Heteroaryl-amine compounds and use thereof as hdac6 inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y1 is a 9- or 10-membered bicyclic heteroaryl, Y2 is a 5- or 6-membered heteroaryl or 6-membered aryl, L is a linker, Z1' is selected from -NR23' R24' and -(C3-C7) heterocyclo alkyl comprising at least one nitrogen atom, and R23' and R24' may be various groups. The present invention further relates to a compound of formula (I) as HDAC6 inhibitor, typically for use in the treatment and / or the prevention of an HDAC6-associated disease, such as cancers, neurodegenerative diseases, neuropathies, cardiovascular diseases, or metabolic or hormonal disorders.

Description

HETEROARYL- AMINE COMPOUNDS AND USE THEREOF AS HDAC6INHIBITORSFIELD OF INVENTION

[0001] The present invention relates to heteroaryl-amine compounds useful as Histone Deacetylase subtype 6 (HDAC6) inhibitors. In particular, the present invention relates to compounds for use in the treatment and / or the prevention of proliferative diseases such as cancers, neurodegenerative diseases, neuropathies or cardiovascular diseases.BACKGROUND OF INVENTION

[0002] Inhibition of the enzymes of the HD AC class, especially HDAC6 enzyme, plays a critical role in gene expression in humans. Thus, the development of potent HDAC inhibitors is of upmost clinical importance in severe medical conditions, including both major and rare diseases (Seidel, C et al.: “Histone deacetylase 6 in health and disease.” Epigenomics. 2015, Vol. 7, No. 1, pp. 103-18). HDAC6 inhibitors are expected to be useful for example in oncology, neurology, neuropsychiatry, neurodegeneration, inflammation (e.g., neuroinflammation), nephropathy, neuropathy and pain. Significant examples of HDAC6 inhibitors with potential medical applications in the treatment of proliferative diseases are drugs of the hydroxamate class (hydroxamic acid and salts thereof), which include vorinostat (or “SAHA”, trade name Zolinza®), Trichostatin A (TSA), belinostat (trade name Beleodaq®), panobinostat (Farydak®) or romidepsin (Istodax®).

[0003] However, many HDAC6 inhibitors identified so far are not highly selective, so that they may cause significant side-effects. Poor pharmacokinetics and low bioavailability also limit the potency of some HDAC6 inhibitors. Thus, most of the HDAC6 inhibitors have a poor developability profile, even for life-threatening applications in oncology. For example, high doses of non-selective HDAC inhibitors are responsible of fatigue and nausea. Side-effects may in particular be caused by the inhibition of class I HDACs. In addition, mutagenicity issues related to the hydroxamatefunction in approved HD AC inhibitors has been reported (Shen S. and Kozikowski A. P. ChemMedChem 2016, No. 11, pp. 15-21). Other HD AC inhibitors, notably from the fluoromethyl oxadiazole class, have been reported to be mechanism-based inhibitors forming a quasi-irreversible binding intermediate (Cellupica E. et al.: “Difluoromethyl- 1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity”, J. Biol. Chem. 2023, 299(1), 102800; Konig B. et al.: “Difluoromethyl-l,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6.”, ChemRxiv. Cambridge: Cambridge Open Engage; 2023).

[0004] Therefore, there is an urgent need to develop highly selective HDAC6 inhibitors overcoming the limitations of some of the state-of-the-art HDCA6 inhibitors, such as hydroxamic acid-based HDCA6 inhibitors. Isoform-selective inhibitors over pan-HDAC are potentially advantageous both in terms of therapeutic efficacy and toxicity. In particular, selective inhibition of cytoplasmic HDAC6 may avoid toxicity resulting from inhibition of other HDACs.

[0005] The Applicant surprisingly found out that amine compounds of formula (I) as described herein, which, for some of them, were originally prepared by the Applicant as synthetic intermediates, are actually highly selective HDAC6 inhibitors. The use of these heteroaryl-amine compounds may also represent significant improvements in terms of bioavailability, side-effects, pharmacokinetics and / or water solubility over prior art drugs such as hydroxamates. The Applicant also surprisingly found the amine compounds of formula (I) were able to cross the blood-brain barrier, which makes them suitable candidates to treat neurodegenerative diseases with a central component such as amyotrophic lateral sclerosis (ALS).SUMMARY

[0006] This invention relates to a compound for use in the treatment and / or the prevention of an HDAC6-associated disease; wherein the compound is a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, Y2, L and Z1’ are as described in the claims or the detailed description.

[0007] According to one embodiment, the compound for use is selected from the compounds listed in Table 2 herein, and pharmaceutically acceptable salts and / or solvates thereof.

[0008] This invention also relates to a pharmaceutical composition for use in the treatment and / or the prevention of an HDAC6-associated disease comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0009] According to one embodiment, the HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies (including neuromuscular diseases), psychiatric diseases, neurodevelopmental disorders, sleep disorders and cardiovascular diseases, and metabolic or hormonal disorders.

[0010] This invention also relates to a compound of formula (II)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, Y2, L and Z1’ are as described in the claims or the detailed description.

[0011] According to one embodiment, the compound is selected from the compounds listed in Table 1 herein, and pharmaceutically acceptable salts and / or solvates thereof.

[0012] This invention also relates to a process for manufacturing a compound according to the invention, wherein the process comprises the following steps: (i) reacting an amine- containing alkyl chain or heterocycloalkyl with a halo-heterocycle; then (ii) reacting a heterocycle or halo-heterocycle with first an acetylating reagent, and, where appropriate, subsequently a halogenating reagent, to form a halo-ketone; then (iii) reacting a halo- ketone with a thiol and, where appropriate, (iv) removal of at least one protective group.

[0013] This invention also relates to a compound selected from the compounds listed in Table 3 herein, and pharmaceutically acceptable salts and / or solvates thereof.DEFINITIONS

[0014] In the present invention, the following terms have the following meanings, unless indicated otherwise.Chemical definitions

[0015] When referring to combination of groups, such as, for example, “alkyleneheteroaryl”, the point of attachment to the main structure is on the group cited on the left. Thus, the term “alkylene-cyclyl” and variants thereof (e.g., “alkylene-heteroaryl”, “alkylene-heterocycle”, “alkylene-cycloalkyl”, “alkylene-aryl”, “alkylene- heteroaryl”, “alkylene-heterocycle” and “alkylene-cycloalkyl”) refers to a cyclyl group that is attached via an alkyl moiety to the main structure. In other words, the point of attachment is the alkylene group, and not the cyclyl group.

[0016] “Alkene” or “alkenyl” refers to a linear or branched hydrocarbon chain comprising at least one double bond and typically from 2 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of alkenyl groups include ethynyl, 2propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers and 2,4- pentadienyl.

[0017] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 3 carbon atoms. In the present invention, alkyl groups may bemonovalent or polyvalent (i.e., “alkylene” groups as defined herein are encompassed in “alkyl” definition) but alkyl groups are typically monovalent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s- butyl and t-butyl.

[0018] “Alkylene” refers to a divalent alkyl group. Non-limiting examples of alkylene groups include methylene, ethylene, n-propylene, i-propylene, divalent butyl, divalent pentyl and divalent hexyl. Preferred alkylene groups include methylene, ethylene, n- propylene, and n-butylene.

[0019] “Alkyne” or “alkynyl” refers to a linear or branched hydrocarbon chain comprising at least one triple bond and typically from 2 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, and 2-hexynyl and its isomers.

[0020] “Amine” refers to derivatives of ammonia (NH3), wherein one or more hydrogen atoms have been replaced by a substituent such as, for example, alkyl or aryl.

[0021] “Amino” refers to the -NH2 group.

[0022] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring. Aryl groups may have a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. Typically, aryl groups have from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5- acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. A preferred aryl group is phenyl.

[0023] “Bicyclic”, when referring to a cyclic group, means that the cyclic group consists of exactly two fused rings. In monovalent bicyclic groups, the notation “[x, y]” wherein x and y are integers is used herein to indicated that one cycle is x-membered and the other cycle is y-membered and that the point of attachment to the main structure is located on the x-membered cycle. “Tricyclic” and the like should be construed accordingly.

[0024] “Cyano” refers to the -CN group.

[0025] “Cyclyl” collectively refers to “cycloalkyl”, “heterocyclo alkyl”, “aryl” and “heteroaryl” groups as defined herein.

[0026] “Cycloalkyl” refers to a cyclic monovalent alkyl, typically comprising from 3 to 11 carbon atoms, preferably from 4 to 9 carbon atoms, more preferably from 5 to 7 carbon atoms. This definition encompasses polycyclic cycloalkyls (e.g., bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms.

[0027] “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0028] “Difluoromethyl” refers to the -CHF2 group.

[0029] “Halide”, “halo” or “halogen” refers to a fluorine, chlorine, bromine or iodine atom, typically a chlorine or bromine atom.

[0030] “Heteroalkyl” refers to an alkyl group as defined hereinabove wherein one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulfur. In heteroalkyl groups, the heteroatoms are bound along the alkyl chain only to carbon atoms, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Heteroalkyl groups may further include one or more oxo (=0) groups. A heteroalkyl is bound to another group or molecule only through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included in the heteroalkyl group. When substituted by one or more other group(s), an heteroalkyl may be substituted either through a carbon atom or through aheteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers, secondary amines, tertiary amines and thioethers.

[0031] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms. “Heteroaryl” may also be viewed as an “aryl” group as defined herein, wherein at least one carbon atom in the aryl group is replaced with a heteroatom and wherein the resulting molecule is chemically stable. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclo alkyl or aryl) fused thereto. Heteroaryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3] thiazolyl, thieno [3, 2-b] furanyl, thieno [3 ,2-b] thiophenyl, thieno [2, 3-d] [ 1 ,3 ] thiazolyl, thieno [2,3 -d] imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- a]pyridinyl, 6-oxo-pyridazin-l-(6H)-yl, 2-oxopyridin-l-(2H)-yl, 6-oxo-pyridazin-l- (6H)-yl, 2-oxopyridin-l-(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, and 6,7-dihydro-5H-pyrrolo[l,2- a] imidazolyl.

[0032] “Heterocycloalkyl” refers to a cyclic monovalent heteroalkyl, typically comprising from 2 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, more preferably from 4 to 5 carbon atoms. This definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. In one embodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heterocycloalkyl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heterocycloalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine (also known as “hexahydropyrazine”), morpholine, thiomorpholine, azepane, azocane, octahydro- / 77- isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquiline), hexahydropyridazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline and oxetane.

[0033] “Hydroxy” refers to the -OH group.

[0034] “Ketone” refers to a functional group with the connectivity C-(C=O)-C.

[0035] “Oxo” refers to the =0 group, i.e., one oxygen atom which is double-bonded, typically to a carbon atom.

[0036] “Trifluoromethyl” refers to the -CF3 group.General definitions

[0037] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means more or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifiesthat range by extending the boundaries above and below the numerical values set forth by 10%.

[0038] “Administration", or a variant thereof (e.g., “administering”), means providing a therapeutic agent (e.g., a compound of the invention) alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated and / or prevented.

[0039] “Binding site” or “binding pocket” refers to a specific arrangement of amino acids located on a protein (e.g., on HDAC6) to which a compound (e.g., the compounds of the present invention) bind. Binding sites often consist of a chemically-active surface grouping of amino acids, and have specific 3-D structural characteristics as well as specific charge characteristics. Similarly to epitopes, binding sites can be linear or conformational, i.e., they can involve sequences of amino acids which are not necessarily contiguous in the primary structure of the protein.

[0040] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence herein of “comprise” or a variant thereof also encompasses narrower expression “substantially consist of’ or “consists essentially of’, further narrower expression “consist of’ and any variants thereof (e.g., “consists of’, “consisting of’).

[0041] “HDAC” or “Histone Deacetylase” refers to a class of enzymes that are able to remove acetyl groups (O=C-CH3) from an s-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly and condensate the chromatin. Gene expression is regulated by histone acetylation and de-acetylation, and thus by HDAC activity. In the invention, HDAC is typically “HDAC6” as defined herein.

[0042] “HDAC-associated disease” or “disease related to HDAC6 function” or a variant thereof (e.g., “HDAC6-associated disease”) refers to a disease that it due to, caused by, or characterized by, the dysregulation and in particular the increase of activityof a least one HD AC enzyme in a subject, resulting in an abnormal acetylation profile of HD AC substrates (e.g., histones, tubulin, Hsp90, cortactin). In the present application, “HDAC-associated disease’’ and “disease related to HDAC6 function’’ are synonyms and may be used interchangeably. Typically, HDAC-associated diseases are associated with, inter alia, altered epigenetic regulation of gene expression and / or cell motility. This definition encompasses diseases wherein reducing (inhibiting) normal HD AC activity treat and / or prevent the diseases. Typically, an HDAC-associated disease may be prevented and / or treated by means of HDAC inhibition. Non-limitative examples of HDAC-associated diseases include neuropathies, neurodegenerative diseases, proliferative diseases (e.g., cancer), metabolic disorders, immune disorders and inflammatory diseases.

[0043] “HDAC6 ”, “HDAC6 enzyme’’ or “Histone Deacetylase subtype 6” refers to a HDAC enzyme that is encoded by the HDAC6 gene in humans.

[0044] “HDAC6 gene” refers to the gene coding for HDAC6 in humans. HDAC6 gene is also interchangeably referred to as KIAA0901 or JM21.

[0045] “Human” refers to a male or female subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0046] “Patient” refers to an animal, typically a warm-blooded animal, preferably a mammal (e.g., mouse, rat, cat, guinea-pig, dog, monkey or human), more preferably a human, who / which is awaiting the receipt of, or is receiving medical care, or is / will be the object of a medical procedure. A patient may also be the subject of preventive care or procedure.

[0047] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the patient to which / whom it is administered.

[0048] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

[0049] “Prevent”, “preventing” and “prevention” refer to delaying or precluding the onset of a condition and / or disease and / or any one of its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing the risk for a patient of acquiring a condition and / or disease and / or any one of its attendant symptoms. The effect resulting from “preventing” a condition and / or disease is called “prophylactic”.

[0050] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound of the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs, in particular alkyl esters, cycloalkyl esters and aryl esters.

[0051] “Selected from” is used herein according to common patent application drafting terminology, to introduce a list of elements among which an item is selected. Moreover, any occurrence herein of “selected from” also encompasses the expression “selected from the group comprising or consisting of’ and any variants thereof (e.g., “consists of’).

[0052] “Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub- stoichiometric amounts of one or more molecules of one or more solvents, typically the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to a solvate when the solvent is water (H2O).

[0053] “Therapeutic agent ”, “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound of the invention) may be indicated for treating and / or preventing a disease, preferably an infectious disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0054] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which / whom it is administered.

[0055] “Treat”, “treating” and “treatment” refer to alleviating, attenuating or abrogating a condition and / or disease and / or any one of its attendant symptoms, e.g., an infectious disease. DETAILED DESCRIPTION Compounds General formula

[0056] This invention relates to a compound of formula (I) (I) wherein Y1, Y2, L and Z1’are as defined hereinafter in the detailed description.

[0057] In the compounds of formula (I) as described hereinafter in the detailed description, unless otherwise indicated, any alkyl group (which encompass alkylene group) may be “optionally substituted”, i.e., each hydrogen atom bound to a carbon atom in the alkyl moiety can optionally be replaced by at least one low-molecular weight substituent such as, for example, a substituent selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2. Only substitutions wherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the (C1-C6) alkyl group(s) present in the substituents are not themselves further substituted. Preferred substituted alkyls include alkyls substituted by one or more fluorine atom(s) and / or hydroxy such as, for example, trifluoromethyl.

[0058] In the compounds of formula (I) as described hereinafter in the detailed description, unless otherwise indicated, any cyclyl group (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl group) may be “optionally substituted”, i.e., each hydrogen atom bound to a carbon atom in the cyclyl moiety can optionally be replaced by at least one low-molecular weight substituent such as, for example, a group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2- NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2. Only substitutions wherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the (C1-C6) alkyl group(s) present in the substituents are not themselves further substituted. Preferred substituted cyclyl groups include cyclyl substituted by substituted by one or more fluorine atom(s) and / or hydroxy such as, for example, difluorocyclopropyl.

[0059] In the formulae represented herein, the dotted line ---- represents the point of attachment of the depicted moiety to the main molecular structure. Y1definitions

[0060] In formula (I) above, Y1is a 9- or 10-membered bicyclic heteroaryl, preferably selected from the following group of formulae (Y1-I) (also referred as “Scaffolds 1-16” or “Sc1-16”)wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10and A11are each independently selected from C-R7and N, provided that at least one of A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; and B is selected from O, S and N-R5, provided that when A5, A6and A7are C-R7, then B is not S.

[0061] According to one preferred embodiment, Y1is a 9- or 10-membered bicyclic heteroaryl, preferably selected from the following group of formulae (Y1-Ia) (also referred as “Scaffolds 1-14” or “Sc1-14”)wherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10and A11are each independently selected from C-R7and N, provided that at least one of A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; and B is selected from O, S and N-R5, provided that when A5, A6and A7are C-R7, then B is not S.

[0062] In Y1as defined herein, R2is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2-C6) alkylene-NR17R18, -(C1-C6) alkylene-SO2-NR17R18, -NR16-SO2-R15, -(C1-C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene-NR16-SO2-R15, -NR16-(C2-C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)- NR17R18, -O-(C1-C6) alkylene-C(O)-NR17R18, -NR16-(C1-C6) alkylene-C(O)-NR17R18, -NR16C(O)-R15, -(C1-C6) alkylene-NR16C(O)-R15, -O-(C2-C6) alkylene-NR16C(O)-R15,-NR16-(C2-C6) alkylene-NR16C(O)-R15, -C(O)-R15, -C(O)OR15, -(C1-C6) alkylene- C(O)OR15, -O-(C1-C6) alkylene-C(O)OR15, and -NR16-(C1-C6) alkylene-C(O)OR15.

[0063] In Y1as defined herein, R3is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, - OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2- C6) alkylene-NR17R18, -(C1-C6) alkylene-SO2-NR17R18, -NR16-SO2-R15, -(C1- C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene-NR16-SO2-R15, -NR16-(C2- C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -O-(C1- C6) alkylene-C(O)-NR17R18, -NR16-(C1-C6) alkylene-C(O)-NR17R18, -NR16C(O)-R15, - (C1-C6) alkylene-NR16C(O)-R15, -O-(C2-C6) alkylene-NR16C(O)-R15, -NR16-(C2- C6) alkylene-NR16C(O)-R15, -C(O)-R15, -C(O)OR15, -(C1-C6) alkylene-C(O)OR15, -O- (C1-C6) alkylene-C(O)OR15, and -NR16-(C1-C6) alkylene-C(O)OR15.

[0064] In Y1as defined herein, R4is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-OR15, -(C1-C6) alkylene-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -(C1-C6) alkylene-NR16C(O)-R15, -(C1-C6) alkylene-C(O)OR15, and -(C1-C6) alkylene- OC(O)-R15.

[0065] In Y1as defined herein, R5is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3- C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-OR15, -(C1-C6) alkylene-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -(C1-C6) alkylene-NR16C(O)-R15, -(C1-C6) alkylene- C(O)OR15, and -(C1-C6) alkylene-OC(O)-R15.

[0066] In Y1as defined herein, R7is selected from hydrogen, halogen, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl,-OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2-C6) alkylene-NR17R18, -SO-R15, -SO2-R15, -SO2NR17R18, -(C1-C6) alkylene- SO2-NR17R18, -NR16-SO2-R15, -(C1-C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene- NR16-SO2-R15, -NR16-(C2-C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -O-(C1-C6) alkylene-C(O)-NR17R18, -NR16-(C1-C6) alkylene-C(O)-NR17R18, -NR16C(O)-R15, -(C1-C6) alkylene-NR16C(O)- R15, -O-(C2-C6) alkylene-NR16C(O)-R15, -NR16-(C2-C6) alkylene-NR17C(O)-R15, -C(O)-R15, -C(O)-OR15, -(C1-C6) alkylene-C(O)-OR15, -O-(C1-C6) alkylene-C(O)-OR15, -NR16-(C1-C6) alkylene-C(O)-OR15, -OC(O)-R15, -(C1-C6) alkylene-OC(O)-R15, -O-(C2-C6) alkylene-OC(O)-R15, -NR16-(C2-C6) alkylene-OC(O)-R15, and -NR16-C(O)- OR15.

[0067] Moreover, in Y1as defined herein, each of the -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; and each of the -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl,-CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.

[0068] In Y1as defined herein, R15, R16, R17and R18are each independently selected from hydrogen, -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1- C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1- C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1- C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together a cycle selected from -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl.

[0069] Moreover, in Y1as defined herein, each of the -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; and each of the -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, arylor heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl,-CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.

[0070] According to one embodiment, in Y1as defined herein: R2is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15,-NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R3is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15,-NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18; R4is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, and -(C1-C6) alkylene-(C3-C7) heterocycloalkyl; R5is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-OR15, and -(C1-C6) alkylene- NR17R18; and R7is selected from hydrogen, halogen, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) heterocycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15,-NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, and -NR16-(C2-C6) alkylene-NR17R18;wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5or R7is optionally substituted as defined hereinabove; and R15, R16, R17and R18are independently as defined hereinabove.

[0071] According to one preferred embodiment, Y1is a 9- or 10-membered bicyclic heteroaryl selected from the following formulae (Sc1) and (Sc2) (Sc1) (Sc2) wherein A1-A4, A6, A7, G1and R2are independently as defined hereinabove.

[0072] According to one preferred embodiment, Y1is a 9- or 10-membered bicyclic heteroaryl of the following formula (Sc8) (Sc8) wherein A8-A11and G2are independently as defined hereinabove.

[0073] According to one preferred embodiment, Y1is a 9- or 10-membered bicyclic heteroaryl selected from the following formulae (Sc15) and (Sc16) (Sc15) (Sc16) wherein A1-A4, A5-A7, R2and R3are independently as defined hereinabove.

[0074] In one embodiment, Y1is a 10-membered bicyclic [6,6] heteroaryl selected from the following group of formulae (Y1-1) and the following group of formulae (Y1-1a) wherein R2, R3and R7are independently as defined hereinabove.

[0075] In one embodiment, Y1is a 9-membered bicyclic [6,5] heteroaryl selected from the following group of formulae (Y1-2)the following group of formulae (Y1-3) the following group of formulae (Y1-4)the following group of formulae (Y1-5) the following group of formulae (Y1-6)the following group of formulae (Y1-6a) wherein R2, R3, R5and R7are independently as defined hereinabove.

[0076] In one embodiment, Y1is a 9-membered bicyclic [5,6] heteroaryl selected from the following group of formulae (Y1-7) and the following group of formulae (Y1-8) wherein A1, A3, A3, A4, R2, R4and R7are independently as defined hereinabove.

[0077] In one preferred embodiment, Y1is a 10-membered bicyclic [6,6] heteroaryl of the following formula wherein R2, R3and R7are independently as defined hereinabove.

[0078] In one preferred embodiment, Y1is a 9-membered bicyclic [6,5] heteroaryl of the following formula wherein R2, R3, R5and R7are independently as defined hereinabove.

[0079] In one preferred embodiment, Y1is a 9-membered bicyclic [6,5] heteroaryl of the following formula wherein R2and R7are independently as defined hereinabove.

[0080] In one further preferred embodiment, Y1is selected from 1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl, 5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl, 2-(trifluoromethyl)quinazolin-4-yl, 1-(2-methoxyethyl)-6-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl), 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-yl, 2-(difluoromethyl)-6- methoxypyrido[2,3-d]pyrimidin-4-yl, 2-(trifluoromethyl)quinazolin-4-yl, and 6-methoxy-2-(trifluoromethyl)quinazolin-4-yl.

[0081] In one further preferred embodiment, Y1is selected from 1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl, 5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl, 2-(trifluoromethyl)quinazolin-4-yl, 1-(2-methoxyethyl)-6-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl), 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-yl, 2-(difluoromethyl)-6- methoxypyrido[2,3-d]pyrimidin-4-yl, 2-(trifluoromethyl)quinazolin-4-yl, 6-methoxy-2- (trifluoromethyl)quinazolin-4-yl, 6-methoxy-2-methylquinazolin-4-yl, 2-methylpyrido[2,3-d]pyrimidin-4-yl, 2-cyclopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4-yl, 6-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl, 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl, 6-methoxy-2-methyl- 1,8-naphthyridin-4-yl, 7-(difluoromethyl)-1,6-naphthyridin-5-yl, 3-methoxy-7-methyl- 1,6-naphthyridin-5-yl, 6-chloro-8-fluoro-2-methylquinazolin-4-yl, 2-methyl-6- (trifluoromethyl)quinazolin-4-yl, 6-ethoxy-2-methylquinazolin-4-yl, 6-chloro-7-fluoro- 2-methylquinazolin-4-yl, 5-methoxy-2-methylquinazolin-4-yl, 6,7-dimethoxy-2- methylquinazolin-4-yl, 6,7-dimethoxyquinolin-4-yl, 3-chloro-7-methyl-1,6- naphthyridin-5-yl, 6-methoxyquinolin-4-yl, 6-methoxy-2-methylquinolin-4-yl, 6-chloro-8-fluoro-2-methylquinazolin-4-yl, 6-chloroquinolin-4-yl, 7-methoxyquinolin-4-yl, 6-fluoro-2-methylpyrido[2,3-d]pyrimidin-4-yl, 7-(trifluoromethyl)imidazo[1,2- a]pyrimidin-5-yl, 7-methylimidazo[1,2-a]pyrimidin-5-yl, 2-methyl-1,8-naphthyridin-4- yl, 6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4-yl, 2-methyl-6- (trifluoromethyl)quinolin-4-yl, 6-methoxy-2-methyl-1,5-naphthyridin-4-yl, (6-methoxy- 2-methyl-1,5-naphthyridin-4-yl, 2-methyl-6-(trifluoromethyl)-1,8-naphthyridin-4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin- 4-yl, 2-methyl-6-(trifluoromethoxy)quinazolin-4-yl, and 7-methyl-3-(trifluoromethyl)- 1,6-naphthyridin-5-yl.

[0082] In one embodiment, Y1is not thieno[2,3-d]pyrimidin-4-yl.

[0083] In one embodiment, Y1is not 7H-pyrrolo[2,3-d]pyrimidinyl. In one embodiment, Y1is not 9H-purinyl. Y2definitions

[0084] In formula (I) above, Y2is a 5- or 6-membered heteroaryl or 6-membered aryl, preferably selected from the following group of formulaewherein R12, R13, R14and R25’are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,-(C3-C6) cycloalkyl,-CH2-O-(C1-C6) alkyl, -O-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; wherein each of the -(C1-C6) alkyl in R12, R13, R14or R25’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -O-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.

[0085] According to one embodiment, Y2is not the following formula wherein R13and R14are each independently as defined hereinabove.

[0086] According to one embodiment, Y2is not the following formula wherein R12and R14are each independently as defined hereinabove.

[0087] According to one embodiment, Y2is not the following formulae wherein R12is as defined hereinabove.

[0088] According to one embodiment, Y2is not the following formulae wherein R13is as defined hereinabove.

[0089] According to one embodiment, Y2is not selected from the following formulae wherein R12, R13, R14and R25’are as defined hereinabove (i.e., Y2is not a 6-membered aryl).

[0090] According to one preferred embodiment, Y2is selected from the following formulae wherein R13and R14are each independently as defined hereinabove.

[0091] According to one embodiment, R12, R13, R14and R25’are each independently selected from hydrogen, halogen, cyano, hydroxy, -(C1-C6) alkyl, -(C3-C6) cycloalkyl, -CH2-O-(C1-C6) alkyl, and -O-(C1-C6) alkyl; wherein each of the -(C1-C6) alkyl in R12, R13, R14or R25’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, and -O-(C1-C6) alkyl.

[0092] According to one embodiment, R12, R13, R14or R25’may optionally comprise at least one (C1-C6) haloalkyl. In one embodiment, the -(C1-C6) haloalkyl is trifluoromethyl (CF3).

[0093] In one embodiment, R12, R13, R14and R25’are independently selected from hydrogen and (C1-C3) alkyl. In one preferred embodiment, R12, R13, R14and R25’are each hydrogen. L definitions

[0094] In formula (I) above, - L is selected from -(CR10R11)n; wherein n is an integer selected from 0, 1, 2, 3 and 4; R10and R11are independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2; or R10and R11form together with the carbon atom to which they are bond a (C3-C6) cycloalkyl.

[0095] According to one embodiment, n is 0, 1, 2 or 3. In one embodiment, n is 0, 1, 2 or 3. In one particular embodiment, n is 0, 1 or 2. In one preferred embodiment, n is 0 or 1. In one preferred embodiment, n is 0. In one preferred embodiment, n is 1.

[0096] According to one embodiment, R10and R11are independently selected from hydrogen, halogen, hydroxy, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl and -O-(C1-C4) alkyl; or R10and R11form together with the carbon atom to which they are bond a (C3-C6) cycloalkyl. In one embodiment, R10and R11are independently selected from hydrogen, (C1-C3) alkyl and hydroxy. In one embodiment, R10and R11are independently selected from hydrogen and (C1-C3) alkyl. In one embodiment, R10and R11are independently selected from hydrogen and hydroxy. In one particular embodiment, R10and R11are each hydrogen. In one preferred embodiment, L is -CH2-. In one preferred embodiment, L is -CH(OH)-. In one preferred embodiment, L is -CH(OH)CH2-.

