Use of heteroarylamine compounds and HDAC6 inhibitors

Abstract

The present invention relates to a compound of formula (I) 【Chemical 1】 TIFF2026522613000317.tif21170(wherein Y 1 is a 9- or 10-membered bicyclic heteroaryl, Y 2 is a 5- or 6-membered heteroaryl or 6-membered aryl, L is a linker, Z 1’ is selected from -NR 23’ R 24’ and -(C3-C7)heterocycloalkyl containing at least one nitrogen atom, and R 23’ and R 24’ may be various groups) or a pharmaceutically acceptable salt and / or solvate thereof. Further, the present invention relates to a compound of formula (I) as an HDAC6 inhibitor for use in the treatment and / or prevention of HDAC6-related diseases such as cancer, neurodegenerative diseases, neuropathy, cardiovascular diseases, or metabolic or hormonal disorders.

Description

[Technical Field]

[0001] (Field of Invention) This invention relates to compounds useful as histone deacetylase subtype 6 (HDAC6) inhibitors. In particular, this invention relates to compounds for use in the treatment and / or prevention of proliferative disorders such as cancer, neurodegenerative diseases, neuropathy, or cardiovascular diseases. [Background technology]

[0002] (Background of the invention) Inhibition of HDAC class enzymes, particularly HDAC6 enzyme, plays a crucial role in human gene expression. Therefore, the development of potent HDAC inhibitors is clinically paramount 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 considered useful, for example, in oncology, neurology, neuropsychiatry, neurodegeneration, inflammation (e.g., neuroinflammation), nephropathy, neuropathy, and pain. Notable examples of HDAC6 inhibitors with potential medical applications in the treatment of proliferative disorders are the hydroxamate class of drugs (hydroxamic acids and their salts), which include vorinostat (or "SAHA," trademark Zolinza®), trichostatin A (TSA), belinostat (trademark Beleodaq®), panobinostat (Farydak®), or romidepsin (Istodax®).

[0003] However, many HDAC6 inhibitors identified to date have low selectivity and therefore can cause serious side effects. Poor pharmacokinetics and low bioavailability also limit the efficacy of some HDAC6 inhibitors. Consequently, most HDAC6 inhibitors have a poor development potential profile, even for life-threatening applications in oncology. For example, high doses of non-selective HDAC inhibitors can cause fatigue and nausea. Side effects can be caused particularly by inhibition of class I HDACs. Furthermore, mutagenicity issues related to hydroxysamate functional groups have been reported in approved HDAC inhibitors (see Shen S. and Kozikowski AP, ChemMedChem 2016, No. 11, pp. 15-21). Other HDAC inhibitors, particularly those of the fluoromethyloxadiazole class, have been reported to be mechanism-based inhibitors that form quasi-irreversible binding intermediates (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-1,3,4-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 that overcome some of the limitations of state-of-the-art HDAC6 inhibitors, such as hydroxamic acid-based HDCA6 inhibitors. Isoform-selective inhibitors, rather than pan-HDAC inhibitors, may offer advantages in terms of both therapeutic efficacy and toxicity. In particular, selective inhibition of cytoplasmic HDAC6 can avoid the toxicity resulting from the inhibition of other HDACs.

[0005] The applicant has surprisingly found that the amine compounds of formula (I) described herein, some of which were originally prepared by the applicant as synthetic intermediates, are in fact highly selective HDAC6 inhibitors. The use of these heteroarylamine compounds may also show significant improvements over prior art drugs such as hydroxamates in terms of bioavailability, side effects, pharmacokinetics, and / or water solubility. Furthermore, the applicant has surprisingly found that the amine compounds of formula (I) were able to cross the blood-brain barrier, making these amine compounds suitable candidate substances for the treatment of neurodegenerative diseases involving central nervous system components, such as amyotrophic lateral sclerosis (ALS). [Overview of the project]

[0006] (overview) The present invention relates to a compound for use in the treatment and / or prevention of HDAC6-related diseases; wherein the compound is a compound of formula (I). [ka] or a pharmaceutically acceptable salt and / or solvate thereof; where Y 1 , Y 2 , L and Z 1’ This is as described in the claims or detailed description.

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

[0008] The present invention also relates to a pharmaceutical composition for use in the treatment and / or prevention of HDAC6-related diseases, comprising a compound according to the present invention and at least one pharmaceutically acceptable carrier.

[0009] According to one embodiment, HDAC6-related diseases are selected from inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancer), neurodegenerative diseases (including neuromuscular diseases), pain, neuropathy (including neuromuscular diseases), psychiatric disorders, neurodevelopmental disorders, sleep disorders, and cardiovascular diseases, as well as metabolic or hormonal disorders.

[0010] The present invention also relates to the compound of formula (II). [ka] or relating to pharmaceutically acceptable salts and / or solvates thereof; where Y 1 , Y 2 , L and Z 1’ This is as described in the claims or detailed description.

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

[0012] The present invention also relates to a process for producing compounds according to the present invention, the process comprising the steps of: (i) reacting an amine-containing alkyl chain or heterocycloalkyl with a halo-heterocyclic ring; then (ii) reacting the heterocyclic ring or halo-heterocyclic ring first with an acetylating agent, and optionally subsequently with a halogenating agent, to produce a haloketone; then (iii) reacting the haloketone with a thiol; and optionally (iv) removing at least one protecting group.

[0013] The present invention also relates to compounds selected from the compounds listed in Table 3 herein and their pharmaceutically acceptable salts and / or solvates.

[0014] (definition) In this invention, the following terms have the meanings set forth below unless otherwise specified.

[0015] (chemical definition) For example, when referring to combinations of groups such as "alkylene-heteroaryl," the bond site to the main structure is on the group listed on the left. Therefore, the term "alkylene-cyclil" and its variations (e.g., "alkylene-heteroaryl," "alkylene-heterocyclic," "alkylene-cycloalkyl," "alkylene-aryl," "alkylene-heteroaryl," "alkylene-heterocyclic," and "alkylene-cycloalkyl") refer to a cyclyl group bonded to the main structure via the alkyl moiety. In other words, the bond site is the alkylene group, not the cyclyl group.

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

[0017] "Alkyl" typically refers to a saturated linear or branched hydrocarbon chain containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. In the present invention, alkyl groups can be monovalent or polyvalent (i.e., the "alkylene" group as defined herein is encompassed in the definition of "alkyl"), 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 containing at least one triple bond and typically 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 their isomers, and 2-hexynyl and its isomers.

[0020] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms are replaced by substituents such as alkyl or aryl atoms.

[0021] "Amino" refers to the -NH2 group.

[0022] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbyl group containing at least one aromatic ring. The aryl group may have a single ring (i.e., phenyl), multiple aromatic rings fused together (e.g., naphthyl), or multiple covalently bonded aromatic rings. Typically, the aryl group has 5 to 12 carbon atoms, preferably 6 to 10. The aromatic ring may optionally contain 1 to 2 further rings fused to it (either cycloalkyl, heterocycloalkyl, or heteroaryl). The aryl group is also intended to include partially hydrogenated carbocyclic derivatives listed herein, as long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1- or -2-yl, 4-, 5-, 6- or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthenyl, 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, and 1-, 2-, 3-, 4- or 5-pyrenyl. The preferred aryl group is phenyl.

[0023] When referring to a cyclic group, "bicyclic" means that the cyclic group consists of exactly two fused rings. In a monovalent bicyclic group, the notation "[x,y]" (where x and y are integers) is used herein to indicate that one ring is x-membered, the other is y-membered, and that the bond to the main structure lies on the x-membered ring. "Tricyclic," etc., should be interpreted accordingly.

[0024] "Cyano" refers to the -CN group.

[0025] "Sicryl" refers collectively to the "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl" groups as defined herein.

[0026] "Cycloalkyl" typically refers to a cyclic monovalent alkyl group containing 3 to 11 carbon atoms, preferably 4 to 9 carbon atoms, and more preferably 5 to 7 carbon atoms. This definition includes polycyclic cycloalkyl (e.g., bicyclic) and bridging cycloalkyl structures, which include rings bonded together via one atom ("spiro") or two atoms.

[0027] The "(C x -C y The term ")" means that the group contains x to y carbon atoms, in accordance with common chemistry terminology.

[0028] "Difluoromethyl" refers to the -CHF2 group.

[0029] "Halide," "halo," or "halogen" refers to fluorine, chlorine, bromine, or iodine atoms, usually chlorine or bromine atoms.

[0030] A "heteroalkyl" refers to an alkyl group as defined above, in which one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen, and sulfur. In a heteroalkyl group, the heteroatoms are bonded only to carbon atoms along the alkyl chain; that is, each heteroatom is separated from any other heteroatoms by at least one carbon atom. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. A heteroalkyl group may further contain one or more oxo (=O) groups. A heteroalkyl group is bonded to another group or molecule only via carbon atoms; that is, the bonded atom is not selected from the heteroatoms contained in the heteroalkyl group. If substituted by one or more other groups, the heteroalkyl group may be substituted either via carbon atoms or via heteroatoms (e.g., nitrogen) unless otherwise specified. Non-limiting examples of heteroalkyl groups include alkoxys, ethers and polyethers, secondary amines, tertiary amines, and thioethers.

[0031] A "heteroaryl" refers to an aromatic ring or aromatic ring system containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms, having one or two rings that are fused together or covalently bonded, with at least one ring being aromatic and one or more carbon atoms in one or more of these rings being replaced by oxygen, nitrogen, and / or sulfur atoms. A "heteroaryl" can also be considered an "aryl" group as defined herein, in which at least one carbon atom in the aryl group is replaced by a heteroatom and the resulting molecule is chemically stable. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The aromatic ring may optionally contain one or two further rings (any of which are cycloalkyl, heterocycloalkyl, or aryl) fused thereto. Furthermore, heteroaryls are intended to include partially hydrogenated derivatives of carbocyclic systems listed herein, as long as at least one ring is aromatic.Non-restrictive examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridadinyl, oxazinyl, dioxynyl, thiadinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolidinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-ben Zooxazolyl, 1,2-benzoisoxazolyl, 2,1-benzoisoxazolyl, 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[1,2- Examples include pyridinyl, 6-oxopyridazine-1-(6H)-yl, 2-oxopyridine-1-(2H)-yl, 6-oxopyridazine-1-(6H)-yl, 2-oxopyridine-1-(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, sinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, and 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl.

[0032] "Hypercycloalkyl" typically refers to a cyclic monovalent heteroalkyl group containing 2 to 7 carbon atoms, preferably 3 to 6 carbon atoms, more preferably 4 to 5 carbon atoms. This definition includes polycyclic heterocycloalkyl groups (e.g., bicyclic) and bridging heterocycloalkyl structures, which include rings bonded together via one atom ("spiro") or two atoms. In one embodiment, the heterocycloalkyl group is bonded to another group or molecule via carbon atoms, i.e., the bonded atom is not selected from the heteroatoms contained therein. In one embodiment, the heterocycloalkyl group is bonded to another group or molecule via one of the heteroatoms contained therein. If substituted by one or more other groups, the heterocycloalkyl group may be substituted either via carbon atoms or via heteroatoms (e.g., nitrogen), unless otherwise specified. Non-exclusive examples of heterocycloalkyls include aziridine, pyrrolidine, piperidine, piperazine (also known as "hexahydropyrazine"), morpholine, thiomorpholine, azepane, azocane, octahydro-1H-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 that has a C-(C=O)-C linkage.

[0035] "Oxo" refers to an =O group, that is, a single oxygen atom that is usually double-bonded to a carbon atom.

[0036] "Trifluoromethyl" refers to the -CF3 group.

[0037] (General definition) The term "approximately" is used herein to mean roughly, roughly, around, or nearly. When the term "approximately" precedes a number, it means within 10% above or below the value of that number. When the term "approximately" is used in conjunction with a numerical range, it modifies that range by extending the boundary by 10% above and below the indicated number.

[0038] "Administer" or its variation (e.g., "to administer") means to provide a therapeutic agent (e.g., a compound of the present invention) to a patient whose disease, symptoms, or condition will be treated and / or prevented, either alone or as part of a pharmaceutically acceptable composition.

[0039] A "binding site" or "binding pocket" refers to a specific arrangement of amino acids located on a protein (e.g., HDAC6) to which a compound (e.g., the compound of the present invention) binds. Binding sites often consist of a group of chemiactive surfaces of amino acids and possess specific 3-D structural and charge properties. Similar to epitopes, binding sites can be linear or steric; that is, they may include sequences of amino acids that are not necessarily continuous in the primary structure of the protein.

[0040] The terms “comprise” or its variations (e.g., “comprises,” “comprising”) are used herein in accordance with general patent application drafting terminology. Thus, “comprise,” where the subject matter precedes the components, means that the presence of the components in the subject matter is required (usually as components of a composition), but does not exclude the presence of any further components in that subject matter. Furthermore, any occurrence of “comprise” or its variations herein also includes the narrower expressions “substantially from” or “essentially from,” the even narrower expression “consist of” and its variations (e.g., “consists of,” “consisting of”).

[0041] "HDAC" or "histone deacetylase" refers to a class of enzymes that can remove an acetyl group (O=C-CH3) from the ε-N-acetyllysine amino acid on histones, allowing histones to wrap DNA more tightly and condense chromatin. Gene expression is regulated by histone acetylation and deacetylation, and therefore by HDAC activity. In this invention, HDAC is typically "HDAC6" as defined herein.

[0042] "HDAC-related disease" or "disease associated with HDAC6 function" or its variation (e.g., "HDAC6-related disease") refers to a disease resulting from, caused by, or characterized by, abnormal regulation of at least one HDAC enzyme in a subject, and in particular by increased activity, leading to an abnormal acetylation profile of HDAC substrates (e.g., histones, tubulin, Hsp90, cortactin). In this application, "HDAC-related disease" and "disease associated with HDAC6 function" are synonymous and can be used interchangeably. Typically, HDAC-related diseases are associated, among other things, with alterations in the epigenetic regulation of gene expression and / or cell motility. This definition includes diseases in which the disease is treated and / or prevented by reducing (inhibiting) normal HDAC activity. Typically, HDAC-related diseases can be prevented and / or treated by HDAC inhibition. Non-limiting examples of HDAC-related diseases include neuropathy, neurodegenerative diseases, proliferative disorders (e.g., cancer), metabolic disorders, immunodeficiencies, and inflammatory diseases.

[0043] "HDAC6," "HDAC6 enzyme," or "histone deacetylase subtype 6" refers to the HDAC enzyme encoded by the human HDAC6 gene.

[0044] The "HDAC6 gene" refers to the gene that codes for human HDAC6. The HDAC6 gene is also interchangeably called KIAA0901 or JM21.

[0045] "Human" refers to subjects of both genders at any stage of development, including neonates, infants, children, adolescents, and adults.

[0046] "Patient" refers to an animal, usually a warm-blooded animal, preferably a mammal (such as a mouse, rat, cat, guinea pig, dog, monkey, or human), more preferably a human, that is waiting to receive medical care, is receiving medical care, or is the subject of / going to be the subject of a medical procedure. A patient may also be the subject of preventive care or treatment.

[0047] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and not harmful to the patient to whom it is administered.

[0048] "Pharmaceutically acceptable carrier" refers to an excipient that does not cause harmful, allergic, or other adverse reactions when administered to an animal, preferably a human. This includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. In the case of administration to humans, the preparation should meet the standards of sterility, pyrogenicity, general safety, and purity required by regulatory authorities such as the FDA or EMA.

[0049] "Prevent", "preventing", and "prevention" refer to delaying or interfering with the onset of any one of a disease and / or disorder and / or its associated symptoms, preventing a patient from acquiring a disease or disorder, or reducing the risk that a patient will acquire any one of a disease and / or disorder and / or its associated symptoms. The effect obtained from "preventing" a disease and / or disorder is called "preventive".

[0050] A "prodrug" refers to a pharmaceutically acceptable derivative of a therapeutic agent (e.g., the compound of the present invention) whose in vivo biodegradable product is a therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo to an active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs, particularly alkyl esters, cycloalkyl esters, and aryl esters.

[0051] The phrase "selected from" is used herein, in accordance with general patent application drafting terminology, to introduce a list of elements from which an item is selected. Furthermore, any occurrence of "selected from" herein also includes the expression "selected from a group including or consisting of" and any variations thereof (e.g., "consisting of").

[0052] A "solvate" refers to a molecular complex containing a compound along with one or more molecules of a solvent in a stoichiometric or substoichiometric amount. Typically, the solvent is a pharmaceutically acceptable solvent, such as 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 compounds for therapeutic use and health-related purposes. In particular, therapeutic agents (e.g., compounds of the present invention) may be used for the treatment and / or prevention of diseases, preferably infectious diseases. Active ingredients may also be used to improve the therapeutic activity of another therapeutic agent.

[0054] The "therapeutic effective dose" (in short, the "effective dose") refers to the amount of therapeutic agent (e.g., the compound of the present invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient / animal to which it is administered.

[0055] "To treat," "to treat," and "treatment" refer to alleviating, reducing, or suppressing any disease and / or disorder, and / or any of its associated symptoms, such as an infectious disease.

Best Mode for Carrying Out the Invention

[0056] (Detailed Description) (Compound) (General Formula) The present invention relates to a compound of formula (I) [Chemical Formula] (wherein Y 1 , Y 2 , L and Z 1’ are as defined below in the detailed description) and relates to compounds of

[0057] In the compounds of formula (I) described below in the detailed description, unless otherwise indicated, any alkyl group (which includes alkylene groups) may be "optionally substituted", i.e., each hydrogen atom attached to a carbon atom of the alkyl moiety may be optionally replaced by at least one low molecular weight substituent such as 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 that result in a chemically stable molecule are included in this definition. Usually, the (C1-C6)alkyl groups present in the substituents are not further substituted themselves. Preferred substituted alkyls include, for example, alkyl substituted by one or more fluorine atoms and / or hydroxy such as trifluoromethyl.

[0058] In the detailed description below, in the compounds of formula (I), unless otherwise indicated, any cyclyl group (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group) may be "optionally substituted," that is, each hydrogen atom bonded to the carbon atom of the cyclyl moiety may be optionally replaced by at least one low molecular weight substituent, such as a 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 that result in a chemically stable molecule are included in this definition. Typically, (C1-C6)alkyl groups present in substituents are not further substituted themselves. Preferred substituted cyclyl groups include, for example, cyclyls substituted with one or more fluorine atoms and / or hydroxyls, such as difluorocyclopropyl.

[0059] In the formulas expressed herein, the dotted line ---- represents a bond point to the main molecular structure of the indicated portion.

[0060] (Y 1 (Definition) In the above equation (I), Y 1 Preferably, the following formula (Y 1 -I) [ka] (In the formula, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 Each of them operates independently, CR 7 and selected from N; A 8 , A 9 , A 10 , and A 11is independently selected from C-R 7 and N, provided that A 8 , A 9 , A 10 , or A 11 at least one of which is N; G 1 is selected from C-R 3 and N; G 2 is selected from O and N-R 4 ; and B is selected from O, S, and N-R 5 , provided that A 5 , A 6 , and A 7 when is C-R 7 , B is not S) selected from the group (also referred to as "scaffolds 1 to 16" or "Sc1 to Sc16") is a 9- or 10-membered bicyclic heteroaryl.

[0061] According to a preferred embodiment, Y 1 is preferably the following formula (Y 1 -Ia)

Chemical formula

[0062] Y as defined herein 1 in which R 2 is 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, -OR 15 -(C1-C6)alkylene-OR 15 -O-(C2-C6)alkylene-OR 15 -NR 16 (C2-C6)alkylene-OR 15 -NR 17 R 18 -(C1-C6)alkylene-NR 17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 ​​​​​​​​​​​​​​​​​​​​​​​​​​-SO2-R 15 、 -C(O)-NR 17 R 18 、 -(C1-C6) alkylene-C(O)-NR 17 R 18 、 -O-(C1-C6) alkylene-C(O)-NR 17 R 18 、 -NR 16 -(C1-C6) alkylene-C(O)-NR 17 R 18 、 -NR 16 C(O)-R 15 、 -(C1-C6) alkylene-NR 16 C(O)-R 15 、 -O-(C2-C6) alkylene-NR 16 C(O)-R 15 、 -NR 16 -(C2-C6) alkylene-NR 16 C(O)-R 15 、 -C(O)-R 15 、 -C(O)OR 15 、 -(C1-C6) alkylene-C(O)OR 15 、 -O-(C1-C6) alkylene-C(O)OR 15 、 and -NR 16 -(C1-C6) alkylene-C(O)OR 15 is selected from.

[0063] Y as defined in this specification 1 wherein, R 3 is 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, -OR 15 、 -(C1-C6) alkylene-OR 15 、 -O-(C2-C6) alkylene-OR 15 、 -NR 16 (C2-C6) alkylene-OR​​​​​​17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 , -NR 16 -(C2-C6)Alkylene-NR 17 R 18 -(C1-C6)alkylene-SO2-NR 17 R 18 , -NR 16 -SO2-R 15 -(C1-C6)alkylene-NR 16 -SO2-R 15 -O-(C2-C6)alkylene-NR 16 -SO2-R 15 , -NR 16 -(C2-C6)Alkylene-NR 17 -SO2-R 15 -C(O)-NR 17 R 18 -(C1-C6)alkylene-C(O)-NR 17 R 18 -O-(C1-C6)alkylene-C(O)-NR 17 R 18 , -NR 16 -(C1-C6)alkylene-C(O)-NR 17 R 18 , -NR 16 C(O)-R 15 -(C1-C6)alkylene-NR 16 C(O)-R 15 -O-(C2-C6)alkylene-NR 16 C(O)-R 15 , -NR 16 -(C2-C6)Alkylene-NR 16 C(O)-R 15 , -C(O)-R 15 , -C(O)OR 15 -(C1-C6)alkylene-C(O)OR 15 -O-(C1-C6)alkylene-C(O)OR 15 , and -NR 16 -(C1-C6)alkylene-C(O)OR 15 Selected from.

[0064] Y as defined herein 1 In R 4 These include 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, and -(C1-C6)alkylene-OR 15 -(C1-C6)alkylene-NR 17 R 18 -(C1-C6)alkylene-C(O)-NR 17 R 18 -(C1-C6)alkylene-NR 16 C(O)-R 15 -(C1-C6)alkylene-C(O)OR 15 , and -(C1-C6)alkylene-OC(O)-R 15 Selected from.

[0065] Y as defined herein 1 In R 5 This includes 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-OR 15 -(C1-C6)alkylene-NR 17 R 18 -(C1-C6)alkylene-C(O)-NR 17 R 18 -(C1-C6)alkylene-NR 16 C(O)-R 15 -(C1-C6)alkylene-C(O)OR 15 , and -(C1-C6)alkylene-OC(O)-R 15 Selected from.

[0066] Y as defined herein 1 In R7 This includes 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, -OR 15 ,-(C1-C6)alkylene-OR 15 -O-(C2-C6)alkylene-OR 15 , -NR 16 (C2-C6) Alkilen-OR 15 , -NR 17 R 18 -(C1-C6)alkylene-NR 17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 , -NR 16 -(C2-C6)Alkylene-NR 17 R 18 , -SO-R 15 , -SO2-R 15 -SO2NR 17 R 18 -(C1-C6)alkylene-SO2-NR 17 R 18 , -NR 16 -SO2-R 15 -(C1-C6)alkylene-NR 16 -SO2-R 15 -O-(C2-C6)alkylene-NR 16 -SO2-R 15 , -NR 16 -(C2-C6)Alkylene-NR 17 -SO2-R 15 -C(O)-NR 17 R 18 -(C1-C6)alkylene-C(O)-NR 17 R 18 -O-(C1-C6)alkylene-C(O)-NR 17 R 18 , -NR 16 -(C1-C6)alkylene-C(O)-NR 17 R 18 , -NR 16C(O)-R 15 -(C1-C6)alkylene-NR 16 C(O)-R 15 -O-(C2-C6)alkylene-NR 16 C(O)-R 15 , -NR 16 -(C2-C6)Alkylene-NR 17 C(O)-R 15 , -C(O)-R 15 , -C(O)-OR 15 -(C1-C6)alkylene-C(O)-OR 15 -O-(C1-C6)alkylene-C(O)-OR 15 , -NR 16 -(C1-C6)alkylene-C(O)-OR 15 -OC(O)-R 15 -(C1-C6)alkylene-OC(O)-R 15 -O-(C2-C6)alkylene-OC(O)-R 15 , -NR 16 -(C2-C6)alkylene-OC(O)-R 15 , and -NR 16 -C(O)-OR 15 Selected from.

[0067] Furthermore, Y as defined herein 1 In R 2 , R 3 , R 4 , R 5 , or R 7 Each of the -(C1-C6)alkyl or -(C1-C6)alkylene in is 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 R 2 , R 3 , R 4 , R 5 , or R 7Each of the -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, or heteroaryl groups in the formula is 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] Y as defined herein 1 In R 15 , R 16 , R 17 , and R 18 Each is 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 R 15 , R 16 , R 17 , and R 18 Two groups selected from the above form a ring together, selected from -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, and heteroaryl groups.

