Compounds and their use as HDAC6 inhibitors - Patents.com

Abstract

The present invention relates to a compound of formula (I) [Formula 1] or a pharma- ceutically acceptable salt and / or solvate thereof, wherein Y 1 is a 9- or 10-membered bicyclic heteroaryl; Y 2 is a 5-membered heteroaryl; Z 1 is (C=O)-R 9 , S(O)-R 9 , and S(O 2 )-R 9 L is an alkyl, cycloalkyl, or heterocycloalkyl based linker, and R 1 and R 9 may be various groups. The present invention further relates to compounds of formula (I) as HDAC6 inhibitors, generally for use in the treatment and / or prevention of HDAC6-related diseases, such as cancer, neurodegenerative diseases, neurological disorders, or cardiovascular diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to compounds useful as histone deacetylase subtype 6 (HDAC6) inhibitors. In particular, the present invention relates to compounds for use in the treatment and / or prevention of proliferative diseases such as cancer, neurodegenerative diseases, neurological disorders, or cardiovascular diseases. [Background technology]

[0002] BACKGROUND OF THEINVENTION Inhibition of HDAC class enzymes, especially HDAC6 enzyme, plays a key role in human gene expression. Therefore, the development of potent HDAC inhibitors is of primary clinical importance in severe medical conditions, including both major and rare diseases (Seidel C et al.: Histone deacetylase 6 in health and disease, Epigenomics. 2015, Vol. 7, No. 1, pp. 103-18). HDAC6 inhibitors are believed to be useful, for example, in oncology, neurology, neuropsychiatry, neurodegeneration, inflammation (e.g., neuroinflammation), nephropathy, neuropathy, and pain. Prominent examples of HDAC6 inhibitors with potential medical use in the treatment of proliferative diseases are the hydroxamate class of drugs (hydroxamic acids and their salts), which include vorinostat (or "SAHA", trade name Zolinza®), trichostatin A (TSA), belinostat (trade name Beleodaq®), panobinostat (Farydak®), or romidepsin (Istodax®).

[0003] However, many HDAC6 inhibitors identified so far are not highly selective and may cause significant side effects. Poor pharmacokinetics and low bioavailability also limit the efficacy of some HDAC6 inhibitors. Therefore, most HDAC6 inhibitors have poor exploitability profiles, even for life-threatening applications in oncology. For example, high doses of non-selective HDAC inhibitors cause fatigue and nausea. Side effects may be caused, in particular, by inhibition of class I HDACs. In addition, mutagenicity problems associated with hydroxamate function in approved HDAC inhibitors have been reported (Shen S. and Kozikowski AP, ChemMedChem 2016, No. 11, pp. 15-21).

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

[0005] The applicants have surprisingly found that the compounds of formula (I) described herein are highly selective HDAC6 inhibitors. The use of these compounds may also show significant improvements over prior art drugs such as hydroxamates in terms of bioavailability, side effects, pharmacokinetics, and / or water solubility. Summary of the Invention

[0006] (overview) The present invention relates to a compound for use in the treatment and / or prevention of HDAC6-related diseases; [ka] or a pharma- ceutically acceptable salt and / or solvate thereof; 1 , Y 2 , L, R 1 , and Z 1 is as set forth in the claims or detailed description.

[0007] The present invention also relates to a pharmaceutical composition for use in the treatment and / or prevention of HDAC6-related diseases, wherein the pharmaceutical composition comprises a compound according to the invention and at least one pharma- ceutically acceptable carrier.

[0008] In one embodiment, the HDAC6-related disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases such as cancer, neurodegenerative diseases, pain, neurological disorders, psychiatric diseases, neurodevelopmental disorders, sleep disorders, and cardiovascular diseases. In one embodiment, the HDAC6-related disease is a cancer selected from malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer, and Hodgkin's disease. In one embodiment, the HDAC6-related disease is a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down's syndrome, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. In one embodiment, the HDAC6-related disease is a neuropathy selected from Guillain-Barre 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 chemotherapy anticancer drugs, diabetic peripheral neuropathy (DPN), neuralgia, pain, and / or neuropathic pain. In one embodiment, the HDAC6-related disease is a cardiovascular disease selected from heart failure, cardiomyopathy, and / or myocarditis.

[0009] According to one embodiment, the compound is selected from the compounds listed in Table 2 herein, and pharma- ceutically acceptable salts and / or solvates thereof.

[0010] The present invention also relates to a compound of formula (I) [ka] or a pharma- ceutically acceptable salt and / or solvate thereof; 1 , Y 2 , L, R 1 , and Z 1 is as set forth in the claims or detailed description.

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

[0012] The present invention also relates to a process for preparing a compound according to the invention, which process comprises the steps of reacting: (i) a linear or cyclic amine with an acyl chloride, a carboxylic acid, or a sulfonyl chloride; or (ii) a halo-ketone with a thiol.

[0013] The present invention also relates to pharmaceutical compositions comprising a compound according to the invention and at least one pharma- ceutically acceptable carrier.

[0014] The present invention also relates to the compound according to the present invention or the pharmaceutical composition according to the present invention for use as a medicament.In one embodiment, the compound or pharmaceutical composition is for use in treating and / or preventing HDAC6-related disease.In one embodiment, the HDAC6-related disease is selected from inflammatory disease, autoimmune disease, proliferative disease such as cancer, neurodegenerative disease, pain, neurological disorder, psychiatric disease, neurodevelopmental disorder, sleep disorder and cardiovascular disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] (definition) As used herein, the following terms have the following meanings unless otherwise indicated.

[0016] (chemical definition) When referring to group combinations such as, for example, "alkylene-heteroaryl," the point of attachment to the main structure is on the group depicted to the left. Thus, the term "alkylene-cyclyl" and variations thereof (e.g., "alkylene-heteroaryl," "alkylene-heterocycle," "alkylene-cycloalkyl," "alkylene-aryl," "alkylene-heteroaryl," "alkylene-heterocycle," and "alkylene-cycloalkyl") refers to a cyclyl group that is attached to the main structure via the alkyl portion. In other words, the point of attachment is on the alkylene group, not the cyclyl group.

[0017] "Alkene" or "alkenyl" refers to a linear or branched hydrocarbon chain containing at least one double bond and typically from 2 to 12 carbon atoms, preferably from 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.

[0018] "Alkyl" refers to a saturated linear or branched hydrocarbon chain, typically containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. In the present invention, alkyl groups can be monovalent or polyvalent (i.e., "alkylene" groups as defined herein are included 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.

[0019] "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, n-butylene, and n-butylene.

[0020] "Alkyne" or "alkynyl" refers to a linear or branched hydrocarbon chain containing at least one triple bond and typically from 2 to 12 carbon atoms, preferably from 3 to 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, and 2-hexynyl and its isomers.

[0021] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced with a substituent such as alkyl or aryl.

[0022] "Amino" refers to the group -NH2.

[0023] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbyl group containing at least one aromatic ring. An aryl group can have a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently bonded. Typically, aryl groups have 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. The aromatic ring can optionally contain 1 to 2 additional rings (either cycloalkyl, heterocycloalkyl, or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein, so 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-acenaphthylenyl, 3-, 4-, or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4-, or 5-pyrenyl. A preferred aryl group is phenyl.

[0024] "Bicyclic" when referring to a cyclic group means that the cyclic group consists of exactly two fused rings. In monovalent bicyclic groups, the notation "[x, y]" (where x and y are integers) is used herein to indicate that one ring is x-membered and the other ring is y-membered, and that the point of attachment to the main structure is located on the x-membered ring. "Tricyclic," etc. should be construed accordingly.

[0025] "Cyano" refers to the radical -CN.

[0026] "Cycyl" refers collectively to "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl" groups as defined herein.

[0027] "Cycloalkyl" refers to a cyclic monovalent alkyl group typically 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 bridged cycloalkyl structures.

[0028] The "(C x -C y )" means that the group contains x to y carbon atoms, in accordance with common terminology in the chemical arts.

[0029] "Difluoromethyl" refers to the group -CHF2.

[0030] "Halide," "halo," or "halogen" refers to a fluorine, chlorine, bromine, or iodine atom, typically a chlorine or bromine atom.

[0031] "Heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur. In a heteroalkyl group, the heteroatoms are only bonded to carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroalkyl group may further include one or more oxo (=O) groups. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e., the bonded atom is not selected from the heteroatoms contained in the heteroalkyl group. When substituted by one or more other groups, a heteroalkyl may be substituted either by a carbon atom or by a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers, secondary amines, tertiary amines, and thioethers.

[0032] "Heteroaryl" refers to an aromatic ring or ring system containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms, having one or two rings fused together or covalently bonded, in which at least one ring is aromatic and one or more carbon atoms in one or more of the rings are replaced by oxygen, nitrogen, and / or sulfur atoms. "Heteroaryl" can also be considered as 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 be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.Non-limiting examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-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, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzyl, phenyl ... benzoimidazolyl, 1,3-benzoxazolyl, 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, thia These include enopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and phthalazinyl.

[0033] "Heterocycloalkyl" refers to a cyclic monovalent heteroalkyl, typically containing 2 to 7 carbon atoms, preferably 3 to 6 carbon atoms, more preferably 4 to 5 carbon atoms. This definition encompasses polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings linked together through one atom ("spiro") or through two atoms. In one embodiment, a heterocycloalkyl is linked to another group or molecule through a carbon atom, i.e., the linking atom is not selected from the heteroatoms contained therein. In one embodiment, a heterocycloalkyl is linked to another group or molecule through one of the heteroatoms contained therein. When substituted by one or more other groups, a heterocycloalkyl may be substituted either by a carbon atom or by a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting 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-tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, and oxetane.

[0034] "Hydroxy" refers to the group --OH.

[0035] "Ketone" refers to a functional group having the connection C-(C=O)-C.

[0036] "Oxo" refers to the group =O, ie, one oxygen atom typically double bonded to a carbon atom.

[0037] "Trifluoromethyl" refers to the group -CF3.

[0038] (General definition) "About" is used herein to mean approximately, in the region of, around, or near. The term "about" preceding a number means plus or minus 10% of the value of that number. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values ​​set forth by 10%.

[0039] "Administration" or variations thereof (e.g., "administering") means providing a therapeutic agent (e.g., a compound of the invention), either alone or as part of a pharma- ceutical acceptable composition, to a patient whose disease, condition, or disorder is to be treated and / or prevented.

[0040] "Binding site" or "binding pocket" refers to a specific arrangement of amino acids located on a protein (e.g., on HDAC6) to which a compound (e.g., a compound of the invention) binds. A binding site often consists of a chemically active surface grouping of amino acids and has specific 3-D structural and charge characteristics. Like an epitope, a binding site can be linear or conformational, i.e., it can comprise a sequence of amino acids that is not necessarily contiguous in the primary structure of the protein.

[0041] "Comprise" or variations thereof (e.g., "comprises", "comprising") are used herein in accordance with typical patent application drafting terminology. Thus, "comprise" precedes an object and follows a component means that the presence of the component in the object is required (usually as a component of a composition), but does not exclude the presence of any additional component in the object. Furthermore, any occurrence of "comprise" or variations thereof herein also encompasses the narrower expressions "consisting essentially of" or "consisting essentially of", the even narrower expression "consist of" and any variations thereof (e.g., "consists of", "consisting of").

[0042] "HDAC" or "histone deacetylase" refers to a class of enzymes that can remove acetyl groups (O=C-CH3) from ε-N-acetyl lysine amino acids on histones, allowing the histones to wrap more tightly around DNA and condense chromatin. Gene expression is regulated by histone acetylation and deacetylation, and thus by HDAC activity. In the present invention, HDAC is typically "HDAC6" as defined herein.

[0043] "HDAC-associated disease" or "disease associated with HDAC6 function" or variants thereof (e.g., "HDAC6-associated disease") refers to a disease resulting from, caused by, or characterized by dysregulation and, in particular, increased activity of at least one HDAC enzyme in a subject, resulting in an abnormal acetylation profile of HDAC substrates (e.g., histones, tubulin, Hsp90, cortactin). In the present application, "HDAC-associated disease" and "disease associated with HDAC6 function" are synonymous and can be used interchangeably. Typically, HDAC-associated diseases are associated with, among other things, altered epigenetic regulation of gene expression and / or cell motility. This definition encompasses diseases in which the disease is treated and / or prevented by reducing (inhibiting) normal HDAC activity. Typically, HDAC-associated diseases can be prevented and / or treated by HDAC inhibition. Non-limiting examples of HDAC-associated diseases include neurological disorders, neurodegenerative diseases, proliferative diseases (e.g., cancer), metabolic disorders, immune disorders, and inflammatory diseases.

[0044] "HDAC6," "HDAC6 enzyme," or "histone deacetylase subtype 6" refers to the HDAC enzyme encoded by the HDAC6 gene in humans.

[0045] "HDAC6 gene" refers to the gene encoding human HDAC6. HDAC6 gene is also interchangeably referred to as KIAA0901 or JM21.

[0046] "Human" refers to male and female subjects at any stage of development, including neonates, infants, children, adolescents, and adults.

[0047] "Patient" refers to an animal, typically a warm-blooded animal, preferably a mammal (e.g., a mouse, rat, cat, guinea pig, dog, monkey, or human), more preferably a human, who is awaiting or receiving medical care, or who is / will be the subject of medical treatment. A patient may also be the subject of preventive care or treatment.

[0048] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and not harmful to the patient to whom they are administered.

[0049] A "pharmaceutical acceptable carrier" refers to an excipient that does not produce adverse, allergic, or other untoward reactions when administered to an animal, preferably a human. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by regulatory authorities, such as, for example, the FDA or EMA.

[0050] "Prevent", "preventing" and "prevention" refer to delaying or halting the onset of a disease and / or disorder and / or any one of its attendant symptoms, barring a patient from acquiring a disease or disorder, or reducing a patient's risk of acquiring a disease and / or disorder and / or any one of its attendant symptoms. The effect obtained from "preventing" a disease and / or disorder is referred to as "prophylactic".

[0051] "Prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound of the present invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are usually characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs, particularly alkyl esters, cycloalkyl esters, and aryl esters.

