoxy-d3)phenyl)ethan-1-one (820 mg, > theoretical) as a brown-colored oil. It was submitted to next step, considering it was 92% pure w / w.1H NMR (300 MHz, CDCI3) 6 7.82 (dd, J = 7.7, 1.7 Hz, 1 H), 7.61-7.46 (m, 1 H), 7.09-6.90 (m, 2H), 4.60 (s, 2H).

[0513] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (220 mg, 0.893 mmol, 1 eq) and 2-bromo-1-(2-(methoxy-d3)phenyl)ethan-1-one (270 mg, 92% pure w / w, 1.07 mmol, 1.2 eq) in EtOH (8 mL) was refluxed for 1 h. It was cooled down to r.t., HCI (4 M in dioxane, 2.00 mL, 8 mmol, 2.24 eq) was added and the solution was stirred at r.t. for 18 h. It was poured into NaHCOs (saturated aqueous solution, 120 mL) and it was extracted with EtOAc (2x40 mL). Combined organic layers were washed with brine (50 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-10% MeOH / CH2Cl2), to give (R)-2-(4-(2-(methoxy-d3)phenyl)thiazol-2-yl)morpholine (160 mg, 64% yield).1H NMR (300 MHz, CDCI3) δ 8.21 (dd, J = 7.7, 1.8 Hz, 1 H), 7.91 (s, 1 H), 7.35-7.24 (m, 2H), 7.10-6.94 (m, 2H), 4.88 (dd, J = 9.7, 2.9 Hz, 1 H), 4.11-4.00 (m, 1 H), 3.83 (td, J = 11 .0, 3.3 Hz, 1 H), 3.50 (dd, J = 12.6, 2.8 Hz, 1 H), 3.09-2.89 (m, 3H); MS (ESI) m / z 280 [M + H]+; SFC: RT 3.68 min

[0514] HATU (130 mg, 0.341 mmol, 1 .2 eq) and DIPEA (146 mL, 0.852 mmol, 3 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (30 mg, 0.284 mmol, 1 eq) and (R)-2-(4- (2-(methoxy-d3)phenyl)thiazol-2-yl)morpholine (80 mg, 0.286 mmol, 1.01 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 55%] to give (R)-(2-(4-(2-(methoxy-d3)phenyl)thiazol-2-yl)morpholino)(1 - methylcyclopropyl)methanone (74 mg, 72% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.26 (dd, J = 7.7, 1.8 Hz, 1 H), 7.96 (s, 1 H), 7.36-7.27 (m, 1 H), 7.12-6.94 (m, 2H), 4.90-4.75 (m, 2H), 4.34 (d, J = 13.5 Hz, 1 H), 4.19-4.07 (m, 1 H), 3.82-3.68 (m, 1 H), 3.27-3.05 (m, 2H), 1.38 (s, 3H), 1.08-0.91 (m, 2H), 0.73-0.58 (m, 2H); MS (ESI) m / z 362 [M + H]+; SFC: RT 3.14 min

[0515] EXAMPLE 1.39: SYNTHESIS OF (38)

[0516] Synthesis of compound 2

[0517] To the mixture of compound 1 (200 mg, 1 .07 mmol, 1 eq) in EtOH (1 mL) and DCM (3 mL) was added BLAH; pyridin- 1 -ium (343.61 mg, 1.07 mmol, 1 eq). The mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 30: 1 , TLC: Petroleum ether: Ethyl acetate = 20: 1 , Rf = 0.41). Compound 2 (270 mg, crude) was obtained as a colorless oil.1H NMR: (400 MHz, CDCI3) δ = 7.84 (dd, J = 1.8, 7.8 Hz, 1 H), 7.59 (ddd, J = 1.8, 7.5, 8.2 Hz, 1 H), 7.34 (dt, J = 0.9, 7.6 Hz, 1 H), 7.21 (dd, J = 0.8, 8.3 Hz, 1 H), 6.64 (t, J = 72.9 Hz, 1 H), 4.53 (s, 2H).

[0518] Synthesis of compound 3

[0519] To a solution of compound 1 (43.04 mg, 162.39 1 eq) inμ EmtOolH, (1 mL) was added tert-butyl (2R)-2-carbamothioylmorpholine-4-carboxylate (40 mg, 162.39 1 eq). The μmol, mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under vacuum to give compound 2 (60 mg, crude) as yellow gum. LCMS: RT = 0.647 min, m / z = 413.2 (M+H)+.

[0520] Synthesis of compound 4

[0521] To a solution of compound 2 (60 mg, 145.47 1 eq) μ inmo DlC, M (1.5 mL) was added HCI / EtOAc (0.5 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum to give compound 3 (50 mg, crude, HCI) as yellow gum. LCMS: RT = 0.421 min, m / z = 313.1 (M+H)+.

[0522] Synthesis of (38)

[0523] To a solution of compound 3 (50 mg, 143.35 1 eq, HμCmI)o,l, EDCI (32.98 mg, 172.02 pmol, 1 .2 eq), HOBt (23.24 mg, 172.02 1 .2 eq)μ amndol D, IEA (55.58 mg, 430.05 pmol, 74.91 μL, 3 eq) in DMF (1 mL) was added benzoic acid (17.51 mg, 143.35 21.88 μL, 1 eμqm).ol, Then the mixture was stirred at 25 °C for 16 h. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; gradient: 60%- 90% B over 7 min) to give (38) (36.58 mg, 87.84 61 .28% yieldμ,m 1o0l0, % purity) as pink gum.1H NMR: (400 MHz, CDCI3) δ = 8.38 - 7.97 (m, 1 H), 7.92 - 7.75 (m, 1 H), 7.52 - 7.42 (m, 5H), 7.38 - 7.28 (m, 2H), 7.18 (d, J = 8.1 Hz, 1 H), 6.79 - 6.26 (m, 1 H), 5.30 - 4.50 (m, 2H), 4.30 - 3.72 (m, 3H), 3.54 - 3.15 (m, 2H); LCMS: RT = 0.582 min, m / z = 416.9 (M+H)+. SFC: RT = 1.957 min.

[0524] EXAMPLE 1.40: SYNTHESIS OF (39)

[0525] 2-Methoxyphenacyl bromide (911 mg, 3.976 mmol, 1 eq) was added to a solution of (R)- te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (980 mg, 3.978 mmol, 1 eq) in EtOH (15 mL) and the mixture was refluxed for 1 h. It was cooled down to r.t. HCI (4M in dioxane, 10 mL, 40 mmol, 10 eq) was added and the solution was stirred at rt for 2h. It was poured into NaHCOs (200 mL, saturated aqueous solution) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (1-5% MeOH / CH2Cl2 using 1 % of NH3 as additive) to give (R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)morpholine (755 mg, 69% yield) as a pale brown solid.1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J = 7.5 Hz, 1 H), 7.91 (s, 1 H), 7.37- 7.22 (m, 1 H), 7.16-6.91 (m, 2H), 4.87 (dd, J = 9.8, 2.8 Hz, 1 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.94 (s, 3H), 3.89-3.75 (m, 1 H), 3.50 (d, J = 12.4 Hz, 1 H), 3.09 - 2.88 (m, 3H); MS (ESI) mlz 211 [M + H]+; SFC: RT 4.57 min

[0526] HATU (130 mg, 0.341 mmol, 1.1 eq) and DIPEA (160 mL, 0.934 mmol, 3 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (33 mg, 0.313 mmol, 1 eq) and (R)-2-(4- (2-methoxyphenyl)thiazol-2-yl)morpholine (86 mg, 0.311 mmol, 1 eq) in DMF (3 mL). The solution was stirred at r.t. for 6 h, it was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-30% EtOAc / hexanes) to give (R)-(2-(4-(2-methoxyphenyl)thiazol-2- yl)morpholino)(1-methylcyclopropyl)methanone (96 mg, 86% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.26 (d, J = 7.7 Hz, 1 H), 7.96 (s, 1 H), 7.42-7.22 (m, 1 H), 7.17-6.90 (m, 2H), 4.98-4.66 (m, 2H), 4.35 (d, J = 13.6 Hz, 1 H), 4.13 (d, J = 11.6 Hz, 1 H), 3.96 (s, 3H), 3.75 (t, J = 11 .5 Hz, 1 H), 3.33-2.98 (m, 2H), 1 .37 (s, 3H), 0.99 (d, J = 6.3 Hz, 2H), 0.82 -0.53 (m, 2H); MS (ESI) m / z 359 [M + H]+; SFC: RT 5.21 min

[0527] EXAMPLE 1.41: SYNTHESIS OF (40)

[0528] To a mixture of compound 1 (50 mg, 182.23 1 eq) aμnmdo clo, mpound 12 (28.09 mg, 200.45 μmo 1l,.1 eq) in DMF (1 mL) was added DIEA (70.66 mg, 546.69 95.22 μL, 3 eq) μmol, and HOBt (29.55 mg, 218.67 1.2μm eqo)l, and EDCI (41.92 mg, 218.67 1.2 eq). The μmol, mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 urn; mobile phase: [water (FA) -ACN]; B%: 54%-84%, 7 min) to give (40) (25.9 mg, 64.02 35.13%μm yioell,d, 98% purity) as yellow solid.1H NMR: (400 MHz, CD3OD) 6 = 8.21 - 7.94 (m, 1 H), 7.88 (br s, 1 H), 7.45 (br s, 2H), 7.36 - 7.26 (m, 1 H), 7.16 (br s, 2H), 7.08 (br d, J = 8.3 Hz, 1 H), 7.00 (br s, 1 H), 4.80 - 4.19 (m, 2H), 3.93 (s, 3H), 3.78 - 3.46 (m, 1 H), 3.31 (br s, 2H), 2.30 (br dd, J = 4.3, 8.9 Hz, 1 H), 2.09 - 1 .58 (m, 3H); LCMS: RT = 1.041 min, m / z = 397.1 (M+H)+.

[0529] EXAMPLE 1.42: SYNTHESIS OF (41)

[0530] A degassed solution of 1 -bromo-2-(1 ,1-difluoroethyl)benzene (210 mg, 0.94 mmol, 1 eq), butyl vinyl ether (1 .26 mL, 9.76 mmol, 10.27 eq), dppp (78 mg, 0.186 mmol, 0.2 eq), Pd(OAc)2 (21 mg, 0.093 mmol, 0.1 eq) and EtsN (397 mL, 2.826 mmol, 3 eq) in DMF (6 mL) was reacted at 120 °C for 17 h in a salad tube. The mixture was cooled down to r.t., was poured into H2O (20 mL) and it was extracted with EtOAc (15 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated, to give crude 1 -(1-butoxyvinyl)- 2-(1 ,1-difluoroethyl)benzene (230 mg, quantitative yield) as a yellow oil.

[0531] HCI (10% aqueous solution, 3 mL) was added to a solution of 1 -(1-butoxyvinyl)-2-(1 ,1- difluoroethyl)benzene (crude from previous step, 0.94 mmol, 1 eq) in THF (10 mL) and the mixture was vigorously stirred at r.t. for 2 h. It was poured into H2O (20 mL) and extracted with EtOAc (2x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (2-5% EtOAc / hexanes) to give 1 -(2-(1 ,1-difluoroethyl)phenyl)ethan-1-one (55 mg, 32% yield) as a colorless oil.1H NMR (300 MHz, CDCI3) 6 7.55-7.43 (m, 3H), 7.34 (m, 1 H), 2.57 (s, 3H), 2.01 (t, J = 18.7 Hz, 3H).

[0532] Copper (II) bromide (230 mg, 1.029 mmol, 2.01 eq) was added to a solution of 1 -(2-(1 ,1- difluoroethyl)phenyl)ethan-1-one (105 mg, 0.513 mmol, 1 eq) in a mixture of EtOAc (3 mL) and CHCh (3 mL), and the suspension was refluxed for 18 h. It was cooled down to r.t., filtered through a pad of Celite and product was eluted with EtOAc (2x10 mL) and THF (2x10 mL). Volatiles were concentrated off to give crude 2-bromo-1-(2-(1 ,1-difluoroethyl)phenyl)ethan-1- one (120 mg, 89% yield) as an orange oil, which was submitted to next step without purification.1H NMR (300 MHz, CDCI3) 6 7.55-7.43 (m, 3H), 7.34 (m, 1 H), 2.57 (s, 3H), 2.01 (t, J = 18.7 Hz, 3H). A solution of 2-bromo-1-(2-(1 ,1-difluoroethyl)phenyl)ethan-1-one (110 mg, 0.263 mmol, 1.3 eq) and (R)-fe / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (50 mg, 0.202 mmol, 1 eq) in EtOH (5 mL) was refluxed for 7 h. It was cooled down to r.t., HCI (4 M in dioxane, 760 mL, 3.04 mmol, 9.98 eq) was added and the solution was stirred at r.t. for 20 h. It was poured into NaHCOs (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x5 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH / CH2Cl2 using NH3 as additive) to give (R)-2-(4-(2-(1 ,1-difluoroethyl)phenyl)thiazol-2-yl)morpholine (17mg, 18% yield) as a brown oil. MS (ESI) mlz 311 [M + H]+; SFC: RT 3.93 min

[0533] HATU (53 mg, 0.139 mmol, 1.1 eq) and DIPEA (65 mL, 0.379 mmol, 3 eq) were added to a solution of bicyclo[2.1 .1]hexane-1-carboxylic acid (17 mg, 0.128 mmol, 1 eq) and (R)-2-(4-(2- (1 ,1-difluoroethyl)phenyl)thiazol-2-yl)morpholine (39 mg, 0.125 mmol, 1 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 19 h. It was poured into H2O (15 mL) and extracted with EtOAc (5 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20- 30% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2-(1 ,1- difluoroethyl)phenyl)thiazol-2-yl)morpholino)methanone (35 mg, 65% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.68-7.62 (m, 1 H), 7.49-7.41 (m, 3H), 7.29 (s, 1 H), 4.76 (d, J = 10.2 Hz, 1 H), 4.60-3.99 (m, 2H), 3.76 (m, 1 H), 3.38-2.85 (m, 2H), 2.42 (s, 1 H), 2.02-1.69 (m, 10H), 1.51-1.38 (m, 2H); MS (ESI) mlz 419 [M + H]+; SFC: RT 2.56 min

[0534] EXAMPLE 1.43: SYNTHESIS OF (42) Copper (II) bromide (1.720 g, 7.7 mmol, 2.04 eq) was added to a solution of 1-(2- bromophenyl)-ethanone (750 mg, 3.767 mmol, 1 eq) in a mixture of CHCh (15 mL) and EtOAc (15 mL) and the suspension was refluxed for 5 h. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting the product with EtOAc (50 mL). Volatiles were concentrated off to give crude 2-bromo-1-(2-bromophenyl)ethan-1-one (1 g, 95% yield) as a brown oil, which was submitted to next step without purification.

[0535] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (250 mg, 1 .014 mmol, 1 eq) and 2-bromo-1-(2-bromophenyl)ethan-1-one (450 mg, 1.619 mmol, 1.6 eq) in EtOH (6 mL) was refluxed for 90 min. It was cooled down to r.t. HCI (4 M in dioxane, 2.00 mL, 8 mmol, 7.88 eq) was added and the mixture was stirred at r.t. for 2 days. Volatiles were concentrated off and the residue was partitioned between NaHCOs (saturated aqueous solution, 60 mL) and CH2CI2 (30 mL). It was extracted with CH2CI2 (30 mL), and combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (3-5% MeOH / CH2Cl2 using NH3 as additive), to give (R)-2-(4-(2- bromophenyl)thiazol-2-yl)morpholine (210 mg, 64% yield) as a brown solid. MS (ESI) m / z 325 & 327 [M + H]+

[0536] BOC2O (207 mg, 0.945 mmol, 1.5 eq) and EtsN (263 mL, 1.886 mmol, 3 eq) were added to a solution of (R)-2-(4-(2-bromophenyl)thiazol-2-yl)morpholine (205 mg, 0.63 mmol, 1 eq) in CH2CI2 (10 mL) and the reaction mixture was stirred at r.t. for 90 min. It was poured into H2O (10 mL) and it was extracted with CH2CI2 (2x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (2-5% MeOH / CH2Cl2) to give fe / Y-butyl (R)-2-(4-(2- bromophenyl)thiazol-2-yl)morpholine-4-carboxylate (247 mg, 92% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) 6 7.78 (m, 2H), 7.64 (d, J = 8.0 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 4.81 (dd, J = 10.3, 3.1 Hz, 1 H), 4.43 (m, 1 H), 4.13-3.91 (m, 2H), 3.76 (t, J = 11 .4 Hz, 1 H), 3.07 (m, 2H), 1 .47 (s, 9H); MS (ESI) m / z 425 & 427 [M + H]+

[0537] Pd(OAc)2 (13 mg, 0.057 mmol, 0.1 eq) was added to a degassed suspension of fe / Y-butyl (R)-2-(4-(2-bromophenyl)thiazol-2-yl)morpholine-4-carboxylate (245 mg, 0.576 mmol, 1 eq), butyl vinyl ether (745 mL, 5.757 mmol, 10 eq), dppp (47 mg, 0.115 mmol, 0.2 eq) and EtsN (240 mL, 1 .721 mmol, 3 eq) in DMF (6 mL) and the mixture was reacted at 120 °C for 20 h in a sealed tube. It was cooled down to r.t., poured into brine (20 mL) and it was extracted with EtOAc (20 mL). Organic layer was washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated.

