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, 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.

Description

[0001] PLA2G15 INHIBITORS

[0002] FIELD OF THE INVENTION

[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] SUMMARY OF THE INVENTION

[0008] One aspect of the invention pertains to certain N-substituted-3,4-(fused ring)- pyrrolidinone and / or N-substituted-3,4-(fused ring)-pyrrolidindione compounds (also referred to herein as" PLA2G15 inhibitors"), as described herein.

[0009] Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a PLA2G15 inhibitor, as described herein, and a pharmaceutically acceptable carrier or diluent.

[0010] Another aspect of the present invention pertains to use in a treatment of a disorder of the human or animal body associated with abnormal PLA2G15 enzyme activity, comprising administering to a subject in need of treatment a therapeutically effective amount of compound of formula I or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present invention pertains to use in the inhibition of PLA2G15 activity in a subject, comprising administering to said subject an effective amount of compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0012] Another aspect of the present invention pertains to use in the inhibition of PLA2G15 protein / activity comprising contacting the PLA2G15 protein / enzyme, in vitro or in vivo, with an effective amount of a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0013] Another aspect of the present invention pertains to use in the inhibition of PLA2G15 protein / activity in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention pertains to use in a method of treatment of the human or animal body by therapy.

[0015] Another aspect of the present invention pertains to its use in a method of treating diseases or disorders associated with abnormal PLA2G15 activity or PLA2G15 protein.

[0016] Another aspect of the present invention pertains for use in the preparation of a medicament for treating conditions associated with abnormal PLA2G15 activity.

[0017] Another aspect of the present invention pertains for use in the manufacture of a medicament for the treatment of a disorder or disease of the human or animal body that is associated by the abnormal PLA2G15 activity.

[0018] Another aspect of the present invention pertains to a kit comprising (a) a compound of formula I, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound. Another aspect of the present invention pertains to a compound of formula I obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

[0019] Another aspect of the present invention pertains to a compound of formula I obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

[0020] Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

[0021] Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.

[0022] DETAILED DESCRIPTION

[0023] PLA2G15 inhibitors

[0024] In a first aspect, the invention provides a PLA2G15 inhibitor represented by compound of formula I :

[0025] Formula I or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0026] X= CH or N; Ring ‘A’ is a phenyl, heterocyclyl, or heteroaryl; m = 0 or 1 ; p = 0 or 1 ;

[0027] Xi and X2 are independently methyl or

[0028] Xi and X2 taken together form wherein X3 is carbon, nitrogen or oxygen, however, if X3 is oxygen Ri and R2 are absent and if X3 is nitrogen R2 is absent;

[0029] R1 is independently selected from a group comprising hydrogen, methyl, flouro, CH2CF3, trifluoromethyl or ; n=0, 1 or 2;

[0030] Ring ‘B’ is selected from a group comprising phenyl, cyclopropyl, cyclobutyl or oxetyl; R2 is either hydrogen or flouro;

[0031] R3 is hydrogen, flouro, chloro, methoxy or ethoxy;

[0032] R4 is hydrogen or methyl;

[0033] R is independently selected from a group comprising methyl,

[0034]

[0035] n is 2, B is phenyl; and if R3 is present at para position to the point of attachment of phenyl group then R3 is not chloro. In embodiments, when X is CH then Ring A is a phenyl moiety.

[0036] In embodiments, when X is N then Ring A is either a piperazinyl or a pyrrolyl moiety.

[0037] In a further aspect, the invention provides compound of formula la :

[0038] Formula la or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

[0039] Xi and X2 taken together form wherein X3 is carbon or nitrogen, however, if X3 is nitrogen R2 is absent; Ri is independently selected from a group comprising hydrogen, methyl, CH2CF3, or n=0, 1 or 2; R2 is hydrogen;

[0040] R.3 is hydrogen, chloro, or ethoxy;

[0041] R.4 is hydrogen or methyl;

[0042] R is independently selected from a group comprising n is 2, and if R3 is present at para position to the point of attachment of phenyl group of Ri then R3 is not chloro.

[0043] In a further aspect, the invention provides compound of formula lb

[0044] Formula lb or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein p = 0 or 1 ;

[0045] Xi and X2 are independently methyl or

[0046] Xi and X2 taken together form wherein X3 is carbon, nitrogen or oxygen, however, if X3 is oxygen Ri and R2 are absent and if X3 is nitrogen R2 is absent;

[0047] Ri is independently selected from a group comprising hydrogen, methyl, flouro, CH2CF3, or; n=0, 1 or 2;

[0048] Ring ‘B’ is selected from a group comprising phenyl, cyclopropyl, cyclobutyl or oxetyl;

[0049] R2 is either hydrogen or flouro;

[0050] R3 is hydrogen, flouro, chloro, methoxy or ethoxy;

[0051] R4 is hydrogen;

[0052] R is independently selected from a group comprising methyl, In a further aspect, the invention provides a compound of formula Ic:

[0053] Formula Ic or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

[0054] R either hydrogen or methyl.

[0055] Unless otherwise indicated, where a compound is shown or described which has one or more chiral centres, and two or more stereoisomers are possible, all such stereoisomers are disclosed and encompassed, both individually (e.g., as isolated from the other stereoisomer(s)) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, where a compound has one chiral centre, each of the (R) and (S) enantiomers are disclosed and encompassed, both individually (e g., as isolated from the other enantiomer) and as a mixture (e.g., as equimolar or non-equimolar mixtures of the two enantiomers).

[0056] Note that, depending upon the identity of Ring A, and any substituents thereon, Ring A may be susceptible to tautomerism. Unless otherwise indicated, where a compound is shown or described which is susceptible to tautomerism, and two tautomers are possible, both tautomers are disclosed and encompassed, both individually (e g., as isolated from the other tautomer) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two tautomer).

[0057] In embodiments, compound of one of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0058]

[0059] SC-001924

[0060] SC-001948 SC-003542

[0061] SC-003546

[0062] SC-001952

[0063]

[0064] SC-001955

[0065]

[0066] SC-001958

[0067]

[0068] SC-001961 SC-002327

[0069] SC-002449

[0070]

[0071] SC-002459

[0072]

[0073]

[0074] SC-002633

[0075]

[0076] SC-002766

[0077] SC-002867

[0078] Compositions

[0079] 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. 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.

[0080] 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.

[0081] In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula I or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient. Formula I wherein R, m, p, X, Xi, X2, and Ring ‘A’ are as defined according to Formula I in above;

[0082] In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula la or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.

[0083]

[0084] Formula la wherein R, Xi and X2 are as defined according to Formula la in above;

[0085] In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula lb or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.

[0086] Formula lb wherein R, p, Xi and X2 are as defined according to Formula lb above;

[0087] In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula Ic or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.

[0088] Formula Ic wherein R is as defined according to Formula Ic above;

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] A composition according to the invention may be formulated for transmucosal or transdermal 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.

[0098] 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.

[0099] Combinations

[0100] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., Ring A, -R, -X, -Xi, -X2 etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub -combination of chemical groups was individually and explicitly disclosed herein.

[0101] Substantially Purified Forms

[0102] In a further aspect, the present invention pertains to PLA2G15 inhibitors, as described herein, in substantially purified form and / or in a form substantially free from contaminants.

[0103] In one embodiment, the substantially purified form is at least 50% by weight, e g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.

[0104] Unless otherwise specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).

[0105] In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer. In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight. Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer. In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e g., at least 99% optically pure.

[0106] Isomers

[0107] Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, 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 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and b- forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as“isomers” (or“isomeric forms”). A reference herein to one tautomer is intended to encompass both tautomers.

[0108] Keto-Enol Tautomerism

[0109] Note that specifically included in the term“isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D), and3H (T); C may be in any isotopic form, including12C,13C, and14C, O may be in any isotopic form, including16O and18O; and the like.

[0110] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

[0111] Salts

[0112] It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol.66, pp.1 -19.

[0113] For example, if the compound 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 Al3+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., NH3R+, NH2R2+, NHR3+, NR4+), for example, where each R is independently linear or branched saturatedCi-is alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, and phenyl-C1-6alkyl, 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+.

[0114] If the compound 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. For example, if a parent structure 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. For example, in the PLA2G15 inhibitors described herein and a salt may be formed with a suitable anion.

[0115] 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.

[0116] 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.

[0117] Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0118] Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

[0119] Solvates and Hydrates

[0120] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound. A PLA2G15 inhibitor according to the invention may be present as a pharmaceutically acceptable solvate or hydrate.

[0121] 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. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof. Chemically Protected Forms

[0122] It may be convenient or desirable to prepare, purify, and / or handle the compound in a chemically protected form. The term “chemically protected form” is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, reactive chemical reagents, and the like). In practice, well-known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (alternatively as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed or the masking group transformed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

[0123] A wide variety of such “protecting, ’’“blocking,” or“masking” methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups“protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be “deprotected” to return it to its original functionality.

[0124] For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (- OC(=O)CH3, -OAC).

[0125] For example, an amine group may be protected, for example, as an amide (-NRCO-R), for example: as an acetamide (-NHCO-CH3); or as a carbamate (-NRCO-OR), for example: as a benzyloxy carbamate (-NHCO-OCH2C6H5, -NH-Cbz), as a t-butoxy carbamate (-NHCO- 0C(CHS)3, -NH-BOC); as a 2-biphenyl-2-propoxy carbamate (-NHCO-OC(CH3)2C6H4CeH5, - NH-Bpoc), as a 9-fluorenylmethoxy carbamate (-NH-Fmoc), as a 6-nitroveratryloxy carbamate (-NH-Nvoc), as a 2-trimethylsilylethyloxy carbamate (-NH-Teoc), a 2,2,2-trichloroethyloxy carbamate (-NH-Troc), as an allyloxy amide (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyloxy carbamate (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O»); or, in suitable cases (e.g., heterocyclic nitrogens), as a 2-trimethylsilylethoxymethyl (N-SEM).

[0126] Prodrugs

[0127] It may be convenient or desirable to prepare, purify, and / or handle the compound in the form of a prodrug. The term“prodrug,” as used herein, pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

[0128] For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

[0129] Also, some prodrugs are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), lipid directed enzyme prodrug therapy (LIDEPT), etc ). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. General Chemical Synthesis Several methods for the chemical synthesis of the FRPPO compounds are described herein. These and / or other well-known methods may be modified and / or adapted in known ways in order to facilitate the synthesis of additional compounds described herein. Uses and therapeutic uses

[0130] 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.

[0131] 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.

[0132] In a further aspect, the invention provides the use of a compound of formula I according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15.

[0133] Formula I wherein R, m, p, X, Xi, X2, and Ring ‘A’ are as defined according to Formula I in above; In a further aspect, the invention provides the use of a compound of formula la according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15.

[0134]

[0135] Formula la wherein R, Xi and X2 are as defined according to Formula la in above;

[0136] In a further aspect, the invention provides the use of a compound of formula lb according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15.

[0137] Formula lb wherein R, p, Xi and X2 are as defined according to Formula lb above; In a further aspect, the invention provides the use of a compound of formula Ic according to the invention or a composition according to the invention for binding and / or inhibiting PLA2G15.

[0138]

[0139] Formula Ic wherein R is as defined according to Formula Ic above;

[0140] 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.

[0141] 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 (PLA2G1B), 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 4-Nitrophenyl butyrate activity assay protocol of Example 2. Claimable summary of IC50 are provided in Example 2.

[0142] 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 equal to or lower than 250pM, 240pM, 230pM, 220pM, 210pM, 200pM, 190pM, 180pM, 170pM, 160pM, 150pM, 140pM, 130pM, 120pM, 1 lOpM, lOOpM, 90pM, 80pM, 70pM, 60pM, 50pM, 45pM, 40pM, 35pM, 30pM, 25pM, 20pM, 15pM, lOpM, 9.5pM, 9pM, 8.5pM, 8pM, 7.5pM, 7pM, 6.5pM, 6pM, 5.5pM, 5pM, 4.5pM, 4pM, 3.5pM, 3pM, 2.5pM, 2pM, 1.5pM, I pM, 0.5pM, 490nM, 480nM, 470nM, 460nM, 450nM, 440nM, 430nM, 420nM, 410nM, 400nM, 390nM, 380nM, 370nM, 360nM, 350nM, 340nM,

[0143] 330nM, 320nM, 310nM, 300nM, 290nM, 280nM, 270nM, 260nM, 250nM, 240nM, 230nM,

[0144] 220nM, 210nM, 200nM, 190nM, 180nM, 170nM, 160nM, 150nM, 140nM, 130nM, 120nM,

[0145] HOnM, lOOnM, 90nM, 80nM, 70nM, 60nM, 50nM, 45nM, 40nM, 35nM, 30nM, 25nM, 20nM,

[0146] 15nM, lOnM, 9.5nM, 9nM, 8.5nM, 8nM, 7.5nM, 7nM, 6.5nM, 6nM, 5.5nM, or 5nM.

[0147] 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.

[0148] In embodiments, the uses above are for use in vitro.

[0149] In embodiments, the uses above are for use in vivo.

[0150] Kits;

[0151] In a further aspect, the invention pertains to a kit comprising (a) a compound of formula I, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0152] Formula I wherein R, m, p, X, Xi, X2, and Ring ‘A’ are as defined according to Formula I in above;

[0153] In a further aspect, the invention pertains to a kit comprising (a) a compound of formula la, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0154] Formula la wherein R, Xi and X2 are as defined according to Formula la in above;

[0155] In a further aspect, the invention pertains to a kit comprising (a) a compound of formula lb, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0156]

[0157] Formula lb wherein R, p, Xi and X2 are as defined according to Formula lb above;

[0158] In a further aspect, the invention pertains to a kit comprising (a) a compound of formula Ic, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0159] Formula Ic wherein R is as defined according to Formula Ic above;

[0160] In a further aspect, the invention provides a PLA2G15 inhibitor according to the invention or a composition according to the invention for use as a medicament. Likewise, all specific embodiments for an inhibitor according to the invention, a composition according to the invention, and the uses presented above may be applied accordingly.

[0161] 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.

[0162] 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.

[0163] A medicament according to the invention, may be administered separately, sequentially or simultaneously in combination with another medicaments.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in a treatment of a disorder of the human or animal body associated with abnormal PLA2G15 enzyme activity , comprising administering to a subject in need of treatment a therapeutically -effective amount of the said compound.

[0169] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in the inhibition of PLA2G15 activity in a subject, comprising administering to said subject an effective amount of said compound.

[0170] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in the inhibition of PLA2G15 protein / activity comprising contacting the PLA2G15 protein / enzyme, in vitro or in vivo, with an effective amount of said compound.

[0171] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in the inhibition of PLA2G15 protein / activity in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of said compound. The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in a method of treatment of the human or animal body by therapy.

[0172] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for use in a method of treating diseases or disorders associated with abnormal PLA2G15 activity or PLA2G15 protein.

[0173] The compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I for the preparation of a medicament for treating conditions associated with abnormal PLA2G15 activity.

[0174] Use of the compound of formula I as defined above and the pharmaceutical composition comprising the compound of formula I in the manufacture of a medicament for the treatment of a disorder or disease of the human or animal body that is associated by the abnormal PLA2G15 activity.

[0175] Therapy

[0176] Diseases

[0177] In an aspect, the invention provides a PLA2G15 inhibitor according to the invention or a composition according to the invention, for use as a medicament. In embodiments, the PLA2G15 inhibitor or the composition is 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.

[0178] 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.

[0179] 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. 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.

[0180] 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 detected 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 sphingolipi doses. PLA2G15 inhibition can therefore be expected to have broad therapeutic benefit across this class of diseases.

[0181] In a specific embodiment, said disease is a sphingolipidosis. Sphingolipi dosis is characterized by a disturbance of the sphingolipid metabolism.

[0182] 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 (32).

[0183] 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 (38). 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. 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.

[0184] In a specific embodiment, said sphingolipidosis is a mucopolysaccharidosis (MPS), including, MPS

[0185] I (Hurler syndrome, MPS II (Hunter syndrome) , MPS IIIA (Sanfilippo syndrome), MPS IIIB (Sanfilippo syndrome), MPS IIIC (Sanfilippo syndrome), MPS IIID (Sanfilippo syndrome), MPS VI (Maroteaux-Lamy syndrome), MPS VII (Sly syndrome).

[0186] In a specific embodiment, said sphingolipidosis is a Mucolipidosis, including Mucolipidosis II (I- cell disease), Mucolipidosis III (pseudo-Hurler polydystrophy) and Mucolipidosis IV.

[0187] In a specific embodiment, said disease is glycoproteinosis, including galactosialidosis, mannosidosis, sialidosis.

[0188] In a specific embodiment, said sphingolipidosis is a Neuronal ceroid lipofuscinosis (NCL), including NCL 3 (Batten disease), NCL 10 and Hereditary spastic paraplegia (HSP).

[0189] In a specific embodiment, said disease is Alzheimer disease.

[0190] In a specific embodiment, said disease is Parkinson’s disease.

[0191] 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.

[0192] In specific embodiments, said condition is selected from the diseases mentioned in Table 1.

[0193] 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.

[0194] 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).

[0195] NPC disease is characterized by the secondary accumulation of (glyco)-sphingolipids and therefore considered a member of a group of diseases called shingolipidoses (32).

[0196] 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.

[0197] 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.

[0198] In specific aspects, Niemann-Pick disease type C is caused by mutation in an NPC1 gene (chromosome location 18ql 1) 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 Cl (NPC1) or Niemann-Pick disease type Cl (NPC2), respectively.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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 NPC 1 protein and / or NPC2 protein expression level, respectively, and / or the expression of a defective decreased NPC1 protein and / or NPC2 protein, respectively.

[0203] 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 NPC 1 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. 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.

[0204] 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:

[0205] — 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, 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

[0206] — 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, 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

[0207] — 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, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50; and / or

[0208] — 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, 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

[0209] — 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 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

[0210] — 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.

[0211] 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.

[0212] 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).

[0213] 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).

[0214] 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.

[0215] 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.

[0216] 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).

[0217] Treatment options

[0218] 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.

[0219] 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.

[0220] A medicament according to the invention, may be administered separately, sequentially or simultaneously in combination with another medicaments.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] Compositions

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] Supplementary active compounds, besides an inhibitor according to the invention, can also be incorporated into the compositions.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] A composition according to the invention may be formulated for transmucosal or transdermal 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.

[0241] 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.

[0242] Uses 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.

[0243] 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.

[0244] 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.

[0245] 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 (PLA2G1B), 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.

[0246] 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.

[0247] 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. 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.

[0248] In embodiments, the uses above are for use in vitro.

[0249] In embodiments, the uses above are for use in vivo.

[0250] 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.

[0251] 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.

[0252] The data obtained from 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.

[0253] Definitions

[0254] 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. 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.

[0255] As used herein, the singular forms 'a', 'an', and 'the' include both singular and plural referents unless the context clearly dictates otherwise.

[0256] 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.

[0257] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

[0258] 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.

[0259] A concentration is preferably a molar concentration, preferably a molar concentration per weight or per volume, most preferably measured under physiological conditions.

[0260] 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.

[0261] An organelle is preferably a lysosome or an endosome, more preferably a lysosome. An endosome is preferably a late endosome.

[0262] 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. 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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. 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 (i.e. over its whole length or as a whole).

[0268] 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%.

[0269] 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).

[0270] 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.

[0271] 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).

[0272] Preferred parameters for nucleic acid comparison include the following: Algorithm: 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-EBI. The aforementioned parameters are the default parameters for a Global Pairwise Sequence alignment of nucleotide sequences (along with no penalty for end gaps).

[0273] 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; He to Leu, Vai, or Met; Leu to He, Met or Vai; Lys to Arg, Gin or Glu; Met to Vai, Leu or He; 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.

[0274] Additional embodiments and features of the present disclosure will be apparent to one of ordinary skill in art based upon description provided herein. The embodiments herein provide various features and advantageous details thereof in the description. Descriptions of well- known / conventional methods and techniques are omitted so as to not unnecessarily obscure the embodiments herein. Further, the disclosure herein provides for examples illustrating one or more of the above-described embodiments. The examples used herein for such illustration are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the following examples should not be construed as limiting the scope of the embodiments herein.

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[0324] Examples

[0325] Several methods for the chemical synthesis of the PLA2G15 inhibitors are described herein. Examples of such methods are illustrated in the following schemes.

[0326] Example 1:

[0327] Experimental Series A

[0328] Synthesis of int-4

[0329] Synthesis of compound 3

[0330] To a solution of compound 1 (2 g, 16.24 mmol, 1 eq), NMM (1.81 g, 17.86 mmol, 1.96 mL, 1.1 eq) in DCM (20 mL) was added CDI (2.90 g, 17.86 mmol, 1.1 eq) and the mixture was stirred at 25 °C for 2 h. To the mixture was added compound 2 (2.99 g, 12.99 mmol, 0.8 eq) and NMM (2.63 g, 25.98 mmol, 2.86 mL, 1.6 eq), then the mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 30-45% Ethyl acetate / Petroleum ether gradient @ 60 mL / min; TLC (Petroleum ether: Ethyl acetate = 2: 1; Rf = 0.41)), the eluent was concentrated. Compound 3 (4.9 g, 13.56 mmol, 83.49% yield) was obtained as a yellow oil. ’H NMR: (400 MHz, CHLOROFORM-d) δ = 7.49 (dd, J= 3.0, 6.5 Hz, 2H), 7.41 - 7.36 (m, 3H), 5.21 - 5.13 (m, 2H), 4.43 (br s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 4.00 (dd, J = 3.3, 13.4 Hz, 1H), 3.86 (dd, J = 4.6, 11.0 Hz, 1H), 2.96 (dt, J = 3.7, 12.8 Hz, 1H), 2.68 (br d, J= 10.3 Hz, 1H), 2.46 (br t, J = 11.0 Hz, 1H), 1.47 (s, 9H) Synthesis of compound Int-4

[0331] To a solution of compound 3 (3 g, 8.30 mmol, 1 eq) in EtOAc (30 mb) was added Pd / C (0.2 g, 8.30 mmol, 10% purity, 1.00 eq) under N2 at 25 °C, then the mixture was stirred under H2 (15 psi) at 25 °C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 60% Ethyl acetate / Petroleum ethergradient @ 60 mL / min; TLC (Petroleum ether: Ethyl acetate = 0: 1; Rf = 0.59)), the eluent was concentrated. Compound 7 (1.4 g, 5.16 mmol, 62.17% yield) was obtained as a white solid.JH NMR: (400 MHz, CHLOROFORM-d) δ = 9.23 - 8.97 (m, 1H), 4.65 - 4.45 (m, 1H), 4.28 - 4.09 (m, 1H), 4.08 - 3.97 (m, 2H), 3.05 (dt, J = 3.0, 12.7 Hz, 1H), 2.89 - 2.67 (m, 2H), 1.49 (s, 9H)

[0332] Synthetic Scheme SC-001921

[0333] Experimental Procedure for SC-001921:

[0334] Synthesis of compound 2

[0335] To the mixture of compound 1 (1 g, 6.57 mmol, 1 eq) in DCM (10 mL) was added SOCI2 (1.17 g, 9.86 mmol, 714.99μL, 1.5 eq) and DMF (95.00 mg, 1.30 mmol, 0.1 mL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated to give compound 2 (1.1 g, 6.45 mmol, 98.11% yield) as yellow oil. The crude product was used directly.1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.34 - 7.28 (m, 2H), 6.91 - 6.85 (m, 2H), 4.58 (s, 2H), 4.04 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H)

[0336] Synthesis of compound 3

[0337] The mixture of compound 2 (1.1 g, 6.45 mmol, 1 eq), PPI13 (1.69 g, 6.45 mmol, 1 eq) in toluene (20 mL) was stirred at 120 °C for 16 h under N2. Some solid were formed. The mixture was cooled to room temperature. The mixture was filtered, the solid was washed with toluene (30 mL), dried, to give compound 3 (1.6 g, crude) as brown solid. NMR: (EW31975-63-P1A, 400 MHz, DMSO-d6) δ = 7.94 - 7.86 (m, 3H), 7.74 (dt, J= 3.6, 7.8 Hz, 6H), 7.70 - 7.63 (m, 6H), 6.91 - 6.84 (m, 2H), 6.77 (d, J= 8.6 Hz, 2H), 5.14 (d, J= 15.0 Hz, 2H), 3.94 (q, J= 6.9 Hz, 2H), 1.27 (t, J= 6.9 Hz, 3H)

[0338] Synthesis of compound 5 To the mixture of compound 3 (1.6 g, 3.70 mmol, 9.85e-l eq) in THF (20 mL) was added NaH (600.17 mg, 15.00 mmol, 60% purity, 4 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2. Then to the mixture was added compound 4 (0.8 g, 3.75 mmol, 1 eq). The mixture was stirred at 0 °C for 4 h under N2. The reaction mixture was poured into sat. NH4CI (40 mL) slowly, extracted with EtOAc (30 mL * 3). The combined organic layers were washed with birne (30 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 : 0 to 8: 1, TLC: Petroleum ether / Ethyl acetate = 5: 1) to give compound 5 (590 mg, 1.78 mmol, 47.45% yield) as white solid. NMR (400 MHz, CHLOROFORM-d) δ = 7.29 - 7.15 (m, 2H), 6.90 - 6.81 (m, 2H), 6.33 (d, J = 15.5 Hz, 1H), 6.00 (dd, J = 6.9, 15.9 Hz, 1H), 4.21 - 4.07 (m, 2H), 4.03 (q, J= 7.1 Hz, 2H), 2.84 - 2.68 (m, 2H), 2.31 - 2.21 (m, 1H), 1.79 - 1.64 (m, 2H), 1.49 - 1.46 (m, 9H), 1.45 - 1.33 (m, 5H)

[0339] Synthesis of compound 7

[0340] To a solution of compound 5 (590 mg, 1.78 mmol, 1 eq) in EtOAc (10 mL) was added Pd / C (60 mg, 10% purity) (wet) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The mixture was filtered, the filter Liquid was concentrated to give compound 7 (540 mg, crude) as colorless oil. ’H NMR: (400 MHz, CHLOROFORM-d) δ = 7.12 - 7.03 (m, 2H), 6.87 - 6.79 (m, 2H), 4.16 - 3.97 (m, 4H), 2.74 - 2.62 (m, 2H), 2.61 - 2.53 (m, 2H), 1.70 (br d, J= 12.9 Hz, 2H), 1.56 - 1.50 (m, 2H), 1.46 (s, 9H), 1.41 (t, J = 7.0 Hz, 4H), 1.13 (dq, J= 4.3, 12.2 Hz, 2H);

[0341] 5. Synthesis of compound 8 To the mixture of compound 7 (540 mg, 1.62 mmol, 1 eq) in DCM (5 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give compound 8 (430 mg, crude, HC1) as white solid. The crude was used directly.