[0069] Furthermore, Y as defined herein 1 In R 15 , R 16 , R 17 , or R 18 Each of the -(C1-C6)alkyl or -(C1-C6)alkylene in is 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 R 15 , R16 , R 17 , or R 18 Each of the -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, or heteroaryl groups in the formula is 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, Y as defined herein 1 In:R 2 This includes 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, -OR 15 ,-(C1-C6)alkylene-OR 15 -O-(C2-C6)alkylene-OR 15 , -NR 16 (C2-C6) Alkilen-OR 15 , -NR 17 R 18 -(C1-C6)alkylene-NR 17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 , and -NR 16 -(C2-C6)Alkylene-NR 17 R 18 Selected from; R 3 This includes 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, -OR 15,-(C1-C6)alkylene-OR 15 -O-(C2-C6)alkylene-OR 15 , -NR 16 (C2-C6) Alkilen-OR 15 , -NR 17 R 18 -(C1-C6)alkylene-NR 17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 , and -NR 16 -(C2-C6)Alkylene-NR 17 R 18 Selected from; R 4 This is selected from hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, and -(C1-C6)alkylene-(C3-C7)heterocycloalkyl; R 5 This includes 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-OR 15 , and -(C1-C6)alkylene-NR 17 R 18 Selected from; and R 7 This includes 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, -OR 15 ,-(C1-C6)alkylene-OR 15 -O-(C2-C6)alkylene-OR 15 , -NR 16 (C2-C6) Alkilen-OR 15, -NR 17 R 18 -(C1-C6)alkylene-NR 17 R 18 -O-(C2-C6)alkylene-NR 17 R 18 , and -NR 16 -(C2-C6)Alkylene-NR 17 R 18 Selected from; Here, R 2 , R 3 , R 4 , R 5 , or R 7 Each of the -(C1-C6)alkyl, -(C1-C6)alkylene, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, or heteroaryl in is optionally substituted as defined above; and R 15 , R 16 , R 17 , and R 18 It is defined independently as described above.

[0071] According to one preferred embodiment, Y 1 This is expressed by the following equations (Sc1) and (Sc2) [ka] (In the formula, A 1 ~A 4 , A 6 , A 7 , G 1 , and R 2 (These are independent, as defined above.) It is a 9 or 10-membered bicyclic heteroaryl selected from the following.

[0072] According to one preferred embodiment, Y 1 This is expressed by the following formula (Sc8) [ka] (In the formula, A 8 ~A 11 and G 2(These are independent, as defined above.) It is a 9 or 10-membered bicyclic heteroaryl.

[0073] According to one preferred embodiment, Y 1 This is expressed by the following equations (Sc15) and (Sc16) [ka] (In the formula, A 1 ~A 4 , A 5 ~A 7 , R 2 , and R 3 (These are independent, as defined above.) It is a 9 or 10-membered bicyclic heteroaryl selected from the following.

[0074] One embodiment, Y 1 This is expressed by the following equation (Y 1 -1) group [ka] and the following equation (Y 1 -1a) group [ka] (In the formula, R 2 , R 3 , and R 7 (These are independent, as defined above.) It is a 10-membered bicyclic [6,6] heteroaryl selected from the following.

[0075] One embodiment, Y 1 This is expressed by the following equation (Y 1 -2) group [ka] The following equation (Y 1 -3) group [ka] The following equation (Y 1-4) group [ka] The following equation (Y 1 -5) group [ka] The following equation (Y 1 -6) group [ka] The following equation (Y 1 -6a) group [ka] (In the formula, R 2 , R 3 , R 5 , and R 7 (These are independent, as defined above.) It is a 9-membered bicyclic [6,5] heteroaryl selected from the following.

[0076] One embodiment, Y 1 This is expressed by the following equation (Y 1 -7) group [ka] and the following equation (Y 1 -8) group [ka] (In the formula, A 1 , A 3 , A 3 , A 4 , R 2 , R 4 , and R 7 (These are independent, as defined above.) It is a 9-membered bicyclic [5,6] heteroaryl selected from the following.

[0077] In one preferred embodiment, Y 1 The following formula [ka] (In the formula, R 2 , R 3 , and R 7 (These are independent, as defined above.) It is a 10-membered bicyclic [6,6] heteroaryl.

[0078] In one preferred embodiment, Y 1 The following formula [ka] (In the formula, R 2 , R 3 , R 5 , and R 7 (These are independent, as defined above.) It is a 9-membered bicyclic [6,5] heteroaryl.

[0079] In one preferred embodiment, Y 1 The following formula [ka] (In the formula, R 2 and R 7 (These are independent, as defined above.) It is a 9-membered bicyclic [6,5] heteroaryl.

[0080] In a more preferred embodiment, Y 1The following are selected from 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-yl, 2-(trifluoromethyl)quinazolin-4-yl, 1-(2-methoxyethyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidine-4-yl, 2-(difluoromethyl)-6-methoxypyrido[2,3-d]pyrimidine-4-yl, 2-(trifluoromethyl)quinazolin-4-yl, and 6-methoxy-2-(trifluoromethyl)quinazolin-4-yl.

[0081] In a more preferred embodiment, Y 1These include 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-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]pyrimidine-4-yl, 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidine-4-yl, and 2-(difluoromethyl)-6-methoxypyrid [2,3-d]pyrimidine-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]pyrimidine-4-yl, 2-cyclopropyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-yl, 6-methoxy-2-methylpyrido[2,3-d]pyrimidine-4-yl, 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-yl , 6-Methoxy-2-methyl-1,8-naphthyridine-4-yl, 7-(difluoromethyl)-1,6-naphthyridine-5-yl, 3-Methoxy-7-methyl-1,6-naphthyridine-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-Dimethoxyquinoline-4-yl, 3-Chloro-7-methyl-1,6-naphthyridin-5-yl, 6-Methoxyquinoline-4-yl, 6-Methoxy-2-methylquinoline-4-yl, 6-Chloro-8-fluoro-2-methylquinazoline-4-yl, 6-Chloroquinoline-4-yl, 7-Methoxyquinoline-4-yl, 6-Fluoro-2-methylpyrido[2,3-d]pyrimidine-4-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-5-yl, 7-Methylimidazo[1,2-a]pyrimidine-5-yl, 2-methyl-1,Selected from 8-naphthiridine-4-yl, 6-methoxy-2-methylpyrido[3,4-d]pyrimidine-4-yl, 2-methyl-6-(trifluoromethyl)quinoline-4-yl, 6-methoxy-2-methyl-1,5-naphthiridine-4-yl, (6-methoxy-2-methyl-1,5-naphthiridine-4-yl, 2-methyl-6-(trifluoromethyl)-1,8-naphthiridine-4-yl, 5-fluoro-6-methoxy-2-methylquinazoline-4-yl, 6-(difluoromethoxy)-2-methylquinazoline-4-yl, 2-methyl-6-(trifluoromethoxy)quinazoline-4-yl, and 7-methyl-3-(trifluoromethyl)-1,6-naphthiridine-5-yl.

[0082] One embodiment, Y 1 It is not thieno[2,3-d]pyrimidine-4-yl.

[0083] One embodiment, Y 1 This is not 7H-pyrrolo[2,3-d]pyrimidinyl. In one embodiment, Y 1 It is not 9H-prinyl.

[0084] (Y 2 (Definition) In the above equation (I), Y 2 Preferably, the following formula [ka] (In the formula, R 12 , R 13 , R 14 , and R 25’ Each is 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; Here, R 12 , R 13 , R 14 , or R 25’Each of the -(C1-C6)alkyl groups in the above is optionally substituted with at least one group selected from halogen, cyano, hydroxy, amino, -O-(C1-C6)alkyl, and -N-((C1-C6)alkyl)2. A 5- or 6-membered heteroaryl or 6-membered aryl selected from the group.

[0085] According to one embodiment, Y 2 The following formula [ka] (In the formula, R 13 and R 14 (Each is independent and as defined above.) isn't it.

[0086] According to one embodiment, Y 2 The following formula [ka] (In the formula, R 12 and R 14 (Each is independent and as defined above.) isn't it.

[0087] According to one embodiment, Y 2 The following formula [ka] (In the formula, R 12 (As defined above) isn't it.

[0088] According to one embodiment, Y 2 The following formula [ka] (In the formula, R 13 (As defined above) isn't it.

[0089] According to one embodiment, Y 2 The following formula [ka] (In the formula, R 12 , R 13 , R 14 , and R 25’ (As defined above) It is not selected from (i.e., Y 2 (This is not the six-member Ariel.)

[0090] According to one preferred embodiment, Y 2 The following formula [ka] (In the formula, R 13 and R 14 (Each is independent and as defined above.) Selected from.

[0091] According to one embodiment, R 12 , R 13 , R 14 , and R 25’ Each is independently selected from hydrogen, halogen, cyano, hydroxy, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -CH2-O-(C1-C6)alkyl, and -O-(C1-C6)alkyl; where R 12 , R 13 , R 14 , or R 25’ Each of the -(C1-C6)alkyl groups in is optionally substituted with at least one group selected from halogen, cyano, hydroxy, and -O-(C1-C6)alkyl groups.

[0092] According to one embodiment, R 12 , R 13 , R 14 , or R 25’The compound may optionally contain at least one (C1-C6) haloalkyl group. In one embodiment, the (C1-C6) haloalkyl group is trifluoromethyl (CF3).

[0093] In one embodiment, R 12 , R 13 , R 14 , and R 25’ R is independently selected from hydrogen and (C1-C3) alkyl. In a preferred embodiment, R 12 , R 13 , R 14 , and R 25’ Each of these is hydrogen.

[0094] (Definition of L) In the above equation (I), -L is -(CR 10 R 11 ) n Selected from; here, n is an integer selected from 0, 1, 2, 3, and 4; R 10 and R 11 These are independently selected from hydrogen, halogen, hydroxyl, 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 R 10 and R 11 These, together with the carbon atoms to which they are bonded, form a (C3-C6) cycloalkyl group.

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

[0096] According to one embodiment, R 10 and R11 is independently selected from hydrogen, halogen, hydroxyl, -(C1-C3)alkyl, -(C1-C2)haloalkyl, -(C1-C2)hydroxyalkyl, and -O-(C1-C4)alkyl; or R 10 and R 11 These, together with the carbon atoms to which they are bonded, form a (C3-C6) cycloalkyl group. In one embodiment, R 10 and R 11 R is independently selected from hydrogen, (C1-C3) alkyl, and hydroxyl. In one embodiment, R 10 and R 11 R is independently selected from hydrogen and (C1-C3) alkyl. In one embodiment, R 10 and R 11 R is independently selected from hydrogen and hydroxyl. In a particular embodiment, R 10 and R 11 Each of these is 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] R 10 and R 11 Based on the above definition, L cannot contain a carbonyl group, and in particular, L cannot be -C(O)-, -CH2C(O)-, or -C(O)CH2-.

[0098] (Z 1’ (Definition) In the above equation (I), Z 1’ -NR 23’ R 24’ and selected from -(C3-C7) heterocycloalkyls containing at least one nitrogen atom; Here, Z 1’Each nitrogen atom in the (C3-C7) heterocycloalkyl 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; Z 1’ Each carbon atom of the (C3-C7) heterocycloalkyl in the (C3-C7) heterocycloalkyl 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; Here, Z 1’ Each of the -(C1-C6)alkyl, -(C1-C6)alkylene, -(C3-C7)cycloalkyl, or -(C3-C7)heterocycloalkyl in is optionally substituted with at least one halogen (this definition applies to alkyl, alkylene, cycloalkyl, or heterocycloalkyl present in substituents on both the nitrogen and carbon atoms of the heterocycloalkyl); and Here, Z 1’Each of the aryl or heteroaryl in is optionally substituted with at least one group selected from halogens, CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -O-(C3-C7)cycloalkyl (this definition applies to aryl or heteroaryl present in substituents on both the nitrogen and carbon atoms of the heterocycloalkyl); and R 23’ and R 24’ Each is 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; Here, R 23’ or R 24’ Each of the -(C1-C6)alkyl, -(C1-C6)alkylene, -(C3-C7)cycloalkyl, and -(C3-C7)heterocycloalkyl groups in the above 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 R 23’ or R 24’ Each of the aryl or heteroaryl in 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, Z 1’ is, Z 1’ In the above (C3-C7) heterocycloalkyl, each nitrogen atom is not substituted with -(C1-C6)alkylene-(C3-C7) cycloalkyl, and Z 1’The (C3-C7) heterocycloalkyl in the above is defined as above, except that each carbon atom is not substituted with a -(C1-C6)alkylene-(C3-C7) cycloalkyl.

[0100] According to one embodiment, Z 1’ It may optionally contain at least one -(C1-C6) haloalkyl or -(C3-C7) halocycloalkyl. In one embodiment, Z 1’ The compound may optionally contain at least one (C1-C6) haloalkyl group. In one particular embodiment, the (C1-C6) haloalkyl group is trifluoromethyl (CF3).

[0101] According to one embodiment, Z 1’ is a -(C3-C7) heterocycloalkyl group containing one nitrogen atom, two nitrogen atoms, or one nitrogen atom and one oxygen atom as intraring heteroatoms; where Z 1’ In the (C3-C7) heterocycloalkyl, each nitrogen atom and each carbon atom are optionally substituted as defined above.

[0102] According to one embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ This 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; R 22’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 portion of the (C3-C7) heterocycloalkyl group has at least one R 22’’ It may be arbitrarily substituted by the base; Here, Each R 22’’ These are 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; Here, R 21’ , R 22’ , or R 22’’ Each of the -(C1-C6)alkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, or -(C3-C7)heterocycloalkyl in is optionally substituted with at least one halogen; and Here, R 21’ , R 22’ , or R 22’’Each of the aryl or heteroaryl in the above is optionally substituted with at least one group selected from halogens, CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and O-(C3-C7)cycloalkyl. It is a (C3-C7) heterocycloalkyl selected from the following.

[0103] According to another embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ and R 22’ They are independent, as defined above; and Each carbon atom in the cyclic portion of the (C3-C7) heterocycloalkyl group has at least one R 22’’ It may be arbitrarily substituted by the base; here, each R 22’’ (These are independent, as defined above.) It is a (C3-C7) heterocycloalkyl selected from the following.

[0104] In another manifestation, Z 1’ teeth, The following formula [ka] (In the formula, R 21’ , and R 22’ , and each R 22’’ (These are independent, as defined above.) It is a (C3-C7) heterocycloalkyl selected from the following.

[0105] In another manifestation, Z 1’ The following formula is used to select the correct answer. [ka] (In the formula, R 21’ and R 22’ (As defined above) -(C3-C7) heterocycloalkyl

[0106] According to another embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ It is as defined above; and Each carbon atom in the cyclic portion of the (C3-C7) heterocycloalkyl group has at least one R 22’’ It may be arbitrarily substituted by the base; here, each R 22’’ (These are independent, as defined above.) It is a (C3-C7) heterocycloalkyl group.

[0107] In another preferred embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ It is as defined above; and Each carbon atom in the cyclic portion of the (C3-C7) heterocycloalkyl group has at least one R 22’’ It may be arbitrarily substituted by the base; here, each R 22’’ (These are independent, as defined above.) It is a (C3-C7) heterocycloalkyl group.

[0108] In one embodiment, only one carbon atom in the cyclic portion of the -(C3-C7) heterocycloalkyl group is at least one R 22’’ It is substituted with a group. In one embodiment, each carbon atom in the cyclic portion of the -(C3-C7) heterocycloalkyl is either unsubstituted or has one R group. 22’ or R 22’’ It is either substituted by a single element or by a single element.

[0109] In one embodiment, the carbon atoms in the cyclic portion of the -(C3-C7) heterocycloalkyl group are at least one R 22’’ It is not substituted by the base.

[0110] In one embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ and R 22’ (These are independent, as defined above.) It is a (C3-C7) heterocycloalkyl selected from the following.

[0111] One embodiment, Z 1’ The following formula [ka] (In the formula, R 21’ (As defined above) It is a (C3-C7) heterocycloalkyl group.

[0112] In one particular embodiment, R 21’ R 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 a preferred embodiment, R 21’ The element 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, R 21’R is selected from hydrogen, -(C1-C6)alkyl, and -(C1-C6)alkylene-O-(C1-C6)alkyl. In a preferred embodiment, R 21’ This is selected from hydrogen, -(C1-C3)alkyl, and -(C1-C3)alkylene-O-(C1-C3)alkyl.

[0114] In one particular embodiment, R 22’ R 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, R 21’ The element is selected from hydrogen, fluoro, trifluoromethyl, cyano, hydroxy, and -O-(C1-C3)alkyl.

[0115] In one particular embodiment, R 22’ The elements are hydrogen, halogen, hydroxyl, and -O-(C1-C6)alkyl; preferably selected from hydrogen, fluoro, hydroxyl, and -O-(C1-C3)alkyl.

[0116] According to one preferred embodiment, Z 1’ The 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, Z 1’These include azetidine-3-yl, 1-methylazetidine-3-yl, 3-fluoroazetidine-3-yl, 3-hydroxyazetidine-3-yl, 3-methoxyazetidine-3-yl, 1-methylpiperidine-4-yl, 1-(2-methoxyethyl)azetidine-3-yl, pyrrolidine-3-yl, 3-fluoropyrrolidine-3-yl, 3-hydroxypyrrolidine-3-yl, 3-methoxypyrrolidine-3-yl, morpholinomethyl, 3-methoxy-1-methylpyrrolidine-3-yl, piperidine-4-yl, 4-hydroxypiperidine-4-yl, 4- Cyano-1-methylpiperidine-4-yl, 3-hydroxy-1-methylpyrrolidine-3-yl, 4-methoxypiperidine-4-yl, 4-hydroxy-1-isopropylpiperidine-4-yl, 1-hydroxy-2-(methylamino)ethyl, 1-(2-fluoroethyl)-4-hydroxypiperidine-4-yl, 4-hydroxy-1-methylpiperidine-4-yl, 4-hydroxy-1,3-dimethylpiperidine-4-yl, 1-(cyclopropylmethyl)-4-hydroxypiperidine-4-yl, 4-hydroxy-1-(2-methoxyethyl) Peridine-4-yl, 1-cyclobutyl-4-hydroxypiperidine-4-yl)thiophen-2-yl, 1-cyclopropyl-4-hydroxypiperidine-4-yl, piperazine-1-yl, 3-hydroxy-1-methylpiperidine-4-yl, 4-hydroxy-1-(oxetane-3-yl)piperidine-4-yl, 4-methoxy-1-methylpiperidine-4-yl, 3-hydroxy-1-methylpiperidine-3-yl, morpholine-4-yl, morpholine-2-yl, 4-methylmorpholine-2-yl, 4-methylmorpholine-3-yl, mol Foline-3-yl, 2-aminoethyl, aminomethyl, and N-(methylamino)-methyl, 3-hydroxy-1-methylazetidine-3-yl, 5-(hydroxy(1-methylpiperidine-4-yl)methyl, 3-hydroxy-1-isopropylazetidine-3-yl, 6-oxa-3-azabicyclo[3.2.1]octane-5-yl, 3-methyl-6-oxa-3-azabicyclo[3.2.1]octane-5-yl, 3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-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-methylmorpholine-2-yl, 2-(trifluoromethyl)morpholine-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] Selected from 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(pyrrolizin)-7a(5H)-yl)methyl, and 2-(dimethylamino)-1-hydroxyethyl.

[0117] In a preferred embodiment, Z 1’ The following are 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 a preferred embodiment, Z 1’These include azetidine-3-yl, 1-methylazetidine-3-yl, 3-fluoroazetidine-3-yl, 3-hydroxyazetidine-3-yl, 3-methoxyazetidine-3-yl, 1-(2-methoxyethyl)azetidine-3-yl, pyrrolidine-3-yl, 3-fluoropyrrolidine-3-yl, 3-hydroxypyrrolidine-3-yl, 3-methoxypyrrolidine-3-yl, piperidine-4-yl, 4-H Selected from droxypiperidine-4-yl, piperazine-1-yl, morpholine-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, Z 1’ This is selected from aminoethyl, aminomethyl, and (methylamino)methyl.

[0120] (Further general formula) According to one embodiment, the compound of formula (I) is of formula (II) [ka] (In the formula, Y 1 , Y 2 , and L are independently defined as in equation (I) above; and Z 1’ It is a -(C3-C7) heterocycloalkyl containing at least one nitrogen atom; Here, Z 1’Each nitrogen atom in the (C3-C7) heterocycloalkyl 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; Z 1’ Each carbon atom of the (C3-C7) heterocycloalkyl in the (C3-C7) heterocycloalkyl 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; Here, Z 1’ Each of the -(C1-C6)alkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, or -(C3-C7)heterocycloalkyl in is optionally substituted with at least one halogen (this definition applies to alkyl, alkylene, cycloalkyl, or heterocycloalkyl present in substituents on both the nitrogen and carbon atoms of the heterocycloalkyl); and Here, Z 1’Each of the aryl or heteroaryl in is optionally substituted with at least one group selected from halogens, CN, -(C1-C6)alkyl, -O-(C1-C6)alkyl, and -O-(C3-C7)cycloalkyl (this definition applies to aryl or heteroaryl present in substituents on both the nitrogen and carbon atoms of the heterocycloalkyl); and) It is a compound of or a pharmaceutically acceptable salt and / or solvate thereof.

[0121] In other words, in this application, the compound of formula (II) is Z 1’ However, it is a compound of formula (I) that is a -(C3-C7) heterocycloalkyl containing at least one nitrogen atom as defined in formula (I) above.

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

[0123] According to one embodiment, the compound of formula (I) is of formula (III) [ka] (In the formula, Y 1 , Y 2 , and L are independently defined as in equation (I) above; and Z 1’ -NR 23’ R 24’ And here, R 23’ and R 24’Each is 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; Here, R 23’ or R 24’ Each of the -(C1-C6)alkyl, -(C1-C6)alkylene, -(C3-C7)cycloalkyl, and -(C3-C7)heterocycloalkyl groups in the above 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 R 23’ or R 24’ Each of the aryl or heteroaryl in the above 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. It is a compound of or a pharmaceutically acceptable salt and / or solvate thereof.

[0124] In other words, in this application, the compound of formula (III) is Z 1’ However, -NR as defined in equation (I) above 23’ R 24’ It is a compound of formula (I).

[0125] In one preferred embodiment, a compound of formula (I), particularly a compound of formula (III), is: [Table 1] It is not selected from TIFF2026522613000041.tif233170, TIFF2026522613000042.tif239170, or TIFF2026522613000043.tif77170.

[0126] The compounds listed above in this specification were named using ChemDraw® Professional 22.0 (PerkinElmer).

[0127] In one embodiment, a compound of formula (I), particularly a compound of formula (III), is: [Table 2] It's not something that's selected from a set of options.

[0128] The compounds listed above in this specification 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]pyrimidine-4-ylthio)acetyl)thiophen-2-yl)ethane-1-one.

[0130] (Specific compounds) According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below. (Table 1) [Table 3] TIFF2026522613000046.tif210170TIFF2026522613000047.tif218170TIFF2026522613000048.tif21 9170TIFF2026522613000049.tif228170TIFF2026522613000050.tif200170TIFF2026522613000051.t if232170TIFF2026522613000052.tif214170TIFF2026522613000053.tif233170TIFF20265226130000 54.tif228170TIFF2026522613000055.tif233170TIFF2026522613000056.tif241170TIFF20265226130 00057.tif220170TIFF2026522613000058.tif232170TIFF2026522613000059.tif243170TIFF2026522 613000060.tif215170TIFF2026522613000061.tif241170TIFF2026522613000062.tif240170TIFF202 6522613000063.tif231170TIFF2026522613000064.tif227170TIFF2026522613000065.tif215170TIF F2026522613000066.tif238170TIFF2026522613000067.tif211170TIFF2026522613000068.tif169170

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

[0132] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 2 below. (Table 2) [Table 4] TIFF2026522613000070.tif182170

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

[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 in Table 2 of this specification.

[0135] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 3 below. (Table 3) [Table 5]

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

[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 in Table 3 of this specification. The compounds in Tables 1, 2, and 3 were named using ChemDraw® Professional 22.0 (PerkinElmer).

[0138] (Another compound) All references herein to the compounds of the present invention (e.g., "compounds of formula (I)") include references to their salts—preferably pharmaceutically acceptable salts, solvates, multicomponent complexes, and liquid crystals. All references herein to the compounds of the present invention include references to their polymorphs and crystal habits. All references to the compounds of the present invention include references to their pharmaceutically acceptable prodrugs. All references to the compounds of the present invention include references to isotope-labeled compounds, including deuterated compounds.

[0139] The compounds of the present invention (e.g., "compound of formula (I)") and its subformulas may contain at least one chiral center and therefore may exist in different stereoisomer forms. Accordingly, all references to the compounds of the present invention include references to all possible stereoisomers and include not only racemic compounds but also individual enantiomers and their non-racemic mixtures. If the compound is desired as a single enantiomer, such a single enantiomer may be obtained by stereospecific synthesis, resolution of the final product or any convenient intermediate, or by chiral chromatography, each of which is known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art.

[0140] The compounds of the present invention (for example, "compound of formula (I)") may be in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include acid addition salts and base salts thereof. Preferred acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipine, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionic acid. Examples include salts, lactates, malates, maleates, malons, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, and xinafoates. Preferred base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi salts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. If a compound contains acidic and basic groups, it may also form internal salts, and such compounds are within the scope of the present invention. If a compound contains a hydrogen-donating heteroatom (e.g., NH), the present invention also covers salts and / or isomers formed by the transfer of such hydrogen atoms to the basic group or atom within the molecule.Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of the following methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid- or base-unstable protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid; and / or (iv) by converting a salt of the compound to another salt by reaction with a suitable acid or by a suitable ion-exchange column. All of these reactions are usually carried out in solution. The salts may precipitate from the solution and be collected by filtration, or recovered by evaporation of the solvent. The degree of ionization in the salts can vary from fully ionized to almost unionized.