[0538] The residue was dissolved with THF (5 mL), HCI (10% aqueous solution, 3 mL) was added, and the mixture was stirred at r.t. for 1 h. Volatiles were concentrated off and the residue was poured into NaHCOs (saturate aqueous solution, 40 mL) and extracted with EtOAc (3x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (3-10% MeOH / CH2Cl2 using NH3 as additive) to give (R)-1-(2-(2-(morpholin-2-yl)thiazol-4-yl)phenyl)ethan-1-one (138 mg, 83% yield) as an orange oil.1H NMR (300 MHz, CDCI3) δ 7.74-7.32 (m, 5H), 4.81 (d, J = 9.6 Hz, 1 H), 4.03 (d, J = 11.2 Hz, 1 H), 3.80 (t, J = 10.0 Hz, 1 H), 3.44 (d, J = 12.8 Hz, 1 H), 3.05- 2.81 (m, 2H), 2.24 (s, 3H), 1 .82 (m, 2H); MS (ESI) m / z 289 [M + H]+

[0539] HATU (202 mg, 0.531 mmol, 1 eq) and DIPEA (272 mL, 1.588 mmol, 2.99 eq) were added to a solution of (R)-1-(2-(2-(morpholin-2-yl)thiazol-4-yl)phenyl)ethan-1-one (170 mg, 0.53 mmol, 1 eq) and bicyclo[2.1 .1]hexane-1-carboxylic acid (71 mg, 0.534 mmol, 1.01 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 2 h. It was poured into a mixture of H2O (15 mL) and brine (5 mL), and it was extracted with EtOAc (2x10 mL). Combined organic layers were washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 35% to 55%] to give (R)-1-(2-(2-(4- (bicyclo[2.1 .1]hexane-1-carbonyl)morpholin-2-yl)thiazol-4-yl)phenyl)ethan-1-one (122 mg, 58% yield) as a colorless oil.1H NMR (300 MHz, CDCb) δ 7.62 (d, J = 7.5 Hz, 1 H), 7.56-7.35 (m, 4H), 4.72-4.48 (m, 2H), 4.31-4.03 (m, 2H), 3.82-3.60 (m, 1 H), 3.25-2.70 (m, 2H), 2.50-2.19 (m, 5H), 1 .89 (m,5H), 1 .60 (m, 2H); MS (ESI) m / z 397 [M + H]+; SFC: RT 6.02 min

[0540] TMSCI (48 mL, 0.378 mmol, 1.24 eq) and a solution of Nal (149 mg, 0.994 mmol, 3.26 eq) in CH3CN (1 mL) were added to a solution of (R)-1-(2-(2-(4-(bicyclo[2.1 .1]hexane-1- carbonyl)morpholin-2-yl)thiazol-4-yl)phenyl)ethan-1-one (121 mg, 0.305 mmol, 1 eq) in CH3CN (4 mL), and the mixture was stirred at r.t. for 3 h. EtsN (53 mL, 0.38 mmol, 1 .25 eq) and TMSOTf (88 mL, 0.455 mmol, 1.5 eq) were added and the mixture was stirred at r.t. for 22 h. It was diluted with EtOAc (15 mL) and it was washed with H2O (30 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-60% EtOAc / hexanes) to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2- (1-((trimethylsilyl)oxy)vinyl)phenyl)thiazol-2-yl)morpholino)methanone (91 mg, 64% yield) as a beige oil. MS (ESI) m / z 469 [M + H]+

[0541] CH2I2 (23 mL, 0.285 mmol, 1.48 eq) and ZnEt2 (1 M in hexanes, 288 mL, 0.288 mmol, 1.5 eq) were added to a 0 °C cooled solution of (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2-(1- ((trimethylsilyl) oxy)vinyl)phenyl)thiazol-2-yl)morpholino)methanone (90 mg, 0.192 mmol, 1 eq) in CH2CI2 (5 mL). The suspension was allowed to reach r.t. and it was stirred for 22 h. It was poured into NH4CI (saturated aqueous solution, 35 mL), it was filtered to remove solids in suspension, and it was extracted with CH2CI2 (2x15 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 43% to 57%] to give (R)-bicyclo[2.1.1]hexan-1-yl(2-(4-(2-(1- hydroxycyclopropyl)phenyl)thiazol-2-yl)morpholino)methanone (15 mg, 19% yield) as a beige solid and (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2-(1-((trimethylsilyl)oxy)cyclopropyl)phenyl)thiazol- 2-yl)morpholino)methanone (31 mg, 33% yield) as a yellow oil.

[0542] TMSCI (1 drop) was added to a 0 °C cooled solution of (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2- (1-((trimethylsilyl)oxy)cyclopropyl)phenyl)thiazol-2-yl)morpholino)methanone (30 mg, 0.062 mmol, 1 eq) in MeOH (3 mL) and the mixture was stirred at low temperature for 30 min. It was poured into NH4CI (saturated aqueous solution, 15 mL) and it was extracted with EtOAc (2x7 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was lyophilized to give (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4-(2-(1- hydroxycyclopropyl)phenyl)thiazol-2-yl)morpholino)methanone (22 mg, 86% yield) as a pale yellow solid. 1 H NMR (300 MHz, CDCI3) δ 7.60 (d, J = 6.5 Hz, 1 H), 7.52 (d, J = 6.7 Hz, 1 H), 7.41 (s, 1 H), 7.39-7.31 (m, 2H), 6.26 (bs, 1 H), 4.88-4.70 (m, 1 H), 4.64-4.46 (m, 1 H), 4.35-4.02 (m, 2H), 3.88-3.59 (m, 1 H), 3.31 -3.1 1 (m, 1 H), 3.00-2.81 (m, 1 H), 2.40 (s, 1 H), 1.82-1.76 (m, 1 H), 1.66-1.53 (m, 4H), 1 .51-1.39 (m, 2H), 1 .32 -1 .18 (m, 1 H), 1 .02-0.76 (m, 2H), 0.74-0.54 (m, 2H); MS (ESI) m / z 411 [M + H]+; SFC: RT 5.68 min

[0543] EXAMPLE 1.44: SYNTHESIS OF (43)

[0544] A suspension of 1-(4-fluoro-2-methoxyphenyl)ethanone (760 mg, 4.293 mmol, 1 eq) and copper (II) bromide (2.100 g, 9.402 mmol, 2.08 eq) in a mixture of EtOAc (15 mL) and CHCH (15 mL) was refluxed for 90 min. It was cooled down to r.t. and it was filtered through a pad of Celite, eluting with EtOAc (100 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered, and concentrated, to give crude 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (1.2 g, 113% yield) as a beige solid. It was submitted to next step without purification, considering it was 88% pure (w / w).1H NMR (300 MHz, CDCI3) δ 7.88 (dd, J = 8.7, 6.8 Hz, 1 H), 6.82-6.62 (m, 2H), 4.55 (s, 2H), 3.95 (d, J = 7.0 Hz, 3H).

[0545] A solution of te / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (100 mg, 0.384 mmol, 1 eq) and 2-bromo-1-(4-fluoro-2-methoxyphenyl)ethan-1-one (107 mg, 88% pure w / w, 0.381 mmol, 0.99 eq) in EtOH (4 mL) was refluxed for 3 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (6 mL), TFA (588 mL, 7.678 mmol, 20 eq) was added and the reaction mixture was stirred at r.t. for 2 h. It was poured into NaHCOs (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (2x10 mL). Combined organic layers were dried over Na3SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% MeOH:CH2Cl2 using NH3 as additive) to give (2R,6R)-2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (64 mg, 54% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) δ 8.16 (m, 1 H), 7.80 (s, 1 H), 6.80-6.64 (m, 2H), 4.91 (dd, J = 10.4, 2.8 Hz, 1 H), 3.92 (s, 3H), 3.84 (m, 1 H), 3.53-3.43 (m, 1 H), 2.97 (d, J = 12.6 Hz, 1 H), 2.81 (m, 1 H), 2.60 (m, 1 H), 1.25 (d, J = 6.3 Hz, 3H); MS (ESI) m / z 309 [M + H]+

[0546] HATU (72 mg, 0.189 mmol, 1.21 eq) and DIPEA (80 mL, 0.467 mmol, 3 eq) were added to a solution of 2-oxabicyclo[2.1 .1]hexane-1-carboxylic acid (20 mg, 0.156 mmol, 1 eq) and (2R,6R)-2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (57 mg, 0.184 mmol, 1.18 eq) in DMF (3 mL) and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na3SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 15% to 60%] to give (2-oxabicyclo[2.1.1]hexan-1-yl)((2R,6R)- 2-(4-(4-fluoro-2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholino)methanone (37 mg, 57% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCh) 5 8.30-8.09 (m, 1 H), 7.95- 7.77 (m, 1 H), 6.83-6.59 (m, 2H), 5.13-4.71 (m, 2H), 4.58-4.31 (m, 1 H), 4.05-3.69 (m, 6H), 3.30- 2.41 (m, 3H), 2.27-2.11 (m, 2H), 1.91 -1.71 (m, 2H), 1.32 (d, J = 6.2 Hz, 3H); MS (ESI) m / z 419 [M + H]+; SFC: RT 3.24 min

[0547] EXAMPLE 1.45: SYNTHESIS OF (44)

[0548] A solution of te / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (180 mg, 0.691 mmol, 1 eq) and 2-methoxyphenacyl bromide (158 mg, 0.689 mmol, 1 eq) in EtOH (10 mL) was refluxed for 3 h. It was cooled down to r.t., HCI (4 M in dioxane, 1 .8 mL, 7.2 mmol, 10.41 eq) was added and the solution was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (20 mL). Organic layer was washed with NaHCO3(saturated aqueous solution, 30 mL), dried over Na3SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (1-3% MeOH / CH2Cl2 using NH3as additive) to give (2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (83 mg, 41 % yield) as a yellow solid.1H NMR (300 MHz, CDCI3) δ 8.20 (dd, J = 7.7, 1.8 Hz, 1 H), 7.89 (s, 1 H), 7.34-7.28 (m, 1 H), 7.10-6.91 (m, 2H), 4.90 (dd, J = 10.4, 2.6 Hz, 1 H), 3.94 (s, 3H), 3.90- 3.76 (m, 1 H), 3.53-3.39 (m, 1 H), 3.05-2.74 (m, 2H), 2.60 (dd, J = 12.6, 10.3 Hz, 1 H), 1.25 (d, J = 6.2 Hz, 3H); MS (ESI) m / z 291 [M + H]+; SFC: RT 3.13 min

[0549] HATU (93 mg, 0.244 mmol, 1.1 eq) and DIPEA (114 mL, 0.665 mmol, 3 eq) were added to a solution of 1 -(difluoromethyl)cyclopropane-1 -carboxylic acid (30 mg, 0.22 mmol, 1 eq) and (2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6-methylmorpholine (65 mg, 0.223 mmol, 1 eq) in DMF (4 mL), and the mixture was stirred at r.t. for 90 min. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-30% EtOAc / hexanes) to give (1 - (difluoromethyl)cyclopropyl)((2R,6R)-2-(4-(2-methoxyphenyl)thiazol-2-yl)-6- methylmorpholino)methanone (80 mg, 87% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) 6 8.26 (d, J = 7.6 Hz, 1 H), 7.95 (s, 1 H), 7.39-7.28 (m, 1 H), 7.12-6.94 (m, 2H), 5.87 (t, J = 57.2 Hz, 1 H), 4.98-4.78 (m, 2H), 4.41 (d, J = 13.3 Hz, 1 H), 3.95 (s, 3H), 3.87-3.74 (m, 1 H), 3.15-2.98 (m, 1 H), 2.80-2.60 (m, 1 H), 1.33 (d, J = 6.1 Hz, 3H), 1.29-1.02 (m, 4H); MS (ESI) m / z 409 [M + H]+; SFC: RT 2.53 min

[0550] EXAMPLE 1.46: SYNTHESIS OF (45)

[0551] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (420 mg, 1 .705 mmol, 1 eq) and 2-bromo-1-(2-(difluoromethoxy)phenyl)ethan-1-one (700 mg, 77%, 2.033 mmol, 1 .19 eq) in EtOH (12 mL) was refluxed for 90 min. The mixture was cooled down to r.t., HCI (4 M in dioxane, 3.5 mL, 14 mmol, 8.21 eq) was added and it was reacted for 2 h. The reaction mixture was poured into NaHCOs (sat. aqueous solution, 100 mL) and it was extracted with EtOAc (2x40 mL). Combined organic layers were washed with brine (30 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was flash chromatographed on SiO2 (0- 5% MeOH / CH2Cl2 using NHs as additive) to give (R)-2-(4-(2-(difluoromethoxy)phenyl)thiazol-2- yl)morpholine (380 mg, 71 % yield) as an orange oil.1H NMR (300 MHz, CDCI3) δ 8.17 (m, 1 H), 7.80 (s, 1 H), 7.37-7.26 (m, 2H), 7.17 (m, 1 H), 6.55 (t, J = 74.2 Hz, 1 H), 4.86 (dd, J = 9.7, 2.9 Hz, 1 H), 4.06 (d, J = 11 .6 Hz, 1 H), 3.82 (td, J = 10.9, 3.2 Hz, 1 H), 3.48 (m, 1 H), 3.05-2.86 (m, 3H); MS (ESI) m / z 313 [M + H]+; SFC: RT 4.23 min HATU (255 mg, 0.67 mmol, 1.1 eq) and DIPEA (312 mL, 1.822 mmol, 3 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (61 mg, 0.578 mmol, 0.95 eq) and (R)-2- (4-(2-(difluoromethoxy)phenyl)thiazol-2-yl)morpholine (190 mg, 0.608 mmol, 1 eq) in DMF (6 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (15 mL) and extracted with EtOAc (10 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20-40% EtOAc / hexanes) to give (R)-(2-(4-(2-(difluoromethoxy)phenyl)thiazol-2- yl)morpholino)(1 -methylcyclopropyl) methanone (174 mg, 73% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.21 (m, 1 H), 7.86 (s, 1 H), 7.35 (m, 2H), 7.22 (m, 1 H), 6.59 (t, J = 74.3 Hz, 1 H), 4.92-4.75 (m, 2H), 4.37 (d, J = 13.5 Hz, 1 H), 4.15 (dd, J = 12.3, 3.4 Hz, 1 H), 3.77 (td, J = 11.7, 2.7 Hz, 1 H), 3.36-3.07 (m, 2H), 1.39 (s, 3H), 1.00 (t, J = 7.9 Hz, 2H), 0.67 (bs, 2H); MS (ESI) m / z 395 [M + H]+; SFC: RT 1 .89 min

[0552] EXAMPLE 1.47: SYNTHESIS OF (46)

[0553] Synthesis of compound 2

[0554] To a solution of compound 1 (500 mg, 2.16 mmol, 1 eq) in THF (5 mL) was added CDI (420.72 mg, 2.59 mmol, 1.2 eq). The mixture was stirred at 25 °C for 2 h. Then the mixture reaction poured into NH3. H2O (2.71 g, 21.62 mmol, 2.97 mL, 28% purity, 10 eq) and the resulting mixture was stirred at 25 °C for 16 h. To the mixture was added water (10 mL) and the resulting mixture was extracted with EtOAc (5 mL*3), the combined organic phase was washed with brine (5 mL*3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give compound 3 (490 mg, 2.13 mmol, 98.42% yield) as white solid.1H NMR: (400 MHz, CDCI3) δ = 6.67 - 6.17 (m, 2H), 4.33 (br d, J = 11 .4 Hz, 1 H), 4.01 - 3.86 (m, 3H), 3.58 (dt, J = 2.8, 1 1 .7 Hz, 1 H), 3.01 - 2.71 (m, 2H), 1 .47 (s, 9H).