[0342] Synthesis of SC-001921

[0343] To the mixture of compound 8 (149.19 mg, 552.96 pmol, 1 eq, HC1) in MeCN (3 mL) was added CDI (98.63 mg, 608.25 μmol, 1.1 eq) and EtiN (167.86 mg, 1.66 mmol, 230.89μL, 3 eq). The mixture was stirred at 25 °C for 1 h. Then to the mixture was added compound 6 (150 mg, 552.96μmol, 1 eq), DMAP (6.76 mg, 55.30 μmol, 0.1 eq). The mixture was stirred at 70 °C for 16 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 48%-78%, 10 min) to give SC-001921 (124.35 mg, 232.01μmol, 41.96% yield, 99% purity) as off-white solid. ’H NMR: (400 MHz, CHLOROFORM-d) δ = 7.07 (d, J= 8.6 Hz, 2H), 6.87 - 6.78 (m, 2H), 4.55 (br dd, J = 2.9, 4.4 Hz, 1H), 4.20 (br d, J = 13.1 Hz, 2H), 4.12 - 3.96 (m, 5H), 3.10 - 2.74 (m, 5H), 2.64 - 2.54 (m, 2H), 1.79 (br d, 11.8 Hz, 2H), 1.63 - 1.55 (m, 3H), 1.49 (s, 9H), 1.41 (t, J= 7.0 Hz, 3H), 1.36 - 1.22 (m, 2H); LCMS: RT = 0.847 min, m / z = 553.2 (M + Na)+

[0344] Synthetic Scheme SC-001923, SC-001925 and SC-001930:

[0345] Experimental Procedure for SC-001923: 1. Synthesis of SC-001923

[0346] To the mixture of 4-[(3-chlorophenyl)methyl]piperidine (90.75 mg, 368.64μmol, 1 eq, HC1) in MeCN (2 ml) was added CDI (71.73 mg, 442.37μmol, 1.2 eq), Et3N (111.91 mg, 1.11 mmol, 153.93 μL, 3 eq), the mixture was stirred at 25 °C for 1 h. Then to the mixture was added DMAP (9.01 mg, 73.73μmol, 0.2 eq), compound 1 (100 mg, 368.64μmol, 1 eq). The mixture was stirred at 70 °C for 16 h. The mixture was concentrated. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 unpmobile phase: [water(FA)-ACN];B%: 58%-88%,10min) to give SC-001923 (54.93 mg, 107.26 μmol, 29. 10% yield, 99% purity) as off- white solid. ' H NMR: (400 MHz, CHLOROFORM-d) δ = 7.25 - 7.18 (m, 2H), 7.14 (s, 1H), 7.02 (d, J = 6.8 Hz, 1H), 4.68 - 4.44 (m, 1H), 4.29 - 4.03 (m, 5H), 3.11 - 2.76 (m, 5H), 2.55 (d, J = 6.8 Hz, 2H), 1.79 - 1.67 (m, 3H), 1.49 (s, 9H), 1.41 - 1.22 (m, 2H); LCMS: RT = 0.833 min, m / z = 451.0 (M + H - tBu)+

[0347] Synthesis of compound SC-001924

[0348] A mixture of 4-(4-chlorobenzyl)piperidine (203 mg, 967.98 μmol, 1 eq), CDI (188.35 mg, 1.16 mmol, 1.2 eq) and TEA (195.90 mg, 1.94 mmol, 269.46μL, 2 eq) in THF (2 mb) was stirred at 25 °C for 2 h. To the mixture was added compound 1 (262.58 mg, 967.98 μmol, 1 eq), DMAP (23.65 mg, 193.60μmol, 0.2 eq) and TEA (293.85 mg, 2.90 mmol, 404.19μL, 3 eq), then the mixture was stirred at 25 °C for 16 h. The mixture was concentrated. The residue was purified by reversed-phase HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 50%-80%, 10 min), the eluent was concentrated and then freeze dried. SC-001924 (55.09 mg, 103.23μmol, 10.66% yield, 95% purity) was obtained as a white solid. ’H NMR: (400 MHz, CHLOROFORM-d) δ = 7.27 (s, 2H), 7.07 (d, J = 8.3 Hz, 2H), 4.68 - 4.47 (m, 1H), 4.21 (br d, J = 12.3 Hz, 2H), 4.07 (dt, J= 3.7, 10.7 Hz, 3H), 3.12 - 2.75 (m, 5H), 2.54 (d, J = 7.0 Hz, 2H), 1.70 (br d, J = 10.5 Hz, 3H), 1.49 (s, 9H), 1.38 - 1.25 (m, 2H); LCMS: RT =1.036 min, m / z = 451.3 (M + H - tBu)+.

[0349] Synthesis of SC-001925

[0350] To the mixture of 4-(2-chlorobenzyl)piperidine (70 mg, 284.35μmol, 0.77 eq, HC1) in MeCN (2 mL) was added CDI (71.73 mg, 442.37μmol, 1.2 eq), Et3N (111.91 mg, 1.11 mmol, 153.93 μL, 3 eq), the mixture was stirred at 25 °C for 1 h. Then to the mixutre was added DMAP (9.01 mg, 73.73μmol, 0.2 eq), compound 1 (100 mg, 368.64μmol, 1 eq). The mxiture was stirred at 70 °C for 16 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 45%-75%, 10 min) to give SC-001925 (49.72 mg, 97.09μmol, 26.34% yield, 99% purity) as yellow solid. ’H NMR: (400 MHz, CHLOROFORM-d) δ = 7.39 - 7.32 (m, 1H), 7.22 - 7.12 (m, 3H), 4.67 - 4.41 (m, 1H), 4.27 - 4.04 (m, 5H), 3.12 - 2.78 (m, 5H), 2.71 (d, J= 7.3 Hz, 2H), 1.87 (ttd, J = 3.8, 7.5, 11.2 Hz, 1H), 1.72 (br d, J = 12 6 Hz, 2H), 1 49 (s, 9H), 1.44 - 1.33 (m, 2H); LCMS: RT = 0.953 min, m / z = 451.2 (M + H- / Bu)

[0351] Synthesis of SC-001930 To the mixture of 4-benzylpiperidine (64.61 mg, 368.64μmol, 65.59 1 eq) in MeμCLN, (2 mL) was added CDI (71.73 mg, 442.37μmol, 1.2 eq), EtiN (111.91 mg, 1.11 mmol, 153.93 pL, 3 eq), the mixture was stirred at 25 °C for 1 h. Then to the mixture was added DMAP (9.01 mg, 73.73μmol, 0.2 eq), compound 1 (100 mg, 368.64 μmol, 1 eq). The mxiture was stirred at 70 °C for 16 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 50%-80%, 10 min) to give SC-001930 (50.71 mg, 103.56μmol, 28.09% yield, 96.5% purity) as off-white solid. ’ H NMR: (400 MHz, CHLOROFORM-d) δ = 7.32 - 7.27 (m, 2H), 7.24 - 7.19 (m, 1H), 7.17 - 7.12 (m, 2H), 4.66 - 4.46 (m, 1H), 4.27 - 4.13 (m, 2H), 4.13 - 4.02 (m, 3H), 3.10 - 2.78 (m, 5H), 2.58 (d, J= 7.0 Hz, 2H), 1.78 - 1.68 (m, 3H), 1.49 (s, 9H), 1.41 - 1.24 (m, 2H); LCMS: RT = 0.913 min, m / z = 417.2 (M + H - tBu)+

[0352] Synthetic Scheme SC-001942;

[0353] Experimental Procedure for SC-001942:

[0354] Synthesis of compound 2

[0355] A mixture of Compound 1 (1.6 g, 3.07 mmol, 1 eq) and HCl / dioxane (2.5 M, 5 mL, 4.07 eq) in dioxane (10 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. Without further purification and the products was used for next step directly. Compound 2 (1.4 g, 3.06 mmol, 99.68% yield, HC1) was obtained as a white solid. Synthesis of compound SC-001942

[0356] A mixture of compound 2 (100 mg, 218.65μmol, 1 eq, HC1), cyclohexanecarboxylic acid (33.63 mg, 262.38μmol, 32.65 1.2μ eLq,), EDCI (50.30 mg, 262.38 μmol, 1.2 eq), HOBt (35.45 mg, 262.38μmol, 1.2 eq) and TEA (110.63 mg, 1.09 mmol, 152.17 5 eq) in DμLC,M (1 mL) was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. 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%: 48%-78%, 10 min), the eluent was concentrated and then freeze dried. Compound SC-001942 (26.14 mg, 47.75μmol, 21.84% yield, 97% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ = 7.33 - 7.29 (m, 2H), 7.26 - 7.22 (m, 2H), 4.61 - 4.41 (m, 1H), 4.38 - 4.29 (m, 1H), 4.25 - 4.10 (m, 1H), 4.01 - 3.84 (m, 3H), 3.05 - 2.95 (m, 4H), 2.91 (br dd, J= 2.4, 7.3 Hz, 1H), 2.67 (br d, J= 2.0 Hz, 3H), 1.63 (br s, 7H), 1.60 - 1.52 (m, 3H), 1.41 - 1.30 (m, 4H), 1.23 - 1.13 (m, 3H); LCMS: RT = 0.946 min, m / z = 531.2 (M+H)+.

[0357] Synthetic Scheme SC-001948;

[0358] Experimental Procedure SC-004948;

[0359] Synthesis of compound 2

[0360] A mixture of Compound 1 (1.6 g, 3.07 mmol, 1 eq) and HCl / dioxane (2.5 M, 5 mL, 4.07 eq) in dioxane (10 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. Without further purification and the products was used for next step directly. Compound 2 (1.4 g, 3.06 mmol, 99.68% yield, HC1) was obtained as a white solid.

[0361] Synthesis of SC-001948

[0362] A mixture of 2-methylbenzaldehyde (85.64 mg, 712.78 μmol, 82.35 3 eq), compouμnLd, 2 (100 mg, 237.59μmol, 1 eq) and CH3COOH (2.85 mg, 47.52 μmol, 2.72 0.2 eq) in THμFL (,1 mL) was stirred at 60 °C for 0.5 h. To the mixture was added NaBH (OAc)s (201.42 mg, 950.37 pmol, 4 eq), then the mixture was stirred at 60 °C for 16 h. The mixture was concentrated. The residue was purified by reversed-phase HPLC (column: Phenomenex Synergi C18 150*25 mm* 10um;mobile phase: [water (FA) -ACN];B%: 68%-98%, 10 min), the eluent was concentrated and then freeze dried. SC-001948 (27.34 mg, 52.07μmol, 21.92% yield, 100% purity) was obtained as a yellow solid. ' II NMR: (400 MHz, CHLOROFORM-d) δ = 7.29 (s, 2H), 7.26 - 7.16 (m, 4H), 7.13 (d, J = 8.3 Hz, 2H), 4.29 - 4.03 (m, 4H), 3.63 - 3.52 (m, 2H), 3.29 (dd, J = 4.0, 11.1 Hz, 1H), 3.12 (dt, J= 3.9, 12.6 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.93 - 2.84 (m, 2H), 2.67 - 2.61 (m, 2H), 2.39 (s, 3H), 2.25 - 2.12 (m, 2H), 1.81 (br d, J= 13.2 Hz, 2H), 1.61 (br d, J= 8.3 Hz, 3H), 1.43 - 1.25 (m, 2H); LCMS: RT = 1.006 min, m / z = 525.4 (M + H)+.

[0363] Synthetic Scheme SC-001952, SC-001953, SC-001954, SC-001955, SC-001956 SC-

[0364] 001958:

[0365]

[0366] Experimental Procedure SC-001952, SC-001953, SC-001954, SC-001955, SC-

[0367] 001956 SC-001958:

[0368] Synthesis of compound 2

[0369] A mixture of compound 1 (1.5 g, 4.44 mmol, 1 eq, TFA), CDI (1.08 g, 6.66 mmol, 1.5 eq) and TEA (898.76 mg, 8.88 mmol, 1.24 mL, 2 eq) in THF (15 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate / Petroleum ethergradient @ 60 mL / min; TLC (Petroleum ether : Ethyl acetate = 0: 1; Rf = 0.30) ) to give compound 2 (1.2 g, 3.78 mmol, 85.02% yield) as a white solid. ’ H NMR: (400 MHz, CHLOROFORM-d) δ = 7.93 (s, 1H), 7.36 - 7.31 (m, 2H), 7.27 (s, 1H), 7.18 (d, J= 8.3 Hz, 3H), 4.19 (br d, J = 13.1 Hz, 2H), 3.08 (dt, J = 2.4, 13.0 Hz, 2H), 2.74

[0370] - 2.66 (m, 2H), 1.98 - 1.88 (m, 2H), 1.74 - 1.59 (m, 3H), 1.44 - 1.30 (m, 2H). Synthesis of compound 4

[0371] To the mixture of compound 3 (400 mg, 1.65 mmol, 1 eq), compound 2 (577.78 mg, 1.82 mmol, 1.1 eq) in THF (5 mL) was added EtaN (334.48 mg, 3.31 mmol, 460.08 2 eq), DMAPμL, (20.19 mg, 165.27μmol, 0.1 eq). The mixture was stirred at 40 °C for 4 h. The mixture was concentrated. The residue was purified by column chromatography (Si O2, Petroleum ether / Ethyl acetate = 1 :0 to 10: 1) to give compound 4 (220 mg, 447.37μmol, 27.07% yield) as white solid. ’II NMR: (400 MHz, DMSO-d6) δ = 8.20 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 1.8, 8.0 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.28 - 7.23 (m, 2H), 4.14 - 4.05 (m, 1H), 3.93 - 3.82 (m, 1H), 3.16 - 3.05 (m, 1H), 3.01 - 2.92 (m, 1H), 2.64 - 2.59 (m, 2H), 1.86 - 1.74 (m, 2H), 1.58 - 1.44 (m, 3H), 1.26 - 1.14 (m, 2H)

[0372] Synthesis of SC-001952

[0373] To the mixture of compound 4 (40 mg, 81.34μmol, 1 eq), phenylboronic acid (11.90 mg, 97.61μmol, 1.2 eq) in dioxane (0.8 mL), H2O (0.1 mb) was added K2CO3 (22.48 mg, 162.68 pmol, 2 eq), Pd(dppf) CI2 (11.90 mg, 16.27 μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 :0 to 4: 1, Rf = 0.3). The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um;mobile phase: [water (FA) - ACN];B%: 58%-88%, 7 min) to give SC-001952 (17.34 mg, 35.11μmol, 43.16% yield, 99% purity) as white solid. NMR: (400 MHz, DMSO-d6) δ = 8.25 - 8.18 (m, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.86 (d, J= 1.3 Hz, 2H), 7.58 - 7.47 (m, 3H), 7.38 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 4.18 - 4.07 (m, 1H), 3.89 (br dd, J = 3.3, 11.7 Hz, 1H), 3.17 - 3.05 (m, 1H), 3.01 - 2.92 (m, 1H), 2.62 (br t, J= 7.6 Hz, 2H), 1.88 - 1.75 (m, 2H), 1.60 - 1.45 (m, 3H), 1.25 - 1.11 (m, 2H); LCMS: RT = 0.938 min, m / z = 489.1 (M+H)+.

[0374] Synthesis of SC-001953

[0375] To the mixture of compound 4 (60 mg, 122.01 μmol, 1 eq), o-tolylboronic acid (19.91 mg, 146.41μmol, 1.2 eq) in dioxane (1 mL), H2O (0. 1 mL) was added K2CO3 (33.73 mg, 244.02 pmol, 2 eq), Pd(dppf) CI2 (17.86 mg, 24 40 μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 :0 to 4: 1, Rf = 0.5). The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 unpmobile phase: [water (FA) - ACN];B%: 60%-90%, 7 min) give SC-001953 (6.92 mg, 13.62 μmol, 11.16% yield, 99% purity) as white solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 8.03 (d, J= 8.2 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.40 - 7.29 (m, 6H), 7.29 - 7.23 (m, 2H), 4.17 - 4.09 (m, 1H), 3.95 - 3.86 (m, 1H), 3.18 - 3.08 (m, 1H), 3.03 - 2.93 (m, 1H), 2.63 (br t, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.88 - 1.76 (m, 2H), 1.60 - 1.48 (m, 3H), 1.27 - 1.11 (m, 2H); LCMS: RT = 0.958 min, m / z = 503.1 (M+H)+.

[0376] Synthesis of SC-001954

[0377] To the mixture of compound 4 (40 mg, 81.34μmol, 1 eq), m-tolylboronic acid (14.38 mg, 105.74μmol, 1.3 eq) in dioxane (1 mL), H2O (0. 1 mL) was added K2CO3 (22.48 mg, 162.68 pmol, 2 eq), Pd(dppf) CI2 (11.90 mg, 16.27 μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 :0 to 4:1, TLC: Petroleum ether / Ethyl acetate = 2: 1, Rf = 0.5). The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 60%-90%, 7 min) to give SC-001954 (16.06 mg, 31.61μmol, 38.86% yield, 99% purity) as off white solid.1H NMR: (400 MHz, CHLOROFORM-d) δ = 8.10 (d, J = 1.0 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.48 - 7.38 (m, 3H), 7.30 - 7.28 (m, 2H), 7.26 (s, 1H), 7.12 (d, J= 8.5 Hz, 2H), 4.32 (br d, J = 12.0 Hz, 1H), 4.14 (br d, J = 12.6 Hz, 1H), 3.06 (br t, J = 11.9 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.69 - 2.60 (m, 2H), 2.46 (s, 3H), 1.88 - 1.77 (m, 2H), 1.67 - 1.58 (m, 2H), 1.52 (br dd, J = 3.4, 7.5 Hz, 1H), 1.46 - 1.26 (m, 2H); LCMS: RT = 0.964 min, m / z = 503.1 (M+H)+

[0378] Synthesis of SC-001955

[0379] To the mixture of compound 4 (40 mg, 81.34μmol, 1 eq), p-tolylboronic acid (14.38 mg, 105.74μmol, 1.3 eq) in dioxane (1 mL), H2O (0.1 mL) was added K2CO3 (22.48 mg, 162.68 pmol, 2 eq), Pd(dppf) CI2 (11.90 mg, 16.27 μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 :0 to 4: 1, TLC: Petroleum ether / Ethyl acetate = 2: 1, Rf = 0.5). The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 unpmobile phase: [water (FA) -ACN];B%: 60%-90%, 7 min) to give SC-001955 (16.79 mg, 33.05μmol, 40.63% yield, 99% purity) as white solid. ’ H NMR: (400 MHz, CHLOROFORM- d) δ = 8.09 (d, J= 0.9 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.55 (d, J= 8.3 Hz, 2H), 7.32 (d, J= 7.9 Hz, 2H), 7.29 - 7.27 (m, 1H), 7.26 (s, 1H), 7.12 (d, J= 8.3 Hz, 2H), 4.38 - 4.27 (m, 1H), 4.14 (br d, J= 11.5 Hz, 1H), 3.11 - 2.99 (m, 1H), 2.96 - 2.84 (m, 1H), 2.69 - 2.58 (m, 2H), 2.44 (s, 3H), 1.89 - 1.76 (m, 2H), 1.66 - 1.59 (m, 2H), 1.51 (br dd, J= 3.9, 7.3 Hz, 1H), 1.44 - 1.26 (m, 2H); LCMS: RT = 0.960 min, m / z = 503.1 (M+H)+ 7. Synthesis of SC-001956

[0380] To the mixture of compound 4 (40 mg, 81.34 μmol, 1 eq), (4-chlorophenyl) boronic acid (16.54 mg, 105.74μmol, 1.3 eq) in dioxane (1 mL), H2O (0.1 mL) was added K2CO3 (22.48 mg, 162.68μmol, 2 eq), Pd(dppf) Ch (11.90 mg, 16.27μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 :0 to 4: 1, TLC: Petroleum ether / Ethyl acetate = 2: 1, Rf = 0.5). The residue was purified by prep-HPLC (column: Unisil 3-100 C 18 Ultra 150*50 mm*3 unpmobile phase: [water (FA) -ACN];B%: 60%-90%, 7 min) to give SC-001956 (4.21 mg, 7.96μmol, 9.79% yield, 99% purity) as off white solid. ’ H NMR: (400 MHz, DMSO- d6) δ = 8.27 - 8.21 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.36 - 7.31 (m, 2H), 7.30 - 7.24 (m, 2H), 4.17 - 4.08 (m, 1H), 3.93 - 3.86 (m, 1H), 3.16 - 3.07 (m, 1H), 3.02 - 2.92 (m, 1H), 2.65 - 2.60 (m, 2H), 1.88 - 1.79 (m, 2H), 1.60 - 1.51 (m, 3H), 1.27 - 1.17 (m, 2H); LCMS: RT = 0.961 min, m / z = 523.1 (M+H)+

[0381] Synthesis of SC-001958

[0382] To the mixture of compound 4 (40 mg, 81.34μmol, 1 eq), 2-benzyl-4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolane (23.06 mg, 105.74μmol, 1.3 eq) in dioxane (1 mL), H2O (0.1 mL) was added K2CO3 (22.48 mg, 162.68 μmol, 2 eq), Pd(dppf) CI2 (11.90 mg, 16.27μmol, 0.2 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 :0 to 4: 1, TLC: Petroleum ether / Ethyl acetate = 2: 1, Rf = 0.5). The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 58%-88%, 7 min) to give SC-001958 (2.55 mg, 5.02μmol, 6.17% yield, 99% purity) as off-white solid.1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.79 (d, J = 1.1 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.28 - 7.27 (m, 1H), 7.26 (br d, J = 2.4 Hz, 2H), 7.18 (d, J = 7.1 Hz, 2H), 7.11 (d, J= 8.3 Hz, 2H), 4.35 - 4.24 (m, 1H), 4.13 (s, 3H), 3.02 (br d, J= 11.6 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.68 - 2.57 (m, 2H), 1.81 (br d, J = 10.6 Hz, 2H), 1.64 - 1.58 (m, 2H), 1.50 (br d, J= 2.7 Hz, 1H), 1.42 - 1.27 (m, 2H); LCMS: RT = 0.941 min, m / z = 503.1 (M+H)+

[0383] Synthetic Scheme SC-001959

[0384] Experimental Procedure for SC-001959:

[0385] Synthesis of compound 2

[0386] The mixture of compound 1 (200 mg, 832.60μmol, 1 eq), O-benzylhydroxylamine (132.89 mg, 832.60μmol, 1 eq, HC1), AcONa (136.60 mg, 1.67 mmol, 2 eq) in AcOH (5 mL) was stirred at 120 °C for 3 h. The mixture was cooled to room temperature and neutralized with sat.NaHCOs to about pH = 7, extracted with EtOAc (30mL * 3). The combined organic layers were dried overNa2SO4, 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 1: 1, TLC: Petroleum ether / Ethyl acetate = 2: 1) to give compound 2 (240 mg, 694.95 pmol, 83.47% yield) as light yellow solid. ’H NMR: (400 MHz, DMSO-d6) δ = 7.86 (d, J = 8.3 Hz, 1H), 7.54 - 7.47 (m, 4H), 7.44 - 7.38 (m, 3H), 7.36 - 7.29 (m, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.21 - 7.16 (m, 2H), 5.15 (s, 2H).

[0387] Synthesis of compound 3

[0388] To the mixture of compound 2 (230 mg, 666.00μmol, 1 eq) in EtOAc (5 mL) was added Pd / C (30 mg, 10% purity) (wet) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 2 h. The mixture was filtered to give compound 3 (120 mg, crude) as yellow oil. LCMS: RT = 0.865 min, m / z = 256.0 (M+H)+

[0389] Synthesis of SC-001959

[0390] To the mixture of compound 3 (120 mg, 470.17μmol, 1 eq), compound 4 (149.43 mg, 470.17μmol, 1 eq) in THF (2 mL) was added EtaN (95.15 mg, 940.35 μmol, 130.89 2 eq), μL, DMAP (5.74 mg, 47.02μmol, 0.1 eq). The mixture was stirred at 40 °C for 16 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 53%-83%, 7 min) to give SC-001959 (88.1 mg, 172.72μmol, 36.74% yield, 99% purity) as yellow solid.1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.83 (d, J = 8.4 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.36 (d, J = 2.1 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.29 - 7.27 (m, 2H), 7.26 - 7.25 (m, 1H), 7. 11 (dd, J= 6. 1, 8.0 Hz, 4H), 4.35 - 4.24 (m, 1H), 4.18 - 4.07 (m, 1H), 3. 10 - 2.97 (m, 1H), 2.94 - 2.82 (m, 1H), 2.68 - 2.58 (m, 2H), 1.81 (br d, J = 13.1 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.51 (ddd, J = 3.4, 7.1, 14.1 Hz, 1H), 1.45 - 1.25 (m, 2H); LCMS: RT = 1.017 min, m / z = 505.0 (M+H)+.