[0052] "Selected from" is used herein in accordance with common patent application drafting language to introduce a list of elements from which an item is selected. Any occurrence of "selected from" herein can be replaced by "selected from the group including or consisting of" and without mutually changing the meaning.

[0053] "Solvate" refers to a molecular complex that includes a compound with one or more molecules of one or more solvents in stoichiometric or substoichiometric amounts, typically a pharma- ceutically acceptable solvent such as, for example, ethanol. When the solvent is water (HO), the term "hydrate" refers to a solvate.

[0054] "Therapeutic agent", "active pharmaceutical ingredient" and "active ingredient" refer to a compound for therapeutic use and related to health. In particular, a therapeutic agent (e.g., a compound of the present invention) may be indicated for the treatment and / or prevention of a disease, preferably an infectious disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0055] A "therapeutically effective amount" (or, briefly, "effective amount") refers to an amount of a therapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which it is administered.

[0056] "Treat", "treating", and "treatment" refer to alleviating, attenuating, or arresting a disease and / or disorder and / or any one of its associated symptoms, e.g., an infectious disease.

[0057] (Detailed Description) (compound) The present invention relates to compounds of formula (I) [ka] (where Y 1 , Y 2 , L, R 1 , and Z 1 are defined hereafter in the Detailed Description).

[0058] In the compounds of formula (I) described hereafter in the detailed description, unless otherwise indicated, any alkyl group (including alkylene group) may be "optionally substituted", i.e., each hydrogen atom bonded 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). Only those substitutions that result in a chemically stable molecule are included in this definition. Usually, the (C1-C6)alkyl group present in the substituent is itself not further substituted. Preferred substituted alkyls include alkyl substituted by one or more fluorine atoms and / or hydroxy, such as, for example, trifluoromethyl.

[0059] In the compounds of formula (I) described hereinafter in the detailed description, unless otherwise indicated, any cyclyl group (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group) may be "optionally substituted", i.e., each hydrogen atom bonded to a carbon atom of the cyclyl moiety may be optionally substituted with, for example, halogen, cyano, hydroxy, oxo, amino, -(C1-C6)alkyl ... 、It can be optionally replaced by at least one low molecular weight substituent, such as a group selected from -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). Only those substitutions for which the resulting molecule is chemically stable are included in this definition. Typically, (C1-C6)alkyl groups present in a substituent are themselves not further substituted. Preferred substituted cyclyl groups include cyclyl substituted by one or more fluorine atoms and / or hydroxy, such as, for example, difluorocyclopropyl.

[0060] In the formulae depicted herein, the dotted line ---- represents the point of attachment of the indicated moiety to the primary molecular structure.

[0061] (Y 1 (Definition of In the above formula (I), Y 1 is a bicyclic heteroaryl. 1 is a 9-11 membered bicyclic heteroaryl. 1 is a 9- or 10-membered bicyclic heteroaryl. 1 contains two fused rings selected from 5-membered heteroaryl and 6-membered heteroaryl.

[0062] According to one embodiment, Y 1 contains two fused rings, the rings being The following: * Formula (Y 1 -0-1-Aa) [ka] (Here, G A CR 2 and N; G B CR 3 and N, and G C and GD Independently, CR 2 , C.R. 3 , and N, where R 2 and R 3 are independently as defined below), and * Formula (Y 1 -0-1-Ab) [ka] (Here, G A and G B Independently, CR 2 , C.R. 3 , and N; G E is O, S, and NR 4 from, in particular, O and NR 4 (where R 2 , R 3 , and R 4 are independently defined below) a first 5- or 6-membered heteroaryl ring selected from: a second ring selected from 5-membered heteroaryl, 6-membered heteroaryl, and aryl, wherein the second ring is at least one of the G of the first ring; A and G B , G B and G C , G C and G D , or G B and G E to form a 5-membered heteroaryl, a 6-membered heteroaryl, or an aryl. : consists of.

[0063] According to one embodiment, Y 1 is the formula (Y 1 -I) the following groups [ka] (Here, A 1 , A 2 , A 3 , A 4 , A 5 , A6 , and A 7 are each independently 7 and N; 8 , A 9 , A 10 , and A 11 are each independently 7 and N; 1 CR 3 and N; 2 is O and NR 4 and B is selected from O, S, and NR 5 (selected from "(Scaffold n°X)" means "(Scaffold n°X)".

[0064] According to one embodiment, Y 1 is the formula (Y 1 -I') the following group [ka] (Here, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 are each independently 7 and N; 8 , A 9 , A 10 , and A 11 are each independently 7 and N; 1 CR 3 and N; 2 is O and NR 4 and B is selected from O, S, and NR 5 (selected from "(Scaffold n°X)" means "(Scaffold n°X)".

[0065] According to one embodiment, Y1 is the formula (Y 1 -Ia) the following group [ka] (Here, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 are each independently 7 and N; 8 , A 9 , A 10 , and A 11 are each independently 7 and N; 1 CR 3 and N; and B is selected from O, S, and NR 5 (selected from "(Scaffold n°X)" means "(Scaffold n°X)".

[0066] In one embodiment, A 8 , A 9 , A 10 , and A 11 If A exists, 8 , A 9 , A 10 , or A 11 At least one of A is N. 5 and A 6 In one embodiment when present, A 5 and A 6 CR 7 If B is not S, then A is not S. 5 , A 6 , and A 7 In one embodiment when present, A 5 , A 6 , and A 7 CR 7 When B is not S, in one embodiment, G 1 is N.

[0067] According to one embodiment, Y 1 is the formula (Y 1 -I-1) the following group [ka] (Here, A 1 ~A 4 , A 6 , A 7 , G 1 , and R 2 are independently as defined herein. is a 9- or 10-membered bicyclic heteroaryl selected from:

[0068] According to one embodiment, Y 1 is the formula (Y 1 -I-2) the following group [ka] (Here, A 1 ~A 4 , A 8 ~A 11 , G 1 , and G 2 are independently as defined herein. is a 9-membered bicyclic heteroaryl selected from:

[0069] According to one embodiment, Y 1 is the formula (Y 1 -0-2) [ka] (Here, G 1 CR 3 and N; B 1 ~B 5 is O, S, and A as defined herein. 5 , A 6 , or A 7 and B 1 ~B 5 together form a 5-membered heteroaryl, i.e., B 1~B 5 The bonds between the rings are so arranged that the ring is aromatic and B 1 ~B 5 At least one of the groups is O, S, or NR. 5 (selected from ).

[0070] According to one embodiment, Y 1 is the formula (Y 1 -Ia-1) is a 10-membered bicyclic heteroaryl [ka] (Here, A 1 ~A 4 , G 1 , and R 2 are independently as defined herein).

[0071] Y as defined herein 1 In 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 , -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 , -NR 16 -(C1-C6)alkylene-C(O)OR 15 is selected from.

[0072] In one embodiment, R 2 is, for example, -(C1-C6)alkyl, such as methyl, iso-propyl, ethyl, or alkyl, where the alkyl is optionally substituted with at least one fluorine atom. Preferred substituted -(C1-C6)alkyl include difluoromethyl and trifluoromethyl.

[0073] In one embodiment, R 2is hydrogen. In one embodiment, R 2 is -(C3-C7)cycloalkyl, such as, for example, cyclopropyl optionally substituted with at least one methyl, hydroxy, or fluorine atom. 2 is, for example, -(C3-C7)heterocycloalkyl, such as tetrahydrothiophene or tetrahydrofuran, optionally substituted with at least one methyl. In one embodiment, R 2 is heteroaryl, such as, for example, thiophene or furan, optionally substituted with at least one methyl or ethyl. 2 is, for example, -(C3-C7)heterocycloalkyl, such as morpholine optionally substituted with at least one methyl, hydroxy, or fluorine atom.

[0074] Y as defined herein 1 In R 3 is 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 , -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 , -NR 16 -(C1-C6)alkylene-C(O)OR 15 is selected from.

[0075] Y as defined herein 1 In R 4 is hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)heterocycloalkyl, -(C1-C6)alkylene-aryl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-OR 15 , -(C1-C6)alkylene-NR17 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 is selected from.

[0076] In one embodiment, R 4 is hydrogen.

[0077] Y as defined herein 1 In R 5 is 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 is selected from.

[0078] In one embodiment, R 5 is -(C1-C6)alkyl, such as methyl. In one embodiment, R 5 is aryl, such as, for example, phenyl optionally substituted with at least one halo or methyl.

[0079] Y as defined herein 1 In R7 is 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)Alkylene-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 , or -NR 16 -C(O)OR 15 are independently selected from

[0080] In one embodiment, R 7 is hydrogen. In one embodiment, R 7 is, for example, -(C1-C6)alkyl, such as methyl.

[0081] In one embodiment, R 7 is (C3-C7)heterocycloalkyl, such as, for example, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted 1,4-oxazepanyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, or optionally substituted 2-oxa-5-azabicyclo[2.2.2]octan-5-yl. In one embodiment, the (C3-C7)heterocycloalkyl is substituted by one or two -(C1-C6)alkyl, such as, for example, one or two methyl.

[0082] R as defined herein 2 , R 3 , R 4 , and R 7 In R 15 , R 16 , R 17 , and R 18 are each independently selected from hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, heteroaryl, -(C1-C6)alkylene-(C3-C7)heterocycloalkyl, -(C1-C6)alkylene-heteroaryl, and -(C1-C6)alkylene-aryl; and / or R 15 , R 16 , R 17 , and R 18 Two groups selected from together form a ring selected from -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, and heteroaryl.

[0083] In one embodiment, Y 1 is a 10-membered [6,6] bicyclic heteroaryl.

[0084] In one embodiment, Y 1 is the formula (Y 1 -1) the following group [ka] (where R 2 , R 3 , and R 7 are independently as defined herein. is selected from.

[0085] In one embodiment, Y 1 is a 9-membered bicyclic [6,5]heteroaryl.

[0086] In one embodiment, Y 1 is the formula (Y 1 -2) the following group [ka] (where R 2 , R 3 , R 5 , and R 7 are independently as defined herein. is selected from.

[0087] In one embodiment, Y 1 is the formula (Y 1 -3) the following group [ka] (where R 2 , R 3 , R 5 , and R 7 are independently as defined herein. is selected from.

[0088] In one embodiment, Y 1 is the formula (Y 1 -4) the following group [ka] (where R 2 , R 3 , R 5 , and R 7 are independently as defined herein. is selected from.

[0089] In one embodiment, Y 1 is the formula (Y 1 -5) the following groups [ka] (where R 2 , R 3 , and R 7 are independently as defined herein. is selected from.

[0090] In one embodiment, Y 1 is the formula (Y 1 -6) the following groups [ka] (where R 2 , R 3 , and R 7 are independently as defined herein. is selected from.

[0091] In one embodiment, Y 1 is a 9-membered bicyclic [5,6]heteroaryl.

[0092] In one embodiment, Y 1 is the formula (Y 1 -7) the following groups [ka] (where R 2 and R 7 are independently as defined herein. is selected from.

[0093] In one embodiment, Y 1 is the formula (Y 1 -8) the following groups [ka] (Here, A 1 , A 2 , A 3 , A 4 , and R 4 are independently as defined herein. is selected from.

[0094] In one embodiment, Y 1is an optionally substituted naphthyridine (e.g., an optionally substituted 1,7-naphthyridine, 1,6-naphthyridine, or 2,7-naphthyridine, etc.), an optionally substituted 1H-pyrazolo-pyrimidine, an optionally substituted 2H-pyrazolo-pyrimidine, an optionally substituted benzimidazole, an optionally substituted benzoxazole, an optionally substituted imidazo[1,2-a]pyrazine, an optionally substituted imidazo[1,5-a]pyrazine, an optionally substituted imidazo[4,5-b]pyridine, an optionally substituted pyrazolo[1,5-a][1,3,5]triazine ... azine, optionally substituted pyrazolo[1,5-a]pyrazine, optionally substituted pyrido[2,3-d]pyrimidine, optionally substituted pyrido[3,2-d]pyrimidine, optionally substituted pyrido[3,4-d]pyrimidine, optionally substituted oxazolo[4,5-b]pyridine, optionally substituted oxazolo[4,5-c]pyridine, optionally substituted oxazolo[5,4-b]pyridine, substituted oxazolo[5,4-c]pyridine, optionally substituted quinazoline, optionally substituted quinoline, and optionally substituted phthalazine.

[0095] In one embodiment, Y 1 is an optionally substituted 1H-pyrazolo-pyrimidine. 1 is 1H-pyrazolo-pyrimidine. 1 is an optionally substituted 2H-pyrazolo-pyrimidine. 1 is 2H-pyrazolo-pyrimidine. 1 is selected from optionally substituted pyrido[2,3-d]pyrimidine, optionally substituted pyrido[3,2-d]pyrimidine, and optionally substituted pyrido[3,4-d]pyrimidine. 1 is selected from pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, and pyrido[3,4-d]pyrimidine. 1 is an optionally substituted quinazoline. 1 is a quinazoline.

[0096] In one embodiment, Y 1 is the formula (Y 1 -1a) the following groups [ka] (where R 2 and R 7 are independently as defined herein. is selected from.

[0097] In one embodiment, Y 1 is the formula (Y 1 -2a) the following groups [ka] (where R 2 , R 5 , and R 7 are independently as defined herein. is selected from.

[0098] In one embodiment, Y 1 is the formula (Y 1 -3a) the following groups [ka] (where R 2 , R 5 , and R 7 are independently as defined herein. is selected from.

[0099] In one embodiment, Y 1 is the formula (Y 1 -4a) the following groups [ka] (where R 2 , R 5 , and R 7 are independently as defined herein. is selected from.

[0100] In one embodiment, Y 1 is the formula (Y 1 -5a) the following groups [ka] (where R 2 and R 7 are independently as defined herein. is selected from.

[0101] In one embodiment, Y 1 is an optionally substituted phthalazine (eg, phthalazin-1-yl, etc.).

[0102] In one embodiment, Y 1 The bicyclic heteroaryl in is substituted by one or two -(C1-C6)alkyl, such as, for example, one or two methyl.