[0555] Synthesis of compound 3

[0556] To a solution of compound 2 (490 mg, 2.13 mmol, 1 eq) in THF (5 mL) was added LAWESSON'S REAGENT (516.43 mg, 1 .28 mmol, 0.6 eq). The reaction mixture was stirred at 25 °C for 16 h. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1 , TLC (Petroleum ether : Ethyl acetate = 1 : 1 , Rf = 0.38) ) to give compound 3 (330 mg, 1 .34 mmol, 62.95% yield) as white solid. LCMS: RT = 0.452 min, m / z =

[0557] 191.1 (M + H -tBu)+; SFC: RT = 1.141 min

[0558] Synthesis of compound 5

[0559] A mixture of compound 3 (150 mg, 608.95 1 eq)μ amnodl, compound 4 (139.49 mg, 608.95 μmol 1, eq) in EtOH (2 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuum. Then HCI / EtOAc (3 mL) was added into the reaction mixture and the mixture was stirred at 25 °C for 2 h. Then the reaction mixture was concentrated in vacuum to give compound 5 (125 mg, 399.60 65.62μ%mo yli,eld, HCI) as yellow oil. LCMS: RT = 0.403 min, m / z = 277.2 (M+H)+.

[0560] Synthesis of (46)

[0561] To a solution of compound 5 (125 mg, 399.60 1 eq, HCμIm) o aln,d compound 6 (48.80 mg, 399.60 μm 6o1l, .00 μL, 1 eq) in DMF (1 mL) was added HOBt (64.79 mg, 479.52 pmol, 1 .2 eq), EDCI (91 .92 mg, 479.52 1 .2 eμqm)o aln, d DIEA (206.58 mg, 1 .60 mmol, 278.41 μL, 4 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep- HPLC(column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 55%- 85% B over 10 min) followed by lyophilization to give (46) (89.29 mg, 234.69 pmol, 58.73% yield, 100% purity) as off-white solid.1H NMR: (400 MHz, CDCI3) δ = 8.43 - 8.03 (m, 1 H), 7.95 (br s, 1 H), 7.54 - 7.41 (m, 5H), 7.31 (br t, J = 7.7 Hz, 1 H), 7.12 - 6.96 (m, 2H), 5.34 - 4.42 (m, 2H), 4.40-4.10 (m, 2H), 3.95 (s, 3H), 3.89 - 3.75 (m, 1 H), 3.54 - 3.11 (m, 2H); LCMS: RT = 0.578 min, m / z = 381 .3 (M+H)+; SFC: RT = 1 .338 min.

[0562] EXAMPLE 1.48: SYNTHESIS OF (48)

[0563] A mixture of compound 1 (20.16 mg, 159.84 1 eq), μ cmooml,pound 2 (50 mg, 159.84 pmol, 1 eq, HCI), HOBt (25.92 mg, 191.81 1.2 eqμ),m EoDl,CI (36.77 mg, 191.81 pmol, 1.2 eq) and DIEA (51 .65 mg, 399.60 69.6μ0m poLl,, 2.5 eq) in DMF (1 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 58%- 88% B over 10 min). (48) (32.35 mg, 84.14 pmol, 52.64% yield, 100% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 8.30 - 8.24 (m, 1 H), 7.98 - 7.93 (m, 1 H), 7.36 - 7.28 (m, 1 H), 7.10 (br t, J = 7.4 Hz, 1 H), 7.04 - 6.97 (m, 1 H), 5.02 - 4.62 (m, 2H), 4.47 - 4.06 (m, 2H), 4.00 - 3.92 (m, 3H), 3.81 - 3.70 (m, 1 H), 3.42 - 3.28 (m, 1 H), 3.02 - 2.89 (m, 1 H), 2.10 (s, 4H), 2.07 - 2.00 (m, 2H), 1 .22 (s, 3H); LCMS: RT = 0.601 min, m / z = 385.1 (M+H)+.

[0564] EXAMPLE 1.49: SYNTHESIS OF (49)

[0565] AcCI (710 mL, 9.985 mmol, 1.3 eq) was added to a solution of 3,5-difluorophenol (1.000 g, 7.686 mmol, 1 eq) and pyridine (935 mL, 11.56 mmol, 1.5 eq) in CH2CI2 (15 mL), and the solution was stirred at r.t. for 15 min. It was poured into NaHCOs (saturated aqueous solution, 50 mL) and it was extracted with CH2CI2 (2x30 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (20% EtOAc / hexanes) to give 3,5-difluorophenyl acetate (1.1 g, 83% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) δ 6.77-6.62 (m, 3H), 2.30 (s, 3H).

[0566] AlCb (852 mg, 6.389 mmol, 1 eq) was added to a solution of 3,5-difluorophenyl acetate (1.100 g, 6.39 mmol, 1 eq) in CICH2CH2CI (30 mL), and the reaction mixture was reacted at 80 °C for 20 h. It was cooled down to r.t., poured into H2O (150 mL) and it was extracted with EtOAc (2x100 mL). Combined organic layers were dried Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-5% EtOAc / hexanes) to give 1-(2,4-difluoro-6-hydroxyphenyl)ethan-1-one (675 mg, 61 % yield) as a yellow oil. 1 H NMR (300 MHz, CDCI3) δ 13.14 (bs, 1 H), 6.49 (d, J = 10.2 Hz, 1 H), 6.37 (m, 1 H), 2.66 (d, J = 7.2 Hz, 3H).

[0567] CS2CO3 (1 .902 g, 5.837 mmol, 1 .5 eq) and Mel (242 mL, 3.887 mmol, 1 eq) were added to a solution of 1 -(2,4-difluoro-6-hydroxyphenyl)ethan-1-one (670 mg, 3.892 mmol, 1 eq) in CH3CN (25 mL), and the suspension was stirred for 2.5 h. It was poured into H2O (100 mL) and it was extracted with EtOAc (2x50 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (5-8% EtOAc / hexanes) to give 1 -(2,4-difluoro-6-methoxyphenyl)ethan-1-one (228 mg, 31 % yield) as a white solid.1H NMR (300 MHz, CDCI3) δ 6.69-6.52 (m, 1 H), 6.49-6.34 (m, 1 H), 3.84 (s, 3H), 2.51 (s, 3H).

[0568] A suspension of 1-(2,4-difluoro-6-methoxyphenyl)ethan-1-one (225 mg, 1 .208 mmol, 1 eq) and copper (II) bromide (530 mg, 2.372 mmol, 1.96 eq) in a mixture of CHCI3 (10 mL) and EtOAc (10 mL) was refluxed for 4 h. It was cooled down to r.t. and it was filtered through a pad of celite, eluting the product with EtOAc (100 mL). Organic layer was washed with NH4CI (saturated aqueous solution, 100 mL), dried over Na2SO4 (anhydrous), filtered and concentrated, to give 2-bromo-1-(2,4-difluoro-6-methoxyphenyl)ethan-1-one (330 mg, quantitative yield) as a red oil. It was immediately submitted to next step.

[0569] A solution of 2-bromo-1-(2,4-difluoro-6-methoxyphenyl)ethan-1-one (320 mg, 1.207 mmol, 1 eq) and (R)-fe / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (295 mg, 1.197 mmol, 0.99 eq) in EtOH (5 mL) was refluxed for 2 h. It was cooled down to r.t. , HCI (4 M in dioxane, 2.00 mL, 8 mmol, 6.63 eq) was added and the solution was stirred at r.t. for 1 h. Volatiles were concentrated off and the residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes, then 5% MeOH / CH2Cl2 using NH3 as additive). It was repurified by flash chromatography [Column C18, Redisep Gold, 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 20% to 40%] to give (R)-2-(4-(2,4-difluoro-6- methoxyphenyl)thiazol-2-yl)morpholine (153 mg, 41 % yield) as a beige oil.1H NMR (300 MHz, CDCI3) δ 7.34 (s, 1 H), 6.59-6.46 (m, 2H), 4.87 (dd, J = 9.8, 2.8 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.86-3.73 (m, 1 H), 3.79 (s, 3H), 3.45 (dd, J = 12.4, 2.8 Hz, 1 H), 3.08-2.87 (m, 3H); MS (ESI) m / z 313 [M + H]+; SFC: RT 2.15 min.

[0570] HATU (200 mg, 0.525 mmol, 1 .1 eq) and DIPEA (250 mL, 1 .46 mmol, 3.04 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (50 mg, 0.48 mmol, 1 eq) and (R)-2-(4- (2,4-difluoro-6-methoxyphenyl)thiazol-2-yl)morpholine (150 mg, 0.48 mmol, 1 eq) in DMF (5 mL), and the mixture was stirred at r.t. for 1 h. It was poured into H2O (20 mL) and it was extracted with EtOAc (2x10 mL). Combined organic layers were washed with brine (2x10 mL), dried over Na3SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography [Column C18, Redisep Gold, 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 30% to 50%] to give (R)-(2-(4-(2,4-difluoro-6- methoxyphenyl)thiazol-2-yl)morpholino)(1 -methylcyclopropyl)methanone (156 mg, 82% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.40 (s, 1 H), 6.61-6.46 (m, 2H), 4.87-4.73 (m, 2H), 4.38-4.28 (m, 1 H), 4.18-4.07 (m, 1 H), 3.80 (s, 3H), 3.78-3.69 (m, 1 H), 3.25-3.07 (m, 2H), 1.35 (s, 3H), 1.04-0.83 (m, 2H), 0.71-0.54 (m, 2H); MS (ESI) m / z 395 [M + H]+; SFC: RT 2.09 min

[0571] EXAMPLE 1.50: SYNTHESIS OF (50)

[0572] Synthesis of compound 2

[0573] To a solution of compound 1 (800 mg, 7.61 mmol, 1 eq) and Na2COs (1.61 g, 15.22 mmol, 2 eq) in dioxane (15 mL) and H2O (5 mL) was added BOC2O (1 .99 g, 9.13 mmol, 2.10 mL, 1 .2 eq) dropwise, the mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (20 mL) and the resulting mixture was extracted with ethyl acetate (10 mL*3), the combined organic phase was discarded. The aqueous phase was acidified to pH = 2 - 3 with 1 N HCI and extracted with ethyl acetate (10 mL*3), the organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 2 (1.4 g, 6.82 mmol, 89.62% yield) as white solid.1H NMR: (400 MHz, DMSO-d6) δ = 6.69 (br t, J = 5.6 Hz, 1 H), 3.97 (dd, J = 4.8, 7.0 Hz, 1 H), 3.22 (td, J = 5.2, 13.5 Hz, 1 H), 3.06 (td, J = 6.6, 13.5 Hz, 1 H), 1.37 (s, 9H).

[0574] Synthesis of compound 3

[0575] To a solution of compound 2 (1 .4 g, 6.82 mmol, 1 eq) in THF (20 mL) was added CDI (2.21 g, 13.64 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed there was no compound 2 remained, then the mixture reaction was poured into NH3°H2O (8.54 g, 68.22 mmol, 9.38 mL, 28% purity, 10 eq) and the resulting mixture was stirred at 25 °C for 16 h. The §ixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL*3), the organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 3 (1 .4 g, crude) as white solid.1H NMR: (400 MHz, DMSO-d6) δ = 7.19 (br d, J = 14.3 Hz, 2H), 6.61 - 6.52 (m, 1 H), 5.54 (br d, J = 5.4 Hz, 1 H), 3.83 (td, J = 4.3, 8.4 Hz, 1 H), 3.28 - 3.23 (m, 1 H), 2.96 (ddd, J = 6.2, 7.8, 13.7 Hz, 1 H), 1 .37 (s, 9H).

[0576] Synthesis of compound 4

[0577] To a mixture of compound 3 (1 g, 4.90 mmol, 1 eq), NMM (544.80 mg, 5.39 mmol, 592.18 μL, 1.1 eq) and DMAP (59.82 mg, 489.66 0.1 eμq)m ionl, EtOAc (10 mL) was added AC2O (1.50 g, 14.69 mmol, 1 .38 mL, 3 eq), the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (5 mL), the organic phase was separated, washed with 1 N HCI (5 mL*2), saturated NaHCOs (5 mL*1) and brine (5 mL*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 4 (400 mg, 1 .62 mmol, 33.17% yield) as white solid.1H NMR: (400 MHz, DMSO-cfe) δ = 7.49 (br s, 1 H), 7.28 (br s, 1 H), 6.91 (br t, J = 5.8 Hz, 1 H), 4.87 (dd, J = 3.6, 8.5 Hz, 1 H), 3.32 (br d, J = 3.3 Hz, 1 H), 3.16 (ddd, J = 6.1 , 8.4, 14.2 Hz, 1 H), 2.06 (s, 3H), 1 .37 (s, 9H);_LCMS: RT = 0.475 min, m / z = 269.1 (M+Na)+.

[0578] Synthesis of compound 5

[0579] To a mixture of compound 4 (300 mg, 1.22 mmol, 1 eq) in toluene (5 mL) was added LAWESSON'S REAGENT (246.37 mg, 609.11 0.5 eqμ)m, tohle, mixture was stirred at 60 °C for 4 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1 , TLC (SiO2, Petroleum ether: Ethyl acetate = 1 : 1 , Rf = 0.36)) to give compound 5 (130 mg, 495.57 pmol, 40.68% yield) as yellow gum._LCMS: RT = 0.530 min, m / z = 285.1 (M+Na)+.

[0580] Synthesis of compound 7

[0581] A mixture of compound 5 (130 mg, 495.57 1 eq)μ amnodl, compound 6 (124.87 mg, 545.12 μmo 1l,.1 eq) in EtOH (2 mL) was stirred at 90 °C for 2 h. The mixture was concentrated in vacuum to give compound 7 (150 mg, crude) as yellow gum.

[0582] Synthesis of compound 8

[0583] To a mixture of compound 7 (150 mg, 513.08 1 eq) in MμemOoHl, (2 mL) was added HCI (187.07 mg, 513.08 1μ8m3o.4l,1 μL, 10% purity, 1 eq), the mixture was stirred at 25 °C for 16 h. LCMS showed 16% of compound 7 remained and 61 % of peak desired mass detected. Then the mixture was stirred at 40 °C for 4 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (HCI) -ACN]; gradient: 3%- 33% B over 10 min) followed by lyophilization to give compound 8 (100 mg, 348.70 67.96% yield, μ HmCoI)l, as white solid._LCMS: RT = 0.403 min, m / z = 251 .2 (M+H)+. Synthesis of compound 9

[0584] To a mixture of compound 8 (100 mg, 348.70 1 eq, HCI)μm anodl, DIEA (135.20 mg, 1.05 mmol, 182.21 μL, 3 eq) in DCM (1 mL) was added 2-chloroacetyl chloride (39.38 mg, 348.70 pmol, 27.77 μL, 1 eq) at 0 °C under N2, the mixture was stirred at 25 °C for 2 h. LCMS showed 40% of compound 8 remained and -56% of peak with desired mass. Then 2-chloroacetyl chloride (19.69 mg, 174.35 13μ.m89ol p, L, 0.5 eq) was added to the reaction mixture, the mixture was stirred at 25 °C for 1 h. LCMS showed 14% of compound 8 remained and -82% of peak with desired mass. Then 2-chloroacetyl chloride (7.88 mg, 69.74 5.55 μL, 0.2 eq) μmol, was added to the reaction mixture, the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL*3), the organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 9 (120 mg, crude) as yellow gum. LCMS: RT = 0.462 min, m / z = 327.0 (M+H)+.