[0097] From the above definitions for R10and R11, it results that L cannot include a carbonyl group, in particular, L cannot be -C(O)-, -CH2C(O)- or -C(O)CH2-.Z1’definitions

[0098] In formula (I) above, Z1’is selected from -NR23’R24’and a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom; wherein each nitrogen atom of the (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O- (C1-C6) alkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O-(C3-C7) cycloalkyl; each carbon atom of the (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-O- (C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene- aryl, -(C1-C6) alkylene-heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one halogen (this definition applies to alkyl, alkylene, cycloalkyl or heterocycloalkyl present in the substituents of both nitrogen and carbon atom(s) of the heterocycloalkyl); and wherein each of the aryl or heteroaryl in Z1’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl (this definition applies to aryl or heteroaryl present in the substituents of both nitrogen and carbon atom(s) of the heterocycloalkyl); and R23’and R24’are each independently selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene- heteroaryl, and -(C1-C6) alkylene-aryl; whereineach of the -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; and each of the aryl or heteroaryl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -(C1-C6) alkyl, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.

[0099] According to one preferred embodiment, Z1’is as defined hereinabove, except that each nitrogen atom of the (C3-C7) heterocycloalkyl in Z1’is not substituted by -(C1-C6) alkylene-(C3-C7) cycloalkyl and each carbon atom of the (C3-C7) heterocycloalkyl in Z1’is not substituted by -(C1-C6) alkylene-(C3-C7) cycloalkyl.

[0100] According to one embodiment, Z1’may optionally comprise at least one -(C1-C6) haloalkyl or -(C3-C7) halocycloalkyl. In one embodiment, Z1’may optionally comprise at least one (C1-C6) haloalkyl. In one particular embodiment, the -(C1-C6) haloalkyl is trifluoromethyl (CF3).

[0101] According to one embodiment, Z1’is a -(C3-C7) heterocycloalkyl comprising as intracyclic heteroatoms: one nitrogen atom, or two nitrogen atoms, or one nitrogen atom and one oxygen atom; wherein each nitrogen and carbon atom of the -(C3-C7) heterocycloalkyl in Z1’is optionally substituted as defined hereinabove.

[0102] According to one embodiment, Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewhereinR21’is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O- (C1-C6) alkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O-(C3-C7) cycloalkyl; R22’is selected from hydrogen, halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-O- (C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene- aryl, -(C1-C6) alkylene-heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; and each carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl may optionally be substituted by at least one R22’’group; wherein each R22’’is independently selected from hydrogen, halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene- O-(C1-C6) alkyl, -(C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in R21’, R22’or R22’’is optionally substituted with at least one halogen; and wherein each of the aryl or heteroaryl in R21’, R22’or R22’’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and O-(C3-C7) cycloalkyl.

[0103] According to another embodiment, Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewherein R21’and R22’are independently as defined hereinabove; and each carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl may optionally be substituted by at least one R22’’group; wherein each R22’’is independently as defined hereinabove.

[0104] In another embodiment, Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewherein R21’and R22’and each R22’’are independently as defined hereinabove.

[0105] In another embodiment, Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewherein R21’and R22’are as defined hereinabove.

[0106] According to another embodiment, Z1’is a -(C3-C7) heterocycloalkyl of the following formulawherein R21’is as defined hereinabove; and each carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl may optionally be substituted by at least one R22’’group; wherein each R22’’is independently as defined hereinabove.

[0107] In another preferred embodiment, Z1’is a -(C3-C7) heterocycloalkyl of the following formulawherein R21’is as defined hereinabove; and each carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl may optionally be substituted by at least one R22’’group; wherein each R22’’is independently as defined hereinabove.

[0108] In one embodiment, only one carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl is substituted by at least one R22’’group. In one embodiment, each carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl is either not substituted or substituted by only one R22’or R22’’group.

[0109] In one embodiment, no carbon atom in the cyclic moiety of the -(C3-C7) heterocycloalkyl is substituted by at least one R22’’group.

[0110] In one embodiment, Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewherein R21’and R22’are independently as defined hereinabove.

[0111] In one embodiment, Z1’is a -(C3-C7) heterocycloalkyl of the following formulawherein R21’is as defined hereinabove.

[0112] In one particular embodiment, R21’is selected from hydrogen, -(C1-C6) alkyl, -(C1-C6) alkyl substituted with at least one fluoro, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, and -(C1-C6) alkylene-O-(C1-C6) alkyl. In one preferred embodiment, R21’is selected from hydrogen, -(C1-C3) alkyl, -(C3- C5) cycloalkyl, -(C1-C3) alkylene-(C3-C5) cycloalkyl, oxetanyl, and -(C1-C3) alkylene-O- (C1-C3) alkyl.

[0113] In one particular embodiment, R21’is selected from hydrogen, -(C1-C6) alkyl and -(C1-C6) alkylene-O-(C1-C6) alkyl. In one preferred embodiment, R21’is selected from hydrogen, -(C1-C3) alkyl and -(C1-C3) alkylene-O-(C1-C3) alkyl.

[0114] In one particular embodiment, R22’is selected from hydrogen, halogen, -(C1- C6) alkyl, -(C1-C6) alkyl substituted with at least one fluoro, cyano, hydroxy and -O-(C1- C6) alkyl. In one preferred embodiment, R21’is selected from hydrogen, fluoro, trifluoromethyl, cyano, hydroxy and -O-(C1-C3) alkyl.

[0115] In one particular embodiment, R22’is selected from hydrogen, halogen, hydroxy and -O-(C1-C6) alkyl; preferably hydrogen, fluoro, hydroxy and -O-(C1-C3) alkyl.

[0116] According to one preferred embodiment, Z1’is selected from azetidinyl, 1-methylazetidinyl, 3-fluoroazetidinyl, 3-hydroxyazetidinyl, 3-methoxyazetidinyl, 1-(2-methoxyethyl)azetidinyl, pyrrolidinyl, 3-fluoropyrrolidinyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, piperidinyl, 4-hydroxypiperidinyl, piperazinyl, morpholinyl, aminoethyl, aminomethyl, and N-(methylamino)-methyl. In one preferred embodiment, Z1’is selected from azetidin-3-yl, 1-methylazetidin-3-yl, 3-fluoroazetidin-3-yl, 3-hydroxyazetidin-3-yl, 3-methoxyazetidin-3-yl, 1-methylpiperidin-4-yl, 1-(2-methoxyethyl)azetidin-3-yl, pyrrolidin-3-yl, 3-fluoropyrrolidin-3-yl, 3-hydroxypyrrolidin-3-yl, 3-methoxypyrrolidin-3-yl, morpholinomethyl, 3-methoxy-1- methylpyrrolidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin-4-yl, 4-cyano-1- methylpiperidin-4-yl, 3-hydroxy-1-methylpyrrolidin-3-yl, 4-methoxypiperidin-4-yl, 4-hydroxy-1-isopropylpiperidin-4-yl, 1-hydroxy-2-(methylamino)ethyl, 1-(2-fluoroethyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-methylpiperidin-4-yl, 4-hydroxy-1,3-dimethylpiperidin-4-yl, 1-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-(2-methoxyethyl)piperidin-4-yl, 1-cyclobutyl-4-hydroxypiperidin-4- yl)thiophen-2-yl, 1-cyclopropyl-4-hydroxypiperidin-4-yl, piperazin-1-yl, 3-hydroxy-1-methylpiperidin-4-yl, 4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl, 4-methoxy-1- methylpiperidin-4-yl, 3-hydroxy-1-methylpiperidin-3-yl, morpholin-4-yl, morpholin-2- yl, 4-methylmorpholin-2-yl, 4-methylmorpholin-3-yl, morpholin-3-yl, 2-aminoethyl, aminomethyl, and N-(methylamino)-methyl, 3-hydroxy-1-methylazetidin-3-yl, 5-(hydroxy(1-methylpiperidin-4-yl)methyl, 3-hydroxy-1-isopropylazetidin-3-yl, 6-oxa-3-azabicyclo[3.2.1]octan-5-yl, 3-methyl-6-oxa-3-azabicyclo[3.2.1]octan-5-yl, 3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-1- yl, 5-methyl-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-3- yl, 6,6-difluoro-1,4-oxazepan-2-yl, 2-methylmorpholin-2-yl, 2-(trifluoromethyl)morpholin-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-isopropyl-2,5- diazabicyclo[2.2.1]heptan-2-yl, 7-hydroxy-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7- yl, 5-hydroxy-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl, 3-hydroxyquinuclidin-3-yl, 5-hydroxy-2-azabicyclo[2.2.1]heptan-5-yl, 1-hydroxy-2-morpholinoethyl, 5-(hydroxy(4- methylmorpholin-2-yl)methyl, 5-(hydroxy(tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl, and 2-(dimethylamino)-1-hydroxyethyl.

[0117] In one preferred embodiment, Z1’is selected from azetidinyl, 1-methylazetidinyl, 3-fluoroazetidinyl, 3-hydroxyazetidinyl, 3-methoxyazetidinyl, 1-(2-methoxyethyl)azetidinyl, pyrrolidinyl, 3-fluoropyrrolidinyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, piperidinyl, 4-hydroxypiperidinyl, piperazinyl, and morpholinyl.

[0118] In one preferred embodiment, Z1’is selected from azetidin-3-yl, 1-methylazetidin- 3-yl, 3-fluoroazetidin-3-yl, 3-hydroxyazetidin-3-yl, 3-methoxyazetidin-3-yl, 1-(2-methoxyethyl)azetidin-3-yl, pyrrolidin-3-yl, 3-fluoropyrrolidin-3-yl, 3-hydroxypyrrolidin-3-yl, 3-methoxypyrrolidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin- 4-yl, piperazin-1-yl, morpholin-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-1-yl, 5-methyl-2- oxa-5-azabicyclo[2.2.1]heptan-1-yl, 6-oxa-3-azabicyclo[3.2.1]octan-5-yl, and 3-methyl- 6-oxa-3-azabicyclo[3.2.1]octan-5-yl.

[0119] In another preferred embodiment, Z1’is selected from aminoethyl, aminomethyl, and (methylamino)methyl.Further general formulae

[0120] According to one embodiment, the compound of formula (I) is a compound of formula (II)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, Y2and L are independently as defined hereinabove under formula (I); and Z1’is a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom; wherein each nitrogen atom of the (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O-(C3- C7) cycloalkyl; each carbon atom of the (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one halogen (this definition applies to alkyl, alkylene, cycloalkyl or heterocycloalkyl present in the substituents of both nitrogen and carbon atom(s) of the heterocycloalkyl); andwherein each of the aryl or heteroaryl in Z1’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl (this definition applies to aryl or heteroaryl present in the substituents of both nitrogen and carbon atom(s) of the heterocycloalkyl); and

[0121] In other words, in the present application, a compound of formula (II) is a compound of formula (I), wherein Z1’is a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom as defined hereinabove under formula (I).

[0122] In one preferred embodiment, the compound of formula (I), in particular the compound of formula (II), is not selected from 1-(5-(pyrrolidin-3-yl)thiophen-2-yl)-2- ((2-(trifluoromethyl)quinazolin-4-yl)thio)ethan-1-one, and 2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-yl)thio)-1-(5-(pyrrolidin-3-yl)thiophen-2-yl)ethan-1-one.

[0123] According to one embodiment, the compound of formula (I) is a compound of formula (III)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, Y2and L are independently as defined hereinabove under formula (I); and Z1’is -NR23’R24’; wherein R23’and R24’are each independently selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, - (C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; wherein each of the -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl, -(C3- C7) heterocycloalkyl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and - N-((C1-C6) alkyl)2; andeach of the aryl or heteroaryl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -(C1-C6) alkyl,-O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2.

[0124] In other words, in the present application, a compound of formula (III) is a compound of formula (I), wherein Z1’is -NR23’R24’as defined hereinabove under formula (I).

[0125] In one preferred embodiment, the compound of formula (I), in particular the compound of formula (III), is not selected from:

[0126] The compounds listed hereinabove were named using ChemDraw® Professional 22.0 (PerkinElmer).

[0127] In one embodiment, the compound of formula (I), in particular the compound of formula (III), is not selected from:

[0128] The compounds listed hereinabove were named using ChemDraw® Professional 22.0 (PerkinElmer).

[0129] In one embodiment, the compound of formula (I), in particular the compound of formula (II), is not 1-morpholino-2-(5-(2-(thieno[2,3-d]pyrimidin-4- ylthio)acetyl)thiophen-2-yl)ethan-1-one. Specific compounds

[0130] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below.Table 1

[0131] According to one preferred embodiment, the compound of formula (I) is selected from the compounds of Table 1 herein and pharmaceutically acceptable salts and / or solvates thereof. 5

[0132] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 2 below.Table 2

[0133] According to one preferred embodiment, the compound of formula (I) is selected from the compounds of Table 2 herein and pharmaceutically acceptable salts and / or solvates thereof.

[0134] According to another embodiment, the compound of formula (I), in particular the compound of formula (II) or the compound of formula (III), is not selected from the compounds of Table 2 herein.

[0135] According to one embodiment, the compound of formula (I) is selected from the compounds of Table 3 below.Table 3

[0136] According to one preferred embodiment, the compound of formula (I) is selected from the compounds of Table 3 herein and pharmaceutically acceptable salts and / or solvates thereof.

[0137] According to another embodiment, the compound of formula (I), in particular the compound of formula (II) or the compound of formula (III), is not selected from the compounds of Table 3 herein. The compounds of Table 1, Table 2 and Table 3 were named using ChemDraw® Professional 22.0 (PerkinElmer). Alternative compounds

[0138] All references herein to a compound of the invention (e.g., a “compound of formula (I)”) include references to salts – preferably pharmaceutically acceptable salts, solvates, multi component complexes and liquid crystals thereof. All references herein toa compound of the invention include references to polymorphs and crystal habits thereof. All references to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof. All references to a compound of the invention include references to isotopically-labelled compounds, including deuterated compounds.

[0139] A compound of the invention (e.g., a “compound of formula (I)”) and subformulae thereof may contain at least one asymmetric center(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to a compound of the invention include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0140] The compounds of the invention (e.g., a “compound of formula (I)”) may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, forexample, hemisulphate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Manufacturing process

[0141] This invention also relates to a process for manufacturing a compound of the invention as described herein. According to one embodiment, the process comprises the following steps (i-iv): (i) reacting an amine-containing alkyl chain or heterocycloalkyl with a halo-heterocycle; then (ii) reacting a heterocycle or halo-heterocycle with first an acetylating reagent, and, where appropriate, subsequently a halogenating reagent, to form a halo-ketone; then (iii) reacting a halo-ketone with a thiol and, where appropriate, (iv) removal of at least one protective group. Pharmaceutical compositions

[0142] This invention also relates to a pharmaceutical composition comprising a compound of the invention as described herein and at least one pharmaceutically acceptable carrier.

[0143] According to one embodiment, the pharmaceutical composition does not comprise any therapeutic agent other than the compound of the invention. According to anotherembodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the at least another therapeutic agent is selected from therapeutic agent known in the art for treating inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and / or idiopathic diseases.

[0144] The compound of the invention may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. Medical uses and methods of treatment

[0145] This invention also relates to a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for use as a medicament.

[0146] According to one particular embodiment, the compound or pharmaceutical composition of the invention is for use in the treatment and / or prevention of an HDAC6-associated disease as defined herein.

[0147] This invention also relates to a method of inhibiting an HDAC6 enzyme. According to one embodiment, the inhibition of an HDAC6 enzyme treats and / or prevents an HDAC6-associated disease. According to one embodiment, the method comprises a step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein.

[0148] This invention also relates to a method for treating and / or preventing a HDAC6-associated disease comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein. This invention alsorelates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the manufacture of a medicament for the treatment and / or prevention of an HDAC6-associated disease. This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the treatment and / or prevention of an HDAC6-associated disease.

[0149] Advantageously, the compound of the invention shows a superior inhibitory activity against an HDAC enzyme (e.g., class II HDAC enzyme, preferably HDAC6 enzyme) compared to state-of-the art compounds for treating and / or preventing an HDAC-associated disease. Advantageously, the compound of the invention shows a low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) against an HDAC enzyme (e.g., class II HDAC enzyme, preferably HDAC6 enzyme) compared to state-of-the art compounds for treating and / or preventing an HDAC-associated disease. In particular, the compound of the invention shows a low genetic toxicity.

[0150] According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies (including neuromuscular diseases), psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders and cardiovascular diseases. According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of proliferative diseases (such as cancers), neurodegenerative diseases, neuropathies and cardiovascular diseases.Neurodegenerative diseases include neuromuscular diseases. Neuropathies include neuromuscular diseases.

[0151] A selection of references evidencing that inhibition of HDAC6 has the effect of treating and / or preventing a given class of diseases are listed as follows.

[0152] According to one embodiment, the HDAC6-associated disease is an inflammatory disease such as, for example, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory pulmonary disease, 5 inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory responsesyndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, and the like. In one embodiment, the inflammatory disease is selected from the group comprising or consisting of acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis and Crohn’s disease.

[0153] According to one embodiment, the HDAC6-associated disease is an autoimmune disease, such as, for example, arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), Sjogren’s syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman’s disease, ankylopoietic spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves’ disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft versus host disease, dermatitis, radiodermatitis, primary biliary cirrhosis, and the like. In one embodiment, the autoimmune disease is selected from the group comprising or consisting of arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), Sjogren’s syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman’s disease, ankylopoietic spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma,lupus erythematosus profundus, chronic thyroiditis, Graves’ disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft versus host disease, dermatitis, radiodermatitis and primary biliary cirrhosis.

[0154] According to one embodiment, the HDAC6-associated disease is a proliferative disease, e.g., cancer, such as, for example, malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastasis melanoma, Kaposi’s sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney or transitional cell carcinoma in urinary duct), uterine cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, chorionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin’s disease, myelodysplastic syndrome, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine, tumor fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary,leukemia (such as acute leukemia (e.g., acute lymphatic leukemia or acute myelocytic leukemia), chronic leukemia (e.g., chronic lymphatic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor), myelofibrosis, and the like. In one embodiment, the proliferative disease, e.g., cancer is selected from the group comprising or consisting of malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastasis melanoma, Kaposi’s sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney or transitional cell carcinoma in urinary duct), uterine cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, chorionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin’s disease, myelodysplastic syndrome, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine, tumor fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary, leukemia (such as acute leukemia (e.g., acute lymphatic leukemia oracute myelocytic leukemia), chronic leukemia (e.g., chronic lymphatic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor) and myelofibrosis. In one particular embodiment, the proliferative disease is cancer. In one embodiment, the cancer is selected from the group comprising or consisting of malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer and Hodgkin’s disease.

[0155] According to one embodiment, the HDAC6-associated disease is a neurodegenerative disease, such as, for example, Alzheimer’s disease, dementia of Alzheimer type, Alzheimer-type senile dementia, Parkinson’s disease, muscular dystrophy, Parkinson’s disease associated with dementia, senile dementia, age-related cognition memory disorders, Huntington’s disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick’s disease, Parkinson’s type dementia, Niemann-Pick syndrome, Down’s disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt, and the like. In one embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer’s disease, dementia of Alzheimer type, Alzheimer-type senile dementia, Parkinson’s disease, muscular dystrophy, Parkinson’s disease associated with dementia, senile dementia, age-related cognition memory disorders, Huntington’s disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick’s disease, Parkinson’s type dementia, Niemann-Pick syndrome, Down’s disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND) and Creutzfeldt. In one particular embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, frontotemporal dementia, Pick’s disease, Niemann-Pick syndrome, Down’s disease, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[0156] According to one embodiment, the HDAC6-associated disease is a pain (including central or peripheral pain), such as, for example, pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (e.g., incision pain, deep pain, visceral pain or chronic pain after operation), muscular pain (e.g., muscular pain associated with chronic pain disease or stiff shoulder), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, catatonic headache, headache associated with fever or headache associated with hypertension), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, renal pain, urinary tract pain or bladder pain), obstetric and gynecologic pain (mittelschmerz, dysmenorrhea, labor pain), neuropathic pain (e.g., hernia of intervertebral disk, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia or lumbago), migraine, stress headache, catatonic headache, muscular spasm, irritable bowel syndrome, and the like. In one embodiment, the pain is selected from the group comprising or consisting of pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (e.g., incision pain, deep pain, visceral pain or chronic pain after operation), muscular pain (e.g., muscular pain associated with chronic pain disease or stiff shoulder), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, catatonic headache, headache associated with fever or headache associated with hypertension), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, renal pain, urinary tract pain or bladder pain), obstetric and gynecologic pain (e.g., mittelschmerz, dysmenorrhea, or labor pain), neuropathic pain (e.g., hernia of intervertebral disk, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia or lumbago), migraine, stress headache, catatonic headache, muscular spasm and irritable bowel syndrome.

[0157] According to one embodiment, the HDAC6-associated disease is a neuropathy (including central or peripheral neuropathy), such as, for example, demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloidotic polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomicataxia, injury-related neuropathy (e.g., traumatic brain injury or cerebral apoplexy), and the like. Anticancer drugs susceptible to cause neuropathy include taxanes (e.g., paclitaxel (Taxol)), vinca alkaloids (e.g., vincristine), platinum-based agents (e.g., cisplatin, carboplatin or oxaliplatin), or other molecularly targeted drugs (e.g., bortezomib). In one embodiment, the neuropathy is selected from the group comprising or consisting of demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot- Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloidotic polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia and injury-related neuropathy (e.g., traumatic brain injury or cerebral apoplexy).

[0158] In one particular embodiment, the neuropathy is selected from the group comprising or consisting of Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloidotic polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using chemotherapeutic anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain and neuropathic pain.

[0159] According to one embodiment, the HDAC6-associated disease is a psychiatric disease, such as, for example, depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depression symptom, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptom, negative symptom or cognitive symptom), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, emotional disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, neurotic anorexia, eating disorder, anorexianervosa, hyperorexia or other eating disorder, pharmacophilia, pharmacophobia, pharmacomania, and the like. In one embodiment, the psychiatric disease is selected from the group comprising or consisting of depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depression symptom, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptom, negative symptom or cognitive symptom), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, emotional disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, neurotic anorexia, eating disorder, anorexia nervosa, hyperorexia or other eating disorder, pharmacophilia, pharmacophobia, and pharmacomania.

[0160] According to one embodiment, the HDAC6-associated disease is a neurodevelopmental disorder, such as, for example, Tourette syndrome, autism, autistic spectrum syndrome, fragile X syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD), and the like. In one embodiment, the neurodevelopmental disorder is selected from the group comprising or consisting of Tourette syndrome, autism, autistic spectrum syndrome, fragile X syndrome, Rett syndrome, and attention deficit hyperactivity disorder (ADHD).

[0161] According to one embodiment, the HDAC6-associated disease is a sleep disorder, such as, for example, intrinsic sleep disorders (e.g., psychophysiological insomnia), extrinsic sleep disorder, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome or non-24-hour sleep-wake), parasomnia, sleep disorders associated with internal medical or psychiatric disorder (e.g., chronic obstructive pulmonary diseases, Alzheimer’s disease, Parkinson’s disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomniac neurosis, sleep apnea syndrome, and the like. In one embodiment, the sleep disorder is selected from the group comprising or consisting ofintrinsic sleep disorders (e.g., psychophysiological insomnia), extrinsic sleep disorder, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome or non-24-hour sleep-wake), parasomnia, sleep disorders associated with internal medical or psychiatric disorder (e.g., chronic obstructive pulmonary diseases, Alzheimer’s disease, Parkinson’s disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomniac neurosis and sleep apnea syndrome.

[0162] According to one embodiment, the HDAC6-associated disease is a cardiovascular disease, such as, for example, chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, cardiac disease, tachycardia, congestive cardiac failure, and the like. In one embodiment, the cardiovascular disease is selected from the group comprising or consisting of chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, cardiac disease, tachycardia and congestive cardiac failure. In one particular embodiment, the heart-related disease is selected from the group comprising or consisting of heart failure, cardiomyopathy and myocarditis.

[0163] According to one embodiment, the HDAC6-associated disease is an addiction-related disorder, such as, for example, alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcoholic insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic insanity, drug withdrawal, and the like. In one embodiment, the addiction related disorder is selected from the group comprising or consisting of alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcoholic insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic insanity and drug withdrawal.

[0164] According to one embodiment, the HDAC6-associated disease is a gastrointestinal disease, such as, for example, peptic ulcer, stress gastrointestinal disorder,stress vomiting, peptic ulcer, diarrhea, constipation or postoperative ileus, and the like. In one embodiment, the gastrointestinal disease is selected from the group comprising or consisting of peptic ulcer, stress gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation ileus and postoperative ileus.

[0165] According to one embodiment, the HDAC6-associated disease is a pulmonary disease, such as, for example, hyperventilation, bronchial asthma, apnea, and the like. In one embodiment, the pulmonary disease is selected from the group comprising or consisting of hyperventilation, bronchial asthma and apnea.

[0166] According to one embodiment, the HDAC6-associated disease is a metabolic or hormonal disorder, such as, for example, obesity, diabetes, acromegaly, infertility, metabolic syndrome, and the like. In one embodiment, the metabolic or hormonal disorder is selected from the group comprising or consisting of obesity, diabetes, acromegaly, infertility and metabolic syndrome.

[0167] According to one embodiment, the HDAC6-associated disease is an immune disorder, such as, for example, allergic disease, immunodeficiency syndrome caused by HIV infection, immunodeficiency syndrome caused by stress, and the like. In one embodiment, the immune disorder is selected from the group comprising or consisting of immunodeficiency syndrome caused by HIV infection and immunodeficiency syndrome caused by stress.

[0168] According to one embodiment, the HDAC6-associated disease is an age-related disease, such as, for example, alopecia, glaucoma, impotence, climacteric disorder, incontinence, osteoporosis, and the like. In one embodiment, the age-related disease is selected from the group comprising or consisting of alopecia, glaucoma, impotence, climacteric disorder, incontinence and osteoporosis.

[0169] According to one embodiment, the HDAC6 associated disease is an idiopathic disease, such as, for example, Meniere’s disease, sudden infant death syndrome, and the like. In one embodiment, the idiopathic disease is Meniere’s disease or sudden infant death syndrome.

[0170] The compound or pharmaceutical composition of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration. In the treatment and / or prevention of an infectious disease an appropriate dosage level may be from about 0.01 to 500 mg per kg patient body weight per day (mg / kg / day), which can be administered in single or multiple doses. Typically, the dosage level will be from about 0.1 to about 250 mg / kg / day, preferably from about 0.5 to about 100 mg / kg / day, more preferably from about 2.5 to about 20 mg / kg / day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular diseases and the host undergoing therapy.

[0171] Advantageously, the compound of the invention is selective over at least one HDAC other than HDAC6, preferably over at least one class II HDAC other than HDAC6, more preferably over any class II HDAC other than HDAC6, furthermore preferably over HDAC other than HDAC6. Particularly advantageously, the compound of the invention is selective over HDAC1. Particularly advantageously, the compound of the invention is selective over HDAC10. Selectivity is strongly associated with the avoidance of side-effects of HDAC inhibitors. Kit

[0172] This invention also relates to a kit comprising a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, and means to administer the compound or pharmaceutical composition.

[0173] Means for administering a compound or a pharmaceutical composition are well-known in the art and may be identified by a person skilled in the art depending of the desired administration route. EXAMPLES

[0174] The present invention is further illustrated by the following examples. Example 1: Synthesis of the compounds

[0175] The compounds of formula (I) (1)-(190) represented on Table 1, Table 2 and / or Table 3 hereinabove were prepared as described hereinafter. General synthetic methods

[0176] The compounds according to the invention, in particular the compounds according to the formula (I), may be prepared by methods known to the person skilled in the art of organic synthesis or by using the following synthesis schemes. In all of the schemes described below it is understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with the general principles of organic chemistry. Protecting groups are manipulated according to standard methods (T.W. Green and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.). These groups are then removed at a convenient stage of the synthesis using methods that are readily apparent to those skilled in the art. Many of the heterocyclic compounds of formula (I) where Y1or Y2is a heteroaryl may be prepared using synthetic routes well known in the art (A.R. Katrizky and C. W. Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0177] The synthesis of the HDAC6 inhibitors disclosed in the present invention have been prepared using the following synthetic schemes. Specific conditions for carrying out these reactions are provided in the detailed examples. The synthetic schemes described below show exemplified approaches to compounds of the present invention, but these routes should not be taken as the only possible synthetic routes to compounds of the present invention.