[0103] (Y 2 (Definition of In the above formula (I), Y 2 is a monocyclic heteroaryl or aryl. 2 is a 5- or 6-membered heteroaryl. 2 is a 5-membered heteroaryl.

[0104] According to one embodiment, Y 2 is the formula (Y 2 -0) [ka] (where R 12 , R 13 , and R 14 is hydrogen, halogen, cyano, hydroxy, amino, -(C1-C6) alkyl 、each independently selected from -CH2-O-(C1-C6)alkyl, -CH2-NH-(C1-C6)alkyl), -CH2-N-((C1-C6)alkyl), -O-(C1-C6)alkyl, -NH-(C1-C6)alkyl), and -N-((C1-C6)alkyl); is selected from.

[0105] According to one embodiment, Y 2 is the formula (Y 2 -I) the following groups [ka] (where R 12 , R 13 , and R 14 is hydrogen, halogen, cyano, hydroxy, amino, -(C1-C6) alkyl 、 each independently selected from -CH2-O-(C1-C6)alkyl, -CH2-NH-(C1-C6)alkyl), -CH2-N-((C1-C6)alkyl), -O-(C1-C6)alkyl, -NH-(C1-C6)alkyl), and -N-((C1-C6)alkyl); is selected from.

[0106] In one embodiment, Y 2 is the formula (Y 2 -1) the following group [ka] (where R 12 , R 13 , and R 14 are independently as defined herein. is selected from.

[0107] In one embodiment, Y 2 is selected from optionally substituted thiadiazole, optionally substituted thiazole, and optionally substituted thiophene. 2 is selected from thiophene, fluoro-thiophene, thiadiazole, and thiazole.

[0108] In one embodiment, R 12 and R 13 or R 12 and R 14 is selected from hydrogen and (C1-C3) alkyl. 12 and R 13 or R 12 and R 14 are each hydrogen, i.e., Y 2 is a divalent unsubstituted thiophene.

[0109] (Definition of L) In the above formula (I), L is -(CR 10 R 11 ) n , -(C3-C7)cycloalkyl, and -(C3-C7)heterocycloalkyl, where n is an integer ranging from 1 to 10; and R 10 and R 11 is independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -NH-(C1-C6)alkyl, and -N-((C1-C6)alkyl).

[0110] According to one embodiment, n is an integer selected from 1, 2, 3, and 4.

[0111] According to one embodiment, R 10 and R 11 is independently selected from hydrogen, halogen, hydroxy, amino, -(C1-C3)alkyl, -(C1-C2)haloalkyl, -(C1-C2)hydroxyalkyl, -(C1-C2)aminoalkyl, -O-(C1-C4)alkyl, -NH-(C1-C3)alkyl, and -N-((C1-C3)alkyl).

[0112] In one embodiment, L is selected from -(C4-C7)cycloalkyl and -(C4-C7)heterocycloalkyl. In one particular embodiment, L is selected from -(C5-C6)cycloalkyl and -(C5-C6)heterocycloalkyl.

[0113] In one embodiment, n is an integer selected from 1, 2, and 3. In one embodiment, n is an integer selected from 1 and 2. In one embodiment, n is 1. In one embodiment, n is 2.

[0114] In one embodiment, R 10 and R 11 are each independently selected from hydrogen and (C1-C3) alkyl. 10 and R 11 are each hydrogen.

[0115] (Z 1 (Definition of In the above formula (I), Z 1 is (C=O)-R 9 , S(O)-R 9 , and S(O2)-R 9 According to one embodiment, Z 1 is (C=O)-R 9 and S(O2)-R 9 is selected from.

[0116] Z as defined herein 1 In R 9 is an amino, -(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 21 , -(C1-C6)alkylene-NR 23 R 24 , -(C1-C6)alkylene-C(O)-NR 23 R 24 , -(C1-C6)alkylene-C(O)-NR 23 R 24 , -(C1-C6)alkylene-NR 22 -C(O)-R21 , -(C1-C6)alkylene-C(O)OR 21 , -OR 21 , -NR 23 R 24 , -NR 22 -(C2-C6)alkylene-OR 21 , -NR 22 -(C2-C6)alkylene-NR 23 R 24 , -NR 22 -(C1-C6)alkylene-C(O)OR 21 is selected from.

[0117] R as defined herein 9 In R 21 , R 22 , R 23 , and R 24 are each independently selected from hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)halocycloalkyl, -(C3-C7)heterocycloalkyl, aryl, heteroaryl, -(C1-C6)alkylene-(C3-C7)heterocycloalkyl, -(C1-C6)alkylene-heteroaryl, and -(C1-C6)alkylene-aryl; and / or R 21 , R 22 , R 23 , and R 24 Two groups selected from together form a ring selected from -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, aryl, and heteroaryl.

[0118] In one embodiment, R 9is selected from methyl, tert-butyl, cyclopropyl, O-tert-butyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, methoxymethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, phenylmethyl, phenyl 2,2-difluorocyclopropyl 2,2,3,3,3-pentafluoro-propyl, H2N-methyl, N-methyl-NH-methyl, methylazetidinyl, 1-hydroxyethyl (e.g., (S)-1-hydroxyethyl or (R)-1-hydroxyethyl), and pyrrolidinyl. 9 is selected from cyclopropyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, 2,2-difluorocyclopropyl, and 2,2,3,3,3-pentafluoro-propyl.

[0119] (R 1 (Definition of In the above formula (I), R 1 is the only non-cyclic moiety or R 1 either combines with another moiety in formula (I) to form a heterocycloalkyl containing at least one nitrogen atom.

[0120] According to a first embodiment of the present invention, R 1 is hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C3-C7)heterocycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)heterocycloalkyl, -(C1-C6)alkylene-OR 19 and -(C1-C6)alkylene-NR 19 R 20 where R 19 and R 20 are each independently selected from hydrogen, -(C1-C6)alkyl, and -(C3-C7)cycloalkyl; or R 19and R 20 together form a ring selected from -(C3-C7)cycloalkyl and -(C3-C7)heterocycloalkyl.

[0121] According to a second embodiment of the present invention, R 1 and R 10 or R 11 together form a (C3-C7)heterocycloalkyl containing at least one nitrogen atom;

[0122] According to a third embodiment of the present invention, R 1 and R 9 (In this specification, R 9 (as defined in the definition of) together form a (C3-C7)heterocycloalkyl containing at least one nitrogen atom.

[0123] In one embodiment, R 1 is selected from hydrogen and (C1-C3) alkyl, preferably R 1 is hydrogen or methyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 and R 10 or R 11 together form a 5- or 6-membered heterocycloalkyl containing one nitrogen atom. 1 and R 10 or R 11 together form a pyrrolidine. 1 and R 9 together form a 5- or 6-membered heterocycloalkyl containing one nitrogen atom. In one embodiment, R 1 and R 9 together form pyrrolidinone or morpholin-3-one.

[0124] (Specific Compound) According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below. [Table 1] TIFF2025503502000031.tif230170TIFF2025503502000032.tif223170TIFF20255035020000 33.tif233170TIFF2025503502000034.tif221170TIFF2025503502000035.tif231170TIFF202 5503502000036.tif219170TIFF2025503502000037.tif228170TIFF2025503502000038.tif21 7170TIFF2025503502000039.tif226170TIFF2025503502000040.tif223170TIFF20255035020 00041.tif227170TIFF2025503502000042.tif210170TIFF2025503502000043.tif210170TIF F2025503502000044.tif226170TIFF2025503502000045.tif216170TIFF2025503502000046.t if210170TIFF2025503502000047.tif227170TIFF2025503502000048.tif221170TIFF2025503 502000049.tif230170TIFF2025503502000050.tif222170TIFF2025503502000051.tif102170

[0125] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 2 below. [Table 2] The compounds in Tables 1 and 2 were named using ChemDraw® Professional 15.0 (PerkinElmer).

[0126] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 or Table 2 herein.

[0127] (Another compound) All references to compounds of the invention (e.g., "compounds of formula (I)") include references to salts thereof - preferably pharma- ceutically acceptable salts, solvates, multi-component complexes, and liquid crystals. All references to compounds of the invention include references to polymorphs and crystal habits thereof. All references to compounds of the invention include references to pharma- cetically acceptable prodrugs thereof. All references to compounds of the invention include references to isotopically labelled compounds, including deuterated compounds.

[0128] The compounds of the present invention (e.g., "compounds of formula (I)") and subformulas thereof may contain at least one asymmetric center and therefore may exist in different stereoisomeric forms. Thus, all references to the compounds of the present invention include references to all possible stereoisomers and include not only racemates but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such a single enantiomer can be obtained by stereospecific synthesis, by separation of the final product or any convenient intermediate, or by chiral chromatographic methods, each as known in the art. Separation of the final product, intermediate, or starting material can be carried out by any suitable method known in the art.

[0129] The compounds of the present invention (e.g., "compounds of formula (I)") may be in the form of pharma- ceutically acceptable salts. Pharmaceutically acceptable salts include acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, and the like. Salts include, but are not limited to, salts, lactates, malates, maleates, malonates, 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. Suitable 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, 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.When a compound contains an acidic group and a basic group, the compound may also form internal salts, and such compounds are within the scope of the present invention.When a compound contains a hydrogen-donating heteroatom (e.g., NH), the present invention also covers salts and / or isomers formed by the transfer of the hydrogen atom to a 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-labile protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; and / or (iv) by converting the salt of the compound into 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 salt may precipitate from the solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0130] Further compound definitions According to one embodiment, the compound of formula (I) is not CAS # 1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide) or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma- ceutically acceptable salt or solvate thereof.According to one embodiment, the compound of formula (I) is not CAS # 1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof.

[0131] In one embodiment, the compound of formula (I) is CAS # 2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, CAS # 1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide, CAS # 871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, CAS # 1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, CAS # 1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide, CAS # 1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, CAS # 1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, CAS # 1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and Pharmaceutically acceptable salts and solvates thereof are not selected from:

[0132] In one embodiment, the compound of formula (I) is CAS # 1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS # 2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS # 1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS # 1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS # 871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS # 1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS # 1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS # 1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS # 1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS # 1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS # 1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and Pharmaceutically acceptable salts and solvates thereof are not selected from:

[0133] According to one embodiment, Y 1 When R is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), 2 is not optionally substituted (C1-C6)alkyl, such as, for example, methyl or trifluoromethyl. 1 When R is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), 2 is not an optionally substituted (C-C)cycloalkyl, such as, for example, cyclopropyl. 1 When R is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), 2is not optionally substituted heteroaryl, such as, for example, furanyl or thiophenyl. 1 When R is an optionally substituted quinazolinyl, such as quinazolin-4-yl, 2 is not an optionally substituted -(C1-C6)alkylene-(C3-C7)heterocycloalkyl, such as, for example, -CH2-morpholinyl.

[0134] In one embodiment, Y 1 is not optionally substituted quinazolin-4-yl. 1 is not optionally substituted quinazolinyl.

[0135] According to one embodiment, Y 1 is optionally substituted quinazolinyl (e.g., quinazolin-4-yl), and R 1 When is hydrogen, Z 1 is not optionally substituted -C(O)-(C1-C6)alkyl, such as, for example, -C(O)-methyl.

[0136] According to one embodiment, Y 1 is optionally substituted quinazolinyl (e.g., quinazolin-4-yl), and R 1 When is hydrogen, Z 1 is not optionally substituted -S(O)2-(C1-C6)alkyl, such as, for example, -S(O)2-methyl.

[0137] According to one embodiment, the compound of formula (I) is not CAS# 1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide [CAS# 1326255-51-9] or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma-ceutically acceptable salt or solvate thereof.According to one embodiment, the compound of formula (I) is not CAS# 1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide and or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof.

[0138] In one embodiment, the compound of formula (I) is CAS# 1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, CAS# 1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, CAS# 1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide, CAS# 920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, CAS# 1324562-11-9; N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide, CAS# 1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and Pharmaceutically acceptable salts and solvates thereof are not selected from:

[0139] In one embodiment, the compound of formula (I) is CAS# 1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide CAS# 1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS# 920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS# 1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and Pharmaceutically acceptable salts and solvates thereof are not selected from:

[0140] According to one embodiment, Y 1 is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl); 5 is not optionally substituted (C1-C6)alkyl, such as, for example, methyl. 1 is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl); 5 is not optionally substituted aryl, such as, for example, phenyl or fluorophenyl (eg, 4-fluorophenyl).

[0141] In one embodiment, Y 1 is not optionally substituted 1H-pyrazolo[3,4-d]pyrimidin-4-yl. 1 is not optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl.

[0142] According to one embodiment, Y 1 is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl), and R 1 When is hydrogen, Z 1 is not optionally substituted -C(O)-(C1-C6)alkyl, such as, for example, -C(O)-methyl and -C(O)-t-butyl.

[0143] According to one embodiment, Y 1 is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl), and R1 When is hydrogen, Z 1 is not optionally substituted -S(O)2-(C1-C6)alkyl, such as, for example, -SO2-methyl.

[0144] According to one embodiment, the compound of formula (I) is not CAS # 1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma- ceutically acceptable salt or solvate thereof.According to one embodiment, the compound of formula (I) is not CAS # 1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof.According to one embodiment, the compound of formula (I) is not CAS # 919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharma- ceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS # 1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharma- ceutically acceptable salt or solvate thereof.

[0145] In one embodiment, the compound of formula (I) is CAS# 1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS# 1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide CAS# 1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS# 1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide CAS# 1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide CAS# 2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide CAS# 1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one CAS# 874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide CAS# 1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and Pharmaceutically acceptable salts and solvates thereof are not selected from:

[0146] In one embodiment, Y 1 is not optionally substituted imidazo[1,5-a]pyridin-3-yl. 1 is not optionally substituted imidazo[1,5-a]pyridinyl. 1 is not optionally substituted imidazo[1,5-b]pyridazin-7-yl. 1is not optionally substituted imidazo[1,5-b]pyridazinyl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyrimidin-3-yl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyrimidinyl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. 1 is not optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl.

[0147] In one particular embodiment, Y 1 is the formula (Sc7) [ka] (Here, A 1 ~A 4 and G 1 are independently as defined herein above. It is not based on.