[0141] (Manufacturing process) The present invention also relates to a process for producing the compounds of the present invention as described herein. According to one embodiment, the process comprises the following steps (i-iv): (i) reacting an amine alkyl chain or heterocycloalkyl with a halo-heterocyclic ring; then (ii) reacting the heterocyclic ring or halo-heterocyclic ring first with an acetylating agent, and optionally subsequently with a halogenating agent, to produce a halo ketone; then (iii) reacting the halo ketone with a thiol; and optionally (iv) removing at least one protecting group.

[0142] (Pharmaceutical composition) The present invention also relates to a pharmaceutical composition comprising the compounds of the present invention described herein and at least one pharmaceutically acceptable carrier.

[0143] According to one embodiment, the pharmaceutical composition does not contain any therapeutic agent other than the compound of the present invention. According to another embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent. In one embodiment, the at least one other therapeutic agent is selected from therapeutic agents known in the art for treating inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neuropathy, psychiatric disorders, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, lung diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and / or idiopathic diseases.

[0144] The compounds of the present invention can be formulated alone or together into suitable drug unit formulations containing a conventionally non-toxic, pharmaceutically acceptable carrier, adjuvant, and vehicle suitable for each route of administration.

[0145] (Medical use and treatment methods) The present invention also relates to the compounds of the present invention described herein, or to the pharmaceutical compositions of the present invention described herein, for use as pharmaceuticals.

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

[0147] The present invention also relates to a method for inhibiting the HDAC6 enzyme. According to one embodiment, inhibition of the HDAC6 enzyme treats and / or prevents HDAC6-related diseases. According to one embodiment, the method comprises administering a therapeutically effective amount of a compound of the present invention described herein or a pharmaceutical composition of the present invention described herein to a subject in need thereof.

[0148] The present invention also relates to a method for treating and / or preventing HDAC6-related diseases, comprising the step of administering a therapeutically effective amount of the compounds or pharmaceutical compositions of the present invention described herein to a subject in need thereof. The present invention also relates to the use of the compounds or pharmaceutical compositions of the present invention described herein in the manufacture of a medicament for the treatment and / or prevention of HDAC6-related diseases. The present invention also relates to the use of the compounds or pharmaceutical compositions of the present invention described herein in the treatment and / or prevention of HDAC6-related diseases.

[0149] Advantageously, the compounds of the present invention exhibit superior inhibitory activity against HDAC enzymes (e.g., class II HDAC enzymes, preferably HDAC6 enzymes) compared to state-of-the-art compounds for treating and / or preventing HDAC-related diseases. Furthermore, the compounds of the present invention exhibit lower toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, hematological toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) to HDAC enzymes (e.g., class II HDAC enzymes, preferably HDAC6 enzymes) compared to state-of-the-art compounds for treating and / or preventing HDAC-related diseases. In particular, the compounds of the present invention exhibit low genotoxicity.

[0150] According to one embodiment, HDAC6-related diseases are selected from or include the group comprising inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases (including neuromuscular diseases), pain, neuropathy (including neuromuscular diseases), psychiatric disorders, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, lung diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. According to one embodiment, HDAC6-related diseases are selected from or include the group comprising inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases (e.g., cancer), pain, neuropathy, psychiatric disorders, neurodevelopmental disorders, sleep disorders, and cardiovascular diseases. According to one embodiment, HDAC6-related diseases are selected from or include the group comprising proliferative diseases (e.g., cancer), neurodegenerative diseases, neuropathy, and cardiovascular diseases. Neurodegenerative diseases include neuromuscular diseases. Neuroopathy includes neuromuscular diseases.

[0151] The following are various references demonstrating that inhibition of HDAC6 has therapeutic and / or preventive effects on a given disease class. [Table 6] TIFF2026522613000073.tif216170TIFF2026522613000074.tif197170

[0152] According to one embodiment, HDAC6-related diseases include, for example, inflammatory diseases such as acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. In one embodiment, the inflammatory disease is selected from or includes the group comprising acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0153] According to one embodiment, HDAC6-related diseases are autoimmune diseases such as arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjögren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman disease, ankylosing spondyloarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type 1 diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, dermatitis, radiation dermatitis, and primary biliary cirrhosis. In one embodiment, the autoimmune disease includes or is selected from the group comprising arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjögren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman disease, ankylosing spondyloarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type 1 diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, dermatitis, radiation dermatitis, and primary biliary cirrhosis.

[0154] According to one embodiment, HDAC6-related diseases include, for example, cancer, malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, angiogenesis, cachexia, metastatic breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, or gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., ductal carcinoma), and gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, or adenosquamous carcinoma). Breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, or low-grade ovarian tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone-dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic cholangiocarcinoma), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the kidney, or transitional cell carcinoma of the ureter), uterine cancer, brain tumors (e.g., pineal astrocytoma, pilosynoblastoma) These include cellular astrocytoma, diffuse astrocytoma, or anaplastic astrocytoma, melanoma, sarcoma, bladder cancer, hematological cancers, multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, gestational trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, These are proliferative disorders including Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disorders, pancreatic endocrine tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary origin, leukemia (e.g., acute leukemia (e.g., acute lymphoblastic leukemia or acute myeloid leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myeloid leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor), and myelofibrosis.In one embodiment, proliferative disorders, such as cancer, include malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastatic breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, or gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, or adenosquamous carcinoma), and breast cancer (e.g., invasive breast cancer). (e.g., ductal carcinoma, non-invasive ductal carcinoma, or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, or low-grade ovarian tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone-dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic cholangiocarcinoma), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the kidney, or transitional cell carcinoma of the ureter), uterine cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma) These include melanoma, sarcoma, bladder cancer, hematological cancers, multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, gestational trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, and adult T cell The following are included, or selected from the group comprising, leukemia, chronic myeloproliferative disorders, pancreatic endocrine tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary origin, leukemia (e.g., acute leukemia (e.g., acute lymphoblastic leukemia or acute myeloid leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myeloid leukemia)), myelodysplastic syndromes, uterine sarcomas (e.g., mixed mesodermal tumors, uterine leiomyosarcoma, or endometrial stromal tumors), and myelofibrosis. In a particular embodiment, the proliferative disorder is cancer. In a particular embodiment, cancer includes, or is selected from the group comprising, malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer, and Hodgkin's disease.

[0155] According to one embodiment, HDAC6-related diseases include, for example, Alzheimer's disease, Alzheimer's type dementia, senile Alzheimer's type dementia, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognitive impairment, Huntington's disease, multiple infarct dementia, frontotemporal dementia, frontotemporal dementia, Pick's disease, Parkinson's type dementia, Niemann-Pick syndrome, Down syndrome, vascular dementia, post-encephalitis parkinsonism, Lewy body dementia, Rubinstein-Taybe syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurodevelopmental disorders (MND), Creutzfeldt syndrome, and other neurodegenerative diseases. In one embodiment, the neurodegenerative disease is selected from or includes Alzheimer's disease, Alzheimer's type dementia, Alzheimer's type senile dementia, Parkinson's disease, muscular dystrophy, dementia-associated Parkinson's disease, senile dementia, age-related cognitive impairment, Huntington's disease, multiple infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinsonian dementia, Niemann-Pick syndrome, Down syndrome, vascular dementia, post-encephalitis parkinsonism, Lewy body dementia, Rubinstein-Taybe syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neuron developmental disorders (MND), and Creutzfeldt's disease. In a particular embodiment, the neurodegenerative disease includes or is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down syndrome, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[0156] According to one embodiment, HDAC6-related diseases include, for example, pain, cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, postoperative pain (e.g., postoperative incision pain, deep pain, visceral pain, or chronic pain), muscle pain (e.g., muscle pain or stiff shoulders associated with chronic pain disorders), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, tension headache, fever-associated headache, or hypertension-associated headache), visceral pain (e.g., cardiac pain, angina, abdominal pain, kidney pain, urinary tract pain, or bladder pain), obstetric and gynecological pain (ovulation pain, dysmenorrhea, labor pains), neuropathic pain (e.g., herniated disc, radiculopathy, postherpetic neuralgia, trigeminal neuralgia, or lower back pain), migraine, stress headache, tension headache, muscle spasms, irritable bowel syndrome, and other pains (including central or peripheral pain). In one embodiment, pain includes or is selected from the group consisting of pain, cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, postoperative pain (e.g., postoperative incision pain, deep pain, visceral pain, or chronic pain), myalgia (e.g., myalgia or stiff shoulders associated with chronic pain disorders), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, tension headache, headache associated with fever, or headache associated with hypertension), visceral pain (e.g., cardiac pain, angina, abdominal pain, kidney pain, urinary tract pain, or bladder pain), obstetric and gynecological pain (e.g., ovulation pain, dysmenorrhea, or labor pains), neuropathic pain (e.g., herniated disc, radiculopathy, postherpetic neuralgia, trigeminal neuralgia, or lower back pain), migraine, stress headache, tension headache, muscle spasms, and irritable bowel syndrome.

[0157] According to one embodiment, HDAC6-related diseases include, for example, demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory autonomic neuropathy, or familial amyloid polyneuropathy), drug-induced peripheral neuropathy (CIPN) and associated neurological symptoms (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, injury-related neuropathy (e.g., traumatic brain injury or stroke), and other neuropathy (including central or peripheral neuropathy). Anticancer drugs that are likely to cause neuropathy include taxanes (e.g., paclitaxel (Taxol)), vinca alkaloids (e.g., vincristine), platinum-based drugs (e.g., cisplatin, carboplatin, or oxaliplatin), or other molecularly targeted drugs (e.g., bortezomib). In one embodiment, the neuropathy includes or is selected from the group consisting of demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barré syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory autonomic neuropathy, or familial amyloid polyneuropathy), drug-induced peripheral neuropathy (CIPN) and associated neurological symptoms (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, and injury-related neuropathy (e.g., traumatic brain injury or stroke).

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

[0159] According to one embodiment, HDAC6-related disorders are psychiatric disorders such as depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depressive symptoms, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms, or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorders, mania, anxiety disorders, generalized anxiety disorder, anxiety syndromes, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymia, affective disorders (e.g., seasonal affective disorder), phobias, social phobias, neuroses, chronic fatigue syndrome, epilepsy, cyclothymic disorder, intoxication, anorexia nervosa, eating disorders, anorexia nervosa, bulimia nervosa or other eating disorders, drug addiction, drug phobia, drug addiction. In one embodiment, psychiatric disorders include or are selected from the group consisting of depression, major depressive disorder, bipolar depression, psychotic major depressive disorder, refractory major depressive disorder, treatment-resistant depression, depressive symptoms, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms, or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorders, mania, anxiety disorders, generalized anxiety disorder, anxiety syndromes, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymia, affective disorders (e.g., seasonal affective disorder), phobias, social phobias, neuroses, chronic fatigue syndrome, epilepsy, cyclothymic disorder, intoxication, anorexia nervosa, eating disorders, anorexia nervosa, bulimia nervosa or other eating disorders, drug addiction, drug phobias, and drug addiction.

[0160] According to one embodiment, HDAC6-related disorders are neurodevelopmental disorders such as Tourette syndrome, autism, autism spectrum disorder, fragile X syndrome, Rett syndrome, and attention-deficit hyperactivity disorder (ADHD). In one embodiment, the neurodevelopmental disorder includes or is selected from the group consisting of Tourette syndrome, autism, autism spectrum disorder, fragile X syndrome, Rett syndrome, and attention-deficit hyperactivity disorder (ADHD).

[0161] According to one embodiment, HDAC6-related disorders include, for example, endogenous sleep disorders (e.g., psychophysiological insomnia), exogenous sleep disorders, circadian rhythm disorders (e.g., jet lag syndrome, shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24-hour sleep-wake cycle), parasomnias, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, or anxiety disorders), stress, insomnia, insomnia neurosis, sleep apnea syndrome, and other sleep disorders. In one embodiment, sleep disorders include or are selected from the group consisting of endogenous sleep disorders (e.g., psychophysiological insomnia), exogenous sleep disorders, circadian rhythm disorders (e.g., jet lag syndrome, shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24-hour sleep-wake), parasomnias, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, or anxiety disorders), stress, insomnia, insomnia neurosis, and sleep apnea syndrome.

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

[0163] According to one embodiment, HDAC6-related disorders include, for example, addiction-related disorders such as alcohol dependence, alcohol abuse, alcoholic amnesia, alcoholic delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol intoxication, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, and drug withdrawal. In one embodiment, addiction-related disorders include or are selected from the group consisting of alcohol dependence, alcohol abuse, alcoholic amnesia, alcoholic delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol intoxication, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, and drug withdrawal.

[0164] According to one embodiment, HDAC6-related disorders include, for example, gastrointestinal disorders such as peptic ulcers, stress-induced gastrointestinal disorders, stress-induced vomiting, peptic ulcers, diarrhea, constipation, or postoperative ileus. In one embodiment, the gastrointestinal disorder includes or is selected from the group consisting of peptic ulcers, stress-induced gastrointestinal disorders, stress-induced vomiting, peptic ulcers, diarrhea, constipation, ileus, and postoperative ileus.

[0165] According to one embodiment, HDAC6-related diseases are, for example, lung diseases such as hyperventilation, bronchial asthma, and sleep apnea. In one embodiment, the lung disease includes or is selected from the group consisting of hyperventilation, bronchial asthma, and sleep apnea.

[0166] According to one embodiment, HDAC6-related diseases are metabolic or hormonal disorders such as obesity, diabetes, acromegaly, infertility, and metabolic syndrome. In one embodiment, the metabolic or hormonal disorder includes or is selected from the group consisting of obesity, diabetes, acromegaly, infertility, and metabolic syndrome.

[0167] According to one embodiment, HDAC6-related diseases are immune disorders such as allergic diseases, immunodeficiency syndromes caused by HIV infection, and immunodeficiency syndromes caused by stress. In one embodiment, the immune disorders include or are selected from the group consisting of immunodeficiency syndromes caused by HIV infection and immunodeficiency syndromes caused by stress.

[0168] According to one embodiment, HDAC6-related diseases are age-related diseases such as alopecia, glaucoma, impotence, menopausal symptoms, incontinence, and osteoporosis. In one embodiment, age-related diseases include or are selected from the group consisting of alopecia, glaucoma, impotence, menopausal symptoms, incontinence, and osteoporosis.

[0169] According to one embodiment, HDAC6-related diseases are idiopathic diseases such as Meniere's disease and sudden infant death syndrome. In one embodiment, the idiopathic disease is Meniere's disease or sudden infant death syndrome.

[0170] The compounds or pharmaceutical compositions of the present invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, intraventricular (ICV), intracisional injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical administration route. In the treatment and / or prevention of infectious diseases, appropriate dosage levels may be about 0.01 to 500 mg / kg of patient body weight / day (mg / kg / day), which can be administered as a single or multiple dose. Typically, dosage levels are about 0.1 to about 250 mg / kg / day, preferably about 0.5 to about 100 mg / kg / day, and more preferably about 2.5 to about 20 mg / kg / day. The compounds can be administered 1 to 4 times a day, preferably in a regimen of 1 or 2 times a day. However, it will be understood that the specific dose levels and frequency of administration for any particular patient may vary considerably and will depend on a variety of factors, including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, rate of excretion, drug combinations, severity of the particular disease, and the treatment the host is receiving.

[0171] Advantageously, the compounds of the present invention are more selective to at least one HDAC other than HDAC6, preferably to at least one class II HDAC other than HDAC6, more preferably to any class II HDAC other than HDAC6, and even more preferably to HDACs other than HDAC6. Particularly advantageous, the compounds of the present invention are more selective to HDAC1. Particularly advantageous, the compounds of the present invention are more selective to HDAC10. Selectivity is strongly related to avoiding the side effects of HDAC inhibitors.

[0172] (kit) The present invention also relates to a compound of the present invention as described herein, or a pharmaceutical composition of the present invention as described herein, and a kit comprising means for administering the compound or pharmaceutical composition.

[0173] Means for administering compounds or pharmaceutical compositions are well known in the art and can be specified by those skilled in the art depending on the desired route of administration. [Examples]

[0174] (Examples) The present invention will be further explained by the following examples.

[0175] (Example 1: Compound Synthesis) Compounds (1) to (190) of formula (I) shown in Tables 1, 2, and / or 3 above were prepared as described below.

[0176] (Common synthesis method) The compounds according to the present invention, in particular the compound of formula (I), can be prepared by methods known to those skilled in the art of organic synthesis or by using the following synthetic schemes. It is understood that in all of the following schemes, protecting groups of sensitive or reactive groups are used as necessary, in accordance with general principles of organic chemistry. The protecting groups are handled according to standard methods (see TW Green and PGM Wuts, *Protecting Groups in Organic Synthesis*, 1991, John Wiley & Sons). These groups are then removed at a convenient stage of the synthesis using methods readily apparent to those skilled in the art. 1 or Y 2 Many heterocyclic compounds of formula (I) in which is a heteroaryl compound can be prepared using synthetic routes well known in the art (AR Katrizky and CW Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0177] The HDAC6 inhibitors disclosed in this invention are prepared using the following synthetic scheme. Specific conditions for carrying out these reactions are provided in the detailed examples. While the following synthetic schemes represent exemplary approaches to the compounds of the present invention, these routes should not be construed as the only possible synthetic routes to the compounds of the present invention.

[0178] L is a direct bond, and Z 1’ However, for example, it represents a cyclic amine such as pyrrolidine, and Y 1 and Y 2 However, as defined above, the compound of formula (I) is as shown in Scheme 1 (Method 1): [ka] It can also be obtained through [another method].

[0179] Protected cyclic amine T-1 can be commercially available or synthesized by those skilled in organic chemistry using various methods described in the literature. Compound T-1 is reacted with phenyltrifluimide, N-(5-chloropyridine-2-yl)-1,1,1-trifluoro-N-trifluoromethylsulfonyl)methanesulfonamide, or trifluoromethanesulfonic anhydride at a suitable temperature in the presence of a suitable base (e.g., LiHMDS) and a solvent (e.g., THF) to obtain X 1However, a triflate enol ether T-2, which is an OSO2CF3 group, can be provided (Step 1). Intermediate ketone T-5 can be provided by a Suzuki cross-coupling reaction of triflate T-3 with a boronic acid or boronic ester of formula T-4 in a solvent (e.g., DMF) at a suitable temperature in the presence of a catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., Cs2CO3) (Step 2). The boronic acid or boronic ester of formula T-4 may be commercially available or may be synthesized by those skilled in organic chemistry using various methods described in the literature. The double bond of the cyclic amine intermediate T-5 can then be reduced by hydrogenation with H2 in a solvent (e.g., MeOH) in the presence of a catalyst (e.g., Pd / C or Pd(OH)2) to provide the corresponding saturated amine intermediate T-6 (Step 3). Ketone T-6 is involved in a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at an appropriate temperature, X 2 However, for example, a halogen such as bromide, halo ketone T-7 can be provided (step 4). Then, halo ketone T-7 is heated in a solvent (e.g., DMF or ACN) at a suitable temperature in the presence of a base (e.g., MeONa or K2CO3) to form formula Y 1 -SH can be reacted with a thiol heteroaryl derivative to provide a heteroaryl intermediate T-8 (step 5). Heteroaryl Y 1 -SH is commercially available or known to those skilled in the art, for example, by using Lawson's reagent or P2S5 reagent in a solvent (e.g., toluene) at an appropriate temperature, to obtain the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1-OH can be commercially available or prepared by methods known to those skilled in the art. The protected amine T-8 can be deprotected in an acidic, neutral, or basic medium depending on the selection of the protecting group, for example, in an acidic medium to remove the Boc-protecting group using formic acid or an aqueous solution of HCl, to provide the corresponding amine T-9 (step 6). Some amine T-9 can be treated as compounds of formula (I), and other amine T-9 can be further alkylated using a suitable alkylating agent such as formaldehyde or 2-methoxyethanal in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, for example, in a suitable solvent such as DCM, at a suitable temperature such as 0°C to room temperature (step 7), to provide the N-alkylated amine of formula (I).

[0180] L is a direct bond, and Z 1’ However, for example, it represents a cyclic amine such as azetidine, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in Scheme 2 (Method 2): [ka] It can also be obtained through [another method].

[0181] Halide T-10 can be commercially available or synthesized by those skilled in the art using various methods described in the literature. Intermediate T-11 can be prepared by reacting intermediate T-10 with a suitable metallating agent, such as zinc metal and catalyst I2, and then reacting the resulting organometallic compound with a suitable acylated (hetero)aromatic halide T-33, such as 2-bromo-5-acetylthiophene, in a suitable solvent, such as toluene, in the presence of a suitable catalyst, such as Pd2(dba)3 / S-Phos, at a suitable temperature, such as 15°C. Compound T-33 can be commercially available or prepared by methods known to those skilled in the art. The acetyl group of intermediate T-11 can be halogenated using a suitable halogenating agent, such as tetrabutylammonium tribromide, in a suitable solvent, such as DCM / MeOH, at a suitable temperature, such as 20°C, to provide halo ketone T-12 (step 2). The halo of intermediate T-12 is heated in a solvent (e.g., DMF or ACN) at a suitable temperature in the presence of a suitable base (e.g., MeONa or K2CO3) and a suitable formula Y 1 By substituting with a thiol of -SH, a heteroaryl intermediate T-13 can be provided (step 3). Heteroaryl Y 1 -SH is commercially available or known to those skilled in the art, for example, by using Lawson's reagent or P2S5 reagent in a solvent (e.g., toluene) at an appropriate temperature to obtain the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1-OH can be commercially available or prepared by methods known to those skilled in the art. The protected amine T-13 can be deprotected in an acidic, neutral, or basic medium depending on the selection of the protecting group, for example, in an acidic medium to remove the Boc-protecting group using formic acid or an aqueous solution of HCl, to provide the corresponding amine T-14 (Step 4). Some amine T-14 can be treated as compounds of formula (I), and other amine T-14 can be further alkylated using a suitable alkylating agent such as formaldehyde or 2-methoxyethanal in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, for example, in a suitable solvent such as DCM, at a suitable temperature such as 0°C to room temperature, for example (Step 5), to provide an N-alkylated amine of formula (I).

[0182] L is a direct bond, and Z 1’ However, for example, it represents a cyclic amine such as azetidine, pyrrolidine, or piperidine, and Y 1 and Y 2 However, as defined above, the compound of formula (I) is as shown in Scheme 3 (Method 3): [ka] It can also be obtained through [another method].

[0183] Protected cyclic amine T-15 can be commercially available or synthesized by those skilled in organic chemistry using various methods described in the literature. The keto functional group in compound T-15 can be converted to the intermediate of formula T-17 by reaction with the bis-halogenated(hetero)aryl group after the most reactive halogen of the bis-halogenated(hetero)aryl group has been converted to an organometallic compound using a suitable metallating reagent such as n-butyllithium in a suitable solvent such as THF at a suitable temperature such as -78°C (Step 1). Alternatively, compound T-15 can be converted to the intermediate of formula T-16 by reaction with the mono-halogenated(hetero)aryl group after the halogen of the mono-halogenated(hetero)aryl group has been converted to an organometallic compound using a suitable metallating reagent such as n-butyllithium in a suitable solvent such as THF at a suitable temperature such as -78°C (Step 2). In the next step, intermediate T-16 can be halogenated in a suitable solvent such as acetonitrile at a suitable temperature such as room temperature using a suitable halogenating reagent such as N-bromosuccinimide together with a catalyst such as N,N-dimethylaminopyridine to provide intermediate T-17 (Step 3). Intermediate T-17 can be acetylated in a suitable solvent such as toluene at a suitable temperature such as 120°C in the presence of a suitable catalyst such as Pd(PPh3)4, and then work-up using a suitable enol ether deprotecting agent such as 0.5M aqueous HCl at a suitable temperature such as room temperature to provide intermediate T-18 (Step 4). The acetyl group of intermediate T-18 can be halogenated in a suitable solvent such as DCM / MeOH or SiO / CHCl3 at a suitable temperature such as room temperature or 85°C using a suitable reagent such as tetrabutylammonium tribromide (TBATB), trimethylphenylammonium tribromide, or CuBr2 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 ethoxyvinyl tributyltin, in a suitable solvent, such as 1,4-dioxane, in the presence of a suitable catalyst, such as Pd(PPh3)2Cl2, at a suitable temperature, such as 90°C, and then involving the resulting enol ether in a subsequent halogenation reaction using a suitable halogenating reagent, such as N-bromosuccinimide, in a suitable solvent, such as THF / water, at a suitable temperature, such as room temperature (step 6). The halogen in intermediate T-19 can be obtained by reacting it with a suitable compound of formula Y, such as NaOMe or K2CO3, in a suitable solvent, such as DMF or ACN, at a suitable temperature, such as room temperature or 50°C. 1 -The thiol of SH can be further reacted to provide intermediate T-20 (step 8). Heteroaryl Y 1 -SH is commercially available or known to those skilled in the art, for example, by using Lawson's reagent or P2S5 reagent in a solvent (e.g., toluene) at an appropriate temperature to obtain the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1 -OH can be commercially available or prepared by methods known to those skilled in the art. The protected amine T-20 can be deprotected in an acidic, neutral, or basic medium depending on the selection of the protecting group, for example, in an acidic medium to remove the Boc-protecting group using formic acid or an aqueous solution of HCl, to provide the corresponding amine T-21 (step 9). Some amine T-21 can be treated as compounds of formula (I), and other amine T-21 can be further alkylated using a suitable alkylating agent such as formaldehyde or 2-methoxyethanal in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, for example, in a suitable solvent such as DCM, at a suitable temperature such as 0°C to room temperature (step 10), to provide an N-alkylated amine of formula (I).