[0178] Compounds of formula (I) in which L is a direct bond, and Z1’represents a cyclic amine such as, for example, pyrrolidine, and Y1and Y2are as defined above, may be obtained also according to Scheme 1 (Method 1) below: Scheme 1 / Method 1

[0179] Protected cyclic amines T-1 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Compound T-1 can be reacted with phenyltriflimide, N-(5-chloropyridin-2-yl)- 1,1,1-trifluoro-N-trifluoromethylsulfonyl) methanesulfonamide or trifluoromethanesulfonic anhydride in the presence of a suitable base (e.g., LiHMDS) and solvent (e.g., THF) at the appropriate temperature to provide the triflate enol ether T-2 in which X1is an OSO2CF3 group (Step 1). A Suzuki cross coupling-type reaction of triflate T-3 with a boronic acid or boronic ester of Formula T-4 in the presence of a catalyst (e.g., Pd(dppf)Cl2), a base (e.g., Cs2CO3), in a solvent (e.g., DMF) at the appropriate temperature may provide intermediate ketone T-5 (Step 2). Boronic acid or boronic ester of Formula T-4 may be commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. The double- bond of the cyclic amine intermediate T-5 can then be reduced upon hydrogenation using H2 in the presence a of catalyst (e.g., Pd / C or Pd(OH)2) in a solvent (e.g., MeOH) to provide the corresponding saturated amine intermediate T-6 (Step 3). Ketone T-6 can be engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at the appropriate temperature to provide halo-ketone T-7, in which X2is a halogen such as, for example, bromide (Step 4). Halo-ketone T-7 can then be reacted with thiol hetero-aryl derivativesof Formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide heteroaryl intermediate T-8 (Step 5). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared by methods known to the person skilled in the art. The protected amine T-8 can be deprotected in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine T-9 (Step 6). Some amines T-9 can be treated as compounds of formula (I), while other amines T-9 can be further alkylated with an appropriate alkylating agent (Step 7) such as, for example, formaldehyde or 2-methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide N- alkylated amines of formula (I).

[0180] Compounds of formula (I) in which L is a direct bond, and Z1’represents a cyclic amine such as, for example, azetidine, and Y1and Y2are as defined above, may also be obtained according to Scheme 2 (Method 2) below: Scheme 2 / Method 2

[0181] Halides T-10 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Intermediate T-11 can be prepared by reacting intermediate T-10 with a suitable metalating agent such as, for instance zinc metal with catalytic I2, and reacting the resulting organometal with a suitable acylated (hetero)aromatic halide T-33 such as, for instance, 2-bromo-5-acetylthiophene, in presence of a suitable catalyst such as, for example, Pd2(dba)3 / S-Phos, in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for example 15 °C. Compounds T-33 are commercially available or may be prepared by methods known to the person skilled in the art. The acetyl group of intermediate T-11 can be halogenated with a proper halogenating agent such as, for example, tetrabutylammonium tribromide, in a suitable solvent such as, for example, DCM / MeOH, at a suitable temperature such as, for example, 20 °C, providing halo- ketone T-12 (Step 2). The halo of intermediate T-12 can be substituted by a suitable thiol of Formula Y1-SH, in presence of a suitable base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide heteroaryl intermediate T- 13 (Step 3). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1- OH derivatives using Lawesson’s reagent or P2S5reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared by methods known to the person skilled in the art. The protected amine T-13 can be deprotected in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine T-14 (Step 4). Some amines T-14 can be treated as compounds of formula (I), while other amines T-14 can be further alkylated with an appropriate alkylating agent (Step 5) such as, for example, formaldehyde or 2-methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide N- alkylated amines of formula (I).

[0182] Compounds of formula (I) in which L is a direct bond, and Z1’represents a cyclic amine such as, for example, azetidine or pyrrolidine or piperidine, and Y1and Y2are as defined above, may be obtained also according to Scheme 3 (Method 3) below:Scheme 3 / Method 3

[0183] Protected cyclic amines T-15 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. The keto function in compound T-15 can be converted to intermediate of formula T-17 by reaction with bis-halogenated (hetero)aryl groups, after conversion of the most reactive halogen of the latter into an organometal with a suitable metalating reagent such as, for instance, n-butyllithium in a suitable solvent such as, for instance, THF, at a suitable temperature such as, for instance, -78 °C (Step 1). Alternatively, compound T-15 can be converted to an intermediate of formula T-16 by reaction with mono-halogenated (hetero)aryl groups, after conversion of the halogen of the latter into an organometal with a suitable metalating reagent such as, for instance, n-butyllithium in a suitable solvent such as, for instance, THF, at a suitable temperature such as, for instance, -78 °C (Step 2). Intermediate T-16 can in a next step be halogenated with a suitable halogenating reagent such as, for instance, N-bromosuccinimide with a catalyst such as, for instance N,N-dimethylaminopyridine, in a suitable solvent such as, for instance, acetonitrile, at a suitable temperature such as, for example, room temperature to provide intermediate T-17 (Step 3). Intermediate T-17 can be acetylated with a suitable acylating reagent such as, for example, ethoxyvinyltributyltin, in presence of a suitable catalyst such as, for example, Pd(PPh3)4, in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for instance, 120 °C, and an ensuing work up with a suitable enol ether deprotection agent such as, for example 0.5 M aq. HCl, at a suitable temperature such as, for example, room temperature, to provide intermediate T- 18 (Step 4). The acetyl group of intermediate T-18 can be halogenated with a suitable reagent such as, for example, tetrabutylammonium tribromide (TBATB) or trimethylphenylammonium tribromide or CuBr2, in a suitable solvent such as, for example, DCM / MeOH or EtOAc / CHCl3, at a suitable temperature such as, for instance room temperature or 85 °C, to provide intermediate T-19 (Step 5). Alternatively, intermediate T-19 can be obtained by reacting T-18 with a suitable 1-alkoxyvinylating reagent such as, for example, ethoxyvinyltributyltin, in presence of a suitable catalyst such as, for example, Pd(PPh3)2Cl2, in a suitable solvent such as, for example, 1,4- dioxane, at a suitable temperature such as, for instance, 90 °C, and engaging the resulting enol ether in a subsequent halogenation reaction with a suitable halogenating reagent such as, for example, N-bromosuccinimide, in a suitable solvent such as, for example,THF / water, at a suitable temperature such as, for example, room temperature (Step 6). The halogen in intermediate T-19 can be further reacted with a suitable thiol of formula Y1-SH in presence of a suitable base such as, for instance NaOMe or K2CO3, in a suitable solvent such as, for example, DMF or ACN, at a suitable temperature such as, for example, room temperature or 50 °C, to provide intermediate T-20 (Step 8). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared by methods known to the person skilled in the art. The protected amine T-20 can be deprotected in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine T-21 (Step 9). Some amines T-21 can be treated as compounds of formula (I), while other amines T-21 can be further alkylated with an appropriate alkylating agent (Step 10) such as, for example, formaldehyde or 2-methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide N- alkylated amines of formula (I).

[0184] Intermediates of formula T-17 may also be converted to intermediates of formula T-22 in which R1is a fluoro (F) atom by treatment with a suitable deoxofluorinating agent such as, for example, diethylaminosulfur trifluoride (DAST), in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for instance, 0 °C (Step 7). Alternatively, intermediates of formula T-17 may also be converted to intermediates of formula T-22 in which R1is a methoxy (OMe) group by treatment with a suitable methylating agent such as, for example, methyl iodide, in presence of a suitable base such as, for example, sodium hydride, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for instance, room temperature. Intermediates of formula T- 22 in which R1is a fluoro (F) atom or methoxy (OMe) group may be further carried on to compounds of formula (I) using Steps 4, 5, 6, 8, 9 and 10 as described hereinabove.

[0185] Compounds of formula (I) in which Y2represents a heterocycle N-linked to an amine-containing heterocycloalkyl such as, for example, pyrazole, and Y1is as defined above, may also be obtained also according to Scheme 4 (Method 4).Scheme 4 / Method 4

[0186] Protected cyclic amines T-28, and 1-ethanone substituted NH-containing heteroaromatic cycles T-27 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. The NH function of T-27 can be N-alkylated to an intermediate of formula T-28 with a hydroxy-substituted N-protected cyclic amine such as, for example, tert-butyl 3- hydroxypyrrolidine-1-carboxylate, using a suitable reagent such as, for example, diisopropylazodicarboxylate (DIAD) and triphenylphosphine, in a suitable solvent such as, for example, tetrahydrofuran, at a suitable temperature such as, for 20 °C (Step 1). The acetyl group of intermediate T-29 can be further halogenated with a suitable reagent such as, for example, tetrabutylammonium tribromide (TBATB) or trimethylphenylammonium tribromide or CuBr2, in a suitable solvent such as, for example, DCM / MeOH or EtOAc / CHCl3, at a suitable temperature such as, for instance room temperature or 85 °C, to provide intermediate T-30 (Step 2). The halogen X1in intermediate T-30 can be further reacted with a suitable thiol of formula Y1-SH in presence of a suitable base such as, for instance NaOMe or K2CO3, in a suitable solvent such as, for example, DMF or ACN, at a suitable temperature such as, for example, roomtemperature or 50 °C, to provide intermediate T-31 (Step 3). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5 reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared by methods known to the person skilled in the art. The protected amine T-31 can be deprotected in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine T-32 (Step 4). Some amines T-32 can be treated as compounds of formula (I), while other amines T-32 can be further alkylated with an appropriate alkylating agent (Step 5) such as, for example, formaldehyde or 2-methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide N- alkylated amines of formula (I).

[0187] Compounds of formula (I) in which L is a direct bond, Z1’represents an amine linked to Y2, of which W1is a (substituted) carbon, (substituted) nitrogen or O, and Y1and Y2are as defined above, may also be obtained also according to Scheme 5 (Method 5) below:Scheme 5 / Method 5

[0188] Intermediates T-33, in which X1is a suitable halogen such as, for example, bromo, and Y2is a heteroaryl such as, for example, thiazole, can be obtained commercially or prepared via art known conditions. The halo X1on intermediate T-33 can be substituted with a suitable amine such as, for example, tert-butyl piperazine-1-carboxylate, in presence of a suitable base such as, for example, K2CO3, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 85 °C, to provide intermediate T-34 (Step 1). The acetyl group of intermediate T-34 can be further halogenated with a suitable reagent such as, for example, tetrabutylammonium tribromide (TBATB) or trimethylphenylammonium tribromide or CuBr2, in a suitable solvent such as, for example, DCM / MeOH or EtOAc / CHCl3, at a suitable temperature such as, for instance room temperature or 85 °C, to provide intermediate T-35 (Step 2). The halogen X2in intermediate T-35 can be further reacted with a suitable thiol of formula Y1-SH in presence of a suitable base such as, for instance NaOMe or K2CO3, in a suitable solvent such as, for example, DMF or ACN, at a suitable temperature such as, for example, room temperature or 50 °C, to provide intermediate T-36 (Step 3). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared by methods known to the person skilled in the art. Intermediates of formula T-36 in which W1is a protected amine can be N-deprotected to compounds of formula (I) in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine (Step 4). A skilled person will understand that compounds of formula (I) containing a free amine (NH) can be further alkylated with an appropriate alkylating agent such as, for example, formaldehyde or 2-methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide N-alkylated amines of formula (I). Intermediates in which W1is a (substituted) carbon (C) or oxygen (O) atom can be reacted with a suitable thiol of formula Y1-SH in presence of a suitable base such as, for instance NaOMe or K2CO3, in a suitable solvent such as, for example, DMF or ACN, at a suitabletemperature such as, for example, room temperature or 50 °C, to immediately provide compounds of formula (I) (Step 5).

[0189] Compounds of formula (I) in which L is an alkylene, and Z1’represents an amine which is N-linked to L, and Y1and Y2are as defined above, may also be obtained also according to Scheme 6 (Method 6) below:Scheme 6 / Method 6

[0190] Alcohols T-37 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Intermediate T-38, in which X1is a halogen such as, for example, bromide, can be obtained by halogenation of T-37 with a suitable halogenating reagent such as, for example, N-iodosuccinimide (NIS) with para-toluenesulfonic acid catalysis, in a suitable solvent such as, for example, ethanol, at a suitable temperature such as, for example, 25 °C (Step 1). The halogen of intermediate T-38 can be acetylated with a suitable acylating reagent such as, for example, ethoxyvinyltributyltin, in presence of a suitable catalyst such as, for example, Pd(PPh3)4, in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for instance, 120 °C, and an ensuing work up with a suitable enol ether deprotection agent such as, for example 0.5 M aq. HCl, at a suitable temperature such as, for example, room temperature, to provide intermediate T-39 (Step2). The alcohol of intermediate T-39 can be protected with a suitable protective group (PG) such as, for example, tert-butyl diphenylsilyl (TBDPS), by treatment with a suitable silylating reagent such as, for example, TBDPS-Cl, in presence of a suitable base such as, for example, imidazole and catalytic DMAP, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 15 °C, to provide intermediate T- 40 (Step 3). The acetyl group of intermediate T-40 can be halogenated with a suitable reagent such as, for example, tetrabutylammonium tribromide (TBATB) or trimethylphenylammonium tribromide or CuBr2, in a suitable solvent such as, for example, DCM / MeOH or EtOAc / CHCl3, at a suitable temperature such as, for instance room temperature or 85 °C, to provide intermediate T-41, in which X2is a halogen such as, for example, bromide (Step 4). A skilled person will understand a silyl protective group might be removed during Step 4, while other protective groups might require an additional deprotection step following art known conditions. The halogen in intermediate T-41 can be further reacted with a suitable thiol of formula Y1-SH in presence of a suitable base such as, for instance NaOMe or K2CO3, in a suitable solvent such as, for example, DMF or ACN, at a suitable temperature such as, for example, room temperature or 50 °C, to provide intermediate T-42 (Step 5). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5 reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1- OH are commercially available or may be prepared by methods known to the person skilled in the art. The alcohol of T-42 can be oxidized to the corresponding aldehyde T- 43 by a suitable oxidant such as, for example, Dess-Martin periodinane (DMP), in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 25 °C. Intermediates T-43 can be engaged in a reductive amination reaction to provide compounds of formula (I) by reaction with a suitable amine such as, for example, morpholine, in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 25 °C. A skilled person will understand that if Z1’in compounds of formula (I) carries a protected amine, this amine can be deprotected in acidic, neutral or basic media depending on the choice of the protecting group, for example in acidic media to remove of a Boc-protecting group using formic acid oraqueous HCl solution, to provide the corresponding free amine (NH), which presents another compound of formula (I). Alternatively, such free amine can be further alkylated with an appropriate alkylating agent such as, for example, formaldehyde or 2- methoxyethanal in presence of a suitable reductant such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example 0 °C to room temperature, to provide other N-alkylated amines of formula (I).

[0191] A skilled person will understand that while the Schemes 1-6 above depict monocyclic amines, it is equally possible to engage polycyclic amines in the same type of reactions to prepare compounds of formula (I) in which Z1’is a polycyclic amine such as, for example, a bicycle, spirocycle or bridged cycle.

[0192] Compounds of formula (I) in which Z1’represents a non-cyclic amine of formula -NR23’R24’, and Y1and Y2are as defined above, may be obtained according to Scheme 7 (Method 7) below:Scheme 7 / Method 7

[0193] Amines T-44 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature.Intermediates T-45, in which PG is a suitable protective group such as, for example, Boc, may be prepared by protecting the amine group of T-44 (Step 1) by, for example using Boc2O in the presence of a base (e.g., Et3N or NaHCO3) and in a solvent (e.g. DCM or THF) at the appropriate temperature. Protected amine intermediate T-45 can be engaged into a halogenation step to provide a T-46 in which X1is a halo such as, for instance, bromo (Br) using, for example NBS or Br2 in a solvent (e.g., DCM) at the appropriate temperature (Step 2). Halide T-46 can next be transformed into the corresponding ketone T-47 in a single or multiple step-sequence, for example: (Option 1) a 2-step sequence such as (i) metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at the appropriate temperature to provide the enol ether intermediate, which is turn transformed into the desired ketone T-47 using acidic media such as aqueous HCl or formic acid at the appropriate temperature (Step 3); or (Option 2) in a 3-step sequence such as (i) a metal-halide exchange, using for example n-BuLi, under inert atmosphere like nitrogen atmosphere, at controlled temperature like -78 °C, in a non protic solvent like dry THF, followed by the introduction of dimethylformaldehyde, or equivalent reagent, to provide the corresponding aldehyde intermediate T-48 (Step 4). Intermediate T-48 can be treated with a methylating agent such as, for instance, MeMgBr, in a non-protic solvent (e.g., THF) at the appropriate temperature to provide the resulting alcohol T-49 (Step 5). Alcohol T-49 can be transformed into the corresponding ketone T-47 by the use of an oxidizing agent for example DMP or PCC in a solvent (e.g., DCM) at the appropriate temperature (Step 6). Ketone T-47 can be further engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at the appropriate temperature to provide halo-ketone T- 50, in which X2is a suitable halogen such as, for example, bromide (Step 7). Halo-ketone T-50 is then reacted with thiol hetero-aryl derivatives of Formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide heteroaryl intermediate T-51 (Step 8). Heteroaryl Y1-SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y1-OH derivatives using Lawesson’s reagent or P2S5 reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y1-OH are commercially available or may be prepared bymethods known to the person skilled in the art. The protected amine T-51 can then be deprotected in acidic or basic media depending of the choice of the protecting group, for example in acidic media such as, for example, formic acid or aqueous HCl, to remove of a Boc-protecting group, or upon hydrogenolysis using H2 in the presence a of catalyst (e.g., Pd(OH)2) in a protic solvent (e.g., MeOH) to remove a benzyl-type protecting group such as, for example, Cbz, to finally provide the corresponding amine intermediate T-52 (Step 9). Amine T-52 can directly be considered a compound of formula (I), or can be further alkylated with a suitable alkylating reagent such as, for example, formaldehyde, in presence of a suitable reducing agent such as, for example, sodium triacetoxyborohydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as for example, 0-25 °C, to provide compounds of formula (I) in which the amine carries an alkyl group. A skilled person will understand that the alkylation of the amine in compounds of formula (I) can also occur at an earlier stage of the synthesis, for instance when a primary amine is Boc-protected, by alkylating the NH-Boc function with a suitable alkylating reagent such as, for example, methyl iodide, in presence of a suitable base such as, for example sodium hydride, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 0 °C.

[0194] Compounds of formula (I) in which L is a direct bond and in which Z1’represents a substituted morpholine or homomorpholine, and Y1and Y2are as defined above, may be obtained also according to Scheme 8 (Method 8) below:Scheme 8 / Method 8

[0195] Intermediates T-33, in which X1is a suitable halogen such as, for example, bromo, and Y2represents a heteroaryl such as, for example, thiophene, can be obtained commercially or prepared via art known conditions. The acetyl group of intermediate T- 33 can be halogenated with a suitable reagent such as, for example, tetrabutylammonium tribromide (TBATB) or trimethylphenylammonium tribromide or CuBr2, in a suitable solvent such as, for example, DCM / MeOH or EtOAc / CHCl3, at a suitable temperature such as, for instance room temperature or 85 °C, to provide intermediate T-53 in which X2is a halide such as, for example, bromide (Step 1). Intermediate T-54 can be obtained by reacting intermediate T-53 with a suitable amino alcohol of formula HOCH2(CH2)nNH-PG1, in which n is 1 or 2, and in which PG1is a suitable protective group such as, for example, benzyl, in presence of a suitable base such as, for example K2CO3, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C. Intermediate T-55 in which R22’is a hydrogen can be obtained byreacting intermediate T-54 with a suitable reducing agent such as, for example, NaBH4, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, 25 °C (Step 3). A skilled person will understand that alternatively nucleophiles such as, for example, MeMgBr or TMS-CF3 / TBAF can be reacted with the ketone of T- 54 yielding tertiary alcohols T-55 in which R22’is, for example, a methyl or a CF3group, and a skilled person will also understand that this may require protection of the primary OH group with a suitable protective group such as, for example, TBDMS. Intermediate T-56 can be obtained from intermediate T-55 using suitable intramolecular ether formation conditions such as, for example, HBr in acetic acid (used as solvent), at a suitable temperature such as, for example, 25 °C (Step 4). Intermediate T-57, in which PG2is a suitable alternative protective group to PG1, such as, for example, Boc, can be obtained by first removing the protective group PG1using a suitable deprotecting method such as, for example in case PG1is a benzyl group, 1-chloroethyl chloroformate, in a suitable solvent such as, for example, DME, followed by treatment with MeOH, and subsequent re-protection of the resulting amine with a suitable reagent such as, for example, Boc2O, in presence of a suitable base such as, for example, triethylamine, a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 25 °C (Step 5). Intermediate T-57 can be converted to T-58, in which X3is a halogen such as, for example, bromo, via a suitable haloacetylation method such as, for example, metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at the appropriate temperature to provide the enol ether intermediate, which can in turn be transformed into haloketone T-58 using a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step 6). Halo-ketone T-58 can be reacted with heteroaryl thiol derivatives of formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide intermediate T-59 (Step 7). Intermediate thiols Y1-SH can be prepared as described hereinbefore. Compounds of formula (I) in which Z1’is a N- unsubstituted morpholine or homomorpholine can be obtained by reacting intermediate T-59 with a suitable protective group removing reagent such as, for example, HCl / EtOAc (used as solvent), at a suitable temperature such as, for example, 25 °C (Step 8).Compounds of formula (I) in which the morpholine or homomorpholine is N-alkylated can be obtained by subsequent reaction of the deprotected amine with a suitable alkylating reagent such as, for example, formaldehyde, in presence of a suitable reducing agent such as, for example, NaBH(OAc)3, in a suitable solvent such as, for example, AcOH / DCM, at a suitable temperature such as, for example, 25 °C. A skilled person will understand that racemic compounds of formula (I) can be further subjected to chiral separation such as, for example, chiral SFC to provide enantiopure compounds of formula (I).

[0196] Compounds of formula (I) in which L is a direct bond and in which Z1’represents a bridged substituted morpholine or homomorpholine and Y1and Y2are as defined above may be obtained also according to Scheme 9 (Method 9) below:Scheme 9 / Method 9

[0197] Keto-acid intermediates T-60, in which PG is a suitable protective group such as, for example, Boc, and n is 1 or 2, can be obtained commercially or prepared via art known conditions. Intermediate T-61 can be obtained by reacting intermediate T-60 with asuitable organometal such as, for example, thiophen-2-ylmagnesium bromide, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0 °C (Step 1). Intermediate T-62 can be obtained by reacting intermediate T-61 with a suitable acid reducing reagent such as, for example, BH3.THF, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0-70 °C (Step 2). Intermediate T-63 can be obtained by reacting intermediate T-62 under suitable intramolecular ether formation conditions such as, for example, PPh3 / DIAD, in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for example, 25 °C (Step 3). Intermediate T-64, in which X1is a halogen such as, for example, bromide, can be obtained by reacting intermediate T-63 with a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 4). Intermediate T-64 can be converted to haloketone T-65 in which X2is a halide such as, for example, bromide, via a suitable haloacetylation method such as, for example, metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at the appropriate temperature to provide the enol ether intermediate, which can in turn be transformed into haloketone T-65 using a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, room temperature (Step 5). Halo-ketone T-65 can be reacted with heteroaryl thiol derivatives of formula Y1-SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide intermediate T- 66 (Step 6). Intermediate thiols Y1-SH can be prepared as described hereinbefore. Compounds of formula (I) in which Z1’is a N-unsubstituted bridged morpholine or homomorpholine can be obtained by reacting intermediate T-66 with a suitable protective group removing reagent such as, for example, HCl / EtOAc (used as solvent), at a suitable temperature such as, for example, 25 °C (Step 7). Compounds of formula (I) in which the bridged morpholine or homomorpholine is N-alkylated can be obtained by subsequent reaction of the deprotected amine with a suitable alkylating reagent such as, for example, formaldehyde, in presence of a suitable reducing agent such as, for example, NaBH(OAc)3, in a suitable solvent such as, for example, AcOH / DCM, at a suitable temperature such as, for example, 25 °C. A skilled person will understand that other N-protected cyclic amines containing both a ketone and an acid, such as, for example, 1- (tert-butyl) 3-methyl 5-oxopiperidine-1,3-dicarboxylate can similarly be converted to compounds of formula (I). A skilled person will also understand that starting from the opposite enantiomer of T-60 will provide a compound of formula (I) with opposite stereochemistry, hence the stereochemistry of the acid group in a starting material such as T-60 will determine the stereochemistry in the compound of formula (I).

[0198] Compounds of formula (I) in which L is a direct bond and in which Z1’represents a substituted morpholine or homomorpholine, and Y1and Y2are as defined above, may be obtained also according to Scheme 10 (Method 10) below:Scheme 10 / Method 10

[0199] Alpha-keto esters T-67 in which PG1is a suitable acid protective group such as, for example, methyl, are commercially available or may be synthesized by a personskilled in the art of organic chemistry using multiple ways described in the literature. Intermediates T-68 in which R22’is as defined above may be prepared by reacting T-67 with an organometallic nucleophile such as, for example, methylmagnesium bromide, in a solvent (e.g., THF) at a suitable temperature such as, for example -40 °C (Step 1). Intermediates T-68 may also be prepared by reacting T-67 with other ketone-reactive nucleophiles such as, for example, trifluoromethyltrimethylsilane in presence of a suitable anionic initiator such as, for example, tetrabutylammonium fluoride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 0°C to room temperature. Intermediate T-69 in which X1is a halide such as, for example bromide, can be prepared by reacting intermediate T-68 with a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 2). Intermediates T-70 may be prepared by reacting T-69 with a suitable base such as, for example, KOH, in a suitable solvent such as, for example, EtOH / water, at a suitable temperature such as, for example, 25 °C (Step 3). Intermediates T-71 may be prepared by reacting T-70 with 2-chloroethylamine using a suitable amide coupling reagent such as, for example, HATU, in presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 0-25 °C (Step 4). Intermediates T-72 may be obtained by reacting T-71 with a suitable base such as, for example, tBuOK, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0-80 °C (Step 5). Intermediates T-73 may be obtained by reacting T-72 with a suitable reducing agent such as, for example, BH3.THF, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -60 to 25 °C (Step 6). Intermediate T-74, in which PG2is a suitable protective group such as, for example, Boc, may be obtained by reacting T-73 with a suitable protecting reagent such as, for example, Boc2O, in presence of a suitable base such as, for example, K2CO3, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, 25 °C (Step 7). Intermediate T-74 can be converted to haloketone T-75 in which X2is a halide such as, for example, bromide, via a suitable haloacetylation method such as, for example, metal- catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at the appropriate temperature to provide the enol ether intermediate, whichcan in turn be transformed into T-75 in which X2is a halide such as, for example, bromide, using a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, THF / water, at a suitable temperature such as, for example, 25 °C (Step 5). Halo-ketone T-75 can be reacted with heteroaryl thiol derivatives of formula Y1- SH in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide intermediate T-76 (Step 9). Intermediate thiols Y1-SH can be prepared as described hereinbefore. Compounds of formula (I) in which Z1’is a morpholine can be obtained by reacting intermediate T-76 with a suitable protective group removing reagent such as, for example, HCl / EtOAc (used as solvent), at a suitable temperature such as, for example, 25 °C (Step 10). Compounds of formula (I) in which the morpholine is N-alkylated can be obtained by subsequent reaction of the deprotected amine with a suitable alkylating reagent such as, for example, formaldehyde, in presence of a suitable reducing agent such as, for example, NaBH(OAc)3, in a suitable solvent such as, for example, AcOH / DCM, at a suitable temperature such as, for example, 25 °C. A skilled person will understand that racemic compounds of formula (I) can be further subjected to chiral separation such as, for example, chiral SFC to provide enantiopure compounds of formula (I).

[0200] Intermediates T-74 in which Y2is as described above, X1is a halo such as, for example, bromide, PG is a protective group, and R22’is a CF3group may be obtained also according to Scheme 11 (Method 11) below:T-74 T-83 T-82 T-81 Scheme 11 / Method 11

[0201] Intermediates T-77 are commercially available or can be made using art known conditions. Intermediates T-78 can be prepared by reacting T-77 with a suitable reagent such as, for example, nitromethane, in presence of a suitable base such as, for example, K2CO3, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 25 °C (Step 1). Intermediates T-79 can be obtained by reacting T-78 with a suitable reducing agent such as, for example, hydrogen gas, in presence of a suitable catalyst such as, for example Pd / C, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example, 25 °C (Step 2). Intermediates T-80 can be obtained by reacting T-79 with chloroacetyl chloride, in presence of a suitable base such as, for example, triethylamine, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 0 °C (Step 3). Intermediate T-81 can be obtained by reacting T-80 with a suitable base such as, for example, NaH, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0 °C (Step 4). Intermediate T-82 can be obtained by reducing intermediate T-81 with a suitable reagent such as, for example, LiAlH4, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 0-70 °C (Step 5). Intermediate T-83, in which PG is a suitable protective group such as, for example, Boc, can be prepared by reacting intermediate T-82 with a suitable protecting reagent such as, for example, Boc2O, in presence of a suitable base such as, for example, triethylamine, in a suitable solvent such as, for example, MeOH, at a suitable temperature such as, for example, 25 °C (Step 6). Intermediate T-74 in which R22’is a CF3 group can be prepared by reacting intermediate T-83 with a suitable halogenating reagent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 7). A skilled person will understand that intermediate T-74 in which R22’is a CF3 group can be progressed to compounds of formula (I) in a similar manner as described in Scheme 10 hereinabove.