[0148] According to one embodiment, the compound of formula (I) has CAS# 2419446-18-5: N-(2-(5-(2-((5-methyloxazolo[4,5-b]pyridin-2-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide [naming using ChemDraw® Professional 15.0 (PerkinElmer)] [ka] nor its pharma- ceutically acceptable salts and / or solvates.

[0149] According to one embodiment, Y 1 is not optionally substituted oxazolo[4,5-b]pyridin-2-yl, such as, for example, 5-methyloxazolo[4,5-b]pyridin-2-yl. 1 is not optionally substituted oxazolo[4,5-b]pyridinyl, such as, for example, 5-methyloxazolo[4,5-b]pyridinyl.

[0150] According to one embodiment, Y 1 is optionally substituted oxazolo[4,5-b]pyridin-2-yl (e.g., 5-methyloxazolo[4,5-b]pyridin-2-yl), and R 1 When is hydrogen, Z 1 is not optionally substituted -C(O)-(C1-C6)alkyl, such as, for example, -C(O)-methyl and -C(O)-t-butyl.

[0151] (Manufacturing Process) The present invention also relates to a process for preparing the compounds of the present invention described herein. According to one embodiment, the process comprises the steps of reacting: (i) a linear or cyclic amine with an acyl chloride, a carboxylic acid, or a sulfonyl chloride; or (ii) a halo-ketone with a thiol.

[0152] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising a compound of the invention described herein and at least one pharma- ceutically acceptable carrier.

[0153] 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 another therapeutic agent. In one embodiment, the at least another therapeutic agent is selected from therapeutic agents known in the art for treating inflammatory disease, autoimmune disease, proliferative disease (e.g., cancer), neurodegenerative disease, pain, neurological disorder, psychiatric disease, neurodevelopmental disorder, sleep disorder, cardiovascular disease, addiction-related disorder, gastrointestinal disease, pulmonary disease, metabolic or hormonal disorder, immune disorder, age-related disease, and / or idiopathic disease.

[0154] The compounds of the present invention, alone or together, can be formulated into suitable dosage unit formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles appropriate for each route of administration.

[0155] (Medical Uses and Treatment Methods) The present invention also relates to a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for use as a medicament.

[0156] According to a particular embodiment, the compounds or pharmaceutical compositions according to the invention are for use in the treatment and / or prevention of a HDAC6-related disease as defined herein.

[0157] The present invention also relates to a method for inhibiting HDAC6 enzyme. According to one embodiment, inhibiting HDAC6 enzyme treats and / or prevents HDAC6-related diseases. According to one embodiment, the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound of the present invention described herein or the pharmaceutical composition of the present invention described herein.

[0158] The present invention also relates to a method for treating and / or preventing HDAC6-related diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein.The present invention also relates to the use of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein in the manufacture of a medicament for treating and / or preventing HDAC6-related diseases.The present invention also relates to the use of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein in the treatment and / or prevention of HDAC6-related diseases.

[0159] Advantageously, the compounds of the present invention show 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. Advantageously, the compounds of the present invention show low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) 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. In particular, the compounds of the present invention show low genotoxicity.

[0160] In one embodiment, the HDAC6-related disease comprises or is selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neurological disorders, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. In one embodiment, the HDAC6-related disease comprises or is selected from the group consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neurological disorders, psychiatric diseases, neurodevelopmental disorders, sleep disorders, and cardiovascular diseases. In one embodiment, the HDAC6-related disease comprises or is selected from the group consisting of proliferative diseases (e.g., cancer), neurodegenerative diseases, neurological disorders, and cardiovascular diseases.

[0161] Various references demonstrating that inhibition of HDAC6 has therapeutic and / or prophylactic effects on given disease classes are listed in Table 3 below. [Table 3] TIFF2025503502000056.tif217170TIFF2025503502000057.tif168170

[0162] In one embodiment, the HDAC6-related disease is an inflammatory disease such as, for example, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease. In one embodiment, the inflammatory disease comprises or is selected from the group consisting of 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), post-operative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

[0163] In one embodiment, the HDAC6-related disease is an autoimmune disease, such as, for example, arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjogren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosing spondylitis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, dermatitis, radiation dermatitis, primary biliary cirrhosis, and the like. In one embodiment, the autoimmune disease comprises or is selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjogren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosing spondylitis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I 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.

[0164] In one embodiment, the HDAC6-associated disease is, for example, cancer, e.g., malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonadenomatous colorectal cancer, or gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, or adenosquamous carcinoma), breast cancer, Cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or hormone-independent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct carcinoma), 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 tumor (e.g., pineal astrocytoma, pilonidal cytoma, cytomegalovirus ... These include multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, liver cancer, pancreatic endocrine tumors, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, hodgkin's lymphoma, and others. and proliferative diseases including myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary site, leukemia (e.g., acute leukemia (e.g., acute lymphocytic leukemia or acute myelocytic leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mesodermal mixed tumor, uterine leiomyosarcoma or endometrial stromal tumor), myelofibrosis, etc.In one embodiment, the proliferative disorder, e.g., cancer, is selected from the group consisting of malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonadenomatous colorectal cancer, or gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, , ductal carcinoma in situ, or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or hormone-independent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct carcinoma), 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, or anaplastic astrocytoma), melanoma, sarcoma, bladder cancer, blood cancer, etc., and include multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, liver cancer, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, In one particular embodiment, the proliferative disorder is selected from the group consisting of: myeloproliferative disorders, chronic myeloproliferative disorders, pancreatic endocrine tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, carcinoma of unknown primary, leukemia (e.g., acute leukemia (e.g., acute lymphocytic leukemia or acute myelocytic leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma, or endometrial stromal tumor), and myelofibrosis. In one particular embodiment, the proliferative disorder is cancer. In one embodiment, the cancer is selected from the group consisting of: malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer, and Hodgkin's disease.

[0165] In one embodiment, the HDAC6-associated disease is a neurodegenerative disease, such as, for example, Alzheimer's disease, dementia of the Alzheimer's type, senile dementia of the Alzheimer's type, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognitive memory impairment, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's dementia, Niemann-Pick syndrome, Down's syndrome, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt's disease, and the like. In one embodiment, the neurodegenerative disease comprises or is selected from the group consisting of Alzheimer's disease, dementia of the Alzheimer's type, senile dementia of the Alzheimer's type, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognitive memory impairment, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's dementia, Niemann-Pick syndrome, Down's syndrome, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disorders (MND), and Creutzfeldt's disease. In one particular embodiment, the neurodegenerative disease is selected from the group including or consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down's syndrome, dementia with Lewy bodies, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[0166] In one embodiment, the HDAC6-related disease is pain (including central or peripheral pain), such as pain, cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, post-operative pain (e.g., post-operative incision pain, deep pain, visceral pain, or chronic pain), muscular pain (e.g., muscular pain associated with chronic pain disorders or stiff neck), joint pain, dental pain, temporomandibular joint pain, headache (e.g., migraine, tension headache, headache associated with fever, or headache associated with high blood pressure), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, kidney pain, urinary tract pain, or bladder pain), obstetric and gynecological pain (ovulation pain, dysmenorrhea, labor pain), neuropathic pain (e.g., herniated disc, radicular pain, post-herpetic neuralgia, trigeminal neuralgia, or lower back pain), migraine, stress headache, tension headache, muscle spasm, irritable bowel syndrome, and the like. In one embodiment, the pain comprises or is selected from the group consisting of pain, cancer pain, acute pain due to inflammation, pain associated with chronic inflammation, post-operative pain (e.g., post-operative incisional pain, deep pain, visceral pain, or chronic pain), muscular pain (e.g., muscular pain associated with a chronic pain disorder or stiff neck), joint pain, dental pain, temporomandibular joint pain, headache (e.g., migraine, tension headache, headache associated with fever, or headache associated with high blood pressure), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, kidney pain, urinary tract pain, or bladder pain), obstetric and gynecological pain (e.g., ovulation pain, dysmenorrhea, or labor pain), neuropathic pain (e.g., herniated disc, radicular pain, post-herpetic neuralgia, trigeminal neuralgia, or lower back pain), migraine, stress headache, tension headache, muscle spasm, and irritable bowel syndrome.

[0167] In one embodiment, the HDAC6-associated disease is a neuropathic disorder (including central or peripheral neuropathies), such as, for example, demyelinating diseases and neuropathies (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory autonomic neuropathy, or familial amyloid polyneuropathy), anti-cancer drug-induced peripheral neuropathy (CIPN) and associated neurological conditions (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, injury-related neuropathies (e.g., traumatic brain injury or stroke). Anticancer drugs that are likely to cause neuropathy include taxanes (e.g., paclitaxel (taxol)), vinca alkaloids (e.g., vincristine), platinum-based agents (e.g., cisplatin, carboplatin, or oxaliplatin), or other molecular targeted agents (e.g., bortezomib). In one embodiment, the neuropathy is selected from the group comprising or consisting of demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory autonomic neuropathy, or familial amyloid polyneuropathy), anti-cancer drug-induced peripheral neuropathy (CIPN) and neurological conditions associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, and injury-related neuropathy (e.g., traumatic brain injury or stroke).

[0168] In one particular embodiment, the neuropathy comprises or is selected from the group consisting of Guillain-Barre 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 chemotherapy anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain, and neuropathic pain.

[0169] In one embodiment, the HDAC6-related disorder is a psychiatric disorder, such as, for example, depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depressive syndrome, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms, or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety disorder, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, dysthymic disorder, affective disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, anorexia nervosa, eating disorder, anorexia nervosa, bulimia or other eating disorders, drug addiction, drug phobia, drug mania, etc. In one embodiment, the psychiatric disorder comprises or is selected from the group consisting of depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depressive syndrome, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms, or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety disorder, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, dysthymic disorder, affective disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, anorexia nervosa, eating disorder, anorexia nervosa, bulimia or other eating disorders, drug addiction, drug phobia, and drug mania.

[0170] In one embodiment, the HDAC6-related disease is a neurodevelopmental disorder, such as Tourette's syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett's syndrome, attention deficit hyperactivity disorder (ADHD), etc. In one embodiment, the neurodevelopmental disorder is selected from the group comprising or consisting of Tourette's syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett's syndrome, and attention deficit hyperactivity disorder (ADHD).

[0171] In one embodiment, the HDAC6-related disease is a sleep disorder such as, for example, an intrinsic sleep disorder (e.g., psychophysiological insomnia), an exogenous sleep disorder, a circadian rhythm disorder (e.g., jet lag, shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24-hour sleep-wake), a parasomnia, a sleep disorder associated with a medical or psychiatric disorder (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, or anxiety neurosis), stress, insomnia, insomnia, insomnia neurosis, or sleep apnea syndrome. In one embodiment, the sleep disorder comprises or is selected from the group consisting of intrinsic sleep disorder (e.g., psychophysiological insomnia), exogenous sleep disorder, circadian rhythm disorder (e.g., jet lag, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24-hour sleep-wake), parasomnia, sleep disorder associated with a medical or psychiatric disorder (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, or anxiety neurosis), stress, insomnia, insomnia, insomnia neurosis, and sleep apnea syndrome.

[0172] In one embodiment, HDAC6-related disease is cardiovascular disease, such as chronic or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, heart disease, tachycardia, congestive heart failure, etc. In one embodiment, cardiovascular disease comprises or is selected from the group consisting of chronic or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, heart disease, tachycardia, and congestive heart failure.In one particular embodiment, heart-related disease comprises or is selected from the group consisting of heart failure, cardiomyopathy, and myocarditis.

[0173] In one embodiment, the HDAC6-related disease is an addiction-related disorder, such as, for example, alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcoholism, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, drug withdrawal, etc. In one embodiment, the addiction-related disorder is selected from the group comprising or consisting of alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcoholism, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, and drug withdrawal.

[0174] In one embodiment, the HDAC6-related disease is a gastrointestinal disease, such as peptic ulcer, stress-induced gastrointestinal disorder, stress-induced emesis, peptic ulcer, diarrhea, constipation, or postoperative ileus. In one embodiment, the gastrointestinal disease comprises or is selected from the group consisting of peptic ulcer, stress-induced gastrointestinal disorder, stress-induced emesis, peptic ulcer, diarrhea, constipation ileus, and postoperative ileus.

[0175] In one embodiment, the HDAC6-related disease is a pulmonary disease, such as hyperpnea, bronchial asthma, apnea, etc. In one embodiment, the pulmonary disease is selected from the group including or consisting of hyperpnea, bronchial asthma, and apnea.

[0176] In one embodiment, the HDAC6-related disease is a metabolic or hormonal disorder, such as, for example, obesity, diabetes, acromegaly, infertility, metabolic syndrome, etc. In one embodiment, the metabolic or hormonal disorder is selected from the group comprising or consisting of obesity, diabetes, acromegaly, infertility, and metabolic syndrome.

[0177] In one embodiment, the HDAC6-related disease is an immune disorder, such as, for example, allergic disease, immunodeficiency syndrome caused by HIV infection, immunodeficiency syndrome caused by stress, etc. In one embodiment, the immune disorder comprises or is selected from the group consisting of immunodeficiency syndrome caused by HIV infection and immunodeficiency syndrome caused by stress.

[0178] In one embodiment, the HDAC6-related disease is an age-related disease, such as, for example, alopecia, glaucoma, impotence, menopause, incontinence, osteoporosis, etc. In one embodiment, the age-related disease is selected from the group comprising or consisting of alopecia, glaucoma, impotence, menopause, incontinence, and osteoporosis.

[0179] In one embodiment, the HDAC6-related disease is an idiopathic disease, such as, for example, Meniere's disease, sudden infant death syndrome, etc. In one embodiment, the idiopathic disease is Meniere's disease or sudden infant death syndrome.

[0180] The compounds or pharmaceutical compositions of the present invention can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, intracerebroventricularly (ICV), intravesicular injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, intravaginal, rectal, sublingual, or topical routes of administration. In the treatment and / or prevention of infectious diseases, suitable dosage levels can be about 0.01 to 500 mg / kg of patient body weight / day (mg / kg / day), which can be administered in single or multiple doses. 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 per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosing for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease, and treatments the host is undergoing.