[0184] Furthermore, the intermediate of formula T-17 can be treated with a suitable deoxygenating fluorinating agent such as diethylaminosulfurtrifluoride (DAST) in a suitable solvent such as DCM, at a suitable temperature such as 0°C, to obtain R 1 However, it may be converted to an intermediate of formula T-22 which is a fluoro(F) atom (step 7). Alternatively, the intermediate of formula T-17 may be treated with a suitable methylating agent such as methyl iodide, for example, in the presence of a suitable base such as sodium hydride, for example, in a suitable solvent such as THF, for example, at a suitable temperature such as room temperature, for example, to R 1 However, it may be converted to an intermediate of formula T-22, which is a methoxy (OMe) group. Furthermore, R 1 However, an intermediate of formula T-22, which is a fluoro (F) atom or a methoxy (OMe) group, can be converted to a compound of formula (I) using steps 4, 5, 6, 8, 9, and 10 described herein above.

[0185] Also, Y 2 However, for example, it represents a heterocyclic ring bonded by N to an amine-containing heterocycloalkyl such as pyrazole, and Y 1 However, the compound of formula (I), as defined above, can also be obtained by scheme 4 (method 4). [ka]

[0186] Protected cyclic amine T-28 and 1-ethanone-substituted NH heteroaromatic ring T-27 can be synthesized by those skilled in organic chemistry using various commercially available or literature-described methods. The NH functional group of T-27 can be N-alkylated to the intermediate of formula T-28 using a suitable reagent such as diisopropyl azodicarboxylic acid (DIAD) and triphenylphosphine, for example, in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as 20°C (Step 1). Furthermore, the acetyl group of intermediate T-29 can be halogenated using a suitable reagent such as tetrabutylammonium tribromide (TBATB), trimethylphenylammonium tribromide, or CuBr2, in a suitable solvent such as DCM / MeOH or siRNA / CHCl3, at a suitable temperature such as room temperature or 85°C, for example, to provide intermediate T-30 (Step 2). Halogen X in intermediate T-30 1 For example, in the presence of a suitable base such as NaOMe or K2CO3, in a suitable solvent such as DMF or ACN, at a suitable temperature such as room temperature or 50°C, formula Y 1 -SH can be further reacted with a suitable thiol to provide intermediate T-31 (step 3). Heteroaryl Y 1 -SH is commercially available or obtained by methods known to those skilled in the art, for example, using Lawson's reagent or P2S5 reagent in a solvent (e.g., toluene) at an appropriate temperature, to obtain the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1-OH can be commercially available or prepared by methods known to those skilled in the art. The protected amine T-31 can be deprotected in an acidic, neutral, or basic medium depending on the selection of the protecting group, for example, in an acidic medium to remove the Boc-protecting group using formic acid or an aqueous solution of HCl, to provide the corresponding amine T-32 (Step 4). Some amine T-32 can be treated as compounds of formula (I), and other amine T-32 can be further alkylated using a suitable alkylating agent such as formaldehyde or 2-methoxyethanal in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, for example, in a suitable solvent such as DCM, at a suitable temperature such as 0°C to room temperature, for example (Step 5), to provide an N-alkylated amine of formula (I).

[0187] Furthermore, L is a direct bond, and Z 1’ However, Y 2 The amine (that W) that is bonded to it 1 represents (substituted) carbon, (substituted) nitrogen, or O, and Y 1 and Y 2 However, the compound of formula (I), as defined above, is also subject to the following scheme 5 (method 5): [ka] It can be obtained through [method].

[0188] X 1 However, for example, a suitable halogen such as bromo, and Y 2 However, intermediate T-33, which is a heteroaryl such as thiazole, can be commercially obtained or prepared under conditions known in the art. Halo X on intermediate T-33 1For example, intermediate T-34 can be provided by substituting it with a suitable amine, such as tert-butylpiperazine-1-carboxylate, in the presence of a suitable base such as K2CO3, in a suitable solvent such as DMF, at a suitable temperature such as 85°C (Step 1). Furthermore, intermediate T-35 can be provided by halogenating the acetyl group of intermediate T-34 using a suitable reagent such as tetrabutylammonium tribromide (TBATB), trimethylphenylammonium tribromide, or CuBr2, in a suitable solvent such as DCM / MeOH or siRNA / CHCl3, at a suitable temperature such as room temperature or 85°C (Step 2). Furthermore, halogen X in intermediate T-35 2 For example, in the presence of a suitable base such as NaOMe or K2CO3, in a suitable solvent such as DMF or ACN, at a suitable temperature such as room temperature or 50°C, a suitable formula Y 1 -It can be reacted with a thiol of SH to provide intermediate T-36 (step 3). Heteroaryl Y 1 -SH is commercially available or known to those skilled in the art, for example, by using Lawson's reagent or P2S5 reagent in a solvent (e.g., toluene) at an appropriate temperature to obtain the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1 -OH can be commercially available or prepared by methods known to those skilled in the art. 1 However, the intermediate of formula T-36, which is a protected amine, can be N-deprotected in an acidic medium to remove the Boc-protecting group, for example using formic acid or an aqueous solution of HCl, depending on the selection of the protecting group, to provide the compound of formula (I) (step 4). Those skilled in the art will understand that the compound of formula (I) having a free amine (NH) can be further alkylated using a suitable alkylating agent, for example formaldehyde or 2-methoxyethanal, in the presence of a suitable reducing agent, for example sodium triacetoxyborohydride, in a suitable solvent, for example DCM, at a suitable temperature, for example 0°C to room temperature.1 An intermediate in which is a (substituted) carbon (C) or oxygen (O) atom is subjected to a suitable formula Y in the presence of a suitable base such as NaOMe or K2CO3, in a suitable solvent such as DMF or ACN, at a suitable temperature such as room temperature or 50°C. 1 The compound of formula (I) can be immediately provided by reacting it with a thiol of -SH (step 5).

[0189] L is alkylene and Z 1’ However, it represents an amine bonded to L by N, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in Scheme 6 (Method 6): [ka] It can also be obtained through [another method].

[0190] Alcohol T-37 can be commercially available or synthesized by those skilled in organic chemistry using various methods described in the literature. 1However, intermediate T-38, which is a halogen such as bromide, can be obtained by halogenating T-37 with a suitable halogenating reagent such as N-iodosuccinimide (NIS) using the catalytic action of p-toluenesulfonic acid in a suitable solvent such as ethanol at a suitable temperature such as 25°C (Step 1). The halogen of intermediate T-38 can be acetylated with a suitable acylation reagent such as ethoxyvinyl tributyltin in a suitable solvent such as toluene in the presence of a suitable catalyst such as Pd(PPh3)4 at a suitable temperature such as 120°C, and then work-up with a suitable enol ether deprotecting agent such as 0.5 M HCl water at a suitable temperature such as room temperature to provide intermediate T-39 (Step 2). The alcohol of intermediate T-39 can be protected with a suitable protecting group (PG) such as tert-butyl diphenylsilyl (TBDPS) by treatment with a suitable silylation reagent such as TBDPS-Cl in a suitable solvent such as DCM in the presence of a suitable base such as imidazole and a catalyst DMAP, at a suitable temperature such as 15°C, thereby providing intermediate T-40 (step 3). The acetyl group of intermediate T-40 can be halogenated with a suitable reagent such as tetrabutylammonium tribromide (TBATB), trimethylphenylammonium tribromide, or CuBr2 in a suitable solvent such as DCM / MeOH or siRNA / CHCl3, at a suitable temperature such as room temperature or 85°C, to obtain X 2 However, an intermediate T-41, which is a halogen such as bromide, can be provided (step 4). Those skilled in the art will understand that while silyl protecting groups can be removed during step 4, other protecting groups will require an additional deprotection step according to conditions known in the art. The halogen in intermediate T-41 can be deprotected in a suitable solvent such as DMF or ACN, in the presence of a suitable base such as NaOMe or K2CO3, at a suitable temperature such as room temperature or 50°C, using a suitable formula Y 1 -The thiol of SH can be further reacted to provide intermediate T-42 (step 5). Heteroaryl Y 1-SH can be prepared using Lawson's reagent or P2S5 reagent at an appropriate temperature in a solvent (e.g., toluene) by commercially available methods or by methods known to those skilled in the art, for example, the corresponding heteroaryl Y 1 It can be prepared from -OH derivatives. Heteroaryl Y 1 -OH can be commercially available or prepared by methods known to those skilled in the art. The alcohol of T-42 can be oxidized to the corresponding aldehyde T-43 by a suitable oxidizing agent such as Dess-Martin periodinane (DMP) in a suitable solvent such as DCM at a suitable temperature such as 25°C. The intermediate T-43 can be subjected to a reductive amination reaction by reacting with a suitable amine such as morpholine in the presence of a suitable reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as DCM at a suitable temperature such as 25°C to provide the compound of formula (I). Those skilled in the art will know that Z in the compound of formula (I) 1’ However, if a protected amine is present, the amine can be deprotected in an acidic, neutral, or basic medium depending on the selection of the protecting group, for example, in an acidic medium where the Boc-protecting group is removed using formic acid or an aqueous solution of HCl, to provide the corresponding free amine (NH), which will be a compound of another formula (I). Alternatively, such a free amine can be further alkylated using a suitable alkylating agent, for example, formaldehyde or 2-methoxyethanal, in the presence of a suitable reducing agent, for example, sodium triacetoxyborohydride, in a suitable solvent, for example, DCM, at a suitable temperature, for example, 0°C to room temperature, to provide an N-alkylated amine of another formula (I).

[0191] Those skilled in the art will see that although monocyclic amines are shown in schemes 1 to 6 above, polycyclic amines can be involved in the same type of reaction, Z 1’ However, it will be understood that it is equally possible to prepare compounds of formula (I), such as polycyclic amines, including bicyclic, spirocyclic, or bridging rings.

[0192] Z 1’However, formula -NR 23’ R 24’ It represents an acyclic amine, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in Scheme 7 (Method 7): [ka] It can be obtained by [method].

[0193] Amine T-44 can be commercially available or synthesized by those skilled in organic chemistry using various methods described in the literature. Intermediate T-45, where PG is a suitable protecting group such as Boc, can be prepared by protecting the amine group of T-44 (step 1) by using Boc2O in the presence of a base (e.g., Et3N or NaHCO3) and in a solvent (e.g., DCM or THF) at a suitable temperature. The protected amine intermediate T-45 is then subjected to a halogenation step to obtain T-46 (where X 1For example, a halo such as bromo (Br) can be provided using NBS or Br2 in a solvent (e.g., DCM) at a suitable temperature (Step 2). Next, the halide T-46 can be converted to the corresponding ketone T-47 in one or more step sequences, for example: (Option 1) a two-step sequence, for example, (i) tributyl(1-ethoxyvinyl)tin is provided in a metal catalyst cross-coupling sequence using a catalyst / ligand system (e.g., Pd(PPh3)4 in a solvent (e.g., dioxane), and a base (e.g., t-BuOK)) at a suitable temperature to provide an enol ether intermediate, which is then converted to the desired ketone T-47 at a suitable temperature using an acidic medium such as aqueous HCl or formic acid (Step 3); or (Option 2) Step 4 provides the corresponding aldehyde intermediate T-48 by a three-step sequence, for example, metal-halide exchange using (i)n-BuLi in an aprotic solvent such as anhydrous THF at a controlled temperature such as -78°C under an inert atmosphere such as a nitrogen atmosphere, followed by the introduction of dimethylformaldehyde or an equivalent reagent. Step 5 provides the alcohol T-49 obtained by treating intermediate T-48 with a methylating agent such as MeMgBr in an aprotic solvent (e.g., THF) at a suitable temperature. Step 6 converts alcohol T-49 to the corresponding ketone T-47 by using an oxidizing agent such as DMP or PCC in a solvent (e.g., DCM) at a suitable temperature. Step 6 further involves a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at a suitable temperature to obtain X 2 However, a suitable halogen such as bromide can be provided as halo ketone T-50 (step 7). Then, halo ketone T-50 is heated in a solvent (e.g., DMF or ACN) at a suitable temperature in the presence of a base (e.g., MeONa or K2CO3) to form formula Y 1 -SH is reacted with a thiol heteroaryl derivative to provide heteroaryl intermediate T-51 (step 8). Heteroaryl Y 1-SH is commercially available or can be obtained by methods known to those skilled in the art, for example, by the corresponding heteroaryl Y 1 Heteroaryl Y derivatives can be prepared from -OH derivatives in a solvent (e.g., toluene) at an appropriate temperature using Lawson's reagent or P2S5 reagent. 1 -OH is commercially available or can be prepared by methods known to those skilled in the art. Subsequently, the protected amine T-51 can be deprotected in an acidic or basic medium, for example in an acidic medium such as formic acid or aqueous HCl, depending on the selection of the protecting group, to remove the BoC- protecting group, or to remove a benzyl protecting group such as Cbz by hydrogenolysis using H2 in a protic solvent (e.g., MeOH) in the presence of a catalyst (e.g., Pd(OH)2) to finally provide the corresponding amine intermediate T-52 (step 9). Amine T-52 can be considered as a compound of formula (I) as is, or it can be further alkylated with a suitable alkylating reagent such as formaldehyde in a suitable solvent such as DCM in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, for example, at a suitable temperature such as 0 to 25°C, to provide a compound of formula (I) in which the amine has an alkyl group. Those skilled in the art will understand that the alkylation of the amine in the compound of formula (I) can occur earlier in the synthesis, for example, if the primary amine is Boc protected, by alkylating the NH-Boc functional group with a suitable alkylating reagent such as methyl iodide, in the presence of a suitable base such as sodium hydride, in a suitable solvent such as DMF, at a suitable temperature such as 0°C.

[0194] L is a direct bond, and Z 1’ However, it represents substituted morpholine or homomorpholine, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in Scheme 8 (Method 8): [ka] It can also be obtained through [another method].

[0195] X 1 However, for example, a suitable halogen such as bromo, and Y 2 However, intermediate T-33, which represents a heteroaryl such as thiophene, can be commercially obtained or prepared under conditions known in the art. The acetyl group of intermediate T-33 is halogenated in a suitable solvent such as DCM / MeOH or siRNA / CHCl3 at a suitable temperature such as room temperature or 85°C using a suitable reagent such as tetrabutylammonium tribromide (TBATB), trimethylphenylammonium tribromide, or CuBr2, and X 2 However, for example, an intermediate T-53, which is a halide such as bromide, can be provided (Step 1). The intermediate T-54 is prepared in the presence of a suitable base such as K2CO3, in a suitable solvent such as DMF, at a suitable temperature such as 25°C, where n is 1 or 2 and PG 1 However, for example, a suitable protecting group such as benzyl is a suitable formula HOCH2(CH2) n NH-PG 1 It can be obtained by reacting the amino alcohol with the intermediate T-53. 22’ However, the intermediate T-55, which is hydrogen, can be obtained by reacting intermediate T-54 with a suitable reducing agent, such as NaBH4, in a suitable solvent such as MeOH, at a suitable temperature such as 25°C (Step 3). Those skilled in the art may instead react a nucleophile such as MeMgBr or TMS-CF3 / TBAF with the ketone of T-54 to obtain R 22’ However, it will be understood that a tertiary alcohol T-55, for example, a methyl or CF3 group, can be obtained, and that those skilled in the art will understand that this may require protection of the primary OH group with a suitable protecting group, such as TBDMS. Intermediate T-56 can be obtained from intermediate T-55 using suitable intramolecular ether formation conditions, such as HBr in acetic acid (used as a solvent), at a suitable temperature, such as 25°C (step 4). PG 2 However, for example, PG such as Boc 1First, intermediate T-57, which is a suitable protecting group other than PG, is prepared in a suitable solvent such as DME. 1 However, in the case of a benzyl group, a suitable deprotection method such as ethyl 1-chlorochloroformate is used to protect the PG group. 1 The amine can be obtained by removing the amine, then treating it with MeOH, and then reprotecting the amine with a suitable reagent such as Boc2O in a suitable solvent such as DCM, in the presence of a suitable base such as triethylamine, at a suitable temperature such as 25°C (Step 5). Intermediate T-57 can be obtained by a suitable haloacetylation method such as a metal-catalyzed cross-coupling sequence using tributyl(1-ethoxyvinyl)tin in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4 in a solvent (e.g., dioxane), and a base (e.g., t-BuOK)) at a suitable temperature, X 3 However, for example, it can be converted to a halogen such as bromo, T-58, to provide an enol ether intermediate, which can then be converted to halo ketone T-58 using a suitable halogenating reagent such as NBS in a suitable solvent such as THF / water at a suitable temperature such as room temperature (step 6). The halo ketone T-58 can be converted to a solvent (such as DMF or ACN) in the presence of a base (such as MeONa or K2CO3) at a suitable temperature using formula Y 1 Intermediate T-59 can be provided by reacting it with a heteroarylthiol derivative of -SH (step 7). Intermediate thiol Y 1 -SH can be prepared as already described herein. 1’However, a compound of formula (I) which is N-unsubstituted morpholine or homomorpholine can be obtained by reacting intermediate T-59 with a suitable protecting group removal reagent, such as HCl / SiO (used as a solvent), at a suitable temperature, such as 25°C (step 8). A compound of formula (I) in which morpholine or homomorpholine is N-alkylated can be obtained by reacting the deprotected amine with a suitable alkylating reagent, such as formaldehyde, in the presence of a suitable reducing agent, such as NaBH(OAc)3, in a suitable solvent, such as AcOH / DCM, at a suitable temperature, such as 25°C. Those skilled in the art will understand that the racemic compound of formula (I) can be further subjected to chiral separation, such as chiral SFC, to provide an enantiomerically pure compound of formula (I).

[0196] L is a direct bond, and Z 1’ However, it represents cross-linked substituted morpholine or homomorpholine, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in scheme 9 (method 9) below: [ka] It can also be obtained through [another method].

[0197] Keto acid intermediate T-60, in which PG is a suitable protecting group such as Boc and n is 1 or 2, can be commercially obtained or prepared under conditions known in the art. Intermediate T-61 can be obtained by reacting intermediate T-60 with a suitable organometallic agent such as thiophene-2-ylmagnesium bromide in a suitable solvent such as THF at a suitable temperature such as 0°C (Step 1). Intermediate T-62 can be obtained by reacting intermediate T-61 with a suitable acid reducing reagent such as BH3·THF in a suitable solvent such as THF at a suitable temperature such as 0-70°C (Step 2). Intermediate T-63 can be obtained by reacting intermediate T-62 in a suitable solvent such as toluene at a suitable temperature such as 25°C under suitable intramolecular ether formation conditions such as PPh3 / DIAD (Step 3). 1 However, intermediate T-64, which is a halogen such as bromide, can be obtained by reacting intermediate T-63 with a suitable halogenating reagent such as NBS in a suitable solvent such as DMF at a suitable temperature such as 25°C (Step 4). Intermediate T-64 can be converted to X by a suitable haloacetylation method, such as a metal-catalyzed cross-coupling sequence using tributyl(1-ethoxyvinyl)tin in the presence of a catalyst / ligand system (solvent (e.g., dioxane), e.g., Pd(PPh3)4, base (e.g., t-BuOK)) at a suitable temperature. 2 However, for example, it can be converted to a halide such as bromide, which is a halide, to provide an enol ether intermediate, which can then be converted to halidetone T-65 in a suitable solvent such as THF / water, at a suitable temperature such as room temperature, using a suitable halogenating reagent such as NBS (step 5). The halidetone T-65 can be converted in a solvent (such as DMF or ACN) in the presence of a base (such as MeONa or K2CO3) at a suitable temperature using formula Y 1 Intermediate T-66 can be provided by reacting it with a heteroarylthiol derivative of -SH (step 6). Intermediate thiol Y 1-SH can be prepared as already described herein. 1’ However, compounds of formula (I) that are N-unsubstituted crosslinked morpholine or homomorpholine can be obtained by reacting intermediate T-66 with a suitable protecting group removal reagent, such as HCl / SiO (used as a solvent), at a suitable temperature, such as 25°C (step 7). Compounds of formula (I) in which the crosslinked morpholine or homomorpholine is N-alkylated can then be obtained by reacting the deprotected amine with a suitable alkylating reagent, such as formaldehyde, in the presence of a suitable reducing agent, such as NaBH(OAc)3, in a suitable solvent, such as AcOH / DCM, at a suitable temperature, such as 25°C. Those skilled in the art will understand that other N-protected cyclic amines containing both ketones and acids, such as 1-(tert-butyl)3-methyl5-oxopiperidine-1,3-dicarboxylate, can similarly be converted to compounds of formula (I). Those skilled in the art will understand that starting from the inverse enantiomer of T-60, a compound of formula (I) having the inverse stereochemistry can be obtained, and therefore the stereochemistry of the acid group in the starting material such as T-60 determines the stereochemistry of the compound of formula (I).

[0198] L is a direct bond, and Z 1’ However, it represents substituted morpholine or homomorpholine, and Y 1 and Y 2 However, the compound of formula (I) as defined above is shown in scheme 10 (method 10) below: [ka] It can also be obtained through [another method].

[0199] PG 1 However, suitable acid protecting groups such as methyl α-ketoester T-67 can be commercially available or synthesized by those skilled in organic chemistry using various methods described in the literature. 22’However, intermediate T-68, as defined above, can be prepared by reacting T-67 with an organometallic nucleophile, such as methylmagnesium bromide, in a solvent (e.g., THF) at a suitable temperature, such as -40°C (Step 1). Alternatively, intermediate T-68 can also be prepared by reacting T-67 with another ketone-reactive nucleophile, such as trifluoromethyltrimethylsilane, in a suitable solvent (e.g., DCM) in the presence of a suitable anionic initiator, such as tetrabutylammonium fluoride, at a suitable temperature, such as 0°C to room temperature. 1 However, intermediate T-69, which is a halide such as bromide, can be prepared by reacting intermediate T-68 with a suitable halogenating reagent such as NBS in a suitable solvent such as DMF at a suitable temperature such as 25°C (Step 2). Intermediate T-70 can be prepared by reacting T-69 with a suitable base such as KOH in a suitable solvent such as EtOH / water at a suitable temperature such as 25°C (Step 3). Intermediate T-71 can be prepared by reacting 2-chloroethylamine with T-70 using a suitable amide coupling reagent such as HATU in the presence of a suitable base such as DIPEA in a suitable solvent such as DMF at a suitable temperature such as 0-25°C (Step 4). Intermediate T-72 can be obtained by reacting T-71 with a suitable base, such as tBuOK, in a suitable solvent such as THF at a suitable temperature such as 0 to 80°C (Step 5). Intermediate T-73 can be obtained by reacting T-72 with a suitable reducing agent, such as BH3·THF, in a suitable solvent such as THF at a suitable temperature such as -60 to 25°C (Step 6). PG 2However, intermediate T-74, which is a suitable protecting group such as Boc, can be obtained by reacting T-73 with a suitable protecting reagent such as Boc2O in a suitable solvent such as THF / water, in the presence of a suitable base such as K2CO3, at a suitable temperature such as 25°C (step 7). Intermediate T-74 can be converted to X by a suitable haloacetylation method such as a metal-catalyzed cross-coupling sequence using tributyl(1-ethoxyvinyl)tin, at a suitable temperature in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4 in a solvent (e.g., dioxane), and a base (e.g., t-BuOK)) 2 However, for example, it can be converted to a halo ketone T-75, which is a halide such as bromide, to provide an enol ether intermediate, and then, in a suitable solvent such as THF / water, at a suitable temperature such as 25°C, using a suitable halogenating reagent such as NBS, X 2 However, it can be converted to T-75, a halide such as bromide (step 5). The halocetone T-75 is converted in a solvent (e.g., DMF or ACN) at a suitable temperature in the presence of a base (e.g., MeONa or K2CO3) and formula Y 1 Intermediate T-76 can be provided by reacting it with a heteroarylthiol derivative of -SH (step 9). Intermediate thiol Y 1 -SH can be prepared as already described herein. 1’However, a compound of formula (I) that is morpholine can be obtained by reacting intermediate T-76 with a suitable protecting group removal reagent, such as HCl / SiO (used as a solvent), at a suitable temperature, such as 25°C (step 10). A compound of formula (I) in which morpholine is N-alkylated can then be obtained by reacting the deprotected amine with a suitable alkylating reagent, such as formaldehyde, in the presence of a suitable reducing agent, such as NaBH(OAc)3, in a suitable solvent, such as AcOH / DCM, at a suitable temperature, such as 25°C. Those skilled in the art will understand that the racemic compound of formula (I) can be further subjected to chiral separation, such as chiral SFC, to provide an enantiomerically pure compound of formula (I).

[0200] Y 2 However, as stated above, X 1 However, for example, if the halo is bromide, and PG is a protecting group, and R 22’ However, the intermediate T-74, which has CF3 units, is as shown in Scheme 11 (Method 11): [ka] It can also be obtained through [another method].