[0585] Synthesis of compound 10

[0586] To a mixture of compound 9 (120 mg, 367.20 1 eq) in THμFm (o5l, mL) was added ABuOK (82.41 mg, 734.40 μ 2m eoql), , the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL*3), the organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 10 (58 mg, 199.77 54μ.m40o%l, yield) as yellow gum. LCMS: RT = 0.472 min, m / z = 313.1 (M+Na)+.

[0587] Synthesis of (50)

[0588] To a solution of compound 11 (19.99 mg, 158.44 2 eq) in DCμmMo (l0, .5 mL) was added (COCI)2(24.13 mg, 190.12 16μ.6m4o pl,L, 2.4 eq) and DMF (1.74 mg, 23.77 1 .83 μL, μmol, 0.3 eq) at 0 °C under N2 and the mixture was stirred at 25 °C for 15 min. The reaction mixture was diluted with toluene (1 mL) and concentrated in vacuum to give a solution A. To another solution of compound 10 (23 mg, 79.22 1 eq) inμ tmoolule, ne (1 mL) was added DIEA (20.48 mg, 158.44 μm 2o7l.,60 μL, 2 eq), CuCI (784.25 pg, 7.92 1 .89e- 1 μL, 0.μ1m eoql), and solution A, the mixture was stirred at 70 °C for 2 h under N2. LCMS showed compound 10 remained and -6% of peak with desired mass. To a solution of compound 11 (19.99 mg, 158.44 pmol, 2 eq) in DCM (0.5 mL) was added (COCI)2 (24.13 mg, 190.12 16.64 μL, 2.4 eμq)m aonl,d DMF (1.74 mg, 23.77 μm 1.o8l3, μL, 0.3 eq), the mixture was stirred at 25 °C for 15 min to give a solution B. To the previous reaction mixture was added DIEA (20.48 mg, 158.44 pmol, 27.60 μL, 2 eq), CuCI (784.25 pg, 7.92 1.8μ9meo-1l, μL, 0.1 eq) and solution B, the mixture was stirred at 70 °C for 2 h under N2. LCMS showed compound 10 remained and -13% of peak with desired mass. Then CuCI (0.1 eq) was added to the reaction mixture and the mixture was stirred at 70 °C for 4 h under N2. LCMS showed compound 10 remained and -12% of peak with desired mass. To a solution of compound 11 (19.99 mg, 158.44 2 eq) in DCM (0.5μmol, mL) was added (COCI)2(24.13 mg, 190.12 16.64 pμLm, 2o.4l, eq) and DMF (1.74 mg, 23.77 pmol, 1.83 μL, 0.3 eq), the mixture was stirred at 25 °C for 15 min to give a solution C. To the previous reaction mixture was added DIEA (20.48 mg, 158.44 27.60 μL, 2 μ emq)o, l, CuCI (784.25 pg, 7.92 μ 1m.8o9l,e-1 μL, 0.1 eq) and solution C, the mixture was stirred at 70 °C for 4 h under N2.

[0589] To a solution of compound 11 (13.04 mg, 103.33 2 eq) in DCμmMo (l0, .5 mL) was added (COCI)2(15.74 mg, 123.99 10μ.8m5o pl,L, 2.4 eq) and DMF (1.13 mg, 15.50 1 .19 μL, μmol, 0.3 eq) at 0 °C under N2and the mixture was stirred at 25 °C for 15 min. The reaction mixture was diluted with Toluene (1 mL) and concentrated in vacuum to give a solution A. To another solution of compound 10 (15 mg, 51 .66 1 eq) inμ Tmool.l, (1 mL) was added DIEA (13.35 mg, 103.33 μmo 1l,8.00 μL, 2 eq), CuCI (511.47 pg, 5.17 1.24e- 1 pLμ, m 0.o1l, eq) and solution A, the mixture was stirred at 70 °C for 4 h. LCMS showed compound 10 remained and ~6% of peak with desired mass. To a solution of compound 11 (13.04 mg, 103.33 2 eq) in DCM μmol, (0.5 mL) was added (COCI)2(15.74 mg, 123.99 10.85 pLμ,m 2o.4l, eq) and DMF (1.13 mg, 15.50 μmol 1, .19 μL, 0.3 eq), the mixture was stirred at 25 °C for 15 min to give a solution B. To the previous reaction mixture was added DIEA (13.35 mg, 103.33 18.00 μL, 2 eq),μmol, CuCI (511.47 pg, 5.17 μ 1.m24oel,-1 μL, 0.1 eq) and solution B, the mixture was stirred at 70 °C for 4 h under N2.

[0590] Two batch of above crude reaction mixture were combined and quenched with NH3«H2O (3 mL) and H2O (10 mL), the resulting mixture was extracted with ethyl acetate (5 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 63%- 93% B over 10 min) to give a brown gum. The brown gum was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50*1 Oum; mobile phase: [Hexane-EtOH]; gradient: 1 %- 20% B over 15 min) followed by concentration and lyophilization to give (50) (7.84 mg, 18.49 14.15% yield, 9μ4m%ol p, urity) as brown gum.1H NMR: (400 MHz, CDCI3) δ = 8.23 (dd, J = 1 .7, 7.8 Hz, 1 H), 8.00 (s, 1 H), 7.36 - 7.30 (m, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 5.22 (dd, J = 3.5, 9.3 Hz, 1 H), 4.58 - 4.40 (m, 3H), 4.01 - 3.91 (m, 4H), 2.35 (br s, 1 H), 2.06 - 2.00 (m, 2H), 1 .80 - 1 .75 (m, 2H), 1 .72 (br s, 1 H), 1 .69 (br s, 1 H), 1 .60 - 1 .57 (m, 2H); LCMS: RT = 0.600 min, m / z = 421 .1 (M+Na)+. SFC: RT = 2.478 min

[0591] EXAMPLE 1.51: SYNTHESIS OF (51)

[0592]

[0593] Methylmagnesium chloride (3 M in THF solution, 4.44 mL, 13.323 mmol, 1 eq) was added to a -10 °C cooled solution of benzo[d][1 ,3]dioxole-4-carbaldehyde (2.00 g, 13.321 mmol, 1 eq) in THF (20 mL). The solution was stirred at low temperature for 1 h and at r.t. for 1 h. It was poured into H2O (100 mL) and it was extracted with EtOAc (2x25 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (15-20% EtOAc / hexanes) to give 1 -(benzo[d][1 ,3]dioxol-4- yl)ethan-1-ol (2.05 g, 93% yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 6.92-6.66 (m, 3H), 5.95 (d, 2H), 4.99 (q, J = 6.5 Hz, 1 H), 1.52 (d, J = 6.5 Hz, 2H).

[0594] MnO2 (5.232 g, 54.163 mmol, 5 eq) was added to a solution of 1 -(benzo[d][1 ,3]dioxol-4- yl)ethan-1-ol (2.0 g, 12.035 mmol, 1 eq) in THF (20 mL). The suspension was stirred at r.t. for 4 h and at 50 °C for 3 h. It was filtered through a pad of celite, eluting with EtOAc (50 mL). Volatiles were concentrated off and the residue was purified by flash chromatography on SiO2 (5-20% EtOAc / hexanes) to give 1-(benzo[d][1 ,3]dioxol-4-yl)ethan-1-one (1.7 g, 86% yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 7.37 (d, J = 8.1 Hz, 1 H), 7.05-6.95 (m, 1 H), 6.94-6.80 (m, 1 H), 6.09 (s, 2H), 2.60 (s, 3H); MS (El) m / z 164 [M]

[0595] Copper (II) bromide (1.361 g, 6.093 mmol, 2 eq) was added to a solution of 1 - (benzo[d][1 ,3]dioxol-4-yl)ethan-1-one (500 mg, 3.045 mmol, 1 eq) in a mixture of EtOAc (6 mL) and CHCb (6 mL) and the suspension was refluxed for 24 h. It was cooled down to r.t., filtered through a pad of Celite, and product was eluted with EtOAc (45 mL) and THF (20 mL). Volatiles were concentrated off, to give crude 1 -(benzo[d][1 ,3]dioxol-4-yl)-2-bromoethan-1-one (735 mg, 99% yield) as a pale green solid. It was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.44 (d, J = 8.2 Hz, 1 H), 7.09-6.85 (m, 2H), 6.16-6.08 (m, 2H), 4.50 (s, 2H).

[0596] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (170 mg, 0.69 mmol, 1 eq) and 1 -(benzo[d][1 ,3]dioxol-4-yl)-2-bromoethan-1-one (390 mg, 1.042 mmol, 1.51 eq) in EtOH (15 mL) was refluxed for 2 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (10 mL) and TFA (530 mL, 6.921 mmol, 10.03 eq) was added. The reaction mixture was stirred at r.t. for 1 h, it was poured into NaHCOs (saturated aqueous solution, 40 mL) and it was extracted CH2CI2 (2x15 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (1-5% MeOH / CH2Cl2 using NH3 as additive) to give (R)-2-(4- (benzo[d][1 ,3]dioxol-4-yl)thiazol-2-yl)morpholine (66 mg, 33% yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 7.78 (s, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 6.94-6.73 (m, 2H), 6.08 (s, 2H), 4.92- 4.80 (m, 1 H), 4.06 (d, J = 11.4 Hz, 1 H), 3.88-3.71 (m, 1 H), 3.50 (d, J = 12.5 Hz, 1 H), 3.08-2.85 (m, 3H); MS (ESI) m / z 291 [M + H]+; SFC: RT 4.02 min

[0597] HATU (86 mg, 0.226 mmol, 1 .09 eq) and DIPEA (106 mL, 0.619 mmol, 3 eq) were added to a solution of bicyclo[2.1 .1]hexane-1 -carboxylic acid (27 mg, 0.203 mmol, 0.98 eq) and (R)-2- (4-(benzo[d][1 ,3]dioxol-4-yl)thiazol-2-yl)morpholine (60 mg, 0.206 mmol, 1 eq) in DMF (5 mL) and the solution was stirred at r.t. for 3 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was flash chromatographed on SiO2 (20-30% EtOAc / hexanes) to give (R)-(2-(4-(benzo[d][1 ,3]dioxol-4-yl)thiazol-2- yl)morpholino)(bicyclo[2.1 .1]hexan-1-yl)methanone (75 mg, 91 % yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.81 (s, 1 H), 7.68 (m, 1 H), 6.93 (t, J = 7.9 Hz, 1 H), 6.81 (d, J = 7.7 Hz, 1 H), 6.08 (s, 2H), 5.12-4.67 (m, 1 H), 4.52-3.98 (m, 2H), 3.82-3.67 (m, 1 H), 3.41-2.78 (m, 2H), 2.45 (s, 1 H), 1.98-1.75 (m, 6H), 1 .52-1.21 (m, 3H); MS (ESI) m / z 399 [M + H]+; SFC: RT 5.12 min

[0598] EXAMPLE 1.52: SYNTHESIS OF (53)

[0599] Synthesis of compound 2

[0600] To a solution of compound 1 (2 g, 9.29 mmol, 1 eq) in THF (25 mL) was added CDI (1 .81 g, 11.15 mmol, 1.2 eq). The mixture was stirred at 25 °C for 2 h. Then the mixture reaction poured into NH3. H2O (11.63 g, 92.92 mmol, 12.78 mL, 28% purity, 10 eq) and the mixture was stirred at 25 °C for 16 h. To the mixture was added water (80 mL) and extracted with EtOAc (25 mL*3), the combined organic phase was washed with brine (25 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (1.69 g, 7.89 mmol, 84.89% yield) as colorless oil.1H NMR: (400 MHz, CDCI3) δ = 5.67 (br s, 2H), 3.69 - 3.45 (m, 3H), 3.34 (br d, J = 7.3 Hz, 1 H), 2.97 - 2.88 (m, 1 H), 2.21 - 2.07 (m, 2H), 1 .46 (s, 9H).

[0601] Synthesis of compound 3-

[0602] To a solution of compound 2 (1.69 g, 7.89 mmol, 1 eq) in THF (15 mL) was added LAWESSON'S REAGENT (1 .91 g, 4.73 mmol, 0.6 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. Then the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to give compound 3 (1.36 g, 5.90 mmol, 74.86% yield) as yellow oil. LCMS: RT =0.501 min, m / z =131.1 (M+H-Boc)+; SFC: RT=1.104 min

[0603] Synthesis of compound 6

[0604] To a solution of compound 3 (300 mg, 1.30 mmol, 1 eq) in EtOH (4 mL) was added compound 4 (321.80 mg, 1.30 mmol, 1 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuum. Then added HCI / EtOAc (3 mL) was added and the resulting mixture was stirred at 25 °C for 2 h. Then the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm* 15um; mobile phase: [water (HCI) -ACN]; B%: 15%- 45%, 10 min) followed by lyophilization to give compound 6 (265 mg, 952.06 73.09% yield, HμCmIo sla, lt) as yellow gum. LCMS: RT =0.661 min, m / z =279.1 (M+H)+. SFC: RT=1 .865 min

[0605] Synthesis of (53)

[0606] To a solution of compound 6 (100 mg, 317.66 1 eq, HCμIm) o aln,d compound 7 (38.79 mg, 317.66 μm 4o8l,.49 μL, 1 eq) in DMF (1 mL) was added HOBt (51 .51 mg, 381 .19 pmol, 1 .2 eq) and EDCI (73.07 mg, 381 .19 1 .2 eμqm) o aln,d DIEA (164.22 mg, 1 .27 mmol, 221 .32 μL, 4 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by prep- HPLC(column: Unisil 3 - 100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 51 %- 81 %, 7 min) followed by lyophilization to give (53) (73.19 mg, 189.46 pmol, 59.64% yield, 99% purity) as yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.28 - 8.12 (m, 1 H), 7.76 (d, J = 19.1 Hz, 1 H), 7.59 - 7.51 (m, 2H), 7.42 (br s, 3H), 6.81 - 6.68 (m, 2H), 4.26 - 4.02 (m, 1 H), 3.98 - 3.91 (m, 4H), 3.91 - 3.85 (m, 1 H), 3.84 - 3.76 (m, 1 H), 3.76 - 3.56 (m, 1 H), 2.58 - 2.27 (m, 2H); LCMS: RT =0.868 min, m / z =383.2 (M+H)+; SFC: RT=2.503 min.

[0607] EXAMPLE 1.53: SYNTHESIS OF (54)

[0608] To a solution of compound 4 (80 mg, 291.57 1μm eqo)l, and 1 -(trifluoromethyl) cyclopropanecarboxylic acid (44.93 mg, 291.57 1 eq) in DμMmFol (,1 mL) was added DIEA (75.37 mg, 583.13 μ 1m0o1l.,57 μL, 2 eq), HOBt (47.28 mg, 349.88 1.2 eq) and EDμCmIol, (67.07 mg, 349.88 1μ .m2o elq, ). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (FA) -ACN]; B%: 52%-82%, 10 min), the eluent was concentrated and then freeze dried. To give (54) (46.34 mg, 111.77 μm 3o8l,.33% yield, 99% purity) as off white solid.1H NMR: (400 MHz, CDCb) 6 = 8.26 (d, J = 7.6 Hz, 1 H), 7.85 (s, 1 H), 7.31 (t, J = 7.9 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 4.78-4.71 (m, 1 H), 3.96 (s, 3H), 3.29 - 3.14 (m, 2H), 2.33 (br d, J = 12.0 Hz, 1 H), 2.00 - 1.87 (m, 2H), 1 .65 - 1.50 (m, 3H), 1.36 (s, 2H), 1.25 - 1.13 (m, 2H); LCMS: RT = 0.685 min, m / z = 411.3 (M+H)+.