[0181] Advantageously, the compound of the present invention is selective for at least one HDAC other than HDAC6, preferably for at least one class II HDAC other than HDAC6, more preferably for any class II HDAC other than HDAC6, even more preferably for HDAC other than HDAC6.Particularly advantageously, the compound of the present invention is selective for HDAC1.Particularly advantageously, the compound of the present invention is selective for HDAC10.Selectivity is strongly related to avoiding the side effects of HDAC inhibitors.

[0182] (kit) The present invention also relates to kits comprising the compounds of the invention described herein, or the pharmaceutical compositions of the invention described herein, and means for administering said compounds or pharmaceutical compositions.

[0183] Means for administering compounds or pharmaceutical compositions are well known in the art and can be determined by the skilled artisan depending on the desired route of administration. EXAMPLES

[0184] (Example) The present invention is further illustrated by the following examples.

[0185] Example 1: Synthesis of compounds Compounds (1) to (196) of formula (I) shown in Table 1 and / or Table 2 above were prepared as described below. Compounds 99 (CAS 1287068-38-5), 100 (CAS 1147354-39-9), 102 (CAS 1210761-93-5), and 104 (CAS 2419446-18-5) were purchased commercially. However, they may have been prepared using similar methods.

[0186] (General synthesis method) Compounds according to the invention, in particular compounds according to formula (I), can be prepared by methods known to those skilled in the art of organic synthesis or by using the following synthetic schemes. In all of the following schemes, it is understood that protecting groups for sensitive or reactive groups are utilized where necessary in accordance with general principles of organic chemistry. Protecting groups are manipulated according to standard methods (TW Green and PGM Wuts, Protecting Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.). These groups are then removed at a convenient stage of the synthesis using methods readily apparent to those skilled in the art. 1 Or Y 2 Many of the heterocyclic compounds of formula (I) where is heteroaryl can be prepared using synthetic routes well known in the art (AR Katrizky and CW Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0187] The synthesis of HDAC6 inhibitors disclosed in the present invention is prepared using the following synthesis scheme.The specific conditions for carrying out these reactions are provided in the detailed examples.The following synthesis schemes show exemplary approaches to the compounds of the present invention, but these routes should not be construed as the only possible synthetic routes to the compounds of the present invention.

[0188] Compounds of formula (I) can be obtained according to Scheme 1 below: [ka]

[0189] Amines T-1 are commercially available or can be synthesized by one skilled in the art of organic chemistry using a number of methods described in the literature. Intermediate T-2 can be prepared by protecting the amine group of T-1 (step 1), for example, 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-2 can be involved in a halogenation step to provide T-3 (wherein X is halo, such as, for example, bromo (Br)) using, for example, NBS or Br2 in a solvent (e.g., DCM) at a suitable temperature (step 2). The halide T-3 can then be converted to the corresponding ketone T-4 in a single or multiple step sequence, for example: (option 1) a two-step sequence, for example: (i) a metal-catalyzed cross-coupling sequence using tributyl(1-ethoxyvinyl)tin in the presence of a catalyst / ligand system (e.g., Pd(PPh3)4, base (e.g., t-BuOK) in a solvent (e.g., dioxane) at a suitable temperature to provide an enol ether intermediate, which is converted to the desired ketone T-4 using an acidic medium such as aqueous HCl or formic acid at a suitable temperature (step 3); or (option 2) a three-step sequence, for example: (i) a metal-halide exchange using n-BuLi in an aprotic solvent such as anhydrous THF under an inert atmosphere such as nitrogen at a controlled temperature such as −78° C., followed by introduction of dimethylformaldehyde or an equivalent reagent to provide the corresponding aldehyde intermediate T-5 (step 4). Intermediate T-5 can be treated with a methylating agent such as MeMgBr in an aprotic solvent (e.g., THF) at a suitable temperature to provide the resulting alcohol T-6 (Step 5). Alcohol T-6 can be converted to the corresponding ketone T-4 by use of an oxidizing agent such as DMP or PCC in a solvent (e.g., DCM) at a suitable temperature (Step 6). Ketone T-4 can be further involved in a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at a suitable temperature to provide halo-ketone T-7 (Step 7).Halo-ketone T-7 is then reacted with the ketone of formula Y in the presence of a base (eg, MeONa or K2CO3) in a solvent (eg, DMF or ACN) at a suitable temperature. 1 Reaction of the heteroaryl intermediate Y with a thiol hetero-aryl derivative of -SH provides the heteroaryl intermediate T-8 (Step 8). 1 -SH is commercially available or can be obtained by methods known to those skilled in the art, for example, from the corresponding heteroaryl Y 1 Heteroaryl Y can be prepared from the -OH derivative using Lawesson's reagent or P2S5 reagent in a solvent (e.g., toluene) at a suitable temperature. 1 -OH is commercially available or can be prepared by methods known to those skilled in the art. The protected amine T-8 can then be deprotected in acidic or basic medium, depending on the choice of protecting group, for example in acidic medium such as formic acid or aqueous HCl to remove the BoC-protecting group, or by hydrogenolysis with H2 in a protic solvent (e.g. MeOH) in the presence of a catalyst (e.g. Pd(OH)2) to remove a benzylic type protecting group such as Cbz (Step 9) to finally provide the corresponding amine intermediate T-9.

[0190] The final compound of formula (I), 1 CO-R 9 is prepared by reacting amine T-9 with a compound of formula R in the presence of a base (e.g., EtN) and a suitable solvent (e.g., DCM or THF) at a suitable temperature. 9 Alternatively, the final compound of formula (I), where Z 1 CO-R 9 can be prepared by reacting amine T-9 with a compound of formula R in the presence of a coupling agent (e.g., HOBt or HATU), a base (e.g., EtN) in a solvent (e.g., DMF) at a suitable temperature. 9 The final compound of formula (I), where Z is -COH acid, can be obtained by reaction with a carboxylic acid (step 10b). 1 CO-R 9 and R 9The final compounds of formula (I) (where Z is -CH2-OH) can be obtained by reaction of amine T-9 with a carboxylic acid of formula HO2C-CH2-OSiR3 (where SiR3 is, for example, tert-butyldiphenylsilyl (TBDPS-)) in the presence of a coupling agent (e.g., EDCI / HOBt or HATU), a base (e.g., Et3N) in a solvent (e.g., DMF) at a suitable temperature, followed by deprotection of the silyl ether functionality -OSiR3 with a fluorochemical (e.g., TBAF) in an aprotic solvent (e.g., THF) at a suitable temperature (step 10c). 1 SO2-R 9 is prepared by reacting amine T-9 with a compound of formula R in the presence of a base (e.g., EtN) and a solvent (e.g., DCM or THF) at a suitable temperature. 9 It can also be obtained by reaction of --SO.sub.2Cl with a sulfonyl chloride (Step 10b).

[0191] Compounds of formula (I) can also be obtained according to Scheme 2 (Method 2) below: [ka]

[0192] Amines T-10 are either commercially available or can be synthesized by one skilled in the art of organic chemistry using a number of methods described in the literature. Intermediate compounds T-11 (where Z 1 CO-R 9 is prepared by reacting amine T-10 with a compound of formula R in the presence of a base (e.g., EtN) and a solvent (e.g., DCM or THF) at a suitable temperature. 9 -COCl with acyl chloride; or by reaction of amine T-10 with a compound of formula R in the presence of a coupling agent (e.g., EDCI / HOBt or HATU), a base (e.g., EtN) in a solvent (e.g., DMF) at a suitable temperature. 9 The intermediate compound T-11 (wherein Z is a carboxylic acid) can be prepared by either the reaction of -COH acid with a carboxylic acid (Step 1a). 1 SO2-R 9is prepared by reacting amine T-10 with a compound of formula R in the presence of a base (e.g., EtN) and a solvent (e.g., DCM or THF) at a suitable temperature. 9 The heteroaryl intermediate T-11 can be prepared by reaction of -SO2Cl with a sulfonyl chloride (Step 1b). The heteroaryl intermediate T-11 is then reacted with an acylating agent, for example acetyl chloride, in the presence of a suitable catalyst, such as AlCl3, in a suitable solvent (e.g. DCM) at a suitable temperature to provide the intermediate ketone T-12 (Step 2). Alternative methods for preparing ketone T-12 can be used, for example the method described in Scheme 1 (Method 1), using either steps 2 and 3 of Scheme 1, or the synthetic sequence of reactions from steps 2 to 6. The ketone T-12 can be involved in a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g. DCM or THF) at a suitable temperature to provide the halo-ketone T-13 (Step 3). The halo-ketone T-13 can be converted to a compound of formula Y in the presence of a base (e.g. MeONa or K2CO3) in a solvent (e.g. DMF or ACN) at a suitable temperature. 1 Reaction with a heteroaryl thiol derivative of --SH can provide compounds of formula (I) (Step 4).

[0193] In some cases, Z 1 may carry a protecting group, such as, for example, tert-butyldiphenylsilyl (TBDPS), which may be removed in one of the reaction steps, such as, for example, step 3. Alternatively, the protecting group may be removed in a separate deprotection step using a suitable deprotection reagent, such as, for example, pyridinium fluoride (HF.Py), in a suitable solvent, such as, for example, ACN, at a suitable temperature, such as, for example, 30° C.

[0194] A compound of formula (I) (wherein L and R 1 can be linked together to form a cyclic amine) can also be obtained according to Scheme 3 (Method 3) below: [ka]

[0195] The protected cyclic amine T-14 is either commercially available or can be synthesized by one skilled in the art of organic chemistry from the corresponding free cyclic amine using multiple methods described in the literature, for example, using step 1 described in method 1 of scheme 1. Compound T-14 can be reacted with phenyltriflimide, N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethylsulfonyl)methanesulfonamide, or trifluoromethanesulfonic anhydride in the presence of a suitable base (e.g., LiHMDS) and solvent (e.g., THF) at a suitable temperature to provide the triflate enol ether T-15, where X is an OSO2CF3 group (step 1). Suzuki cross-coupling type reaction of triflate T-15 with a boronic acid or boronic ester of formula T-15A in the presence of a catalyst (e.g., Pd(dppf)Cl2), a base (e.g., Cs2CO3) in a solvent (e.g., DMF) at a suitable temperature can provide intermediate ketone T-16 (Step 2). The boronic acid or boronic ester of formula T-15A can be commercially available or synthesized by one skilled in the art of organic chemistry using a number of methods described in the literature. The double bond of cyclic amine intermediate T-16 can then be reduced by hydrogenation using 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-17 (Step 3). Ketone T-17 can be involved in a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at a suitable temperature to provide halo-ketone T-18 (Step 4). Halo-ketone T-18 can then be converted to a halo-ketone of formula Y in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at a suitable temperature. 1Reaction with a thiol hetero-aryl derivative of -SH can provide the heteroaryl intermediate T-19 (Step 5). The protected amine T-19 can be deprotected in acidic, neutral, or basic medium, depending on the choice of protecting group, for example, in acidic medium using formic acid or aqueous HCl solution to remove the BoC-protecting group, to provide the corresponding amine intermediate T-20 (Step 6).

[0196] The final compound of formula (I), 1 CO-R 9 is prepared by reacting cyclic amine T-20 with a compound of formula R in the presence of a base (e.g., EtN) and a solvent (e.g., DCM or THF) at a suitable temperature. 9 -COCl with an acyl chloride; or by reaction of a compound of formula R in the presence of a coupling agent (e.g., EDCI / HOBt or HATU), a base (e.g., EtN) in a solvent (e.g., DMF) at a suitable temperature 9 The final compound of formula (I), where Z 1 SO2-R 9 is prepared by reacting cyclic amine T-20 with a compound of formula R in the presence of a base (e.g., EtN) and a solvent (e.g., DCM or THF) at a suitable temperature. 9 It can also be obtained by reaction of --SO.sub.2Cl with sulfonyl chloride (step 7b).

[0197] A compound of formula (I) (wherein Z 1 Group L and R 9 may be linked together to form a cyclic heterocycle, e.g., a cyclic amide, may also be obtained according to Scheme 4 (Method 4) below: [ka]

[0198] Intermediate T-21 (where X is a halide) is either commercially available or can be synthesized by one skilled in the art of organic chemistry using multiple methods described in the literature, for example, from the corresponding alcohol (X=OH) using a halogenating agent (e.g., SOCl2) in a solvent (e.g., THF) at a suitable temperature. Halide T-21 can be reacted with heterocyclic amide formula T-21A in the presence of a base (e.g., NaH) in a solvent (e.g., THF) at a suitable temperature to provide the corresponding intermediate T-22 (Step 1). Alternatively, compound T-22 can be prepared in a two-step sequence by reacting the aforementioned intermediate T-1 (where R 1 is H) (Step 5, Method 4a), which can be reacted with a chloroalkyl acyl chloride, such as, for example, 3-chloropropionyl chloride, in the presence of a base (e.g., Et3N) in a solvent (e.g., DCM) at a suitable temperature (Step 1), followed by intramolecular cyclization in the presence of a base (e.g., NaH) in a solvent (e.g., DMF) at a suitable temperature (Step 2). Introduction of a ketone group into T-22 can be carried out using the methods previously described in Scheme 1 (Steps 2 and 3; or Steps 2-6) or Scheme 2 (Step 2) to provide the ketone derivative T-23 (Step 2). The ketone intermediate T-23 can be involved in a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., ACN or DCM or THF) at a suitable temperature to provide the halo-ketone T-24 (Step 3).

[0199] Halo-ketone T-24 is then converted to a compound of formula Y in the presence of a base (e.g., MeONa or K2CO3) in a solvent (e.g., DMF or ACN) at a suitable temperature. 1 Reaction with a thiol hetero-aryl derivative of --SH provides the final compound of formula (I) (Step 4).

[0200] (Compound synthesis - 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 the specification:

[0201] Materials and Analytical Methods All reactions were monitored by TLC using 0.25 mm E. Merck precoated silica gel plates (60 F254) and Waters liquid chromatography-mass spectrometry (LCMS).