[0201] Intermediate T-77 is commercially available or can be prepared using conditions known in the art. Intermediate T-78 can be prepared by reacting T-77 with a suitable reagent, such as nitromethane, in a suitable solvent, such as DCM, in the presence of a suitable base, such as K2CO3, at a suitable temperature, such as 25°C (Step 1). Intermediate T-79 can be obtained by reacting T-78 with a suitable reducing agent, such as hydrogen gas, in a suitable solvent, such as EtOH, in the presence of a suitable catalyst, such as Pd / C, at a suitable temperature, such as 25°C (Step 2). Intermediate T-80 can be obtained by reacting T-79 with chloroacetyl chloride, such as triethylamine, in a suitable solvent, such as DCM, at a suitable temperature, such as 0°C (Step 3). Intermediate T-81 can be obtained, for example, by reacting T-80 with a suitable base, such as NaH, in a suitable solvent such as THF, at a suitable temperature such as 0°C (Step 4). Intermediate T-82 can be obtained, for example, by reducing intermediate T-81 with a suitable reagent, such as LiAlH4, in a suitable solvent such as THF, at a suitable temperature such as 0-70°C (Step 5). Intermediate T-83, in which PG is a suitable protecting group such as Boc, can be prepared, for example, by reacting intermediate T-82 with a suitable protecting reagent, such as Boc2O, in a suitable solvent such as MeOH, in the presence of a suitable base such as triethylamine, at a suitable temperature such as 25°C (Step 6). 22’ However, intermediate T-74, which is a CF3 group, can be prepared by reacting intermediate T-83 with a suitable halogenating reagent such as NBS in a suitable solvent such as DMF at a suitable temperature such as 25°C (step 7). Those skilled in the art will understand R 22’ However, you will understand that the intermediate T-74, which has a CF3 group, can be a compound of formula (I), as described in scheme 10 above.

[0202] Y 2 However, as stated above, X 1However, for example, if the halo is bromide, and PG is a protecting group, and R 22’ However, the intermediate T-91, which is a CF3 group, is as shown in Scheme 12 (Method 12): [ka] It can be obtained by [method].

[0203] PG 1 However, intermediate T-84, which is a suitable protecting group such as Boc, is commercially available or can be prepared using conditions known in the art. 1 For example, intermediate T-85, which is an activating group such as diphenylphosphonate or triflate, can be prepared by reacting T-84 with a suitable activating reagent such as diphenylphosphorochloride in a suitable solvent such as THF, in the presence of a suitable base such as LiHMDS, at a suitable temperature such as -30 to 25°C (Step 1). Intermediate T-87 can be prepared by reacting T-85 with a boronate of a suitable formula Y2-B(OH)2, T-86, in the presence of a suitable base such as Pd(tBu3P)2, in a suitable solvent such as ACN / water, at a suitable temperature such as 65°C (Step 2). Intermediate T-88 can be prepared by reacting T-87 with a suitable deprotecting agent such as 2M HCl in dioxane, at a suitable temperature such as 0 to 25°C (Step 3). Intermediate T-89 can be prepared by reacting T-88 with a suitable reducing agent, such as NaBH3CN, in a suitable solvent such as AcOH / MeOH at a suitable temperature such as 25°C (Step 4). PG 2 However, intermediate T-90, which is a suitable protecting group such as Boc, can be prepared by reacting T-89 with a suitable protecting agent such as Boc2O in a suitable solvent such as DCM, in the presence of a suitable base such as DIPEA, at a suitable temperature such as 25°C. 1However, intermediate T-91, which is a suitable halogen such as bromide, can be prepared by reacting T-90 with a suitable halogenating agent such as NBS in a suitable solvent such as DMF at a suitable temperature such as 25°C. Those skilled in the art will understand that intermediate T-91 can be a compound of formula (I) in the same manner as described for intermediate T-74 in scheme 10 above.

[0204] Y 2 However, as stated above, X 1 However, for example, if it is a halide such as bromide, and R 22’ , R 23’ , and R 24’ However, the intermediate T-94, as defined above, is given by the following scheme 13 (method 13): [ka] It can also be obtained through [another method].

[0205] Intermediate T-92 is prepared by dissolving it in a suitable amine R, for example, in the presence of a suitable base such as K2CO3, in a suitable solvent such as CH3CN, and at a suitable temperature such as 25°C. 23’ R 24’ It can be prepared by reacting NH with T-53 (Step 1). 22’ However, the hydrogen intermediate T-94 can be prepared by reducing the ketone of T-92 in a suitable solvent such as EtOH at a suitable temperature such as 0-25°C using a suitable reducing agent such as NaBH4 (Step 2). 22’However, intermediate T-94, which is an alkyl or aryl group, can be prepared by reacting the ketone of T-92 with a suitable organometallic compound, such as methylmagnesium bromide, in a suitable solvent such as THF at a suitable temperature such as -78 to 25°C (Step 2, Alternative Method). Alternatively, intermediate T-94 can be prepared by reacting T-93 with a suitable organometallic compound, such as lithium (5-bromothiophen-2-yl) prepared in situ from 2,5-dibromothiophene / n-BuLi, in a suitable solvent such as THF at a suitable temperature such as -78 to 25°C (Step 3). Those skilled in the art will understand that intermediate T-94 can be a compound of formula (I) in the same manner as described for intermediate T-74 in scheme 10 above. Those skilled in the art will also understand that other amine-containing aldehydes or ketones other than intermediate T-93 may similarly give compounds of formula (I).

[0206] Y 2 However, as defined above, X 1 However, for example, intermediate T-97, which is a halide such as bromide and has PG as a protecting group, is as shown in Scheme 14 (Method 14): [ka] It can be obtained through [method].

[0207] Intermediate T-95, in which PG is a suitable protecting group such as Boc, is commercially available or can be prepared using conditions known in the art. Intermediate T-96 can be prepared by reacting T-95 with a suitable organometallic agent such as thiophene-2-ylmagnesium bromide in a suitable solvent such as THF, in the presence of a suitable catalyst such as copper(I) iodide, at a suitable temperature such as -30 to 25°C (Step 1). 1However, intermediate T-97, which is a halogen such as bromide, can be prepared by reacting T-96 with a suitable halogenating agent such as NBS in a suitable solvent such as DMF at a suitable temperature such as 25°C (Step 2). Alternatively, intermediate T-97 can be prepared by reacting T-95 with a suitable organometallic compound such as lithium (5-bromothiophen-2-yl) prepared in situ from 2,5-dibromothiophene / n-BuLi in a suitable solvent such as THF at a suitable temperature such as -78 to 25°C (Step 3). Those skilled in the art will understand that intermediate T-97 can be a compound of formula (I) in the same manner as described for intermediate T-74 in scheme 10 above. Those skilled in the art will also understand that if T-94 is chiral, the resulting compound of formula (I) will also have a clearly defined chirality.

[0208] (Synthesis of compounds - experimental results) Several methods for preparing the compounds of the present 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 this specification.

[0209] (abbreviation) The abbreviations are used as follows: [Table 7] TIFF2026522613000090.tif232170TIFF2026522613000091.tif184170

[0210] (Analysis method) LC-MS (Method 1): LC-MS was recorded using an Agilent 1200-G6140. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH + It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties usually associated with the methods used. The gradient conditions used are described below: [Table 8]

[0211] LC-MS (Method 2): LC-MS was recorded using an Agilent 1200-G6140. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH +It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties usually associated with the methods used. The gradient conditions used are described below: [Table 9]

[0212] LC-MS (Method 3): Liquid chromatography-mass spectroscopy (LC-MS) spectra were recorded using a Waters Acquity Class I UPLC system. The gradient conditions used are described below: [Table 10]

[0213] LC-MS (Method 4): Liquid chromatography-mass spectrometry (LC-MS) spectra were recorded using a Waters Acquity Class I UPLC system. The gradient conditions used are described below: [Table 11]

[0214] LCMS (Method 5): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded using a Waters Acquity Class I UPLC system. The gradient conditions used are described below: [Table 12]

[0215] LC-MS (Method 6): Liquid chromatography-mass spectroscopy (LC-MS) spectra were recorded using a Waters Acquity Class I UPLC system. The gradient conditions used are described below: [Table 13]

[0216] LC-MS (Method 7): LC-MS spectra were recorded on a Waters Acquity Class I UPLC system using the following solvent systems: [Solvent A: Acetonitrile, Solvent B: 0.1% Formic Acid 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 / or ammonia or TFA were used as HPLC grades. All separations were performed at ambient temperature. Reverse-phase HPLC was performed on a Waters HPLC system using the following solvent systems: [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 the HPLC grade. All separations were performed at ambient temperature. For analytical RP-HPLC analysis [Interchim: Acquity BEH C18 (2.1 × 100 mm, 1.7 μm)], the flow rate was 0.4 mL / min⁻¹; the injection volume was 10 μL; and the detection wavelengths were 220 nm and 254 nm. The following gradient was used: 90% B for 0.01 minutes, 10% B for 8 minutes, and 10% B for 4 minutes.

[0217] LC-MS (Method 8): LC-MS was recorded using Agilent 1200 & 6120B. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH +It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results are obtained with the experimental uncertainties usually associated with the methods used.

[0218] The gradient conditions used are described below: [Table 14]

[0219] LC-MS (Method 9): LC-MS was recorded using a Shimadzu LC-20AD&MS 2020. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH + It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties usually associated with the methods used. The gradient conditions used are described below: [Table 15]

[0220] LC-MS (Method 10): LC-MS was recorded using a Shimadzu LC-20AD&MS 2020. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH + It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties usually associated with the methods used. The gradient conditions used are described below: [Table 16]

[0221] LC-MS (Method 11): LC-MS was recorded using Agilent Agilent 1260 & 6125B. High-performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode array, or UV detector. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting the adjustment parameters to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) and / or precise mass monoisotopic molecular weight of the compound is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. Data was acquired using an ES MS detector in positive or negative ionization mode. The compound was [M+H + ](protonated molecule) or [MH +It can be described by the molecular ion corresponding to the deprotonated molecule. For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are obtained for the lowest isotopic mass. All results were obtained with the experimental uncertainties usually associated with the methods used. The gradient conditions used are described below: [Table 17]

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

[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) cooled to -78°C in anhydrous THF (10 mL), LiHMDS (1.0 M solution in THF) (6.0 mL, 5.934 mmol) was added dropwise, and the resulting mixture was stirred for 60 minutes. N-(5-chloropyridine-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (2.33 g, 5.934 mmol) in THF was added to the solution, and the mixture was stirred at the same temperature for 30 minutes. Next, the reaction mixture was warmed to room temperature, quenched with saturated NaHCO3 water (10 mL), and extracted with RINKAN (2 × 50 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh) eluted with 10% phenyl in hexane to obtain compound I-1-1 (0.63 g, 37% yield) as a rubbery 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) were added. The reaction was purged with N2 for 15 minutes and then heated at 100°C for 16 hours. The mixture was then quenched with saturated NaHCO3 water (20 mL) and extracted with siRNA (2 × 50 mL). The organic layer was separated, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh, eluent: 50% phenylacetate in hexane) to obtain the title compound I-1-2 (2.7 g, yield 75%) as a rubbery 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), 10% Pd-C (2.0 g) was added, and then H2 gas was added at 60 psi for 5 hours. The reaction mixture was filtered through a Celite bed under vacuum. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography using silica gel (60-120 mesh, eluent: 50% siRNA in hexane) to obtain the title compound I-1-3 (1.5 g, yield 74%) as a 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 anhydrous THF (5 mL), tetrabutylammonium tribromide (0.8 g, 1.360 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain the crude compound, which was purified by combi-flash reverse-phase chromatography to obtain I-1 (0.07 g, yield 27%) as a white solid. [ka]

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

[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, branched round-bottom flask. Anhydrous DMF (35.0 mL) was added by syringe, followed by a catalytic amount of I2 (928 mg, 3.66 mmol, 737 μL). A color change of DMF from colorless to yellow and back to its original color was observed. Tert-butyl 3-iodoazetidine-1-carboxylate (8.97 g, 31.7 mmol) was added, followed immediately by a catalytic amount of I2 (928 mg, 3.66 mmol, 737 μL). When the solution was stirred at 15°C, significant exothermic reaction occurred. 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 stirred at 15°C for 12 hours under positive nitrogen pressure. The reaction mixture was diluted with water (60.0 mL) and extracted with DCM (30.0 mL × 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 / 1~1 / 1) to obtain compound I-2-1 (3.50 g, yield 51.0%) 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), TBATB (5.40 g, 11.2 mmol) was added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched at 25°C by adding H2O (10.0 mL), and then extracted with SiO2 (5.00 mL × 3). The combined organic layer was 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 obtain compound I-2 (1.1 g, yield 28.6%) as a yellow oil.

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

[0231] (Synthesis of tert-butyl 3-(4-acetyl-1H-pyrazole-1-yl)pyrrolidine-1-carboxylate (I-3-1)) To a solution of 1-(1H-pyrazole-4-yl)ethane-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), DIAD (13.8 g, 68.1 mmol, 13.2 mL) and PPh3 (17.8 g, 68.1 mmol) were added. The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding H2O (50.0 mL) at 25°C, and then extracted with RINKAN (25.0 mL × 3). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions) to obtain compound I-3-1 (5.40 g, yield 42.6%) as a white solid.

[0232] (Synthesis of tert-butyl 3-(4-(2-bromoacetyl)-1H-pyrazole-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), TBATB (3.62 g, 7.52 mmol) was added. The mixture was stirred at 20°C for 2 hours. 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 Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-3 (500 mg, yield 19.5%) as a colorless oil.

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

[0234] (Synthesis of tert-butyl 3-carbamotioylpyrrolidine-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), Lawson's reagent (4.34 g, 10.7 mmol) was added. The mixture was stirred at 80°C for 16 hours. The suspension was filtered through a Celite pad and washed with siRNA (100 mL). The combined filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-4-1 (1.30 g, yield 26.2%) as a white solid.

[0235] (Synthesis of tert-butyl 3-(5-formylthiazole-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), NaOAc (534 mg, 6.51 mmol) and 2-bromomalonaldehyde (721 mg, 4.78 mmol) were added. The mixture was stirred at 100°C for 0.3 hours. H2O (3.00 mL) was added to the reaction and extracted with siRNA (10.0 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was separated into preparative TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1, compound I-4-2, R f The compound I-4-2 (0.70 g, yield 57.1%) was purified using a method (=0.5) to obtain a yellow oil.

[0236] (Synthesis of tert-butyl 3-(5-(1-hydroxyethyl)thiazole-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), MeMgBr (135 mg, 1.13 mmol) was added at -20°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl water (2.00 mL) and extracted with siRNA (10.0 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-4-3 (140 mg, yield 82.8%) as a white solid.

[0237] (Synthesis of tert-butyl 3-(5-acetylthiazole-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), Dess-Martin reagent (256 mg, 603 μmol, 187 μL) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to obtain compound I-4-4 (108 mg, yield 90.6%) as a colorless oil.

[0238] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazole-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), pyridinium tribromide (129 mg, 344 μmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with H2O (2.00 mL) and extracted with HCl (2.00 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain compound I-4 (100 mg, yield 44.1%, 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)) [ka]

[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), n-BuLi (2.50 M, 233 mL) was added all at once under N2 at -60°C. The mixture was stirred at -60°C for 1 hour, and then tert-butyl 3-oxoazetidine-1-carboxylate (109 g, 640 mmol) was added. The mixture was stirred at -60°C for 2 hours. The reaction mixture was poured into ice-water (1.50 L) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum to obtain compound I-5-1 (160 g, yield 49.4%, 92.6% purity) as a white solid.

[0241] (Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)-3-hydroxyazetidine-1-carboxylate (I-5-2)) 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, purged three times with N2, and then the mixture was stirred at 25°C for 2 hours under an N2 atmosphere. The reaction mixture was poured into water (500 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-5-2 (117 g, yield 42.9%) as a yellow solid.

[0242] (Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-3-hydroxyazetidine-1-carboxylate (I-5-3)) 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, purged three times with N2, and then the mixture was stirred at 70°C for 12 hours under an N2 atmosphere. The reaction mixture was acidified with aqueous HCl (1 M) to pH=4 and extracted with SiO2 (30.0 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound I-5-3 (7.30 g, yield 82.0%) as a white solid.

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

[0244] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)-3-methoxyazetidine-1-carboxylate (I-6)) [ka]

[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), NaH (1.44 g, 35.9 mmol, 60.0% purity) was added at 0°C. After addition, the mixture was stirred at this temperature for 0.5 hours, 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 hours. The reaction mixture was quenched at 25°C by adding NH4Cl (100 mL) 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 obtain compound I-6-1 (8.40 g, yield 80.6%) 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), 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) were added. The mixture was stirred at 70°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched at 20°C by adding HCl (100 mL), and then extracted with CHCl3 / isopropanol (20.0 mL × 6). The combined organic layers were washed with brine (30.0 mL × 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 obtain compound I-6-2 (0.800 g, yield 10.7%) 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), TBATB (325 mg, 674 μmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (10.0 mL) and extracted with RINKAN (10.0 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-6 (97.8 mg, yield 39.0%) as a yellow oil.

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

[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), DAST (10.9 g, 67.3 mmol, 8.89 mL) was added under an N2 atmosphere at -78 °C. The mixture was stirred at -78 °C for 12 hours. The reaction mixture was quenched at -60 °C by adding NaHCO3 aqueous solution (200 mL), diluted with H2O (100 mL), and extracted with DCM (100 mL x 3). The combined organic layers were washed with NaHCO3 aqueous solution (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-7-1 (29.0 g, yield 86.5%, 90.0% purity) as a yellow oil.

[0250] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)-3-fluoroazetidine-1-carboxylate (I-7-2)) Compound I-7-1 (10.0 g, 29.7 mmol) and tributyl(1-ethoxyvinyl) stannane (18.8 g, 52.1 mmol, 17.6 mL) were dissolved in dioxane (100 mL). Under an N2 atmosphere, TEA (6.02 g, 59.5 mmol, 8.28 mL) and Pd(PPh3)2Cl2 (2.09 g, 2.97 mmol) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding H2O (200 mL) and extracted with siRNA (150 mL x 3). The combined organic layer was washed with brine (300 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-7-2 (20.0 g, crude product) 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), NBS (4.35 g, 24.4 mmol) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched at 25°C by adding H2O (200 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was 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 obtain compound I-7 (6.00 g, yield 57.8%, 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)) [ka]

[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), n-BuLi (2.50 M, 243 mL) was added dropwise at -60°C under an N2 atmosphere. The mixture was stirred at -60°C for 1 hour, and then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (112 g, 607 mmol) in THF (62.5 mL) was added dropwise at -60°C. The mixture was stirred at -60°C for 2 hours. The residue was poured into saturated NH4Cl water (1 L) and extracted with Â(300 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound I-8-1 (45.0 g, yield 29.1%, 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), NBS (32.7 g, 184 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (700 mL) and extracted with siRNA (300 mL x 3). The combined organic layers were washed with H2O (100 mL x 5), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-8-2 (61.9 g, yield 97.9%) as a pale 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), 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) were added under N2. The mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with SiO2 (30.0 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-8-3 (7.50 g, yield 64.1%, 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), NBS (472 mg, 2.65 mmol) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with siRNA (30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain compound I-8 (720 mg, yield 62.6%) as a yellow solid.

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

[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), NaH (230 mg, 5.74 mmol, 60.0% purity) was added. The mixture was stirred at 0°C under N2 for 1 hour. Then, MeI (1.63 g, 11.5 mmol) was added to the mixture and stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (5.00 mL) and extracted with RINKAN (5.00 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain compound I-9-1 (550 mg, 1.52 mmol, yield 52.9%) 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), 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) were added under N2. The mixture was stirred at 80°C for 2 hours. The reaction was quenched with H2O (10.0 mL) and extracted with RINKAN (30.0 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-9-2 (760 mg, yield 64.9%, 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), NBS (136 mg, 764 μmol) was added. The mixture was stirred at 25°C for 1.5 hours. The reaction was quenched with H2O (10.0 mL) and extracted with RINKAN (30.0 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain compound I-9 (220 mg, yield 64.1%) as a yellow solid.

[0261] (Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4-hydroxypiperidine-1-carboxylate (I-10)) [ka]

[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), n-BuLi (2.50 M, 43.2 mL) was added dropwise at -60°C, and the mixture was stirred at -60°C for 1 hour. Then, tert-butyl 4-oxopiperidine-1-carboxylate (21.5 g, 108 mmol) was added dropwise to a solution of THF (96.0 mL) at -60°C. The mixture was stirred at -60°C for 2 hours. The residue was poured into saturated NH4Cl water (300 mL) and extracted with siRNA (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain compound I-10-1 (15.8 g, yield 53.7%, 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), NBS (3.45 g, 19.4 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (50.0 mL × 3). The combined organic layers were washed with saturated NaCl water (50.0 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain compound I-10-2 (6.00 g, yield 75.1%, 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), 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) were added under N2. The mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with H2O (60 mL), extracted with RINKAN (50.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-10-3 (9.30 g, crude product) 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), NBS (4.13 g, 23.2 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (100 mL) and extracted with SiO2 (40.0 mL x 3). The combined organic layers were washed with saturated NaCl water (50.0 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~2 / 1) to obtain compound I-10 (1.34 g, yield 40.1%, 93.3% purity) as a yellow solid.

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

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

[0268] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)pyridine-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), TEA (2.36 g, 23.3 mmol, 3.24 mL) and Pd(PPh3)2Cl2 (818 mg, 1.17 mmol) were added under N2. The mixture was stirred at 90°C for 16 hours. The reaction mixture was quenched by the addition of H2O (80.0 mL) and extracted with SiO2 (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain I-11-2 (10.3 g, crude) as a brown oil.

[0269] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridine-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), NBS (3.84 g, 21.6 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-11 (3.07 g, yield 35.0%, 50.0% purity) as a yellow oil.

[0270] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridine-2-yl)-3-methoxypyrrolidine-1-carboxylate (I-12)) [ka]

[0271] (Synthesis of tert-butyl 3-(5-bromopyridine-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), NaH (454 mg, 11.4 mmol, 60.0% purity) was added at 0°C under N2. The mixture was stirred at 0°C for 1 hour. MeI (4.96 g, 35.0 mmol, 2.18 mL) was added to the mixture and stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (50.0 mL) at 0°C under N2 and extracted with RINKAN (70.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-12-1 (3.26 g, yield 93.8%, 89.8% purity) as a yellow oil.

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

[0273] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridine-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), NBS (1.79 g, 10.0 mmol) was added 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 layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-12 (803 mg, yield 36.5%, 85.9% purity) as a yellow oil.

[0274] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridine-2-yl)-3-fluoropyrrolidine-1-carboxylate (I-13)) [ka]

[0275] (Synthesis of tert-butyl 3-(5-bromopyridine-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), DAST (9.16 g, 56.8 mmol, 7.51 mL) was added under N2 at -70°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 9 / 1) to obtain compound I-13-1 (10.2 g, yield 64.4%, 95.3% purity) as a yellow solid.

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

[0277] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)pyridine-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), NBS (10.7 g, 59.9 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with H2O (300 mL) at 25°C and then extracted with DCM (300 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-13 (5.12 g, yield 35.6%, 75.0% purity) as a yellow solid.

[0278] (Synthesis of 2-bromo-1-(6-morpholinopyridine-3-yl)ethane-1-one (I-14)) [ka]

[0279] (Synthesis of 1-(6-morpholino-3-pyridyl)etanone (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), K2CO3 (10.4 g, 75.0 mmol) was added. The mixture was stirred at 80°C for 16 hours. The residue was diluted with H2O (300 mL) and extracted with DCM (300 mL x 2). The combined organic layers were washed with saturated NaHCO3 aqueous solution (300 mL x 2), dried over MgSO4, filtered, and concentrated under vacuum to obtain compound I-14-1 (5.16 g, yield 97.1%, 97.0% purity) as a white solid.

[0280] (Synthesis of 2-bromo-1-(6-morpholinopyridine-3-yl)ethane-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), CuBr2 (4.87 g, 21.8 mmol) was added under N2. The mixture was stirred at 85°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 8 / 1) to obtain compound I-14 (1.80 g, yield 10.9%, 37.7% purity) as a white solid.

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

[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), K2CO3 (6.91 g, 50.0 mmol) and tert-butylpiperazine-1-carboxylate (6.98 g, 37.5 mmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with siRNA (200 mL x 2). The combined organic layer was washed with saturated NaCl water (200 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~2 / 1) to obtain compound I-15-1 (5.52 g, yield 72.3%, 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), CuBr2 (1.10 g, 4.91 mmol) was added under N2. The mixture was stirred at 85°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 8 / 1) to obtain compound I-15 (1.00 g, yield 21.8%, 41.1% purity) as a white solid.

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

[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), 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) were added under N2. The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with H2O (50.0 mL) and extracted with ELISA (30.0 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to obtain compound I-16-1 (7.00 g, yield 97.8%, 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), Pd / C (7.51 g, 7.06 mmol, 10.0% purity) was added. The mixture was stirred at 25°C under H2 (50 psi) for 16 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to obtain compound I-16-2 (5.90 g, yield 84.9%, 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), TBATB (1.71 g, 3.55 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H2O (10.0 mL) and extracted with HCl (10.0 mL × 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to obtain compound I-16 (1.20 g, 2.24 mmol, yield 66.3%, 70.0% purity) as a yellow solid.

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

[0289] (Synthesis of tert-butyl 3-(4-acetylpyridine-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-17-1)) 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), and Pd(PPh3)4 (1.44 g, 1.25 mmol) in dioxane (50.0 mL) and H2O (10.0 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C under an N2 atmosphere for 16 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with ELISA (50.0 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound I-17-1 (6.50 g, yield 70.3%) as a yellow solid.

[0290] (Synthesis of tert-butyl 3-(4-(1-hydroxyethyl)pyridine-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), Pd / C (1.08 g, 1.02 mmol, 10.0% purity) was added. The mixture was stirred at 25°C under H2 (20 Psi) for 16 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~1 / 1) to obtain compound I-17-2 (420 mg, yield 40.0%) as a yellow oil.