[0391] Synthetic Scheme SC-001960

[0392] Experimental Procedure for SC-001960:

[0393] 1. Synthesis of compound 2

[0394] 1 2

[0395] The mixture of compound 1 (1 g, 4.41 mmol, 1 eq), O-benzylhydroxylamine (703.11 mg, 4.41 mmol, 1 eq, HC1) in toluene (20 mL) was stirred at 130 °C for 3 h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 : 0 to 1 : 1) to give compound 2 (1.4 g, 4.21 mmol, 95.68% yield) as white solid. ’H NMR: (400 MHz, DMSO-d6) δ = 8.09 - 8.02 (m, 2H), 7.79 (d, J= 7.8 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.41 (dd, J= 1.8, 4.9 Hz, 3H), 5.16 (s, 2H) 2. Synthesis of compound 3

[0396] To the mixture of compound 2 (100 mg, 301.07μmol, 1 eq), aniline (28.04 mg, 301.07 pmol, 27.49 μL, 1 eq) in toluene (1 mL) was added CS2CO3 (196.19 mg, 602.14μmol, 2 eq), Pd(OAc)2 (13.52 mg, 60.21 μmol, 0.2 eq), BINAP (74.99 mg, 120.43 μmol, 0.4 eq). The mixture was stirred at 100 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1: 0 tol: 1, TLC: Petroleum ether / Ethyl acetate = 2: 1, Rf = 0.6) to give compound 3 (60 mg, 165.52μmol, 54.98% yield, 95% purity) as yellow solid. ’H NMR: (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 7.66 - 7.62 (m, 1H), 7.52 - 7.46 (m, 2H), 7.43 - 7.36 (m, 5H), 7.28 - 7.20 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H), 5.13 (s, 2H)

[0397] 3. Synthesis of compound 5

[0398] To the mixture of compound 3 (60 mg, 174.23 μmol, 1 eq) in EtOAc (5 mL) was added Pd / C (10 mg, 10% purity) (wet) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 6 h. The mixture was filtered, the liquid was concentrated to give compound 5 (50 mg, crude) as yellow solid. LCMS: RT = 0.829 min, m / z = 255.1 (M+H)+ 3. Synthesis of SC-001960

[0399] To the mixture of compound 5 (50 mg, 196.66μmol, 1 eq), compound 4 (62.50 mg, 196.66μmol, 1 eq) in THF (2 mL) was added Et3N (39.80 mg, 393.33 μmol, 54.75 2 eq), μL, DMAP (2.40 mg, 19.67μmol, 0.1 eq). The mixture was stirred at 40 °C for 16 h. The mixture was concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO:?) -ACN]; B%: 67%-97%, 8 min) to give SC-001960 (20.35 mg, 38.36μmol, 19.51% yield, 95% purity) as yellow solid.1H NMR: (400 MHz, DMSO- d6) δ = 9.33 (s, 1H), 7.73 (d, J = 9.1 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.36 - 7.28 (m, 4H), 7.28 - 7.22 (m, 4H), 7.12 (t, J = 7.4 Hz, 1H), 4.14 - 4.04 (m, 1H), 3.92 - 3.82 (m, 1H), 3.13 - 3.01 (m, 1H), 2.99 - 2.88 (m, 1H), 2.65 - 2.58 (m, 2H), 1.86 - 1.73 (m, 2H), 1.58 - 1.45 (m, 3H), 1.24 - 1.06 (m, 2H); LCMS: RT = 1.206 min, m / z = 504.1 (M+H)+

[0400] Experimental Procedure for SC-001961:

[0401] To the mixture of compound 4 (20 mg, 40.67μmol, 1 eq), ethynylbenzene (5.40 mg, 52.87μmol, 5.81 μ 1L.3, eq) in DMF (0.5 mL) was added EtaN (8.23 mg, 81.34 μmol, 11.32 pL, 2 eq), Pd(PPh3)2Cl2(5.71 mg, 8.13 μmol, 0.2 eq), Cui (2.32 mg, 12.20 μmol, 0.3 eq). The mixture was stirred at 80 °C for 3 h under N2. The mixture (two batches) was cooled to room temperature and concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether : Ethyl acetate = 1 : 0 to 4: 1, TLC: Petroleum ether : Ethyl acetate = 2: 1, Rf = 0.5). The residue was purified by prep-HPLC (column: Unisil 3-100 C18 pLtra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 61%-91%, 7 min) to give SC-001961 (9.7 mg, 18.72μmol, 23.01% yield, 99% purity) as yellow solid. ' H NMR: (400 MHz, CHLOROFORM-d) δ = 8.01 (s, 1H), 7.92 - 7.84 (m, 2H), 7.60 - 7.55 (m, 2H), 7.44 - 7.37 (m, 3H), 7.28 (br s, 1H), 7.26 (s, 1H), 7.12 (d, J= 8.4 Hz, 2H), 4.35 - 4.27 (m, 1H), 4.17 - 4.09 (m, 1H), 3.10 - 3.00 (m, 1H), 2.96 - 2.85 (m, 1H), 2.68 - 2.60 (m, 2H), 1.88 - 1.76 (m, 2H), 1.65 - 1.59 (m, 2H), 1.53 - 1.48 (m, 1H), 1.42 -

[0402] 1.26 (m, 2H); LCMS: RT = 1.059 min, m / z = 513.1 (M+H)+

[0403] Synthetic Scheme SC-001957: Experimental Procedure SC-001957:

[0404] Synthesis of compound 2

[0405] To the mixture of compound 1 (380 mg, 1.00 mmol, 1 eq) in acetone (4 mL) was added NaIO4(428.67 mg, 2.00 mmol, 111.05 2 eqμ)L, N, H4OAc (154.48 mg, 2.00 mmol, 2 eq), H2O (2 mL) at 20 °C. The mixture was stirred at 40 °C for 16 h. The mixture was diluted with EtOAc

[0406] (20 mL), washed with saturated Na2SOs aqueous solution (20 mL*2), saturated NaCl aqueous solution (20 mL*2), the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2 (180 mg, crude) as white solid. LCMS: RT = 0.651 min, m / z = 298.2 (M+H)+.

[0407] Synthesis of compound 3

[0408] To the mixture of benzoyl benzoate (80 mg, 353.63μmol, 66.67 1 eq), comμpLou, nd 2 (126.06 mg, 424.35μmol, 1.2 eq) in THF (2 mL) was added Pd(OAc)2 (7.94 mg, 35.36μmol, 0.1 eq), PPh3(18.55 mg, 70.73 μmol, 0.2 eq), H2O (15.93 mg, 884.07 μmol, 15.93 2.5 eq). μL, The mixture was stirred at 60 °C for 16 h under N2. The mixture was concentrated. The mixture was purified by column chromatography (silica gel, Petroleum ether / Ethyl acetate = 1 : 0 to 5: 1, TLC: Petroleum ether: EtOAc = 3: 1) to give compound 3 (70 mg, crude) as white solid.1H NMR: (400 MHz, DMSO-d6) δ = 8.16 - 8.11 (m, 1H), 8.05 - 8.01 (m, 2H), 7.97 - 7.92 (m, 1H), 7.80 - 7.75 (m, 2H), 7.65 - 7.58 (m, 2H), 7.56 - 7.51 (m, 2H), 7.45 - 7.39 (m, 3H), 5.20 (s, 2H)

[0409] Synthesis of compound 4

[0410] To the mixture of compound 3 (50 mg, 139.92 μmol, 1 eq) in EtOAc (1 mL) was added Pd / C (10 g, 10% purity) under N2. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 h. The mixture was filtered, the filter liquid was concentrated to give compound 4 (25 mg, 92.85 μmol, 66.36% yield) as colorless oil. Synthesis of compound 6

[0411] To the mixture of compound 4 (15 mg, 56.13 μmol, 1 eq), compound 5 (17.84 mg, 56. 13 pmol, 1 eq) in THF (1 mL) was added DIEA (14.51 mg, 112.26μmol, 19.55 2 eq), DMμALP, (1.37 mg, 11.23μmol, 0.2 eq). The mixture was stirred at 40 °C for 16 h.

[0412] To the mixture of compound 4 (25 mg, 92.85 μmol, 1 eq), compound 5 (29.51 mg, 92.85 pmol, 1 eq) in THF (1 mL) was added DIEA (24.00 mg, 185.70μmol, 32.34 2 eq), DMμALP, (2.27 mg, 18.57μmol, 0.2 eq). The mixture was stirred at 40 °C for 16 h.

[0413] The two batches of the reaction mixture were combined and concentrated. The residue was purified by prep-TLC (Petroleum ether: EtOAc = 2: 1) to give compound 6 (15 mg, 27.46 pmol, 95% purity) as yellow oil. LCMS: RT =1.082 min, m / z = 519.0 (M+H)+.

[0414] Synthesis of compound SC-001957

[0415] To the mixture of compound 6 (12 mg, 23.12μmol, 1 eq) in THF (1 mL) was added MnCh (5 mg, 57.51μmol, 2.49 eq). The mixture was stirred at 20 °C for 2 h. The mixture was filtered, the filter was concentrated. To the residue was added MeCN (1 mL), MnCH (5 mg). The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered, the filter was concentrated. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 52%-82%, 7 min) to give SC-001957 (6.91 mg, 13.23μmol, 40.88% yield, 99% purity) as off-white solid. ’ II NMR: (400 MHz, CDC13) 8 = 8.26 - 8.17 (m, 2H), 8.03 (d, J = 7.6 Hz, 1H), 7.83 - 7.78 (m, 2H), 7.71 - 7.65 (m, 1H), 7.58 - 7.51 (m, 2H), 7.28 (br s, 1H), 7.26 (s, 1H), 7.12 (d, J = 8.3 Hz, 2H), 4.38 - 4.24 (m, 1H), 4.20 - 4.08 (m, 1H), 3.13 - 2.99 (m, 1H), 2.98 - 2.86 (m, 1H), 2.70 - 2.60 (m, 2H), 1.83 (td, J = 3.3, 4.5 Hz, 2H), 1.66 - 1.59 (m, 2H), 1.51 (br d, J = 4.2 Hz, 1H), 1.43 - 1.25 (m, 2H); LCMS: RT = 0.950 min, m / z = 517.1 (M+H)+. Synthetic Scheme SC-002984:

[0416] Experimental Procedure SC-002084:

[0417] Synthesis of compound 2 To the mixture of compound 1 (1 g, 3.01 mmol, 1 eq), 4, 4, 5, 5 -tetramethyl -2-(4, 4, 5,

[0418] 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (917.44 mg, 3.61 mmol, 1.2 eq) in dioxane (8 mL) was added AcOK (590.95 mg, 6.02 mmol, 2 eq), Pd(dppf) Ch (220.29 mg, 301.07μmol, 0.1 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 : 0 to 3 : 1, TLC: Petroleum ether: EtOAc = 3 : 1, Rf = 0.56) to give compound 2 (880 mg, 2.32 mmol, 77.08% yield) as yellow solid. ’H NMR: (400 MHz, CDCI3) δ = 8.24 (s, 1H), 8.16 (dd, J = 0.6, 7.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.54 (dd, J = 2.9, 6.6 Hz, 2H), 7.41 - 7.34 (m, 3H), 5.22 (s, 2H), 1.37 (s, 12H).

[0419] Synthesis of compound 3

[0420] To the mixture of compound 2 (200 mg, 527.41μmol, 1 eq) in acetone (3 mL) was added NaIO4(225.62 mg, 1.05 mmol, 58.45 2 eq)μ, NL,H4OAc (81.31 mg, 1.05 mmol, 2 eq), H2O (1.5 mL) at 20 °C. The mixture was stirred at 40 °C for 16 h. The mixture was diluted with EtOAc (20 mL), washed with sat. Na2SOa (20 mL*2), sat.NaCl (20 mL*2), the organic Layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3 (65 mg, crude) as white solid. The crude was used directly.

[0421] Synthesis of compound 4

[0422] To the mixture of compound 4A (1.03 g, 5.55 mmol, 1.1 eq) in MeOH (10 mL) was added dropwise 4-phenoxybenzaldehyde (1 g, 5.04 mmol, 869.57 1 eq) at 0μ °LC, . The mixture was stirred at 20 °C for 1 h. The mixture was filtered. The solid was dried under reduced pressure to give compound 4 (1.7 g, 4.64 mmol, 91.96% yield) as white solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 11.35 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.44 - 7.37 (m, 4H), 7.21 - 7.15 (m, 1H), 7.04 (dd, J= 0.9, 8.6 Hz, 2H), 6.98 (d, J= 8.8 Hz, 2H),

[0423] 2.36 (s, 3H).

[0424] Synthesis of compound 5

[0425] The mixture of compound 4 (80 mg, 218.32 μmol, 1 eq), compound 3 (64.86 mg, 218.32 pmol, 1 eq), K2CO3 (45.26 mg, 327.48 μmol, 1.5 eq) in dioxane (2 mL) was stirred at 110 °C for 2 h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 : 0 to 4: 1, TLC: Petroleum ether: EtOAc = 3 : 1, Rf = 0.5) to give compound 5 (50 mg, 93.00μmol, 42.60% yield, 81% purity) as yellow solid. ' H NMR: (400 MHz, DMSO-d6) δ = 7.81 - 7.77 (m, 1H), 7 75 (d, J = 1.0 Hz, 2H), 7.53 - 7.47 (m, 2H), 7.43 - 7.34 (m, 5H), 7.33 - 7.29 (m, 2H), 7.15 - 7.09 (m, 1H), 7.00 - 6.91 (m, 4H), 5.14 (s, 2H), 4.12 (s, 2H).

[0426] Synthesis of compound 6

[0427] To a solution of compound 5 (50 mg, 114.82μmol, 1 eq) in EtOAc (2 mL) was added Pd / C (10 mg, 10% purity, wet) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 h. The mixture was filtered, the filter liquid was concentrated to give compound 6 (40 mg, crude) as white solid. The crude was used directly. LCMS: RT = 0.862 min, m / z = 346.1 (M+H)+. Synthesis of compound SC-002084

[0428] To the mixture of compound 6 (40 mg, 115.83 μmol, 1 eq) in DCM (2 mL) was added DIEA (44.91 mg, 347.48μmol, 60.52 μ 3L, eq), DMAP (1.42 mg, 11.58μmol, 0.1 eq), morpholine-4-carbonyl chloride (20.79 mg, 138.99μmol, 16.24 1.2 eq) at 0μL °C, . The mixture was stirred at 40 °C for 1 h. The mixture was concentrated. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (FA) -ACN]; B%: 48%-78%, 7 min) to give SC-002084 (32.71 mg, 67.78μmol, 58.52% yield, 95% purity) as white solid. ’H NMR: (400 MHz, CDCI3) δ = 7.82 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 0.6 Hz, 1H), 7.62 (dd, J = 1.4, 7.8 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.16 - 7.09 (m, 3H), 7.06 - 6.94 (m, 4H), 4.11

[0429] (s, 2H), 3.83 - 3.70 (m, 6H), 3.56 (br s, 2H); LCMS: RT = 0.860 min, m / z = 458.9 (M+H)+.

[0430] Synthetic Scheme SC-002325 and SC-002327: Experimental Procedure SC-002325 and SC-002327;

[0431] Synthesis of Compound 2

[0432] To a solution of compound 1 (1 g, 3.01 mmol, 1 eq) in THF (15 mL) was added Pd(dppf) Ch (220.29 mg, 301.07μmol, 0.1 eq), KF (349.82 mg, 6.02 mmol, 141.06 2 eq) andμL m, - tolylboronic acid (450.25 mg, 3.31 mmol, 1.1 eq) at 25 °C. The mixture was stirred at 40 °C for 4 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Then, The residue was purified by prep-HPLC (FA condition). Compound 2 (250 mg, 706.23μmol, 23.46% yield, 97% purity) was obtained as a white solid. LCMS: RT = 0.948 min, m / z = 366.1 (M+Na)+.

[0433] Synthesis of Compound 3

[0434] To a solution of compound 2 (250 mg, 728.07μmol, 1 eq) in EtOH (5 mL) and EtOAc (5 mL) was added Pd / C (20 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with Fh several times. The mixture was stirred under H2 (xpsi) at 25 °C for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. Without purification. Compound 3 (250 mg, crude) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.15 - 8.03 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.28 (d, J= 7.5 Hz, 1H), 2.40 (s, 3H). Synthesis of Compound 5

[0435] A mixture of Compound 4 (100 mg, 406.21 μmol, 1 eq, HC1), CDI (98.80 mg, 609.32 pmol, 1.5 eq) and TEA (123.31 mg, 1.22 mmol, 169.62 3 eq) inμ TLH, F (3 mL) was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 40-60% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound 5 (90 mg, 284.41μmol, 70.02% yield, 96% purity) was obtained as a colorless oil. LCMS: RT = 0.706 min, m / z = 304.1 (M+H)+.

[0436] Synthesis of Compound SC-002325

[0437] To the mixture of compound 3 (90 mg, 296.26μmol, 1 eq), compound 5 (75.03 mg, 296.26μmol, 1 eq) in THF (2 mL) was added TEA (59.96 mg, 592.52μmol, 82.47 2 eq), μL, DMAP (3.62 mg, 29.63μmol, 0.1 eq). The mixture was stirred at 60 °C for 14 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ethergradient @ 30 mL / min). Then purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 70%-100%, 10 min). Compound SC-002325 (22.54 mg, 46.10μmol, 15.56% yield, 100% purity) was obtained as a white solid. ' H NMR: (400 MHz, CDC13) δ ppm 1.27 - 1.45 (m, 2 H) 1.68 - 1.79 (m, 3 H) 2.46 (s, 3 H) 2.58 (d, J=6.85 Hz, 2 H) 2.87 (br t, J=12.35 Hz, 1 H) δ.02 (br t, J=12.72 Hz, 1 H) 4. 14 (br d, J= 12.10 Hz, 1 H) 4.32 (br d, J=11.49 Hz, 1 H) 7.10 (d, J=8.31 Hz, 2 H) 7.29 (s, 3 H) 7.37 - 7.48 (m, 3 H) 7.91 - 7.99 (m, 2 H) δ.10 (d, J=0.86 Hz, 1 H); LCMS RT = 1.175 min, m / z = 489.1 (M+H)+.

[0438] Synthesis of compound 5A

[0439] A mixture of compound 4A (250 mg, 1.19 mmol, 1 eq), CDI (289.95 mg, 1.79 mmol, 1.5 eq) and TEA (482.51 mg, 4.77 mmol, 663.70 4 eq)μ iLn, THF (5 mL) was stirred at 25 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20-40% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Compound 5A (100 mg, 319.30μmol, 26.79% yield, 97% purity) was obtained as a colorless oil. LCMS: RT = 0.714 min, m / z = 304.1 (M+H)+.

[0440] Synthesis of Compound SC-002327

[0441] To the mixture of compound 3 (50 mg, 197.43μmol, 1 eq), compound 5A (89.97 mg, 296.15μmol, 1.5 eq) in THF (2 mL) was added TEA (79.91 mg, 789.73 μmol, 109.92 4 eq), μL, DMAP (2.41 mg, 19.74μmol, 0.1 eq). The mixture was stirred at 60 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, PE: EtOAc = 2: 1). Compound SC-002327 (40.74 mg, 80.82 μmol, 40.94% yield, 97% purity) was obtained as a yellow solid. ’ H NMR: (400 MHz, DMSO-d6) 8 ppm 8.25 - 8.17 (m, 2 H), 8.02 (d, J=8.31 Hz, 1 H), 7.69 (s, 1 H), 7.64 (br d, J=7.70 Hz, 1 H), 7.46 - 7.40 (m, 2 H), 7.37 - 7.33 (m, 1 H), 7.33 - 7.23 (m, 3 H), 4.12 (br d, J=11.98 Hz, 1 H), 3.90 (br d, J=12.23 Hz, 1 H), 3.09 (br t, J=12.72 Hz, 1 H), 3.01 -2.91 (m, 1 H), 2.71 (d, J=7.21 Hz, 2 H), 2.41 (s, 3 H), 1.89 (ddt, J=10.96, 7.29, 3.65, 3.65 Hz, 1 H), 1.67 (br s, 2 H), 1.20 - 1.34 (m, 2 H); LCMS: RT =1.073 min, m / z = 489.1 (M+H)+.

[0442] Synthetic Scheme SC-002326:

[0443] Experimental Procedure SC-002326:

[0444] Synthesis of Compound 2

[0445] A mixture of Compound 1 (500 mg, 2.03 mmol, 1 eq, HC1), CDI (658.67 mg, 4.06 mmol, 2 eq) and TEA (822.10 mg, 8.12 mmol, 1.13 mL, 4 eq) in THF (6 mL) was stirred at 25 °C for 2 h. The reaction mixture was cooled to room temperature. EtOAc (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). Combined extracts were washed with brine (30 mL), dried over Na?SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; B%: 38%-68%, 8.5 min). Compound 2 (300 mg, 987.54μmol, 48.62% yield) was obtained as a white solid. ’H NMR: (400 MHz, CDCI3) δ = 7.86 (s, 1H), 7.27 - 6.99 (m, 6H), 4.12 (br d, J = 13.3 Hz, 2H), 2.98 (dt, J = 2.3, 13.0 Hz, 2H), 2.58 (d, J = 7.1 Hz, 2H), 1.88 - 1.73 (m, 3H), 1.38 - 1.24 (m, 2H); LCMS: RT = 1.073 min, m / z = 489.2 (M+H)+.

[0446] Synthesis of Compound SC-002326

[0447] To the mixture of Compound 2 (80 mg, 263.34μmol, 1 eq), Compound 3 (66.69 mg, 263.34μmol, 1 eq) in THF (3 mL) was added TEA (53.29 mg, 526.69μmol, 73.31 2 eq), μL, DMAP (3.22 mg, 26.33μmol, 0.1 eq). The mixture was stirred at 60 °C for 14 h. The reaction mixture was cooled to room temperature. EtOAc (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO?, PE: EtOAc = 3 : 1). Compound SC-002326 (26.02 mg, 51.09μmol, 19.40% yield, 96% purity) was obtained as a white solid. ’H NMR (400 MHz, CDC13) δ = 8.10 (d, J = 0.9 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.47 - 7.37 (m, 3H), 7.29 (s, 1H), 7.26 - 7.19 (m, 2H), 7.17 (s, 1H), 7.07 - 7.02 (m, 1H), 4.39 -

[0448] 4.27 (m, 1H), 4.20 - 4.08 (m, 1H), 3.03 (br t, J = 11.4 Hz, 1H), 2.96 - 2.82 (m, 1H), 2.59 (d, J = 6.9 Hz, 2H), 2.46 (s, 3H), 1.81 - 1.67 (m, 3H), 1.47 - 1.31 (m, 2H); LCMS: RT = 1.073 min, m / z = 489.2 (M+H)+.

[0449]

[0450] Experimental Procedure SC-002328: Synthesis of Compound 2

[0451] A mixture of compound 1 (500 mg, 2.85 mmol, 507.61 1 eq), CDμLI, (693.85 mg, 4.28 mmol, 1.5 eq) and TEA (577.33 mg, 5.71 mmol, 794.13 2 eq) in TμLH,F (15 mL) was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residueThe residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Compound 2 (760 mg, 2.79 mmol, 97.92% yield, 99% purity) was obtained as a colorless oil. LCMS: RT = 0.673 min, m / z = 270.2 (M+H)+. Synthesis of Compound 4 To the mixture of compound 2 (300 mg, 1.11 mmol, 1 eq), compound 3 (269.58 mg, 1.11 mmol, 1 eq) in THF (5 mL) was added TEA (225.41 mg, 2.23 mmol, 310.06 2 eq), DMAμLP, (13.61 mg, 111.38μmol, 0.1 eq). The mixture was stirred at 60 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ethergradient @ 36 mL / min). Compound 4 (80 mg, 144.38 pmol, 12.96% yield, 80% purity) was obtained as a yellow oil. LCMS: RT = 0.964 min, m / z = 465.0 (M+Na)+.