[0202] Intermediates T-91 in which Y2is as described above, X1is a halo such as, for example, bromide, PG is a protective group, and R22’is a CF3group may be obtained according to Scheme 12 (Method 12) below:Scheme 12 / Method 12

[0203] Intermediates T-84 in which PG1is a suitable protective group such as, for example, Boc, are commercially available or can be prepared using art known conditions. Intermediates T-85, in which Q1is an activating group such as, for example, diphenyl phosphonate or triflate, can be prepared by reacting T-84 with a suitable activating reagent such as, for example, diphenyl phosphorochloridate, in the presence of a suitable base such as, for example, LiHMDS, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -30 to 25 °C (Step 1). Intermediate T-87 can be prepared by reacting T-85 with a suitable boronate T-86 of formula Y2-B(OH)2, in presence of a suitable catalyst such as, for example, Pd(tBu3P)2, in presence of a suitable base such as, for example, K3PO4, in a suitable solvent such as, for example, ACN / water, at a suitable temperature such as, for example, 65 °C (Step 2). Intermediate T-88 prepared by reacting T-87 with a suitable deprotecting agent such as, for example, 2 M HCl in dioxane, at a suitable temperature such as, for example, 0-25 °C (Step 3). Intermediate T- 89 can be prepared by reacting T-88 with a suitable reducing agent such as, for example,NaBH3CN, in a suitable solvent such as, for example, AcOH / MeOH, at a suitable temperature such as, for example, 25 °C (Step 4). Intermediate T-90, in which PG2is a suitable protective group such as, for example, Boc, can be prepared by reacting T-89 with a suitable protecting agent such as, for example, Boc2O, in presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, 25 °C. Intermediate T-91 in which X1is a suitable halogen such as, for example, bromide, can be prepared by reacting T-90 with a suitable halogenating agent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C. A skilled person will understand that intermediate T-91 can be progressed to compounds of formula (I) in a similar manner as described for intermediate T-74 in Scheme 10 hereinabove.

[0204] Intermediates T-94 in which Y2is as described above, X1is a halide such as, for example, bromide, and R22’, R23’and R24’are as defined hereinabove may be obtained also according to Scheme 13 (Method 13) below:Scheme 13 / Method 13

[0205] Intermediate T-92 can be prepared by reacting T-53 with a suitable amine R23’R24’NH, in presence of a suitable base such as, for example K2CO3, in a suitable solvent such as, for example, CH3CN, at a suitable temperature such as, for example, 25 °C (Step 1). Intermediate T-94 in which R22’is hydrogen can be prepared by reducing the ketone of T-92 with a suitable reducing agent such as, for example, NaBH4, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example 0-25°C (Step 2). Intermediate T-94 in which R22’is an alkyl or aryl group can be prepared by reacting the ketone of T-92 with a suitable organometal such as, for example, methylmagnesium bromide, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example -78 to 25 °C (Step 2, alternative). Intermediate T-94 can alternatively be prepared by reacting T-93 with a suitable organometal such as, for example, (5-bromothiophen-2-yl)lithium prepared in situ from 2,5-dibromothiophene / n- BuLi, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -78 to 25 °C (Step 3). A skilled person will understand that intermediate T- 94 can be progressed to compounds of formula (I) in a similar manner as described for intermediate T-74 in Scheme 10 hereinabove. A skilled person will also understand that other amine-containing aldehydes or ketones than intermediate T-93 can similarly provide compounds of formula (I).

[0206] Intermediates T-97 in which Y2is as defined above, X1is a halide such as, for example, bromide, and PG is a protective group may be obtained according to Scheme 14 (Method 14):Scheme 14 / Method 14

[0207] Intermediates T-95 in which PG is a suitable protective group such as, for example, Boc, are commercially available or can be prepared using art known conditions. Intermediate T-96 can be prepared by reacting T-95 with a suitable organometal such as, for example, thiophen-2-ylmagnesium bromide, in presence of a suitable catalyst such as, for example, copper(I) iodide, in a suitable solvent such as, for example THF, at a suitabletemperature such as, for example, -30 to 25 °C (Step 1). Intermediate T-97, in which X1is a halogen such as, for example, bromide, can be prepared by reacting T-96 with a suitable halogenating agent such as, for example, NBS, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 25 °C (Step 2). Intermediate T-97 can alternatively be prepared by reacting T-95 with a suitable organometal such as, for example, (5-bromothiophen-2-yl)lithium prepared in situ from 2,5-dibromothiophene / n-BuLi, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -78 to 25 °C (Step 3). A skilled person will understand that intermediate T-97 can be progressed to compounds of formula (I) in a similar manner as described for intermediate T-74 in Scheme 10 hereinabove. A skilled person will also understand that when T-94 is chiral, the resulting compounds of formula (I) will also have well-defined chirality. Synthesis of the compounds – Experimental results

[0208] Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification. Abbreviations

[0209] Abbreviations are used as follows.Analytical methods

[0210] LCMS (Method 1): LC-MS were recorded on an Agilent 1200-G6140. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the 5 Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order toobtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

[0211] LCMS (Method 2): LC-MS were recorded on an Agilent 1200-G6140. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtainedwith experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

[0212] LCMS (method 3): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:

[0213] LCMS (method 4): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:

[0214] LCMS (method 5): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:

[0215] LCMS (method 6): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:MS Range: 100-1000

[0216] LCMS (Method 7): LC-MS spectra were recorded on a Waters Acquity I class UPLC system using the following system [solvent A: acetonitrile, solvent B: 0.1% formic in water or solvent A: acetonitrile, solvent B: 0.1% ammonia in water or solvent A: acetonitrile, solvent B: 0.1% TFA in water. Formic acid and ammonia or TFA was used as HPLC grade. All the separations were performed at ambient temperatures. Reverse phase HPLC was performed on a Waters HPLC system using following solvent system [solvent A: acetonitrile, solvent B: 0.1% NH3 in water] or [solvent A: acetonitrile, solvent B: 0.1% TFA in water]. Ammonia was used as HPLC grade. All the separations were performed at ambient temperatures. For analytical RP-HPLC analysis [Interchim: Acquity BEH C18 (2.1 x 100 mm, 1.7 µm)], the flow rate was 0.4 mL.min-1; injection volume: 10 µL, detection wavelengths: 220 nm and 254 nm. The following gradient was used: 0.01 min 90 % B, over 8 min to 10 % B, 4 min 10 % B.

[0217] LCMS (Method 8): LC-MS were recorded on an Agilent 1200 & 6120B. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0218] The gradient conditions used are described below:

[0219] LCMS (Method 9): LC-MS were recorded on a Shimadzu LC-20AD&MS 2020. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

[0220] LCMS (Method 10): LC-MS were recorded on a Shimadzu LC-20AD&MS 2020. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmosphericpressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

[0221] LCMS (Method 11): LC-MS were recorded on an Agilent Agilent 1260 & 6125B. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and / or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H+] (protonated molecule) or [M-H+] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtainedwith experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:Preparation of synthetic intermediates

[0222] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1- carboxylate (I-1):

[0223] Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H- pyrrole-1-carboxylate (I-1-1) To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.398 mmol) in dry THF (10 mL) cooled to -78°C was added dropwise LiHMDS (1.0 M soln. in THF) (6.0 mL, 5.934 mmol), and the resulting mixture was stirred for 60 min. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methane- sulfonamide in THF (2.33 g, 5.934 mmol) was added to the solution and stirred for 30 min at the same temperature. Next, the reaction mixture was warmed to rt, quenched with sat. aq. NaHCO3(10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (60-120 mesh) eluting with 10% EtOAc in hexane to afford compound I-1-1 (0.63 g, 37 % yield) as gummy liquid.

[0224] Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (I-1-2) To a stirred solution of (5-acetylthiophen-2-yl) boronic acid (1.6 g,9.463 mmol) and tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole- 1-carboxylate 2 (3 g, 9.463 mmol) in dioxane:H2O (30 mL, 3:1), K2CO3(3.9 g, 28.389 mmol) and Pd(dppf)Cl2 (1.0 g, 0.9463 mmol) was added. The reaction was purged with N2 for 15 min, then heated to 100 °C for 16 h. Next, the mixture was quenched with sat. aq. NaHCO3(20 mL), and then extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over Na2SO4, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography using a silica gel (60-120 mesh, eluent: 50% EtOAc in hexane) to afford the title compound I-1-2 (2.7 g, 75% yield) as a gummy liquid.

[0225] Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)pyrrolidine-1-carboxylate (I- 1-3) To a stirred solution of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole- 1-carboxylate I-1-2 (2 g, 6.825 mmol) in MeOH (20 mL) was added 10% Pd-C (2.0 g), then H2 gas was inserted for 5 h at 60 psi. The reaction mixture was filtered through a celite bed in vacuo. The solvent was evaporated under reduced pressure and the residue purified by column chromatography over silica gel (60-120 mesh, eluent: 50% EtOAc in hexane) to afford the title compound I-1-3 (1.5 g, 74% yield) as yellow liquid.

[0226] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1- carboxylate (I-1) To a solution of compound I-1-3 (0.2 g, 0.680 mmol) in dry THF (5 mL) tetrabutylammonium tribromide (0.8 g, 1.360 mmol) added then stirred at room temperature for 16 h. The reaction mixture was concentrated to get crude compound, which was purified by Combi-flash reversed phase chromatography to afford I-1 (0.07 g, 27% yield) as a white solid.1H NMR [400 MHz, DMSO-d6]: 7.95 (d, J = 3.6 Hz, 1H), 7.15 (d, J = 4 Hz, 1H), 4.78 (s, 2H), 3.73-3.69 (m, 2H), 3.40-3.23 (m, 4H), 2.33-2.29 (m, 1H), 1.40 (s, 9H).

[0227] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)azetidine-1-

[0228] Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)azetidine-1-carboxylate (I-2- 1) Zn (4.78 g, 73.1 mmol) was added to a flame dried, nitrogen purged side arm round bottom flask. Dry DMF (35.0 mL) was added via syringe followed by a catalytic amount of I2 (928 mg, 3.66 mmol, 737 μL). A color change of the DMF was observed from colorless to yellow and back. Tert-butyl 3-iodoazetidine-1-carboxylate (8.97 g, 31.7 mmol) was added immediately followed by a catalytic amount of I2 (928 mg, 3.66 mmol, 737 μL). The solution was stirred at 15 °C and gave a noticeable exotherm. When the solution was cooled to 25 °C, SPhos (500 mg, 1.22 mmol, 0.05 eq), Pd2(dba)3(447 mg, 488 μmol) and 1-(5-bromo-2-thienyl)ethanone (5.00 g, 24.4 mmol) were added to the flask and stir at 15 °C for 12 h under positive pressure of nitrogen. The reaction mixture was diluted with water (60.0 mL) and extracted with DCM (30.0 mL x 2). The combined organic layers were washed with water (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound I-2-1 (3.50 g, 51.0% yield) as a brown oil.

[0229] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)azetidine-1- carboxylate (I-2) To a solution of compound I-2-1 (3.00 g, 10.7 mmol) in DCM (18.0 mL) and MeOH (45.0 mL) was added TBATB (5.40 g, 11.2 mmol) and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of H2O (10.0 mL) at 25 °C, and then extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-2 (1.1 g, 28.6% yield) as a yellow oil.

[0230] Synthesis of tert-butyl 3-(4-(2-bromoacetyl)-1H-pyrazol-1-yl)pyrrolidine-1- carboxylate (I-3):

[0231] Synthesis of tert-butyl 3-(4-acetyl-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (I-3-1) To a solution of 1-(1H-pyrazol-4-yl)ethan-1-one (5.00 g, 45.4 mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (8.50 g, 45.4 mmol) in THF (35.0 mL) was added DIAD (13.8 g, 68.1 mmol, 13.2 mL) and PPh3(17.8 g, 68.1 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition of H2O (50.0 mL) at 25 °C, and then extracted with EtOAc (25.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition) to give compound I-3-1 (5.40 g, 42.6% yield) as a white solid.

[0232] Synthesis of tert-butyl 3-(4-(2-bromoacetyl)-1H-pyrazol-1-yl)pyrrolidine-1- carboxylate (I-3) To a solution of compound I-3-1 (2.00 g, 7.16 mmol) in MeOH (20.0 mL) and DCM (3.00 mL) was added TBATB (3.62 g, 7.52 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with DCM (50.0 mL) and washed with water (50.0 mL x 2). The organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-3 (500 mg, 19.5% yield) as a colorless oil.

[0233] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)pyrrolidine-1- carboxylate (I-4):

[0234] Synthesis of tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate (I-4-1) To a solution of tert-butyl 3-carbamoylpyrrolidine-1-carboxylate (4.60 g, 21.5 mmol) in toluene (46.0 mL) was added Lawesson's reagent (4.34 g, 10.7 mmol). The mixture was stirred at 80 °C for 16 h. The suspension was filtered through a pad of celite and washed with EtOAc (100 mL). The combined filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-4-1 (1.30 g, 26.2% yield) as a white solid.

[0235] Synthesis of tert-butyl 3-(5-formylthiazol-2-yl)pyrrolidine-1-carboxylate (I- 4-2) To a solution of compound I-4-1 (1.00 g, 4.34 mmol) in AcOH (10.0 mL) was added NaOAc (534 mg, 6.51 mmol) and 2-bromomalonaldehyde (721 mg, 4.78 mmol). Themixture was stirred at 100 °C for 0.3 h. The reaction was added H2O (3.00 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1, compound I-4-2 Rf = 0.5) to give compound I-4-2 (0.70 g, 57.1% yield) as a yellow oil.

[0236] Synthesis of tert-butyl 3-(5-(1-hydroxyethyl)thiazol-2-yl)pyrrolidine-1- carboxylate (I-4-3) To a solution of compound I-4-2 (160 mg, 567 μmol) in THF (2.00 mL) was added MeMgBr (135 mg, 1.13 mmol) at -20 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of sat. NH4Cl aq. (2.00 mL) and extracted with EtOAc (10.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a compound I-4-3 (140 mg 82.8% yield) as a white solid.

[0237] Synthesis of tert-butyl 3-(5-acetylthiazol-2-yl)pyrrolidine-1-carboxylate (I-4- 4) To a solution of compound I-4-3 (120 mg, 402 μmol) in DCM (1.50 mL) was added Dess-Martin reagent (256 mg, 603 μmol, 187 μL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give compound I- 4-4 (108 mg, 90.6% yield) as a colorless oil.

[0238] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)pyrrolidine-1- carboxylate (I-4) To a solution of compound I-4-4 (68.0 mg, 229 μmol) in THF (1.00 mL) was added pyridinium tribromide (129 mg, 344 μmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (2.00 mL) and extracted with EtOAc (2.00 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuum to give compound I-4 (100 mg, 44.1% yield, 38.0% purity) as a yellow solid.

[0239] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxyazetidine-1-carboxylate (I-5):(I-5)

[0240] Synthesis of tert-butyl 3-hydroxy-3-(thiophen-2-yl)azetidine-1-carboxylate (I-5-1) To a solution of 2-bromothiophene (95.0 g, 582 mmol, 56.4 mL) in THF (950 mL) was added n-BuLi (2.50 M, 233 mL) in one portion at -60 °C under N2. The mixture was stirred at -60 °C for 1 h, then added tert-butyl 3-oxoazetidine-1-carboxylate (109 g, 640 mmol). The mixture was stirred at -60 °C for 2 h. The reaction mixture was poured into ice-water (1.50 L) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give compound I-5-1 (160 g, 49.4% yield, 92.6% purity) as a white solid.

[0241] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-hydroxyazetidine-1- carboxylate (I-5-2) To a solution of compound I-5-1 (114 g, 734 mmol), DMAP (4.49 g, 36.7 mmol) and NBS (156 g, 881 mmol) in ACN (798 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give compound I-5-2 (117 g, 42.9% yield) as a yellow solid.

[0242] Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-3-hydroxyazetidine-1- carboxylate (I-5-3) To a solution of compound I-5-2 (10.0 g, 29.9 mmol), 1- (vinyloxy)butane (7.49 g, 74.8 mmol, 9.62 mL), Pd(OAc)2 (806 mg, 3.59 mmol), DPPP (2.96 g, 7.18 mmol) and Na2CO3 (7.93 g, 74.8 mmol) in MeOH (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The reaction mixture was acidified with aqueous HCl (1 M) until pH = 4 was reached and extracted with EtOAc (30.0 mL x 3). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give compound I-5-3 (7.30 g, 82.0% yield) as a white solid.

[0243] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxyazetidine-1-carboxylate (I-5) To a solution of compound I-5-3 (6.27 g, 21.0 mmol), TBATB (10.6 g, 22.1 mmol) in MeOH (94.0 mL) and DCM (37.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2h under N2 atmosphere. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give compound I-5 (1.93 g, 21.8% yield, 90.0% purity) as a white solid.

[0244] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-

[0245] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-methoxyazetidine-1- carboxylate (I-6-1) To a solution of compound I-5-2 (10.0 g, 29.9 mmol) in THF (70.0 mL) was added NaH (1.44 g, 35.9 mmol, 60.0% purity) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then MeI (16.9 g, 119 mmol, 7.45 mL) was added at 0 °C. The resulting mixture was stirred at 20 °C for 3.5 h. The reaction mixture was quenched by addition NH4Cl (100 mL) at 25 °C and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound I-6-1 (8.40 g, 80.6% yield) as a white solid.

[0246] Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-3-methoxyazetidine-1- carboxylate (I-6-2) To a solution of compound I-6-1 (8.30 g, 23.8 mmol) in MeOH (58.0 mL) was added 1-(vinyloxy)butane (5.97 g, 59.5 mmol, 7.66 mL), Pd(OAc)2 (642 mg, 2.86 mmol), Na2CO3 (6.32 g, 59.5 mmol) and DPPP (2.36 g, 5.72 mmol). The mixture was stirred at 70 °C for 12 h under N2atmosphere. The reaction mixture was quenched by addition HCl (100 mL) at 20 °C, and then extracted with CHCl3 / isopropanol (20.0 mL x 6). The combined organic layers were washed with brine (30.0 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give compound I-6-2 (0.800 g, 10.7% yield) as a yellow solid.

[0247] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- methoxyazetidine-1-carboxylate (I-6) To a solution of compound I-6-2 (200 mg, 642 μmol) in DCM (1.20 mL) and MeOH (3.00 mL) was added TBATB (325 mg, 674 μmol) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-6 (97.8 mg, 39.0% yield) as a yellow oil.

[0248] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-fluoroazetidine- 1-carboxylate (I-7):

[0249] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-fluoroazetidine-1- carboxylate (I-7-1) To a solution of compound I-5-1 (15.0 g, 44.9 mmol) in DCM (150 mL) was added DAST (10.9 g, 67.3 mmol, 8.89 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 12 h. The reaction mixture was quenched by addition aqueous NaHCO3(200 mL) at -60 °C, diluted with H2O 100 mL and extracted with DCM (100 mL x 3). The combined organic layers were washed with aqueous NaHCO3(200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give compound I-7-1 (29.0 g, 86.5% yield, 90.0% purity) as yellow oil.

[0250] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3-fluoroazetidine- 1-carboxylate (I-7-2) To a solution of compound I-7-1 (10.0 g, 29.7 mmol) and tributyl(1-ethoxyvinyl)stannane (18.8 g, 52.1 mmol, 17.6 mL) in dioxane (100 mL) was added TEA (6.02 g, 59.5 mmol, 8.28 mL) and Pd(PPh3)2Cl2(2.09 g, 2.97 mmol) under N2 atmosphere. The mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (200 mL) at 25 °C and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (300 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give compound I-7-2 (20.0 g, crude) as a brown oil.

[0251] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-fluoroazetidine- 1-carboxylate (I-7) To a solution of compound I-7-2 (20.0 g, 24.4 mmol) in THF (100 mL) and H2O (50.0 mL) was added NBS (4.35 g, 24.4 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by addition H2O (200 mL) at 25°C and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 4 / 1) to give compound I-7 (6.00 g, 57.8% yield, 89.0% purity) as a yellow oil.

[0252] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-8):

[0253] Synthesis of tert-butyl 3-hydroxy-3-(thiophen-2-yl)pyrrolidine-1-carboxylate (I-8-1) To a solution of 2-bromothiophene (90.0 g, 552 mmol) in THF (900 mL) was added n-BuLi (2.50 M, 243 mL) at -60 °C dropwise under N2 atmosphere. The mixture was stirred at -60 °C for 1 h, then added a solution of tert-butyl 3-oxopyrrolidine-1- carboxylate (112 g, 607 mmol) in THF (62.5 mL) dropwise at -60 °C. The mixture was stirred at -60 °C for 2 h. The residue was poured into sat. aq NH4Cl (1 L) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give s residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give compound I-8-1 (45.0 g, 29.1% yield, 96.1% purity) as a white solid.

[0254] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-hydroxypyrrolidine-1- carboxylate (I-8-2) To a solution of compound I-8-1 (45.0 g, 167 mmol) in DMF (315 mL) was added NBS (32.7 g, 184 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by H2O (700 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with H2O (100 mL x 5), dried overanhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-8-2 (61.9 g, 97.9% yield) as a light yellow solid.

[0255] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-8-3) To a solution of compound I-8-2 (3.00 g, 8.61 mmol) in dioxane (30.0 mL) was added tributyl(1-ethoxyvinyl)stannane (4.67 g, 12.9 mmol), TEA (1.74 g, 17.2 mmol) and Pd(PPh3)2Cl2 (604 mg, 861 μmol) under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by H2O (20.0 mL) and was extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound I-8-3 (7.50 g, 64.1% yield, 25.0% purity) as a brown solid.

[0256] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-8) To a solution of compound I-8-3 (4.00 g, 2.95 mmol) in THF (30.0 mL) and H2O (10.0 mL) was added NBS (472 mg, 2.65 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by H2O (20.0 mL) and was extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I- 8 (720 mg, 62.6% yield) as a yellow solid.

[0257] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-9):

[0258] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-methoxypyrrolidine-1- carboxylate (I-9-1) To a solution of compound I-8-1 (1.00 g, 2.87 mmol) in THF (10.0 mL) was added NaH (230 mg, 5.74 mmol, 60.0% purity). The mixture was stirred at 0 °C for 1 h under N2. Then the mixture was added MeI (1.63 g, 11.5 mmol) and stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (5.00 mL) and extracted with EtOAc (5.00 mL x 3). The combined organic layers were dried over MgSO4, filtered andconcentrated in vacuum to give compound I-9-1 (550 mg, 1.52 mmol, 52.9% yield) was obtained as a yellow oil.

[0259] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-9-2) To a solution of compound I-9-1 (300 mg, 828 μmol) in dioxane (3.00 mL) was added tributyl(1-ethoxyvinyl)stannane (570 mg, 1.58 mmol), TEA (168 mg, 1.66 mmol) and Pd(PPh3)2Cl2 (58.1 mg, 82.8 μmol) under N2. The mixture was stirred at 80 °C for 2 h. The reaction was quenched by H2O (10.0 mL) and extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound I-9-2 (760 mg, 64.9% yield, 25.0% purity) as a black solid.

[0260] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-9) To a solution of compound I-9-2 (300 mg, 848 μmol) in THF (2.20 mL) and H2O (0.800 mL) was added NBS (136 mg, 764 μmol). The mixture was stirred at 25 °C for 1.5 h. The reaction was quenched by H2O (10.0 mL) and extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I-9 (220 mg, 64.1% yield) as a yellow solid.

[0261] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4-

[0262] Synthesis of tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (I-10-1) To a solution of 2-bromothiophene (16.0 g, 9.50 mL, 98.1 mmol) in THF (160 mL) was added n-BuLi (2.50 M, 43.2 mL) at -60 °C dropwise and the mixture was stirred at -60 °C for 1 h, and then was added to a solution of tert-butyl 4-oxopiperidine-1- carboxylate (21.5 g, 108 mmol) in THF (96.0 mL) dropwise at -60 °C. The mixture was stirred at -60 °C for 2 h. The residue was poured into sat. aq. NH4Cl (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine(200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-10-1 (15.8 g, 53.7% yield, 94.6% purity) as a white solid.

[0263] Synthesis of tert-butyl 4-(5-bromothiophen-2-yl)-4-hydroxypiperidine-1- carboxylate (I-10-2) To a solution of compound I-10-1 (5.00 g, 17.6 mmol) in DMF (35.0 mL) was added NBS (3.45 g, 19.4 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with sat NaCl (50.0 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I- 10-2 (6.00 g, 75.1% yield, 79.1% purity) as a brown solid.

[0264] Synthesis of tert-butyl 4-(5-(1-ethoxyvinyl)thiophen-2-yl)-4- hydroxypiperidine-1-carboxylate (I-10-3) To a solution of compound I-10-2 (3.00 g, 8.28 mmol) in dioxane (30.0 mL) was added tributyl(1-ethoxyvinyl)stannane (5.98 g, 16.6 mmol, 5.59 mL), TEA (1.68 g, 16.6 mmol, 2.30 mL) and Pd(PPh3)2Cl2 (581 mg, 828 μmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (50.0 mL x 3), dried over Na2SO4, filtered and concentrated in vacuum to give compound I-10-3 (9.30 g, crude) was obtained as a black oil.

[0265] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4- hydroxypiperidine-1-carboxylate (I-10) To a solution of compound I-10-3 (8.20 g, 23.2 mmol) in THF (80.0 mL) and H2O (40.0 mL) was added NBS (4.13 g, 23.2 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by H2O (100 mL) and extracted with EtOAc (40.0 mL x 3). The combined organic layers were washed with sat NaCl (50.0 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give compound I-10 (1.34 g, 40.1% yield, 93.3% purity) as a yellow solid.

[0266] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-11):

[0267] Synthesis of tert-butyl 3-(5-bromopyridin-2-yl)-3-hydroxypyrrolidine-1- carboxylate (I-11-1) To a solution of 2, 5-dibromopyridine (105 g, 443 mmol) in toluene (1200 mL) was added n-BuLi (1.60 M, 305 mL, 1.10 eq) dropwise at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. To the mixture was added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (90.3 g, 487 mmol, 1.10 eq) in toluene (300 mL) dropwise at -70 °C and stirred at -70 °C for 1 h under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition of sat. NH4Cl aq. (750 mL) dropwise at 0 °C under N2and extracted with EtOAc (750 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give I-11-1 (30.1 g, 19.8% yield) as a yellow solid.

[0268] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)pyridin-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-11-2) To a solution of I-11-1 (4.00 g, 11.7 mmol) and tributyl(1-ethoxyvinyl)stannane (7.76 g, 21.5 mmol, 7.26 mL) in dioxane (40.0 mL) was added TEA (2.36 g, 23.3 mmol, 3.24 mL) and Pd(PPh3)2Cl2(818 mg, 1.17 mmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched by addition of H2O (80.0 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum to give I-11-2 (10.3 g, crude) as a brown oil.

[0269] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-11) To a solution of compound I-11-2 (10.3 g, 30.8 mmol) in THF (100 mL) and H2O (70.0 mL) was added NBS (3.84 g, 21.6 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified bycolumn chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-11 (3.07 g, 35.0% yield, 50.0% purity) as a yellow oil.

[0270] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3-

[0271] Synthesis of tert-butyl 3-(5-bromopyridin-2-yl)-3-methoxypyrrolidine-1- carboxylate (I-12-1) To a solution of compound I-11-1 (3.00 g, 8.74 mmol) in THF (30.0 mL) was added NaH (454 mg, 11.4 mmol, 60.0% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. The mixture was added MeI (4.96 g, 35.0 mmol, 2.18 mL) and stirred at 25 °C for 2 h. The reaction mixture was quenched by H2O (50.0 mL) at 0 °C under N2 and extracted with EtOAc (70.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give compound I-12-1 (3.26 g, 93.8% yield, 89.8% purity) as a yellow oil.

[0272] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-12-2) To a solution of compound I-12-1 (3.26 g, 9.13 mmol) and tributyl(1-ethoxyvinyl)stannane (5.66 g, 15.7 mmol, 5.29 mL) in dioxane (33.0 mL) was added TEA (1.85 g, 18.3 mmol, 2.54 mL) and Pd(PPh3)2Cl2(641 mg, 913 μmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched by H2O (60.0 mL) at 25 °C, and then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum to give compound I-12-2 (8.30 g, crude) as a brown oil.

[0273] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-12) To a solution of compound I-12-2 (5.00 g, 14.4 mmol) in THF (50.0 mL) and H2O (35.0 mL) was added NBS (1.79 g, 10.0 mmol) at 0 °C. The reaction mixture was diluted with H2O (50.0 mL) and extracted with DCM (70.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2,petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-12 (803 mg, 36.5% yield, 85.9% purity) as a yellow oil.

[0274] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3-

[0275] Synthesis of tert-butyl 3-(5-bromopyridin-2-yl)-3-fluoropyrrolidine-1- carboxylate (I-13-1) To a solution of compound I-11-1 (15.0 g, 43.7 mmol) in DCM (600 mL) was added DAST (9.16 g, 56.8 mmol, 7.51 mL) at -70 °C under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 9 / 1) to give compound I-13-1 (10.2 g, 64.4% yield, 95.3% purity) as a yellow solid.

[0276] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)pyridin-2-yl)-3-fluoropyrrolidine- 1-carboxylate (I-13-2) To a solution of compound I-13-1 (10.2 g, 29.6 mmol) and tributyl(1-ethoxyvinyl)stannane (18.6 g, 51.5 mmol, 17.4 mL) in dioxane (102 mL) was added TEA (5.98 g, 59.1 mmol, 8.23 mL) and Pd(PPh3)2Cl2 (2.07 g, 2.95 mmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched by addition of H2O (200 mL) at 25 °C, and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuum to give compound I-13-2 (28.8 g, crude) as a brown oil.