[0291] (Synthesis of tert-butyl 3-(4-acetylpyridine-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), Dess-Martin reagent (870 mg, 2.05 mmol) was added at 0°C for 10 minutes. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with siRNA (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~1 / 1) to obtain compound I-17-3 (300 mg, yield 75.5%) as a yellow solid.

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

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

[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), TMSCl (0.200 mL) and 1,2-dibromoethane (0.200 mL) were added. The mixture was then 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 hours under an N2 atmosphere. To a solution of 2,5-dibromothiazole (5.00 g, 20.6 mmol) in DMF (50.0 mL), Pd(PPh3)4 (1.19 g, 1.03 mmol) and the above solution were added under N2. The mixture was stirred at 65°C for 16 hours under N2. The reaction mixture was quenched with H2O (200 mL) and extracted with siRNA (150 mL x 3). The combined organic layers were washed with saturated NaCl water (50 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to obtain compound I-18-1 (2.40 g, yield 23.5%, 64.4% purity) as a yellow oil.

[0295] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazole-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), 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) were added under an N2 atmosphere. The mixture was stirred at 90°C for 16 hours under an N2 atmosphere. H2O (60.0 mL) was added to the reaction mixture, extracted with SiO (50.0 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound I-18-2 (7.80 g, crude product) as a black oil.

[0296] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazole-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), NBS (3.90 g, 21.9 mmol) was added. The mixture was stirred at 25°C for 2 hours. H2O (50.0 mL) was added to the reaction mixture and extracted with RINKAN (100 mL x 3). The combined organic layers were washed with saturated NaCl water (50 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~3 / 1) to obtain compound I-18 (1.40 g, yield 15.4%, 86.8% purity) as a brown solid.

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

[0298] (Synthesis of (5-iodothiophen-2-yl)methanol (I-19-1)) A mixture of thiophene-2-ylmethanol (25.0 g, 219 mmol, 20.7 mL), NIS (54.2 g, 241 mmol), and PTSA (3.77 g, 21.9 mmol) in EtOH (175 mL) was degassed, purged three times with N2, and then stirred under an N2 atmosphere at 25°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with ELISA (50.0 mL), 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 obtain compound I-19-1 (44.0 g, yield 83.7%) as a yellow oil.

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

[0300] (Synthesis of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)thiophen-2-yl)ethane-1-one (I-19-3)) Compound I-19-2 (4.20 g, 26.9 mmol), imidazole (3.66 g, 53.8 mmol), and DMAP (164 mg, 1.34 mmol) were dissolved in DCM (25.0 mL), to which TBDPSCl (8.87 g, 32.2 mmol, 8.29 mL) was added. The mixture was stirred at 15°C for 12 hours. The reaction mixture was quenched at 25°C by adding H2O (30.0 mL), extracted with Depositphotos (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 obtain compound I-19-3 (8.60 g, yield 67.3%, 83.1% purity) as a yellow oil.

[0301] (Synthesis of 2-bromo-1-(5-(hydroxymethyl)thiophen-2-yl)ethane-1-one (I-19)) A mixture of compound I-19-3 (3.00 g, 7.60 mmol) and TBAB (3.85 g, 7.98 mmol) in DCM (18.0 mL) and MeOH (45.0 mL) was degassed, purged three times with N2, and then stirred at 0°C for 1 hour under an N2 atmosphere. The resulting mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched at 25°C by adding H2O (100 mL) and then extracted with siRNA (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 obtain compound I-19 (800 mg, yield 44.7%) as a brown oil.

[0302] (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-20)) [ka]

[0303] (Synthesis of tert-butyl (thiophene-2-ylmethyl)carbamate (I-20-1)) To a solution mixture of thiophene-2-ylmethaneamine (50.0 g, 441.770 mmol) in THF (500 mL), NaHCO3 (37.1 g, 485.947 mmol) and (Boc)2O (111.5 mL, 441.770 mmol) were slowly added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with 30% SiO2 in hexane and passed through silica, yielding compound (I-20-1) (100 g, quantitatively) as a white, rubbery 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), NBS (45.9 g, 258.2 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction mixture and extracted with ELISA (2 × 500 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 10% ELISA in hexane to obtain compound (I-20-2) (60.5 g, yield: 87%) as a brown, rubbery 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 anhydrous THF (600.0 mL), n-BuLi (1.6 M in hexane) (321 mL, 513.7 mmol) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. DMF (39 mL, 513.7 mmol) was added dropwise at -78°C and the mixture was stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated NH4Cl aqueous solution (200 mL) and extracted with siRNA (2 × 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 12% siRNA in hexane to obtain compound I-20-3 (12.0 g, yield: 49%) as a brown, rubbery liquid. [ka]

[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 anhydrous THF (400.0 mL), methylmagnesium bromide (1.0 M in THF) (767 mL, 767.0 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) and washed with siRNA (2 × 500 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 20% siRNA in hexane to obtain compound I-20-4 (13.0 g, yield: 66%) as a brown, rubbery liquid. [ka]

[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), PCC (13.6 g, 63.15 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered under vacuum and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 20% ethyl acetate in hexane to obtain compound I-20-5 (4.9 g, yield: 75%) as a brown, rubbery liquid.

[0308] (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-20)) Phenylentrimethylammonium tribromide (4.95 g, 13.1 mmol) was added at 0°C to a solution mixture of I-20-5 (4.8 g, 18.8 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered through a Celite bed and concentrated under vacuum. The crude compound was purified using combi-flash C-18 purification to obtain compound I-20 (1.5 g, yield: 24%) as a light brown solid. [ka]

[0309] (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-21)) [ka]

[0310] (Synthesis of tert-butyl (2-(thiophen-2-yl)ethyl)carbamate (I-21-1)) To a stirred solution of 2-(thiophen-2-yl)ethane-1-amine (20.0 g, 157.22 mmol) cooled to 0°C in dichloromethane (200 mL), (Boc)2O (41.1 g, 188.66 mmol) and then Et3N (24.6 g, 243.10 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The crude residue was diluted with water (100 mL), extracted with DCM (2 × 100 mL), and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 10% siRNA in hexane, and the pure fraction was evaporated to obtain compound I-21-1 (28 g, yield: 74%) as a brown, rubbery 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) cooled to 0°C in DMF (400 mL), NBS (21.9 g, 123.172 mmol) was gradually added. The mixture was then stirred at room temperature for 2 hours, and then poured into a mixture of ice water (100 mL) and SiO (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 on silica gel (100-200 mesh), and the compound was eluted with 10% SiO in hexane to obtain 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) cooled to -78°C in anhydrous THF (200 mL), n-BuLi (1.6 M solution in hexane) (204.0 mL, 326.563 mmol) was added dropwise. The resulting mixture was stirred for 15 minutes, then anhydrous DMF (35.9 g, 491.80 mmol) was added, and stirring was continued at the same temperature for 30 minutes. After the reaction was complete, the reaction mixture was quenched with saturated aqueous NH4Cl (150 mL) and extracted with RINKAN (2 × 200 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 15% RINKAN in hexane to obtain compound I-21-3 (10.0 g, yield: 57%) as a rubbery 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) cooled to 0°C in anhydrous THF (180 mL), methylmagnesium bromide (1.0 M solution in THF) (705.0 mL, 70.496 mmol) was added dropwise, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with ice water (100 mL) and extracted with siRNA (2 × 300 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 20% siRNA in hexane to obtain compound I-21-4 (15.0 g, yield: 78%) as a rubbery solid.

[0314] (Synthesis of tert-butyl (2-(5-acetylthiophen-2-yl)ethyl)carbamate (I-21-5)) To a 100 mL solution of compound I-21-4 (10 g, 36.849 mmol) cooled to 0°C in anhydrous DCM, Dess-Martin periodinane (46.8 g, 110.547 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was filtered through a Celite pad, washed with dichloromethane, and then the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluted with 15% siRNA in hexane, yielding compound I-21-5 (7.1 g, yield: 72%) as a rubbery 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 anhydrous THF (70.0 mL), trimethylphenylammonium tribromide (7.8 g, 20.789 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After evaporating the solvent, the crude product was purified by combi-flash reverse-phase chromatography to obtain 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)) [ka]

[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), NaH (6.56 g, 273.0 mmol) and then methyl iodide (12.8 mL, 205.5 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with ice water (150 mL), extracted with ethyl acetate (2 × 500 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain 43 g of crude compound I-22-1, which was then proceeded 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 anhydrous THF (400.0 mL), n-BuLi (1.6 M in hexane) (224 mL, 359.47 mmol) was added at -78°C and the mixture was stirred at -78°C for 30 minutes. DMF (27.9 mL, 359.47 mmol) was added at -78°C and the mixture was stirred for 2 hours. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (200.0 mL), extracted with siRNA (2 × 500 mL), and the combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluted with 12% siRNA in hexane to obtain compound I-22-2 (6.5 g, yield: 35%) as a rubbery liquid, which was 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 anhydrous THF (250.0 mL), methylmagnesium bromide (1.0 M in THF) (509 mL, 509.0 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (500 mL) and washed with siRNA (2 × 500 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluted with 20% siRNA in hexane, yielding compound I-22-3 (10 g, yield: 72%) as a rubbery liquid, which was 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), PCC (19.8 g, 92.2 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted with 20% siRNA in hexane to obtain compound I-22-4 (7.6 g, yield: 77%) as a rubbery liquid, which was used without further purification.

[0321] (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)-carbamate (I-22)) Phenylentrimethylammonium tribromide (4.20 g, 11.1 mmol) was added at 0°C to a solution mixture of compound I-22-4 (4.3 g, 15.9 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a Celite bed and concentrated under vacuum. The crude compound was purified using combi-flash reverse-phase purification (using ACN and 0.001% TFA in water) to obtain compound I-22 (1.5 g, yield: 27%) as a light brown solid.

[0322] (Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)piperidine-1-carboxylate (I-23)) [ka]

[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 anhydrous THF (10 mL) was cooled to -78°C, and then LiHMDS (1.0 M in THF, 6.0 mL, 5.934 mmol) was added dropwise. The mixture was stirred for 60 minutes, and then N-(5-chloropyridine-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (2.33 g, 5.934 mmol) in THF was added. The reaction mixture was stirred at the same temperature for 30 minutes, and then slowly warmed to room temperature. The reaction mixture was quenched with saturated NaHCO3 water (10 mL) and then extracted with toluene (2 × 50 mL). The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh, 10% ethyl acetate in hexane) to obtain the title compound I-23-1 (0.63 g, 37% yield) as a rubbery liquid.

[0324] (Synthesis of tert-butyl 4-(5-acetylthiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(I-23-2)) (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) were stirred in 1,4-dioxane:H2O (10:2 mL). Under N2, K2CO3 (652 mg, 4.731 mmol) and Pd(PPh3)4 (182 mg, 0.155 mmol) were added. The mixture was stirred for 15 minutes and then heated at 90°C for 16 hours. The reaction mixture was quenched with saturated NaHCO3 water (20 mL) and then extracted with siRNA (2 × 50 mL). The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to obtain the crude compound. The residue was purified by column chromatography using silica gel (60-120 mesh, 20% ethyl acetate in hexane) to obtain the title compound I-23-2 (201 mg, yield 44%) as a rubbery 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), 10% Pd-C (1.5 g) was added, and then H2 gas was added at 60 psi for 5 hours. The reaction mixture was filtered under vacuum. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh, 50% ethyl acetate in hexane) to obtain the title compound I-23-3 (852 mg, 66% yield) as a 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 anhydrous THF (5 mL), tetrabutylammonium tribromide (3 g, 6.261 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain the title compound I-23 (310 mg, 49% yield). This crude product was used directly in the next step.

[0327] (Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-thienyl]-4-methoxypiperidine-1-carboxylate (I-24)) [ka]

[0328] (Synthesis of tert-butyl 4-(5-bromo-2-thienyl)-4-methoxypiperidine-1-carboxylate (I-24-1)) To a solution of I-10-2 (11 g, 30.36 mmol) in THF (100 mL), NaH (1.46 g, 36.44 mmol, 16.56 μL, 60% purity) was added at 0°C. After addition, the mixture was stirred at this temperature for 20 minutes, 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 hours. The reaction mixture was quenched at 0°C by adding H2O (100 mL) and extracted with siRNA (300 mL (100 mL x 3)). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-24-1 (7 g, 18.60 mmol, yield 61.26%) as a yellow oil.

[0329] (Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)-2-thienyl]-4-methoxypiperidine-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, purged three times with N2, and then stirred at 85°C under an N2 atmosphere for 16 hours. The reaction mixture was quenched with saturated KF (100 mL) and extracted with SiO2 (100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-24-2 (11 g, 23.95 mmol, yield 90.11%, 80% purity) as a black oil.

[0330] (Synthesis of tert-butyl 4-[5-(2-bromoacetyl)-2-thienyl]-4-methoxypiperidine-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), NBS (187.43 mg, 1.05 mmol, 0.9 eq) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (10 mL) and extracted with siRNA (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the 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 obtain compound I-24 (500 mg, 956.15 μmol, yield 81.72%, 80% purity) as a yellow solid.

[0331] (2-(difluoromethyl)-6-methoxypyrido[2,3-d]pyrimidine-4-yl]sulfanyl-1-[2-(4-hydroxy-4-piperidyl)thiazole-5-yl]ethanone(I-25)) [ka]

[0332] (Synthesis of tert-butyl 4-(5-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (I-25-1)) To a solution of tert-butyl 4-hydroxy-4-thiazole-2-ylpiperidine-1-carboxylate (12.0 g, 42.2 mmol) in MeCN (120 mL), NBS (9.01 g, 50.6 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was quenched with H₂O (30 mL) and extracted with siRNA (90 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-17% siRNA / petroleum ether gradient @ 100 mL / min) to obtain compound I-25-1 (9.3 g, 25.60 mmol, yield 60.67%) as a yellow oil.

[0333] (Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)thiazole-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), 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) were added under N2. The mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 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-methoxypyrido[2,3-d]pyrimidine-4-yl]sulfanyl-1-[2-(4-hydroxy-4-piperidyl)thiazole-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), NBS (1.27 g, 7.14 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% siRNA / petroleum ether gradient @ 40 mL / min) to obtain compound I-25 (694 mg, 1.71 mmol, 26.4% yield) as a yellow solid.

[0335] (Synthesis of tert-butyl 4-[5-(2-bromoacetyl)thiazole-2-yl]-4-methoxypiperidine-1-carboxylate (I-26)) [ka]

[0336] (Synthesis of tert-butyl 4-(5-bromothiazol-2-yl)-4-methoxypiperidine-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), NaH (198 mg, 4.95 mmol, 60.0% purity) was added under N2 conditions at 0°C. The mixture was stirred at 0°C for 2 hours. Then, MeI (2.34 g, 16.5 mmol) was added to the mixture and stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (10 mL) and extracted with RINKAN (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent of 0-12% siRNA / petroleum ether gradient @ 40 mL / min) to obtain 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)thiazole-2-yl]-4-methoxypiperidine-1-carboxylate (I-26-2)) To a solution of I-26-1 (1.10 g, 2.92 mmol) in dioxane (10 mL), tributyl(1-ethoxyvinyl) stannane (1.58 g, 4.37 mmol), Pd(PPh3)2Cl2 (205 mg, 292 μmol), and TEA (590 mg, 5.83 mmol) were added under N2. The mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-26-2 (2.70 g, 2.20 mmol, 75.4% yield, 30.0% purity) as a brown solid.

[0338] (Synthesis of tert-butyl 4-[5-(2-bromoacetyl)thiazole-2-yl]-4-methoxypiperidine-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), NBS (587 mg, 3.30 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% siRNA / petroleum ether gradient @ 40 mL / min) to obtain compound I-26 (320 mg, 789 μmol, 23.9% yield) as a yellow solid.

[0339] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate (I-27)) [ka]

[0340] (Synthesis of tert-butyl 3-hydroxy-3-(thiazole-2-yl)pyrrolidine-1-carboxylate (I-27-1)) To a solution of 2-bromothiazole (54 g, 329 mmol) in THF (500 mL), n-BuLi (2.5 M, 145 mL) was added dropwise at -78°C. After addition, the mixture was stirred at this temperature for 0.5 hours, 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 hours. TLC showed that the 2-bromothiazole was completely consumed and a new spot had formed. The reaction mixture was quenched at 0°C by adding saturated aqueous NH4Cl (500 mL), then diluted with H2O (1000 mL), and extracted with Â(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 obtain the 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 obtain compound I-27-1 (45.5 g, yield 46.1%) as a yellow oil.

[0341] (Synthesis of tert-butyl 3-(5-bromothiazol-2-yl)-3-hydroxypyrrolidine-1-carboxylate (I-27-2)) NBS (35.8 g, 201 mmol) was added to a solution of I-27-1 (45.3 g, 168 mmol) in DMF (220 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was partitioned between H2O (800 mL) and siRNA (1500 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-27-2 (29 g, yield 49.6%) as a brown oil.

[0342] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazole-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, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (100 mL), then diluted with H2O (50 mL), extracted with SiO2 (200 mL (100 mL × 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 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), NBS (680 mg, 3.82 mmol) was added dropwise at 0°C. After addition, the mixture was stirred at this temperature for 0.5 hours. The resulting mixture was stirred at 25°C for 1.5 hours. The reaction mixture was partitioned between RINKAN (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine (100 mL (50 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-27 (3.5 g, crude) as a yellow oil.

[0344] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-methoxypyrrolidine-1-carboxylate (I-28)) [ka]

[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), NaH (1.13 g, 28.35 mmol, 60% purity) was added at 0°C under an N2 atmosphere. After the addition, the mixture was stirred at this temperature for 0.5 hours, 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 hours. The reaction mixture was quenched at 0°C by adding saturated NH4Cl aqueous solution (50 mL), then diluted with H2O (100 mL), and extracted with siRNA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 60 mL / min) to obtain compound I-28-1 (6.4 g, yield 91.4%) as a yellow oil.

[0346] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazole-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 mmol), and Pd(PPh3)2Cl2 (386 mg, 551 μmol) in dioxane (40 mL) was degassed, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (100 mL), then diluted with H2O (100 mL), extracted with SiO2 (200 mL (100 mL × 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain compound I-28-2 (2.9 g, yield 67.1%) as a yellow oil.

[0347] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-methoxypyrrolidine-1-carboxylate (I-28)) NBS (894 mg, 5.02 mmol) was added to a solution of I-28-2 (1.78 g, 5.02 mmol) in THF (20 mL) and H2O (10 mL). The mixture was stirred at 0°C for 1 hour. The reaction mixture was partitioned between siRNA (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 obtain the 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 obtain compound I-28 (1.38 g, yield 67.0%) as a yellow oil.

[0348] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiazol-2-yl)-3-fluoropyrrolidine-1-carboxylate (I-29)) [ka]

[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), DAST (4.06 g, 25.2 mmol) was added at -78 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched at 0 °C by adding H2O (50 mL), then diluted with H2O (100 mL), and extracted with DCM (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 obtain the 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 obtain compound I-29-1 (6.5 g, yield 76.0%, 94.1% purity) as a brown solid.

[0350] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiazole-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, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (100 mL), then diluted with H2O (50 mL), extracted with SiO2 (200 mL (100 mL × 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain compound I-29-2 (3.99 g, yield 94.3%, 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), NBS (1.04 g, 5.84 mmol, 1 eq) was added. The mixture was stirred at 0°C for 2 hours. TLC showed that the I-29-2 was completely consumed and that one new spot had formed. According to TLC, the reaction was clean. The reaction mixture was partitioned between siRNA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-15% ethyl acetate / petroleum ether gradient @ 60 mL / min) to obtain compound I-29 (1.6 g, 67.0% yield, 96.1% purity) as a yellow solid.

[0352] Compounds I-30 to I-33 listed below were prepared using the same experimental conditions as those described for I-27 to I-29. [Table 18]

[0353] (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxyethyl)carbamate (I-34)) [ka]

[0354] (Synthesis of tert-butyl (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), n-BuLi (2.5 M, 19.8 mL) was added dropwise at -78 °C. After the addition, the mixture was stirred at this temperature for 0.5 hours, 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 hours. The reaction mixture was quenched at 0 °C by adding saturated aqueous NH4Cl (500 mL), then diluted with H2O (1000 mL), and extracted with ELISA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® silica flash column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 60 mL / min) to obtain compound I-34-1 (4.5 g, yield 28.2%) 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, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (100 mL), then diluted with H2O (100 mL), and extracted with SiO2 (400 mL (200 mL x 2)). It was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-34-2 (13 g, crude) as a black oil.

[0356] (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxyethyl)carbamate (I-34)) NBS (2.21 g, 12.4 mmol) was added to a solution of I-34-2 (3.89 g, 12.4 mmol) in THF (40 mL) and H2O (20 mL). The mixture was stirred at 0°C for 1 hour. TLC showed that the I-34-2 was completely consumed and two new spots had formed. The reaction mixture was partitioned between RINKAN (80 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 obtain the 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 obtain compound I-34 (5 g, yield 34.3%, 31% purity) as a yellow solid.

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

[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-iodopyridine (4.00 g, 14.09 mmol) in THF (60 mL), n-BuLi (2.5 M, 6.20 mL) was added under N2 at -78°C. The mixture was stirred under N2 at -78°C for 1 hour. 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 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.46) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched at 0°C by adding H2O (80 mL) and extracted with siRNA (80 mL (50 mL x 3)). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-30% THF / petroleum ether gradient @ 60 mL / min) to obtain compound I-35-1 (2.23 g, 6.50 mmol, yield 46.11%) 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) stannan (631.35 mg, 1.75 mmol, 590.60 μL), TEA (176.90 mg, 1.75 mmol, 243.32 μL), and Pd(PPh3)2Cl2 (61.35 mg, 87.41 μmol) in dioxane (15 mL) was degassed, purged three times with N2, and then stirred at 90°C under an N2 atmosphere for 16 hours. The reaction mixture was quenched with saturated KF (10 mL) and extracted with HCl (30 mL (10 mL x 3)). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain compound I-35-2 (800 mg, 717.68 μmol, yield 82.11%, 30.00% purity) as a black oil.

[0360] (Synthesis of tert-butyl 3-[6-(2-bromoacetyl)-3-pyridyl]-3-hydroxypyrrolidine-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), NBS (212.89 mg, 1.20 mmol) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (10 mL) and extracted with siRNA (10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the 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 obtain compound I-35 (200 mg, 519.14 μmol, yield 43.40%) as a yellow solid.

[0361] (Synthesis of a mixture 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 (I-36)) [ka]

[0362] (Synthesis of tert-butyl 4-hydroxy-3-methyl-4-(2-thienyl)piperidine-1-carboxylate (I-36-1)) 2-bromothiophene (10 g, 61.34 mmol) was dissolved in THF (100 mL) and n-BuLi (2.5 M, 26.99 mL) was added at -78°C under N2. The mixture was stirred at -78°C under N2 for 1 hour. Tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (15.70 g, 73.60 mmol) was added to the mixture at -78°C and stirred at -78°C under N2 for 1 hour. The mixture was then stirred at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched by adding H2O (100 mL) at 0°C and extracted with SiO2 (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® silica flash column, eluent of 0-30% THF / petroleum ether gradient @ 60 mL / min) to obtain compound I-36-1 (17 g, 57.16 mmol, yield 93.19%) as a colorless oil.

[0363] (Synthesis of tert-butyl 4-(5-bromo-2-thienyl)-4-hydroxy-3-methylpiperidine-1-carboxylate (I-36-2)) To a solution of I-36-1 (5.5 g, 18.49 mmol) in DMF (30 mL), NBS (3.62 g, 20.34 mmol) was added. The mixture was stirred at 25°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched at 0°C by adding H2O (100 mL) and extracted with SiO2 (300 mL (100 mL x 3)). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluent of 0-40% THF / petroleum ether gradient @ 60 mL / min) to obtain compound I-36-2 (6g, 15.94 mmol, yield 86.22%) as a yellow oil.

[0364] (Synthesis of tert-butyl 4-[5-(1-ethoxyvinyl)-2-thienyl]-4-hydroxy-3-methylpiperidine-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) stannan (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, purged three times with N2, and then stirred at 85°C for 16 hours under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.68) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched with saturated KF (100 mL) and extracted with SiO2 (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain compound I-36-3 (6 g, 11.43 mmol, yield 71.68%, 70% purity) as a black oil.

[0365] (Synthesis of a mixture 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 (I-36)) To a solution of I-36-3 (6 g, 11.43 mmol) in THF (40 mL) and H2O (20 mL), NBS (4.07 g, 22.86 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (80 mL) and extracted with siRNA (80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the 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 obtain compound I-36 (5 g, 8.13 mmol, yield 71.11%, 68% purity) 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)) [ka]

[0367] (Synthesis of tert-butyl 3-hydroxy-3-(2-thienyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (I-37-1)) 2-bromothiophene (2 g, 12.27 mmol) was dissolved in THF (50 mL) and n-BuLi (2.5 M, 5.40 mL) was added under N2 at -78°C. The mixture was stirred under N2 at -78°C for 1 hour. 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 under N2 at -78°C for 1 hour. The mixture was then stirred at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched at 0°C by adding H2O (80 mL) and extracted with SiO2 (80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® silica flash column, eluent of 0-30% THF / petroleum ether gradient @ 60 mL / min) to obtain compound I-37-1 (2.4 g, 7.76 mmol, yield 63.23%) 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), NBS (3.51 g, 19.75 mmol) was added. The mixture was stirred at 25°C for 1 hour. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched at 0°C by adding H2O (100 mL) and extracted with SiO2 (300 mL (100 mL x 3)). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluent of 0-40% THF / petroleum ether gradient @ 60 mL / min) to obtain compound I-37-2 (4.3 g, 11.07 mmol, yield 72.90%) 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, purged three times with N2, and then stirred at 85°C for 16 hours under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.64) showed that the starting compound had been consumed and a new spot had formed. The reaction mixture was quenched with saturated KF (60 mL) and extracted with SiO2 (60 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain compound I-37-3 (6 g, 6.32 mmol, 57.11% yield, 40% purity) 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), NBS (3.75 g, 21.08 mmol) was added. The mixture was stirred at 0-25°C for 2 hours. The reaction mixture was quenched with H2O (80 mL) and extracted with siRNA (80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the 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 obtain compound I-37 (2.3 g, 5.34 mmol, yield 50.71%) as a yellow oil.