[0452] Synthesis of Compound SC-002328

[0453] To the mixture of compound 4 (80 mg, 180.47 μmol, 1 eq), m-tolylboronic acid (36.80 mg, 270.70μmol, 1.5 eq) in dioxane (1 mL), H2O (0. 1 mL) was added K2CO3 (49.88 mg, 360.94 pmol, 2 eq), Pd(dppf) CI2 (13.20 mg, 18.05 μmol, 0.1 eq). The mixture was stirred at 80 °C for 2 h under N2. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (column: Welch Ultimate XB-CN 250*50* 10um; mobile phase: [Hexane -EtOH]; B%: l%-35%, 15 min). Compound SC- 002328 (14.94 mg, 30.90μmol, 17.12% yield, 94% purity) was obtained as a off-white solid. ’H NMR: (400 MHz, DMSO-d6) δ = 8.24 - 8.15 (m, 2H), 8.02 (d, J= 8.4 Hz, 1H), 7.69 (s, 1H), 7.64 (br d, J= 8.1 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 - 7.26 (m, 3H), 7.23 - 7.17 (m, 3H), 4.18 - 4.05 (m, 1H), 3.94 - 3.84 (m, 1H), 3.14 - 3.05 (m, 1H), 2.98 - 2.91 (m, 1H), 2.58 (br s, 2H), 2.41 (s, 3H), 1.83 (br s, 1H), 1.67 (br dd, J = 2.6, 8.1 Hz, 2H), 1.25 - 1.16 (m, 2H); LCMS: RT = 1.031 min, m / z = 455.2 (M+H)+. Synthetic Scheme SC-002447, SC-002449 and SC-002450:

[0454] Experimental Procedure SC-002447, SC-002449 and SC-002450: Synthesis of compound 3

[0455] A mixture of compound 1 (2 g, 6.02 mmol, 1 eq), compound 2 (900.51 mg, 6.62 mmol, 1.1 eq), Pd(dppf)Cl2(440.59 mg, 602.14μmol, 0.1 eq), KF (699.69 mg, 12.04 mmol, 282.13 pL, 2 eq) in THF (15 mL) was stirred at 40 °C for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH3 H2O condition), the eluent was concentrated and then freeze dried to give compound 3 (600 mg, 1.50 mmol, 24.96% yield, 86% purity) as a white solid. LCMS: RT = 1.104 min, m / z = 366.0 (M + Na)+. Synthesis of compound 4

[0456] To a mixture of compound 3 (600 mg, 1.75 mmol, 1 eq) in EtOAc (10 mL) was added Pd / C (100 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 ( 15psi) at 25°C for 4 hours. The mixture was concentrated under reduced pressure to give compound 4 (410 mg, 1.54 mmol, 88.02% yield, 95% purity) as a yellow solid. LCMS: RT = 0.848 min, m / z = 254.1 (M + H)+.

[0457] Synthesis of SC-002447

[0458] A mixture of CDI (762.27 mg, 4.70 mmol, 2 eq), 1 -benzylpiperazine (500 mg, 2.35 mmol, 1 eq, HC1) and TEA (951.39 mg, 9.40 mmol, 1.31 mL, 4 eq) in THF (6 mL) was stirred at 60 °C for 16 hr. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was poured into water (50 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (50 mL*2). The combined organic phase was washed with Saturated NaHCCh (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give (4-benzylpiperazin-l-yl) -imidazol-l-yl-methanone (500 mg, crude) as a colorless Oil.

[0459] A mixture of (4-benzylpiperazin-l-yl) -imidazol-l-yl-methanone (70.45 mg, 260.61 pmol, 1.1 eq), compound 4 (60 mg, 236.92μmol, 1 eq), DMAP (2.89 mg, 23.69μmol, 0.1 eq), TEA (47.95 mg, 473.84 μmol, 65.95 2 eqμ)L in, THF (3 mL) was stirred at 40 °C for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)- ACN];B%: 18%-48%,7min) to give SC-002447 (3.9 mg, 8.48μmol, 3.58% yield, 99% purity) as a white solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 8.22 - 8.19 (m, 2H), 8.04 - 8.01 (m, 1H), 7.69 (s, 1H), 7.64 (br d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.37 - 7.33 (m, 4H), 7.32 - 7.27 (m, 2H), 3.65 (br s, 2H), 3.55 (s, 2H), 3.46 (br s, 2H), 2.47 - 2.43 (m, 4H), 2.41 (s, 3H); LCMS: RT = 0.855 min, m / z = 456.2 (M + H)+.

[0460] Synthesis of SC-002449

[0461] A mixture of compound 4 (64.05 mg, 252.89μmol, 1 eq), N, N-dimethylcarbamoyl chloride (40.79 mg, 379.34μmol, 34.86 1.5μ eLq,), DIEA (98.05 mg, 758.68μmol, 132.15 pL, 3 eq) and DMAP (3.09 mg, 25.29μmol, 0. 1 eq) in DCM (2 mL) was stirred at 40 °C for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 49%-79%, 10min) to give SC-002549 (13.76 mg, 42.00μmol, 16.61% yield, 99% purity) as a white solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 8.25 - 8.17 (m, 2H), 8.02 (d, J = 8.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 3.11 (s, 3H), 2.96 (s, 3H), 2.41 (s, 3H); LCMS: RT = 1.039 min, m / z = 325.0 (M + H)+.

[0462] Synthesis of SC-002450

[0463] A mixture of compound 4 (64.05 mg, 252.89μmol, 1 eq), morpholine-4-carbonyl chloride (56.74 mg, 379.34μmol, 44.33 1.5μ eLq,), DIEA (98.05 mg, 758.68μmol, 132.15 pL, 3 eq) and DMAP (3.09 mg, 25.29μmol, 0. 1 eq) in DCM (2 mL) was stirred at 40 °C for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 47%-77%,10min) to give SC-002450 (25.27 mg, 65.53μmol, 25.91% yield, 95% purity) as a white solid. ’H NMR: (400 MHz, DMSO-d6) δ = 8.21 (dd, J = 2.4, 4.1 Hz, 2H), 8.03 (d, J= 8.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.30 (d, J= 7.5 Hz, 1H), 3.68 (br s, 6H), 3.45 (br s, 2H), 2.41 (s, 3H); LCMS: RT = 0.863 min, m / z = 367.2 (M + H)+.

[0464] Synthetic Scheme SC-002454 to SC-002460:

[0465]

[0466] Experimental Procedure SC-002454 to SC-002460:

[0467] Synthesis of compound 3

[0468] A mixture of compound 2 (4.93 g, 28.10 mmol, 5.00 mL, 1 eq), CDI (9.11 g, 56.20 mmol, 2 eq), TEA (11.37 g, 112.40 mmol, 15.64 mL, 4 eq) in THF (10 mL) was stirred at 60 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was poured into water (50 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (50 mL*2). The combined organic phase was washed with saturated NaHCCL aqueous solution (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give (4-benzyl-l -piperidyl) -imidazol-l-yl-methanone (7.0 g, 24.69 mmol, 87.87% yield, 95% purity)

[0469] A mixture of (4-benzyl-l -piperidyl) -imidazol-l-yl-methanone (2.14 g, 7.93 mmol, 1.2 eq), compound 1 (1.6 g, 6.61 mmol, 1 eq), DMAP (80.76 mg, 661.09μmol, 0.1 eq), TEA (1.34 g, 13.22 mmol, 1.84 mL, 2 eq) in THF (20 mL) was stirred at 40 °C for 16 hr. 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 2: 1) to give (1.9 g, 3.69 mmol, 55.76% yield, 86% purity) as colorless oil. ’H NMR: (400 MHz, DMSO-d6) δ = 8.20 (d, J = 1.5 Hz, 1H), 8.14 (dd, J = 1.7, 8.0 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.20 (d, J = 6.6 Hz, 3H), 4.08 (br d, J = 13.1 Hz, 1H), 3.87 (br d, J = 11.6 Hz, 1H), 3.08 (br s, 1H), 2.94 (br s, 1H), 2.56 (br d, J = 7.2 Hz, 2H), 1.99 (s, 1H), 1.84 - 1.74 (m, 1H), 1.66 (br s, 2H), 1.27 - 1.20 (m, 1H); LCMS: RT = 1.175 min, m / z = 283.1 (M + H)+.

[0470] Synthesis of SC-002454

[0471] A mixture of compound 3 (100 mg, 225.59μmol, 1 eq), compound 4 (103.45 mg, 270.70μmol, 1.2 eq), Pd(PPhs)4 (13.03 mg, 11.28 μmol, 0.05 eq) in Tol. (5 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. To the mixture was added aqueous (IM) KF solution (20 mL) and EtOAc (20 mL), the mixture was stirred at 20°C for 0.5h. Then the mixture was filtered and washed withe EtOAc (20 mL). The organic phase was washed with aqueous (IM) KF solution (10 mL) and brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 61%-91%,7min) to give SC-002454 (13.07 mg, 27.26μmol, 12.08% yield, 95% purity) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ = 8.65 (br d, J = 8.0 Hz, 1H), 8.60 (br d, J = 3.9 Hz, 2H), 8.13 (s, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.21 (br d, J = 1.3 Hz, 3H), 4.12 (br d, J = 11.9 Hz, 1H), 3.89 (br d, J = 11.8 Hz, 1H), 3.09 (br t, J = 11.9 Hz, 1H), 3.01 - 2.90 (m, 1H), 2.57 (br d, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.85 - 1.77 (m, 1H), 1.67 (br s, 2H), 1.27 - 1.15 (m, 2H); LCMS: RT = 0.900 min, m / z = 456.2 (M + H)+.

[0472] Synthesis of SC-002455 A mixture of compound 3 (100 mg, 225.59μmol, 1 eq), compound 4 (30.89 mg, 225.59μmol, 1 eq), Pd(PPh3)4(13.03 mg, 11.28 μmol, 0.05 eq), KF (39.32 mg, 676.76μmol, 15.85 μL, 3 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 50%-80%,7min) to give SC-002455 (6.58 mg, 14.16μmol, 6.28% yield, 98% purity) as off-white solid.1H NMR:(400 MHz, DMSO-d6) δ = 8.86 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.28 (dd, J = 1.4, 7.9 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.21 (d, J = 7.4 Hz, 3H), 4.12 (br d, J = 11.9 Hz, 1H), 3.89 (br d, J = 11.6 Hz, 1H), 3.15 - 3.03 (m, 1H), 3.01 - 2.90 (m, 1H), 2.57 (br d, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.81 (ddd, J = 4.0, 7.3, 10.8 Hz, 1H), 1.68 (br s, 2H), 1.28 - 1.16 (m, 2H); LCMS: RT = 0.825 min, m / z = 456.2 (M + H)+.

[0473] Synthesis of SC-002456

[0474] A mixture of compound 3 (100 mg, 225.59μmol, 1 eq), compound 4 (46.34 mg, 338.38μmol, 1.5 eq), Pd(PPh3)4(13.03 mg, 11.28 μmol, 0.05 eq), KF (39.32 mg, 676.76 μmol, 15.85 μL, 3 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 36%-66%,7min) to give SC-002456 (6.34 mg, 13.92 μmol, 6.17% yield, 100% purity) as off-white solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 8.58 (d, J= 5.3 Hz, 1H), 8.37 - 8.30 (m, 2H), 8.09 (d, J= 7.8 Hz, 1H), 7.79 (s, 1H), 7.70 - 7.66 (m, 1H), 7.32 - 7.28 (m, 2H), 7.21 (d, J = 7.3 Hz, 3H), 4.12 (br d, J = 12.4 Hz, 1H), 3.89 (br d, J= 12.8 Hz, 1H), 3.14 - 3.04 (m, 1H), 2.95 (br t, J= 12.1 Hz, 1H), 2.58 (br s, 1H), 2.57 (s, 3H), 2.54 (s, 1H), 1.81 (ddd, J = 3.5, 7.4, 14.5 Hz, 1H), 1.68 (br s, 2H), 1.27 - 1.15 (m, 2H); LCMS: RT = 0.878 min, m / z = 456.1 (M + H)+. Synthesis of SC-002457

[0475] A mixture of compound 4 (51.73 mg, 135.35μmol, 1.2 eq), compound 3 (50 mg, 112.79μmol, 1 eq), Pd(PPh3)4 (6.52 mg, 5.64 μmol, 0.05 eq) in Tol. (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. To the mixture was added aqueous (IM) KF solution (20 mL) and EtOAc (20 mL), the mixture was stirred at 20°C for 0.5 h. Then the mixture was filtered and washed withe EtOAc (20 mL). The organic phase was washed with aqueous (IM) KF solution (10 mL) and brine (10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 61%-91%,7min) to give SC-002457 (5.75 mg, 12.24μmol, 10.86% yield, 97% purity) as white solid. NMR: (400 MHz, DMSO-d6) δ = 8.66 - 8.60 (m, 2H), 8.06 (dd, J = 7.8, 10.9 Hz, 2H), 7.87 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.22 (d, J = 7.3 Hz, 3H), 4.20 - 4.06 (m, 1H), 3.96 - 3.84 (m, 1H), 3.13 (br s, 1H), 3.02 - 2.92 (m, 1H), 2.60 (s, 3H), 2.58 (br d, J = 7.3 Hz, 2H), 1.81 (ddd, J = 3.4, 7.2, 14.6 Hz, 1H), 1.69 (br s, 2H), 1.29 - 1.18 (m, 2H); LCMS: RT = 1.023 min, m / z = 456.1 (M + H)

[0476] Synthesis of SC-002458

[0477] A mixture of compound 4 (23.67 mg, 169.19μmol, 1.5 eq), compound 3 (50 mg, 112.79μmol, 1 eq), KF (19.66 mg, 338.38μmol, 7.93 μL 3 , eq), Pd(PPh3)4(6.52 mg, 5.64μmol, 0.05 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [water(FA)-ACN];B%: 65%-95%,7min) to give SC-002458 (12.34 mg, 26.92μmol, 23.86% yield, 100% purity) as white solid.1H NMR: (400 MHz, CHLOROFORM-d) δ = 8.08 (s, 1H), 7.96 (s, 2H), 7.50 - 7.41 (m, 2H), 7.35 - 7.28 (m, 3H), 7.26 - 7.20 (m, 2H), 7.17 (br d, J = 7.7 Hz, 2H), 4.31 (br d, J = 12.8 Hz, 1H), 4.13 (br d, J= 11.7 Hz, 1H), 3.03 (br s, 1H), 2.88 (br s, 1H), 2.61 (br d, J = 6.7 Hz, 2H), 1.80 - 1.71 (m, 3H), 1.46 - 1.31 (m, 2H); LCMS: RT = 0.990 min, m / z = 459.2 (M + H)+.

[0478] Synthesis of SC-002459

[0479] A mixture of compound 3 (50 mg, 112.79μmol, 1 eq), compound 4 (18.94 mg, 135.35μmol, 1.2 eq), KF (19.66 mg, 338.38μmol, 7.93 3 μ eLq),, Pd(PPh3)4 (6.52 mg, 5.64μmol, 0.05 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr 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*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 68%- 98%,10min) to give SC-002459 (3.72 mg, 7.95 μmol, 7.05% yield, 98% purity) as yellow solid. ’H NMR: (400 MHz, DMSO-d6) δ = 8.29 - 8.24 (m, 2H), 8.04 (d, J= 7.8 Hz, 1H), 7.77 (td, J = 2.1, 10.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.58 (dt, J = 6.3, 8.0 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.21 (d, J = 7.3 Hz, 3H), 4.16 - 4.07 (m, 1H), 3.94 - 3.84 (m, 1H), 3.14 - 3.05 (m, 1H), 2.95 (br t, J = 11.8 Hz, 1H), 2.57 (br d, J = 7.1 Hz, 2H), 1.81 (tdd, J = 3.6, 7.4, 11.0 Hz, 1H), 1.68 (br s, 2H), 1.27 - 1.15 (m, 2H); LCMS: RT = 1.115 min, m / z = 459. 1 (M + H)+. Synthesis of SC-002460

[0480] A mixture of compound 3 (20 mg, 45.12μmol, 1 eq), compound 4 (9.47 mg, 67.68μmol, 1.5 eq), KF (7.86 mg, 135.35μmol, 3.17 μ 3L, eq), Pd(PPh3)4 (5.21 mg, 4.51μmol, 0.1 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr 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*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 67%- 97%,10min) to give SC-002460 (13.73 mg, 29.95 μmol, 66.38% yield, 100% purity) as a yellow solid. ’ H NMR: (400 MHz, DMSO-d6) δ = 8.23 - 8.19 (m, 2H), 8.03 (dd, J = 0.7, 7.8 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.41 - 7.34 (m, 2H), 7.33 - 7.27 (m, 2H), 7.21 (d, J = 7.2 Hz, 3H), 4.18 - 4.04 (m, 1H), 3.89 (br d, J= 11.9 Hz, 1H), 3.15 - 3.03 (m, 1H), 3.01 - 2.89 (m, 1H), 2.57 (d, J = 7.2 Hz, 2H), 1.80 (dtd, J = 3.5, 7.2, 14.6 Hz, 1H), 1.73 - 1.62 (m, 2H), 1.27 - 1.16 (m, 2H); LCMS: RT = 1.002 min, m / z = 459.2 (M + H)+.

[0481] Synthetic Scheme SC-002623: Experimental Procedure SC-002623:

[0482] Synthesis of Compound 2

[0483] To a solution of compound 1 (4 g, 17.62 mmol, 1 eq) and hydroxylamine; hydrochloride (2.45 g, 35.24 mmol, 2 eq) in Py (14 mL) was heated at 80 °C for 14 h. The mixture was diluted with H2O (130 mL) and the resulting mixture was adjusted pH to about 2 with concentrated HC1. The precipitate was filtered and the filter cake was collected, washed with water, dried under reduced presure. Without purification. Compound 2 (2.6 g, 10.74 mmol, 60.97% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) δ = 10.94 (br d, J = 16.4 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.78 - 7.72 (m, 1H).

[0484] Synthesis of Compound 4

[0485] A mixture of compound 3 (5 g, 22.45 mmol, 1 eq), CDI (7.28 g, 44.90 mmol, 2 eq) and TEA (9.09 g, 89.80 mmol, 12.50 mL, 4 eq) in THF (50 mL) was stirred at 60 °C for 14 h. The reaction mixture was cooled to room temperature. EtOAc (100 mL) and water (100 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (100 mL x 2). Combined organic phase was washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Without purification. Compound 4 (8 g, crude) was obtained as a white solid. ’H NMR: (400 MHz, DMSO-d6) δ = 8.03 (s, 1H), 7.49 - 7.44 (m, 1H), 7.04 (s, 1H), 3.54 - 3.38 (m, 8H), 1.41 (s, 9H). Synthesis of Compound 5

[0486] To the mixture of Compound 4 (3.24 g, 11.57 mmol, 1.4 eq), Compound 2 (2 g, 8.26 mmol, 1 eq) in THF (50 mL) was added TEA (1.67 g, 16.53 mmol, 2.30 mL, 2 eq), DMAP (100.96 mg, 826.36μmol, 0.1 eq). The mixture was stirred at 40 °C for 5 h. The reaction mixture was cooled to room temperature. EtOAc (60 mL) and water (60 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (60 mL x 2). Combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ethergradient @ 45 mL / min). Compound 5 (770 mg, 1.42 mmol, 17.23% yield, 84% purity) was obtained as a white solid. ’H NMR: (400 MHz, CDC13) δ = 8.03 (d, J= 1.6 Hz, 1H), 7.93 (dd, J= 1.7, 7.9 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 3.78 - 3.44 (m, 8H), 1.49 (s, 9H).

[0487] Synthesis of Compound 5

[0488] To a solution of Compound 5 (770 mg, 1.70 mmol, 1 eq) in dioxane (6 mL) was added HCl / dioxane (4 M, 2 mL) at 25 °C. The mixture was stirred at 25 °C for 14 h. The mixture was concentrated under vacuum to give a residue. Without purification. Compound 6 (600 mg, 1.54 mmol, 90.62% yield, HC1) was obtained as a white solid. LCMS: RT = 0.433 min, m / z = 355.9 (M+H)+. Synthesis of Compound 8

[0489] To a solution of compound 6 (600 mg, 1.40 mmol, 1 eq, HC1) in DCM (10 mL) was added TEA to free compound 6, the mixture was stirred at 25 °C for 30 min, the pH of the mixture was adjusted to about 5 with HO Ac, then compound 7 (298.18 mg, 2.81 mmol, 283.98 2 eq), μL, NaBH (OAC)3(893.27 mg, 4.21 mmol, 3 eq) were added. The mixture was stirred at 25 °C for 13.5 h. EtOAc (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). Combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound 8 (380 mg, 795.45μmol, 56.62% yield, 93% purity) was obtained as a yellow solid. LCMS: RT = 0.701 min, m / z = 446.0 (M+H)+.

[0490] Synthesis of Compound SC-002623

[0491] A mixture of compound 8 (60 mg, 135.05 μmol, 1 eq), compound 9 (32.93 mg, 270.10 pmol, 2 eq), Pd(dppf)Ch (9.88 mg, 13.51 μmol, 0.1 eq), KF (23.54 mg, 405.15μmol, 9.49 pL, 3 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 2 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiCh, PE: EtOAc = 2: 1). Then, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; B%: 6%-90%, 9 min). Compound SC- 002623 (11.84 mg, 25.21μmol, 18.67% yield, 94% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 8.11 (d, J= 0.9 Hz, 1H), 8.00 - 7.97 (m, 1H), 7.96 - 7.93 (m, 1H), 7.66 - 7.63 (m, 2H), 7.56 - 7.46 (m, 3H), 7.36 (d, J = 4.4 Hz, 4H), 7.32 - 7.29 (m, 1H), 3.76 (br s, 2H), 3.60 (br s, 4H), 2.58 (br s, 4H); LCMS: RT = 0.770 min, m / z = 442.2 (M+H)+.

[0492] Synthetic Scheme SC-002625:

[0493] Experimental Procedure SC-002625:

[0494] Synthesis of compound 3

[0495] 1 2

[0496] To a solution of compound 1 (5 g, 21.83 mmol, 5.00 mL, 1 eq) in CCh (100 mL) was added NBS (4.08 g, 22.92 mmol, 1.05 eq) and AIBN (179.21 mg, 1.09 mmol, 0.05 eq). The mixture was stirred at 85 °C for 6 h. The mixture was poured into H2O (100 mL), the resulting mixture was extracted with DCM (50 mL*3). The combined organic was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ethergradient @ 50 mL / min). Compound 2 (3.2 g, 10.39 mmol, 47.60% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCI3) δ = 7.85 (d, J = 8.50 Hz, 1 H), 7.64 (d, J= 1.75 Hz, 1 H), 7.52 (dd, J= 8.38, 1.88 Hz, 1 H), 4.91 (s, 2 H), 3.95 (s, 3 H). Synthesis of compound 3

[0497] To a solution of compound 2 (1.5 g, 4.87 mmol, 1 eq) in Tol. (20 mL) was added O- benzylhydroxylamine (659.82 mg, 5.36 mmol, 1.1 eq) and DIEA (1.57 g, 12.18 mmol, 2.12 mL, 2.5 eq). The mixture was stirred at 120 °C for 4 h. Then 3,4,6,7,8,9-hexahydro-2H-pyrimido[l,2- a]pyrimidine (67.80 mg, 487.07μmol, 0.1 eq) was added and the mixture was stirred at 110°C for 16 h. The mixture was filtered, the filter cake was dried under reduced pressure. Compound 3 (1.3 g, crude) was obtained as a white solid.JH NMR (400 MHz, CDCI3) δ = 7.73 (d, J= 8.00 Hz, 1 H), 7.60 (d, J = 8.13 Hz, 1 H), 7.43 - 7.50 (m, 3 H), 7.37 - 7.42 (m, 3 H), 5.16 (s, 2 H), 4.19 (s, 2 H).

[0498] Synthesis of compound 4

[0499] To a solution of compound 3 (300 mg, 942.91 μmol, 1 eq) in dioxane (3 mL) and H2O (0.6 mL) was added m-tolylboronic acid (153.83 mg, 1.13 mmol, 1.2 eq), Pd(dppf) CI2 (68.99 mg, 94.29μmol, 0.1 eq) and K2CO3 (260.63 mg, 1.89 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. The mixture was poured into H2O (10 mL), the resulting mixture was extracted with EtOAc (10 mL*3). The combined organic was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound 4 (160 mg, 485.74μmol, 51.52% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCI3) δ = 7.92 (d, J= 7.88 Hz, 1 H), 7.67 (d, J = 8.13 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.32 - 7.44 (m, 6 H), 7.22 (br d, J= 6.50 Hz, 1 H), 5.20 (s, 2 H), 4.29 (s, 2 H), 2.43 (s, 3 H). Synthesis of compound 5

[0500] To a solution of compound 4 (120 mg, 364.31 μmol, 1 eq) in EtOAc (10 mL) was added Pd / C (10%, 0.01 g) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 h. The mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound 5 (80 mg, 334.35 pmol, 91.78% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO-d6 ) δ = 10.16 (s, 1H), 7.71 - 7.84 (m, 3 H) 10.16 (s, 1 H), 7.49 - 7.57 (m, 2 H), 7.39 (t, J= 7.63 Hz, 1 H), 7.24 (br d, J= 7.50 Hz, 1 H), 4.65 (s, 2 H), 2.40 (s, 3 H).

[0501] Synthesis of compound 7

[0502] A mixture of compound 6 (55.85 mg, 250.76μmol, 1 eq), CDI (48.79 mg, 300.91 μmol, 1.2 eq), TEA (76.12 mg, 752.28 μmol, 104.71 3 eq)μ iLn, THF (1 mL) was stirred at 20 °C for 2 h. Then to the mixture was added compound 5 (60 mg, 250.76 gmol, 1 eq) and DMAP (3.06 mg, 25.08μmol, 0.1 eq) at 20 °C, the mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 1 :1). Compound 7 (70 mg, 155.03 μmol, 61.83% yield) was obtained as a white solid. Synthesis of compound 8

[0503] 8

[0504] To a solution of compound 7 (70 mg, 155.03 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 mL, 25.80 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound 8 (40 mg, crude, HC1 salt) as a white solid.