[0277] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridin-2-yl)-3- fluoropyrrolidine-1-carboxylate (I-13) To a solution of compound I-13-2 (28.8 g, 85.6 mmol) in THF (300 mL) and H2O (210 mL) was added NBS (10.7 g, 59.9 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O (300 mL) at 25 °C, and then extracted with DCM (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to givecompound I-13 (5.12 g, 35.6% yield, 75.0% purity) as a yellow solid.

[0278] Synthesis of 2-bromo-1-(6-morpholinopyridin-3-yl)ethan-1-one (I-14):

[0279] Synthesis of 1-(6-morpholino-3-pyridyl)ethanone (I-14-1) To a solution of morpholine (2.40 g, 27.5 mmol, 2.42 mL) and 1-(6-bromo-3-pyridyl)ethanone (5.00 g, 25.0 mmol) in DMF (70.0 mL) was added K2CO3 (10.4 g, 75.0 mmol). The mixture was stirred at 80 °C for 16 h. The residue was diluted with H2O (300 mL) and extracted with DCM (300 mL x 2). The combined organic layers were washed with sat. aq. NaHCO3solution (300 mL x 2), dried over MgSO4, filtered and concentrated in vacuum to give compound I-14-1 (5.16 g, 97.1% yield, 97.0% purity) as white solid.

[0280] Synthesis of 2-bromo-1-(6-morpholinopyridin-3-yl)ethan-1-one (I-14) To a solution of compound I-14-1 (4.50 g, 21.8 mmol) in MeOH (45.0 mL) and CHCl3(45.0 mL) was added CuBr2 (4.87 g, 21.8 mmol) under N2. The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 8 / 1) to give compound I- 14 (1.80 g, 10.9% yield, 37.7% purity) as a white solid.

[0281] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-pyridyl]piperazine-1- carboxylate (I-15):

[0282] Synthesis of tert-butyl 4-(5-acetyl-2-pyridyl)piperazine-1-carboxylate (I-15- 1) To a solution of 1-(6-bromo-3-pyridyl)ethanone (5.00 g, 25.0 mmol) in DMSO (200 mL) was added K2CO3 (6.91g, 50.0 mmol) and tert-butyl piperazine-1-carboxylate (6.98 g, 37.5 mmol). The mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layerswere washed with sat NaCl (200 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give compound I-15-1 (5.52 g, 72.3% yield, 100% purity) as a white solid.

[0283] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-pyridyl]piperazine-1- carboxylate (I-15) To a solution of compound I-15-1 (1.50 g, 4.91 mmol) in MeOH (15.0 mL) and CHCl3 (15.0 mL) was added CuBr2 (1.10 g, 4.91 mmol) under N2. The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 8 / 1) to give compound I-15 (1.00 g, 21.8% yield, 41.1% purity) as a white solid.

[0284] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-3-yl)pyrrolidine-1- carboxylate (I-16):

[0285] Synthesis of tert-butyl 3-(5-acetylthiophen-3-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (I-16-1) To a solution of 1-(4-bromo-2-thienyl)ethanone (5.00 g, 24.4 mmol) in dioxane (50.0 mL) and H2O (10.0 mL) was added tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (8.64 g, 29.3 mmol), K2CO3 (10.1 g, 73.2 mmol) and Pd(PPh3)4 (1.41 g, 1.22 mmol) under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (30.0 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I- 16-1 (7.00 g, 97.8% yield, 93.3% purity) as a yellow solid.

[0286] Synthesis of tert-butyl 3-(5-acetylthiophen-3-yl)pyrrolidine-1-carboxylate (I- 16-2) To a solution of compound I-16-1 (6.90 g, 23.5 mmol) in MeOH (400 mL) was added Pd / C (7.51 g, 7.06 mmol, 10.0% purity). The mixture was stirred at 25 °C for 16 h under H2(50 psi). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate= 50 / 1 to 4 / 1) to give compound I-16-2 (5.90 g, 84.9% yield, 91.2% purity) as a colorless oil.

[0287] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-3-yl)pyrrolidine-1- carboxylate (I-16) To a solution of compound I-16-2 (1.00 g, 3.39 mmol) in DCM (5.00 mL) and MeOH (2.00 mL) was added TBATB (1.71 g, 3.55 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture was diluted with H2O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I- 16 (1.20 g, 2.24 mmol, 66.3% yield, 70.0% purity) as a yellow solid.

[0288] Synthesis of tert-butyl 3-(4-(2-bromoacetyl)pyridin-2-yl)pyrrolidine-1- carboxylate (I-17):

[0289] Synthesis of tert-butyl 3-(4-acetylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate (I-17-1) To a solution of 1-(2-bromo-4-pyridyl)ethanone (5.00 g, 25.0 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1- carboxylate (8.85 g, 30.0 mmol), K2CO3(10.4 g, 75.0 mmol), Pd(PPh3)4(1.44 g, 1.25 mmol) in dioxane (50.0 mL) and H2O (10.0 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 16 h under N2atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (50.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-17-1 (6.50 g, 70.3% yield) as a yellow solid.

[0290] Synthesis of tert-butyl 3-(4-(1-hydroxyethyl)pyridin-2-yl)pyrrolidine-1- carboxylate (I-17-2) To a solution of compound I-17-1 (1.00 g, 3.47 mmol) in MeOH (10.0 mL) was added Pd / C (1.08 g, 1.02 mmol, 10.0% purity). The mixture was stirred at 25 °C for 16 h under H2(20 Psi). The reaction mixture was filtered and concentrated invacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give compound I-17-2 (420 mg, 40.0% yield) as a yellow oil.

[0291] Synthesis of tert-butyl 3-(4-acetylpyridin-2-yl)pyrrolidine-1-carboxylate (I- 17-3) To a solution of compound I-17-2 (400 mg, 1.37 mmol) in DCM (10.0 mL) was added Dess-Martin reagent (870 mg, 2.05 mmol) at 0 °C for 10 min. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give compound to give compound I-17-3 (300 mg, 75.5% yield) as a yellow solid.

[0292] Synthesis of tert-butyl 3-(4-(2-bromoacetyl)pyridin-2-yl)pyrrolidine-1- carboxylate (I-17) To a solution of compound I-17-3 (100 mg, 258 μmol) in THF (1.00 mL) was added pyridinium tribromide (146 mg, 387 μmol). The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched by H2O (3.00 mL) and extracted with EtOAc (10.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give compound to give compound I-17 (100 mg, 44.1% yield, 38.0% purity) as a yellow solid.

[0293] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)azetidine-1- carboxylate (I-18):

[0294] Synthesis of tert-butyl 3-(5-bromothiazol-2-yl)azetidine-1-carboxylate (I-18- 1) To a solution of Zn (4.62 g, 70.6 mmol) in DMF (50.0 mL) was added TMSCl (0.200 mL) and 1,2-dibromoethane (0.200 mL). Then the mixture was added to a solution of tert- butyl 3-iodoazetidine-1-carboxylate (5.00 g, 17.7 mmol) in DMF (10.0 mL) and stirred at 25 °C for 0.5 h under N2atmosphere. To a solution of 2,5-dibromothiazole (5.00 g, 20.6 mmol) in DMF (50.0 mL) was added Pd(PPh3)4(1.19 g, 1.03 mmol) and abovesolution under N2. The mixture was stirred at 65 °C for 16 h under N2. The reaction mixture was quenched by H2O (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with sat NaCl (50 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I-18-1 (2.40 g, 23.5% yield, 64.4% purity) as a yellow oil.

[0295] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazol-2-yl)azetidine-1- carboxylate (I-18-2) To a solution of compound I-18-1 (2.40 g, 7.52 mmol) in dioxane (24.0 mL) was added tributyl(1-ethoxyvinyl)stannane (5.43 g, 15.0 mmol, 5.08 mL), TEA (1.52 g, 15.0 mmol, 2.09 mL) and Pd(PPh3)2Cl2 (528 mg, 752 μmol) under N2 atmosphere. The mixture was stirred at 90 °C under N2 atmosphere for 16 h. The reaction mixture was added H2O (60.0 mL) and extracted with EtOAc (50.0 mL x 3), dried over Na2SO4, filtered and concentrated in vacuum to give compound I-18-2 (7.80 g, crude) was obtained as a black oil.

[0296] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)azetidine-1- carboxylate (I-18) To a solution of compound I-18-2 (6.80 g, 21.9 mmol) in THF (78.0 mL) and H2O (39.0 mL) was added NBS (3.90 g, 21.9 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was added H2O (50.0 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with sat NaCl (50 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give compound I-18 (1.40 g, 15.4% yield, 86.8% purity) as a brown solid.

[0297] Synthesis of 2-bromo-1-(5-(hydroxymethyl)thiophen-2-yl)ethan-1-one (I-19):

[0298] Synthesis of (5-iodothiophen-2-yl)methanol (I-19-1) A mixture of thiophen-2- ylmethanol (25.0 g, 219 mmol, 20.7 mL), NIS (54.2 g, 241 mmol), PTSA (3.77 g, 21.9 mmol) in EtOH (175 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 6 h under N2atmosphere. The reaction mixture wasconcentrated under reduced pressure to remove EtOH. The residue was diluted with EtOAc (50.0 mL) and washed with H2O (50.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give compound I- 19-1 (44.0 g, 83.7% yield) as a yellow oil.

[0299] Synthesis of 1-(5-(hydroxymethyl)thiophen-2-yl)ethan-1-one (I-19-2) To a solution of compound I-19-1 (20.0 g, 83.3 mmol) in toluene (140 mL) was added dropwise tributyl (1-ethoxyvinyl)stannane (36.1 g, 99.9 mmol, 33.7 mL) at 25 °C, palladium tetrakis(triphenylphosphine) (9.63 g, 8.33 mmol) was added at 25 °C. The resulting mixture was stirred at 110 °C for 16 h. Saturated potassium fluoride solution was added to the reaction mixture and stirred for 30 min at 15 °C. The organic layer was separated and concentrated under reduced pressure to get the crude compound. HCl (0.5 M, 100 mL) was added to the crude reaction mixture and stirred for 30 min and solid Na2CO3 was added until pH~7. The reaction mixture diluted with water (100 mL) extracted with thyl acetate (80.0 mL x 2). The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure to get crude compound. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1) to give compound I-19- 2 (4.40 g, 33.8% yield) as a brown solid.

[0300] Synthesis of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)thiophen-2-yl)ethan- 1-one (I-19-3) To a solution of compound I-19-2 (4.20 g, 26.9 mmol) and imidazole (3.66 g, 53.8 mmol) and DMAP (164 mg, 1.34 mmol) in DCM (25.0 mL) was added TBDPSCl (8.87 g, 32.2 mmol, 8.29 mL). The mixture was stirred at 15 °C for 12 h. The reaction mixture was quenched by addition H2O (30.0 mL) at 25°C, extracted with EtOAc (30.0 mL x 3) dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give compound I-19-3 (8.60 g, 67.3% yield, 83.1% purity) as a yellow oil.

[0301] Synthesis of 2-bromo-1-(5-(hydroxymethyl)thiophen-2-yl)ethan-1-one (I-19) A mixture of compound I-19-3 (3.00 g, 7.60 mmol), TBAB (3.85 g, 7.98 mmol) in DCM (18.0 mL) and MeOH (45.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 1 h under N2 atmosphere. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by addition H2O (100 mL) at25 °C, and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-19 (800 mg, 44.7% yield) as a brown oil.

[0302] Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate

[0303] Synthesis of tert-butyl (thiophen-2-ylmethyl)carbamate (I-20-1) To a solution mixture of thiophen-2-ylmethanamine (50.0 g, 441.770 mmol) in THF (500 mL) was added NaHCO3 (37.1 g, 485.947 mmol) and (Boc)2O (111.5 mL, 441.770 mmol) slowly. The resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with 30% EtOAc in hexane and passed through silica get to afford compound (I-20-1) (100 g, quantitative) as a white gummy solid.

[0304] Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-20-2) To a solution mixture of compound I-20-1 (50 g, 234.741 mmol) in DMF (500.0 mL) was added NBS (45.9 g, 258.2 mmol) at 0oC. The reaction mixture was stirred for 2 h at rt. Cold water was added to reaction mixture and it was extracted with EtOAc (2x 500 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and compound was eluted using 10% EtOAc in hexane to afford compound (I-20-2) (60.5 g, Yield: 87%) as a brown gummy liquid.

[0305] Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)carbamate (I-20-3) To a solution mixture of compound I-20-2 (30.0 g, 102.739 mmol) in dry THF (600.0 mL) was added n-BuLi (1.6 M in hexane) (321 mL, 513.7 mmol) at -78oC and stirring for 30 min at same temperature. DMF (39 mL, 513.7 mmol) was added dropwise at -78oC and stirring was continued for 2 h. After completion of reaction, the reaction mixture was quenched with sat. aq. NH4Cl solution (200 mL) and extracted with EtOAc (2x 500 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh)and compound was eluted using 12% EtOAc in hexane to afford compound I-20-3 (12.0 g, Yield: 49%) as a brown gummy liquid.1H NMR [400 MHz, CDCl3]: 9.83 (s, 1H), 7.63 (d, J = 3.6 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 5.0 (s, 1H) 4.52 (d, J= 6 Hz, 2H) 1.41 (s, 9H).

[0306] Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)carbamate (I-20-4) To a solution of compound I-20-3 (18.5 g, 76.7 mmol) in dry THF (400.0 mL) was added methyl magnesium bromide (1.0 M in THF) (767 mL, 767.0 mmol) at 0oC, after which it was stirred for 2 h at rt. The reaction mixture was quenched with sat. aq. NH4Cl solution (500 mL) and washed with EtOAc (2x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and compound was eluted using 20% EtOAc in hexane to afford compound I-20-4 (13.0 g, Yield: 66%) as a brown gummy liquid.1H NMR [400 MHz, DMSO-d6]: 8.13 (s, 1H), 7.43 (s, 1H), 7.00 (s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 4.19 (d, J = 2.0 Hz, 1H) 1.38-1.23 (m, 12H).

[0307] Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)carbamate (I-20-5) To a solution mixture of compound I-20-4 (6.5 g, 25.26 mmol) in DCM (65.0 mL) was added PCC (13.6 g, 63.15 mmol) at rt. The reaction mixture was stirred for 2 h at rt. After completion of reaction, the mixture was filtered in vacuo and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and the compound was eluted using 20% EtOAc in hexane to afford compound I-20-5 (4.9 g, Yield: 75%) as a brown gummy liquid.

[0308] Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-20) To a solution mixture of I-20-5 (4.8 g, 18.8 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (4.95 g, 13.1 mmol) at 0oC. The reaction mixture was stirred for 16 h at rt. After completion of reaction, mixture was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using combi- flash C-18 purification to afford compound I-20 (1.5 g, Yield: 24%) as pale brown solid.1H NMR [400 MHz, DMSO-d6]: 7.91 (d, J = 4 Hz, 1H), 7.65 (t, J = 6 Hz, 1H), 7.06 (d, J = 3.6 Hz, 1H), 4.77(s, 2H), 4.31(d, J = 6 Hz, 2H), 1.39 (s, 9H).

[0309] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate

[0310] Synthesis of tert-butyl (2-(thiophen-2-yl)ethyl)carbamate (I-21-1) To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (20.0 g, 157.22 mmol) in dichloromethane (200 mL) cooled to 0 °C was added (Boc)2O (41.1 g, 188.66 mmol) followed by Et3N (24.6 g, 243.10 mmol). The resulting mixture was stirred for 16 h at rt, after which it was concentrated under reduced pressure. The crude residue was diluted with water (100 mL), extracted with DCM (2 x 100 mL), and the combined organic layers dried over Na2SO4, and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 10% EtOAc in hexane, and the pure fractions were evaporated to afford compound I-21-1 (28 g, Yield: 74%) as a brown gummy liquid.

[0311] Synthesis of tert-butyl (2-(5-bromothiophen-2-yl)ethyl)carbamate (I-21-2) To a solution of compound I-21-1 (28 g, 123.172 mmol) in DMF (400 mL) cooled to 0 °C was added portion wise NBS (21.9 g, 123.172 mmol). The mixture was then stirred for 2 h at rt before it was poured into a mixture of ice / water (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine solution (100 mL), dried over Na2SO4 and then concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 10% EtOAc in hexane to afford compound I-21-2 (37.08 g, Yield: 98%) as an off-white solid.

[0312] Synthesis of tert-butyl (2-(5-formylthiophen-2-yl)ethyl)carbamate (I-21-3) To a solution of compound I-21-2 (20.0 g, 65.312 mmol) in dry THF (200 mL) cooled to -78°C was added dropwise n-BuLi (1.6 M solution in hexanes) (204.0 mL, 326.563 mmol) and the resulting mixture was stirred for 15 min, after which dry DMF (35.9 g, 491.80 mmol) was added and stirring was continued for 30 min at same temperature. After completion of reaction, the reaction mixture was quenched with sat. aq. NH4Cl solution (150 mL) and extracted with EtOAc (2 x 200 mL). The organic layer wasseparated, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 15% EtOAc in hexane to afford compound I-21-3 (10.0 g, Yield: 57%) as gummy liquid.

[0313] Synthesis of tert-butyl (2-(5-(1-hydroxyethyl)thiophen-2-yl)ethyl)carbamate (I-21-4) To a solution of compound I-21-3 (18.0 g, 70.496 mmol) in dry THF (180 mL) cooled to 0°C was added dropwise of methyl magnesium bromide (1.0 M solution in THF) (705.0 mL, 70.496 mmol), after which it was slowly warmed to rt and stirred for 2 h. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2 x 300 mL). The organic layer was separated, dried over Na2SO4, and concentrated reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 20% EtOAc in hexane to afford compound I-21-4 (15.0 g, Yield: 78%) as gummy solid.

[0314] Synthesis of tert-butyl (2-(5-acetylthiophen-2-yl)ethyl)carbamate (I-21-5) To a solution of compound I-21-4 (10 g, 36.849 mmol) in dry DCM (100 mL) cooled to 0°C was added Dess–Martin periodinane (46.8 g, 110.547 mmol) after which it was slowly warmed to rt and stirred for 16 h. The reaction mixture was filtered through a celite pad and washed with dichloromethane before the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 15% EtOAc in hexane to afford compound I-21-5 (7.1 g, Yield: 72 %) as gummy solid.

[0315] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-21) To a solution of compound I-21-5 (7.0 g, 25.987 mmol) in dry THF (70.0 mL) was added trimethylphenylammonium tribromide (7.8 g, 20.789 mmol), and mixture was then stirred at room temperature for 16 h. The solvent was then evaporated, and the crude was purified by Combi-flash reversed phase chromatography to afford I-21 (2.05 g, Yield: 23%) as an off-white solid.

[0316] Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2- yl)methyl)(methyl)carbamate (I-22)

[0317] Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)(methyl)carbamate (I-22-1) To a solution mixture of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I- 20-2) (40 g, 137.0 mmol) in DMF (400.0 mL) was added NaH (6.56 g, 273.0 mmol) followed by methyl iodide (12.8 mL, 205.5 mmol) at 0oC. The reaction mixture was stirred for 3 h at rt. The reaction mixture was quenched with ice water (150 mL) and extracted with EtOAc (2 x 500 mL) and dried over Na2SO4, concentrated in vacuo gave crude 43 g of compound I-22-1, which was taken to the next step without further purification.

[0318] Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)(methyl)carbamate (I-22-2) To a solution mixture of compound (I-22-1) (22.0 g, 71.89 mmol) in dry THF (400.0 mL) and added n-BuLi (1.6 M in hexane) (224 mL, 359.47 mmol) at -78oC and stirring for 30 min at -78oC. After DMF (27.9 mL, 359.47 mmol) was added at -78oC and stirring for 2 h, reaction mixture was quenched with sat. aq. NH4Cl solution (200.0 mL) and extracted with EtOAc (2 x 500 mL) and the combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 12% EtOAc in hexane to afford compound I-22-2 (6.5 g, Yield: 35%) as gummy liquid, used without further purification.

[0319] Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2- yl)methyl)(methyl)carbamate (I-22-3) To a solution mixture of compound I-22-2 (13.0 g, 50.9 mmol) in dry THF (250.0 mL) was added methyl magnesium bromide (1.0M in THF) (509 mL, 509.0 mmol) at 0oC and stirred the reaction for 2 h at rt. The reaction mixture was quenched with sat. aq. NH4Cl solution (500 mL) and washed with EtOAc (2x 500 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel(100-200 mesh) eluting with 20% EtOAc in hexane to afford compound I-22-3 (10 g, Yield: 72%) as gummy liquid, used without further purification.

[0320] Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)(methyl)carbamate (I-22-4) To a solution mixture of compound I-22-3 (10.0 g, 36.9 mmol) in DCM (100.0 mL) was added PCC (19.8 g, 92.2 mmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture after which it was filtered and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 20% EtOAc in hexane to afford compound I-22-4 (7.6 g, Yield: 77%) as gummy liquid, which was used without further purification.

[0321] Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)- carbamate (I-22) To a solution mixture of compound I-22-4 (4.3 g, 15.9 mmol) in THF (50 mL) and added phenyltrimethylammonium tribromide (4.20 g, 11.1 mmol) at 0oC. The reaction mixture was stirred for 16 h at rt. The reaction mixture was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using combi- flash reverse phase purification (using an ACN and 0.001% TFA in Water) to afford compound I-22 (1.5 g, Yield: 27%) as pale brown solid.

[0322] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)piperidine-1-

[0323] Synthesis of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6- dihydropyridine-1(2H)-carboxylate (I-23-1) A solution of tert-butyl 4-oxopiperidine- 1-carboxylate (1 g, 5.405 mmol) in dry THF (10 mL) was cooled to -78 °C, after which was added dropwise LiHMDS (1.0 M in THF, 6.0 mL, 5.934 mmol). The mixture was stirred for 60 min, then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N- (trifluoromethylsulfonyl)methanesulfonamide in THF (2.33 g, 5.934 mmol) was added. The reaction mixture was stirred for 30 min at the same temperature, after which it was slowly warmed to rt. The reaction mixture was quenched with sat. aq. NaHCO3 (10 mL) and then extracted with EtOAc (2x50 mL). The organic layer was separated, dried overNa2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using a silica gel (60-120 mesh, 10% ethyl acetate in hexanes) to afford title compound I-23-1 (0.63 g, 37 % yield) as gummy liquid.

[0324] Synthesis of tert-butyl 4-(5-acetylthiophen-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate (I-23-2) To a stirred solution of (5-acetylthiophen-2-yl) boronic acid I-23-1 (268 mg, 1.557 mmol) and tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6- dihydropyridine-1(2H)-carboxylate (500 mg, 1.557 mmol) in 1,4-dioxane:H2O (10:2 mL), K2CO3(652 mg, 4.731 mmol) and Pd(PPh3)4(182 mg, 0.155 mmol) was added under N2. The mixture was stirred for 15 min, and then heated to 90 °C for 16 h. The reaction mixture was quenched with sat. aq. NaHCO3 (20 mL), and then extracted with EtOAc (2x50 mL). The organic later was separated, dried over Na2SO4, and evaporated under reduced pressure to get crude compound. The residue was purified by column chromatography using a silica gel (60-120 mesh, 20% ethyl acetate in hexane) to afford title compound I-23-2 (201 mg, 44% yield) as gummy liquid.

[0325] Synthesis of tert-butyl 4-(5-acetylthiophen-2-yl)piperidine-1-carboxylate (I- 23-3) To a stirred solution of tert-butyl 4-(5-acetylthiophen-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate I-23-2 (1.5 g, 4.885 mmol) in MeOH (15 mL) was added 10% Pd-C (1.5 g) then inserted H2gas for 5 h at 60 psi. The reaction mixture was filtered in vacuo. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography using a silica gel (60-120 mesh, 50% ethyl acetate in hexane) to afford title compound I-23-3 (852 mg, 66 % yield) as yellow liquid.

[0326] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)piperidine-1- carboxylate (I-23): To a solution of tert-butyl 4-(5-acetylthiophen-2-yl) piperidine-1- carboxylate I-23-3 (500 mg, 1.618 mmol) in dry THF (5 mL) tetrabutylammonium tribromide (3 g, 6.261 mmol) was added, stirring was continued at room temperature for 16 h. The reaction mixture was concentrated providing title compound I-23 (310 mg, 49% yield). The crude was directly used for the next step.

[0327] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-thienyl]-4-methoxy-

[0328] Synthesis of tert-butyl 4-(5-bromo-2-thienyl)-4-methoxy-piperidine-1- carboxylate (I-24-1) To a solution of I-10-2 (11 g, 30.36 mmol) in THF (100 mL) was added NaH (1.46 g, 36.44 mmol, 16.56 μL, 60% purity) at 0 °C. After addition, the mixture was stirred at this temperature for 20 min, and then MeI (17.24 g, 121.45 mmol, 7.56 mL) in THF (5 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 h. The reaction mixture was quenched by addition H2O 100 mL at 0 °C, and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-24-1 (7 g, 18.60 mmol, 61.26% yield) as a yellow oil.

[0329] Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)-2-thienyl]-4-methoxy- piperidine-1-carboxylate (I-24-2) A mixture of I-24-1 (10 g, 26.57 mmol),TEA (5.38 g, 53.15 mmol, 7.40 mL), Pd(PPh3)2Cl2(932.61 mg, 1.33 mmol,) and tributyl(1- ethoxyvinyl)stannane (16.52 g, 45.74 mmol, 15.45 mL) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N2atmosphere. The reaction mixture was quenched with saturated KF (100 mL) and was extracted with EtOAc 100 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-24-2 (11 g, 23.95 mmol, 90.11% yield, 80% purity) was obtained as a black oil.

[0330] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-thienyl]-4-methoxy- piperidine-1-carboxylate (I-24) To a solution of I-24-2 (430 mg, 1.17 mmol, 1.0 eq) in THF (3 mL) and H2O (1 mL) was added NBS (187.43 mg, 1.05 mmol, 0.9 eq). The mixture was stirred at 25°C for 2 h. The reaction mixture was quenched with H2O (10 mL) and was extracted with EtOAc 10 mL. The combined organic layers are dried overNa2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60 % THF / Petroleum ether gradient @ 60 mL / min) to give compound I-24 (500 mg, 956.15 μmol, 81.72% yield, 80% purity) was obtained as a yellow solid.

[0331] 2-(difluoromethyl)-6-methoxy-pyrido[2,3-d]pyrimidin-4-yl]sulfanyl-1-[2- (4-hydroxy-4-piperidyl)thiazol-5-yl]ethanone (I-25):

[0332] Synthesis of tert-butyl 4-(5-bromothiazol-2-yl)-4-hydroxy-piperidine-1- carboxylate (I-25-1) To a solution of tert-butyl 4-hydroxy-4-thiazol-2-yl-piperidine-1- carboxylate (12.0 g, 42.2 mmol) in MeCN (120 mL) was added NBS (9.01 g, 50.6 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was quenched with H2O 30 mL and extracted with EtOAc 90 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~17% EtOAc / Petroleum ether gradient @ 100 mL / min) to give compound I-25-1 (9.3 g, 25.60 mmol, 60.67% yield) as a yellow oil.

[0333] Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)thiazol-2-yl]-4-hydroxy- piperidine-1-carboxylate (I-25-2) To a solution of I-25-1 (1.00 g, 2.75 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.49 g, 4.13 mmol, 1.39 mL) , Pd(PPh3)2Cl2 (193 mg, 275 μmol) and TEA (557 mg, 5.51 mmol, 766 μL) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (20 mL) and was extracted with EtOAc 30 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound I-25-2 (2.30 g, 1.82 mmol, 66.0 % yield, 28.0 % purity) as a brown oil.

[0334] Synthesis of 2-[2-(difluoromethyl)-6-methoxy-pyrido[2,3-d]pyrimidin-4- yl]sulfanyl-1-[2-(4-hydroxy-4-piperidyl)thiazol-5-yl]ethanone (I-25) To a solution of I-25-2 (2.30 g, 6.49 mmol) in THF (20 mL) and H2O (5 mL) was added NBS (1.27 g,7.14 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (20 mL) and was extracted with EtOAc 30 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / Petroleum ether gradient @ 40 mL / min) to give compound I-25 (694 mg, 1.71 mmol, 26.4 % yield) as a yellow solid.

[0335] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)thiazol-2-yl]-4-methoxy- piperidine-1-carboxylate(I-26):

[0336] Synthesis of tert-butyl 4-(5-bromothiazol-2-yl)-4-methoxy-piperidine-1- carboxylate (I-26-1) To a solution of tert-butyl 4-(5-bromothiazol-2-yl)-4-hydroxy- piperidine-1-carboxylate (1.50 g, 4.13 mmol) in THF (15 mL) was added NaH (198 mg, 4.95 mmol, 60.0 % purity) at 0°C under N2. The mixture was stirred at 0 °C for 2 h. Then the mixture was added MeI (2.34 g, 16.5 mmol) and was stirred at 25°C for 1 h. The reaction mixture was quenched with H2O (10 mL) and was extracted with EtOAc 30 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~12% EtOAc / Petroleum ether gradient @ 40 mL / min) to give compound I-26-1 (1.10 g, 2.92 mmol, 70.6 % yield) as a colorless oil.