[0202] LCMS (Method 1): LC-MS spectra were recorded on a Waters Acquity I class UPLC system using the following system: Formic acid and acetonitrile were used as HPLC grade. For analytical RP-HPLC analysis, the following gradient conditions were used: [Table 4]

[0203] LCMS (Method 2): LCMS were recorded on Agilent 1200 & 6120B instruments. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array, or a UV detector. The effluent from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of a person skilled in the art to set tuning parameters to obtain ions that allow identification of the nominal mass monoisotopic molecular weight (MW) and / or accurate mass monoisotopic molecular weight of the compounds. Data acquisition was performed with appropriate software. An ES MS detector was used and acquired in positive or negative ionization mode. Compounds were analyzed by [M+H + ] (protonated molecule) or [MH +] (deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained for the lowest isotopic mass. All results were obtained with experimental uncertainties generally associated with the method used. The gradient conditions used are listed below: [Table 5]

[0204] LCMS (Method 3): Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions are listed below: [Table 6]

[0205] LCMS (Method 4): Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions are listed below: [Table 7]

[0206] LCMS (Method 5): LCMS spectra were recorded on a Waters Acquity I class UPLC system using the following system. Formic acid and ammonia or TFA were used as HPLC grade. The following gradient conditions were used: [Table 8]

[0207] LCMS (Method 6): LCMS were recorded on an Agilent 1200 instrument. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array, or a UV detector. The following gradient conditions were used: [Table 9]

[0208] LCMS (Method 7): LCMS were recorded on an Agilent 1200 instrument. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array, or a UV detector. The following gradient conditions were used: [Table 10]

[0209] LCMS (Method 8): LCMS were recorded on an Agilent 1200 instrument. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array, or a UV detector. The following gradient conditions were used: [Table 11]

[0210] RP-HPLC: Reverse phase HPLC was performed on a Waters HPLC system using the following system: [Solvent A: acetonitrile, Solvent B: 0.1% NH3 in water] or [Solvent A: acetonitrile, Solvent B: 0.1% TFA in water]. Ammonia was used as HPLC grade. All separations were performed at ambient temperature.

[0211] Flash column chromatography: Purification of reaction products was performed by column chromatography using commercial silica or flash chromatography using Combiflash Rf with Teledyne Isco RediSep Rf High Performance Gold or Silicycle SiliaSep High Performance columns (40, 80, or 120 g). The purity of all final compounds was >95% and analyzed on a Waters LCMS system.

[0212] 1 H NMR: 1H NMR spectra were recorded on a Varian 400 MHz spectrometer and are reported in ppm using the solvent resonances as internal standards [CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm]. Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constants in Hz, integrals).

[0213] DSC: Melting points were determined using Differential Scanning Calorimetry. The following equipment, parameters and procedures were used: [Table 12]

[0214] (abbreviation) Abbreviations are used as follows: [Table 13] TIFF2025503502000072.tif164170

[0215] (Preparation of synthetic intermediates) (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-1) by Method 1 (Scheme 1):) [ka]

[0216] (Synthesis of tert-butyl (thiophen-2-ylmethyl)carbamate (I-1a)) To a solution mixture of thiophen-2-ylmethanamine (50.0 g, 441.770 mmol) in THF (500 mL) was slowly added NaHCO3 (37.1 g, 485.947 mmol) and (Boc)2O (111.5 mL, 441.770 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with 30% EtOAc in hexanes and passed through silica to give compound (I-1a) (100 g, quantitative) as a white gummy solid. (Synthesis of tert-butyl((5-bromothiophen-2-yl)methyl)carbamate (I-1b)) To a solution mixture of compound I-1a (50 g, 234.741 mmol) in DMF (500.0 mL) was added NBS (45.9 g, 258.215 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. Cold water was added to the reaction mixture, which was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh), and the compound was eluted with 10% EtOAc in hexane to give compound (I-1b) (60.5 g, yield: 87%) as a brown gummy liquid. (Synthesis of tert-butyl((5-formylthiophen-2-yl)methyl)carbamate (I-1c)) To a solution mixture of compound I-1b (30.0 g, 102.739 mmol) in anhydrous THF (600.0 mL), n-BuLi (1.6 M in hexane) (321 mL, 513.698 mmol) was added at -78 °C and stirred at the same temperature for 30 min. DMF (39 mL, 513.698 mmol) was added dropwise at -78 °C and stirring was continued for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh), the compound was eluted with 12% EtOAc in hexane to give compound I-1c (12.0 g, yield: 49%) as a brown gummy liquid. [ka] (Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)carbamate (I-1d)) To a solution of compound Ic (18.5 g, 76.7 mmol) in anhydrous THF (400.0 mL) was added methylmagnesium bromide (1.0 M in THF) (767 mL, 767.0 mmol) at 0 °C, and then it was stirred at rt for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (500 mL) and washed with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh), and the compound was eluted with 20% EtOAc in hexane to give compound I-1d (13.0 g, yield: 66%) as a brown gummy liquid. [ka] (Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)carbamate (I-1e)) To a solution mixture of compound I-1d (6.5 g, 25.26 mmol) in DCM (65.0 mL) was added PCC (13.6 g, 63.15 mmol) at rt. The reaction mixture was stirred at rt for 2 h. After completion of the reaction, the mixture was filtered in vacuum and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh), and the compound was eluted with 20% EtOAc in hexane to give compound I-1e (4.9 g, yield: 75%) as a brown gummy liquid. (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-1)) To a solution mixture of compound-6 (4.8 g, 18.8 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (4.95 g, 13.1 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. After completion of the reaction, the mixture was filtered through a celite bed and concentrated in vacuum. The crude compound was purified using combi-flash C-18 purification to give compound I-1 (1.5 g, yield: 24%) as a light brown solid. [ka]

[0217] (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-2) by Method 1 (Scheme 1):) [ka]

[0218] (Synthesis of tert-butyl (2-(thiophen-2-yl)ethyl)carbamate (I-2a)) To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (20.0 g, 157.22 mmol) in dichloromethane (200 mL) cooled to 0 °C was added (Boc)2O (41.1 g, 188.66 mmol) followed by Et3N (24.6 g, 243.10 mmol). The resulting mixture was stirred at rt for 16 h after which it was concentrated under reduced pressure. The crude residue was diluted with water (100 mL) and extracted with DCM (2 × 100 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 10% EtOAc in hexanes and the pure fractions were evaporated to give compound I-2a (28 g, yield: 74%) as a brown gummy liquid. (Synthesis of tert-butyl (2-(5-bromothiophen-2-yl)ethyl)carbamate (I-2b)) To a solution of compound I-2a (28 g, 123.172 mmol) in DMF (400 mL) cooled to 0 °C, NBS (21.9 g, 123.172 mmol) was added portionwise. The mixture was then stirred at rt for 2 h, after which it was poured into a mixture of ice water (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine solution (100 mL), dried over Na2SO4, and then concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh), and the compound was eluted with 10% EtOAc in hexane to give compound I-2b (37.08 g, yield: 98%) as an off-white solid. (Synthesis of tert-butyl (2-(5-formylthiophen-2-yl)ethyl)carbamate (I-2c)) To a solution of compound I-2b (20.0 g, 65.312 mmol) in anhydrous THF (200 mL) cooled to -78 °C, n-BuLi (1.6 M solution in hexane) (204.0 mL, 326.563 mmol) was added dropwise, the resulting mixture was stirred for 15 min, then anhydrous DMF (35.9 g, 491.80 mmol) was added and stirring was continued for 30 min at the same temperature. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh), the compound was eluted with 15% EtOAc in hexane to give compound I-2c (10.0 g, yield: 57%) as a gummy liquid. (Synthesis of tert-butyl (2-(5-(1-hydroxyethyl)thiophen-2-yl)ethyl)carbamate (I-2d)) To a solution of compound I-2c (18.0 g, 70.496 mmol) in anhydrous THF (180 mL) cooled to 0 °C, methylmagnesium bromide (1.0 M solution in THF) (705.0 mL, 70.496 mmol) was added dropwise, then it was slowly warmed to rt and stirred for 2 h. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2 × 300 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh), the compound was eluted with 20% EtOAc in hexane to give compound I-2d (15.0 g, yield: 78%) as a gummy solid. (Synthesis of tert-butyl (2-(5-acetylthiophen-2-yl)ethyl)carbamate (I-2e)) To a solution of compound I-2d (10 g, 36.849 mmol) in anhydrous DCM (100 mL) cooled to 0 °C, Dess-Martin periodinane (46.8 g, 110.547 mmol) was added, which was then slowly warmed to rt and stirred for 16 h. The reaction mixture was filtered through a Celite pad and washed with dichloromethane, after which the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluting with 15% EtOAc in hexane to give compound I-2e (7.1 g, yield: 72%) as a gummy solid. (Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-2)) To a solution of compound I-2e (7.0 g, 25.987 mmol) in anhydrous THF (70.0 mL) was added trimethylphenylammonium tribromide (7.8 g, 20.789 mmol), and then the mixture was stirred at room temperature for 16 h. The solvent was then evaporated and the crude was purified by Combi-flash reverse phase chromatography to give I-2 (2.05 g, yield: 23%) as an off-white solid.

[0219] (Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3) by Method 1 (Scheme 1):) [ka]

[0220] (Synthesis of tert-butyl((5-bromothiophen-2-yl)methyl)(methyl)carbamate (I-3a)) To a solution mixture of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-1b) (40 g, 136.986 mmol) in DMF (400.0 mL) was added NaH (6.56 g, 273.0 mmol) followed by methyl iodide (12.8 mL, 205.479 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice water (150 mL), extracted with EtOAc (2×500 mL), dried over Na2SO4, and concentrated in vacuo to give 43 g of crude compound I-3a, which was carried on to the next step without further purification. (Synthesis of tert-butyl((5-formylthiophen-2-yl)methyl)(methyl)carbamate (I-3b) To a solution mixture of compound (I-3a) (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 stirred at -78 °C for 30 min. DMF (27.9 mL, 359.47 mmol) was added at -78 °C and after stirring for 2 h, the reaction mixture was quenched with saturated NH4Cl solution (200.0 mL), extracted with EtOAc (2 x 500 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 12% EtOAc in hexane to give compound I-3b (6.5 g, yield: 35%) as a gummy liquid, which was used without further purification. (Synthesis of tert-butyl((5-(1-hydroxyethyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3c) To a solution mixture of compound I-3b (13.0 g, 50.9 mmol) in anhydrous THF (250.0 mL) was added methylmagnesium bromide (1.0 M in THF) (509 mL, 509.0 mmol) at 0 °C and the reaction was stirred at rt for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (500 mL) and washed with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 20% EtOAc in hexane to give compound I-3c (10 g, yield: 72%) as a gummy liquid which was used without further purification. (Synthesis of tert-butyl((5-acetylthiophen-2-yl)methyl)(methyl)carbamate (I-3d) To a solution mixture of compound I-3c (10.0 g, 36.9 mmol) in DCM (100.0 mL) was added PCC (19.8 g, 92.2 mmol) at rt. The reaction mixture was stirred at rt for 2 h. Then the reaction mixture was filtered and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) and the compound was eluted with 20% EtOAc in hexane to give compound I-3d (7.6 g, yield: 77%) as a gummy liquid, which was used without further purification. (Synthesis of tert-butyl((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)-carbamate (I-3)) To a solution mixture of compound I-3d (4.3 g, 15.9 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (4.20 g, 11.1 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered through a bed of celite and concentrated in vacuo. The crude compound was purified using combi-flash reverse phase purification (ACN in water and 0.001% TFA) to give compound I-3 (1.5 g, yield: 27%) as a light brown solid.

[0221] (Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pivalamide (I-4) by Method 2 (Scheme 2):) [ka]

[0222] (Synthesis of N-(thiophen-2-ylmethyl)pivalamide (I-4a)) To a solution mixture of thiophen-2-ylmethanamine (30 g, 265.062 mmol) in DCM (300.0 mL) was added Et3N (55.7 mL, 398.230 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 10 min, after which pivaloyl chloride (39.14 mL, 318.584 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (500.0 mL), washed with water (2 × 100 mL), and the organic layer was dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 10% EtOAc in hexane to give compound I-4a (40 g, yield: 77%) as a gummy liquid, which was used without further purification. (Synthesis of N-((5-acetylthiophen-2-yl)methyl)pivalamide (I-4b)) To a solution mixture of AlCl3 (14.05 g, 105.30 mmol) in DCM (166.0 mL) at 0 °C, acetyl chloride (3.60 mL, 50.5 mmol) was added dropwise. After 5 min, compound I-4a (8.3 g, 42.1 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Then, the reaction mixture was quenched with cold water (100 mL) and extracted with DCM (2 × 300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 20% EtOAc in hexane to give compound I-4b (8.0 g, yield: 80%) as a white solid. (Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pivalamide (I-4)) To a solution mixture of compound I-4b (25 g, 104.6 mmol) in THF (460 mL) was added phenyltrimethylammonium tribromide (27.53 g, 73.2 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered through a bed of celite and concentrated in vacuo. The crude compound was purified using combi-flash reverse phase purification (ACN in water and 0.001% TFA) to give I-4 (6.2 g, yield: 19%) as an off-white solid. [ka]

[0223] (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1-carboxylate (I-5) by Method 3 (Scheme 3):) [ka]

[0224] (Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5a)) To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.398 mmol) in anhydrous THF (10 mL) cooled to -78 °C, LiHMDS (1.0 M solution in THF) (6.0 mL, 5.934 mmol) was added dropwise and the resulting mixture was stirred for 60 min. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide in THF (2.33 g, 5.934 mmol) was added to the solution and stirred at the same temperature for 30 min. The reaction mixture was then warmed to rt, quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) eluted with 10% EtOAc in hexanes to give compound I-5a (0.63 g, 37% yield) as a gummy liquid. (Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5b)) 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) was added K2CO3 (3.9 g, 28.389 mmol) and Pd(dppf)Cl2 (1.0 g, 0.9463 mmol). The reaction was purged with N2 for 15 min and then heated to 100 °C for 16 h. The mixture was then quenched with saturated aqueous NaHCO3 (20 mL) and then extracted with EtOAc (2 x 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 on silica gel (60-120 mesh, eluent: 50% EtOAc in hexanes) to afford the title compound I-5b (2.7 g, 75% yield) as a gummy liquid. (Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)pyrrolidine-1-carboxylate (I-5c)) To a stirred solution of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate I-5b (2 g, 6.825 mmol) in MeOH (20 mL) was added 10% Pd-C (2.0 g) followed by H2 gas at 60 psi for 5 h. The reaction mixture was filtered through a bed of Celite under vacuum. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (60-120 mesh, eluent: 50% EtOAc in hexanes) to give the title compound I-5c (1.5 g, 74% yield) as a yellow liquid. (Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1-carboxylate (I-5)) To a solution of compound I-5c (0.2 g, 0.680 mmol) in anhydrous THF (5 mL) was added tetrabutylammonium tribromide (0.8 g, 1.360 mmol), then stirred at room temperature for 16 h. The reaction mixture was concentrated to give the crude compound, which was purified by Combi-flash reverse phase chromatography to give I-5 (0.07 g, 27% yield) as a white solid. [ka]