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

[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), n-BuLi (2.5 M, 13.49 mL) was added all at once under N2 at -70°C. The mixture was stirred at -70°C for 1 hour, and then tert-butyl 4-formylpiperidine-1-carboxylate (7.19 g, 33.73 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into ice-water (100 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-38-1 (4.6 g, 15.47 mmol, yield 50.43%) as a white solid.

[0373] (Synthesis of tert-butyl 4-((5-bromothiophen-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (I-38-2)) 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, purged three times with N2, and then the mixture was stirred at 25°C for 2 hours under an N2 atmosphere. The reaction mixture was poured into water (50 mL) and extracted with SiO2 (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 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 (I-38-3)) Compound I-38-2 (3 g, 7.97 mmol) and tributyl(1-ethoxyvinyl) stannane (5.76 g, 15.94 mmol, 5.39 mL) were dissolved in dioxane (20 mL). Under an N2 atmosphere, TEA (2.42 g, 23.92 mmol, 3.33 mL) and Pd(PPh3)2Cl2 (559.56 mg, 797.22 μmol) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding H2O (100 mL) and extracted with RINKAN (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 under vacuum to obtain 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), NBS (1.45 g, 8.16 mmol) was added. The mixture was stirred at 0°C for 0.5 hours. TLC showed that compound I-38-3 was completely consumed and many new spots had formed. The reaction mixture was quenched at 25°C by adding H2O (20 mL) and extracted with RINKAN (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 obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound I-38 (1.7 g, crude) as a yellow oil.

[0376] (Synthesis of tert-butyl 4-(5-(2-bromoacetyl)thiophen-2-yl)-4-cyanopiperidine-1-carboxylate (I-39)) [ka]

[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), NaNH2 (9.50 g, 243.56 mmol) was added dropwise at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 1 hour. 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 hours. The residue was poured into saturated NH4Cl (10 mL) and extracted with RINKAN (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain 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), NBS (2.19 g, 12.31 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (70 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with H2O (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-39-2 (2.6 g, 7.00 mmol, yield 68.25%) as a pale 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), 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) were added under N2. The mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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), NBS (1.18 g, 6.62 mmol) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with RINKAN (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain 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)) [ka]

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

[0383] (Synthesis of tert-butyl 5-(5-(1-ethoxyvinyl)thiazole-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (I-40-2)) Compound I-40-1 (8 g, 22.21 mmol) and tributyl(1-ethoxyvinyl) stannane (16.04 g, 44.41 mmol, 15.00 mL) were dissolved in dioxane (200 mL). Under an N2 atmosphere, TEA (6.74 g, 66.62 mmol, 9.27 mL) and Pd(PPh3)2Cl2 (1.56 g, 2.22 mmol) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding H2O (100 mL) and extracted with SiO2 (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 under vacuum to obtain compound I-40-2 (15.4 g, crude product) 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), NBS (6.08 g, 34.14 mmol) was added. The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was quenched at 25°C by adding H2O (100 mL) and extracted with SiO2 (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain 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]heptan-5-carboxylate (I-41)) [ka]

[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), thiophene-2-ylmagnesium bromide (1 M, 50.20 mL) was added dropwise at -70°C under N2. The mixture was stirred at 25°C under N2 for 2 hours. The reaction mixture was quenched by the dropwise addition of saturated NH4Cl water (50 mL) at 0°C under N2 and extracted with siRNA (150 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~2 / 1) to obtain I-41-1 (4.8 g, 16.14 mmol, yield 32.15%) 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)) NaBH4 (25.44 mg, 672.56 μmol) was added to a solution of I-41-1 (100 mg, 336.28 μmol) in MeOH (10.0 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding H2O (2.0 mL) and extracted with HCl (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain I-41-2 (68 mg, 227.13 μmol) as a white oil.

[0388] (Synthesis of tert-butyl (1S,3S,4S)-3-(thiophen-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptan-5-carboxylate (I-41-3)) To a solution of compound I-41-2 (3.00 g, 10.02 mmol) in toluene (30 mL), 2-(tributyl-phosphanylidene)acetonitrile (4.84 g, 20.04 mmol) was added at 25 °C. The mixture was stirred at 100 °C for 1 hour. The reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1~5 / 1) to obtain compound I-41-3 (2.5 g, 8.89 mmol, yield 88.67%) 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), NBS (1.21 g, 6.82 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (70 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with H2O (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-41-4 (1.9 g, 5.27 mmol, yield 92.74%) as a pale 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), 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) were added under N2. The mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with RINKAN (30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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]heptan-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), NBS (988.07 mg, 5.55 mmol) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with RINKAN (30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain 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-azabicyclo[2.2.1]heptane-5-carboxylate (I-42)) [ka]

[0393] (Synthesis of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(thiophen-2-yl)pyrrolidine-2-carboxylic acid (I-42-1)) (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (10 g, 43.62 mmol) was dissolved in THF (200 mL) and thiophene-2-ylmagnesium bromide (1 M, 52.35 mL) was added dropwise at -70°C under N2. The mixture was stirred at 25°C under N2 for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl water (50 mL) at 0°C under N2 and extracted with siRNA (250 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~2 / 1) to obtain I-42-1 (9.5 g, 30.32 mmol, yield 69.49%) 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), BH3·THF (1 M, 15.96 mL) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by adding MeOH (20.0 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain I-42-2 (3 g, 10.02 mmol, yield 62.80%) as a 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), 2-(tributyl-phosphanylidene)acetonitrile (4.8 g, 20.04 mmol) was added at 25 °C. The mixture was stirred at 100 °C for 1 hour. The reaction mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 50 / 1~5 / 1) to obtain compound I-42-3 (2.5 g, 8.89 mmol, yield 95.00%) 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), NBS (2.06 g, 11.55 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H2O (70 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with H2O (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound I-42-4 (2.8 g, 7.77 mmol, yield 87.47%) as a pale 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), 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) were added under N2. The mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with SiO2 (30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 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), NBS (2.77 g, 15.54 mmol) was added. The mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with H2O (20.0 mL) and extracted with siRNA (30.0 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~4 / 1) to obtain 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)) [ka]

[0400] (Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate (I-43-1)) 20 g, 99.4 mmol of tert-butyl 3-oxomorpholine-4-carboxylate was dissolved in 200 mL of THF. The mixture was cooled to -30°C, and 109 mL of LiHMDS (1 M) was added dropwise. The resulting mixture was stirred for 1 hour, and then 28.0 g, 104 mmol of chloro(phenoxy)phosphoryl oxybenzene was added dropwise. The resulting mixture was slowly heated to 43°C for 6 hours. The reaction mixture was poured into 1000 mL of saturated ammonium chloride solution and diluted with 1000 mL of toluene. The organic phase was separated, washed with 500 mL of saturated NaHCO3, then with 500 mL of brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 220g SepaFlash® silica flash column, eluent of 0-12% THF / petroleum ether gradient @ 80 mL / min) to obtain compound I-43-1 (26.6 g, yield 61.8%) 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, purged three times with N2, and then stirred at 60°C under an N2 atmosphere for 16 hours. The reaction mixture was partitioned between RINKAN (800 mL) and brine (600 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 220g SepaFlash® silica flash column, eluent of 0-3% ethyl acetate / petroleum ether gradient @ 80 mL / min) to obtain compound I-43-2 (14.5 g, yield 97.9%) 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), HCl / dioxane (2 M, 252 mL) was added. The mixture was stirred at 25°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was poured into a saturated NaHCO3 solution (pH > 7) and extracted with siRNA (900 mL (300 mL x 3)). The organic phase was separated, washed with brine (1200 mL (600 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-43-3 (7.8 g, yield 92.4%) 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), NaBH3CN (4.51 g, 71.8 mmol) and AcOH (6.46 g, 108 mmol) were added. The mixture was stirred at 25°C for 6 hours. The reaction mixture was partitioned between toluene (60 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 obtain 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), DIEA (15.3 g, 118 mmol) and Boc2O (25.79 g, 118.17 mmol, 27.15 mL) were added. The mixture was stirred at 25°C for 16 hours. TLC showed that I-43-4 was completely consumed and a new spot had formed. According to TLC, the reaction was clean. The reaction mixture was concentrated under reduced pressure to remove the 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 obtain I-43-5 (10 g, yield 61.3%, 97.6% purity) as a colorless oil.

[0405] (Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)morpholine-4-carboxylate (I-43-6)) NBS (6.61 g, 37.1 mmol) was added to a solution of I-43-5 (10 g, 37.13 mmol) in DMF (100 mL). The mixture was stirred at 25°C for 6 hours. The reaction mixture was partitioned between siRNA (600 mL) and H2O (600 mL). The organic phase was separated, washed with brine (600 mL (300 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-43-6 (11 g, yield 85.1%) 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), Pd(PPh3)2Cl2 (1.01 g, 1.44 mmol), and TEA (8.72 g, 86.1 mmol) in dioxane (100 mL) was degassed, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (1000 mL), then diluted with H2O (1000 mL), extracted with SiO2 (2000 mL (1000 mL × 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-43-7 (20 g, crude) as a brown oil.

[0407] (Synthesis of tert-butyl 3-(5-(1-ethoxyvinyl)thiophen-2-yl)morpholine-4-carboxylate (I-43)) NBS (5.09 g, 28.6 mmol) was added to a solution of I-43-7 (9.7 g, 28.6 mmol) in THF (90 mL) and H2O (90 mL). The mixture was stirred at 0°C for 1 hour. TLC showed that the I-43-7 was completely consumed and that one new spot had formed. According to TLC, the reaction was clean. The reaction mixture was partitioned between siRNA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 220g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 80 mL / min) to obtain compound I-43 (6 g, yield 30.1%, 56% purity) as a yellow solid.

[0408] (Synthesis of a mixture 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 (I-44)) [ka]

[0409] (Synthesis of tert-butyl 3-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (I-44-1)) To a solution of (2-thienyl)magnesium bromide (1M, 301) in THF (300 mL), CuI (4.78 g, 25.09 mmol, 0.1 eq) was added dropwise at 0°C. After the addition, 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 hours. The reaction mixture was quenched at 0°C by adding saturated aqueous NH4Cl (100 mL), then diluted with H2O (800 mL), and extracted with ELISA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 330g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 80 mL / min), and further separated by preparative HPLC (NH3H2O ​​conditions) to obtain compound I-44-1 (9 g, yield 12.7%) as a yellow oil.

[0410] (Synthesis of tert-butyl 4-(5-bromothiophen-2-yl)-3-hydroxypiperidine-1-carboxylate (I-44-2)) NBS (4.90 g, 27.5 mmol) was added to a solution of I-44-1 (7.8 g, 27.5 mmol) in DMF (60 mL). The mixture was stirred at 0°C for 2 hours. TLC showed that I-44-1 was completely consumed and a new spot had formed. According to TLC, the reaction was clean. The reaction mixture was partitioned between siRNA (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 obtain the 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 obtain compound I-44-2 (8.3 g, yield 83.2%) 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, purged three times with N2, and then stirred at 90°C for 6 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (500 mL), then diluted with H2O (600 mL), extracted with siRNA (800 mL (400 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-44-3 (30 g, crude) as a brown oil.

[0412] (Synthesis of a mixture 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 (I-44)) NBS (4.08 g, 22.9 mmol) was added to a solution of I-44-3 (8.1 g, 22.9 mmol) in THF (100 mL) and H2O (50 mL). The mixture was stirred at 0°C for 1 hour. The reaction mixture was partitioned between siRNA (80 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 obtain the 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 obtain compound I-44 (5 g, yield 32.3%, 59.8% purity) as a yellow solid.

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

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

[0415] (Synthesis of 2-(benzyl(2-hydroxyethyl)amino)-1-(5-bromothiophen-2-yl)ethane-1-one (I-45-2)) Compound I-45-1 (41.4 g, 146 mmol) and 2-(benzylamino)ethanol (33.1 g, 219 mmol, 31.0 mL) were dissolved in DMF (420 mL), to which K2CO3 (60.4 g, 437 mmol) was added. The mixture was stirred at 25°C for 2 hours. Water (800 mL) was added to the reaction mixture and extracted with SiO2 (1000 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 6 / 1) to obtain compound I-45-2 (37.3 g, 104 mmol, yield 71.3%, 98.8% purity) as a brown oil.

[0416] (Synthesis of 2-(benzyl(2-hydroxyethyl)amino)-1-(5-bromothiophen-2-yl)ethane-1-ol(I-45-3)) To a solution of compound I-45-2 (37.3 g, 104 mmol) in MeOH (380 mL), NaBH4 (4.41 g, 117 mmol) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (500 mL) at 0°C under N2 and extracted with SiO4 (800 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-45-3 (34.8 g, 87.4 mmol, yield 84.1%, purity 89.6%) 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 hours. The mixture was quenched with water (400 mL) at 0°C under N2 and extracted with siRNA (600 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1) to obtain compound I-45-4 (26.9 g, 74.7 mmol, yield 76.5%, 94.0% purity) as a brown oil.

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

[0419] (Synthesis of 2-(5-bromothiophen-2-yl)morpholine (I-45-6)) A solution of compound I-45-5 (10.0 g, 25.6 mmol) in dioxane (50.0 mL) was mixed with a solution of NaOH (1.54 g, 38.4 mmol) in H2O (50 mL). The mixture was stirred at 110 °C for 3 hours. Water (100 mL) was added to the reaction mixture and extracted with DCM (200 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound I-45-6 (8.83 g, 17.4 mmol, yield 67.9%, purity 48.8%) 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), Boc2O (5.56 g, 25.5 mmol, 5.85 mL) and TEA (5.16 g, 51.0 mmol, 7.09 mL) were added. The mixture was stirred at 25°C for 2 hours. Water (150 mL) was added to the mixture and extracted with RINKAN (200 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 7 / 1) to obtain compound I-45-7 (3.65 g, 9.61 mmol, yield 56.61%, 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)) Compound I-45-7 (3.65 g, 9.61 mmol) and tributyl(1-ethoxyvinyl) stannane (6.18 g, 17.1 mmol, 5.78 mL) were dissolved in dioxane (37.0 mL). Under N2 conditions, TEA (1.95 g, 19.2 mmol, 2.68 mL) and Pd(PPh3)2Cl2 (675 mg, 961 μmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction was quenched with KF water (60 mL) and extracted with SiO2 (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-45-8 (10.2 g, crude product) 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), NBS (2.00 g, 11.2 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. Water (60 mL) was added to the reaction and extracted with SiO2 (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~4 / 1) to obtain compound I-45 (2.90 g, 5.48 mmol, yield 18.2%, 73.7% purity) as a yellow solid.

[0423] (Synthesis of a mixture 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 (I-46)) [ka]

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

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

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

[0427]

[0423] (Synthesis of a mixture 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 (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), TBATB (1.50 g, 3.11 mmol) was added. The mixture was stirred at 25°C for 4 hours. Water (20 mL) was added to the reaction and extracted with DCM (20 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-46 (1.26 g, 1.55 mmol, yield 52.3%, purity 51.2%) as a yellow solid.

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

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

[0430] (Synthesis of (5-bromothiophene-2-yl)(tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol(I-47-2)) To a 10 mL solution of 2,5-dibromothiophene (1.00 g, 4.13 mmol, 466 μL), n-BuLi (2.50 M, 1.82 mL) was added under N2 at -70°C. The mixture was stirred for 1 hour under N2 at -70°C. A 10 mL solution of compound I-47-1 (1.50 g, 10.8 mmol) was added to the reaction mixture at -70°C and stirred for 1 hour under N2 at -70°C. The mixture was stirred at 25°C for 16 hours. The reaction was quenched with NH4Cl water (30 mL) at 0°C and extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 0 / 1) to obtain compound I-47-2 (225 mg, 744 μmol, yield 18.0%) 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), 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) were added under N2. The mixture was stirred at 90°C for 16 hours under N2. The reaction was quenched with KF water (10 mL) and extracted with SiO2 (20 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-47-3 (721 mg, crude product) as a brown oil.

[0432] (Synthesis of 2-bromo-1-(5-(hydroxy(tetrahydro-1H-pyrrolizin(pyrrolizin)-7a(5H)-yl)methyl)thiophen-2-yl)ethane-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), NBS (219 mg, 1.23 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was extracted with SiO2 (10 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-47 (670 mg, crude product) as a brown oil.

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

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

[0435] (Synthesis of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxypropanoate (I-48-2)) NBS (72.5 g, 407 mmol) was added to a solution of I-48-1 (54.4 g, 271 mmol) in DMF (500 mL). The mixture was stirred at 25°C for 6 hours. The reaction mixture was partitioned between siRNA (800 mL) and H2O (600 mL). The organic phase was separated, washed with brine (800 mL (400 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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, yield 88.4%) 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, 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 hour. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. The combined aqueous layer was washed with DCM (300 mL), and the reaction mixture was poured into a 1N HCl solution (pH < 7). The reaction mixture was partitioned between DCM (600 mL) and H2O (500 mL) to separate the organic phase, washed with brine (600 mL (300 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 220g SepaFlash® silica flash column, eluent of 0-50% THF / petroleum ether gradient @ 90 mL / min) to obtain compound I-48-3 (35 g, yield 97.3%) 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), 2-chloroethane-1-amine (346 mg, 2.99 mmol), HATU (1.14 g, 2.99 mmol), and DIEA (772.1 mg, 5.97 mmol) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was partitioned between siRNA (60 mL) and H2O (60 mL). The organic phase was separated, washed with brine (80 mL (40 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether gradient @ 80 mL / min). Compound I-48-4 (460 mg, yield 73.9%) 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), t-BuOK (29.2 mg, 0.26 mmol) was added under N2. The mixture was stirred at 25°C for 1 hour. The reaction mixture was extracted with RINKAN (15 mL (5 mL x 3)). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 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), 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) were added under N2. The mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with saturated KF solution (50 mL) and extracted with SiO2 (150 mL (50 mL x 3)). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-48-6 (6.0 g, crude product) 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), NBS (702.61 mg, 3.95 mmol) was added. The mixture was stirred at 0°C for 2 hours. LC-MS indicated that the desired product had formed and that the starting material had been completely consumed. The reaction mixture was quenched with H2O (10 mL) and extracted with HCl (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 SepaFlash® silica flash column, eluent of 0-40% HCl / petroleum ether gradient @ 80 mL / min) to obtain 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), BH3·THF (1.00 M, 5.07 mL) was added under N2 at -70°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with 2N HCl (7 mL) and stirred at 25°C for 20 minutes. The mixture was adjusted to pH=11 with 4N NaOH and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 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), Boc2O (1.44 g, 6.61 mmol, 1.52 mL) and K2CO3 (914 mg, 6.61 mmol) were added. The mixture was stirred at 25°C for 1 hour. Water (10 mL) was added to the reaction mixture and extracted with SiO2 (10 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~4 / 1) to obtain compound I-48-9 (897 mg, 2.43 mmol, yield 73.5%, 98.1% purity) as a yellow oil.

[0443] (Synthesis of tert-butyl 2-(5-acetylthiophen-2-yl)-2-methylmorpholine-4-carboxylate (I-48-10)) Compound I-48-9 (897 g, 2.43 mmol) and tributyl(1-ethoxyvinyl) stannane (2.13 g, 5.90 mmol, 1.99 mL) were dissolved in dioxane (10.0 mL). Under N2 conditions, TEA (564 mg, 5.58 mmol, 776 μL) and Pd(PPh3)2Cl2 (196 mg, 279 μmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction was quenched with KF water (20 mL) and extracted with SiO2 (20 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 to 5 / 1) to obtain compound I-48-10 (578 mg, 1.64 mmol, yield 58.9%, 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), TBATB (744 mg, 1.54 mmol) was added. The mixture was stirred at 25°C for 2 hours. Water (5 mL) was added to the reaction and extracted with DCM (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound I-48 (689 mg, crude product) as a brown oil.

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

[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), n-BuLi (2.5 M, 27.3 mL) was added dropwise at -78 °C. After the addition, the mixture was stirred at this temperature for 0.5 hours, 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 hours. The reaction mixture was quenched by adding saturated aqueous NH4Cl (500 mL) at 0 °C, then diluted with H2O (1000 mL), and extracted with siRNA (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 obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® silica flash column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 70 mL / min) to obtain compound I-49-1 (16.2 g, yield 77.8%) 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, purged three times with N2, and then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (500 mL), then diluted with H2O (600 mL), and extracted with siRNA (800 mL (400 mL x 2)). It was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain compound I-49-2 (25 g, crude) as a black oil.

[0448] (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)-2-hydroxyethyl)(methyl)carbamate (I-49)) NBS (7.61 g, 42.8 mmol) was added to a solution of I-49-2 (14 g, 42.8 mmol) in THF (150 mL) and H2O (70 mL). The mixture was stirred at 0°C for 2 hours. The reaction mixture was partitioned between siRNA (800 mL) and H2O (600 mL). The organic phase was separated, washed with brine (1200 mL (600 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-49 (8.1 g, yield 35.0%, 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)) [ka]

[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) in THF (100 mL), CeCl3 (14.3 g, 58.1 mmol) was added dropwise at 25 °C. After addition, the mixture was stirred at this temperature for 1 hour, and then (2-thienyl)magnesium bromide (1 M, 58.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. TLC showed that reactant 1 was completely consumed and that one new spot had formed. According to TLC, the reaction was clean. The reaction mixture was quenched at 0 °C by adding 20% ​​aqueous AcOH (100 mL), then diluted with H2O (200 mL), and extracted with ELISA (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 obtain the 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 obtain compound I-51-1 (5.7 g, yield 90.5%) 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)) NBS (3.74 g, 21.0 mmol) was added to a solution of I-51-1 (5.7 g, 17.5 mmol) in DMF (50 mL). The mixture was stirred at 0°C for 1 hour. TLC showed that I-51-1 was completely consumed and a new spot had formed. According to TLC, the reaction was clean. The reaction mixture was partitioned between siRNA (200 mL) and H2O (200 mL). The organic phase was separated, washed with brine (200 mL (100 mL x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-51-2 (6.4 g, yield 90.4%) 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, purged three times with N2, and then stirred at 90°C for 3 hours under an N2 atmosphere. The reaction mixture was quenched at 25°C by adding saturated KF aqueous solution (500 mL), then diluted with H2O (300 mL), and extracted with SiO2 (600 mL (300 mL x 2)). It was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 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)) NBS (3.96 g, 22.3 mmol) was added to a solution of I-51-3 (5.87 g, 14.8 mmol) in THF (50 mL) and H2O (25 mL). The mixture was stirred at 0°C for 1 hour. TLC showed that I-51-3 was completely consumed and a new spot had formed. According to TLC, the reaction was clean. The reaction mixture was partitioned between RINKAN (80 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 obtain the 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 obtain compound I-51 (3.92 g, yield 59.2%) as a white solid.

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

[0455] (Synthesis of 1,1,1-trifluoro-3-nitro-2-(thiophen-2-yl)propan-2-ol (I-52-1)) TEA (8.43 g, 83.3 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-thienyl)ethanone (10 g, 55.5 mmol) in nitromethane (184 g, 3.01 mol). The mixture was stirred at 35°C for 16 hours. After the reaction was complete, water (500 mL) was added, followed by 1N HCl to adjust the pH to 5-6. The organic phase was separated, and the aqueous phase was extracted with RINKAN (300 mL x 2). The combined organic phase was washed with water (200 mL), then dried, filtered, and concentrated under reduced pressure to obtain compound I-52-1 (13 g, yield 97.1%) 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), PtO2 (1.13 g, 4.98 mmol) was added under an N2 atmosphere. The suspension was degassed and purged twice with H2. The mixture was stirred at 25°C under H2 (50 Psi) for 18 hours. The mixture was filtered through a Celite pad and washed with MeOH (500 mL). The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-50% THF / petroleum ether gradient @ 70 mL / min) to obtain compound I-52-2 (7.8 g, yield 74.2%) 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), TEA (4.48 g, 44.3 mmol) and 2-chloroacetyl chloride (4.62 g, 40.9 mmol) were added. The mixture was stirred at 0°C for 1 hour. 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 x 2)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-52-3 (9.7 g, 33.7 mmol, yield 98.9%) as a colorless 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, purged three times with N2 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 hour. The reaction mixture was quenched at 0°C by adding saturated ammonium chloride solution (100 mL), then diluted with H2O (100 mL), extracted with siRNA (600 mL (200 mL × 3)), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the 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 obtain compound I-52-4 (6 g, yield 60.8%, 77% purity) as a colorless oil.