[0505] Synthesis of SC-002625

[0506] To a solution of compound 8 (40 mg, 113.83 μmol, 1 eq) in DCM (2 mL) was added TEA (11.52 mg, 113.83 μmol, 1 eq) at 20 °C over 5 min. Then compound 9 (14.50 mg, 136.60 μmol, 13.81 μL, 1.2 eq) was added and the mixture was stirred at this temperature for 1 h, and then NaBH(OAc)a (72.38 mg, 341.49μmol, 3 eq) was added. The resulting mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched by addition saturated NaHCOssolution (10 mL), and then 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 prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10um;mobile phase: [water (FA) -ACN];B%: 18%-48%, 8 min), followed by Lyophilization. Compound SC-002625 (10.08 mg, 21.69μmol, 19.05% yield, 95% purity) was obtained as a white solid.1H NMR (400 MHz, CDC13) δ = 7.94 (d, J= 7.88 Hz, 1 H), 7.70 (d, J= 8.00 Hz, 1 H), 7.62 (s, 1 H), 7.31 - 7.44 (m, 8 H), 7.23 (br d, J = 7.38 Hz, 1 H), 4.75 (s, 2 H), 3.58 - 3.83 (m, 6 H), 2.63 (br s, 4 H), 2.45 (s, 3 H); LCMS: RT = 1.630 min, m / z = 442.1 (M+H)+. Synthetic Scheme and experimental procedure SC-002628;

[0507] A mixture of Compound 2 (55.37 mg, 394.86μmol, 1 eq), CDI (76.83 mg, 473.84μmol, 1.2 eq), TEA (119.87 mg, 1.18 mmol, 164.88 3 eq) iμnL T, HF (2 mL) was stirred at 25 °C for 2 h. Then compound 1 (100 mg, 394.86 μmol, 1 eq) and DMAP (4.82 mg, 39.49μmol, 0.1 eq) were added, the mixture was stirred at 40 °C for 16 h. EtOAc (15 mL) and water (15 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (15 mL x 2). Combined organic phase was washed with brine (15 mL), dried over Na?SO4, filtered, and concentrated under vacuum 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]; B%: 19%-49%, 7 min). Then, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (ammonia hydroxide v / v) -ACN]; B%: 57%-87%, 9 min). Compound SC- 002628 (3.34 mg, 7.33 μmol, 1.86% yield, 92% purity) was obtained as a yellow gum.1H NMR: (400 MHz, CDC13) δ = 8.10 (s, 1H), 8.00 - 7.92 (m, 2H), 7.47 - 7.38 (m, 3H), 7.29 (s, 1H), 3.79 (br s, 2H), 3.62 (br s, 2H), 2.75 - 2.59 (m, 4H), 2.46 (s, 3H), 2.35 (br d, J = 6.3 Hz, 2H), 0.95 - 0.86 (m, 1H), 0.57 (br d, J = 7.4 Hz, 2H), 0.15 (br d, J = 4.8 Hz, 2H); LCMS: RT = 0.771 min, m / z = 420.3 (M+H)+.

[0508] Synthetic Scheme SC-002629; Experimental Procedure SC-002629:

[0509] Synthesis of Compound 3

[0510] To a mixture of compound 1 (130 mg, 332.81 1 μ emq,ol H, C1) in DCM (2 mL) was added TEA (33.68 mg, 332.81 μ 4m6o.3l,2 1 eqμ)L, t,he mixture was stirred at 25 °C for 10 min. Then AcOH (20.00 mg, 332.8 μ 1m eoql), was added, followed with compound 2 (55.99 mg, 665.61 μmo 2l, eq), the mixture was stirred at 25 °C for 20 min. Then NaBH(OAc)a (176.34 mg, 832.02 μmo 2l,.5 eq) was added and the mixture was stirred at 25 °C for 2 h. DCM (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with DCM (10 mL x 2). Combined organic phase was washed with brine (30 mL), dried overNa2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 45 mL / min). Compound 3 (110 mg, 250.08 μmol, 75.14% yield, 96% purity) was obtained as a white solid. LCMS: RT = 0.677 min, m / z = 424.1 (M+H)+.

[0511] Synthesis of Compound SC-002629

[0512] A mixture of compound 3 (110 mg, 260.50 1 eqμ)m, cool,mpound 4 (70.83 mg, 520.99 pmol, 2 eq), Pd(dppf)C12 (19.06 mg, 26.05 0.1 eμqm),o Kl,F (45.40 mg, 781.49 18.31 pL, μmol, 3 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 14 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ethergradient @ 35 mL / min) to give a residue. Then, the residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) - ACN]; B%: 65%-95%, 8 min). Compound SC-002629 (10.56 mg, 23.14 8.88μ%mo yli,eld, 95% purity) was obtained as a yellow gum.1H NMR: (400 MHz, CDCI3) δ = 8.09 (d, J= 0.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.91 (m, 1H), 7.48 - 7.42 (m, 2H), 7.42 - 7.37 (m, 1H), 7.29 (s, 1H), 3.73 (br s, 2H), 3.56 (br s, 2H), 2.56-2.46 (m, 5H), 2.45 (s, 3H), 2.14 - 2.04 (m, 2H), 1.99 - 1.69 (m, 6H); LCMS: RT = 0.756 min, m / z = 434.2 (M+H)+.

[0513] Synthetic Scheme SC-002632;

[0514] Experimental Procedure SC-002632:

[0515] Synthesis of Compound 2

[0516] A mixture of compound 1 (300 mg, 1.78 mmol, 1 eq), CDI (433.91 mg, 2.68 mmol, 1.5 eq) and TEA (270.78 mg, 2.68 mmol, 372.47 1.5 eq)μL in, THF (2 mL) was stirred at 25 °C for 14 h. DCM (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with DCM (30 mL x 2). Combined extracts were washed with brine (30 mL), dried overNa2SO4, filtered, and concentrated under vacuum to give a residue. Compound 2 (450 mg, 1.72 mmol, 96.19% yield) was obtained as a colorless oil. Synthesis of Compound SC-002632

[0517] A mixture of compound 2 (124.25 mg, 473.84 1μ.2m eoql,), compound 3 (100 mg, 394.86 μmol, 1 eq), TEA (99.89 mg, 987.16 13μ7m.4o0l, 2.5 eq),μ DL,MAP (4.82 mg, 39.49 pmol, 0.1 eq) in THF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 h under N2 atmosphere. EtOAc (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-36% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Then, the residue was purified by prep-HPLC (column: Waters Xbridge Cl 8 150*50 mm* lOum; mobile phase: [water (NH4HCCh)-ACN]; B%: 55%-85%, 10 min). Compound SC- 002632 (5.78 mg, 12.14 μm 3o.l0,8% yield, 94% purity) was obtained as a yellow solid. *11 NMR: (400 MHz, CDCI3) δ = 8.10 (s, 1H), 8.01 - 7.91 (m, 2H), 7.48 - 7.37 (m, 3H), 7.29 (br s, 1H), 3.77 (br s, 2H), 3.60 (br s, 2H), 3.06 (q, J = 9.4 Hz, 2H), 2.80 (br s, 4H), 2.46 (s, 3H); LCMS: RT = 1.129 min, m / z = 448.0 (M+H)+.

[0518] Synthetic Scheme SC-002326; Experimental Procedure SC-002326:

[0519] Synthesis of Compound 2

[0520] A mixture of compound 1 (500 mg, 5.87 mmol, 579.91 1 eq),μ CLD, I (1.43 g, 8.81 mmol, 1.5 eq) and TEA (1.19 g, 11.74 mmol, 1.63 mL, 2 eq) in THF (10 mL) was stirred at 25 °C for 14 h. DCM (30 mL) and water (30 mL) were added and layers were separated. The aqueous phase was extracted with DCM (30 mL x 2). Combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Without purification. Compound 2 (1 g, 5.58 mmol, 95.02% yield) was obtained as a yellow oil.

[0521] Synthesis of Compound SC-002633

[0522] A mixture of compound 2 (JQ.'l'l mg, 394.86 1 eμq)m, o clo,mpound 3 (100 mg, 394.86 pmol, 1 eq), TEA (99.89 mg, 987.16 μ 1m37o.l4, 0 2.5 eμqL),, DMAP (4.82 mg, 39.49 μmol, 0.1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 14 h under N2 atmosphere. DCM (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with DCM (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ethergradient @ 35 mL / min) to give a residue. Then, the residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50 mm* lOum; mobile phase: [water (NH4HCO3) -ACN]; B%: 55%-85%, 10 min). Compound SC-002633 (18.67 mg, 51.24 12.μ9m8%ol, yield, 100% purity) was obtained as a yellow solid. 'H NMR: (400 MHz, CDC13) δ = 8.10 (d, J= 0.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.91 (m, 1H), 7.48 - 7.42 (m, 2H), 7.42 - 7.37 (m, 1H), 7.29 (s, 1H), 3.68 (br s, 2H), 3.51 (br s, 2H), 2.46 (s, 3H), 1.69 (br s, 6H); LCMS: RT = 0.945 min, m / z = 365.2 (M+H)+. Synthetic Scheme SC-002634:

[0523] Experimental Procedure SC-002634:

[0524] Synthesis of Compound 2 A mixture of compound 1 (485.97 mg, 5.87 mmol, 579.92 1 eq), CDμIL (, 1.43 g, 8.81 mmol, 1.5 eq) and TEA (1.19 g, 11.74 mmol, 1.63 mL, 2 eq) in THF (10 mL) was stirred at 25 °C for 14 h. DCM (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with DCM (30 mL x 2). Combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Compound 2 (1.1 g, 5.69 mmol, 96.94% yield) was obtained as a yellow oil.

[0525] Synthesis of Compound SC-002634 A mixture of compound 2 (76.30 mg, 394.86 1 eqμ),m coolm, pound 3 (100 mg, 394.86 pmol, 1 eq), TEA (99.89 mg, 987.15 μ 1m37o.l4,0 2.5 eqμ)L,, DMAP (4.82 mg, 39.49 μmol, 0.1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. DCM (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with DCM (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Then, the residue was purified by prep-HPLC (column: Waters Xbridge Cl 8 150*50 mm* lOum; mobile phase: [water (NH4HCO3) -ACN]; B%: 58%-88%, 10 min). Compound SC-002634 (11.13 mg, 29.12 7.37μ%mo yli,eld, 99% purity) was obtained as a white solid. ’H NMR: (400 MHz, CDCI3) δ = 8.09 (d, J = 0.9 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.95 - 7.91 (m, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.37 (m, 1H), 7.29 (br d, J= 0.6 Hz, 1H), 4.41 - 4.02 (m, 2H), 3.16 - 2.84 (m, 2H), 2.46 (s, 3H), 1.73 (br s, 2H), 1.62 (ddd, J= 3.9, 7.0, 14.7 Hz, 1H), 1.44 - 1.23 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H); LCMS: RT = 0.994 min, m / z = 379.2 (M+H)+.

[0526] Synthetic Scheme SC-002635 and SC-002636:

[0527] Experimental Procedure for SC-002635:

[0528] Synthesis of compound 2

[0529] A mixture of compound 1 (200 mg, 1.94 mmol, 1 eq) , CDI (377.32 mg, 2.33 mmol, 1.2 eq) and TEA (392.44 mg, 3.88 mmol, 539.81 2 eq) iμnL T, HF (2 mL) was stirred at 25 °C for 2 h. To the mixture was added water (20 mL) and the resulting mixture was extracted with EtOAc (15 mL x 3), the combined organic phase was dried over Na2SO4, filtered and the filterate was concentrated under reduced pressure to give a residue. Without further purification and the products was used for next step directly. Compound 2 (380 mg, 1.93 mmol, 99.37% yield) was obtained as a yellow oil. LCMS: RT =0.318 min, m / z =198.0 (M+H)+.

[0530] Synthesis of compound SC-002635

[0531] SC-002635

[0532] A mixture of compound 4 (64.21 mg, 253.54 1 eqμ)m ,o clo, mpound 6 (50 mg, 253.54 pmol, 1 eq) , DMAP (3.10 mg, 25.35 0μ.m1 eoql,) and TEA (51.31 mg, 507.08 70.58 pL, μmol, 2 eq) in ACN (1 mL) was stirred at 40 °C for 16 h. The mixture was concentrated at 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] ;B% : 53%- 83%, 10 min) , the eluent was concentrated and then freeze dried. Compound SC-002635 (11.19 mg, 28.68 11.31% μmol, yield, 98% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.10 (d, J = 0.9 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.48 - 7.37 (m, 3H), 7.29 (br d, J= 0.6 Hz, 1H), 5.07 - 4.80 (m, 1H), 4.00 - 3.46 (m, 4H), 2.46 (s, 3H), 2.09 - 1.89 (m, 4H); LCMS: RT =0.935 min, m / z =405.2 (M+Na)+. Experimental Procedure for SC-002636:

[0533] Synthesis of compound SC-002636

[0534] A mixture of 4, 4 -difluoropiperidine (47.83 mg, 394.86 1 eqμ)m , o Cl,DI (76.83 mg, 473.83 μmol, 1.2 eq) and TEA (79.91 mg, 789.72 109μ.m92ol, 2 eq) inμ TLH, F (1 mL) was stirred at 25 °C for 2 h. To the mixture was added compound 4 (100 mg, 394.86 1 eq), μmol, DMAP (9.65 mg, 78.97 μm 0o.2l, eq) and TEA (119.87 mg, 1.18 mmol, 164.88 3 eq), then μL, the mixture was stirred at 40 °C for 16h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3 : 1, TLC : Petroleum ether : Ethyl acetate = 3 : 1, RF = 0.34) to give crude product. The crude product was purified by prep-HPLC (column : Shim-pack C18 150*25* 10um;mobile phase : [water (FA) -ACN] ;B% : 65%- 95%, 10 min), the eluent was concentrated and then freeze dried. Compound SC-002636 (7.57 mg, 18.91 μ 4m.7o9l%, yield, 100% purity) was obtained as a yellow solid ’H NMR: (400 MHz, CDC13) δ = 8.11 (s, 1H), 8.01 - 7.92 (m, 2H), 7.48 - 7.37 (m, 3H), 7.30 (s, 1H), 3.92 - 3.57 (m, 4H), 2.46 (s, 3H), 2.26 - 2.00 (m, 4H); LCMS: RT =0.943 min, m / z =401.2 (M+H)+.

[0535] Experimental procedure SC-002637:

[0536] A mixture of compound 1 (100 mg, 225.59 1 eqμ)m, cool,mpound 2 (83.05 mg, 225.59 pmol, 1 eq), PdfPPhsE (26.07 mg, 22.56 0.μ1m eoql), in Tol. (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ethergradient @ 30 mL / min) to give crude product. Then, the crude was purified by prep-TLC (SiCh, PE: EtOAc = 2: 1). Compound SC- 002637 (7.46 mg, 16.22 μ 7m.1o9l%, yield, 96% purity) was obtained as a white solid. ' H NMR: (400 MHz, CDCI3) δ = 8.77 (br d, J = 4.6 Hz, 1H), 8.55 - 8.44 (m, 2H), 7.99 (d, J= 7.9 Hz, 1H), 7.85 (br s, 2H), 7.39 - 7.29 (m, 3H), 7.25 - 7.21 (m, 1H), 7.17 (br d, J= 7.0 Hz, 2H), 4.31 (br d,

[0537] 12.8 Hz, 1H), 4.20 - 4.06 (m, 1H), 3.12 - 2.97 (m, 1H), 2.88 (br t, J = 12.0 Hz, 1H), 2.61 (br d, .7= 6.9 Hz, 2H), 1.75 (br d, J= 12.0 Hz, 3H), 1.36 (br d, J= 1.1 Hz, 2H); LCMS: RT = 0.945 min, m / z = 442.2 (M+H)+.

[0538] Experimental procedure SC-002638:

[0539] A mixture of compound 1 (60 mg, 135.35 1 eμqm),o cl,ompound 2 (18.30 mg, 148.89 pmol, 1.1 eq), Pd(dppf)C12 (9.90 mg, 13.54 0.1 eμqm)o aln, d KF (15.73 mg, 270.70 6.34 μmol, pL, 2 eq) in dioxane (3 mF) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °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=l :l to 0: 1) to give (26.24 mg, 59.44 43.91% μ ymieoldl,, 100% purity) as yellow solid. ’H NMR: (400 MHz, CDCI3) δ = 8.92 (d, J= 1.9 Hz, 1H), 8.72 (dd, J = 1.3, 4.8 Hz, 1H), 8.10 (s, 1H), 8.01 - 7.94 (m, 3H), 7.47 (dd, J= 4.8, 7.9 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.25 - 7.20 (m, 1H), 7.19 - 7.15 (m, 2H), 4.35 - 4.27 (m, 1H), 4.13 (br d, J = 11.5 Hz, 1H), 3.08 - 2.98 (m, 1H), 2.88 (br t, J = 12.1 Hz, 1H), 2.61 (d, J = 7.0 Hz, 2H), 1.80 - 1.72 (m, 3H), 1.45 - 1.31 (m, 2H); LCMS: RT = 0.824 min, m / z = 442.2 (M + H)+.

[0540] SC-002639

[0541] A mixture of compound 1 (60 mg, 135.35 1 μ eqm)o, l c,ompound 2 (18.30 mg, 148.89 pmol, 1.1 eq), Pd(dppf)C12 (9.90 mg, 13.54 0.1 μ emq)o al,nd KF (15.73 mg, 270.70 6.34 μmol, pL, 2 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °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=l :l to 0: 1) to give SC-002639 (19.88 mg, 45.03 33.27% μmol, yield, 100% purity) as yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.78 (br d, J = 5.6 Hz, 2H), 8.14 (s, 1H), 8.05 - 7.99 (m, 2H), 7.62 - 7.53 (m, 2H), 7.34 - 7.29 (m, 2H), 7.24 (d, J = 7.4

[0542] Hz, 1H), 7.17 (d, J= 7.1 Hz, 2H), 4.36 - 4.25 (m, 1H), 4.17 - 4.08 (m, 1H), 3.08 - 2.98 (m, 1H), 2.89 (br t, J = 12.1 Hz, 1H), 2.61 (d, J = 6.8 Hz, 2H), 1.80 - 1.72 (m, 3H), 1.45 - 1.32 (m, 2H); LCMS: RT = 0.799 min, m / z = 442.2 (M + H)+. Synthetic Scheme SC-002758: Experimental Procedure for SC-002758:

[0543] Synthesis of compound 3

[0544] 1 3

[0545] A mixture of compound 2 (500 mg, 1.86 mmol, 1 eq) , compound 1 (503.58 mg, 1.86 mmol, 1 eq), TEA (375.69 mg, 3.71 mmol, 516.77 uL, 2 eq) and DMAP (22.68 mg, 185.64 pmol, 0.1 eq) in ACN (5 mL) was stirred at 40 °C for 16 h. To the mixture was added compound 1 (750 mg) . The mixture was stirred at 60 °C for 24 h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 : 0 to 0 : 1, TLC : Petroleum ether / Ethyl acetate = 1 : 2, RF = 0.7) . Compound 3 (500 mg, 1.06 mmol, 57.00% yield) was obtained as white solid.1H NMR: (400 MHz, CDC13) δ = 7.32 - 7.27 (m, 2H), 7.24 - 7.19 (m, 1H), 7.17 - 7.12 (m, 2H), 4.56 (br d, J = 2.4 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.13 - 4.04 (m, 3H), 3.11 - 2.79 (m, 5H), 2.57 (d, J = 6.9 Hz, 2H), 1.72 (br d, J = 13.6 Hz, 3H), 1.49 (s, 9H), 1.42 - 1.27 (m, 2H).

[0546] Synthesis of compound 4

[0547] A mixture of compound 3 (500 mg, 1.06 mmol, 1 eq) in DCM (10 mL) and TFA (10 mL) was stirred at 25 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. Compound 4 (680 mg, crude, TFA) was obtained as a yellow gum. LCMS: RT =0.493 min, m / z =373.1 (M+H)+. Synthesis of compound SC-002758

[0548] To the mixture of compound 4 (100 mg, 205.58 1 eμqm, o TlF, A) , DIEA (79.71 mg, 616.73 μmol, 107.42 μ 3L, eq) in DCM (1 mL) was added morpholine- 4 -carbonyl chloride (30.75 mg, 205.58 μm 2o4l,.02 1 eμqL) , at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated at reduced pressure to give aresidue. The residue was purified by reversed-phase HPLC (column : Phenom enex luna C18 150*25 mm* 10um;mobile phase : [water (FA) -ACN] ;B% : 36%- 66%, 10 min) , the eluent was concentrated and then freeze dried. Compound SC-002758 (34.1 mg, 68.83 33μ.m48o%l, yield, 98% purity) was obtained as white solid. ’H NMR (400 MHz, CDCI3) δ = 7.33 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 7.14 (d, J= 7.1 Hz, 2H), 4.27 - 4.16 (m, 2H), 4.06 (dt, J= 3.2, 13.0 Hz, 3H), 3.77 - 3.58 (m, 5H), 3.40 - 3.25 (m, 4H), 3.15 (dt, J = 3.4, 12.8 Hz, 1H), 3.05 - 2.79 (m, 4H), 2.57 (d, J = 7.0 Hz, 2H), 1.82 - 1.68 (m, 3H), 1.43 - 1.24 (m, 2H); LCMS: RT =0.815 min, m / z =486.3 (M+H)+.

[0549] Experimental procedure SC-002759:

[0550] To the mixture of compound 3 (100 mg, 205.58 1 eq,μ TmFoAl,), compound 4A (36.33 mg, 267.25 μmol 1, 3.18 μ 1L.3, eq) in DCM (1 mL) was added Cu (OAc) 2 (3.73 mg, 20.56 pmol, 0.1 eq), TEA (62.41 mg, 616.73 8μ5m.8o4l, 3 eq) μ , L th,e mixture was stirred at 25 °C for 16 h under O2 (15Psi).The mixture was concentrated at reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, Petroleum ether : Ethyl acetate = 2 : 1, TLC : Petroleum ether : Ethyl acetate = 2 : 1, RF = 0.24). Compound SC-002759 (45.7 mg, 95.84 pmol, 46.62% yield, 97% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCh) 8 = 7.34 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 7.18 - 7.13 (m, 2H), 6.83 - 6.74 (m, 3H), 4.29 (dd, J= 4.4, 10.9 Hz, 1H), 4.22 (br d, J= 12.5 Hz, 1H), 4.17 - 4.01 (m, 3H), 3.68 - 3.60 (m, 1H), 3.28 (dt, J= 3.8, 12.6 Hz, 1H), 3.04 - 2.79 (m, 4H), 2.58 (d, J= 6.9 Hz, 2H), 2.34 (s, 3H), 1.83 - 1.67 (m, 3H), 1.43 - 1.25 (m, 2H); LCMS: RT =0.939 min, m / z =463.3 (M+H)+.

[0551] Synthetic Scheme SC-002761;

[0552] Experimental procedure SC-002761;

[0553] Synthesis of Compound 2

[0554] A mixture of compound 1 (3 g, 27.00 mmol, 1 eq), O-benzylhydroxylamine (3.33 g, 27.00 mmol, 1 eq), EDCI (6.21 g, 32.40 mmol, 1.2 eq), HOBt (4.38 g, 32.40 mmol, 1.2 eq) and TEA (6.83 g, 67.51 mmol, 9.40 mL, 2.5 eq) in DMF (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 14 h under N2 atmosphere. EtOAc (120 mL) and water (100 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (60 mL x 2). Combined extracts were washed with brine (50 mL), dried overNa2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-35% Ethyl acetate / Petroleum ethergradient @ 70 mL / min). Compound 2 (4.7 g, 21.30 mmol, 78.88% yield, 98% purity) was obtained as a yellow oil. LCMS: RT = 0.724 min, m / z = 217.2 (M+H)+. Synthesis of Compound 3

[0555] To a solution of Compound 2 (4.7 g, 21.74 mmol, 1 eq) and NMM (4.40 g, 43.47 mmol, 4.78 mL, 2 eq) in DCM (200 mL) was added CDI (3.88 g, 23.91 mmol, 1.1 eq) at 40 °C. After stirring for 24 h. EtOAc (60 mL) and water (60 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (60 mL x 2). Combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 45 mL / min). Compound 3 (1.5 g, 6.19 mmol, 28.49% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.59 - 7.49 (m, 2H), 7.46 - 7.36 (m, 3H), 7.23 (dd, J= 0.8, 2.9 Hz, 1H), 6.83 (dd, J= 0.8, 3.5 Hz, 1H), 6.48 (t, J= 3.3 Hz, 1H), 5.20 (s, 2H).

[0556] Synthesis of Compound 4

[0557] To a solution of compound 3 (200 mg, 825.66 1 eqμ)m ino El,tOH (2 mL) and AcOH (2 mL) was added Pd / C (20 mg, 825.66 μ 1m0%ol, purity, 1.00 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 0 °C for 1 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound 4 (100 mg, 657.43 79μ.m62o%l, yield) was obtained as a white solid1H NMR: (400 MHz, DMSO-d6) δ = 11.04 (s, 1H), 7.58 (dd, J= 0.8, 2.9 Hz, 1H), 6.96 (dd, J= 0.8, 3.4 Hz, 1H), 6.54 (t, J = 3.2 Hz, 1H).

[0558] Synthesis of Compound SC-002761

[0559] To a solution of compound 4 (100 mg, 657.43 μm 1 o elq, ) in THF (5 mL) was added compound 5 (177.07 mg, 657.43 1 μ emq)o,l T, EA (166.31 mg, 1.64 mmol, 228.76 pL, 2.5 eq) and DMAP (8.03 mg, 65.74 0μ.m1 eoql,). The mixture was stirred at 40 °C for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 53%-83%, 10 min). Compound SC-002761 (33.11 mg, 92.76 μmol, 14.11% yield, 99% purity) was obtained as an off-white solid. ’ H NMR: (400 MHz, CDCh) 5 = 7.34 - 7.28 (m, 3H), 7.26 - 7.20 (m, 1H), 7.16 (d, J= 7.1 Hz, 2H), 6.91 (d, J= 3.4 Hz, 1H), 6.54 (t, J= 3.2 Hz, 1H), 4.31 - 4.03 (m, 2H), 3.08 - 2.80 (m, 2H), 2.59 (d, J= 6.8 Hz, 2H), 1.74 (br d, J= 12.3 Hz, 3H), 1.46 - 1.23 (m, 2H); LCMS: RT = 0.982 min, m / z = 354.0 (M+H)+.