[0337] Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)thiazol-2-yl]-4-methoxy- piperidine-1-carboxylate (I-26-2) To a solution of I-26-1 (1.10 g, 2.92 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.58 g, 4.37 mmol), Pd(PPh3)2Cl2 (205 mg, 292 μmol) and TEA (590 mg, 5.83 mmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (20 mL) and was extracted with EtOAc 30 mL. The combined organic layers are dried over Na2SO4,filtered and concentrated to give compound I-26-2 (2.70 g, 2.20 mmol, 75.4 % yield, 30.0 % purity) was obtained as a brown solid.

[0338] Synthesis of tert-butyl 4-[5-(2-bromoacetyl)thiazol-2-yl]-4-methoxy- piperidine-1-carboxylate (I-26) To a solution of I-26-2 (2.70 g, 3.30 mmol) in THF (20 mL) and H2O (7 mL) was added NBS (587 mg, 3.30 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (20 mL) and was extracted with EtOAc 30 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / Petroleum ether gradient @ 40 mL / min) give compound I-26 (320 mg, 789 μmol, 23.9 % yield) was obtained as a yellow solid.

[0339] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-

[0340] Synthesis of tert-butyl 3-hydroxy-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (I-27-1) To a solution of 2-bromothiazole (54 g, 329 mmol) in THF (500 mL) was added dropwise n-BuLi (2.5 M, 145 mL) at -78 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then tert-butyl 3-oxopyrrolidine-1-carboxylate (67.1 g, 362 mmol) in THF (300 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 2.5 h. TLC indicated 2-bromothiazole was consumed completely and one new spot formed. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution 500 mL at 0 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 2000 mL (1000 mL * 2). The combined organic layers were washed with brine 1000 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound I-27-1 (45.5 g, 46.1% yield) as a yellow oil.

[0341] Synthesis of tert-butyl 3-(5-bromothiazol-2-yl)-3-hydroxypyrrolidine-1- carboxylate (I-27-2) To a solution of I-27-1 (45.3 g, 168 mmol) in DMF (220 mL) was added NBS (35.8 g, 201 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was partitioned between H2O 800 mL and EtOAc 1500 mL. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give Compound I-27-2 (29 g, 49.6% yield) as a brown oil.

[0342] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazol-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-27-3) A mixture of I-27-2 (1.5 g, 4.30 mmol), tributyl(1-ethoxyvinyl)stannane (3.10 g, 8.59 mmol), TEA (1.30 g, 12.9 mmol) and Pd(PPh3)2Cl2(151 mg, 215 μmol) in dioxane (15 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 100 mL at 25 °C, and then diluted with H2O 50 mL and extracted with EtOAc 200 mL (100 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-27-3 (2.4 g, crude) as a brown oil.

[0343] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3- hydroxypyrrolidine-1-carboxylate (I-27) To a solution of I-27-3 (1.3 g, 3.82 mmol) in THF (13 mL) and H2O (6 mL) was added dropwise NBS (680 mg, 3.82 mmol) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h. The resulting mixture was stirred at 25 °C for 1.5 h. The reaction mixture was partitioned between EtOAc 20 mL and H2O 20 mL. The organic phase was separated, washed with brine 100 mL (50 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-27 (3.5 g, crude) as a yellow oil.

[0344] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-

[0345] Synthesis of tert-butyl 3-(5-bromothiazol-2-yl)-3-methoxypyrrolidine-1- carboxylate (I-28-1) To a solution of I-27-2 (6.6 g, 18.9 mmol) in THF (60 mL) was added NaH (1.13 g, 28.35 mmol, 60% purity) under N2atmosphere at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then CH3I (10.7 g, 75.6 mmol) was added at 0 °C. The resulting mixture was stirred at 25 °C for 3.5 h. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution 50 mL at 0 °C, and then diluted with H2O 100 mL and extracted with EtOAc 200 mL (100 mL x 2). The combined organic layers were washed with brine 100 mL, dried over MgSO4, 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 0~20% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-28- 1 (6.4 g, 91.4% yield) as a yellow oil.

[0346] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazol-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-28-2) A mixture of I-28-1 (4 g, 11.0 mmol), tributyl(1-ethoxyvinyl)stannane (7.95 g, 22.0 mmol), TEA (3.34 g, 33.0 mmo) and Pd(PPh3)2Cl2(386 mg, 551 μmol) in dioxane (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 16h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 100 mL at 25 °C, and then diluted with H2O 100 mL and extracted with EtOAc 200 mL (100 mL x 2). dried over MgSO4, 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 0~10% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give compound I-28-2 (2.9 g, 67.1% yield) was obtained as a yellow oil.

[0347] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3- methoxypyrrolidine-1-carboxylate (I-28) To a solution of I-28-2 (1.78 g, 5.02 mmol) in THF (20 mL) and H2O (10 mL) was added NBS (894 mg, 5.02 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between EtOAc 50 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL x 2), dried over MgSO4, 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 0~20% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-28 (1.38 g, 67.0% yield) as a yellow oil.

[0348] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-

[0349] Synthesis of tert-butyl 3-(5-bromothiazol-2-yl)-3-fluoropyrrolidine-1- carboxylate (I-29-1) To a solution of I-27-2 (8 g, 22.91 mmol) in DCM (80 mL) was added DAST (4.06 g, 25.2 mmol) at -78 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition H2O 50 mL at 0 °C, and then diluted with H2O 100 mL and extracted with DCM 200 mL (100 mL * 2). The combined organic layers were washed with brine 100 mL, dried over MgSO4, 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 0~25% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give Compound I-29-1 (6.5 g, 76.0% yield, 94.1% purity) as a brown solid.

[0350] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazol-2-yl)-3-fluoropyrrolidine- 1-carboxylate (I-29-2) A mixture of I-29-1 (4 g, 11.4 mmol), tributyl(1- ethoxyvinyl)stannane (8.9 g, 24.6 mmol), TEA (3.46 g, 34.2 mmol) and Pd(PPh3)2Cl2(400 mg, 569 μmol) in dioxane (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 100 mL at 25 °C, andthen diluted with H2O 50 mL and extracted with EtOAc 200 mL (100 mL * 2). dried over MgSO4, 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 0~10% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give Compound I-29-2 (3.99 g, 94.3% yield, 92.2% purity) as a yellow oil.

[0351] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3- fluoropyrrolidine-1-carboxylate (I-29) To a solution of I-29-2 (2 g, 5.84 mmol, 1 eq) in THF (20 mL) and H2O (10 mL) was added NBS (1.04 g, 5.84 mmol, 1 eq). The mixture was stirred at 0 °C for 2h. TLC indicated I-29-2 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between EtOAc 60 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~15% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-29 (1.6 g, 67.0 % yield, 96.1% purity) as a yellow solid.

[0352] The compounds I-30 to I-33 below have been prepared using the same experimental conditions as described for I-27 to I-29.

[0353] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2-(2-(5-bromothiophen-2-yl)-2- hydroxyethyl)carbamate (I-34-1) To a solution of 2,5-dibromothiophene (12 g, 49.6 mmol) in THF (100 mL) was added dropwise n-BuLi (2.5 M, 19.8 mL) at -78 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then tert-butyl N-(2- oxoethyl)carbamate (8.69 g, 54.6 mmol) in THF (100 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 2.5 h. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution 500 mL at 0 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 2000 mL (1000 mL * 2). The combined organic layers were washed with brine 1000 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-34-1 (4.5 g, 28.2% yield) as a yellow solid.

[0355] Synthesis of tert-butyl (2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2- hydroxyethyl)carbamate (I-34-2) A mixture of I-34-1 (4 g, 12.4 mmol), tributyl(1- ethoxyvinyl)stannane (9.15 g, 25.3 mmol), Pd(PPh3)2Cl2(871 mg, 1.24 mmol) and TEA (3.77 g, 37.2 mmol) in dioxane (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 100 mL at 25 °C, and then diluted with H2O 100 mL and extracted with EtOAc 400 mL (200 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-34-2 (13 g, crude) was obtained as a black oil.

[0356] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2- hydroxyethyl)carbamate (I-34) To a solution of I-34-2 (3.89 g, 12.4 mmol) in THF (40 mL) and H2O (20 mL) was added NBS (2.21 g, 12.4 mmol). The mixture was stirred at0 °C for 1h. TLC indicated I-34-2 was consumed completely and two new spots formed. The reaction mixture was partitioned between EtOAc 80 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~35% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-34 (5 g, 34.3% yield, 31% purity) was obtained as a yellow solid.

[0357] Synthesis of 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-1- methylpyrrolidin-2-one (I-35):

[0358] Synthesis of tert-butyl 3-(6-bromo-3-pyridyl)-3-hydroxy-pyrrolidine-1- carboxylate (I-35-1) To a solution of 2-bromo-5-iodo-pyridine (4.00 g, 14.09 mmol) in THF (60 mL) was added n-BuLi (2.5 M, 6.20 mL) at -78 °C under N2. The mixture was stirred at -78°C for 1 h under N2. Then tert-butyl 3-oxopyrrolidine-1-carboxylate (2.87 g, 15.50 mmol) in THF (60 mL) was added dropwise at -78 °C. The mixture was stirred at 25°C for 16 h. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.46) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched by addition H2O 80 mL at 0 °C, and extracted with EtOAc 80 mL (50 mL * 3). The combined organic layers were dried over MgSO4, 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 0~30% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-35-1 (2.23 g, 6.50 mmol, 46.11% yield) as a yellow solid.

[0359] Synthesis of tert-butyl 3-[6-(1-ethoxyvinyl)-3-pyridyl]-3-hydroxy- pyrrolidine-1-carboxylate (I-35-2) A mixture of I-35-1 (0.30 g, 874.09 μmol) , tributyl(1-ethoxyvinyl)stannane (631.35 mg, 1.75 mmol, 590.60 μL) ,TEA (176.90 mg, 1.75 mmol, 243.32 μL), Pd(PPh3)2Cl2(61.35 mg, 87.41 μmol,) in dioxane (15 mL) wasdegassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was quenched with saturated KF (10 mL) and was extracted with EtOAc 30 mL (10 mL*3). The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-35-2 (800 mg, 717.68 μmol, 82.11% yield, 30.00% purity) was obtained as a black oil.

[0360] Synthesis of tert-butyl 3-[6-(2-bromoacetyl)-3-pyridyl]-3-hydroxy- pyrrolidine-1-carboxylate (I-35) To a solution of I-35-2 (400.00 mg, 1.20 mmol) in THF (3 mL) and H2O (1 mL) was added NBS (212.89 mg, 1.20 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc 10 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-35 (200 mg, 519.14 μmol, 43.40% yield) was obtained as a yellow solid.

[0361] Synthesis of tert-butyl (3R,4S)-4-(5-(2-bromoacetyl)thiophen-2-yl)-4- hydroxy-3-methylpiperidine-1-carboxylate and tert-butyl (3S,4R)-4-(5-(2- bromoacetyl)thiophen-2-yl)-4-hydroxy-3-methylpiperidine-1-carboxylate mixture (I-36):

[0362] Synthesis of tert-butyl 4-hydroxy-3-methyl-4-(2-thienyl)piperidine-1- carboxylate (I-36-1) To a solution of 2-bromothiophene (10 g, 61.34 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 26.99 mL) at -78 °C under N2. The mixture was stirred at -78°C for 1 h under N2. Tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (15.70 g, 73.60 mmol) was added into the mixture at -78 °C and stirred at - 78°C for 1 h under N2. Then the mixture was stirred at 25°C for 16 h. TLC (petroleum ether / ethyl acetate = 3 / 1,Rf = 0.64) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched by addition H2O 100 mL at 0 °C, extracted with EtOAc 100 mL. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-36-1 (17 g, 57.16 mmol, 93.19% yield) as a colourless oil.

[0363] Synthesis of tert-butyl 4-(5-bromo-2-thienyl)-4-hydroxy-3-methyl- piperidine-1-carboxylate (I-36-2) To a solution of I-36-1 (5.5 g, 18.49 mmol) in DMF (30 mL) was added NBS (3.62 g, 20.34 mmol). The mixture was stirred at 25 °C for 2 h. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched by addition H2O 100 mL at 0 °C, and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were dried over MgSO4, 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 0~40% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-36-2 (6 g, 15.94 mmol, 86.22% yield) as a yellow oil.

[0364] Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)-2-thienyl]-4-hydroxy-3-methyl- piperidine-1-carboxylate (I-36-3) A mixture of I-36-2 (6 g, 15.94 mmol), TEA (3.23 g, 31.89 mmol ), tributyl(1-ethoxyvinyl)stannane (11.510 g, 31.87 mmol, 10.77 mL) and Pd(PPh3)2Cl2(223.83 mg, 318.89 μmol) in dioxane (60 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.68) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched with saturated KF (100 mL) and extracted with EtOAc 100 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-36-3 (6 g, 11.43 mmol, 71.68% yield, 70% purity) was obtained as a black oil.

[0365] Synthesis of tert-butyl (3R,4S)-4-(5-(2-bromoacetyl)thiophen-2-yl)-4- hydroxy-3-methylpiperidine-1-carboxylate and tert-butyl (3S,4R)-4-(5-(2-bromoacetyl)thiophen-2-yl)-4-hydroxy-3-methylpiperidine-1-carboxylate mixture (I-36) To a solution of I-36-3 (6 g, 11.43 mmol) in THF (40 mL) and H2O (20 mL) was added NBS (4.07 g, 22.86 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (80 mL) and was extracted with EtOAc 80 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60 % THF / Petroleum ether gradient @ 60 mL / min) to give compound I-36 (5 g, 8.13 mmol, 71.11% yield, 68% purity) was obtained as a yellow solid.

[0366] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (I-37)

[0367] Synthesis of tert-butyl 3-hydroxy-3-(2-thienyl)-8-azabicyclo[3.2.1]octane-8- carboxylate (I-37-1) To a solution of 2-bromothiophene (2 g, 12.27 mmol) in THF (50 mL) was added n-BuLi (2.5 M, 5.40 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. Tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (3.32 g, 14.72 mmol) was added dropwise at -78 °C and stirred at -78°C for 1 h N2. Then the mixture was stirred at 25 °C for 16 h. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched by addition H2O 80 mL at 0 °C, and extracted with EtOAc 80 mL. The combined organic layers were dried over MgSO4, 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 0~30% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-37-1 (2.4 g, 7.76 mmol, 63.23% yield) as a yellow solid.

[0368] Synthesis of tert-butyl 3-(5-bromo-2-thienyl)-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (I-37-2) To a solution of I-37-1 (4.7 g, 15.19 mmol) in DMF (40 mL) was added NBS (3.51 g, 19.75 mmol). The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched by addition H2O 100 mL at 0 °C, and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were dried over MgSO4, 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 0~40% THF / Petroleum ether gradient @ 60 mL / min) to give compound I-37-2 (4.3 g, 11.07 mmol, 72.90% yield) as a yellow solid

[0369] Synthesis of tert-butyl 3-[5-(1-ethoxyvinyl)-2-thienyl]-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (I-37-3) A mixture of I-37-2 (4.3 g, 11.07 mmol), tributyl(1-ethoxyvinyl)stannane (10.150 g, 28.10 mmol), TEA (2.24 g, 22.15 mmol) and Pd(PPh3)2Cl2(155.45 mg, 221.47 μmol) in dioxane (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 h under N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed the compound starting material was consumed and one new spot was formed. The reaction mixture was quenched with saturated KF (60 mL) and was extracted with EtOAc 60 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-37-3 (6 g, 6.32 mmol, 57.11% yield, 40% purity) was obtained as a black oil.

[0370] Synthesis of tert-butyl 3-[5-(2-bromoacetyl)-2-thienyl]-3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (I-37) To a solution of I-37-3 (4 g, 10.54 mmol) in THF (30 mL) and H2O (15 mL) was added NBS (3.75 g, 21.08 mmol). The mixture was stirred at 0-25 °C for 2 h. The reaction mixture was quenched with H2O (80 mL) and was extracted with EtOAc 80 mL. The combined organic layers are dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60 %THF / Petroleum ether gradient @ 60 mL / min) to give compound I-37 (2.3 g, 5.34 mmol, 50.71% yield) was obtained as a yellow oil.

[0371] Synthesis of tert-butyl 4-((5-(2-bromoacetyl)thiophen-2- yl)(hydroxy)methyl)piperidine-1-carboxylate (I-38):(I-38)

[0372] Synthesis of tert-butyl 4-(hydroxy(thiophen-2-yl)methyl)piperidine-1- carboxylate (I-38-1) To a solution of 2-bromothiophene (5 g, 30.67 mmol, 2.97 mL) in THF (150 mL) was added n-BuLi (2.5 M, 13.49 mL) in one portion at -70 °C under N2. The mixture was stirred at -70 °C for 1 h, then tert-butyl 4-formylpiperidine-1- carboxylate (7.19 g, 33.73 mmol) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into ice-water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-38-1 (4.6 g, 15.47 mmol, 50.43% yield) as a white solid.

[0373] Synthesis of tert-butyl 4-((5-bromothiophen-2- yl)(hydroxy)methyl)piperidine-1-carboxylate (I-38-2) To a solution of compound I- 38-1 (4.5 g, 15.13 mmol ) and NBS (2.96 g, 16.64 mmol) in DMF (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I- 38-2 (4.6 g, 12.22 mmol) as a yellow solid.

[0374] Synthesis of tert-butyl 4-((5-(1-ethoxyvinyl)thiophen-2- yl)(hydroxy)methyl)piperidine-1-carboxylate tert-butyl 4-((5-(1- ethoxyvinyl)thiophen-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (I-38-3) To a solution of compound I-38-2 (3 g, 7.97 mmol) and tributyl(1-ethoxyvinyl)stannane (5.76g, 15.94 mmol, 5.39 mL) in dioxane (20 mL) was added TEA (2.42 g, 23.92 mmol, 3.33 mL) and Pd(PPh3)2Cl2(559.56 mg, 797.22 μmol) under N2atmosphere. The mixture was stirred at 90 °C for 12h under N2 atmosphere. The reaction mixture was quenched by addition H2O (100 mL) at 25 °C and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I- 38-3 (6.1 g, crude) as a brown oil.

[0375] Synthesis of tert-butyl 4-((5-(2-bromoacetyl)thiophen-2- yl)(hydroxy)methyl)piperidine-1-carboxylate (I-38) To a solution of compound I-38- 3 (3 g, 8.16 mmol) in THF (20 mL) and H2O (5.0 mL) was added NBS (1.45 g, 8.16 mmol). The mixture was stirred at 0 °C for 0.5 h. TLC indicated compound I-38-3 was consumed completely and many new spots were formed. The reaction mixture was quenched by addition H2O (20 mL) at 25°C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 4 / 1) to give compound I-38 (1.7 g, crude) as a yellow oil.

[0376] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4-

[0377] Synthesis of tert-butyl 4-cyano-4-(thiophen-2-yl)piperidine-1-carboxylate (I-39-1) To a solution of 2-(thiophen-2-yl)acetonitrile (10 g, 81.19 mmol, 8.65 mL) in DMF (100 mL) was added dropwise NaNH2(9.50 g, 243.56 mmol) at 0 °C under N2atmosphere. The mixture was stirred at 0 °C for 1 h. Then a solution of tert-butyl N,N- bis(2-chloroethyl)carbamate (35.38 g, 146.13 mmol) in DMF (50 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was poured into sat. NH4Cl (10 mL) and extracted with EtOAc (100 mL* 3). The combined organic layerswere washed with brine (300 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give s residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to2 / 1) to give compound I- 39-1 (11 g, 37.62 mmol) as a red solid.

[0378] Synthesis of tert-butyl 4-(5-bromothiophen-2-yl)-4-cyanopiperidine-1- carboxylate (I-39-2) To a solution of compound I-39-1 (3 g, 10.26 mmol) in DMF (30 mL) was added NBS (2.19 g, 12.31 mmol), the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by H2O (70 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with H2O (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-39-2 (2.6 g, 7.00 mmol, 68.25% yield) as light yellow solid.

[0379] Synthesis of tert-butyl 4-cyano-4-(5-(1-ethoxyvinyl)thiophen-2- yl)piperidine-1-carboxylate (I-39-3) To a solution of compound I-39-2 (2.5 g, 6.73 mmol) in dioxane (30 mL) was added tributyl(1-ethoxyvinyl)stannane (4.86 g, 13.47 mmol, 4.55 mL), TEA (2.04 g, 20.20 mmol) and Pd(PPh3)2Cl2(472.60 mg, 673.32 μmol) under N2. The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by H2O (20 mL) and was extracted with EtOAc (30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound I-39-3 (5.3 g, crude) as a brown oil.

[0380] Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4- cyanopiperidine-1-carboxylate (I-39) To a solution of compound I-39-3 (2 g, 5.52 mmol) in THF (30 mL) and H2O (10 mL) was added NBS (1.18 g, 6.62 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by H2O (20 mL) and was extracted with EtOAc (30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I-39 (2.3 g, crude) as a yellow oil.

[0381] Synthesis of tert-butyl 5-(5-(2-bromoacetyl)thiazol-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (I-40):

[0382] Synthesis of tert-butyl 5-(5-bromothiazol-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (I-40-1) To a solution of 2,5- dibromothiazole (9 g, 37.05 mmol) in DMF (100 mL) was added tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (8.81g, 44.46 mmol ), K2CO3 (15.36 g, 111.15 mmol). The mixture was stirred at 85 °C for 2 h. TLC showed starting material was consumed completely, and one new spot was formed. The residue was poured into sat. NH4Cl (30 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound I-40-1 (8 g, 22.21 mmol, 59.94% yield) as a white solid.

[0383] Synthesis of tert-butyl 5-(5-(1-ethoxyvinyl)thiazol-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (I-40-2) To a solution of compound I-40-1 (8 g, 22.21 mmol) and tributyl(1-ethoxyvinyl)stannane (16.04 g, 44.41 mmol, 15.00 mL) in dioxane (200 mL) was added TEA (6.74 g, 66.62 mmol, 9.27 mL) and Pd(PPh3)2Cl2(1.56 g, 2.22 mmol) under N2 atmosphere. The mixture was stirred at 90 °C for 12 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (100 mL) at 25 °C and extracted with EtOAc (150 mL * 3). The combined organic layers were washed with brine (100 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-40-2 (15.4 g, crude) as a brown oil.

[0384] Synthesis of tert-butyl 5-(5-(2-bromoacetyl)thiazol-2-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (I-40) To a solution of compound I-40-2 (6 g, 17.07 mmol) in THF (60 mL) and H2O (30.0 mL) was added NBS (6.08 g, 34.14mmol). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by addition H2O (100 mL) at 25°C and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 4 / 1) to give compound I-40 (8.2 g, crude) as a yellow oil.

[0385] Synthesis of tert-butyl (1S,3S,4S)-3-(5-(2-bromoacetyl)thiophen-2-yl)-2-oxa- 5-azabicyclo[2.2.1]heptane-5-carboxylate (I-41):(I-41)

[0386] Synthesis of tert-butyl (2R,4R)-4-hydroxy-2-(thiophene-2- carbonyl)pyrrolidine-1-carboxylate (I-41-1) To a solution of tert-butyl (1S,4S)-3-oxo- 2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (10 g, 50.20 mmol) in THF (200 mL) was added dropwise thiophen-2-ylmagnesium bromide (1 M, 50.20 mL) at -70 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched by addition of sat. NH4Cl aq. (50 mL) dropwise at 0 °C under N2 and extracted with EtOAc (150 mL * 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give I-41- 1 (4.8 g, 16.14 mmol, 32.15% yield) as a white solid.

[0387] Synthesis of tert-butyl (2S,4S)-4-hydroxy-2-((S)-hydroxy(thiophen-2- yl)methyl)pyrrolidine-1-carboxylate (I-41-2) To a solution of I-41-1 (100 mg, 336.28 μmol) in MeOH (10.0 mL) was added NaBH4(25.44 mg, 672.56 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of H2O (2.0 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum to give I-41- 2 (68 mg, 227.13 μmol) as white oil

[0388] Synthesis of tert-butyl (1S,3S,4S)-3-(thiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-41-3) To a solution of compound I-41-2 (3.00 g, 10.02 mmol) in toluene (30 mL) added 2-(tributyl-phosphanylidene)acetonitrile (4.84 g, 20.04 mmol) at 25 °C. The mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-41-3 (2.5 g, 8.89 mmol, 88.67% yield) as a yellow oil.

[0389] Synthesis of tert-butyl (1S,3S,4S)-3-(5-bromothiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-41-4) To a solution of compound I-41-3 (1.6 g, 5.69 mmol) in DMF (30 mL) was added NBS (1.21 g, 6.82 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by H2O (70 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (100 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-41-4 (1.9 g, 5.27 mmol, 92.74% yield) as a light yellow solid.

[0390] Synthesis of tert-butyl (1S,3S,4S)-3-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-oxa- 5-azabicyclo[2.2.1]heptane-5-carboxylate (I-41-5) To a solution of compound I-41-4 (2 g, 5.55 mmol) in dioxane (30.0 mL) was added tributyl(1-ethoxyvinyl)stannane (8.02 g, 22.21 mmol, 7.50 mL), TEA (1.69 g, 16.65 mmol, 2.32 mL) and Pd(PPh3)2Cl2 (389.65 mg, 555.15 μmol) under N2. The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by H2O (20.0 mL) and was extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound I-41-5 (4.8 g, crude) as a brown oil.

[0391] Synthesis of tert-butyl (1S,3S,4S)-3-(5-(2-bromoacetyl)thiophen-2-yl)-2-oxa- 5-azabicyclo[2.2.1]heptane-5-carboxylate (I-41) To a solution of compound I-41-5 (1.95 g, 5.55 mmol) in THF (30.0 mL) and H2O (10.0 mL) was added NBS (988.07 mg, 5.55 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by H2O (20.0 mL), extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residuewas purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I-41 (2.5 g, crude) as a yellow oil.

[0392] Synthesis of tert-butyl (1S,4S)-1-(5-(2-bromoacetyl)thiophen-2-yl)-2-oxa-5-

[0393] Synthesis of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(thiophen-2- yl)pyrrolidine-2-carboxylic acid (I-42-1) To a solution of (S)-1-(tert-butoxycarbonyl)- 4-oxopyrrolidine-2-carboxylic acid (10 g, 43.62 mmol) in THF (200 mL) was added dropwise thiophen-2-ylmagnesium bromide (1 M, 52.35 mL) at -70 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was quenched by addition of sat. NH4Cl aq. (50 mL) dropwise at 0 °C under N2 and extracted with EtOAc (250 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give I-42-1 (9.5 g, 30.32 mmol, 69.49% yield) as a white solid.

[0394] Synthesis of tert-butyl (2S,4S)-4-hydroxy-2-(hydroxymethyl)-4-(thiophen-2- yl)pyrrolidine-1-carboxylate (I-42-2) To a solution of I-42-1 (5 g, 15.96 mmol) in THF (10.0 mL) was added BH3.THF (1 M, 15.96 mL). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition of MeOH (20.0 mL) and extracted with EtOAc (200 mL* 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum to give I-42-2 (3 g, 10.02 mmol, 62.80% yield) as white oil

[0395] Synthesis of tert-butyl (1S,4S)-1-(thiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-42-3) To a solution of compound I-42-2 (3.0 g, 1.00 mmol) in toluene (30 mL) added 2-(tributyl-phosphanylidene)acetonitrile (4.8 g,20.04 mmol) at 25 °C. The mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-42-3 (2.5 g, 8.89 mmol, 95.00% yield) as a yellow oil.

[0396] Synthesis of tert-butyl (1S,4S)-1-(5-bromothiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-42-4) To a solution of compound I-42-3 (2.5 g, 8.89 mmol) in DMF (30 mL) was added NBS (2.06 g, 11.55 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by H2O (70 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give compound I-42-4 (2.8 g, 7.77 mmol, 87.47% yield) as a light yellow solid.

[0397] Synthesis of tert-butyl (1S,4S)-1-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-42-5) To a solution of compound I-42-4 (2.8 g, 7.77 mmol) in dioxane (30 mL) was added tributyl(1-ethoxyvinyl)stannane (5.61 g, 15.54 mmol, 5.25 mL), TEA (2.36 g, 23.32 mmol, 3.25 mL) and Pd(PPh3)2Cl2 (818.27 mg, 1.17 mmol) under N2. The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by H2O (20.0 mL) and was extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give compound I-42-5 (4.4 g, crude) as a brown oil.

[0398] Synthesis of tert-butyl (1S,4S)-1-(5-(2-bromoacetyl)thiophen-2-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (I-42) To a solution of compound I-42-5 (2.73 g, 7.77 mmol) in THF (30 mL) and H2O (10 mL) was added NBS (2.77 g, 15.54 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by H2O (20.0 mL) and was extracted with EtOAc (30.0 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to give compound I-42 (3.1 g, crude) as a yellow oil.