[0609] EXAMPLE 1.54: SYNTHESIS OF (56)

[0610] Pd(OAc)2 (72 mg, 0.32 mmol, 0.1 eq) and EtsN (1.355 mL, 9.721 mmol, 3 eq) were added to a degassed solution of 1 -bromo-3-methyl-2-nitrobenzene (700 mg, 3.24 mmol, 1 eq), butyl vinyl ether (4.193 mL, 32.402 mmol, 10 eq) and dppp (267 mg, 0.647 mmol, 0.2 eq) in DMF (6 mL) and the mixture was reacted in a sealed tube at 120 °C for 18 h. It was cooled down to r.t. , poured into brine (20 mL) and extracted with EtOAc (2x15 mL). Combined organic layers were washed with brine (2x25 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (15% EtOAc / hexanes) to give 1-(1- butoxyvinyl)-3-methyl-2-nitrobenzene (760 mg, quantitative yield) as a yellow oil. MS (El) m / z 235 [M] HCI (10% aqueous solution, 5.0 mL) was added to a solution of 1 -(1-butoxyvinyl)-3-methyl- 2-nitrobenzene (750 mg, 3.187 mmol, 1 eq) in THF (5 mL) and the mixture was stirred at r.t. for 2 h. It was poured into NaHCOs (saturated aqueous solution, 50 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (10-20% EtOAc / hexanes) to give 1 -(3-methyl-2-nitrophenyl)ethan-1-one (250 mg, 44% yield) as a pale brown solid.1H NMR (300 MHz, CDCI3) δ 7.69-7.56 (m, 1 H), 7.48 (d, J = 4.5 Hz, 2H), 2.58 (s, 3H), 2.37 (s, 3H); MS (ESI) m / z 180 [M + H]+

[0611] Copper (II) bromide (623 mg, 2.79 mmol, 2 eq) was added to a solution of 1 -(3-methyl-2- nitrophenyl)ethan-1-one (250 mg, 1.395 mmol, 1 eq) in a mixture of EtOAc (6 mL) and CHCb (6 mL) and the suspension was refluxed for 18 h. It was cooled down to r.t., and it was filtered through a pad of Celite, eluting the product with EtOAc (30 mL) and THF (10 mL). Volatiles were concentrated off, to give crude 2-bromo-1-(3-methyl-2-nitrophenyl)ethan-1-one (364 mg, quantitative yield) as a green oil, which was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.65-7.48 (m, 3H), 4.34 (s, 2H), 2.44 (s, 3H).

[0612] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (290 mg, 1 .177 mmol, 1 eq) and 2-bromo-1-(3-methyl-2-nitrophenyl)ethan-1-one (364.6 mg, 1 .412 mmol, 1.2 eq) in EtOH (10 mL) was refluxed for 3.5 h. It was cooled down to r.t., HCI (4 M in dioxane, 2.9 mL, 11.60 mmol, 10 eq) was added and the mixture was stirred at r.t. for 2 h. The reaction was poured into NaHCOs (saturated aqueous solution, 20 mL) and it was extracted with EtOAc (3x25 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2 (2-10% MeOH / CH2Cb using NH3 as additive) to give (R)-2-(4-(3-methyl-2-nitrophenyl)thiazol-2- yl)morpholine (170 mg, 47% yield) as a brown oil.1H NMR (300 MHz, CDCI3) δ 7.60 (d, J = 7.8 Hz, 1 H), 7.48-7.36 (m, 2H), 7.35-7.27 (m, 1 H), 4.88-4.69 (m, 1 H), 4.18-3.64 (m, 2H), 3.55-3.34 (m, 1 H), 3.07-2.83 (m, 2H), 2.36 (s, 3H), 1.91 -1.61 (m, 2H); MS (ESI) m / z 306 [M + H]+; SFC: RT 3.14 min

[0613] HATU (232 mg, 0.61 mmol, 1.1 eq) and DIPEA (284 mL, 1.659 mmol, 3 eq) were added to a solution of bicyclo[2.1.1 ]hexane-1 -carboxylic acid (70 mg, 0.527 mmol, 1 eq) and (R)-2-(4-(3- methyl-2-nitrophenyl)thiazol-2-yl)morpholine (169 mg, 0.553 mmol, 1 eq) in DMF (4 mL) and the solution was stirred at r.t. for 3 h. It was poured into H2O (15 mL) and it was extracted with EtOAc (10 mL). Organic layer was washed with brine (3x10 mL), dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was purified by flash chromatography on SiO2(2-5% MeOH / CH2CI2) to give (R)-bicyclo[2.1.1]hexan-1-yl(2-(4-(3-methyl-2- nitrophenyl)thiazol-2-yl)morpholino)methanone (215 mg, 99% yield) as a pale brown solid.1H NMR (300 MHz, CDCI3) δ 7.55 (d, J = 7.9 Hz, 1 H), 7.49 (s, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 4.58 (dd, J = 46.2, 12.1 Hz, 2H), 4.18 (dd, J = 48.6, 12.6 Hz,2H), 3.82-3.68 (m, 1 H), 3.21-3.07 (m, 1 H), 2.98- 2.74 (m, 2H), 2.46 (s, 1 H), 2.37 (s, 3H), 2.05 -1.69 (m, 7H);

[0614] MS (ESI) mlz 414 [M + H]+; SFC: RT 4.93 min

[0615] Fe (204 mg, 3.64 mmol, 7 eq) was added to a solution of (R)-bicyclo[2.1 .1]hexan-1-yl(2-(4- (3-methyl-2-nitrophenyl)thiazol-2-yl)morpholino)methanone (215 mg, 0.519 mmol, 1 eq) in AcOH (10 mL). The reaction mixture was stirred at r.t. for 18 h and extra Fe (290 mg, 5,20 mmol, 10 eq) was added. It was warmed up to 40 °C and reacted for 15 h and finally at 60 °C for 3 days. The reaction was cooled down to r.t., poured into Na2COs (1 M aqueous solution, 120 mL) and it was extracted with EtOAc (3x20 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered, and concentrated. Crude residue was flash chromatographed on SiO2 (50-70% EtOAc / hexanes) to give (R)-(2-(4-(2-amino-3-methylphenyl)thiazol-2- yl)morpholino)(bicyclo[2.1 .1]hexan-1-yl)methanone. It was purified by chiral-SFC [Column: ChiralPak IC PREP 5 pm, 20 x 250 mm. 35% MeOH in CO2] to furnish enantiomerically pure (R)-(2-(4-(2-amino-3-methylphenyl)thiazol-2-yl)morpholino)(bicyclo [2.1 .1]hexan-1- yl)methanone (74 mg, 37% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCh) 5 7.54-7.33 (m, 2H), 7.07 (d, J = 7.4 Hz, 1 H), 6.70 (t, J = 7.7 Hz, 1 H), 5.05-4.37 (m, 2H), 4.29-

[0616] 3.88 (m, 2H), 3.86-3.56 (m, 1 H), 3.45-2.69 (m, 2H), 2.50-2.31 (m, 1 H), 2.22 (s, 3H), 1 .97-1.66 (m, 5H), 1 .51-1 .34 (m, 2H); MS (ESI) m / z 384 [M + H]+; SFC: RT 7.42 min.

[0617] EXAMPLE 1.55: SYNTHESIS OF (57) Synthesis of compound 2

[0618] To a mixture of compound 2 (3 g, 13.89 mmol, 1 eq) in DMF (30 mL) was added K2CO3 (3.84 g, 27.78 mmol, 2 eq) at 0 °C under N2, the mixture was stirred at 0 °C for 15 min. Then Mel (2.96 g, 20.83 mmol, 1 .30 mL, 1 .5 eq) was added to the mixture dropwise at 0 °C and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with H2O (150 mL) and extracted with ethyl acetate (50 mL*3), the combined organic phase was collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 2 (2.7 g, 11.74 mmol, 84.51 % yield) as black solid.1H NMR: (400 MHz, CDCI3) δ = 7.77 (d, J = 6.9 Hz, 1 H), 6.75 (d, J = 10.5 Hz, 1 H), 3.97 (s, 3H).

[0619] Synthesis of compound 4

[0620] To a mixture of compound 2 (2.7 g, 1 1 .74 mmol, 1 eq) and compound 3 (5.83 g, 16.14 mmol, 5.45 mL, 1.38 eq) in dioxane (30 mL) was added Pd(PPhs)4 (1.36 g, 1.17 mmol, 0.1 eq) under N2, the mixture was stirred at 90 °C for 16 h under N2. The reaction mixture was quenched by adding KF aqueous solution (50 mL) and the resulting mixture was stirred at 25 °C for 2 h. Then the mixture was extracted with ethyl acetate (20 mL * 3), the combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound 4 (2.6 g, crude) as yellow gum.

[0621] Synthesis of compound 5

[0622] To a mixture of compound 4 (2.6 g, 11 .75 mmol, 1 eq) in THF (30 mL) and H2O (15 mL) was added NBS (4.18 g, 23.51 mmol, 2 eq) in portions at 0 °C, the mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL) and the resulting mixture was washed with H2O (15 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1 , TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1 , Rf = 0.24)) to give compound 5 (2 g, 7.35 mmol, 62.55% yield) as white solid.1H NMR: (400 MHz, CDCI3) δ = 8.17 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 10.5 Hz, 1 H), 4.49 (s, 2H), 4.05 (s, 3H).

[0623] Synthesis of compound 7

[0624] A mixture of compound 5 (1 g, 3.68 mmol, 1.13 eq) and compound 6 (800 mg, 3.25 mmol, 1 eq) in EtOH (20 mL) was stirred at 90 °C for 2 h. The reaction mixture was filtered, and the filter cake was collected, dried in vacuum to give compound 7 (1 g, 3.13 mmol, 96.42% yield) as white solid. LCMS: RT = 0.417 min, m / z = 320.0 (M+H)+.

[0625] Synthesis of compound (57)

[0626] To a mixture of compound 7 (1 g, 3.13 mmol, 1 eq) and compound 8 (313.49 mg, 3.13 mmol, 1 eq) in pyridine (10 mL) was added EDCI (900.42 mg, 4.70 mmol, 1.5 eq), the mixture was stirred at 25 °C for 2 h. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (30 mL*3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with DMF (10 mL) at 25 °C for 30 min, then the mixture was filtered and the filter cake was collected, dried by concentration to give a yellow solid, the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm* 15um; mobile phase: [water (FA) -ACN]; gradient: 48%- 78% B over 15 min), the eluent was combined with the above yellow solid and lyophilizated to give (57) a yellow solid (813.08 mg, 2.03 mmol, 64.76% yield, 100% purity).1H NMR: (400 MHz, CDCI3) δ = 8.56 (d, J = 7.8 Hz, 1 H), 7.92 (s, 1 H), 6.83 (d, J = 10.9 Hz, 1 H), 4.90 - 4.73 (m, 2H), 4.37 (br d, J = 13.3 Hz, 1 H), 4.15 (dd, J = 2.3, 11 .7 Hz, 1 H), 4.04 (s, 3H), 3.77 (dt, J = 2.8, 11 .7 Hz, 1 H), 3.34 - 3.01 (m, 2H), 1 .40 (s, 3H), 1 .07 - 0.94 (m, 2H), 0.75 - 0.64 (m, 2H). LCMS: RT = 0.542 min, m / z = 402.1 (M+H)+. SFC: RT = 1 .382 min.

[0627] EXAMPLE 1.56: SYNTHESIS OF (58)

[0628] Synthesis of compound 2

[0629] To a solution of compound 1 (4.5 g, 31.22 mmol, 1 eq) in THF (50 mL) was added LDA (2 M, 16.39 mL, 1 .05 eq) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. Tert-butyl 2-chloroacetate (4.94 g, 32.79 mmol, 4.69 mL, 1 .05 eq) in THF (20 mL) was added and the mixture was stirred at 25 °C for 1.5 h under N2. The mixture was quenched with saturated NH4CI (200 mL) under N2, the resulting mixture was extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1 , 3 / 1) to give compound 2 (1 .8 g, 8.16 mmol, 26.13% yield) as yellow oil.1H NMR: (400 MHz, CDCh) 5 = 7.26 - 7.18 (m, 1 H), 6.67 (td, J = 2.4, 9.2 Hz, 1 H), 4.53 (s, 2H), 3.86 (s, 3H).

[0630] Synthesis of compound 4 To a solution of compound 2 (200 mg, 906.62 1 eq) iμnm EotlO, H (4 mL) was added compound 3 (223.32 mg, 906.62 1 eqμ)m. Tolh,e mixture was stirred at 80 °C for 37 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 4 (419 mg, crude) was obtained as brown oil. LCMS: RT = 0.589 min, m / z = 413.1 (M+H)+.

[0631] Synthesis of compound 5

[0632] To the mixture of compound 4 (419 mg, 1 .02 mmol, 1 eq) in DCM (5 mL) was added HCI / EtOAc (2 M, 2 mL, 3.94 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 5 (410 mg, crude, HCI) was obtained as brown oil. LCMS: RT = 0.404 min, m / z = 313.0 (M+H)+.

[0633] Synthesis of (58)

[0634] To a solution of compound 5 (200 mg, 573.40 1 eq, HμCmI)ol i,n pyridine (5 mL) was added EDCI (219.84 mg, 1.15 mmol, 2 eq) and compound 6 (114.81 mg, 1.15 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with H2O (15 mL) and extracted with Ethyl acetate (15 mL *3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3 - 100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; gradient: 40%- 70% B over 10 min). HNMR showed the purity was not enough. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250*50*1 Oum; mobile phase: [Hexane-EtOH]; gradient: 1 %- 35% B over 15 min). Compound (58) (35.8 mg, 90.76 1μ5m.8o3l%, yield, 100% purity) was obtained as a yellow gum.1H NMR: (400 MHz, CDCI3) 6 = 7.51 (s, 1 H), 7.14 (q, J = 9.3 Hz, 1 H), 6.71 - 6.65 (m, 1 H), 4.86 - 4.76 (m, 2H), 4.35 (br d, J = 13.5 Hz, 1 H), 4.18 - 4.11 (m, 1 H), 3.81 (s, 3H), 3.76 (dt, J = 2.8, 11.7 Hz, 1 H), 3.20-3.16 (m, 2H), 1.36 (s, 3H), 1.04 - 0.92 (m, 2H), 0.69 - 0.59 (m, 2H). LCMS: RT = 0.529 min, m / z = 395.1 (M+H)+. SFC: RT=0.787 min.

[0635] EXAMPLE 1.57: SYNTHESIS OF (59) Synthesis of compound 2

[0636] To a solution of compound 1 (280 mg, 709.88 1 eq) in DμCmMol (,5 mL) was added BBrs (2 M, 1 .67 mL, 4.71 eq) under 0 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with Ethyl acetate (20 mL). The resulting mixture was added into the MeOH (20 mL) dropwise with stirring under 0 °C. The resulting mixture was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1 , 3 / 1 . TLC (Petroleum ether: Ethyl acetate = 0: 1); Rf = 0.7)) to give compound 2 (180 mg, 473.18 66.66μ%m yoiel,ld) as colorless oil. LCMS: RT =0.568 min, m / z =381.1 (M+H)+.

[0637] Synthesis of (59)

[0638] To a solution of compound 3 (45.40 mg, 283.91 1.2 eq) inμm DMolF, (1 mL) was added K2CO3 (65.40 mg, 473.18 2μ emqo)l, and compound 2 (90 mg, 236.59 1 eq). The μmol, mixture was stirred at 60 °C for 16 h. LCMS showed compound 2 was remained and then compound 3 (45.40 mg, 283.91 1.2μm eqo)l, was added into the mixture and the resulting mixture was stirred at 60 °C for another 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and H2O (30 mL). The resulting mixture was extracted with ethyl acetate (20 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 35%-65% B over 10 min) to give yellow solid. LCMS showed the solid was impurity, the solid was purified by prep-TLC (Petroleum ether: Ethyl acetate = 1 : 1) to give yellow oil. The oil was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 40%-70% B over 10 min) to give (59) (2.89 mg, 7.01 2.96% yieμldm)o al,s yellow gum.1H NMR: (400 MHz, CD3OD) δ = 7.74 (s, 1 H), 7.35 (q, J = 9.3 Hz, 1 H), 7.11 (br d, J = 8.8 Hz, 1 H), 5.80 - 5.59 (m, 2H), 4.88-4.80 (m, 1 H), 4.78 (br d, J = 13.4 Hz, 1 H), 4.32 (br d, J = 13.6 Hz, 1 H), 4.14 (dd, J = 2.3, 1 1 .9 Hz, 1 H), 3.83 - 3.76 (m, 1 H), 3.28 - 3.04 (m, 2H), 1 .35 (s, 3H), 1 .00 - 0.91 (m, 2H), 0.71 - 0.63 (m, 2H). LCMS: RT =0.534 min, m / z =413.1 (M+H)+.