[0225] (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6) by Method 4 (Scheme 4):) [ka]

[0226] (Synthesis of 2-(chloromethyl)thiophene (I-6a) by step 1 of method 4:) To a solution of thiophen-2-ylmethanol (2.0 g, 17.518 mmol) in THF (20 mL) was added SOCl2 (2.5 g, 21.021 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was concentrated. The crude residue was carried on to the next step without further purification. (Synthesis of 3-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-6b)) To a solution of compound I-6a (0.5 g, 5.043 mmol) in anhydrous THF (5.0 mL), NaH (60% in oil) (0.3 g, 7.575 mmol) was added at 0 °C. 3-Methylpyrrolidin-2-one (0.66 g, 5.043 mmol) was added at the same temperature and the mixture was stirred for 30 min. The previous reaction mixture was brought to rt and stirred for another 16 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography on silica gel (60-120 mesh eluent: 10% EtOAc in hexane) to give compound I-6b (0.45 g, 50% yield) as a yellow gummy liquid. (Synthesis of 1-((5-bromothiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6c)) To a solution of compound I-6b (0.45 g, 2.304 mmol) in acetonitrile (5.0 mL) was added NBS (0.4 g, 2.304 mmol) at 0° C., and the reaction mixture was stirred at rt for 2 h. After completion of the reaction, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na2SO4, and the solvent was concentrated under reduced pressure. The crude was purified by combi-flash reverse phase chromatography to give compound I-6c (0.5 g, 79% yield) as a yellow gummy liquid. (Synthesis of 1-((5-acetylthiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6d)) A stirred solution of compound I-6c (0.5 g, 1.824 mmol) in toluene was purged with N2, then tributyl(1-ethoxyvinyl)stannane (0.78 g, 2.160 mmol) and Pd(PPh3)4 (0.2 g, 0.182 mmol) were added. The reaction mixture was stirred at 110 °C for 16 h. Saturated KF solution was added to the reaction mixture and stirring was continued at rt for 30 min. The organic layer was separated and concentrated under reduced pressure to give the crude compound. THF (20 mL) and concentrated HCl were added to the crude reaction mixture. After stirring for 30 min, solid Na2CO3 was added until pH ~7. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (60-120 mesh, eluent 20% EtOAc in hexanes) to give compound I-6d (0.3 g, 70% yield) as a white solid. (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6)) To a solution of compound I-6d (0.3 g, 1.265 mmol) in anhydrous THF (5 mL) was added tetrabutylammonium tribromide (0.6 g, 1.265 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated, and the residue was purified by Combi-flash reverse phase chromatography to give I-6 (0.07 g, 16% yield) as a white solid.

[0227] (Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophen-2-yl)methyl)pivalamide (I-7) by Method 2 (Scheme 2)) [ka]

[0228] (Synthesis of (3-fluorothiophen-2-yl)methanol (I-7a)) To a stirred solution of methyl 3-fluorothiophene-2-carboxylate (5.0 g, 31.25 mmol) in anhydrous THF (50 mL) was added lithium aluminum hydride (1M solution in THF, 30 mL) dropwise at 0° C., and the reaction mixture was stirred under nitrogen at 0° C. for 1 h. After completion of the reaction, the mixture was quenched with 10 mL of water, 15% NaOH solution (10 mL) and stirred for 1 h. The reaction mixture was filtered over Celite, and the Celite pad was washed with EtOAc and THF. The aqueous layer was extracted, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with 8% EtOAc / Hexane to give pure yellowish liquid compound I-7a (3.0 g, yield: 73%). [ka] (Synthesis of 2-(azidomethyl)-3-fluorothiophene (I-7b)) To a stirred solution of compound I-7a (3 g, 22.7 mmol) in toluene (30 mL) was added DPPA (5.8 mL, 27.2 mmol) followed by DBU (4 mL, 27.2 mmol) at 0° C., and the resulting mixture was stirred at rt under N2 for 1 h. After completion of the reaction (TLC monitoring), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 2% EtOAc / Hexane to give compound I-7b (2.5 g, yield: 71%) as a colorless oil. [ka] (Synthesis of (3-fluorothiophen-2-yl)methanamine (I-7c)) To a stirred solution of compound I-7b (2.6 g, 16.5 mmol) in anhydrous THF (40 mL) was added a solution of LAH in THF (1.2 g, 33.1 mmol) at 0° C. Then the reaction mixture was stirred at 0° C. for 30 min. The reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water and 10% NaOH solution. The reaction mixture was washed with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluted with 2% MeOH / DCM to give compound I-7c (2 g, yield: 95%) as a yellowish oil. [ka] (Synthesis of N-((3-fluorothiophen-2-yl)methyl)pivalamide (I-7d)) According to Method 2 (Step 1): To a stirred solution of compound I-7c (2.5 g, 19.08 mmol) in DCM (25 mL), TEA (6.7 mL, 47.7 mmol) was added followed by pivaloyl chloride (3.5 mL, 28.6 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC and upon completion, the mixture was quenched in water and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude was purified using column chromatography using 10%-30% ethyl acetate:petroleum ether as the eluent to give compound I-7d (2.5 g, yield: 61%). (Synthesis of N-((5-bromo-3-fluorothiophen-2-yl)methyl)pivalamide (I-7e)) According to Method 2 (Step 2): To a stirred solution of compound I-7d (1.2 g, 5.6 mmol) in ACN (12 mL), NBS (1 g, 5.6 mmol) was added and the resulting mixture was stirred at rt for 1 h. After completion of the reaction, the crude compound was purified using RP combi-flash column chromatography using 10% acetonitrile:HO (0.01% FA) as eluent to give compound I-7e (400 mg, yield: 25%). (Synthesis of N-((5-acetyl-3-fluorothiophen-2-yl)methyl)pivalamide (I-7f)) According to Method 2 (Step 3): To a stirred solution of compound I-7e (770 mg, 2.6 mmol) in dioxane (10 mL), tributyl(1-ethoxyvinyl)tin (1.2 g, 3.4 mmol) was added, followed by Pd(PPh3)4 (0.3 g, 2.6 mmol), and the resulting mixture was stirred at 110° C. under N2 for 16 h. After completion of the reaction, the mixture was cooled to rt. Saturated KF solution was added, and the mixture was stirred for 30 min, followed by EtOAc (20 mL). The aqueous layer was extracted, and the combined organic layers were dried over Na2SO4 and concentrated. The solid residue was dissolved in 2N HCl, and the mixture was stirred for 30 min. Then, solid Na2CO3 was added to the mixture until pH>7, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography using 20% ​​ethyl acetate:petroleum ether as the eluent to give pure compound I-7f (290 mg, yield: 43%). (Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophen-2-yl)methyl)pivalamide (I-7)) According to Method 2 (step 4): To a stirred solution of compound 7 (290 mg, 1.1 mmol) in anhydrous THF (4 mL), tetrabutylammonium tribromide (1 g, 2.2 mmol) was added at 0° C., and the resulting mixture was stirred at 50° C. for 16 h. After completion of the reaction, the solvent was concentrated under reduced pressure to give the crude compound, which was purified using combi-flash to give compound I-7 (130 mg, yield: 34%) as a gummy solid.

[0229] (Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8) by Method 2 (Scheme 2)) [ka]

[0230] (Synthesis of (2-bromothiazol-5-yl)methanol (I-8a)) To a solution of methyl 2-bromothiazole-5-carboxylate (24.0 g, 101.69 mmol) in anhydrous THF (200 mL) was added DIBAL-H (1.0 M in toluene) (203.0 mL, 203.38 mmol) at 0 °C. The resulting mixture was stirred for 15 min and then slowly warmed to rt for 2 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh, eluent: 10% EtOAc in hexane) to give compound I-8a (11.1 g, 56% yield) as a gummy solid. (Synthesis of 2-((2-bromothiazol-5-yl)methyl)isoindoline-1,3-dione (I-8b)) To a stirred solution of triphenylphosphine (16.2 g, 61.8 mmol.) in anhydrous THF (100 mL), DEAD (9.8 g, 56.6 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at this temperature for 15 min. Compound I-8a (10.0 g, 51.5 mmol) in THF (20 mL) was added to the reaction mixture, followed by isoindoline-1,3-dione (8.3 g, 56.6 mmol) at 0° C. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (150 mL), extracted with DCM (2×100 mL), the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (60-120 mesh, eluent: 30% EtOAc in hexane) to give compound I-8b (8.0 g, 50% yield) as a white solid. (Synthesis of (2-bromothiazol-5-yl)methanamine (I-8c)) To a stirred solution of compound I-8b (8.0 g, 24.76 mmol) in EtOH (80 mL) was added hydrazine hydrate (3.9 g, 123.8 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and then at 75° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (100 mL) and extracted with DCM (2×100 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give crude compound I-8c (4.0 g crude, 46% pure by LCMS). The crude was carried forward to the next step without further purification. (Synthesis of N-((2-bromothiazol-5-yl)methyl)pivalamide (I-8d)) According to method 2 (step 1): To a stirred solution of compound I-8c (1.0 g, 5.177 mmol) in DCM (10 mL) was added EtN (1.0 g, 10.354 mmol) followed by pivaloyl chloride (0.92 g, 7.765 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The crude residue was diluted with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (60-120 mesh, eluent: 20% EtOAc in hexane) to give crude compound I-8d (0.7 g) as a white solid. (Synthesis of N-((2-acetylthiazol-5-yl)methyl)pivalamide (I-8e)) According to Method 1 (Step 2 and Step 3): To a stirred solution of compound I-8d (2.0 g, 7.220 mmol) and tributyl(1-ethoxyvinyl)stannane (3.3 g, 9.386 mmol) in toluene (20 mL), Pd(PPh3)4 (0.8 g, 0.72 mmol) was added under N2, and the reaction mixture was stirred at 110 °C for 16 h. To the reaction mixture, saturated potassium fluoride was added and stirring was continued at rt for 30 min. The organic layer was separated and concentrated under reduced pressure. THF, followed by concentrated HCl, was added to the residue, and the biphasic mixture was stirred for 30 min. The pH of the reaction mixture was adjusted to >7 by slow addition of solid Na2CO3. The mixture was then diluted with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate:petroleum ether as eluent to give crude compound I-8e (0.5 g, 36% product by LCMS) as a gummy solid which was used as is. (Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8)) According to Method 2 (Step 3): To a solution of compound I-8e (0.450 g, 1.87 mmol) in anhydrous THF (4.0 mL), tetrabutylammonium tribromide (0.9 g, 1.8 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated and the crude residue was purified by Combi-flash reverse phase chromatography to give I-8 (0.15 g, 68% yield) as a white solid.

[0231] (Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9) by Method 2 (Scheme 2):) [ka]

[0232] (Synthesis of (S,E)-N-((5-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (I-9a)) To a solution of 5-bromothiophene-2-carbaldehyde (12.0 g, 62.8 mmol, 7.45 mL) in THF (150 mL) was added Ti(OEt)4 (28.7 g, 126 mmol, 26.1 mL) and (S)-2-methylpropane-2-sulfinamide (9.14 g, 75.4 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by the addition of H2O (50.0 mL) at 25 °C and then extracted with EtOAc (30.0 mL x 4). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-9a (17.0 g, 90% yield, 98.1% purity) as a light yellow solid. (Synthesis of (S)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (I-9b)) To a solution of compound I-9a (17.0 g, 57.8 mmol) in THF (119 mL) was added MeMgBr (3 M, 57.8 mL) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was then quenched by the addition of NH4Cl (50.0 mL) at 25 °C, followed by extraction with DCM (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-9b (13.4 g, 62% yield, 83.5% purity) as a light yellow solid. (Synthesis of (S)-1-(5-bromothiophen-2-yl)ethan-1-amine (I-9c)) To a solution of compound I-9b (3.00 g, 9.67 mmol) in MeOH (21.0 mL) was added acetyl chloride (2.28 g, 29.0 mmol, 2.07 mL) dropwise at 25 °C. After addition, the mixture was stirred at this temperature for 1 h. The solvent was removed in vacuum, and then TEA (10.3 g, 102 mmol, 14.1 mL) and THF (30.0 mL) were added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give compound I-9c (7.40 g, 60.2% yield) as a light yellow oil. (Synthesis of (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9d) To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetic acid (12.4 g, 39.5 mmol) in DCM (66.6 mL) and DMF (7.40 mL) was added HOBt (7.28 g, 53.9 mmol), EDCI (10.3 g, 53.9 mmol), and DIPEA (13.9 g, 108 mmol, 18.8 mL) at 25 °C. Compound I-9c (7.40 g, 35.9 mmol) was then added at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of H2O (30.0 mL) at 25 °C, and then extracted with EtOAc (13.0 mL x 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound I-9d (9.60 g, 52% yield, 96.7% purity) as a light yellow oil. (Synthesis of N-(1-(5-acetylthiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9e)) To a solution of compound I-9d (9.50 g, 18.9 mmol) in toluene (66.5 mL), tributyl(1-ethoxyvinyl)stannane (13.7 g, 37.8 mmol, 12.8 mL) was added dropwise at 25 °C, followed by Pd(PPh3)4 (1.09 g, 945 umol) at 25 °C. The resulting mixture was stirred at 120 °C for 2 h. Saturated potassium fluoride solution (50.0 ml) was added to the reaction mixture and stirred at rt for 30 min. The organic layer was separated and concentrated under reduced pressure to give the crude compound. THF (50.0 mL) and 1 M HCl (20.0 mL) were added to the crude reaction mixture and stirred for 30 min, and solid Na2CO3 was added until pH ~7. The reaction mixture was diluted with water (50.0 mL) and extracted with DCM (50.0 mL x 3). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give crude compound. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1) to give compound I-9e (6.40 g, 71% yield, 98.0% purity) as a yellow oil. (Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9)) To a solution of compound I-9e (6.30 g, 13.5 mmol) in DCM (37.8 mL) and MeOH (94.5 mL) was added TBATB (6.85 g, 14.2 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of H2O (20.0 mL) at 25 °C, and then extracted with EtOAc (40.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give compound I-9 (3.00 g, 61% yield, 83.8% purity) as a light yellow oil.