[0399] Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)morpholine-4- carboxylate (I-43):

[0400] Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine- 4(3H)-carboxylate (I-43-1) Tert-butyl 3-oxomorpholine-4-carboxylate (20 g, 99.4 mmol) was dissolved in THF (200 mL). The mixture was cooled to -30 °C and LiHMDS (1 M, 109 mL) was added dropwise. The resulting mixture was stirred for 1 h, then [chloro(phenoxy)phosphoryl]oxybenzene (28.0 g, 104 mmol) was added dropwise. The resulting mixture was allowed to warm slowly to 43 °C for 6 h. The reaction mixture was poured into saturated ammonium chloride solution (1000 mL) and diluted with EtOAc (1000 mL). The organic phase was separated and washed with sat NaHCO3 (500 mL), then brine (500 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~12% THF / Petroleum ether gradient @ 80 mL / min) to give Compound I-43-1 (26.6 g, 61.8% yield) as a yellow oil.

[0401] Synthesis of tert-butyl 5-(thiophen-2-yl)-2H-1,4-oxazine-4(3H)-carboxylate (I-43-2) A mixture of I-43-1 (24 g, 55.4 mmol), 2-thienylboronic acid (11.3 g, 88.6 mmol), Na2CO3 (2 M, 360 mL) and Pd(PPh3)2Cl2 (3.89 g, 5.54 mmol) in THF (720 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 16 h under N2atmosphere. The reaction mixture was partitioned between EtOAc 800 mL and brine 600 mL. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give Compound I-43-2 (14.5 g, 97.9% yield) as a red oil.

[0402] Synthesis of 5-(thiophen-2-yl)-3,4-dihydro-2H-1,4-oxazine (I-43-3) To a solution of I-43-2 (13.5 g, 50.5 mmol) in DCM (60 mL) was added HCl / dioxane (2 M,252 mL). The mixture was stirred at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was poured into Saturated NaHCO3 solution (pH>7), extracted with EtOAc 900 mL (300 mL * 3). The organic phase was separated, washed with brine 1200 mL (600 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-43-3 (7.8 g, 92.4% yield) as a white solid.

[0403] Synthesis of 3-(thiophen-2-yl)morpholine (I-43-4) To a solution of I-43-3 (6 g, 35.9 mmol) in MeOH (15 mL) was added NaBH3CN (4.51 g, 71.8 mmol) and AcOH (6.46 g, 108 mmol). The mixture was stirred at 25 °C for 6 h. The reaction mixture was partitioned between EtOAc 60 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-43-4 (10 g, crude) as a brown oil.

[0404] Synthesis of tert-butyl 3-(thiophen-2-yl)morpholine-4-carboxylate (I-43-5) To a solution of I-43-4 (10 g, 59.1 mmol) in THF (100 mL) was added DIEA (15.3 g, 118 mmol) and Boc2O (25.79 g, 118.17 mmol, 27.15 mL). The mixture was stirred at 25 °C for 16 h. TLC indicated I-43-4 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~6% THF / Petroleum ether gradient @ 80 mL / min) to give I-43-5 (10 g, 61.3% yield, 97.6% purity) was obtained as a colourless oil.

[0405] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)morpholine-4-carboxylate (I-43-6) To a solution of I-43-5 (10 g, 37.13 mmol) in DMF (100 mL) was added NBS (6.61 g, 37.1 mmol). The mixture was stirred at 25 °C for 6 h. The reaction mixture was partitioned between EtOAc 600 mL and H2O 600 mL. The organic phase was separated, washed with brine 600 mL (300 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~5% THF / Petroleum ether gradient @ 80 mL / min) to give Compound I-43-6 (11 g, 85.1% yield) as a yellow oil.

[0406] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)morpholine-4- carboxylate (I-43-7) A mixture of I-43-6 (10 g, 28.7 mmol), tributyl(1- ethoxyvinyl)stannane (20.7 g, 57.4 mmol) and Pd(PPh3)2Cl2 (1.01 g, 1.44 mmol) TEA (8.72 g, 86.1 mmol) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 1000 mL at 25 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 2000 mL (1000 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-43-7 (20 g, crude) was obtained as a brown oil.

[0407] Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)morpholine-4- carboxylate (I-43) To a solution of I-43-7 (9.7 g, 28.6 mmol) in THF (90 mL) and H2O (90 mL) was added NBS (5.09 g, 28.6 mmol). The mixture was stirred at 0 °C for 1h. TLC indicated I-43-7 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between EtOAc 600 mL and H2O 600 mL. The organic phase was separated, washed with brine 800 mL (400 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give Compound I-43 (6 g, 30.1% yield, 56% purity) as a yellow solid.

[0408] Synthesis of tert-butyl (3S,4R)-4-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxypiperidine-1-carboxylate and tert-butyl (3S,4R)-4-(5-(2- bromoacetyl)thiophen-2-yl)-3-hydroxypiperidine-1-carboxylate mixture (I-44):

[0409] Synthesis of tert-butyl 3-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (I-44-1) To a solution of bromo(2-thienyl)magnesium (1 M, 301) in THF (300 mL) was added dropwise CuI (4.78 g, 25.09 mmol, 0.1 eq) at 0 °C. After addition, and then tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (50 g, 251 mmol) in THF (150 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution 100 mL at 0 °C, and then diluted with H2O 800 mL and extracted with EtOAc 1000 mL (500 mL * 2). The combined organic layers were washed with brine 500 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min), which was further separated by prep-HPLC (NH3H20 condition) to give Compound I-44-1 (9 g, 12.7% yield) was obtained as a yellow oil.

[0410] Synthesis of tert-butyl 4-(5-bromothiophen-2-yl)-3-hydroxypiperidine-1- carboxylate (I-44-2) To a solution of I-44-1 (7.8 g, 27.5 mmol) in DMF (60 mL) was added NBS (4.90 g, 27.5 mmol). The mixture was stirred at 0 °C for 2 h. TLC indicated I-44-1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between EtOAc 600 mL and H2O 600 mL. The organic phase was separated, washed with brine 1200 mL (600 mL * 2), dried over MgSO4, 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 0~20% THF / Petroleum ether gradient @ 60 mL / min) to give Compound I-44-2 (8.3 g, 83.2% yield) as a yellow solid.

[0411] Synthesis of tert-butyl 4-(5-(1-ethoxyvinyl)thiophen-2-yl)-3- hydroxypiperidine-1-carboxylate (I-44-3) A mixture of I-44-2 (8.3 g, 22.9 mmol), tributyl(1-ethoxyvinyl)stannane (17 g, 47.0 mmol), Pd(PPh3)2Cl2 (1.61 g, 2.29 mmol) and TEA (6.95 g, 68.7 mmol) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 6 h under N2atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 500 mL at 25 °C, and then diluted with H2O 600 mL and extracted with EtOAc 800 mL (400 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-44-3 (30 g, crude) was obtained as a brown oil.

[0412] Synthesis of of tert-butyl (3S,4R)-4-(5-(2-bromoacetyl)thiophen-2-yl)-3- hydroxypiperidine-1-carboxylate and tert-butyl (3S,4R)-4-(5-(2- bromoacetyl)thiophen-2-yl)-3-hydroxypiperidine-1-carboxylate mixture (I-44) To a solution of I-44-3 (8.1 g, 22.9 mmol) in THF (100 mL) and H2O (50 mL) was added NBS (4.08 g, 22.9 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between EtOAc 80 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~25% THF / Petroleum ether gradient @ 60 mL / min) to give Compound I-44 (5 g, 32.3% yield, 59.8% purity) as a yellow solid.

[0413] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)morpholine-4- carboxylate (I-45):

[0414] Synthesis of 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (I-45-1) To a solution of 1-(5-bromo-2-thienyl)ethanone (50.0 g, 244 mmol,) in EtOAc (250 mL) and CHCl3 (269 mL) was added CuBr2 (136 g, 607 mmol). The mixture was stirred at 90 °C for 16 h. After cooling, the mixture was concentrated in vacuum to give a residue. The residue was dissolved in EtOAc (1000 mL), filtered through a Celite pad. The combined organic layer was washed with aq. NaHCO3 (500 mL), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 8 / 1) to give compound I-45-1 (42.1 g, 148 mmol, 60.8% yield) as a brown solid.

[0415] Synthesis of 2-(benzyl(2-hydroxyethyl)amino)-1-(5-bromothiophen-2- yl)ethan-1-one (I-45-2) To a solution of compound I-45-1 (41.4 g, 146 mmol) and 2- (benzylamino)ethanol (33.1 g, 219 mmol, 31.0 mL) in DMF (420 mL) was added K2CO3 (60.4 g, 437 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was added water (800 mL) and extracted with EtOAc (1000 mL * 3). The combined organiclayer was dried with Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 6 / 1) to give compound I-45-2 (37.3 g, 104 mmol, 71.3% yield, 98.8% purity) as a brown oil.

[0416] Synthesis of 2-(benzyl(2-hydroxyethyl)amino)-1-(5-bromothiophen-2- yl)ethan-1-ol (I-45-3) To a solution of compound I-45-2 (37.3 g, 104 mmol,) in MeOH (380 mL) was added NaBH4 (4.41 g, 117 mmol,) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched by water (500 mL) at 0 °C under N2and extracted with EtOAc (800 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-45-3 (34.8 g, 87.4 mmol, 84.1% yield, 89.6% purity) as a brown oil.

[0417] Synthesis of 4-benzyl-2-(5-bromothiophen-2-yl)morpholine (I-45-4) A solution of compound I-45-3 (34.8 g, 97.6 mmol,) in HBr (207 g, 845 mmol, 139 mL, 33.0% purity) was stirred at 25 °C for 2 h. The mixture was quenched by water (400 mL) at 0 °C under N2and extracted with EtOAc (600 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give compound I-45-4 (26.9 g, 74.7 mmol, 76.5% yield, 94.0% purity) as a brown oil.

[0418] Synthesis of 2-chloroethyl 2-(5-bromothiophen-2-yl)morpholine-4- carboxylate (I-45-5) To a solution of compound I-45-4 (15.0 g, 44.3 mmol) in DCM (150 mL) was added 2-chloroethyl chloroformate (9.00 g, 63.0 mmol, 6.50 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF= 100 / 1 to 7 / 1) to give compound I-45-5 (10.8 g, 27.7 mmol, 62.4% yield, 90.8% purity) as a brown oil.

[0419] Synthesis of 2-(5-bromothiophen-2-yl)morpholine (I-45-6) To a solution of compound I-45-5 (10.0 g, 25.6 mmol) in dioxane (50.0 mL) was added a solution of NaOH (1.54 g, 38.4 mmol) in H2O (50 mL). The mixture was stirred at 110 °C for 3 h. The reaction mixture was added water (100 mL) and extracted with DCM (200 mL * 3).The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give compound I-45-6 (8.83 g, 17.4 mmol, 67.9% yield, 48.8% purity) as a brown oil.

[0420] Synthesis of tert-butyl 2-(5-bromothiophen-2-yl)morpholine-4-carboxylate (I-45-7) To a solution of compound I-45-6 (8.63 g, 17.0 mmol) in DCM (86 mL) was added Boc2O (5.56 g, 25.5 mmol, 5.85 mL) and TEA (5.16 g, 51.0 mmol, 7.09 mL). The mixture was stirred at 25 °C for 2 h. The mixture was added water (150 mL) and extracted with EtOAc (200 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 7 / 1) to give compound I-45-7 (3.65 g, 9.61 mmol, 56.61% yield, 91.73% purity) as a brown oil.

[0421] Synthesis of tert-butyl 2-(5-(1-ethoxyvinyl)thiophen-2-yl)morpholine-4- carboxylate (I-45-8) To a solution of compound I-45-7 (3.65 g, 9.61 mmol) and tributyl(1-ethoxyvinyl)stannane (6.18 g, 17.1 mmol, 5.78 mL) in dioxane (37.0 mL) was added TEA (1.95 g, 19.2 mmol, 2.68 mL) and Pd(PPh3)2Cl2(675 mg, 961 μmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction was quenched by aq. KF (60 mL) and extracted with EtOAc (100 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-45-8 (10.2 g, crude) as a brown oil.

[0422] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)morpholine-4- carboxylate (I-45) To a solution of compound I-45-8 (10.2 g, 30.1 mmol) in THF (100 mL) and H2O (50 mL) was added NBS (2.00 g, 11.2 mmol ) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was added water (60 mL) and extracted with EtOAc (100 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to give compound I-45 (2.90 g, 5.48 mmol, 18.2% yield, 73.7% purity) as a yellow solid.

[0423] Synthesis of tert-butyl (1S,4S,5S)-5-(5-(2-bromoacetyl)thiophen-2-yl)-5- hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate and tert-butyl (1R,4R,5R)-5-(5- (2-bromoacetyl)thiophen-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2- carboxylate mixture (I-46):

[0424] Synthesis of tert-butyl 5-hydroxy-5-(thiophen-2-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (I-46-1) To a solution of 2-bromothiophene (5.00 g, 30.7 mmol, 2.97 mL) in Tol. (50 mL) was added n-BuLi (2.50 M, 17.2 mL) at - 70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. A solution of tert- butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (5.83 g, 27.6 mmol) in Tol. (12.5 mL) was added into above reaction mixture at -70 °C and stirred at -70 °C for 1 h under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by aq. NH4Cl (80 mL) and extracted with EtOAc (100 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to give compound I-46-1 (6.10 g, 18.7 mmol, 60.9% yield, 90.5% purity) as a yellow solid.

[0425] Synthesis of tert-butyl 5-(5-bromothiophen-2-yl)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate (I-46-2) To a solution of compound I-46-1 (3.03 g, 10.3 mmol) in DMF (35 mL) was added NBS (2.01 g, 11.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was added water (30 mL) and extracted with EtOAc (50 mL* 2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 7 / 1) to give compound I-46-2 (2.68 g, 6.62 mmol, 64.5% yield, 92.4% purity) as a white solid.

[0426] Synthesis of tert-butyl 5-(5-acetylthiophen-2-yl)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate (I-46-3) To a solution of compound I-46-2 (4.00 g, 10.7 mmol), tributyl(1-ethoxyvinyl)stannane (7.82 g, 21.7 mmol, 7.32 mL) in dioxane (40 mL) was added TEA (2.16 g, 21.4 mmol, 2.97 mL) and Pd(PPh3)2Cl2 (750 mg, 1.07 mmol) under N2. The mixture was stirred at 90 °C for 16 h. The reaction was quenched by aq. KF (60 mL) and extracted with EtOAc (100 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 4 / 1) to give compound I-46-3 (2.03 g, 4.05 mmol, 37.9% yield, 72.9% purity) as a white solid.

[0427]

[0423] Synthesis of tert-butyl (1S,4S,5S)-5-(5-(2- bromoacetyl)thiophen-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate and tert-butyl (1R,4R,5R)-5-(5-(2-bromoacetyl)thiophen-2-yl)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate mixture (I-46) To a solution of compound I- 46-3 (1.00 g, 2.96 mmol) in DCM (4.80 mL) and MeOH (12.0 mL) was added TBATB (1.50 g, 3.11 mmol). The mixture was stirred at 25 °C for 4 h. The reaction was added water (20 mL) and extracted with DCM (20 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-46 (1.26 g, 1.55 mmol, 52.3% yield, 51.2% purity) as a yellow solid.

[0428] Synthesis of 2-bromo-1-(5-(hydroxy(tetrahydro-1H-pyrrolizin-7a(5H)- yl)methyl)thiophen-2-yl)ethan-1-one (I-47):

[0429] Synthesis of tetrahydro-1H-pyrrolizine-7a(5H)-carbaldehyde (I-47-1) To a solution of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (10.0 g, 70.8 mmol) in DCM (300 mL) was added Dess-Martin (60.1 g, 142 mmol, 43.9 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction was quenched by aq. NaHCO3 (600 mL) andextracted with DCM (1000 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-47-1 (18 g, crude) as a yellow solid.

[0430] Synthesis of (5-bromothiophen-2-yl)(tetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (I-47-2) To a solution of 2,5-dibromothiophene (1.00 g, 4.13 mmol, 466 μL) in Tol. (10 mL) was added n-BuLi (2.50 M, 1.82 mL) at -70 °C under N2. The mixture was stirred at -70 °C for 1 h under N2. A solution of compound I-47-1 (1.50 g, 10.8 mmol) in Tol. (10 mL) was added into above reaction mixture at -70 °C and stirred at - 70 °C for 1 h under N2. The mixture was stirred at 25 °C for 16 h. The reaction was quenched by aq. NH4Cl (30 mL) at 0 °C and extracted with DCM (100 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 0 / 1) to give compound I-47-2 (225 mg, 744 μmol, 18.0% yield) as a brown oil.

[0431] Synthesis of (5-(1-ethoxyvinyl)thiophen-2-yl)(tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methanol (I-47-3) To a solution of compound I-47-2 (225 mg, 744 μmol) in dioxane (3.50 mL) was added tributyl(1-ethoxyvinyl)stannane (403 mg, 1.12 mmol, 377 μL), TEA (151 mg, 1.49 mmol, 207 μL) and Pd(PPh3)2Cl2 (52.3 mg, 74.5 μmol) under N2. The mixture was stirred at 90 °C for 16 h under N2. The reaction was quenched by aq. KF (10 mL) and extracted with EtOAc (20 mL * 2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-47-3 (721 mg, crude) as a brown oil.

[0432] Synthesis of 2-bromo-1-(5-(hydroxy(tetrahydro-1H-pyrrolizin-7a(5H)- yl)methyl)thiophen-2-yl)ethan-1-one (I-47) To a solution of compound I-47-3 (721 mg, 2.46 mmol) in THF (7 mL) and H2O (3 mL) was added NBS (219 mg, 1.23 mmol,) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was extracted with EtOAc (10 mL*2). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-47 (670 mg, crude) as a brown oil.

[0433] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2- methylmorpholine-4-carboxylate (I-48):

[0434] Synthesis of ethyl 2-hydroxy-2-(thiophen-2-yl)propanoate (I-48-1) To a solution of ethyl 2-oxo-2-(2-thienyl)acetate (50 g, 271 mmol) in THF (500 mL) was added MeMgBr (3 M, 109 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched by addition Saturated ammonium chloride solution 1000 mL at 0 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 3000 mL (1500 mL * 3), dried over MgSO4, filtered and concentrated under reduced pressure to give I-48-1 (60 g, crude) was obtained as a yellow oil.

[0435] Synthesis of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxypropanoate (I-48-2) To a solution of I-48-1 (54.4 g, 271 mmol) in DMF (500 mL) was added NBS (72.5 g, 407 mmol). The mixture was stirred at 25 °C for 6 hrs. The reaction mixture was partitioned between EtOAc 800 mL and H2O 600 mL. The organic phase was separated, washed with brine 800 mL (400 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound I-48-2 (67 g, 88.4% yield) was obtained as a red oil.

[0436] Synthesis of 2-(5-bromothiophen-2-yl)-2-hydroxypropanoic acid (I-48-3) To a solution of I-48-2 (40 g, 143 mmol) in THF (200 mL) and EtOH (200 mL) at 0 °C. and then KOH (16.1 g, 287 mmol) in H2O (200 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove organic solvent. The combined water layers were washed with DCM 300 mL, The reaction mixture was poured into 1N HCl solution (pH<7), The reaction mixture was partitioned between DCM 600 mL and H2O 500 mL. The organic phase was separated, washed with brine 600 mL (300 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~50% THF / Petroleum ether gradient @ 90 mL / min) to give Compound I-48-3 (35 g, 97.3% yield) as a brown solid.

[0437] Synthesis of 2-(5-bromothiophen-2-yl)-N-(2-chloroethyl)-2- hydroxypropanamide (I-48-4) To a solution of I-48-3 (0.5 g, 1.99 mmol) in DMF (50 mL) was added 2-chloroethan-1-amine (346 mg, 2.99 mmol). HATU (1.14 g, 2.99 mmol), DIEA (772.1 mg, 5.97 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was partitioned between EtOAc 60 mL and H2O 60 mL. The organic phase was separated, washed with brine 80 mL (40 mL * 2), dried over MgSO4, 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 0~40% Ethyl acetate / Petroleum ethergradient @ 80 mL / min). Compound I-48-4 (460 mg, 73.9% yield) was obtained as a white oil.

[0438] Synthesis of 2-(5-bromothiophen-2-yl)-2-methylmorpholin-3-one (I-48-5) To a solution of I-48-4 (81.3 mg, 0.26 mmol) in DMF (10 mL) was added t-BuOK (29.2 mg, 0.26 mmol) under N2. The mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc 15 mL (5 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound I-48-5 (32 mg, 0.16 mmol, 44.5 % yield) as a yellow oil.

[0439] Synthesis of 2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2-methylmorpholin-3-one (I-48-6) To a solution of I-48-5 (2 g, 7.24 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane (5.23 g, 14.48 mmol, 4.89 mL), TEA (2.20 g, 21.73 mmol, 3.02 mL) and Pd(PPh3)2Cl2 (508.34 mg, 724.24 μmol) under N2. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with saturated KF solution (50 mL), extracted with EtOAc 150 mL (50 mL*3). The combined organic layers are dried over Na2SO4, filtered and concentrated to give compound I-48-6 (6.0 g, crude) as a black oil.

[0440] Synthesis of 2-(5-(2-bromoacetyl)thiophen-2-yl)-2-methylmorpholin-3-one (I-48-7) To a solution of I-48-6 (1 g, 3.95 mmol) in THF (10 mL) and H2O (4 mL) wasadded NBS (702.61 mg, 3.95 mmol). The mixture was stirred at 0 °C for 2 h. LCMS showed the desired product was formed and the starting material was consumed completely. The reaction mixture was quenched with H2O (10 mL), extracted with EtOAc 15 mL. The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® Silica Flash Column, Eluent of 0~40 % EtOAc / Petroleum ethergradient @ 80 mL / min) to give compound I-48-7 (1.4 g, crude) as a yellow oil.

[0441] Synthesis of 2-(5-bromothiophen-2-yl)-2-methylmorpholine (I-48-8) To a solution of compound I-48-7 (700 mg, 2.53 mmol) in THF (7 mL) was added BH3.THF (1.00 M, 5.07 mL) at -70 °C under N2. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by 2N HCl (7 mL) and stirred at 25 °C for 20 min. The mixture was adjusted pH=11 with 4N NaOH and extracted with DCM (15 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give compound I-48-8 (887 mg, crude) as a yellow oil.

[0442] Synthesis of tert-butyl 2-(5-bromothiophen-2-yl)-2-methylmorpholine-4- carboxylate (I-48-9) To a solution of compound I-48-8 (867 mg, 3.31 mmol) in THF (9 mL) and H2O (4.5 mL) was added Boc2O (1.44 g, 6.61 mmol, 1.52 mL) and K2CO3(914 mg, 6.61 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was added water (10 mL) and extracted with EtOAc (10 mL* 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to give compound I-48-9 (897 mg, 2.43 mmol, 73.5% yield, 98.1% purity) as a yellow oil.

[0443] Synthesis of tert-butyl 2-(5-acetylthiophen-2-yl)-2-methylmorpholine-4- carboxylate (I-48-10) To a solution of compound I-48-9 (897 g, 2.43 mmol) and tributyl(1-ethoxyvinyl)stannane (2.13 g, 5.90 mmol, 1.99 mL) in dioxane (10.0 mL) was added TEA (564 mg, 5.58 mmol, 776 μL) and Pd(PPh3)2Cl2(196 mg, 279 μmol,) under N2. The mixture was stirred at 90 °C for 16 h. The reaction was quenched by aq. KF (20 mL) and extracted with EtOAc (20 mL* 2). The combined organic layer was dried overNa2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 5 / 1) to give compound I-48-10 (578 mg, 1.64 mmol, 58.9% yield, 92.4% purity) as a yellow oil.

[0444] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2- methylmorpholine-4-carboxylate (I-48) To a solution of compound I-48-10 (478 mg, 1.47 mmol) in DCM (3.00 mL) and MeOH (7.50 mL) was added TBATB (744 mg, 1.54 mmol). The mixture was stirred at 25 °C for 2 h. The reaction was added water (5 mL) and extracted with DCM (10 mL* 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give compound I-48 (689 mg, crude) as a brown oil.

[0445] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2- hydroxyethyl)(methyl)carbamate (I-49):

[0446] Synthesis of tert-butyl (2-(5-bromothiophen-2-yl)-2- hydroxyethyl)(methyl)carbamate (I-49-1) To a solution of 2,5-dibromothiophene (15 g, 62.0 mmol) in THF (150 mL) was added dropwise n-BuLi (2.5 M, 27.3 mL) at -78 °C. After addition, the mixture was stirred at this temperature for 0.5 h, and then tert-butyl N- methyl-N-(2-oxoethyl)carbamate (12.9 g, 74.4 mmol) in THF (60 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 2.5 h. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution 500 mL at 0 °C, and then diluted with H2O 1000 mL and extracted with EtOAc 2000 mL (1000 mL * 2). The combined organic layers were washed with brine 1000 mL, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 70 mL / min) to give Compound I-49- 1 (16.2 g, 77.8% yield) as a yellow solid.

[0447] Synthesis of tert-butyl (2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2- hydroxyethyl)(methyl)carbamate (I-49-2) A mixture of I-49-1 (12 g, 35.7 mmol), tributyl(1-ethoxyvinyl)stannane (26.0 g, 72.0 mmol), TEA (10.8 g, 107 mmol) and Pd(PPh3)2Cl2 (2.50 g, 3.57 mmol) in dioxane (150 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 500 mL at 25 °C, and then diluted with H2O 600 mL and extracted with EtOAc 800 mL (400 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-49-2 (25 g, crude) was obtained as a black oil.

[0448] Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2- hydroxyethyl)(methyl)carbamate (I-49) To a solution of I-49-2 (14 g, 42.8 mmol) in THF (150 mL) and H2O (70 mL) was added NBS (7.61 g, 42.8 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was partitioned between EtOAc 800 mL and H2O 600 mL. The organic phase was separated, washed with brine 1200 mL (600 mL * 2), dried over MgSO4, 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 0~40% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-49 (8.1 g, 35.0% yield, 69.8% purity) as a brown oil.

[0449] Synthesis of tert-butyl 7-(5-(2-bromoacetyl)thiophen-2-yl)-7-hydroxy-3-oxa- 9-azabicyclo[3.3.1]nonane-9-carboxylate (I-51):

[0450] Synthesis of tert-butyl 7-hydroxy-7-(thiophen-2-yl)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (I-51-1) To a solution of tert-butyl 7-oxo-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (4.67 g, 19.4 mmol) and in THF (100 mL) was added dropwise CeCl3 (14.3 g, 58.1 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 1 h, and then bromo(2-thienyl)magnesium (1 M, 58.0 mL)was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was quenched by addition 20% aqueous AcOH solution 100 mL at 0 °C, and then diluted with H2O 200 mL and extracted with EtOAc 600 mL (300 mL * 2). The combined organic layers were washed with saturated NaHCO3 aqueous solution 300 mL, dried over MgSO4, 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 0~10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-51-1 (5.7 g, 90.5% yield) as a white solid.

[0451] Synthesis of tert-butyl 7-(5-bromothiophen-2-yl)-7-hydroxy-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (I-51-2) To a solution of I-51-1 (5.7 g, 17.5 mmol) in DMF (50 mL) was added NBS (3.74 g, 21.0 mmol). The mixture was stirred at 0 °C for 1h. TLC indicated I-51-1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between EtOAc 200 mL and H2O 200 mL. The organic phase was separated, washed with brine 200 mL (100 mL * 2), dried over MgSO4, 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 0~6% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-51-2 (6.4 g, 90.4% yield) was obtained as a white solid.

[0452] Synthesis of tert-butyl 7-(5-(1-ethoxyvinyl)thiophen-2-yl)-7-hydroxy-3-oxa- 9-azabicyclo[3.3.1]nonane-9-carboxylate (I-51-3) A mixture of I-51-2 (6 g, 14.8 mmol), tributyl(1-ethoxyvinyl)stannane (10.7 g, 29.7 mmol), TEA (4.50 g, 44.5 mmol) and Pd(PPh3)2Cl2(1.04 g, 1.48 mmol) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 500 mL at 25 °C, and then diluted with H2O 300 mL and extracted with EtOAc 600 mL (300 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-51-3 (10 g, crude) as a black oil.

[0453] Synthesis of tert-butyl 7-(5-(2-bromoacetyl)thiophen-2-yl)-7-hydroxy-3-oxa- 9-azabicyclo[3.3.1]nonane-9-carboxylate (I-51) T To a solution of I-51-3 (5.87 g, 14.8 mmol) in THF (50 mL) and H2O (25 mL) was added NBS (3.96 g, 22.3 mmol). The mixture was stirred at 0 °C for 1 h. TLC indicated I-51-3 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was partitioned between EtOAc 80 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~25% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give Compound I-51 (3.92 g, 59.2% yield) as a white solid.

[0454] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2- (trifluoromethyl)morpholine-4-carboxylate (I-52):

[0455] Synthesis of 1,1,1-trifluoro-3-nitro-2-(thiophen-2-yl)propan-2-ol (I-52-1) To a solution of 2,2,2-trifluoro-1-(2-thienyl)ethanone (10 g, 55.5 mmol) in nitromethane (184 g, 3.01 mol) was added TEA (8.43 g, 83.3 mmol). The mixture was stirred at 35 °C for 16 h. After the reaction was completed, water (500 mL) was added, successively with 1 N HCl to adjust pH to 5-6. The organic phase was separated and the aqueous phase was extracted with EtOAc (300 mL * 2). The combined organic phase was washed with water (200 mL) then dried (Na2SO4). filtered and concentrated under reduced pressure to give Compound I-52-1 (13 g, 97.1% yield) as a yellow solid.