[0560] Synthetic Scheme SC-002762; Procedure SC-002762

[0561] Synthesis of compound 2

[0562] A mixture of compound 1 (500 mg, 4.00 mmol, 1 eq), O-benzylhydroxylamine (492.12 mg, 4.00 mmol, 1 eq), HOBT (647.94 mg, 4.80 mmol, 1.2 eq), EDCI (919.25 mg, 4.80 mmol, 1.2 eq) and TEA (1.01 g, 9.99 mmol, 1.39 mL, 2.5 eq) in DMF (10 mL) was stirred at 20 °C for 16 h. To the mixture was added water (60 mL) and the resulting mixture was extracted with EtOAc (50 mL x 3), the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 45-55% Ethyl acetate / Petr oleum ethergradient @ 60 mL / min; TLC (Petroleum ether: Ethyl acetate = 1 : 1; Rf = 0.52)), the eluent was concentrated. Compound 2 (720 mg, 3.13 mmol, 78.25% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCL) 5 = 9.57 (br s, 1H), 8.94 br s, 1H), 7.44 - 7.35 (m, 5H), 6.71 (br s, 1H), 6.50 (br s, 1H), 4.97 (s, 2H), 2.07 (s, 3H).

[0563] Synthesis of compound 3

[0564] A mixture of compound 2 (720 mg, 3.13 mmol, 1 eq), CDI (507.02 mg, 3.13 mmol, 1 eq) and NMM (632.55 mg, 6.25 mmol, 687.55 2 eqμ)L i,n DCM (10 mL) was stirred at 40 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 45-55% Ethyl acetate / Petroleum ethergradient @ 60 mL / min; TLC (Petroleum ether: Ethyl acetate = 1 : 1; Rf = 0.63)), the eluent was concentrated. Compound 3 (720 mg, 2.81 mmol, 89.86% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.53 (dd, J = 2.9, 6.4 Hz, 2H), 7.43 - 7.37 (m, 3H), 6.97 (s, 1H), 6.65 (s, 1H), 5.18 (s, 2H), 2.14 (s, 3H).

[0565] Synthesis of compound 4

[0566] To a solution of compound 3 (100 mg, 390.23 1 eμqm) ionl, EtOH (2 mL) and MeOH (6 mL) was added Pd / C (25 mg, 390.23 μ 1m0%ol, purity, 1 eq) under Nz atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 0 °C for 0.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 45-55% Ethyl acetate / Petroleum ethergradient @ 60 mL / min; TLC (Petroleum ether: Ethyl acetate = 3: 1; Rf = 0.19)), the eluent was concentrated. Compound 4 (60 mg, 361.15 92.5μ5m%ol y,ield) was obtained as a yellow solid.

[0567] Synthesis of compound SC-002762

[0568] A mixture of compound 4 (60 mg, 361. 15 1 eμq)m, o clo,mpound 5 (116.73 mg, 433.39 pmol, 1.2 eq), TEA (182.72 mg, 1.81 mmol, 251.34 5 eq) anμdLD, MAP (8.82 mg, 72.23 pmol, 0.2 eq) in THF (1 mL) was stirred at 60 °C for 4 h. 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* lOum; mobile phase: [water (FA) -ACN]; B%: 61%- 91%, 10 min), the eluent was concentrated and then freeze dried. Compound SC-002762 (7.77 mg, 20.94 5.80% μmol, yield, 99% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.33 - 7.28 (m, 2H), 7.25 - 7.19 (m, 1H), 7.16 (d, J = 7.0 Hz, 2H), 7.05 (s, 1H), 6.73 (s, 1H), 4.29 - 4.04 (m, 2H), 3.04 - 2.78 (m, 2H), 2.59 (d, J = 6.8 Hz, 2H), 2.17 (s, 3H), 1.82 - 1.68 (m, 3H), 1.44 - 1.25 (m, 2H); LCMS: RT = 1.014 min, m / z = 368.2 (M+H)+.

[0569] Synthetic Scheme SC-002763;

[0570] Experimental Procedure SC-002763;

[0571] Synthesis of Compound 2

[0572] A mixture of compound 1 (1 g, 7.99 mmol, 1 eq), O-benzylhydroxylamine (984.23 mg, 7.99 mmol, 1 eq), EDCI (1.84 g, 9.59 mmol, 1.2 eq), HOBt (1.30 g, 9.59 mmol, 1.2 eq) and TEA (2.02 g, 19.98 mmol, 2.78 mL, 2.5 eq) in DMF (10 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 h under N2 atmosphere. EtOAc (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (30 mL* 2). Combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 50-70% Ethyl acetate / Petroleum ethergradient @ 45 mL / min). Compound 2 (1.6 g, 6.46 mmol, 80.86% yield, 93% purity) was obtained as a yellow solid. LCMS: RT 0.829= min, m / z = 231.1 (M+H)+. Synthesis of Compound 3

[0573] To a solution of compound 2 (1.6 g, 6.95 mmol, 1 eq) and NMM (1.41 g, 13.90 mmol, 1.53 mL, 2 eq) in DCM (80 mL) was added CDI (1.35 g, 8.34 mmol, 1.2 eq) at 40 °C. After stirring for 24 h. EtOAc (60 mL) and water (60 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (60 mL 8* 2). Combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound 3 (850 mg, 3.32 mmol, 47.74% yield, 100% purity) was obtained as a yellow solid. ’ H NMR: (400 MHz, CDC13) δ = 7.54 (dd, J = 2.8, 6.3 Hz, 2H), 7.44 - 7.38 (m, 3H), 7.12 (d, J= 2.9 Hz, 1H), 6.28 (d, J= 2.8 Hz, 1H), 5.19 (s, 2H), 2.31 (s, 3H).

[0574] Synthesis of Compound 4

[0575] To a solution of compound 3 (460 mg, 1.80 mmol, 1 eq) in EtOH (2 mL) and AcOH (2 mL) was added Pd / C (20 mg, 1.80 mmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 0 °C for 1 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-35% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound 4 (210 mg, 1.26 mmol, 70.42% yield) was obtained as a yellow solid.1H NMR: (400 MHz, CDC13) δ = 7.72 (br s, 1H), 7.17 (d, J= 3.0 Hz, 1H), 6.30 (d, J= 2.9 Hz, 1H), 2.33 (s, 3H).

[0576] Synthesis of Compound SC-002763

[0577] To a solution of compound 4 (100 mg, 601.92 μm 1 o elq, ) in THF (5 mL) was added compound 5 (162.12 mg, 601.92 1 μ emq)o,l T, EA (152.27 mg, 1.50 mmol, 209.45 pL, 2.5 eq) and DMAP (7.35 mg, 60.19 0μ.m1 o elq,). The mixture was stirred at 60 °C for 4 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN];

[0578] B%: 54%-84%, 10 min). SC-002763 (38.61 mg, 101.94 16.9μ4m%ol y,ield, 97% purity) was obtained as a white solid. ’ H NMR: (400 MHz, CDCI3) δ = 7.34 - 7.28 (m, 2H), 7.25 - 7.13 (m, 4H), 6.33 (d, J= 2.9 Hz, 1H), 4.32 - 4.01 (m, 2H), 3.06 - 2.78 (m, 2H), 2.59 (d, J= 6.8 Hz, 2H), 2.34 (s, 3H), 1.73 (br d, J = 13.8 Hz, 3H), 1.47 - 1.24 (m, 2H); LCMS: RT = 0.954 min, m / z = 368.2 (M+H)+.

[0579] Synthetic Scheme SC-002766: Experimental Procedure SC-002766:

[0580] Synthesis of Compound 2

[0581] 1 2

[0582] To a mixture of IH-pyrazole (288.77 mg, 4.24 mmol, 1.5 eq) in NMP (10 mL) was added NaH (180.97 mg, 4.52 mmol, 60% purity, 1.6 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 15 min. Then compound 1 (600 mg, 2.83 mmol, 1 eq) was added. The mixture was stirred at 25 °C for 2 h 15 min. The reaction mixture was poured into saturated NH4CI aqueous solution (15 mL) and the resulting mixture was extracted with EtOAc (20 mL*3). The combined organic Layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated at reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 35 mL / min). Compound 2 (260 mg, 999.06 35.33%μm yoiel,ld, 100% purity) was obtained as a colorless oil. LCMS: RT = 0.475 min, m / z = 261.1 (M+H)+.

[0583] Synthesis of Compound 3

[0584] To a solution of compound 2 (260 mg, 999.06 1 eqμ)m inol M, eOH (4 mL) and H2O (1 mL) was added NaOH (119.88 mg, 3.00 mmol, 3 eq) at 25 °C. The mixture was stirred at 25 °C for 14 h. The reaction mixture was adjusted to pH = 3 with IN HC1. EtOAc (10 mL) and water (10 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (10 mL * 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound 3 (130 mg, 559.88 56.04% yieμldm)o wl,as obtained as a white solid. LCMS: RT = 0.516 min, m / z = 233.1 (M+H)+. Synthesis of Compound 4

[0585] A mixture of compound 4 (130 mg, 559.88 1 eμqm) o aln,d Ac?O (2.18 g, 21.35 mmol, 2 mL, 38.14 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 4 h under N2 atmosphere. The reaction was concentrated under vacuum to give compound 5 (130 mg, 412.74 μmo 7l,3.72% yield, 68% purity) was obtained as a white solid. LCMS: RT = 0.552 min, m / z = 215.0 (M+H)+.

[0586] Synthesis of Compound 5

[0587] A mixture of compound 4 (80 mg, 373.52 1 eqμ)m aonld, hydroxylamine; hydrochloride (80.00 mg, 1.15 mmol, 3.08 eq) in Py (1 mL) was heated at 80 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (SiO2, PE: EtOAc = 0:1). Compound 5 (50 mg, 202.89 46.5μ0m%ol, yield, 93% purity) was obtained as a white solid. LCMS: RT = 0.488 min, m / z = 230.0 (M+H)+.

[0588] Synthesis of Compound SC-002766 To a solution of compound 5 (50 mg, 218.16 μm 1ol, eq) in THF (2 mL) was added compound 6 (58.76 mg, 218.16 pmol, 1 eq), TEA (66.23 mg, 654.48 91.09 pL,μm 3 ol, eq) and DMAP (2.67 mg, 21.82 μ 0m.1ol e, q). The mixture was stirred at 60 °C for 14 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 54%-84%, 10 min). Compound SC-002766 (5.29 mg, 12.29 μmol, 5.63% yield, 100% purity) was obtained as a yellow solid.1H NMR: (400 MHz, CDCI3) δ = 8.23

[0589] - 8.14 (m, 2H), 8.06 (d, J= 2.5 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.35

[0590] - 7.29 (m, 2H), 7.25 - 7.20 (m, 1H), 7.20 - 7.14 (m, 2H), 6.62 - 6.55 (m, 1H), 4.43 - 4.05 (m, 2H), 3.16 - 2.79 (m, 2H), 2.61 (d, J= 7.0 Hz, 2H), 1.75 (br d, J = 14.1 Hz, 3H), 1.49 - 1.32 (m, 2H); LCMS: RT = 0.948 min, m / z = 431.2 (M+H)+.

[0591] Synthetic Scheme SC-002770;

[0592] Experimental Procedure SC-002770:

[0593] Synthesis of compound 3

[0594] 1 3

[0595] To a mixture of compound 2 (3.22 g, 24.34 mmol, 2.80 mL, 4 eq) in DMF (30 mL) was added NaH (730.23 mg, 18.26 mmol, 60% purity, 3 eq) at °C, then the mixture stirred at 0 °C for 0.5 h. Then compound 1 (1.9 g, 6.09 mmol, 1 eq) was added at 0 °C, the mixture was stirred at 50 °C for 15.5 h. The mixture was poured into sat. NH4CI (10 mL) and the resulting mixture was extracted with EtOAc (10 mL * 2). The combined organic layers were washed with brine (10 mL * 2), dried over NazSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% NH3 H2O condition), the eluent was concentrated and then freeze dried to give compound 3 (1.5 g, 4.13 mmol, 67.82% yield, 100% purity) as white solid. 'H NMR: (400 MHz, CDCI3) δ = 7.38 - 7.29 (m, 5H), 5.12 (s, 2H), 4.17 (br s, 2H), 3.75 (s, 6H), 3.48 (t, J = 7.6 Hz, 1H), 2.75 (br s, 2H), 1.87 (t, J = 7.3 Hz, 2H), 1.69 (br d, J= 11.9 Hz, 2H), 1.43 (dtd, J= 3.6, 7.4, 14.8 Hz, 1H), 1.18 - 1.08 (m, 2H).

[0596] Synthesis of compound 4

[0597] A mixture of compound 3 (500 mg, 1.38 mmol, 1 eq) in THF (10 mL) was added HBH4 (119.89 mg, 5.50 mmol, 4 eq) at 0 °C under N2 atmosphere. Then the mixture was stirred 20 °C for 16 h. The reaction mixture was poured into sat. NH4CI (30 mL) and the resulting mixture was extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (0.1% NH3 H2O condition), the eluent was concentrated and then freeze dried to give compound 4 (420 mg, 1.16 mmol, 84.41% yield, 85% purity) as white solid.1H NMR: (400 MHz, CDC13) δ = 7.41 - 7.28 (m, 4H), 5.13 (s, 2H), 4.24 - 4.11 (m, 2H), 4.07 - 3.97 (m, 1H), 3.82 (dd, J = 3.6, 10.6 Hz, 1H), 3.65 (dd, J= 7.4, 10.6 Hz, 2H), 2.77 (br s, 2H), 1.94 - 1.85 (m, 1H), 1.73 - 1.67 (m, 2H), 1.50 (dtd, J= 3.7, 7.3, 14.7 Hz, 1H), 1.16 - 1.09 (m, 4H);

[0598] Synthesis of compound 5 To a mixture of compound 4 (120 mg, 259.98 1 eμqm)o iln, DMF (2 mL) was added NaH (20.80 mg, 519.96 μm 6o0l%, purity, 2 eq) at 0 °C. Then the mixture was stirred at 60 °C for 16 h. The mixture was poured into sat. NH4CI (10 mL) and the resulting mixture was extracted with EtOAc (10 mL * 2). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 5 (50 mg, 122.68 μmol 4,7.19% yield, 71% purity) as a white solid.

[0599] Synthesis of compound 6

[0600] To a mixture of compound 5 (93 mg, 201.49 1 eq)μm ino Dl,MF (3 mL) was added NaH (16.12 mg, 402.97 μmo 6l0,% purity, 2 eq) at 0 °C. Then the mixture stirred at 60 °C for 16 h. The mixture was poured into sat. NH4CI (10 mL) and the resulting mixture was extracted with EtOAc (10 mL x* 2). The combined organic layers were washed with brine (10 mL *2), dried over Na2SO4, filtered and concentrated under reduced pressure to give to give compound 6 (40 mg, crude) as white solid. ’H NMR: (400 MHz, CDC13) δ = 7.28-7.24 (m, 5H), 5.06 (s, 2H), 4.70 (dd, J= 5.9, 7.7 Hz, 2H), 4.30 (t, J = 6.2 Hz, 2H), 3.07 - 2.99 (m, 1H), 2.71 - 2.61 (m, 2H), 1.96 (s, 1H), 1.58 (br t, J= 7.2 Hz, 2H), 0.82 - 0.75 (m, 5H);

[0601] Synthesis of compound 7

[0602] To a mixture of compound 6 (40 mg, 138.23 1 μ emq)o iln, MeOH (5 mL) was added Pd / C (4 mg, 10% purity), the mixture was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 16 h. The mixture was concentrated under reduced pressure to give compound 7 (50 mg, crude) as white solid. Synthesis of compound SC-002901

[0603] A mixture of compound 7 (50 mg, 322.09 μm 1 o elq,), di(imidazol-l-yl)methanone (104.45 mg, 644.18 μmo 2l, eq), TEA (97.78 mg, 966.27 13μ4m.49ol, 3 eq) inμL T,HF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 3 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1% TFA condition), the eluent was concentrated and then freeze dried to give imidazol-l-yl-[4-(oxetan-3-ylmethyl)-l- piperidyl]methanone (20 mg, 67.39 20μ.9m2o%l, yield, 84% purity) as white solid.

[0604] A mixture of imidazol-l-yl-[4-(oxetan-3-ylmethyl)-l-piperidyl]methanone (20 mg, 160.44 μmol, 1 eq), compound 8 (48.76 mg, 192.53 1.2 eq)μ,m ToElA, (32.47 mg, 320.89 pmol, 44.66 μL, 2 eq), DMAP (1.96 mg, 16.04 0μ.m1 eoql,) in THF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °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: UniSil 3-100 C18 Ultra (150*25mm*3um);mobile phase: [water(FA)- ACN];B%: 61%-81%,7min) to give SC-002770 (3.61 mg, 8.31 5. 18%μ ymieolld, , 100% purity) as off-white gum. ’H NMR: (400 MHz, CDC13) δ = 8.09 (s, 1H), 7.99 - 7.92 (m, 2H), 7.46 - 7.38 (m, 3H), 7.29 (br s, 1H), 4.82 (dd, J = 5.9, 7.8 Hz, 2H), 4.42 (t, J = 6.2 Hz, 2H), 4.35 - 4.28 (m, 1H), 4.18 - 4.09 (m, 1H), 3.18 - 3.10 (m, 1H), 3.09 - 2.99 (m, 1H), 2.93 - 2.84 (m, 1H), 2.46 (s, 3H), 1.74 (t, J = 7.1 Hz, 2H), 1.68 - 1.65 (m, 1H), 1.51 - 1.41 (m, 2H), 1.39 - 1.25 (m, 2H); LCMS: RT = 0.647 min, m / z = 457.2 (M+H)+.

[0605]

[0606] Experimental Procedure SC-002794:

[0607] Synthesis of compound 2

[0608] To a solution of compound 1 (5 g, 21.83 mmol, 5.00 mL, 1 eq) in CC14 (100 mL) was added NBS (4.08 g, 22.92 mmol, 1.05 eq) and AIBN (179.21 mg, 1.09 mmol, 0.05 eq). The mixture was stirred at 80 °C for 19 h. The reaction mixture was quenched by addition of H2O (100 mL) and then the mixture was extracted with DCM (100 mL * 3). The combined organic layers were washed brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ethergradient @ 40 mL / min), followed by concentration. Compound 2 (550 mg, 1.45 mmol, 6.63% yield, 81% purity) was obtained as a white solid. 1H NMR (400 MHz, CDCI3) δ = 7.85 (d, J= 8.5 Hz, 1H), 7.64 (d, J= 1.8 Hz, 1H), 7.52 (dd, J= 1.8, 8.4 Hz, 1H), 4.91 (s, 2H), 3.88 (s,

[0609] 3H). LCMS: RT = 0.506 min, m / z = 330.1 (M+H)+. Synthesis of compound 4

[0610] To a solution of compound 2 (1.7 g, 5.52 mmol, 1 eq) in Tol. (20 mL) was added DIEA (1.78 g, 13.80 mmol, 2.40 mL, 2.5 eq) and compound 3 (762.63 mg, 6.07 mmol, 1.1 eq). The mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched by addition ofFLO (10 mL), and then the mixture was extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 50 mL / min). Compound 4 (189 mg, 439.00 7.95% yμiemldo,l 6, 6% purity) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.82 - 7.77 (m, 2H), 7.73 - 7.68 (m, 1H), 7.64 - 7.64 (m, 1H), 7.66 - 7.61 (m, 1H), 5.40 (s, 2H), 4.67 (s, 2H), 1.31 (s, 9H). LCMS: RT = 0.495 min, m / z = 228(M+H)+.

[0611] Synthesis of compound 5

[0612] To a solution of compound 4 (400 mg, 1.41 mmol, 1 eq) in DCM (2 mL) was added TFA (10.78 g, 94.54 mmol, 7 mL, 67.16 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 5 (380 mg, crude, TFA) was obtained as a white solid. Synthesis of compound 7

[0613] A mixture of compound 6 (89.84 mg, 482.37 gmol, 1.1 eq), CDI (85.33 mg, 526.22 gmol, 1.2 eq), TEA (133.12 mg, 1.32 mmol, 183.11 gL, 3 eq) in THF (1 mL) was stirred at 25 °C for 2 h. Then compound 5 (100 mg, 438.51 gmol, 1 eq), DMAP (5.36 mg, 43.85 gmol, 0.1 eq) and TEA (88.75 mg, 877.03 gmol, 122.07 gL, 2 eq) was added, the resulting mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted with H2O (10 mL), and then the resulting mixture was extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL562), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 40 mL / min), followed by concentration. Compound 7 (100 mg, 174.89 gmol, 39.88% yield, 77% purity) was obtained as a white solid. LCMS: RT = 0.478 min, m / z = 446.0 (M+H)+.

[0614] Synthesis of compound 9

[0615] To a solution of compound 7 (100 mg, 227.12 gmol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 1 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue (70 mg, 205.78 gmol, 1 eq) in DCM (1 mL) was added compound 8 (24.02 mg, 226.36 gmol, 22.88 gL, 1.1 eq) and the mixture was stirred at 25 °C for 30 min. Then the NaBH(OAc)a (109.03 mg, 514.45 gmol, 2.5 eq) and TEA was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (10 mL) and the mixture was extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, Petroleum ether : Ethyl acetate = 2: 1), followed by concentration. Compound 9 (70 mg, 144.78 μmol 7, 0.36% yield, 89% purity) was obtained as some white oil. *11 NMR (400 MHz, CDCI3) δ = 7.76 (d, J= 8.0 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.41 - 7.28 (m, 5H), 4.68 (s, 2H), 3.77 - 3.49 (m, 6H), 2.53 (br s, 4H); LCMS: RT = 0.349 min, m / z = 431.3 (M+H)+.

[0616] Synthesis of compound SC-002794

[0617] To a mixture of compound 9 (35 mg, 81.34 1 μ emq)o al,nd compound 10 (11.90 mg, 97.61 μmol, 1.2 eq) in dioxane (1 mL) and H2O (0.2 mL) was added Pd(dppf)C12 (5.95 mg, 8.13 pmol, 0.1 eq) and K2CO3 (22.48 mg, 162.68 2 eμqm). o Tl,he mixture was stirred at 80 °C for 2h. The reaction mixture was diluted with H2O (10 mL) and the mixture was extracted with EtOAc (10 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: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 18%-48%,10min), followed by lyophilization. Compound SC-002794 (24 mg, 52.77 μmo 6l,4.88% yield, 94% purity) was obtained as a white solid. ’ H NMR (400 MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.84 (s, 2H), 7.74 (br d, J = 7.5 Hz, 2H), 7.52 (br t, J = 7.4 Hz, 2H), 7.47 - 7.41 (m, 1H), 7.37 - 7.31 (m, 4H), 7.28 (br dd, J= 2.8, 7.9 Hz, 1H), 4.77 (s, 2H), 3.57 (br d, J = 1.6 Hz, 2H), 3.54 (s, 2H), 3.48 - 3.41 (m, 2H), 2.52-2.45 (m, 4H); LCMS: RT = 1.647 min, m / z = 428.3 (M+H)+. Experimental Procedure SC-002867:

[0618] Synthesis of compound 2

[0619] To a solution of compound 1 (2 g, 8.73 mmol, 1 eq) in CCk (40 mL) was added NBS (1.63 g, 9.17 mmol, 1.05 eq) and AIBN (71.68 mg, 436.55 0.0μ5m eoql),. The mixture was stirred at 80 °C for 16 h. The mixture was poured into H2O (100 mL), the resulting mixture was extracted with DCM (50 mL*3). The combined organic was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ethergradient @ 60 mL / min), followed by concentration. Compound 2 (2.17 g, 7.05 mmol, 80.70% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCI3) 5 = 8.12 (d, J= 2.0 Hz, 1H), 7.63 (dd, J= 2.0, 8.3 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 4.91 (s, 2H), 3.96 (s, 3H).

[0620] Synthesis of compound 3

[0621] To a solution of compound 2 (1 g, 3.25 mmol, 1 eq) in Tol. (15 mL) was added DIEA (1.05 g, 8.12 mmol, 1.41 mL, 2.5 eq) and O-benzylhydroxylamine (439.88 mg, 3.57 mmol, 1.1 eq). The mixture was stirred at 110 °C for 16 h. LC-MS showed -40% of compound 2 was remained and -10% of compound 3 was detected. Then TBD (45.20 mg, 324.71 μmol, 0.1 eq) was added into the mixture and the resulting mixture was stirred at 110 °C for another 16 h. The mixture was followed by filtration, the filter cake was dried under reduce pressure. Compound 3 (360 mg, 1.13 mmol, 34.85% yield, 100% purity) was obtained as a white solid. LCMS: RT = 0.442 min, m / z = 340.1(M+Na)+. Synthesis of compound 5

[0622] To a solution of compound 3 (360 mg, 1.13 mmol, 1 eq) in dioxane (4 mL) and H2O (0.8 mL) was added compound 4 (165.55 mg, 1.36 mmol, 1.2 eq), Pd(dppf) CI2 (82.79 mg, 113.15 pmol, 0.1 eq) and K2CO3 (312.76 mg, 2.26 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. The residue was diluted with H2O (20 mL) and the resulting mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over NaiSCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ethergradient @ 40 mL / min), followed by concentration. Compound 5 (350 mg, 1.11 mmol, 98.09% yield, 100% purity). LCMS: RT = 0.493min, m / z = 316.2 (M+H)+.