[0459] (Synthesis of 2-(thiophen-2-yl)-2-(trifluoromethyl)morpholine (I-52-5)) A solution of I-52-4 (5.5 g, 21.9 mmol, 1 eq) in THF (50 mL) was degassed, purged three times with N2 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 hours. The reaction mixture was quenched at 0°C by adding Na2SO4·10H2O (10 g), the reaction mixture was filtered as is, and the filtrate was concentrated. Compound I-52-5 (6 g, crude product) was obtained as a colorless oil. 【0...

Claims

1. A compound for use in the treatment and / or prevention of HDAC6-related diseases; Equation (I) 【Chemistry 1】 (In the formula, ・Y 1 The following formula 【Chemistry 2】 A 9 or 10-membered bicyclic heteroaryl selected from, Here, A 1 、 A 2 、 A 3 、 A 4 、 A 5 、 A 6 、 and A 7 are each independently selected from C-R 7 and N; A 8 , A 9 , A 10 , and A 11 Each of them operates independently, CR 7 and are selected from N, however A 8 , A 9 , A 10 , or A 11 At least one of them is N; G 1 CR 3 and selected from N; G 2 O and NR 4 Selected from; B is O, S, and NR 5 Selected from, However, A 5 , A 6 , and A 7 CR 7 When B is not S; and R 2 These are hydrogen, halogen, cyano, amino, hydroxy, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -OR 15 ,-(C 1 -C 6 ) Alkilen-OR 15 ,-O-(C 2 -C 6 ) Alkilen-OR 15 , -NR 16 (C 2 -C 6 ) Alkilen-OR 15 , -NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-NR 17 R 18 ,-O-(C 2 -C 6 ) Alkilen-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 ,-(C 1 -C 6 ) Alkilen-NR 16 -SO 2 -R 15 ,-O-(C 2 -C 6 )alkylene-NR 16 -SO 2 -R 15 、-NR 16 -(C 2 -C 6 )alkylene-NR 17 -SO 2 -R 15 、-C(O)-NR 17 R 18 、-(C 1 -C 6 )alkylene-C(O)-NR 17 R 18 、-O-(C 1 -C 6 )alkylene-C(O)-NR 17 R 18 、-NR 16 -(C 1 -C 6 )alkylene-C(O)-NR 17 R 18 、-NR 16 C(O)-R 15 、-(C 1 -C 6 )alkylene-NR 16 C(O)-R 15 、-O-(C 2 -C 6 )alkylene-NR 16 C(O)-R 15 、-NR 16 -(C 2 -C 6 )alkylene-NR 16 C(O)-R 15 、-C(O)-R 15 、-C(O)OR 15 、-(C 1 -C 6 )alkylene-C(O)OR 15 、-O-(C 1 -C 6 )alkylene-C(O)OR 15 、and-NR 16 -(C 1 -C 6 )alkylene-C(O)OR 15 is selected from; R 3 These are hydrogen, halogen, cyano, amino, hydroxy, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -OR 15 ,-(C 1 -C 6 ) Alkilen-OR 15 ,-O-(C 2 -C 6 ) Alkilen-OR 15 , -NR 16 (C 2 -C 6 ) Alkilen-OR 15 , -NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-NR 17 R 18 ,-O-(C 2 -C 6 ) Alkilen-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 ,-(C 1 -C 6 ) Alkilen-NR 16 -SO 2 -R 15 ,-O-(C 2 -C 6 ) Alkilen-NR 16 -SO 2 -R 15 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 -SO 2 -R 15 -C(O)-NR 17 R 18 ,-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 ,-O-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 , -NR 16 -(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 , -NR 16 C(O)-R 15 ,-(C 1 -C 6 ) Alkilen-NR 16 C(O)-R 15 ,-O-(C 2 -C 6 ) Alkilen-NR 16 C(O)-R 15 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 16 C(O)-R 15 , -C(O)-R 15 , -C(O)OR 15 ,-(C 1 -C 6 )Alkylene-C(O)OR 15 ,-O-(C 1 -C 6 )Alkylene-C(O)OR 15 , and -NR 16 -(C 1 -C 6 )Alkylene-C(O)OR 15 Selected from; R 4 is hydrogen, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl,-(C 1 -C 6 ) Alkilen-OR 15 ,-(C 1 -C 6 ) Alkilen-NR 17 R 18 ,-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-NR 16 C(O)-R 15 ,-(C 1 -C 6 )Alkylene-C(O)OR 15 , and -(C 1 -C 6 ) Alkylene-OC(O)-R 15 Selected from; R 5 is hydrogen, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl,-(C 1 -C 6 ) Alkilen-OR 15 ,-(C 1 -C 6 ) Alkilen-NR 17 R 18 ,-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-NR 16 C(O)-R 15 ,-(C 1 -C 6 )Alkylene-C(O)OR 15 , and -(C 1 -C 6 ) Alkylene-OC(O)-R 15 Selected from; R 7 is hydrogen, halogen, amino, hydroxy, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -OR 15 ,-(C 1 -C 6 ) Alkilen-OR 15 ,-O-(C 2 -C 6 ) Alkilen-OR 15 , -NR 16 (C 2 -C 6 ) Alkilen-OR 15 , -NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-NR 17 R 18 ,-O-(C 2 -C 6 ) Alkilen-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 R 18 , -SO-R 15 , -SO 2 -R 15 , -SO 2 NR 17 R 18 ,-(C 1 -C 6 ) Alkilen-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 ,-(C 1 -C 6 ) Alkilen-NR 16 -SO 2 -R 15 ,-O-(C 2 -C 6 ) Alkilen-NR 16 -SO 2 -R 15 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 -SO 2 -R 15 -C(O)-NR 17 R 18 ,-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 ,-O-(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 , -NR 16 -(C 1 -C 6 ) Alkylene-C(O)-NR 17 R 18 , -NR 16 C(O)-R 15 ,-(C 1 -C 6 ) Alkilen-NR 16 C(O)-R 15 ,-O-(C 2 -C 6 ) Alkilen-NR 16 C(O)-R 15 , -NR 16 -(C 2 -C 6 ) Alkilen-NR 17 C(O)-R 15 , -C(O)-R 15 , -C(O)-OR 15 ,-(C 1 -C 6 ) Alkylene-C(O)-OR 15 ,-O-(C 1 -C 6 ) Alkylene-C(O)-OR 15 , -NR 16 -(C 1 -C 6 ) Alkylene-C(O)-OR 15 -OC(O)-R 15 ,-(C 1 -C 6 ) Alkylene-OC(O)-R 15 ,-O-(C 2 -C 6 ) Alkylene-OC(O)-R 15 , -NR 16 -(C 2 -C 6 ) Alkylene-OC(O)-R 15 , and -NR 16 -C(O)-OR 15 Selected from; Here, R 2 , R 3 , R 4 , R 5 , or R 7 In the case of -(C 1 -C 6 ) Alkyl or -(C 1 -C 6 Each of the alkylenes is a halogen, cyano, hydroxy, oxo, amino, -O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally replaced by at least one element selected from; R 2 , R 3 , R 4 , R 5 , or R 7 In the case of -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Each of the heterocycloalkyl, aryl, or heteroaryl is a halogen, cyano, hydroxy, oxo, amino, -(C 1 -C 6 ) alkyl, -CH 2 -O-(C 1 -C 6 ) alkyl, -CH 2 -NH-(C 1 -C 6 ) alkyl, -CH 2 -N-((C 1 -C 6 )alkyl) 2 ,-O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally replaced by at least one element selected from; R 15 , R 16 , R 17 , and R 18 These are, independently, hydrogen and -(C 1 -C 6 ) Haloalkyl, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 ) Selected from alkylene-aryl; and / or R 15 , R 16 , R 17 , and R 18 The two bases selected from are -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) forming a ring selected from heterocycloalkyl, aryl, and heteroaryl rings together; Here, R 15 , R 16 , R 17 , or R 18 In the case of -(C 1 -C 6 ) Alkyl or -(C 1 -C 6 Each of the alkylenes is a halogen, cyano, hydroxy, oxo, amino, -O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally replaced by at least one element selected from; R 15 , R 16 , R 17 , or R 18 In the case of -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Each of the heterocycloalkyl, aryl, or heteroaryl is a halogen, cyano, hydroxy, oxo, amino, -(C 1 -C 6 ) alkyl, -CH 2 -O-(C 1 -C 6 ) alkyl, -CH 2 -NH-(C 1 -C 6 ) alkyl, -CH 2 -N-((C 1 -C 6 )alkyl) 2 ,-O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally replaced by at least one element selected from; ・Y 2 The following formula 【Transformation 3】 A 5- or 6-membered heteroaryl or 6-membered aryl selected from: Here, R 12 , R 13 , R 14 , and R 25’ These are, independently, hydrogen, halogen, cyano, hydroxyl, amino, and -(C) 1 -C 6 )alkyl, -(C 3 -C 6 ) Cycloalkyl, -CH 2 -O-(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 Selected from; Here, R 12 , R 13 , R 14 , or R 25’ In the case of -(C 1 -C 6 Each of the alkyl groups is a halogen, cyano, hydroxy, amino, -O-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally replaced by at least one element selected from; L is -(CR 10 R 11 ) n and; Here, n is an integer selected from 0, 1, 2, 3, and 4; R 10 and R 11 is hydrogen, halogen, hydroxyl, amino, -(C 1 -C 3 )alkyl, -(C 1 -C 2 ) Haloalkyl, -(C 1 -C 2 ) Hydroxyalkyl, -(C 1 -C 2 )aminoalkyl, -O-(C 1 -C 4 )alkyl, -NH-(C 1 -C 3 )alkyl, and -N-((C 1 -C 3 )alkyl) 2 Whether selected independently of; or R 10 and R 11 (C 3 -C 6 ) form a cycloalkyl group; ・Z 1’ -NR 23’ R 24’ and containing at least one nitrogen atom -(C 3 -C 7 ) Selected from heterocycloalkyl groups; Here, Z 1’ (C 3 -C 7 Each nitrogen atom of the heterocycloalkyl group is -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 ) optionally substituted with at least one group selected from cycloalkyl groups; Z 1’ (C 3 -C 7 ) Each carbon atom of a heterocycloalkyl group is a halogen, cyano, hydroxy, oxo, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, -O-(C 1 -C 6 )alkyl, and -O-(C 3 -C 7 ) optionally substituted with at least one group selected from cycloalkyl groups; Here, Z 1’ In the case of -(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, or -(C 3 -C 7 Each of the heterocycloalkyl groups is optionally substituted with at least one halogen; and Here, Z 1’ Each of the aryl or heteroaryl in the above is a halogen, CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, and O-(C 3 -C 7 ) optionally substituted with at least one group selected from cycloalkyl groups; and R 23’ and R 24’ These are, independently, hydrogen and -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 ) Selected from alkylene-aryl; Here, R 23’ or R 24’ In the case of -(C 1 -C 6 )alkyl, -(C 1 -C 6 ) Alkilen, -(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 Each of the heterocycloalkyl groups is a halogen, cyano, hydroxy, -O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 It is optionally substituted with at least one base selected from; and R 23’ or R 24’ In each of the aryl or heteroaryl groups, the elements are halogen, cyano, hydroxy, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, -NH-(C 1 -C 6 )alkyl, and -N-((C 1 -C 6 )alkyl) 2 (Optionally substituted with at least one base selected from) The compound is a compound of or a pharmaceutically acceptable salt and / or solvate thereof.

2. Y 1 but: The following formula 【Chemistry 4】 (In the formula, A 1 ~A 4 , A 6 , A 7 , G 1 , and R 2 These are independently as defined in claim 1); and The following formula 【Transformation 5】 (In the formula, A 8 ~A 11 and G 2 (These are independently defined in claim 1.) The compound for use according to claim 1, which is a 9 or 10-membered bicyclic heteroaryl selected from the above.

3. Y 1 but: (i) The following formula 【Transformation 6】 and the following formula 【Transformation 7】 (In the formula, R 2 , R 3 , and R 7 (These are independently defined in claim 1.) A 10-membered bicyclic [6,6] heteroaryl selected from; (ii) The following formula 【Transformation 8】 The following formula 【Chemistry 9】 The following formula 【Chemistry 10】 The following formula 【Chemistry 11】 and the following formula 【Chemistry 12】 (In the formula, R 2 , R 3 , R 5 , and R 7 These are independently as defined in claim 1; and the following formula 【Chemistry 13】 (In the formula, R 2 , R 3 , and R 7 (These are independently defined in claim 1.) A 9-membered bicyclic [6,5] heteroaryl selected from; and (iii) The following formula 【Chemistry 14】 and the following formula 【Chemistry 15】 (In the formula, A 1 , A 3 , A 3 , A 4 , R 2 , R 4 , and R 7 (These are independently defined in claim 1.) A 9-membered bicyclic [5,6] heteroaryl selected from: A compound for use according to claim 1, selected from the following.

4. Y 1 but: (i) The following formula 【Chemistry 16】 (In the formula, R 2 , R 3 , and R 7 (These are independently defined in claim 1.) A 10-membered bicyclic [6,6] heteroaryl selected from; (ii) The following formula 【Chemistry 17】 (In the formula, R 2 , R 3 , R 5 , and R 7 (These are independently defined in claim 1.) A 9-membered bicyclic [6,5] heteroaryl selected from; (iii) The following formula [Chemistry 18] (In the formula, R 2 , R 5 , and R 7 (These are independently defined in claim 1.) A 9-membered bicyclic [5,6] heteroaryl selected from Selected from; Preferably, Y 1 However, 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-yl, 2-(trifluoromethyl)quinazolin-4-yl, 1-(2-methoxyethyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl), 1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 2-(trifluoromethyl)pyrido[2,3-d]pyrimidine-4-yl, 2-(difluoromethyl)-6-methoxypyrid [2,3-d]pyrimidine-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]pyrimidine-4-yl, 2-cyclopropyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-yl, 6-methoxy-2-methylpyrido[2,3-d]pyrimidine-4-yl, 2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidine-4-yl , 6-Methoxy-2-methyl-1,8-naphthyridine-4-yl, 7-(difluoromethyl)-1,6-naphthyridine-5-yl, 3-Methoxy-7-methyl-1,6-naphthyridine-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-Dimethoxyquinoline-4-yl, 3-Chloro-7-methyl-1,6-naphthyridin-5-yl, 6-Methoxyquinoline-4-yl, 6-Methoxy-2-methylquinoline-4-yl, 6-Chloro-8-fluoro-2-methylquinazoline-4-yl, 6-Chloroquinoline-4-yl, 7-Methoxyquinoline-4-yl, 6-Fluoro-2-methylpyrido[2,3-d]pyrimidine-4-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-5-yl, 7-Methylimidazo[1,2-a]pyrimidine-5-yl, 2-methyl-1,A compound for use according to any one of claims 1 to 3, selected from 8-naphthyridine-4-yl, 6-methoxy-2-methylpyrido[3,4-d]pyrimidine-4-yl, 2-methyl-6-(trifluoromethyl)quinoline-4-yl, 6-methoxy-2-methyl-1,5-naphthyridine-4-yl, (6-methoxy-2-methyl-1,5-naphthyridine-4-yl, 2-methyl-6-(trifluoromethyl)-1,8-naphthyridine-4-yl, 5-fluoro-6-methoxy-2-methylquinazoline-4-yl, 6-(difluoromethoxy)-2-methylquinazoline-4-yl, 2-methyl-6-(trifluoromethoxy)quinazoline-4-yl, and 7-methyl-3-(trifluoromethyl)-1,6-naphthyridine-5-yl.

5. R 12 , R 13 , R 14 , or R 25’ However, each independently, hydrogen and (C 1 -C 3 ) Selected from alkyl groups, preferably R 12 , R 13 , R 14 , and R 25’ A compound for use according to any one of claims 1 to 4, wherein the compound is hydrogen.

6. R 10 and R 11 However, hydrogen and (C 1 -C 3 ) Independently selected from alkyl, preferably R 10 and R 11 The compound for use according to any one of claims 1 to 5, wherein each of the compounds is hydrogen.

7. Z 1’ However, the following formula 【Chemistry 19】 (In the formula, R 21’ is hydrogen, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 ) Selected from cycloalkyl; and R 22’ These are hydrogen, halogen, cyano, hydroxy, oxo, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, -O-(C 1 -C 6 )alkyl, and -O-(C 3 -C 7 ) Selected from cycloalkyl; Here, R 21’ or R 22’ In the case of -(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, or -(C 3 -C 7 Each of the heterocycloalkyl groups is optionally substituted with at least one halogen; and Here, R 21’ or R 22’ Each of the aryl or heteroaryl in the above is a halogen, CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, and -O-(C 3 -C 7 (Optionally substituted with at least one group selected from cycloalkyl groups) Selected from -(C 3 -C 7 A compound for use according to any one of claims 1 to 6, wherein the compound is a heterocycloalkyl.

8. Z 1’ However, the following formula 【Chemistry 20】 (In the formula, R 21’ is selected from hydrogen, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 1 -C 6 )alkylene-(C 3 -C 7 )cycloalkyl, -(C 3 -C 7 )heterocycloalkyl, aryl, heteroaryl, -(C[[ID=Twenty-three]] 1 [[ID=Twenty-four]]-C[[ID=Twenty-five]] 6 [[ID=Twenty-six]])alkylene-O-(C[[ID=Twenty-seven]] 1 [[ID=Twenty-eight]]-C[[ID=Twenty-nine]] 6 )alkyl, -(C 1 -C 6 )alkylene-(C 3 -C 7 )heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl, -(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 )alkylene-O-(C<S 3 -C 7 )cycloalkyl; and R 22’ These are hydrogen, halogen, cyano, hydroxy, oxo, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, -O-(C 1 -C 6 )alkyl, and -O-(C 3 -C 7 ) Selected from cycloalkyl; Here, R 21’ In the case of -(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, or -(C 3 -C 7 Each of the heterocycloalkyl groups is optionally substituted with at least one halogen; and Here, R 21’ Each of the aryl or heteroaryl in the above is a halogen, CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, and O-(C 3 -C 7 (Optionally substituted with at least one group selected from cycloalkyl groups) no-(C 3 -C 7 A compound for use according to any one of claims 1 to 6, wherein the compound is a heterocycloalkyl.

9. Z 1’ However, the following formula 【Chemistry 21】 (In the formula, R 21’ is selected from hydrogen, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )cycloalkyl, -(C 1 -C 6 )alkylene-(C 3 -C 7 )cycloalkyl, -(C 3 -C 7 )heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 )alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkylene-(C 3 -C 7 )heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl, -(C 1 -C 6 )alkylene-heteroaryl, and -(C 1 -C 6 )alkylene-O-(C 3 -C 7 )cycloalkyl; and R 22’ These are hydrogen, halogen, cyano, hydroxy, oxo, -(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 )alkyl, -(C 1 -C 6 ) Alkylene-O-(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 ) Heterocycloalkyl, -(C 1 -C 6 )alkylene-aryl,-(C 1 -C 6 )alkylene-heteroaryl, -O-(C 1 -C 6 )alkyl, and -O-(C 3 -C 7 ) Selected from cycloalkyl; Here, R 21’ In the case of -(C 1 -C 6 )alkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, or -(C 3 -C 7 Each of the heterocycloalkyl groups is optionally substituted with at least one halogen; and Here, R 21’ Each of the aryl or heteroaryl in the above is a halogen, CN, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, and O-(C 3 -C 7 (Optionally substituted with at least one group selected from cycloalkyl groups) no-(C 3 -C 7 A compound for use according to any one of claims 1 to 6, wherein the compound is a heterocycloalkyl.

10. R 21’ However, hydrogen, -(C 1 -C 6 )alkyl, substituted with at least one fluoro-(C 1 -C 6 )alkyl, -(C 3 -C 7 )Cycloalkyl, -(C 1 -C 6 )Alkilen-(C 3 -C 7 )Cycloalkyl, -(C 3 -C 7 )heterocycloalkyl, and -(C 1 -C 6 ) Alkylene-O-(C 1 -C 6 ) Selected from alkyl groups; preferably, R 21’ However, hydrogen, -(C 1 -C 3 )alkyl, -(C 3 -C 5 )Cycloalkyl, -(C 1 -C 3 )Alkilen-(C 3 -C 5 )Cycloalkyl, oxetanyl, and -(C 1 -C 3 ) Alkylene-O-(C 1 -C 3 ) Selected from alkyl; and R 22’ However, hydrogen, halogen, -(C 1 -C 6 )alkyl, substituted with at least one fluoro-(C 1 -C 6 )alkyl, cyano, hydroxy, and -O-(C 1 -C 6 ) Selected from alkyl groups; preferably, R 22’ However, hydrogen, fluoro, trifluoromethyl, cyano, hydroxy, and -O-(C 1 -C 3 A compound selected from alkyl groups for use according to any one of claims 7 to 9.

11. Z 1’ However, azetidine-3-yl, 1-methylazetidine-3-yl, 3-fluoroazetidine-3-yl, 3-hydroxyazetidine-3-yl, 3-methoxyazetidine-3-yl, 1-methylpiperidine-4-yl, 1-(2-methoxyethyl)azetidine-3-yl, pyrrolidine-3-yl, 3-fluoropyrrolidine-3-yl, 3-hydroxypyrrolidine-3-yl, 3-methoxypyrrolidine-3-yl, morpholinomethyl, 3-methoxy-1-methylpyrrolidine-3-yl, piperidine-4-yl, 4-hydroxypiperidine-4-yl, 4- Cyano-1-methylpiperidine-4-yl, 3-hydroxy-1-methylpyrrolidine-3-yl, 4-methoxypiperidine-4-yl, 4-hydroxy-1-isopropylpiperidine-4-yl, 1-hydroxy-2-(methylamino)ethyl, 1-(2-fluoroethyl)-4-hydroxypiperidine-4-yl, 4-hydroxy-1-methylpiperidine-4-yl, 4-hydroxy-1,3-dimethylpiperidine-4-yl, 1-(cyclopropylmethyl)-4-hydroxypiperidine-4-yl, 4-hydroxy-1-(2-methoxyethyl) Peridine-4-yl, 1-cyclobutyl-4-hydroxypiperidine-4-yl)thiophen-2-yl, 1-cyclopropyl-4-hydroxypiperidine-4-yl, piperazine-1-yl, 3-hydroxy-1-methylpiperidine-4-yl, 4-hydroxy-1-(oxetane-3-yl)piperidine-4-yl, 4-methoxy-1-methylpiperidine-4-yl, 3-hydroxy-1-methylpiperidine-3-yl, morpholine-4-yl, morpholine-2-yl, 4-methylmorpholine-2-yl, 4-methylmorpholine-3-yl, mol Foline-3-yl, 2-aminoethyl, aminomethyl, and N-(methylamino)-methyl, 3-hydroxy-1-methylazetidine-3-yl, 5-(hydroxy(1-methylpiperidine-4-yl)methyl, 3-hydroxy-1-isopropylazetidine-3-yl, 6-oxa-3-azabicyclo[3.2.1]octane-5-yl, 3-methyl-6-oxa-3-azabicyclo[3.2.1]octane-5-yl, 3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-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-methylmorpholine-2-yl, 2-(trifluoromethyl)morpholine-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] Selected from 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(pyrrolizin)-7a(5H)-yl)methyl, and 2-(dimethylamino)-1-hydroxyethyl; Preferably, Z 1’ However, azetidine-3-yl, 1-methylazetidine-3-yl, 3-fluoroazetidine-3-yl, 3-hydroxyazetidine-3-yl, 3-methoxyazetidine-3-yl, 1-(2-methoxyethyl)azetidine-3-yl, pyrrolidine-3-yl, 3-fluoropyrrolidine-3-yl, 3-hydroxypyrrolidine-3-yl, 3-methoxypyrrolidine-3-yl, piperidine-4-yl, 4-hydroxypiperidine-4-yl A compound for use according to any one of claims 1 to 6, selected from piperazine-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. 【Request Item 12】 【Table 1】 A compound for use according to claim 1, selected from pharmaceutically acceptable salts and / or solvates thereof.

13. A pharmaceutical composition for use in the treatment and / or prevention of HDAC6-related diseases, comprising a compound according to 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 the HDAC6-related disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases (including neuromuscular diseases), pain, neuropathy (including neuromuscular diseases), psychiatric disorders, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, and metabolic or hormonal disorders.

15. Formula (II) 【Chemistry 22】 (In the formula, Y 1 , Y 2 , and L are independently as defined in claim 1; Z 1’ -(C) comprises at least one nitrogen atom as defined in claim 1. 3 -C 7 (It is a heterocycloalkyl group.) Compounds thereof or pharmaceutically acceptable salts and / or solvates thereof; However, the compound is: 1-(5-(pyrrolidine-3-yl)thiophen-2-yl)-2-((2-(trifluoromethyl)quinazoline-4-yl)thio)ethane-1-one, 2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)thio)-1-(5-(pyrrolidine-3-yl)thiophen-2-yl)ethane-1-one, and Pharmaceutically acceptable salts and / or solvates thereof The aforementioned compound or a pharmaceutically acceptable salt and / or solvate thereof, which is not selected from the above. 【Request Item 16】 【Table 2】 The compound according to claim 13, selected from pharmaceutically acceptable salts and / or solvates thereof.

17. A process for producing the compound according to claim 13 or claim 14, comprising the steps of: (i) reacting an amine-containing alkyl chain or heterocycloalkyl with a halo-heterocyclic ring; then (ii) reacting the heterocyclic ring or halo-heterocyclic ring first with an acetylating agent and, where appropriate, subsequently with a halogenating agent to produce a haloketone; then (iii) reacting the haloketone with a thiol; and, where appropriate, (iv) removing at least one protecting group. 【Request Item 18】 【Table 3】 and compounds selected from pharmaceutically acceptable salts and / or solvates thereof.

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