[0456] Synthesis of 3-amino-1,1,1-trifluoro-2-(thiophen-2-yl)propan-2-ol (I-52-2) To a solution of I-52-1 (12 g, 49.8 mmol) in EtOH (200 mL) was added PtO2(1.13 g, 4.98 mmol) under N2atmosphere. The suspension was degassed and purged with H2for 2 times. The mixture was stirred under H2 (50 Psi) at 25 °C for 18 h. The mixture was filtered through a pad of celite and washed with MeOH (500 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% THF / Petroleum ether gradient @ 70 mL / min) to give Compound I-52-2 (7.8 g, 74.2% yield) was obtained as a white solid.

[0457] Synthesis of 2-chloro-N-(3,3,3-trifluoro-2-hydroxy-2-(thiophen-2- yl)propyl)acetamide (I-52-3) To a solution of I-52-2 (7.2 g, 34.1 mmol) in DCM (30 mL) was added TEA (4.48 g, 44.3 mmol) and 2-chloroacetyl chloride (4.62 g, 40.9 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between DCM 30 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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% THF / Petroleum ether gradient @ 60 mL / min) to give Compound I-52-3 (9.7 g, 33.7 mmol, 98.9% yield) as a colourless oil.

[0458] Synthesis of 6-(thiophen-2-yl)-6-(trifluoromethyl)morpholin-3-one (I-52-4) A solution of I-52-3 (8.7 g, 30.2 mmol) in THF (100 mL) was degassed and purged with N2 for 3 times at 0 °C. and then NaH (2.42 g, 60.5 mmol, 60% purity) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by addition Saturated ammonium chloride solution 100 mL at 0 °C, and then diluted with H2O 100 mL and extracted with EtOAc 600 mL (200 mL * 3), dried over MgSO4, 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 ether gradient @ 70 mL / min) to give Compound I-52-4 (6 g, 60.8% yield, 77% purity) as a colorless oil.

[0459] Synthesis of 2-(thiophen-2-yl)-2-(trifluoromethyl)morpholine (I-52-5) To a solution of I-52-4 (5.5 g, 21.9 mmol, 1 eq) in THF (50 mL) was degassed and purged with N2 for 3 times at 0 °C. and then LiAlH4 (2.08 g, 54.7 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was quenched by addition Na2SO410 H2O (10 g) at 0 °C, the reaction liquid is filtered directly and the filtrate was concentrated. Compound I-52-5 (6 g, crude) was obtained as a colourless oil.

[0460] Synthesis of tert-butyl 2-(thiophen-2-yl)-2-(trifluoromethyl)morpholine-4- carboxylate (I-52-6) To a solution of I-52-5 (5.19 g, 21.9 mmol) in MeOH (200 mL) was added TEA (3.32 g, 32.8 mmol) and Boc2O (7.16 g, 32.8 mmol). The mixture was stirred at 25 °C for 16h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% THF / Petroleum ether gradient @ 60 mL / min) to give Compound I-52-6 (6.3 g 85.4% yield) as a colourless oil.

[0461] Synthesis of tert-butyl 2-(5-bromothiophen-2-yl)-2- (trifluoromethyl)morpholine-4-carboxylate (I-52-7) To a solution of I-52-6 (5.2 g, 15.4 mmol) in DMF (50 mL) was added NBS (3.29 g, 18.5 mmol). The mixture was stirred at 70 °C for 2 h. The reaction mixture was partitioned between EtOAc 200 mL and H2O 300 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~15% THF / Petroleum ether gradient @ 60 mL / min) to give Compound I-52-7 (6.3 g, 98.2% yield) was obtained as a yellow oil.

[0462] Synthesis of tert-butyl 2-(5-(1-ethoxyvinyl)thiophen-2-yl)-2- (trifluoromethyl)morpholine-4-carboxylate (I-52-8) A mixture of I-52-7 (6.3 g, 15.1 mmol), tributyl(1-ethoxyvinyl)stannane (11.5 g, 31.7 mmol), TEA (4.59 g, 45.4 mmol) and Pd(PPh3)2Cl2 (1.06 g, 1.51 mmol) in dioxane (60 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 6 h under N2 atmosphere. The reaction mixture was quenched by addition saturated KF aqueous solution 500 mL at 25 °C, and then diluted with H2O 300 mL and extracted with EtOAc 200 mL (100 mL * 2). dried over MgSO4, filtered and concentrated under reduced pressure to give Compound I-52-8 (12 g, crude) was obtained as a black oil.

[0463] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-2- (trifluoromethyl)morpholine-4-carboxylate (I-52) To a solution of I-52-8 (6 g, 14.7 mmol, 1 eq) in THF (60 mL) and H2O (30 mL) was added NBS (5.24 g, 29.5 mmol), The mixture was stirred at 0 °C for 1 h. TLC indicated I-52-8 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixturewas partitioned between EtOAc 80 mL and H2O 60 mL. The organic phase was separated, washed with brine 120 mL (60 mL * 2), dried over MgSO4, 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 0~12% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to Compound I-52 (3.1 g, 45.9% yield) as a yellow solid.

[0464] Synthesis of tert-butyl 2-((5-(2-bromoacetyl)thiophen-2-

[0465] Synthesis of tert-butyl 2-formylmorpholine-4-carboxylate (I-53-1) A solution of (COCl)2(29.2 g, 230 mmol, 20.1 mL) in DCM (250 mL) was treated with DMSO (27.0 g, 345 mmol, 27.0 m) for 0.5 h at -78 °C under nitrogen atmosphere followed by the addition of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (25.0 g, 115 mmol) in DCM (250 mL) dropwise at -78 °C. The resulting mixture was stirred for 1 h at -78 °C, and then TEA (34.9 g, 345 mmol, 48.1 mL) was added dropwise at -78 °C. The reaction was maintained at -78 °C for 1 h and then warmed to 25°C for 24 h. The residue was diluted with H2O 500 mL and extracted with DCM 1500 mL (500mL *3). The combined organic layers were washed with brine 2000 mL (1000 mL *2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Compound I-53-1 (24.0 g, 105 mmol, 91.6% yield, 94.5% purity) was obtained as a yellow oil.

[0466] Synthesis of tert-butyl 2-(hydroxy(thiophen-2-yl)methyl)morpholine-4- carboxylate (I-53-2) To a solution of 2-bromothiophene (7.35 g, 45.1 mmo) in THF (100 mL) was added dropwise n-BuLi (2.5 M, 19.8 mL, 1.1 eq) at -78 °C for 10 min. After addition, the mixture was stirred at this temperature for 30min, and then I-53-1 (4.50 g, 20.9 mmol) in THF (100 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 24 h. The residue was diluted with H2O 100 mL and extracted with EtOAc 200 mL (100 mL *2). The combined organic layers were washed with brine 200mL (100 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=3 / 1). Compound I-53-2 (3.00 g, 6.92 mmol, 15.4% yield, 69.1% purity) was obtained as a red oil.

[0467] Synthesis of tert-butyl 2-((5-bromothiophen-2- yl)(hydroxy)methyl)morpholine-4-carboxylate (I-53-3) To a solution of I-53-2 (2.86 g, 9.55 mmol) in DMF (30 mL) was added NBS (1.87 g, 10.5 mmol). The mixture was stirred at 0 °C for 3 h. The residue was diluted with H2O 200 mL and extracted with EtOAc 400 mL (200 mL *2). The combined organic layers were washed with brine 400 mL (200 mL*2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1). Compound I-53-3 (2.60 g, 4.81 mmol, 50.3% yield, 69.9% purity) was obtained as a red oil.

[0468] Synthesis of tert-butyl 2-((5-(1-ethoxyvinyl)thiophen-2- yl)(hydroxy)methyl)morpholine-4-carboxylate (I-53-4) To a solution of I-53-3 (2.40 g, 6.34 mmol) and tributyl(1-ethoxyvinyl)stannane (4.58 g, 12.7 mmol) in dioxane (80 mL) was added TEA (1.93 g, 19.0 mmol) and Pd(PPh3)2Cl2 (445 mg, 634 μmol) under N2. The mixture was stirred at 80 °C for 2 h. The reaction was quenched with H2O (100 mL) and stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc 200 mL. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Compound I-53-4 (4.00 g, 5.97 mmol, 94.1% yield, 55.1% purity) was obtained as a black oil.

[0469] Synthesis of tert-butyl 2-((5-(2-bromoacetyl)thiophen-2- yl)(hydroxy)methyl)morpholine-4-carboxylate (I-53) To a solution of I-53-4 (2.34 g, 6.33 mmol) in THF (70 mL) and H2O (35 mL) was added NBS (1.13 g, 6.33 mmol). The mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by addition sat. NH4Cl solution 10 mL at 25 °C, and then diluted with H2O 100 mL and extracted with EtOAc 200 mL (100 mL * 2). The combined organic layers were washed with brine 200 mL (100 mL * 2), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Compound I-53 (7.00 g, 3.27 mmol, 51.6% yield, 19.6% purity) wasobtained as a white solid.

[0470] Synthesis of tert-butyl 2-(5-(2-bromoacetyl)thiophen-2-yl)-6,6-difluoro-1,4- oxazepane-4-carboxylate (I-54):

[0471] Synthesis of 3-(benzylamino)-2,2-difluoropropan-1-ol (I-54-1) To a solution of 3-amino-2,2-difluoropropan-1-ol (5.00 g, 45.0 mmol) in DCM (50 mL) was added benzaldehyde (4.78 g, 45.0 mmol, 4.55 mL) and AcOH (270 mg, 4.50 mmol) at 25 °C. After addition, the mixture was stirred at 25°C for 0.5 hr, and then NaBH(OAc)3 (28.6 g, 135 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H2O 100 mL at 0 °C, extracted with DCM 400 mL (200 mL * 2). The aqueous layers adjust the pH to ...

Claims

CLAIMS 1. Compound for use in the treatment and / or the prevention of an HDAC6-associated disease; wherein said compound is a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein - Y1is a 9- or 10-membered bicyclic heteroaryl selected from the following formulaewherein A1, A2, A3, A4, A5, A6and A7are each independently selected from C-R7and N; A8, A9, A10and A11are each independently selected from C-R7and N, provided that at least one of A8, A9, A10or A11is N; G1is selected from C-R3and N; G2is selected from O and N-R4; B is selected from O, S and N-R5, provided that when A5, A6and A7are C-R7, then B is not S; and R2is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15,-NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2- C6) alkylene-NR17R18, -(C1-C6) alkylene-SO2-NR17R18, -NR16-SO2-R15, -(C1-C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene-NR16-SO2-R15,-NR16-(C2-C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)- NR17R18, -O-(C1-C6) alkylene-C(O)-NR17R18, -NR16-(C1-C6) alkylene-C(O)- NR17R18, -NR16C(O)-R15, -(C1-C6) alkylene-NR16C(O)-R15, -O-(C2-C6) alkylene- NR16C(O)-R15, -NR16-(C2-C6) alkylene-NR16C(O)-R15, -C(O)-R15, -C(O)OR15, -(C1-C6) alkylene-C(O)OR15, -O-(C1-C6) alkylene-C(O)OR15, and -NR16-(C1-C6) alkylene-C(O)OR15; R3is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2- C6) alkylene-NR17R18, -(C1-C6) alkylene-SO2-NR17R18, -NR16-SO2-R15, -(C1-C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene-NR16-SO2-R15, -NR16-(C2-C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)- NR17R18, -O-(C1-C6) alkylene-C(O)-NR17R18, -NR16-(C1-C6) alkylene-C(O)- NR17R18, -NR16C(O)-R15, -(C1-C6) alkylene-NR16C(O)-R15, -O-(C2-C6) alkylene- NR16C(O)-R15, -NR16-(C2-C6) alkylene-NR16C(O)-R15, -C(O)-R15, -C(O)OR15, -(C1-C6) alkylene-C(O)OR15, -O-(C1-C6) alkylene-C(O)OR15, and -NR16-(C1-C6) alkylene-C(O)OR15; R4is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-OR15, -(C1-C6) alkylene-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -(C1-C6) alkylene- NR16C(O)-R15, -(C1-C6) alkylene-C(O)OR15, and -(C1-C6) alkylene-OC(O)-R15; R5is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-OR15, -(C1-C6) alkylene-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -(C1-C6) alkylene-NR16C(O)-R15, -(C1-C6) alkylene-C(O)OR15, and -(C1-C6) alkylene-OC(O)-R15;R7is selected from hydrogen, halogen, amino, hydroxy, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -OR15, -(C1-C6) alkylene-OR15, -O-(C2-C6) alkylene-OR15, -NR16(C2-C6) alkylene-OR15, -NR17R18, -(C1-C6) alkylene-NR17R18, -O-(C2-C6) alkylene-NR17R18, -NR16-(C2-C6) alkylene-NR17R18, -SO-R15, -SO2-R15, -SO2NR17R18, -(C1-C6) alkylene-SO2-NR17R18, -NR16-SO2-R15, -(C1-C6) alkylene-NR16-SO2-R15, -O-(C2-C6) alkylene-NR16-SO2-R15, -NR16-(C2-C6) alkylene-NR17-SO2-R15, -C(O)-NR17R18, -(C1-C6) alkylene-C(O)-NR17R18, -O-(C1-C6) alkylene-C(O)- NR17R18, -NR16-(C1-C6) alkylene-C(O)-NR17R18, -NR16C(O)-R15, -(C1-C6) alkylene-NR16C(O)-R15, -O-(C2-C6) alkylene-NR16C(O)-R15, -NR16-(C2-C6) alkylene-NR17C(O)-R15, -C(O)-R15, -C(O)-OR15, -(C1-C6) alkylene-C(O)-OR15, -O-(C1-C6) alkylene-C(O)-OR15, -NR16-(C1-C6) alkylene-C(O)-OR15, -OC(O)-R15, -(C1-C6) alkylene-OC(O)-R15, -O-(C2-C6) alkylene-OC(O)-R15, -NR16-(C2-C6) alkylene-OC(O)-R15, and -NR16- C(O)-OR15; wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R2, R3, R4, R5or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R2, R3, R4, R5or R7is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1-C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; R15, R16, R17and R18are each independently selected from hydrogen, -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and-(C1-C6) alkylene-aryl; and / or two groups selected from R15, R16, R17and R18form together a cycle selected from -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, and heteroaryl; wherein each of said -(C1-C6) alkyl or -(C1-C6) alkylene in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1- C6) alkyl)2; each of said -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl or heteroaryl in R15, R16, R17or R18is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -(C1-C6) alkyl, -CH2-O-(C1- C6) alkyl, -CH2-NH-(C1-C6) alkyl, -CH2-N-((C1-C6) alkyl)2, -O-(C1- C6) alkyl, -NH-(C1-C6) alkyl and -N-((C1-C6) alkyl)2; - Y2is a 5- or 6-membered heteroaryl or 6-membered aryl selected from the following formulaewherein R12, R13, R14and R25’are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -(C1-C6) alkyl,-(C3-C6) cycloalkyl,-CH2-O- (C1-C6) alkyl, -O-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; wherein each of said -(C1-C6) alkyl in R12, R13, R14or R25’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -O-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; - L is -(CR10R11)n; wherein n is an integer selected from 0, 1, 2, 3 and 4; R10and R11are independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C3) alkyl, -(C1-C2) haloalkyl, -(C1-C2) hydroxyalkyl, -(C1-C2) aminoalkyl, -O-(C1-C4) alkyl, -NH-(C1-C3) alkyl, and -N-((C1-C3) alkyl)2; or R10and R11form together with the carbon atom to which they are bond a (C3-C6) cycloalkyl; - Z1’is selected from -NR23’R24’and a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom; whereineach nitrogen atom of said (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O- (C1-C6) alkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene- aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O- (C3-C7) cycloalkyl; each carbon atom of said (C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; wherein each of said -(C1-C6) alkyl, -(C1-C6) alkylene -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in Z1’is optionally substituted with at least one halogen; and wherein each of said aryl or heteroaryl in Z1’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and O-(C3-C7) cycloalkyl; and R23’and R24’are each independently selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene- (C3-C7) heterocycloalkyl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-aryl; wherein each of said -(C1-C6) alkyl, -(C1-C6) alkylene, -(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2; andeach of said aryl or heteroaryl in R23’or R24’is optionally substituted with at least one group selected from halogen, cyano, hydroxy, -(C1-C6) alkyl,-O-(C1-C6) alkyl, -NH-(C1-C6) alkyl, and -N-((C1-C6) alkyl)2.

2. The compound for use according to claim 1, wherein Y1is a 9- or 10-membered bicyclic heteroaryl selected from: the following formulaewherein A1-A4, A6, A7, G1and R2are independently as defined in claim 1; and the following formulawherein A8-A11and G2are independently as defined in claim 1.

3. The compound for use according to claim 1, wherein Y1is selected from: (i) a 10-membered bicyclic [6,6] heteroaryl selected from the following formulaeand the following formulaewherein R2, R3and R7are independently as defined in claim 1; (ii) a 9-membered bicyclic [6,5] heteroaryl selected from the following formulaethe following formulaeand the following formulaewherein R2, R3, R5and R7are independently as defined in claim 1; and the following formulawherein R2, R3and R7are independently as defined in claim 1; and (iii) a 9-membered bicyclic [5,6] heteroaryl selected from: the following formulaeand the following formulaewherein A1, A3, A3, A4, R2, R4and R7are independently as defined in claim 1.

4. The compound for use according to any one of claims 1 to 3, wherein Y1is selected from: (i) a 10-membered bicyclic [6,6] heteroaryl selected from the following formulaewherein R2, R3and R7are independently as defined in claim 1; (ii) a 9-membered bicyclic [6,5] heteroaryl selected from the following formulaewherein R2, R3, R5and R7are independently as defined in claim 1; (iii) a 9-membered bicyclic [5,6] heteroaryl selected from the following formulaewherein R2, R5and R7are independently as defined in claim 1; preferably Y1is selected from 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 5-(trifluoromethyl)oxazolo[5,4-b]pyridin-2-yl, 2-(trifluoromethyl)quinazolin-4-yl, 1-(2-methoxyethyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl), 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-yl, 2-(difluoromethyl)-6- methoxypyrido[2,3-d]pyrimidin-4-yl, 2-(trifluoromethyl)quinazolin-4-yl, 6-methoxy-2-(trifluoromethyl)quinazolin-4-yl, , 6-methoxy-2-methylquinazolin-4- yl, 2-methylpyrido[2,3-d]pyrimidin-4-yl, 2-cyclopropyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4-yl, 6-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl,2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl, 6-methoxy-2- methyl-1,8-naphthyridin-4-yl, 7-(difluoromethyl)-1,6-naphthyridin-5-yl, 3-methoxy-7-methyl-1,6-naphthyridin-5-yl, 6-chloro-8-fluoro-2- methylquinazolin-4-yl, 2-methyl-6-(trifluoromethyl)quinazolin-4-yl, 6-ethoxy-2- methylquinazolin-4-yl, 6-chloro-7-fluoro-2-methylquinazolin-4-yl, 5-methoxy-2- methylquinazolin-4-yl, 6,7-dimethoxy-2-methylquinazolin-4-yl, 6,7-dimethoxyquinolin-4-yl, 3-chloro-7-methyl-1,6-naphthyridin-5-yl, 6-methoxyquinolin-4-yl, 6-methoxy-2-methylquinolin-4-yl, 6-chloro-8-fluoro-2- methylquinazolin-4-yl, 6-chloroquinolin-4-yl, 7-methoxyquinolin-4-yl, 6-fluoro-2- methylpyrido[2,3-d]pyrimidin-4-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyrimidin- 5-yl, 7-methylimidazo[1,2-a]pyrimidin-5-yl, 2-methyl-1,8-naphthyridin-4-yl, 6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4-yl, 2-methyl-6- (trifluoromethyl)quinolin-4-yl, 6-methoxy-2-methyl-1,5-naphthyridin-4-yl, (6-methoxy-2-methyl-1,5-naphthyridin-4-yl, 2-methyl-6-(trifluoromethyl)-1,8- naphthyridin-4-yl, 5-fluoro-6-methoxy-2-methylquinazolin-4-yl, 6-(difluoromethoxy)-2-methylquinazolin-4-yl, 2-methyl-6- (trifluoromethoxy)quinazolin-4-yl, and 7-methyl-3-(trifluoromethyl)-1,6- naphthyridin-5-yl.

5. The compound for use according to any one of claims 1 to 4, wherein R12, R13, R14or R25’are each independently selected from hydrogen and (C1-C3) alkyl, preferably R12, R13, R14and R25’are hydrogen.

6. The compound for use according to any one of claims 1 to 5, wherein R10and R11are independently selected from hydrogen and (C1-C3) alkyl, preferably R10and R11are each hydrogen.

7. The compound for use according to any one of claims 1 to 6, wherein Z1’is a -(C3-C7) heterocycloalkyl selected from the following formulaewherein R21’is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene- (C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene- heteroaryl, and -(C1-C6) alkylene-O-(C3-C7) cycloalkyl; and R22’is selected from hydrogen, halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O- (C1-C6) alkyl, -(C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene- (C3-C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene- heteroaryl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl; wherein each of said -(C1-C6) alkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in R21’or R22’is optionally substituted with at least one halogen; and wherein each of said aryl or heteroaryl in R21’or R22’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl, and -O-(C3-C7) cycloalkyl.

8. The compound for use according to any one of claims 1 to 6, wherein Z1’is a -(C3-C7) heterocycloalkyl of the following formulawherein R21’is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O-(C3-C7) cycloalkyl; and R22’is selected from hydrogen, halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl,-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3- C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, - (C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, - O-(C1-C6) alkyl and -O-(C3-C7) cycloalkyl; wherein each of said -(C1-C6) alkyl, -(C1-C6) alkylene -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in R21’is optionally substituted with at least one halogen; and wherein each of said aryl or heteroaryl in R21’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl and O-(C3-C7) cycloalkyl.

9. The compound for use according to any one of claims 1 to 6, wherein Z1’is a -(C3-C7) heterocycloalkyl of the following formulaR21’is selected from hydrogen, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, and -(C1-C6) alkylene-O-(C3-C7) cycloalkyl; and R22’is selected from hydrogen, halogen, cyano, hydroxy, oxo, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3- C7) heterocycloalkyl, aryl, heteroaryl, -(C1-C6) alkylene-O-(C1-C6) alkyl, - (C1-C6) alkylene-O-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3- C7) heterocycloalkyl, -(C1-C6) alkylene-aryl, -(C1-C6) alkylene-heteroaryl, - O-(C1-C6) alkyl and -O-(C3-C7) cycloalkyl; wherein each of said -(C1-C6) alkyl, -(C1-C6) alkylene -(C3-C7) cycloalkyl or -(C3-C7) heterocycloalkyl in R21’is optionally substituted with at least one halogen; andwherein each of said aryl or heteroaryl in R21’is optionally substituted with at least one group selected from halogen, CN, -(C1-C6) alkyl, -O-(C1-C6) alkyl and O-(C3-C7) cycloalkyl.

10. The compound for use according to any one of claims 7 to 9, wherein: R21’is selected from hydrogen, -(C1-C6) alkyl, -(C1-C6) alkyl substituted with at least one fluoro, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) heterocycloalkyl, and -(C1-C6) alkylene-O-(C1-C6) alkyl; preferably R21’is selected from hydrogen, -(C1-C3) alkyl, -(C3-C5) cycloalkyl, -(C1-C3) alkylene-(C3-C5) cycloalkyl, oxetanyl, and -(C1-C3) alkylene-O- (C1-C3) alkyl; and R22’is selected from hydrogen, halogen, -(C1-C6) alkyl, -(C1-C6) alkyl substituted with at least one fluoro, cyano, hydroxy and -O-(C1-C6) alkyl; preferably R22’is hydrogen, fluoro, trifluoromethyl, cyano, hydroxy and -O-(C1-C3) alkyl.

11. The compound for use according to any one of claims 1 to 6, wherein Z1’is selected from azetidin-3-yl, 1-methylazetidin-3-yl, 3-fluoroazetidin-3-yl, 3-hydroxyazetidin-3-yl, 3-methoxyazetidin-3-yl, 1-methylpiperidin-4-yl, 1-(2-methoxyethyl)azetidin-3-yl, pyrrolidin-3-yl, 3-fluoropyrrolidin-3-yl, 3-hydroxypyrrolidin-3-yl, 3-methoxypyrrolidin-3-yl, morpholinomethyl, 3-methoxy-1-methylpyrrolidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin-4-yl, 4-cyano-1-methylpiperidin-4-yl, 3-hydroxy-1-methylpyrrolidin-3-yl, 4-methoxypiperidin-4-yl, 4-hydroxy-1-isopropylpiperidin-4-yl, 1-hydroxy-2- (methylamino)ethyl, 1-(2-fluoroethyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1- methylpiperidin-4-yl, 4-hydroxy-1,3-dimethylpiperidin-4-yl, 1-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl, 4-hydroxy-1-(2- methoxyethyl)piperidin-4-yl, 1-cyclobutyl-4-hydroxypiperidin-4-yl)thiophen-2-yl, 1-cyclopropyl-4-hydroxypiperidin-4-yl, piperazin-1-yl, 3-hydroxy-1- methylpiperidin-4-yl, 4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl, 4-methoxy-1- methylpiperidin-4-yl, 3-hydroxy-1-methylpiperidin-3-yl, morpholin-4-yl, morpholin-2-yl, 4-methylmorpholin-2-yl, 4-methylmorpholin-3-yl, morpholin-3-yl, 2-aminoethyl, aminomethyl, and N-(methylamino)-methyl, 3-hydroxy-1- methylazetidin-3-yl, 5-(hydroxy(1-methylpiperidin-4-yl)methyl, 3-hydroxy-1- isopropylazetidin-3-yl, 6-oxa-3-azabicyclo[3.2.1]octan-5-yl, 3-methyl-6-oxa-3- azabicyclo[3.2.1]octan-5-yl, 3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-1-yl, 5-methyl-2-oxa-5-azabicyclo[2.2.1]heptan- 1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-3-yl, 6,6-difluoro-1,4-oxazepan-2-yl, 2-methylmorpholin-2-yl, 2-(trifluoromethyl)morpholin-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2- yl, 7-hydroxy-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl, 5-hydroxy-2- methyl-2-azabicyclo[2.2.1]heptan-5-yl, 3-hydroxyquinuclidin-3-yl, 5-hydroxy-2- azabicyclo[2.2.1]heptan-5-yl, 1-hydroxy-2-morpholinoethyl, 5-(hydroxy(4- methylmorpholin-2-yl)methyl, 5-(hydroxy(tetrahydro-1H-pyrrolizin-7a(5H)- yl)methyl, and 2-(dimethylamino)-1-hydroxyethyl; preferably Z1’is selected from azetidin-3-yl, 1-methylazetidin-3-yl, 3-fluoroazetidin-3-yl, 3-hydroxyazetidin-3-yl, 3-methoxyazetidin-3-yl, 1-(2-methoxyethyl)azetidin-3-yl, pyrrolidin-3-yl, 3-fluoropyrrolidin-3-yl, 3-hydroxypyrrolidin-3-yl, 3-methoxypyrrolidin-3-yl, piperidin-4-yl, 4-hydroxypiperidin-4-yl, piperazin-1-yl, morpholin-4-yl, 2-oxa-5- azabicyclo[2.2.1]heptan-1-yl, 5-methyl-2-oxa-5-azabicyclo[2.2.1]heptan-1-yl, 6-oxa-3-azabicyclo[3.2.1]octan-5-yl, and 3-methyl-6-oxa-3- azabicyclo[3.2.1]octan-5-yl.

12. The compound for use according to claim 1, wherein said compound is selected fromand pharmaceutically acceptable salts and / or solvates thereof.

13. Pharmaceutical composition for use in the treatment and / or the prevention of an HDAC6-associated disease comprising a compound as defined in any one of claims 1 to 12 and at least one pharmaceutically acceptable carrier.

14. The compound for use according to any one of claims 1 to 12 or the pharmaceutical composition for use according to claim 13, wherein said HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases (including neuromuscular diseases), pains, neuropathies (including neuromuscular diseases), psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, and metabolic or hormonal disorders.

15. Compound of formula (II)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Y1, Y2and L are independently as defined in claim 1; Z1’is a -(C3-C7) heterocycloalkyl comprising at least one nitrogen atom, as defined in claim 1; provided that the compound is not selected from: 1-(5-(pyrrolidin-3-yl)thiophen-2-yl)-2-((2-(trifluoromethyl)quinazolin-4- yl)thio)ethan-1-one, 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)-1-(5-(pyrrolidin-3- yl)thiophen-2-yl)ethan-1-one, and pharmaceutically acceptable salts and / or solvates thereof.

16. The compound according to claim 13, wherein said compound is selected fromand pharmaceutically acceptable salts and / or solvates thereof.

17. Process for manufacturing a compound according to claim 13 or claim 14, wherein said process comprises the following steps: (i) reacting an amine-containing alkyl chain or heterocycloalkyl with a halo-heterocycle; then (ii) reacting a heterocycle or halo-heterocycle with first an acetylating reagent, and, where appropriate, subsequently a halogenating reagent, to form a halo-ketone; then (iii) reacting a halo- ketone with a thiol and, where appropriate, (iv) removing of at least one protective group.

18. Compound selected fromand pharmaceutically acceptable salts and / or solvates thereof.

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