[0623] Synthesis of compound 6

[0624] To a solution of compound 5 (200 mg, 634.19 1 eqμ)m inol E, tOAc (10 mL) was added Pd / C (10%, 20 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The mixture was followed by filtration, the filtrate was concentrated under reduced pressure to give compound 6 (90 mg, 387.58 umol, 61.11% yield, 97% purity) as a white solid. Synthesis of compound 8

[0625] A mixture of compound 7 (69.21 mg, 310.78 pmol, 1 eq, HC1), CDI (60.47 mg, 372.93 pmol, 1.2 eq), TEA (94.34 mg, 932.33 pmol, 129.77 pL, 3 eq) in THF (1 mL) was stirred at 25 °C for 2 h. Then to the mixture was added compound 6 (70 mg, 310.78 pmol, 1 eq), TEA (62.89 mg, 621.55 pmol, 86.51 pL, 2 eq) and DMAP (3.80 mg, 31.08 pmol, 0.1 eq), the mixture was stirred at 40 °C for 16 h. The mxiture was diluted with H2O (10 mL) and the resulting mixture was extracted with EtOAc (15 mL * 3). The combined organic layers were dried over NaSCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ethergradient @ 20 mL / min). Compound 8 (30 mg, 68.57 pmol, 22.07% yield) was obtained as a white solid.

[0626] Synthesis of compound 9

[0627] To a solution of compound 8 (20 mg, 45.72 μmol, 1 eq )in THF (1 mL) was added HCI / dioxane (4 M, 22.86 pL, 1 eq). The mixture was stirred at 25 °C for 1 h. The filtrate was concentrated in vacuum to give compound 9 (17 mg, crude, HC1) as a white solid. LCMS: RT = 0.352 min, m / z = 338.2 (M+H)+. Synthesis of compound SC-002867

[0628] To a solution of compound 9 (17 mg, crude, HC1) in DCM (1 mL) was added TEA (13.50 mg, 133.38 μmol 1,8.56 3μ eLq,). The mixture was stirred at 25 °C for 10 min. Then the NaBH (OAC)3(23.56 mg, 111.15 μm 2o.5l, eq) and compound 10 (5.19 mg, 48.91 4.94 gLμm, ol, 1.1 eq) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 17%-47%, 10 min), followed by lyophilization. Compound SC-002867 (5 mg, 10.76 2μ4m.2o0l,% yield, 92% purity) was obtained as a white solid. ’ H NMR (400 MHz, CDC13) δ = 8.11 (s, 1H), 7.86 - 7.82 (m, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.52 - 7.46 (m, 4H), 7.43 - 7.32 (m, 5H), 4.75 (s, 2H), 3.80 - 3.48 (m, 6H), 2.72 - 2.41 (m, 4H). LCMS: RT = 1.754 min, m / z = 428.1(M+H)+.

[0629] Experimental Procedure SC-002910:

[0630] A mixture of compound 1 (50 mg, 134.26 1 eμqm),ol c,ompound 2 (18.39 mg, 134.26 pmol, 1 eq), Cu (OAc)2 (2.44 mg, 13.43 0.μ1m eoql), and TEA (40.76 mg, 402.77 56.06 μmol, pL, 3 eq) in DCM (1 mL) was stirred under 02 (15 Psi) at 25 °C for 16 h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 0: 1, TLC: Petroleum ether: Ethyl acetate = 0: 1, RF = 0 14) to give a crude product. The crude was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 19%- 49%, 10 min). Compound SC-002910 (1.71 mg, 3.39 2.μ5m3%ol, yield, 92% purity) was obtained as an off white solid. ’ H NMR: (400 MHz, CDCI3) δ = 8.27 - 7.95 (m, 2H), 7.33 - 7.28 (m, 2H), 7.24 - 7.19 (m, 1H), 7.15 (d, J = 6.9 Hz, 2H), 7.09 (s, 1H), 4.30 (dd, J = 4.3, 11.0 Hz, 1H), 4.26 - 4.14 (m, 2H), 4.14 - 3.99 (m, 2H), 3.70 - 3.60 (m, 1H), 3.29 (dt, J = 2.9, 12.7 Hz, 1H), 3.04 - 2.77 (m, 4H), 2.58 (d, J = 6.9 Hz, 2H), 2.33 (s, 3H), 1.74-1.60 (m, 3H), 1.40 - 1.28 (m, 2H); LCMS: RT =0.661 min, m / z =464.4 (M+H)+.

[0631] Experimental Procedure SC-003056:

[0632] A mixture of compound 1 (50 mg, 134.26 1 eqμ)m, 3ol -,pyridylboronic acid (19.80 mg, 161.11 μmol, 1.2 eq), DIEA (52.06 mg, 402.77 70μ.1m6ol, 3 eq) anμdL C, u(OAc)2(2.44 mg, 13.43 μmol, 0.1 eq) in DCM (2 mL) was stirred under O2(15 psi) at 40 °C for 16 h. The reaction mixture was directly purified by column chromatography (SiO 2, Petroleum ether / Ethyl acetate = 0 / 1, TLC (Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.43) to give a crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* lOum; mobile phase: [water (FA) -ACN]; B%: 15%- 45%, 10 min) to give SC-003056 (890.00 ug, 1.86 μmol, 1.39% yield, 94% purity) as off white solid. 'H NMR: (400 MHz, CDCI3) δ = 8.38 - 8.35 (m, 1H), 8.23 (br s, 1H), 7.33 - 7.28 (m, 2H), 7.26 - 7.19 (m, 3H), 7 15 (br d, J = 7.3 Hz, 2H), 4.35 - 4.26 (m, 1H), 4.26 - 4.14 (m, 2H), 4.12 - 4.00 (m, 2H), 3.76 - 3.61 (m, 2H), 3.35 - 3.24 (m, 1H), 3.01 - 2.93 (m, 2H), 2.89 - 2.80 (m, 1H), 2.58 (br d, J = 6.5 Hz, 2H), 1.73 (br d, J = 11.7 Hz, 3H), 1.38 - 1.30 (m, 2H); LCMS: RT = 0.474 min, m / z = 450.1 (M+H)+.

[0633]

[0634] Experimental Procedure SC-003057:

[0635] Synthesis of Compound 2

[0636] 2

[0637] A mixture of compound 1 (300 mg, 1.78 mmol, 1 eq), CDI (433.91 mg, 2.68 mmol, 1.5 eq) and TEA (361.05 mg, 3.57 mmol, 496.62 2 eq)μ iLn, THF (6 mL) was stirred at 60 °C for 14 h. EtOAc (30 mL) and water (30 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). Combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Compound 2 (499 mg, crude) was obtained as a yellow oil. LCMS: RT = 0.353 min, m / z = 263.1 (MTH)+.

[0638] Synthesis of compound 4 To the mixture of compound 2 (413.79 mg, 1.53 mmol, 1 eq), compound 3 (400 mg, 1.53 mmol, 1 eq) in THF (10 mL) was added TEA (463.06 mg, 4.58 mmol, 636.94 3 eq), DMAPμL, (18.64 mg, 152.54 μm 0o.l1, eq). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound 4 (242 mg, 441.96 28.97% μmol, yield, 85% purity) was obtained as a white solid. LCMS: RT = 0.540 min, m / z = 410.1 (M+H- tBu)+.

[0639] Synthesis of compound 5

[0640] To a solution of compound 4 (242 mg, 519.96 1 eμqm) ionl, EtOAc (9 mL) was added HCl / EtOAc (4 M, 3 mL) at 25 °C. The mixture was stirred at 25 °C for 14 h. The mixture was concentrated under vacuum to give a residue. Compound 6 (300 mg, crude, HC1) was obtained as a white solid. LCMS: RT = 0.370 min, m / z = 366.1 (M+H)+.

[0641] Synthesis of Compound SC-003057

[0642] A mixture of compound 6 (200 mg, 497.80 1 eqμ,m HoCl,1), phenylboronic acid (72.84 mg, 597.36 μmo 1l,.2 eq), DIEA (193.01 mg, 1.49 mmol, 260.12 3 eq) and μ CLu,(OAc)2 (9.04 mg, 49.78 μmol 0, .1 eq) in DCE (8 mL) was stirred under O2 (15 psi) at 80 °C for 3 h. The mixture was filtered and the filtrate was concentrated under vacuum 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]; B%: 50%-80%, 10 min). Compound SC-003057 (32.97 mg, 73.95 μmol, 14.85% yield, 99% purity) was obtained as a yellow gum.1H NMR: (400 MHz, CDCI3) δ = 7.32 (t, J= 8.0 Hz, 2H), 7.05 - 6.91 (m, 3H), 4.31 (dd, J= 4.4, 10.9 Hz, 1H), 4.15 (br dd, J= 2.6, 13.3 Hz, 1H), 4.06 (ddd, J= 1.4, 4.2, 12.3 Hz, 1H), 3.73 - 3.62 (m, 3H), 3.57 (br s, 2H), 3.29 (dt, J = 3.8, 12.7 Hz, 1H), 3.03 (q, J= 9.4 Hz, 2H), 2.96 - 2.85 (m, 2H), 2.77 (br s, 4H); LCMS: RT = 0.546 min, m / z = 442.3 (M+H)+.

[0643] Experimental Procedure SC-003143;

[0644] To the mixture of compound 1 (500 mg, 1.03 mmol, 1 eq, TFA), 3-thienylboronic acid (1.05 g, 8.22 mmol, 8 eq) in DCM (20 mL) was added DIEA (531.38 mg, 4.11 mmol, 716.15 pL, 4 eq), Cu(OAc)2 (373.39 mg, 2.06 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h under air condition. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiC>2, Petroleum ether / Ethyl acetate = 1 : 1, TLC: Petroleum ether / Ethyl acetate = 1 : 1, Rf = 0.3) to give crude product. The crude was purified by prep-HPLC (column: YMC-Actus Triart Cl 8 150*30 mm*7um; mobile phase: [water (FA) -ACN]; gradient: 63%-93% B over 60 min) to give SC-003143 (3.93 mg, 8.30 8.08e- μmol, 1% yield, 96% purity) as off-white solid.1H NMR: (400 MHz, CDCI3) δ = 7.33 - 7.28 (m, 3H), 7.24 - 7.19 (m, 1H), 7.15 (d, J = 7.0 Hz, 2H), 6.87 (dd, J = 1.5, 5.3 Hz, 1H), 6.33 (dd, J = 1.6, 3.0 Hz, 1H), 4.32 (dd, J = 4.5, 11.0 Hz, 1H), 4.21 (br d, J = 14.1 Hz, 1H), 4.17 - 4.04 (m, 2H), 3.95 (br dd, J = 4.0, 12.1 Hz, 1H), 3.54 (br dd, J = 1.6, 11.0 Hz, 1H), 3.29 (dt, J = 3.8, 12.8 Hz, 1H), 3.02 - 2.78 (m, 4H), 2.58 (d, J = 6.9 Hz, 2H), 1.78 - 1.69 (m, 3H), 1.38 - 1.26 (m, 2H); LCMS: RT = 0.604 min, m / z = 455.2 (M+H)+. Experimental Procedure SC-003145:

[0645] Synthesis of compound 3

[0646] To the mixture of compound 1 (275 mg, 565.33 1 eq,μ TmFoAl,) and DIEA (365.33 mg, 2.83 mmol, 492.35 μ 5L e,q) in DCM (3 mL) was added compound 2 (63.85 mg, 565.33 pmol, 45.03 μL, 1 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 16 h. The residue was diluted with H2O (30 mL) and the resulting mixture was extracted with Ethyl acetate (30 mL * 3). The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 3 (313 mg, crude) was obtained as a brown oil.

[0647] Synthesis of compound SC-003145

[0648] To the mixture of compound 3 (313 mg, 697.26 1 eqμ)m inol E, tOH (4 mL) was added compound 4 (52.39 mg, 697.26 μm 1 o elq, ). The mixture was stirred at 90 °C for 2 h. The mixture was diluted with H2O (30 mL) and the resulting mixture was extracted with Ethyl acetate (40 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-TLC (SiO2, Petroleum ether: Ethyl acetate = 1 : 1, Rf = 0.44) to give crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 50%- 80% B over 9 min). CompoundSC-003145 (2.76 mg, 5.64 8.09e- μmol, 1% yield, 96% purity) was obtained as an off-white solid.1H NMR: (400 MHz, CDCI3) δ = 7.29 (d, J = 7.6 Hz, 2H), 7.25 - 7.19 (m, 1H), 7.15 (d, J = 7.0 Hz, 2H), 5.86 (s, 1H), 4.37 - 4.04 (m, 5H), 3.94 (br dd, J = 3.1, 12.9 Hz, 1H), 3.28 (dt, J = 3.5, 12.8 Hz, 1H), 3.04 - 2.79 (m, 4H), 2.64 (s, 3H), 2.58 (d, J = 7.0 Hz, 2H), 1.72 (br d, J = 13.4 Hz, 3H), 1.40 - 1.25 (m, 2H); LCMS: RT = 0.615 min, m / z =470.3 (M+H)+.

[0649] Synthetic Scheme SC-003541:

[0650] Experimental Procedure SC-003541:

[0651] Synthesis of compound 3 To a solution of compound 1 (5 g, 23.14 mmol, 1 eq) in dioxane (50 mL) / H2O (10 mL) was added compound 2 (4.25 g, 34.86 mmol, 1.51 eq), NaHCCL (2.5 g, 29.76 mmol, 1.16 mL, 1.29 eq) and Pd(dppf)C12 (1.50 g, 2.05 mmol, 8.86e- 2 eq), then the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by addition of H2O (300 mL), and then the resulting mixture was extracted with EtOAc (100 mL *3). The combined organic layers were dried over Na2S€)4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-44% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give compound 3 (1.5 g, 4.36 mmol, 18.84% yield, 62% purity) as a yellow oil. LCMS: RT = 0.485 min, m / z = 214.2 (M+H)+. Synthesis of compound 4

[0652] To a solution of compound 3 (2 g, 9.38 mmol, 1 eq) in AcOH (10 mL) was added PtCh (500 mg, 2.20 mmol, 2.35e- 1 eq) under N2, then the mixture was stirred under H2 (30 psi) at 50

[0653] °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 4 (2.1 g, crude) as white solid.

[0654] Synthesis of compound 5

[0655] A solution of compound 4 (2 g, 9.12 mmol, 1 eq) in HCI (2 M, 15 mL, 3.29 eq) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 5 (1.3 g, 6 33 mmol, 69.44% yield) was obtained as a yellow solid and used into the next step without further purification.

[0656] Synthesis of compound 7 To a solution of compound 6 (1 g, 8.12 mmol, 1.39 eq) in DCM (20 mL) was added NMM (600 mg, 5.93 mmol, 652.17 1.0μL1 , eq) and CDI (1 g, 6.17 mmol, 1.05 eq), the mixture was stirred at 20 °C for 2 h, compound 5 (1.2 g, 5.85 mmol, 1 eq) and NMM (1.8 g, 17.80 mmol, 1.96 mL, 3.04 eq) were added, then the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition of H2O (300 mL), and then the resulting mixture was extracted with EtOAc (100 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 flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-32% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give compound 7(500 mg, 1.23 mmol, 19.54% yield, 83% purity) as a colorless oil. LCMS: RT = 0.546 min, m / z = 359.2 (M+Na)+.

[0657] Synthesis of compound 8

[0658] To a solution of compound 7 (200 mg, 594.56 1 eqμ)m inol E, tOAc (10 mL) was added Pd / C (200 mg, 187.93 μm 1o0l,% purity, 3.16e- 1 eq) under N2, then the mixture was stirred under H2 (30 psi) at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 8 (60 mg, crude) as colorless oil.

[0659] Synthesis of compound SC-003541 To a solution of compound 8 (50 mg, 203.04 1μm eqo)l, in THF (1 mL) was added compound 9 (60 mg, 228.81 μ 1m.1o3l, eq), TEA (40 mg, 395.30 55.02 μmo 1l.9, 5 eq) andμL, DMAP (2 mg, 16.37 μm 8o.l0, 6e- 2 eq), then the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched by addition of H2O (30 mL), and then the resulting mixture was extracted with EtOAc (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: Phenomenex luna C18 150*25 mm* lOum; mobile phase: [water (FA) - ACN]; gradient: 48%- 78% B over 8 min) to give compound SC-003541 (45.46 mg, 100.95 pmol, 49.72% yield, 97.8% purity) as a white solid. ’H NMR: (400 MHz, CDCI3) δ = 7.40 - 7.33 (m, 2H), 7.29 (s, 1H), 7.22 (d, J = 7.2 Hz, 2H), 4.34 (dd, J = 3.9, 13.9 Hz, 1H), 4.12 (dd, J =

[0660] 4.2, 12.0 Hz, 1H), 3.78 - 3.57 (m, 4H), 3.15 - 3.01 (m, 3H), 2.91 - 2.76 (m, 5H), 2.47 (br d, J = 12.8 Hz, 1H), 2.00 (br d, J = 13.6 Hz, 1H), 1.75 (dq, J = 4.7, 12.7 Hz, 2H); LCMS: RT = 0.550 min, m / z = 441.2 (M+H)+. Synthetic Scheme SC-003542:

[0661] Experimental Procedure SC-003542:

[0662] Synthesis of compound 3 To the mixture of compound 1 (1 g, 4.99 mmol, 1 eq) in EtOH (10 mL) was added DIEA (2.58 g, 19.97 mmol, 3.48 mL, 4 eq) and compound 2 (1.16 g, 4.99 mmol, 1 eq). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue 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). Compound 3 (625 mg, 2.10 mmol, 42.12% yield, 95% purity) was obtained as a yellow oil.1H NMR: (400 MHz, CDC13) δ = 4.20 (br s, 1H), 3.80 (br d, J = 13.3 Hz, 1H), 3.11 (dt, J = 3.4, 12.7 Hz, 1H), 2.94 (dq, J = 2.1, 9.4 Hz, 2H), 2.83 (br dd, J = 1.4, 10.9 Hz, 1H), 2.68 (br d, J = 11.1 Hz, 1H), 2.54 (dd, J = 3.7, 11.1 Hz, 1H), 2.37 (dt, J = 3.3, 11.6 Hz, 1H), 1.45 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H)

[0663] Synthesis of compound 4

[0664] To the mixture of compound 3 (625 mg, 2.21 mmol, 1 eq) in DCM (8 mL) was added TFA (6.14 g, 53.85 mmol, 4 mL, 24.32 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound4 (940 mg, crude, TFA) was obtained as a yellow oil. ’H NMR: (400 MHz, CDCI3) δ = 3.57 - 3.40 (m, 2H), 3.33 - 3.20 (m, 1H), 3.16 - 3.07 (m, 4H), 2.97 - 2.83 (m, 1H), 2.72 (br t, J = 11.4 Hz, 1H), 1.38 (d, J = 6.8 Hz, 3H).

[0665] Synthesis of compound 5

[0666] To the mixture of compound 4 (840 mg, 2.84 mmol, 1 eq, TFA) in THF (7 mL) was added DIEA (1.47 g, 11.34 mmol, 1.98 mL, 4 eq) and the mixture was stirred at 25 °C for 1 h. To the mixture was added CDI (551.79 mg, 3.40 mmol, 1.2 eq), then the mixture was stirred at 25 °C for 1 h. The mixture was diluted with H2O (30 mL) and the resulting mixture was extracted with Ethyl acetate (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compounds (660 mg, crude) was obtained as a yellow oil.

[0667] Synthesis of compound SC-003542

[0668] To the mixture of compound 5 (50 mg, 180.99 1 eμqm) o inl, THF (2 mL) was added TEA (54.94 mg, 542.97 μmo 7l5,.57 3 μ eLq,), DMAP (11.06 mg, 90.50 0.5 μ emq)ol a,nd compound 6 (53.70 mg, 217.19 μ 1m.2ol e,q). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated at 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). Compound SC-003542 (12.23 mg, 26.59 14.69%μmol, yield, 99% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.35 - 7.28 (m, 2H), 7.02 - 6.93 (m, 3H), 4.31 (br dd, J = 4.4, 11.0 Hz, 2H), 4.15 (dd, J = 3.1, 13.4 Hz, 1H), 4.06 (br dd, J = 4.6, 12.3 Hz, 1H), 3.97 - 3.81 (m, 1H), 3.65 (td, J = 1.8, 12.5 Hz, 1H), 3.46 - 3.35 (m, 1H), 3.29 (dt, J = 3.8, 12.7 Hz, 1H), 3.05 - 2.86 (m, 5H), 2.75 (br s, 2H), 2.57 (dt, J = 1.7, 11.3 Hz, 1H), 1.42 (br s, 3H); LCMS: RT =0.571 min, m / z =456.3 (M+H)+.

[0669]

[0670] Experimental Procedure SC-003543:

[0671] Synthesis of compound 3

[0672] To a solution of compound 1 (1 g, 4.99 mmol, 1 eq) in EtOH (15 mL) was added DIEA (1.61 g, 12.48 mmol, 2.17 mL, 2.5 eq) and compound 2 (1.39 g, 5.99 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. The compound 2 (0.5 g, 2.15 mmol, 4.31e-l eq) and DIEA (742.00 mg, 5.74 mmol, 1 mL, 1.15 eq) were added. The mixture was stirred at 40 °C for 16 h. The mixture was concentrated at reduced pressure to give a residue. The residue 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 concentrated and then freeze dried. Compound 3 (1 g, 3.54 mmol, 70.94% yield) was obtained as a brown solid.1H NMR: (400 MHz, CDC13) δ = 4.21 (br s, 1H), 3.81 (br d, J = 13.1 Hz, 1H), 3.12 (dt, J = 3.4, 12.7 Hz, 1H), 2.95 (dq, J = 2.2, 9.4 Hz, 2H), 2.87 - 2.79 (m, 1H), 2.69 (br d, J = 11.1 Hz, 1H), 2.55 (dd, J =

[0673] 3.6, 11.1 Hz, 1H), 2.38 (dt, J = 3.3, 11.6 Hz, 1H), 1.46 (s, 9H), 1.25 (d, J = 6.8 Hz, 3H). Synthesis of compound 4

[0674] 3 4

[0675] To a solution of compound 3 (1 g, 3.54 mmol, 1 eq) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 2 hr. The mixture was concentrated at reduced pressure to give a residue. Compound 4 (2 g, crude, TFA) was obtained as a yellow oil. LCMS: RT =0.264 min, m / z =183.2 (M+H)+.

[0676] Synthesis of compound 5

[0677] To a solution of compound 4 (1 g, 3.38 mmol, 1 eq, TFA) in THF (10 mL) was added DIEA (1.75 g, 13.50 mmol, 2.35 mL, 4 eq) and CDI (437.93 mg, 2.70 mmol, 0.8 eq). The mixture was stirred at 20 °C for 16 hr. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40 mm*10um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 15%- 45% B over 15 min). The eluent was concentrated and then freeze dried. Compound 5 (30 mg, 108.59 3.22% yield)μmol, was obtained as a yellow gum. LCMS: RT =0.395 min, m / z =277.2 (M+H)+. Synthesis of compound 8

[0678] To a solution of compound 7 (4.06 g, 33.31 mmol, 2.5 eq), compound 6 (5 g, 13.32 mmol, 1 eq, TFA) in DCM (50 mL) was added DIEA (6.89 g, 53.29 mmol, 9.28 mL, 4 eq) and Cu (OAC)2(4.84 g, 26.65 mmol, 2 eq). The mixture was stirred at 20 °C for 16 h under air. The mixture was filtered and the filtrate was concentrated at reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether: Ethyl acetate = 1 : 0 to 1 : 1, TLC: Petroleum ether: Ethyl acetate = 1 : 1, RF = 0.60). Compound 8 (1.4 g, crude) was obtained as a yellow oil. LCMS: RT =0.540 min, m / z =338.3 (M+H)+.

[0679] Synthesis of compound 9

[0680] To a solution of compound 8 (1.4 g, 4.15 mmol, 1 eq) in EtOAc (15 mL) was added Pd / C (300 mg, 4.15 mmol, 10% purity, 1 eq) under N2 at 20 °C, then the mixture was stirred under H2 (15 psi) at 20 °C for 6 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The mixture was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 0: 1, TLC: Petroleum ether: Ethyl acetate = 0: 1, RF = 0.49). Compound 9 (520 mg, 2.10 mmol, 50.68% yield) was obtained as a white solid. LCMS: RT =0.401 min, m / z =248.2 (M+H)+. Synthesis of compound SC-003543

[0681] To a solution of compound 9 (26.85 mg, 108.59 1 eq),μ cmomolp, ound 5 (30 mg, 108.59 pmol, 1 eq) in THF (1 mL) was added TEA (32.97 mg, 325.78 45.34 μmo 3l, eq) and DMμLA,P (6.63 mg, 54.30 pmol, 0.5 eq). The mixture was stirred at 60 °C for 16 h. Compound 9 (26.85 mg, 108.59 μmol 1, eq) was added and the mixture was stirred at 60 °C for 16h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 48%- 78% B over 9 min). The eluent was concentrated and then freeze dried. Compound SC003543 (25.67 mg, 55.24 μm 50o.l8, 7% yield, 98% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.31 (t, J = 8.0 Hz, 2H), 7.01 - 6.93 (m, 3H), 4.30 (br dd, J = 4.4, 11.0 Hz, 2H), 4.19 - 4.02 (m, 2H), 3.99 - 3.77 (m, 1H), 3.65 (td, J = 1.7, 12.5 Hz, 1H), 3.50 - 3.23 (m, 2H), 3.07 - 2.83 (m, 5H), 2.81 - 2.69 (m, 2H), 2.57 (br t, J = 10.7 Hz, 1H), 1.42 (br s, 3H); LCMS: RT =0.575 min, m / z =456.4 (M+H)+

[0682] Synthetic Scheme SC-003545: Experimental Procedure SC-003545:

[0683] Synthesis of compound 3

[0684] 1 3

[0685] A mixture of compound 1(1 g, 5.04 mmol, 1 eq), compound 2 (1.40 g, 6.05 mmol, 1.2 eq) and DIEA (1.96 g, 15.13 mmol, 2.64 mL, 3 eq) in EtOH (20 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: Phenomenex luna C18 150*40 mm* 15um; mobile phase: [water (FA) -ACN]; gradient: 32%- 62% B over 15 min). Compound 3 (314 mg, 1.06 mmol, 21.10% yield, 95% purity) was obtained as a colorless oil.1H NMR: (400 MHz, CDCI3) δ = 4.41 - 4.24 (m, 1H), 3.59 (br d, J = 8.2 Hz, 1H), 3.50 - 3.37 (m, 1H), 3.24 - 3.07 (m, 4H), 2.79 - 2.57 (m, 1H), 1.91 - 1.70 (m, 2H), 1.46 (s, 9H).