[0639] EXAMPLE 1.58: SYNTHESIS OF (60)

[0640]

[0641] AcCI (700 JJ.L, 9.844 mmol, 1.28 eq) was added to a solution of 3,4-difluorophenol (1 g, 7.686 mmol, 1 eq) and EtaN (1.4 mL, 10.044 mmol, 1.31 eq) in CH2CI2 (15 mL) and the mixture was stirred at r.t. for 21 h. It was diluted with CH2CI2 (30 mL) and it was washed with NaHCOs (1 M in H2O, 20 mL), brine (20 mL), HCI (5% aqueous solution, 2x15 mL), NaHCOs (1 M in H2O, 20 mL) and brine (20 mL). Organic layer was dried over Na2SO4 (anhydrous), filtered, and concentrated to give 3,4-difluorophenyl acetate (1.1 g, 83% yield) as a colourless oil.1H NMR (300 MHz, CDCI3) 6 7.24-7.07 (m, 1 H), 7.06-6.93 (m, 1 H), 6.90-6.79 (m, 1 H), 2.29 (s, 3H).

[0642] AlCh (852 mg, 6.389 mmol, 1 eq) was added to a solution of 3,4-difluorophenyl acetate (1.100 g, 6.39 mmol, 1 eq) in 1 ,2-dichlorobenzene (18 mL) and the mixture was reacted at 100 °C for 22 h. It was cooled down to r.t., poured into H2O (30 mL) and it was extracted with EtOAc (2x20 mL). Combined organic layers were washed with brine (30 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash on SiO2 (0-10% EtOAc / hexanes) to give 1-(4,5-difluoro-2-hydroxyphenyl)ethan-1-one (430 mg, 39% yield) as a yellow solid.1H NMR (300 MHz, DMSO-d6) 6 7.96 (dd, J = 11.5, 9.3 Hz, 1 H), 7.14 - 6.96 (m, 1 H), 2.62 (s, 3H).

[0643] A solution of KOH (1 .600 g, 85%, 24.24 mmol, 9.93 eq) in H2O (15 mL) was added to a - 20 °C cooled solution of 1-(4,5-difluoro-2-hydroxyphenyl)ethan-1-one (420 mg, 2.44 mmol, 1 eq) in CH3CN (15 mL). Diethyl (bromodifluoromethyl)phosphonate (2.200 g, 8.239 mmol, 3.38 eq) was added and the solution was vigorously stirred at r.t. for 15 min and at reflux for 10 h. It was cooled down to r.t., poured into brine (100 mL) and extracted with EtOAc (40 mL). Organic layer was washed with brine (20 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (5% EtOAc / hexanes) to give 1- (2-(difluoromethoxy)-4,5-difluorophenyl)ethan-1-one (273 mg, 50% yield) as a colorless oil.1H NMR (300 MHz, CDCI3) δ 7.67 (dd, J = 10.5, 8.9 Hz, 1 H), 7.08 (dd, J = 10.3, 6.3 Hz, 1 H), 6.58 (t, J = 72.6 Hz, 1 H), 2.61 (s, 3H). MS (El) mlz 222 [M],

[0644] A suspension of copper (II) bromide (460 mg, 2.059 mmol, 1.75 eq) and 1 -(2- (difluoromethoxy)-4,5-difluorophenyl)ethan-1-one (261 mg, 1.174 mmol, 1 eq) in a mixture of EtOAc (6 mL) and CHCb (6 mL) was refluxed for 18 h. It was cooled down to r.t. , filtered through a pad of Celite and product was eluted with EtOAc (2x10 mL) and THF (2x10 mL). Volatiles were concentrated off, to give 2-bromo-1-(2-(difluoromethoxy)-4,5-difluorophenyl)ethan-1-one (460 mg, > theoretical) as a yellow oil. It was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.73 (dd, J = 10.2, 8.7 Hz, 1 H), 7.11 (dd, J = 10.2, 6.2 Hz, 1 H), 6.66 (t, J = 72.6 Hz, 1 H), 4.46 (s, 2H).

[0645] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (220 mg, 0.893 mmol, 1 eq) and 2-bromo-1-(2-(difluoromethoxy)-4,5-difluorophenyl)ethan-1-one (crude from previous step, 1 .175 mmol, 1 .32 eq) in EtOH (10 mL) was refluxed for 2 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (15 mL), TFA (1 .4 mL, 18.282 mmol, 20.47 eq) was added and the reaction mixture was stirred at r.t. for 1 h. Volatiles were concentrated off and the crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes, then 5% MeOH / CH2Cb using NH3 as additive) to give (R)-2-(4-(2- (difluoromethoxy)-4,5-difluorophenyl)thiazol-2-yl)morpholine (326 mg, > theoretical) as a beige solid.1H NMR (300 MHz, CDCI3) δ 8.03 (dd, J = 11 .5, 9.0 Hz, 1 H), 7.85 (s, 1 H), 7.07 (dd, J = 10.5, 6.7 Hz, 1 H), 6.49 (t, J = 73.9 Hz, 1 H), 5.21 (d, J = 10.2 Hz, 1 H), 4.29-4.11 (m, 2H), 3.92- 3.81 (m, 1 H), 3.37-3.13 (m, 4H). MS (ESI) m / z 349 [M + H]+

[0646] HATU (408 mg, 1.073 mmol, 1.2 eq) and DIPEA (460 mL, 2.687 mmol, 3.01 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (108 mg, 1.024 mmol, 1.15 eq) and (R)-2-(4-(2-(difluoromethoxy)-4,5-difluorophenyl)thiazol-2-yl)morpholine (311 mg, 0.892 mmol, 1 eq) in DMF (6 mL) and the mixture was stirred at r.t. for 18 h. It was poured into H2O (30 mL) and extracted with EtOAc (20 mL). Organic layer was washed with brine (2x20 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 50% to 70%] to give (60) (258 mg, 67% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.07 (dd, J = 11 .5, 9.0 Hz, 1 H), 7.84 (s, 1 H), 7.09 (dd, J = 10.4, 6.7 Hz, 1 H), 6.51 (t, J = 73.5 Hz, 1 H), 4.89-4.71 (m, 2H), 4.36 (d, J = 13.6 Hz, 1 H), 4.18-4.08 (m, 1 H), 3.76 (td, J = 11 .5, 2.7 Hz, 1 H), 3.15 (m, 2H), 1 .38 (s, 3H), 0.98 (m, 2H), 0.66 (m, 2H). MS (ESI) mlz 431 [M + H]+.

[0647] EXAMPLE 1.59: SYNTHESIS OF (61)

[0648] A solution of KOH (85%, 3.500 g, 53.025 mmol, 10 eq) in H2O (25 mL) was added to a solution of 1-(4-chloro-2-fluoro-6-hydroxyphenyl)ethanone (1.000 g, 5.302 mmol, 1 eq) in CH3CN (25 mL). The mixture was cooled down to -20 °C and diethyl (bromodifluoromethyl)phosphonate (3.400 g, 12.733 mmol, 2.4 eq) was added. The solution was vigorously stirred at low temperature for 15 min and at r.t. for 90 min. It was poured into brine (100 mL) and extracted with EtOAc (80 mL). Organic layer was washed with brine (2x40 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (0-10% EtOAc / hexanes) to give 1-(4-chloro-2-(difluoromethoxy)- 6-fluorophenyl)ethan-1-one (1 .2 g, 95% yield) as a colourless oil.1H NMR (300 MHz, CDCh) 5 7.13-7.03 (m, 2H), 6.54 (t, J = 73.8 Hz, 1 H), 2.57 (s, 3H).

[0649] A suspension of copper (II) bromide (950 mg, 4.253 mmol, 2.03 eq) and 1 -(4-chloro-2- (difluoromethoxy)-6-fluorophenyl)ethan-1-one (500 mg, 2.095 mmol, 1 eq) in a mixture of EtOAc (15 mL) and CHCh (15 mL) was refluxed for 4 h. It was cooled down to r.t., filtered through a pad of Celite and product was eluted with EtOAc (80 mL). Filtrate was washed with NH4CI (saturated aqueous solution, 50 mL) and brine (50 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to give 2-bromo-1-(4-chloro-2-(difluoromethoxy)-6- fluorophenyl)ethan-1-one (580 mg, 87% yield) as an amber oil.1H NMR (300 MHz, CDCh) 5 7.17-7.03 (m, 2H), 6.55 (t, J = 72.1 Hz, 1 H), 4.31 (s, 2H).

[0650] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (250 mg, 1.014 mmol, 1 eq) and 2-bromo-1-(4-chloro-2-(difluoromethoxy)-6-fluorophenyl)ethan-1-one (385 mg, 1 .212 mmol, 1.19 eq) in EtOH (15 mL) was refluxed for 2 h and volatiles were concentrated off. The residue was dissolved in CH2CI2 (15 mL), TFA (1.00 mL, 13.058 mmol, 12.87 eq) was added and the mixture was stirred at r.t. for 1 h. Volatiles were concentrated off and the residue was poured into NaHCOs (saturated aqueous solution, 100 mL) and extracted with EtOAc (2x50 mL). Combined organic layers were washed with brine (50 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (5-10% MeOH / CH2Cl2) to give (R)-2-(4-(4-chloro-2-(difluoromethoxy)-6-fluorophenyl)thiazol-2- yl)morpholine (220 mg, 59% yield) as an orange solid.1H NMR (300 MHz, CDCI3) δ 7.46 (d, J = 1.6 Hz, 1 H), 7.16-7.06 (m, 2H), 6.55 (t, J = 74.3 Hz, 1 H), 4.85 (dd, J = 9.7, 2.9 Hz, 1 H), 4.05 (dt, J = 11.5, 2.7 Hz, 1 H), 3.82 (td, J = 10.9, 3.4 Hz, 1 H), 3.45 (dd, J = 12.6, 2.9 Hz, 1 H), 3.08- 2.87 (m, 3H). MS (ESI) m / z 365 / 367 [M + H]+.

[0651] HATU (240 mg, 0.631 mmol, 1.1 eq) and DIPEA (300 mL, 1.752 mmol, 3.04 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (67 mg, 0.635 mmol, 1.1 eq) and (R)-2-(4-(4-chloro-2-(difluoromethoxy)-6-fluorophenyl)thiazol-2-yl)morpholine (210 mg, 0.575 mmol, 1 eq) in DMF (6 mL) and the mixture was stirred at r.t. for 3 h. It was poured into H2O (20 mL) and extracted with EtOAc (15 mL). Organic layer was washed with brine (2x15 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified flash chromatography [Column C18 Gold 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 50% to 70%] to give (61) (148 mg, 58% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) 5 7.52 (d, J = 1.8 Hz, 1 H), 7.17-7.08 (m, 2H), 6.62 (t, J = 74.5 Hz, 1 H), 4.89- 4.66 (m, 2H), 4.37 (d, J = 13.5 Hz, 1 H), 4.13 (d, J = 8.5 Hz, 1 H), 3.86-3.65 (m, 1 H), 3.27-2.97 (m, 2H), 1.35 (s, 3H), 1.08-0.87 (m, 2H), 0.71-0.56 (m, 2H).

[0652] EXAMPLE 1.60: SYNTHESIS OF (62)

[0653] A solution of KOH (85%, 3.000 g, 45.45 mmol, 8.88 eq in H2O (15 mL) was added to a solution of 4-chloro-3-fluorophenol (750 mg, 5.117 mmol, 1 eq) in CH3CN (20 mL). The mixture was cooled down to -20 °C and diethyl (bromodifluoromethyl)phosphonate (3.400 g, 12.733 mmol, 2.49 eq) was added. The mixture was vigorously stirred at low temperature for 10 min and at r.t. for 1 h. It was poured into brine (100 mL) and it was extracted with EtOAc (2x40 mL). Combined organic layers were washed with NaOH (10% aqueous solution, 20 mL) and brine (20 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (5% EtOAc / hexanes) to give 1 -chloro-4- (difluoromethoxy)-2-fluorobenzene (750 mg, 75% yield) as a colourless oil.1H NMR (300 MHz, CDCI3) δ 7.38 (t, J = 8.4 Hz, 1 H), 7.03-6.86 (m, 2H), 6.49 (t, J = 73.0 Hz, 1 H).

[0654] A solution of 1-chloro-4-(difluoromethoxy)-2-fluorobenzene (1.400 g, 7.122 mmol, 1 eq) was added to a -78 °C cooled solution of LDA [freshly prepared from n-BuLi (3.6 mL, 2.5 M in hexanes, 9 mmol, 1.26 eq) and DIPA (1.4 mL, 9.919 mmol, 1.39 eq)] in THF (20 mL). It was stirred at low temperature for 15 min and DMF (1.2 mL, 15.497 mmol, 2.18 eq) was added. The reaction mixture was stirred at low temperature for 15 min and then poured into brine (100 mL) and pH was adjusted to about 3-4. Compound was extracted with EtOAc (60 mL) and organic layer was washed with brine (2x30 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (5-20% EtOAc / hexanes) to give 3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde (540 mg, 34% yield) as an orange oil.1H NMR (300 MHz, CDCI3) δ 10.38 (d, J = 1.2 Hz, 1 H), 7.65 (m, 1 H), 7.18-7.01 (m, 1 H), 6.65 (t, J = 72.5 Hz, 1 H).

[0655] MeMgCI (850 mL, 3 M in THF solution, 2.55 mmol, 1 .06 eq) was added to a -60 °C cooled solution of 3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde (540 mg, 2.404 mmol, 1 eq) in THF (10 mL). The mixture was reacted at low temperature for 30 min and at r.t. for 1 h. It was poured into H2O (50 mL) and extracted with EtOAc (2x25 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (10% EtOAc / hexanes) to give 1 -(3-chloro-6-(difluoromethoxy)-2- fluorophenyl)ethan-1-ol (480 mg, 83% yield) as a yellow oil.1H NMR (300 MHz, CDCb) 6 7.39- 7.26 (m, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 6.54 (t, J = 73.1 Hz, 1 H), 5.40-5.17 (m, 1 H), 1.62 (d, J = 6.8 Hz, 3H).

[0656] DMP (1.000 g, 2.357 mmol, 1.21 eq) was added to a solution of 1 -(3-chloro-6- (difluoromethoxy)-2-fluorophenyl)ethan-1-ol (470 mg, 1.953 mmol, 1 eq) in CH2CI2 (10 mL) and the mixture was stirred at r.t. for 3 h. It was poured into NaHCOs (saturated aqueous solution, 30 mL) and it was extracted with CH2CI2 (2x20 mL). Combined organic layers were washed with brine (40 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography on SiO2 (5% EtOAc / hexanes) to give 1 -(3-chloro-6- (difluoromethoxy)-2-fluorophenyl)ethan-1-one (427 mg, 92% yield) as a brown oil.1H NMR (300 MHz, CDCI3) δ 7.45 (t, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H), 6.51 (t, J = 73.1 Hz, 1 H), 2.58 (s, 3H). A suspension of copper (II) bromide (700 mg, 3.134 mmol, 1.61 eq) and 1-(3-chloro-6- (difluoromethoxy)-2-fluorophenyl)ethan-1-one (465 mg, 1 .948 mmol, 1 eq) in a mixture of CHCh (10 mL) and EtOAc (10 mL) was refluxed for 18 h. It was cooled down to r.t., and it was filtered through a pad of Celite eluting product with EtOAc (40 mL). The organic layer was washed with NH4CI (saturated aqueous solution, 50 mL), dried over Na2SO4 (anhydrous), filtered and concentrated to give 2-bromo-1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (665 mg, > theoretical) as an orange oil. It was submitted to next step without purification, considering it was 93% w / w pure.1H NMR (300 MHz, CDCI3) δ 7.61-7.45 (m, 1 H), 7.05 (t, J = 8.3 Hz, 1 H), 6.51 (t, J = 73.1 Hz, 1 H), 5.29 (s, 2H).