[0686] Synthesis of compound 4

[0687] 3 4

[0688] A mixture of compound 3(314 mg, 1.12 mmol, 1 eq) and TFA (1.54 g, 13.46 mmol, 1 mL, 12.02 eq) in DCM (4 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 4 (600 mg, crude, TFA) was obtained as a gray oil.

[0689] Synthesis of compound 5 The mixture of compound 2 (220 mg, 747.81 1 eμqm, TolF,A) and DIEA (386.60 mg, 2.99 mmol, 521.02 μ 4L e,q) in THF (5 mL) was stirred at 20 °C for 0.5 h. Then CDI (145.51 mg, 897.37 μmo 1l,.2 eq) was added and the mixture was stirred at 20 °C for 1.5 h. The reaction mixture was diluted with H2O (6 mL) and the resulting mixture was extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na?SO4, filtered and concentrated under reduced pressure to give a residue. Compound 5 (174 mg, 621.79 83.15%μm yioell,d, 98% purity) was obtained as a colorless oil.

[0690] Synthesis of compound

[0691] To a solution of compound 6 (54.09 mg, 218.79 1.2 eμqm) o aln,d compound 5 (50 mg, 182.32 μmol, 1 eq) in THF (2 mL) was added TEA (55.35 mg, 546.96 76.13 μmol 3, eq), μL, DMAP (11.14 mg, 91.16 μm 0o.5l, eq). The mixture was stirred at 60 °C for 32 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: 50%- 80% B over 10 min). SC-003545 (31.8 mg, 70.13 38.47%μm yoiel,ld, 100% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.34 - 7.29 (m, 2H), 7.02 - 6.95 (m, 3H), 4.62 - 4.44 (m, 1H), 4.31 (dd, J = 4.2, 10.8 Hz, 1H), 4.18 - 4.04 (m, 2H), 3.80 - 3.60 (m, 3H), 3.54 - 3.35 (m, 1H), 3.34 - 3.14 (m, 4H), 2.98 - 2.83 (m, 3H), 2.05 - 1.85 (m, 2H); LCMS: RT = 0.529 min, m / z = 454.1(M+H)+.

[0692]

[0693] Experimental Procedure SC-003546:

[0694] Synthesis of compound 3

[0695] To a solution of compound 1 (500 mg, 2 36 mmol, 1 eq), compound 2 (656.00 mg, 2.83 mmol, 1.2 eq) in EtOH (5 mL) was added DIEA (913.22 mg, 7.07 mmol, 1.23 mL, 3 eq). The mixture was stirred at 40 °C for 16 h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*40 mm* 15um; mobile phase: [water (FA) -ACN]; gradient: 50%- 80% B over 15 min). The eluent was concentrated and then freeze dried. Compound 3 (230 mg, 781.48 33.18%μm yoiell,d) was obtained as a brown oil. ’ H NMR: (400 MHz, CDCI3) δ = 4.27 - 4.01 (m, 2H), 2.95 (q, J = 9.4 Hz, 2H), 2.69 (br s, 4H), 1.94 - 1.79 (m, 4H), 1.47 (s, 9H).

[0696] Synthesis of compound 4 34

[0697] To a solution of compound 3 (230 mg, 781.48 1 eμqm) o inl, DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated at reduced pressure to give a residue. Compound 4 (300 mg, crude, TFA) was obtained as a yellow oil. LCMS: RT =0.334 min, m / z =195.2 (M+H)+.

[0698] Synthesis of compound 5

[0699] To a solution of compound 4 (300 mg, 973.33 1μ emqo, l T, FA) in THF (5 mL) was added DIEA (125.80 mg, 973.33 μ 1m69o.l5,4 1 eq)μ. L T,he mixture was stirred at 20 °C for 0.5 h. Then CDI (157.82 mg, 973.33 1 μ emq)o wl,as added and the mixture was stirred at 20 °C for 0.5 h. EtOAc (15 mL) and water (15 mL) were added and Layers were separated. The aqueous phase was extracted with EtOAc (15 mL x 2), the combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Compound 5 (310 mg, crude) was obtained as a yellow oil. LCMS: RT =0.408 min, m / z =289.2 (M+H)+.

[0700] Synthesis of compound SC-003546

[0701] To a solution of compound 6 (51.46 mg, 208.14 1.μ2m eoql),, compound 5 (50 mg, 173.45 μmol, 1 eq) in THF (1 mL) was added TEA (52.65 mg, 520.35 72.43 μm 3 o elq,) and μL, DMAP (6.36 mg, 52.03 μm 0ol.3, eq). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated at reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5um; mobile phase: [water (NH4HCO3) -ACN]; gradient: 50%- 80% B over 9 min). The eluent was concentrated and then freeze dried. Compound SC- 003546 (10.15 mg, 21.28 μm 12o.l2,7% yield, 98% purity) was obtained as a white solid.1H NMR: (400 MHz, CDCI3) δ = 7.35 - 7.28 (m, 2H), 7.01 - 6.94 (m, 3H), 4.42 (br s, 1H), 4.36 - 4.22 (m, 2H), 4.15 (dd, J = 2.6, 13.3 Hz, 1H), 4.11 - 4.02 (m, 1H), 3.66 (td, J = 1.8, 12.6 Hz, 1H), 3.30 (dt, J = 3.8, 12.7 Hz, 1H), 3.06 - 2.87 (m, 5H), 2.79 (q, J = 10.8 Hz, 3H), 2.01 (br d, J = 12.5 Hz, 4H); LCMS: RT =0.586 min, m / z =468.4 (M+H)+. Example 2: Activity Studies and Data

[0702] 4-Nitrophenyl butyrate activity assay

[0703] Compounds were prediluted starting from lOmM DMSO stocks to obtain 10-point 3-fold dilution series in neat DMSO. 0.1 pL of all resulting samples was diluted lOOx to lOpL assay buffer (35mM aq. sodium acetate, pH 4.5, 0.01% BSA, 0.01% pluronic F-127) in a clear 384- well flatbottom plate. The dose responses for each compound were performed in duplicate. To both high and low control wells lOpL 1% DMSO in assay buffer was added. Then, 5pL assay buffer was added to the low control wells or 5pL 24.2pM PLA2G15 (recombinantly produced in HEK293T) solution in PBS to all other wells. 3.5pL neat 4-nitrophenyl butyrate (Sigma) was diluted to 400pL with neat DMSO to obtain a 50mM stock which was stored at -20°C until use.

[0704] Directly prior to an experiment, lOOpL of this substrate stock was diluted to lOmL with assay buffer, and 15pL was added to all wells. The plate was spun at 1000 rpm for 1’, and then incubated at RT for exactly 45’, followed by another spin at 1000 rpm for 1’. After adding 30 pL stop solution (50 mM aq. Tris, pH 9.0) to all wells, the plate was spun at 1000 rpm for 1 ’ and the absorbance at 405 nm measured in a plate reader (SpectraMax). All absorbances were normalized to high control (100%) and low control (0%) and fitted to a 4 -parameter dose-response model with free plateaus in an unweighted fit, yielding the reported IC50S.

[0705] Table 1: IC50 values obtained from activity studies of compounds of formula I. Example 3

[0706] A clear 96-well high content imaging plate was coated with 0.1% gelatin for 1 h at 37°C. HMC3 cells or HMC3 cells with constitutive PLA2G15 knockout (EMEM supplemented with 10% FCS and 1% penstrep was used as medium throughout) were washed with PBS, trypsinized with 0.25% trypsin / EDTA for 5’, resuspended in medium and spun at 1500rpm for 4’. After resuspending in 3mL medium, cells were counted in a BioRad TC20 counter according to vendor protocol, and the cells diluted with medium to 75,000 cells / mL. Of this cell stock, 100uL was plated onto the 96-well plate after aspiration of the gelatin. An 8-point 2-fold serial dilution of the compound as described in Example 8 in DMSO prepared from 10mM stocks so that after adding to the well as below, a final top concentration of 10mM was obtained. For amiodarone a similar serial dilution series was added however starting at 4mM top concentration in well. 12uL LipidTox Green was added to 12mL medium. And pass through a 2um filter. After removing the medium on the plate, to individual wells were added 199.5uL medium with LipidTox Green and 0.5uL compound dilution. A well with medium without LipidTox Green was added as negative control. The plates were then incubated for 48h at 37°C. Lysotracker was diluted 1 :333 in medium, and 50uL was added to each well, followed by further incubation of 1 h at 37°C. Cells were washed with PBS and fixed for 10’ at 37°C in 4% PFA, followed by another wash. A mixture of 1 :10,000 CellMask Far Red (ThermoFisher, C10046) and 1 :1000 Dapi (1 mg / mL stock) in 12mL PBS was prepared, of which 100uL was added to each well, followed by incubation for 1 h at 37°C and 2 PBS washes. Images were taken on a Revvity Operetta confocal microscope employing 4 fluorescence channels (Dapi 350nm ex, 430-500 filter; LipidTox Green 495nm ex, 500-550 filter; Lysotracker 577nm ex, 570-650nm filter; CellMask 650nm ex, 655-760nm filter). Quantification was by spot intensity as mean per well.

[0707] Conclusions: The LipidTox assay effectively distinguishes between compounds that induce phospholipid accumulation and those that do not. Amiodarone, used as a control, clearly causes phospholipid accumulation, validating the assay. In contrast, the specific PLA2G15 inhibitors tested did not show a phospholipidosis phenotype in this assay, making them suitable candidates for further development without the associated risk of inducing this condition.

[0708] Example 4

[0709] Lysosomal storage diseases, in particular Niemann Pick disease type C (NPC) are hallmarked by liver malfunction and progressive neurodegeneration in human. The liver phenotype includes enlargement of the liver (hepatomegaly), macrophage infiltration, foam cell formation and storage of glycosphingolipids, contributing to apoptosis of hepatic cells. The loss of neurons in the central nervous system leads to a multitude of neurological symptoms, and most commonly a loss of motor function is observed. Patients regularly experience ataxia, difficulty walking, swallowing problems, loss of muscle tone and tremors. Both the liver and neurological phenotypes are well recapitulated in animal models. We identified PLA2G15 as genetic modifier of NPC in cellular models, and we hypothesized that Pla2g15 knockout would alleviate the liver and neurological phenotype in Npc1 KO mice. In the experiments below, we tested the effect of Pla2g15 knockout on liver damage using established biomarkers aspartate transaminase (AST) and alanine transaminase (ALT). Both enzymes are highly expressed in liver, and during liver injury, damaged cells will release both enzymes into the bloodstream. Thus, elevated levels of AST and ALT are commonly used as biomarkers to monitor liver damage. Furthermore, we quantified neurological function using a neurological composite score, where an observer scores mouse performance on six neurological-driven behavioral phenotypes. We observed significant improvements in both the liver damage and neurological composite scoring tests, indicating that knockout of Pla2g15 lessens liver and neurological phenotypes in NPC.

[0710] Neurological composite score

[0711] Pla2g15 / - Balb / C animals were crossed with Npc1m1N / Jheterozygous (HET) animals, and from the resulting offspring, double heterozygous mice were used to obtain the following genotypes (gene order: Npc1m1N / J / Pla2g15y. WT / WT, HOM / WT, HOM / HET, HOM / KO and WT / KO. Neurological composite phenotype score (consisting of ledge test, hindlimb clasping, gait, kyphosis, tremor, and grooming scores) was performed on a weekly basis starting at 6 weeks of age. These tests were performed following an established protocol (Davidson et al 2022, PMID 34407999). Higher composite score means worse neurological performance.

[0712] In the Npc1 disease model (HOM / WT), we observed a progressive worsening in the neurological composite score compared to WT / WT starting from week 7, across all domains tested. In mice that lack both Npc1 and Pla2g15 expression (HOM / KO), the neurological phenotype was significantly improved at week 7 compared to HOM / WT. And although slow worsening of the phenotype was observed after week 7, the neurological composite score remained significantly lower compared to HOM / WT at all time points tested. Improvement was found across all domains tested, and was strongest in the gait, tremor and ledge tests. Heterozygous deletion of Pla2g15 (HOM / HET) did not affect performance in the neurological composite score compared to HOM / WT. In conclusion, these results show that deletion of PLA2G15 expression in a NPC1 disease model slows neurological disease progression.

[0713] AST AND ALT PLASMA CONCENTRATION

[0714] At 8 weeks of age (P56 ± 2 days) animals were terminally anesthetized by intraperitoneal injection of Pentobarbital (600 mg / kg) and blood plasma was obtained. AST and ALT levels were determined with a Kit (AST: Cat# 04467493190, Roche; ALT: Cat No 04467388190, Roche) according to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) with pyridoxal phosphate activation (Roche). Therefore, a kinetic measurement of the enzyme activity with a redox reaction of NADH was performed, using L-Aspartate and 2-Oxoglutarat as substrate for the AST measurement and L-Alanine and 2-Oxoglutarat as substrate for the ALT determination. The two enzyme levels were measured on a Roche Cobas 6000 / c501 analyzer.

[0715] To measure the effect of Pla2g15 KO on liver damage in the NPC1 mouse disease model, we measured the levels of biomarkers aspartate transaminase (AST) and alanine transaminase (ALT). We observed a profound increase in both AST and ALT in the disease model (Npc1 KO). Removal of Pla2g15 in the disease model (double knockout, DKO) strongly reduced AST and ALT levels, indicating reduced liver damage. Knock out of Pla2g15 alone did not influence the levels of either biomarker. Thus, Pla2g15 KO lessens liver damage in Npc1 KO mice.

[0716] Example 5: HMC3 PFO cholesterol accumulation assay

[0717] HMC3 cells were used to assess the effects of PLA2G15 inhibitors on lysosomal cholesterol accumulation. A total of 200,000 HMC3 cells / well were plated into 6-well cell culture plates and treated with DMSO or compound SC-003863 for 7 days at 37°C in a CO2incubator. The medium (MDEM supplemented with 10% FCS and 1% PenStrep) was refreshed after 4 days. The experiment utilized wildtype (WT), NPC1 -deficient (NPC1-ko), and NPC1 / PLA2G15 double-knockout (NPC1 / PLA2G15-dko) cells, all derived from the HMC3-WT parent line as polyclonal pools generated by CRISPR / Cas9 modification.

[0718] After 7 days of incubation, the cells reached confluence and were reseeded into individual wells of a Phenoplate-96 plate at 15,000 cells / well. The cells were allowed to attach for at least 6 hours, preferably overnight, in 100 pL medium. Subsequently, 1 :1000 v / v Lysotracker Red reagent was added to each well and incubated for 1 hour at 37°C. After incubation, the medium was aspirated, and the cells were washed with PBS. Fixation was performed using 4% PFA in PBS for 10 minutes at 37°C, followed by washing twice with PBS. The cells were permeabilized with 0.1 % saponin in PBS for 10 minutes at room temperature.

[0719] After washing, the cells were stained with Alexa-647 labelled recombinant perfringolysin O (PFO) to detect cholesterol-rich lysosomal membranes. Staining was performed using 60 pL / well of PFO diluted in PBS (1 :1000 from a 0.3 mg / mL stock). After staining, the cells were washed with PBS and counterstained with CellMask Green and DAPI according to the vendor protocol. Following a final wash with PBS, the plates were imaged using an Operetta CLS Imager, employing appropriate channels for Alexa-647 (PFO), DAPI, CellMask Green, and Lysotracker Red. Viability was assessed by counting DAPI-positive nuclei, and individual cells were segmented based on CellMask Green staining. PFO fluorescence was quantified exclusively in Lysotracker Red-positive puncta.

[0720] Baseline cholesterol accumulation was assessed in WT, NPC1-ko, and NPC1 / PLA2G15-dko cells using the PFO staining assay. NPC1 -ko cells exhibited significant lysosomal cholesterol accumulation compared to WT cells, consistent with the pathological impact of NPC1 deficiency. In NPC1 / PLA2G15-dko cells, cholesterol accumulation was reduced compared to NPC1 -ko cells but remained elevated relative to WT levels, indicating a partial rescue of cholesterol storage in the absence of PLA2G15.

[0721] Further analysis demonstrated the effect of a PLA2G15 inhibitor on lysosomal cholesterol levels in NPC1 - ko and NPC1 / PLA2G15-dko cells. The PLA2G15 inhibitor significantly reduced cholesterol accumulation in NPC1-ko cells while having no effect in NPC1 / PLA2G15-dko cells. This indicates that the observed rescue of lysosomal cholesterol accumulation is specifically dependent on PLA2G15 activity.

[0722] These findings highlight the dual role of PLA2G15 inhibition in restoring lysosomal homeostasis and reducing pathological cholesterol accumulation in NPC1 -deficient cells. Furthermore, they underscore the therapeutic potential of targeting PLA2G15 in NPC, providing robust support for the claims and aligning with the proposed mechanisms of BMP regulation and lysosomal function in NPC pathology.

[0723] Example 6: Evaluation of PLA2G15 Inhibitors in Restoring BMP Levels in Models of Batten Disease and GRN-Mediated Conditions

[0724] This study evaluated the potential of PLA2G15 inhibitors to restore BMP levels in cellular models of Batten disease and GRN-mediated conditions. Cellular models included CLN3- and CLN5-deficient ARPE19 cells generated using CRISPR-Cas9 technology and GRN-deficient bone marrow-derived macrophages (GRN-KO BMDMs) derived from GRN knockout mice. The models were selected to represent lysosomal storage disorders characterized by BMP deficiency, a hallmark of these conditions.

[0725] Cells were grown to confluency for 4 days and treated with 10 pM of PLA2G15 inhibitors SC4395 or SC3863 for an 11-day experimental duration. During the first 2 hours of this period, cells were exposed to the cell cycle inhibitor mitomycin C to synchronize cell division. DMSO-treated cells served as controls. After treatment, BMP levels were quantified using a validated UPLC-MS / MS-based method.

[0726] Cell pellets containing 2 million cells were resuspended in 100 pL water and lysed by sonication. The lysates were transferred to a 96-well plate and spiked with the internal standard d5-36:2-BMP. In-plate protein precipitation was performed by adding 300 pL acetonitrile supplemented with 1 % formic acid. Samples were processed using positive pressure SPE filtration, employing methanol as the eluent (5 min loading followed by 5 min elution). The filtrate was evaporated completely over 2 hours, and the resulting lipid pellet was reconstituted in 100 pL of 10 mM ammonium formate in methanol. A 10 pL aliquot was injected into an ACE3 C18 reversed-phase column mounted on a Vanquish UPLC system and eluted using a gradient of 10 mM ammonium formate in water to 10 mM ammonium formate in methanol. The eluate was analyzed on an inline TSQ Quantiva MS / MS detector in positive mode electron spray ionization, focusing on a predefined library of BMP species with acyl chain profiles of 36:2, 38:5, 40:7, and 44:12.

[0727] The levels of multiple species of Bis(monoacylglycerol)phosphate (BMP) are shown in the ARPE19 retinal pigment epithelial cell line with wildtype, CLN3ko, or CLN5ko genotype. The BMP levels were significantly reduced in untreated CLN3ko and CLN5ko cells compared to wildtype cells. Treatment with SC4395 or SC3863 restored BMP levels in CLN3ko cells, with SC4395 also partly restoring BMP levels in CLN5ko cells.

[0728] These results demonstrate that PLA2G15 inhibitors can restore BMP levels in cellular models of Batten disease and GRN-mediated conditions, addressing a key biochemical defect in these disorders. Restoration of BMP levels is associated with improved lysosomal function and supports the therapeutic relevance of targeting PLA2G15 as a disease-modifying strategy for Batten disease and GRN-mediated conditions.

[0729] The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive. It should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

Claims

CLAIMS1 . A compound of formula I :Formula I or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:X= CH or N;Ring A is a phenyl, heterocyclyl, or heteroaryl; m = 1 ; p = 0 or 1 ;Xi and X2 taken together fromwherein X3 is carbon, nitrogen or oxygen, however, if X3 is oxygen R1 and R2 are absent and if X3 is nitrogen R2 is absent;R1 is independently selected from a group comprising hydrogen, methyl, flouro, CH 2CF3, trifluoromethyl orn=0, or 1 ;Ring ‘B’ is selected from a group comprising phenyl, cyclopropyl, cyclobutyl or oxetyl;R2 is either hydrogen or flouro;R3is hydrogen, flouro, chloro, methoxy or ethoxy;R4 is hydrogen or methyl;R is independently selected from a group comprising methyl,with the proviso that if R isn is 2, B is phenyl; and if R3 is present at para position to the point of attachment of phenyl group then R3 is not chloro.

2. The compound of claim 1 , wherein when X is CH then Ring A is a phenyl moiety.

3. The compound of claim 1 , wherein when X is N then Ring A is either a piperazinyl or a pyrrolyl moiety.

4. A compound according to claim 1 , which is a compound of formula la :or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein:Xi and X2 taken together formwherein X3 is carbon or nitrogen, however, if X3 is nitrogen R2 is absent;R1 is independently selected from a group comprising hydrogen, methyl, CH 2CF3, orn=0 or 1 ;R2 is hydrogen;R3 is hydrogen, chloro, or ethoxy;R4 is hydrogen or methyl;R is independently selected from a group comprisingwith the proviso that if R isn is 2, and if R3 is present at para position to the point of attachment of phenyl group of R1 then R3 is not chloro.

5. A compound according to claim 1 , wherein the compound is a compound of formula lb:Formula lb or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein p = 0 or 1 ;Xi and X2 taken together formwherein X3 is carbon, nitrogen or oxygen, however, if X3 is oxygen R1 and R2 are absent and if X3 is nitrogen R2 is absent;R1 is independently selected from a group comprising hydrogen, methyl, flouro, CH2CF3, orn=0 or 1 ;Ring ‘B’ is selected from a group comprising phenyl, cyclopropyl, cyclobutyl or oxetyl;R2 is either hydrogen or flouro;R3 is hydrogen, flouro, chloro, methoxy or ethoxy;R4 is hydrogen;R is independently selected from a group comprising methyl,6. A compound according to claim 1 , wherein the compound is a compound of formula Ic:Formula Ic or a hydrate, solvate, or pharmaceutically acceptable salt thereof, whereinR either hydrogen or methyl.

7. The compound of claim 1 , which is compound of one of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:SC-001924SC-002910SC-003145SC-003542SC-003543SC-002325SC-002327SC-002633SC-002634SC-002636SC-002638SC-0027638. A pharmaceutical composition comprising a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 -7, and a pharmaceutically acceptable excipient.

9. The compound according to claims 1 -7 or the pharmaceutical composition according to claim 8 for use in a treatment of a disorder of the human or animal body associated with abnormal PLA2G15 enzyme activity, comprising administering to a subject in need of treatment a therapeutically -effective amount of compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 -7 or the composition as defined in claim 8.

10. The compound according to claims 1 -7 or the pharmaceutical composition according to claim 8 for use in the inhibition of PLA2G15 activity in a subject, comprising administering to said subject an effective amount of compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 -7 or the composition as defined in claim 8.

11. The compound according to claims 1 -7 or the pharmaceutical composition according to claim 8 for use in the inhibition of PLA2G15 protein / activity comprising contacting the PLA2G15 protein / enzyme, in vitro or in vivo, with an effective amount of a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8.

12. The compound according to claims 1 -7 or the pharmaceutical composition according to claim 8 for use in the inhibition of PLA2G15 protein / activity in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 -7 or the composition as defined in claim 8.

13. A compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1-7 or the composition as defined in claim 8, for use in a method of treatment of the human or animal body by therapy.

14. A compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8, for use in a method of treating diseases or disorders associated with abnormal PLA2G15 activity or PLA2G 15 protein.

15. The compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8, for treating conditions associated with abnormal PLA2G15 activity.

16. The compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8 for treating a disorder or disease of the human or animal body that is associated by the abnormal PLA2G 15 activity.

17. A kit comprising (a) a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8, preferably provided as a pharmaceutical composition and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder of the human or animal body.

18. A compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8, for use in a method of treatment of a disorder selected from: lysosomal storage diseases, HIV, Alzheimer’s disease, Parkinson’s disease, Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal.

19. The compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defined in claim 8 for treating a disorder or disease selected from: lysosomal storage diseases, HIV, Alzheimer’s disease, Parkinson’s disease, Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal.

20. The compound according to claims 1 -7 or the pharmaceutical composition according to claim 8 for use in a treatment of a disorder, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound or a hydrate, solvate, or pharmaceutically acceptable salt thereof as defined in claims 1 to 7 or the composition as defi ned in claim 8, wherein the disorder is selected from: lysosomal storage diseases, HIV, Alzheimer’s disease, Parkinson’s disease, Niemann Pick type C or a neuronal ceroid lipofuscinosis such as CLN3 disease or Batten disease, CLN5 disease, or GRN frontotemporal.

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