[0657] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (210 mg, 0.852 mmol, 1 eq) and 2-bromo-1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)ethan-1-one (378 mg, 93% w / w, 1.105 mmol, 1.3 eq) in EtOH (10 mL) was refluxed for 3 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (10 mL), TFA (660 mL, 8.618 mmol, 10.11 eq) was added and the reaction mixture was stirred at r.t. for 1 h. Additional TFA (300 mL, 3.917 mmol, 4.6 eq) was added and the mixture was stirred at r.t. for 30 min. Volatiles were concentrated off and the crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes, then 2-5% MeOH / CH2Cl2 using NH3 as additive) to give (R)-2-(4-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)thiazol-2-yl)morpholine (126 mg, 41 % yield) as a beige solid.1H NMR (300 MHz, CDCI3) δ 7.52 (s, 1 H), 7.47-7.36 (m, 1 H), 7.10-7.01 (m, 1 H), 6.53 (t, J = 74.4 Hz, 1 H), 4.92 (dd, J = 9.7, 2.8 Hz, 1 H), 4.16-4.02 (m, 1 H), 3.88 (m, 1 H), 3.52 (m, 1 H), 3.13-2.93 (m, 4H). MS (ESI) mlz 365 / 367 [M + H]+.

[0658] HATU (147 mg, 0.386 mmol, 1.21 eq) and DIPEA (164 mL, 0.958 mmol, 2.99 eq) were added to a solution of 1 -methylcyclopropane-1 -carboxylic acid (41 mg, 0.389 mmol, 1.21 eq) and (R)-2-(4-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)thiazol-2-yl)morpholine (117 mg, 0.32 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (10 mL) and extracted with EtOAc (5 mL). Organic layer was washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 50g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 45% to 65%] to give (62) (98 mg, 68% yield) as a beige solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 7.55 (s, 1 H), 7.43 (dd, J = 8.9, 7.9 Hz, 1 H), 7.12-7.02 (m, 1 H), 6.60 (t, J = 74.8 Hz, 1 H), 4.87-4.73 (m, 2H), 4.38 (d, J = 13.5 Hz, 1 H), 4.19-4.08 (m, 1 H), 3.75 (m, 1 H), 3.15 (m, 2H), 1 .35 (s, 3H), 1.06-0.86 (m, 2H), 0.71-0.56 (m, 2H). MS (ESI) m / z 447 / 449 [M + H]+.

[0659] EXAMPLE 1.61: SYNTHESIS OF (63)

[0660] To a solution of compound 2 (41 .15 mg, 283.91 17.67 μLμ,m 1o .2l, eq) in DMF (1 mL) was added K2CO3 (65.40 mg, 473.18 2 eq) μ amndol c, ompound 1 (90 mg, 236.59 pmol, 1 eq). The mixture was stirred at 60 °C for 16 h. LCMS showed compound 1 remained. The compound 2 (41 .15 mg, 283.91 17.6μ7m μoLl,, 1 .2 eq) was added into the mixture and stirred at 60 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 40%-60% B over 10 min) to give (63) (35.97 mg, 90.50 38.25% yieμldm, o 1l0, 0% purity) as off-white solid.1H NMR: (400 MHz, CDCI3) 6 = 7.51 (s, 1 H), 7.14 (q, J = 9.3 Hz, 1 H), 6.70 - 6.65 (m, 1 H), 4.86 - 4.75 (m, 2H), 4.36 (br d, J = 13.7 Hz, 1 H), 4.14 (dd, J = 2.6, 11.7 Hz, 1 H), 3.76 (dt, J = 2.6, 11 .7 Hz, 1 H), 3.28 - 3.09 (m, 2H), 1 .36 (s, 3H), 1 .03 - 0.91 (m, 2H), 0.69 - 0.59 (m, 2H). LCMS: RT =0.560 min, m / z =398.1 (M+H)+. SFC: RT =1 .958 min.

[0661] EXAMPLE 1.62: SYNTHESIS OF (64)

[0662] 9 (64) Synthesis of compound 2

[0663] To a solution of compound 1 (5 g, 38.43 mmol, 1 eq) in DCM (30 mL) was added pyridine (6.08 g, 76.87 mmol, 6.20 mL, 2 eq) and AC2O (4.32 g, 42.28 mmol, 3.97 mL, 1.1 eq) under 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and poured into H2O (100 mL) slowly. The resulting mixture was extracted with ethyl acetate (50 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 , 10 / 1. TLC (Petroleum ether: Ethyl acetate = 10: 1 ; Rf = 0.43)) to give compound 2 (2.6 g, 15.10 mmol, 39.30% yield) as colorless oil.1H NMR: (400 MHz, CDCI3) δ = 6.75 - 6.71 (m, 2H), 6.69 (s, 1 H), 2.31 (s, 3H).

[0664] Synthesis of compound 3

[0665] To a solution of compound 2 (1 g, 5.81 mmol, 1 eq) in DCE (10 mL) was added AlCb (2.32 g, 17.43 mmol, 952.45 μL, 3 eq) at 0 °C under N2. The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with ethyl acetate (30 mL) and poured into H2O (50 mL) slowly. The resulting mixture was extracted with ethyl acetate (30 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 10 / 1) to give compound 3 (0.6 g, 3.49 mmol, 60.00% yield) as brown solid.1H NMR: (400 MHz, CDCI3) δ = 13.15 (d, J = 1 .0 Hz, 1 H), 6.50 (td, J = 2.0, 10.1 Hz, 1 H), 6.38 (ddd, J = 2.6, 9.1 , 11 .8 Hz, 1 H), 2.67 (d, J = 7.4 Hz, 3H).

[0666] Synthesis of compound 5

[0667] To a solution of compound 3 (200 mg, 1.16 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (321.18 mg, 2.32 mmol, 2 eq) and compound 4 (202.11 mg, 1.39 mmol, 86.78 μL, 1.2 eq). The mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and was poured into H2O (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 , 10 / 1. TLC (Petroleum ether: Ethyl acetate = 10: 1 ; Rf = 0.43)) to give compound 5 (50 mg, 264.31 22.75% yield) as μmol, yellow oil.1H NMR: (400 MHz, CDCI3) δ = 6.50 - 6.43 (m, 2H), 2.53 (d, J = 1 .1 Hz, 3H).

[0668] Synthesis of compound 6

[0669] To a solution of compound 5 (50 mg, 264.31 1 eq) in μ DmCoMl, (0.5 mL) and EtOH (0.5 mL) was added PyBrs (92.98 mg, 290.74 1.1 eqμ)m. Tohl,e mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted with H2O (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 , 10 / 1. TLC (Petroleum ether: Ethyl acetate = 10: 1 ; Rf = 0.6)) to give compound 6 (30 mg, 1 11.91 pmol, 42.34% yield) as colorless oil.

[0670] Synthesis of compound 8

[0671] To a solution of compound 6 (30 mg, 11 1.91 1 eq)μ imno El,tOH (1 mL) was added compound 7 (27.57 mg, 1 11.91 1 eμqm).o Tl,he mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 0 / 1) to give compound 8 (20 mg, 48.14 43μ.m01o%l, yield) as colorless oil. LCMS: RT =0.596 min, m / z =416.2 (M+H)+.

[0672] Synthesis of compound 9

[0673] To a solution of compound 8 (20 mg, 48.14 1 eq) in μ HmCoI / El,tOAc (1 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated at reduced pressure to give compound 9 (20 mg, crude, HCI) as colorless oil. LCMS: RT =0.422min, m / z =316.2 (M+H)+.

[0674] Synthesis of (64)

[0675] To a solution of compound 9 (40 mg, 113.70 1 eq,μ HmCoI)l, in pyridine (1 mL) was added EDCI (26.15 mg, 136.44 1.2μ emqo)l, and compound 10 (11.38 mg, 113.70 pmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 40%-60% B over 10 min) to give (64) (11.04 mg, 27.78 μ 2m4.o4l3, % yield, 100% purity) as brown gum.1H NMR: (400 MHz, CDCb) 5 = 7.41 (s, 1 H), 6.59 - 6.48 (m, 2H), 4.86 - 4.75 (m, 2H), 4.35 (br d, J = 13.1 Hz, 1 H), 4.14 (dd, J = 2.3, 11 .6 Hz, 1 H), 3.75 (dt, J = 2.6, 11 .6 Hz, 1 H), 3.25 - 3.08 (m, 2H), 1 .36 (s, 3H), 1 .02 - 0.93 (m, 2H), 0.68 - 0.61 (m, 2H). LCMS: RT =0.534 min, m / z =398.1 (M+H)+.

[0676] EXAMPLE 1.63: SYNTHESIS OF (65)

[0677]

[0678] Synthesis of compound 3

[0679] To a solution of compound 2 (48.56 mg, 186.52 1 eq) in μ EmtOoHl, (1 mL) was added compound 1 (50 mg, 186.52 1μm eqo)l,. The mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated in vacuum to give compound 3 (70 mg, crude) as colorless oil.

[0680] Synthesis of compound 4

[0681] A mixture of compound 3 (70 mg, 162.98 1 eq) inμ HmCoI / lE, tOAc (1 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated at reduced pressure to give compound 4 (70 mg, crude, HCI) as colorless oil. LCMS: RT =0.440 min, m / z =330.1 (M+H)+.

[0682] Synthesis of (65)

[0683] To a solution of compound 4 (70 mg, 191.34 1 eq,μ HmCoI)l, in pyridine (1 mL) was added EDCI (44.02 mg, 229.61 1 .2 eμqm)o aln, d compound 5 (19.16 mg, 191 .34 pmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 45%-65% B over 10 min) to give (65) (36.43 mg, 88.53 μ 4m6.o2l7, % yield, 100% purity) as yellow gum.1H NMR: (400 MHz, CDCb) 5 = 7.41 (s, 1 H), 6.58 - 6.50 (m, 2H), 4.87 (dd, J = 2.8, 10.8 Hz, 1 H), 4.80 (br d, J = 14 Hz, 1 H), 4.39 (br d, J = 13.2 Hz, 1 H), 3.84 - 3.73 (m, 1 H), 3.16 - 2.98 (m, 1 H), 2.76 - 2.60 (m, 1 H), 1.35 (s, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.02 - 0.93 (m, 2H), 0.68 - 0.59 (m, 2H). LCMS: RT =0.557 min, m / z =412.1 (M+H)+. SFC: RT =1.055 min.

[0684] EXAMPLE 1.64: SYNTHESIS OF (66)

[0685]

[0686] Synthesis of compound 3

[0687] To a solution of compound 2 (684.50 mg, 4.72 mmol, 293.90 μL, 1.2 eq) in DMF (9 mL) was added K2CO3 (1 .09 g, 7.87 mmol, 2 eq) and compound 1 (850 mg, 3.94 mmol, 1 eq). The mixture was stirred at 50 °C for 16 hr. The reaction mixture was diluted with ethyl acetate (20 mL) and H2O (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1 , 10 / 1. TLC (Petroleum ether: Ethyl acetate = 10: 1 ; Rf = 0.43)) to give compound 3 (1 g, crude) as yellow oil.1H NMR: (400 MHz, CDCh) 6 = 7.77 (d, J = 7.0 Hz, 1 H), 6.74 (d, J = 10.5 Hz, 1 H).

[0688] Synthesis of compound 5

[0689] A stirred solution of compound 3 (100 mg, 429.09 1 eq) and μ cmomolp, ound 4 (0.31 g, 858.37 μmo 2l,89.99 μL, 2.00 eq) in dioxane (1 mL) was degassed with N2 for 15 min, followed by addition of Pd(PPh3)2Cl2 (15.06 mg, 21 .45 0.05 eq) atμ 2m5ol °,C. The mixture was heated at 100 °C for 3 h. The mixture was cooled to 0 °C and THF (1 mL): H2O (0.5 mL) (2: 1) was added. NBS (152.74 mg, 858.18 2 eqμ)m woal,s added at 0 °C. The mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with ethyl acetate (10 mL) and saturated KF solution (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 5 / 1) to give compound 5 (120 mg, crude) as yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.17 (d, J = 7.5 Hz, 1 H), 6.85 (d, J = 10.5 Hz, 1 H), 4.49 (s, 2H). Synthesis of compound 7

[0690] To a solution of compound 5 (60 mg, 218.11 1 eq)μ imno El,tOH (1 mL) was added compound 6 (53.73 mg, 218.11 1 eμqm)o. l T, he mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuum to give compound 7 (80 mg, crude) as brown oil.

[0691] Synthesis of compound 8

[0692] A mixture of compound 7 (80 mg, 189.35 1 eq) inμ HmCoI / lE, tOAc (1 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated at reduced pressure to give compound 8 (90 mg, crude, HCI) as colorless oil.

[0693] Synthesis of (66)

[0694] To a solution of compound 8 (90 mg, 250.81 1 eq,μ HmCoI)l, in pyridine (1 mL) was added EDCI (57.70 mg, 300.98 1.2 eμqm)o aln, d compound 9 (25.11 mg, 250.81 pmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 43%-73% B over 10 min) to give (66) (18.77 mg, 46.41 μ 1m8o.5l,0% yield) as off-white solid.1H NMR: (400 MHz, CDCI3) δ = 8.57 (d, J = 7.7 Hz, 1 H), 7.93 (s, 1 H), 6.83 (d, J = 10.8 Hz, 1 H), 4.88 - 4.75 (m, 2H), 4.37 (br d, J = 13.7 Hz, 1 H), 4.15 (br dd, J = 2.1 , 11.1 Hz, 1 H), 3.77 (dt, J = 2.3, 11.8 Hz, 1 H), 3.27 - 3.06 (m, 2H), 1 .40 (s, 3H), 1.01 (q, J = 10.3 Hz, 2H), 0.74 - 0.64 (m, 2H). LCMS: RT =0.541 min, m / z =405.1 (M+H)+.

[0695] EXAMPLE 1.65: SYNTHESIS OF (67)

[0696]

[0697] Synthesis of compound 3

[0698] To a solution of compound 1 (1 g, 6.45 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1.78 g, 12.89 mmol, 2 eq) and compound 2 (934.59 mg, 6.45 mmol, 401.29 μL, 1 eq). The mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and H2O (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL*3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1 , 5 / 1. TLC (Petroleum ether: Ethyl acetate = 3: 1 ; Rf = 0.8)) to give compound 3 (1 g, crude) as yellow oi 1.1H NMR: (400 MHz, CDCh) 6 = 6.61 - 6.53 (m, 2H).

[0699] Synthesis of compound 5

[0700] To a solution of compound 3 (900 mg, 5.23 mmol, 1 eq) in THF (10 mL) was added LDA (2 M, 2.74 mL, 1 .05 eq) dropwise at -70 °C under N2. The mixture was stirred at -70 °C for 0.5 h. compound 4 (826.74 mg, 5.49 mmol, 785.12 μL, 1 .05 eq) in THF (5 mL) was added and the mixture was stirred at 25 °C for 1 .5 h under N2. The mixture was quenched with saturated NH4CI (20 mL) under N2, the resulting mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 1 / 0, 3 / 1) to give compound 5 (50 mg, crude) as yellow oil. Synthesis of compound 7

[0701] To a solution of compound 6 (49.54 mg, 201.10 1 eq) in μ EmtOoHl, (1 mL) was added compound 5 (50 mg, 201.10 1μm eqo)l,. The mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated in vacuum to give compound 7 (80 mg, crude) as colorless oil.

[0702] Synthesis of compound 8

[0703] A mixture of compound 7 (80 mg, 181.62 1 eq) inμ HmCoI / lE, tOAc (2 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 3 / 1 , 0 / 1. TLC (Petroleum ether: Ethyl acetate = 0: 1 ; Rf = 0.2)) to give compound 8 (60 mg, crude, HCI) as brown oil. LCMS: RT =0.419 min, m / z =341.2 (M+H)+.

[0704] Synthesis of (67)

[0705] To a solution of compound 8 (60 mg, 159.23 1 eq,μ HmCoI)l, in pyridine (2 mL) was added EDCI (36.63 mg, 191 .07 1 .2 eμqm)o aln, d compound 9 (15.94 mg, 159.23 pmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 40%-60% B over 10 min) to give (67) (4.51 mg, 10.68 μm 6.o7l0, % yield) as yellow solid.1H NMR: (400 MHz, CDCI3) δ = 7.46 (s, 1 H), 6.65 (dd, J = 1.3, 10.7 Hz, 1 H), 4.80 (dd, J = 2.9, 10.8 Hz, 2H), 4.42 - 4.30 (m, 1 H), 4.15 (dd, J = 2.5, 12.0 Hz, 1 H), 3.76 (dt, J = 2.7, 11 .7 Hz, 1 H), 3.25 - 3.06 (m, 2H), 1 .36 (s, 3H), 1 .03 - 0.92 (m, 2H), 0.70 - 0.61 (m, 2H). LCMS: RT =0.512 min, m / z =423.0(M+H)+.

[0706] EXAMPLE 1.66: SYNTHESIS OF (68)

[0707] Synthesis of compound 3 To a solution of compound 1 (60 mg, 218.11 1 eq)μ imno El,tOH (1 mL) was added compound 2 (56.79 mg, 218.11 1 eμqm)o. l T, he mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuum to give compound 3 (80 mg, crude) as colorless oil.

[0708] Synthesis of compound 4

[0709] A mixture of compound 3 (80 mg, 183.27 1 eq) inμ HmCoI / lE, tOAc (1 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated at reduced pressure to give compound 4 (90 mg, crude, HCI) as colorless oil.

[0710] Synthesis of (68)

[0711] To a solution of compound 4 (90 mg, 241.38 1 eq,μ HmCoI)l, in pyridine (1 mL) was added EDCI (55.53 mg, 289.65 1 .2 eμqm)o aln, d compound 5 (24.17 mg, 241 .38 pmol, 1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (FA) -ACN]; gradient: 45%-75% B over 10 min) to give (68) (21.07 mg, 50.35 μ 2m0o.8l,6% yield) as off-white solid.1H NMR: (400 MHz, CDCI3) δ = 8.56 (d, J = 7.7 Hz, 1 H), 7.92 (s, 1 H), 6.83 (d, J = 10.9 Hz, 1 H), 4.89 - 4.80 (m, 2H), 4.42 (br d, J = 13.1 Hz, 1 H), 3.86 - 3.76 (m, 1 H), 3.16 - 3.01 (m, 1 H), 2.76 - 2.62 (m, 1 H), 1.40 (s, 3H), 1.35 (d, J = 6.2 Hz, 3H), 1 .06 - 0.95 (m, 2H), 0.75 - 0.64 (m, 2H). LCMS: RT =0.567 min, m / z =419.2 (M+H)+. SFC: RT = 2.303 min.

[0712] EXAMPLE 1.67: SYNTHESIS OF (69)

[0713] A solution of fluoromethyl 4-methylbenzenesulfonate (292 mg, 1.429 mmol, 1.24 eq) in DMF (3 mL) was added to a suspension of 5-bromo-2-fluoro-4-hydroxybenzonitrile (250 mg, 1 .157 mmol, 1 eq) and CS2CO3 (754 mg, 2.314 mmol, 2 eq) in DMF (4 mL) and the mixture was reacted at 70 °C for 48 h. It was cooled down to r.t., poured into NH4CI (saturated aqueous solution, 15 mL) and extracted with EtOAc (3x15 mL). Combined organic layers were washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated to give 5- bromo-2-fluoro-4-(fluoromethoxy)benzonitrile (252 mg, 88% yield) as an orange solid. It was submitted to next step without purification.1H NMR (300 MHz, CDCI3) δ 7.84 (d, J = 6.7 Hz, 1 H), 7.04 (d, J = 10.2 Hz, 1 H), 5.81 (d, J = 52.6 Hz, 2H). MS (El) m / z 247 / 249 [M]+.

[0714] A degassed solution of (PPh3)4Pd (116 mg, 0.1 mmol, 0.1 eq), 5-bromo-2-fluoro-4- (fluoromethoxy)benzonitrile (250 mg, 1.007 mmol, 1 eq) and tributyl(1 -ethoxyvinyl)tin (445 mL, 1 .317 mmol, 1 .31 eq) in dioxane (5 mL) was reacted at 90 °C for 21 h. It was cooled down to r.t., poured into H2O (15 mL) and extracted with EtOAc (2x10 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. The residue was dissolved in CH2CI2 (5 mL), HCI (10% aqueous solution) was added, and the mixture was stirred at r.t. for 22 h. It was poured into brine (10 mL) and extracted with CH2CI2 (2x15 mL). Combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. Crude was purified by flash chromatography on SiO2 (20% EtOAc / hexanes) to give 5-acetyl-2-fluoro-4- (fluoromethoxy)benzonitrile (115 mg, 54% yield) as a beige solid.1H NMR (300 MHz, CDCh) 6 8.11 (d, J = 7 A Hz, 1 H), 7.06 (d, J = 10.1 Hz, 1 H), 5.86 (d, J = 52.4 Hz, 2H), 2.63 (s, 3H).

[0715] A suspension of copper (II) bromide (243 mg, 1.087 mmol, 2 eq) and 5-acetyl-2-fluoro-4- (fluoromethoxy)benzonitrile (115 mg, 0.544 mmol, 1 eq) in a mixture of EtOAc (3 mL) and CHCH (3 mL) was refluxed for 20 h. It was cooled down to r.t. and filtered through a plug of Celite, eluting the compound with EtOAc (40 mL). Filtrate was concentrated at rotatory evaporator to give 5-(2-bromoacetyl)-2-fluoro-4-(fluoromethoxy)benzonitrile (144 mg, 91 % yield) as an orange solid.1H NMR (300 MHz, CDCI3) δ 8.18 (d, J = 7.2 Hz, 1 H), 7.10 (d, J = 10.0 Hz, 1 H), 5.89 (d, J = 52.2 Hz, 2H), 4.46 (s, 2H).

[0716] A solution of (R)-te / Y-butyl-2-carbamothioylmorpholine-4-carboxylate (90 mg, 0.365 mmol, 1 eq) and 5-(2-bromoacetyl)-2-fluoro-4-(fluoromethoxy)benzonitrile (140 mg, 0.482 mmol, 1.32 eq) in EtOH (6 mL) was refluxed for 90 min. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (15 mL), TFA (560 μL, 7.312 mmol, 20.02 eq) was added and the mixture was stirred at r.t. for 1 h. Volatiles were concentrated off and crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes then 5% MeOH / CH2Ch using NH3 as additive) to give (69) (98 mg, 80% yield) as a brown oil.1H NMR (300 MHz, CDCI3) δ 8.56 (d, J = 7.4 Hz, 1 H), 7.84 (s, 1 H), 7.07 (d, J = 10.2 Hz, 1 H), 5.87 (d, J = 52.8 Hz, 2H), 4.84 (d, J = 9.7 Hz, 1 H), 4.35-4.14 (m, 1 H), 3.92-3.73 (m, 1 H), 3.15-2.72 (m, 4H). MS (ESI) m / z 338 [M + H]+.

[0717] HATU (126 mg, 0.331 mmol, 1.2 eq) and DIPEA (145 mL, 0.847 mmol, 3.07 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (32 mg, 0.303 mmol, 1.1 eq) and (R)-2-fluoro-4-(fluoromethoxy)-5-(2-(morpholin-2-yl)thiazol-4-yl)benzonitrile (93 mg, 0.275 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 18 h. It was poured into H2O (15 mL) and extracted with EtOAc (10 mL). Organic layer was washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 45% to 65%] to give (R)-2-fluoro-4-(fluoromethoxy)-5-(2-(4-(1-methylcyclopropane-1- carbonyl)morpholin-2-yl)thiazol-4-yl)benzonitrile (84 mg, 73% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCI3) δ 8.57 (d, J = 7.5 Hz, 1 H), 7.89 (s, 1 H), 7.09 (d, J = 10.1 Hz, 1 H), 5.88 (d, J = 52.8 Hz, 2H), 4.98-4.62 (m, 2H), 4.36 (d, J = 13.5 Hz, 1 H), 4.14 (d, J = 10.7 Hz, 1 H), 3.76 (t, J = 11.5 Hz, 1 H), 3.28-3.03 (m, 2H), 1.39 (s, 3H), 1.11-0.91 (m, 2H), 0.77-0.60 (m, 2H). MS (ESI) m / z 420 [M + H]+.

[0718] EXAMPLE 1.68: SYNTHESIS OF (70)

[0719] A solution of fe / Y-butyl (2R,6R)-2-carbamothioyl-6-methylmorpholine-4-carboxylate (100 mg, 0.384 mmol, 1 eq) and 5-(2-bromoacetyl)-2-fluoro-4-(fluoromethoxy)benzonitrile (140 mg, 0.482 mmol, 1 .26 eq) in EtOH (7 mL) was refluxed for 1 h. It was cooled down to r.t. and volatiles were concentrated off. The residue was dissolved in CH2CI2 (15 mL), TFA (590 μL, 7.704 mmol, 20.00 eq) was added and the mixture was stirred at r.t. for 1 h. Volatiles were concentrated off and crude residue was purified by flash chromatography on SiO2 (50% EtOAc / hexanes then 5% MeOH / CH2Cl2 using NH3 as additive) to give 2-fluoro-4-(fluoromethoxy)-5-(2-((2R,6R)-6- methylmorpholin-2-yl)thiazol-4-yl)benzonitrile (60 mg, 44% yield) as a brown oil.1H NMR (300 MHz, CDCI3) δ 8.55 (d, J = 7.4 Hz, 1 H), 7.83 (s, 1 H), 7.07 (d, J = 10.1 Hz, 1 H), 5.87 (d, J = 52.9 Hz, 2H), 4.88 (d, J = 9.5 Hz, 1 H), 3.95-3.77 (m, 1 H), 3.53-3.40 (m, 1 H), 3.04-2.91 (m, 1 H), 2.87- 2.73 (m, 1 H), 2.70-2.49 (m, 1 H), 1 .25 (d, J = 6.3 Hz, 3H). MS (ESI) m / z 352 [M + H]+.

[0720] HATU (70 mg, 0.184 mmol, 1.2 eq) and DIPEA (78 mL, 0.455 mmol, 2.96 eq) were added to a solution of 1-methylcyclopropane-1 -carboxylic acid (17 mg, 0.169 mmol, 1.1 eq) and 2- fluoro-4-(fluoromethoxy)-5-(2-((2R,6R)-6-methylmorpholin-2-yl)thiazol-4-yl)benzonitrile (54 mg, 0.153 mmol, 1 eq) in DMF (4 mL) and the mixture was stirred at r.t. for 2 h. It was poured into H2O (10 mL) and extracted with EtOAc (5 mL). Organic layer was washed with brine (2x10 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. Crude residue was purified by flash chromatography [Column C18 Gold 30g. Buffer pH 7 aqueous (NH4HCO3 / HCO2H) / CH3CN, from 50% to 70%] to give (70) (44 mg, 66% yield) as a white solid after lyophilization.1H NMR (300 MHz, CDCb) 5 8.56 (d, J = 7.5 Hz, 1 H), 7.87 (s, 1 H), 7.08 (d, J = 10.1 Hz, 1 H), 5.88 (d, J = 52.7 Hz, 2H), 4.99-4.71 (m,...

Claims

Claims1. A PLA2G15 inhibitor for use as a medicament represented by formula (I), or a salt or solvate thereof:wherein RBconsists of a single ring system, wherein the single ring system may be substituted with one or more of a halogen, a C1-4 alkyl and a C3-4 cycloalkyl, wherein the single ring system comprises 3 to 8 non-hydrogen ring atoms; wherein X, X1, X2, and X3are independently selected from CR6R7, O, N, NR6or a single bond; wherein RB1, RB2, RB3, RB4, RB5, RB6, RB7and RB8are independently selected from H, a halogen, a C1-4 alkyl, a 3 to 6-membered aromatic ring optionally substituted with a halogen, a 3 to 4 membered aliphatic ring, -CHF2, -CH2F, -CF3, -CHF2, -CH2F wherein Rs, R1, R2, R3, R4, R5, R6, R7and R8are independently H, a C1-4 alkyl, a C3-4 cycloalkyl, a halogen, or a pseudohalogen selected from the group consisting of -CN, -CP, -NC, -OH, -SH, -SeH,-TeH, -OCN, -SCN, -NCS, -SeCN, - TeCN, -N3, -NO, or -NO, wherein each C1-4 alkyl and C3-4 cycloalkyl may be substituted with one or more halogens or one or more pseudohalogens selected from the group consisting of -CN, -CP, -NC, -OH, -SH, -SeH,-TeH, -OCN, -SCN, -NCS, -SeCN, -TeCN, -N3, -NO, or -NO; and wherein R1and R2, and / or R3and R4, and / or R5and R6may alternatively form =0 wherein Y is C-RY2or N; and wherein RY1, RY2, RY3, RY4and RY5are independently H, a C1-4 alkyl, a O-C1-4 alkyl, a S-C1-4 alkyl, a C3-4 cycloalkyl, a O-C3-4 cycloalkyl, a S-C3-4 cycloalkyl, a halogen, or a pseudohalogen selected from the group consisting of -CN, -CP, - NC, -OH, -SH, -SeH,-TeH, -OCN, -SCN, -NCS, -SeCN, -TeCN, -N3, -NO, or - NO, wherein each C1-4 alkyl, O-C1-4 alkyl, S-C1-4 alkyl, C3-4 cycloalkyl, O-C3-4 cycloalkyl and S-C3-4 cycloalkyl may be substituted with one or more halogens or one or more pseudohalogens selected from the group consisting of -CN, -CP, -NC, -OH, -SH, -SeH,-TeH, -OCN, -SON, -NCS, -SeCN, -TeCN, -N3, -NO, or -NO.

2. A PLA2G15 inhibitor as defined in claim 1 , or a salt or solvate thereof, wherein RBcomprises an aliphatic ring, preferably a cyclopropyl.

3. The PLA2G15 inhibitor for use according to claim 1 , or the PLA2G15 inhibitor according to claim 2, wherein RBcomprises a five-membered or a six-membered aromatic ring.

4. The PLA2G15 inhibitor for use according to claim 1 , or the PLA2G15 inhibitor according to claim 2, wherein RBcomprises a single aliphatic ring system.

5. The PLA2G15 inhibitor for use according to any one of claims 1 , 3 or 4, or the PLA2G15 inhibitor according to any one of claims 2 to 4, wherein Y is CH, and RY4and RY5are H or F.

6. The PLA2G15 inhibitor for use according to any one of claims 1 or 3 to 5, or the PLA2G15 inhibitor according to any one of claims 2 to 5, wherein RY1is OCDF2, OCD2F, OCH3, OCF3, OCHF2, OCH2F, OCD3, OCHD2, OCH2D.

7. The PLA2G15 inhibitor for use according to any one of claims 1 or 3 to 6, or the PLA2G15 inhibitor according to any one of claims 2 to 6, wherein RY3is H or F.

8. The PLA2G15 inhibitor for use according to any one of claims 1 and 3 to 7, or the PLA2G15 inhibitor according to any one of claims 2 to 7, wherein Rsis H or F, preferably wherein Rsis H.

9. The PLA2G15 inhibitor for use according to any one of claims 1 and 3 to 8, or the PLA2G15 inhibitor according to any one of claims 2 to 8, wherein R1, R2, R5and R6are H.

10. The PLA2G15 inhibitor for use according to any one of claims 1 and 3 to 9, or the PLA2G15 inhibitor according to any one of claims 2 to 9, wherein R3and R4are independently H or CH3, preferably wherein R3and R4are H.

11. The PLA2G15 inhibitor for use according to any one of claims 1 and 3 to 10, or the PLA2G15 inhibitor according to any one of claims 2 to 10, wherein X is CH2 or O, preferably wherein X is CH2.

12. The PLA2G15 inhibitor as defined in claim 1 , represented by any one of formulae (1) to(75), preferably for use as a medicament:(9) (10)(19) (20)13. Use of the PLA2G15 inhibitor as defined in any one of the preceding claims for specifically binding and / or inhibiting PLA2G15 in vitro, preferably wherein the PLA2G15 inhibitor does not specifically bind and / or inhibit other phospholipases than PLA2G15 in vitro.

14. The PLA2G15 inhibitor as defined in any one of the preceding claims for use as a medicament wherein the use comprises specifically binding and / or inhibiting PLA2G15, preferably wherein the PLA2G15 inhibitor does not specifically bind and / or inhibit other phospholipases than PLA2G15.

15. The PLA2G15 inhibitor for use according to any one of claims 1 and 3 to 12, for use in the treatment of a disease characterized by lysosomal dysregulation, preferably wherein the disease is a lysosomal storage disease, HIV, Alzheimer’s disease or Parkinson’s disease, preferably more preferably wherein the lysosomal storage disease is Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal dementia.

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