[0233] (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10) by Method 4a (Scheme 4)) [ka]

[0234] (Synthesis of 4-chloro-N-(thiophen-2-ylmethyl)butanamide (I-10a)) According to method 4a (step 1): To a solution mixture of thiophen-2-ylmethanamine (5.0 g, 44.1 mmol) and Et3N (19.8 mL, 141.0 mmol) in DCM (130.0 mL) was added dropwise a solution of 4-chlorobutanoyl chloride (6.57 mL, 58.3 mmol) in DCM (20.0 mL) at 0 °C. After the reaction mixture was stirred at 0 °C for 1 h, it was quenched with cold water (100 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was carried on to the next step without further purification to give compound I-10a (7.0 g, yield: 73%) as a gummy liquid. (Synthesis of 1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-10b)) According to method 4a (step 2): To a solution mixture of compound I-10a (3.0 g, 13.7 mmol) in DMF (30.0 mL), NaH (826 mg, 20.6 mmol (60% in mineral oil) was added at rt and the mixture was stirred for 3 h. Then, the reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (100-200 mesh) eluted with 12% EtOAc in hexane to give compound I-10b (1.8 g, yield: 72%) as a gummy liquid. (Synthesis of 1-((5-acetylthiophen-2-yl)methyl)pyrrolidin-2-one (I-10c)) According to method 2 (step 3): To a solution of AlCl3 (1.95 g, 14.91 mmol) in DCM (50.0 mL) was added acetyl chloride (0.80 mL, 11.93 mmol) dropwise at 0 °C. After 5 min, compound I-10b (1.8 g, 9.94 mmol) was added and stirring was continued at 0 °C for 1 h. Then the reaction mixture was quenched with cold water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) eluted with 30% EtOAc in hexane to give compound I-10c (0.99 g, yield: 45%) as a gummy liquid. (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10)) According to method 2 (step 4): To a solution mixture of compound I-10c (500 mg, 2.242 mmol) in THF (10 mL), phenyltrimethylammonium tribromide (576.0 mg, 1.569 mmol) was added at 0° C. The reaction mixture was stirred at rt for 16 h, after which it was filtered through a bed of celite and concentrated in vacuo. The crude compound was purified using Combi-flash reverse phase purification (ACN in water with 0.001% TFA as eluent) to give compound I-10 (0.25 g, yield: 36%) as an off-white solid.

[0235] (Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11) by Method 4a (Scheme 4)) [ka]

[0236] (Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12):) The synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11) was carried out in similar experimental conditions as intermediate I-10 starting from 2-(thiophen-2-yl)ethan-1-amine and reacting with chlorobutanoyl chloride to give compound I-11 (0.45 g, yield: 26%) as an off-white solid.

[0237] (Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12) by Method 2 (Scheme 2):) [ka] (Synthesis of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole (I-12a)) To a stirred solution of 2-bromo-5-methyl-1,3,4-thiadiazole (4.5 g, 25.1 mmol) in CCl4 (100 mL) cooled to 0 °C, N-bromosuccinimide (4.4 g, 25.1 mmol) was added followed by AIBN (0.4 g, 2.51 mmol). The reaction mixture was then stirred at 80 °C for 16 h, after which it was diluted with water (100 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) eluted with 50% EtOAc in hexane to give compound I-12a (2.0 g, 31% yield) as a white solid. (Synthesis of (5-bromo-1,3,4-thiadiazol-2-yl)methanamine (I-12b):) To a stirred solution of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole I-12a (2.0 g, 7.81 mmol) in MeOH (20 mL) cooled to 0 °C was added 7N methanolic ammonia (40 mL). The reaction mixture was then stirred at rt for 16 h, after which it was concentrated in vacuo. The residue was purified by column chromatography using silica gel (60-120 mesh) eluted with 30% EtOAc in hexanes to give compound I-12b (1.5 g) as a gummy solid. (Synthesis of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12c)) To a stirred solution of (5-bromothiazol-2-yl)methanamine I-12b (1.6 g, 8.24 mmol) dissolved in DCM (20 mL) cooled to 0 °C, EtN (1.6 g, 16.2 mmol) was added followed by pivaloyl chloride (1.4 g, 12.3 mmol), then slowly warmed to rt and stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with DCM (2 × 80 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography on silica gel (60-120 mesh) eluted with 30% EtOAc in hexane to give compound I-12c (1.0 g, 45% yield) as a gummy solid. (Synthesis of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12d):) To a stirred solution of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12c (1.0 g, 3.597 mmol) and tributyl(1-ethoxyvinyl)stannane (1.6 g, 4.676 mmol) in toluene (10 mL) was added Pd(PPh3)4 (0.4 g, 0.346 mmol). The mixture was then slowly heated to 110 °C for 16 h. After cooling to rt, saturated KF solution was added and stirring was continued at rt for 30 min. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. To the residue was added THF followed by concentrated HCl and the resulting biphasic mixture was stirred for 30 min. Solid Na2CO3 was then added slowly to adjust the pH of the mixture to >7. The mixture was then diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) eluted with 30% EtOAc in hexane to give compound I-12d (0.7 g, 81% yield) as a pale yellow solid. (Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12)) To a solution of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12d (0.4 g, 1.659 mmol) in anhydrous THF (5 mL) was added tetrabutylammonium tribromide (0.8 g, 1.659 mmol) and the resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated to give the crude compound. The crude was purified by Combi-flash reverse phase chromatography to give compound I-12 (0.2 g, yield: 38%, 70% pure by LCMS) as a white solid.

[0238] (Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13) by Method 2 (Scheme 2):) [ka]

[0239] (Synthesis of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (I-13a)) To a solution of glycolic acid (110 g, 1.45 mol) in THF (770 mL), TEA (293 g, 2.89 mol, 403 mL), DMAP (17.7 g, 145 mmol), and TBDPSCl (477 g, 1.74 mol, 446 mL) were added at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was acidified with aqueous HCl (1 M) until pH = 1 was reached and extracted with EtOAc (300 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by SiO2 column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound I-13a (283 g, 57% yield, 91.0% purity) as a light red oil. [ka] (Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-(thiophen-2-ylmethyl)acetamide (I-13b)) To a solution of I-13a (281 g, 894 mmol) in DMF (644 mL), DIEA (420 g, 3.25 mol, 566 mL), EDCI (233 g, 1.22 mol), and HOBt (165 g, 1.22 mol) were added at 15 °C, and the mixture was stirred at 15 °C for 30 min. To this mixture, thiophen-2-ylmethanamine (92.0 g, 813 mmol, 83.6 mL) was added. The mixture was stirred at 15 °C for 2 h. Then, the reaction mixture was diluted with H2O (1.50 L) and extracted with EtOAc (500 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 100 / 1 to 0 / 1; TLC: ethyl acetate / petroleum ether = 5 / 1, compound I-13b R f =0.60) to afford compound I-13b (246 g, 70% yield, 94.2% purity) as a pale yellow oil. [ka] (Synthesis of N-((5-bromothiophen-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13c)) Two reactions were carried out in parallel on the same scale. To a solution of compound I-13b (82.0 g, 200 mmol) in DMF (574 mL) was added NBS (39.2 g, 220 mmol). The mixture was stirred at 20 °C for 1 h. The two reactions were combined for workup. The reaction mixture was diluted with H2O (3.40 L) and extracted with EtOAc (1.50 L x 3). The combined organic layer was washed with H2O (500 mL x 8), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound I-13c (199 g, 85% yield, 83.1% purity) as a light yellow solid. [ka] (Synthesis of N-((5-acetylthiophen-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13d)) To a solution of compound I-13c (94.0 g, 192 mmol) in toluene (658 mL) was added tributyl(1-ethoxyvinyl)tin (90.4 g, 250 mmol, 84.5 mL) and Pd(PPh3)4 (22.2 g, 19.2 mmol). The mixture was degassed and purged with N2 three times, after which it was stirred at 110 °C under N2 atmosphere for 16 h. The same reaction was carried out in parallel with 105 g of I-13c, and both mixtures were combined for workup. Saturated KF solution (2.00 L) was added to the reaction mixture, and the mixture was stirred at 20 °C for 30 min. The organic layer was separated, HCl (0.5 M, 2.0 L) was added to the crude reaction mixture, and the mixture was stirred for 30 min. The organic layer was separated and extracted with EtOAc (500 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1 to 1 / 1) to give compound I-13d (124 g, 63% yield, 93.6% purity) as a yellow solid. [ka] (Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13)) To a solution of compound I-13d (119 g, 263 mmol) in DCM (714 mL) and MeOH (1.78 L), TBATB (133 g, 276 mmol) was added and the mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated in vacuum, and the residue was diluted with DCM (100 mL) and washed with H2O (40.0 mL × 3). The organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 1 / 0) to give compound I-13 (46.0 g, 55% yield, 91.3% purity) as a colorless oil. [ka]

[0240] 4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14) by Method 4 (Scheme 4): [ka]

[0241] (Synthesis of 2-(chloromethyl)thiophene (I-14a)) To a solution of 2-thienylmethanol (2.00 g, 17.5 mmol, 1.65 mL) in DCM (14.0 mL) was added SOCl2 (4.17 g, 35.0 mmol, 2.54 mL) dropwise under N2 atmosphere at 0°C. The mixture was stirred at 0°C for 30 min, and then the mixture was stirred at 25°C for 30 min. The reaction mixture was quenched with NaHCO3 (110 mL) and extracted with EtOAc (80.0 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound I-14a (1.50 g, 65% yield) as a brown oil. (Synthesis of 4-(thiophen-2-ylmethyl)morpholin-3-one (I-14b)) To a solution of morpholin-3-one (2.29 g, 22.6 mmol) in THF (10.0 mL) was added LiHMDS (1 M, 17.0 mL) dropwise at 0° C. After addition, the mixture was stirred at this temperature for 30 min, and then compound I-14a (1.50 g, 11.3 mmol) in THF (8.00 mL) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 7 h. The reaction was quenched by the addition of 10.0 mL of NH4Cl at 0° C., then diluted with H2O (10.0 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layer was washed with brine (5.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give compound I-14b (1.10 g, 42% yield, 85.4% purity) as a brown oil. [ka] (Synthesis of 4-((5-bromothiophen-2-yl)methyl)morpholin-3-one (I-14c)) To a solution of compound I-14b (1.10 g, 5.58 mmol) in DMF (7.70 mL) was added NBS (993 mg, 5.58 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with H2O (10.0 mL) and washed with EtOAc (10.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=1 / 1) to give compound I-14c (crude) (2.00 g, 88.8% purity) as a light yellow solid. [ka] (Synthesis of 4-((5-acetylthiophen-2-yl)methyl)morpholin-3-one (I-14d)) To a solution of compound I-14c (2.00 g, 7.24 mmol) in toluene (14.0 mL) was added tributyl(1-ethoxyvinyl)stannane (3.22 g, 8.91 mmol, 3.01 mL) and Pd(PPh3)4 (837 mg, 724 umol). The mixture was stirred at 110° C. for 16 h. Saturated KF solution (20.0 mL) was added to the reaction mixture and the mixture was stirred at 20° C. for 30 min. The organic layer was separated and HCl (0.5 M, 20.0 mL) was added to the crude reaction mixture and the mixture was stirred for 30 min. The organic layer was separated and extracted with EtOAc (20.0 mL×2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM / ethyl acetate = 50 / 1 to 0 / 1) to give compound I-14d (1.00 g, 58% yield) as a black solid. (Synthesis of 4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14)) To a solution of compound I-14d (1.00 g, 4.18 mmol) in DCM (2.00 mL) and IPA (5.00 mL) was added TBATB (2.32 g, 4.81 mmol). The mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with H2O (25.0 mL) and washed with EtOAc (25.0 mL×3). The combined organic layers were washed with brine (25.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound I-14 (1.00 g, 3.14 mmol, 75% yield) as a brown oil.

[0242] (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-hydroxypyrrolidin-2-one (I-15) by Method 4 (Scheme 4):) [ka]

[0243] (Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-15a)) To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (25.0 g, 73.6 mmol) in THF (170 mL) was added LiHMDS (1 M, 110 mL) dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-(chloromethyl)thiophene (19.5 g, 147 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 60 °C for 7 h. LCMS showed that 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one was completely consumed and 27% of the desired compound was detected. The reaction mixture was quenched by addition of H2O (100 mL) at 25 °C, and then extracted with 300 mL of EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO.sub.2, petroleum ether / ethyl acetate=3 / 1) to give compound I-15a (9.00 g, 28.0% yield) as a yellow oil. (Synthesis of 1-((5-bromothiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15b)) To a solution of compound I-15a (9.00 g, 20.7 mmol) in DMF (50.0 mL) was added NBS (4.04 g, 22.7 mmol). The mixture was stirred at 20° C. for 2 h, after which it was quenched by the addition of H2O (100 mL) at 25° C., and then extracted with 150 mL of EtOAc (50.0 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give compound I-15b (6.70 g, 63% yield) as a brown oil. (Synthesis of 1-((5-acetylthiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15c)) To a solution of compound I-15b (6.70 g, 13.0 mmol) in Tol (42.0 mL) was added tributyl(1-ethoxyvinyl)stannane (6.58 g, 18.2 mmol, 6.15 mL) and Pd(PPh3)4 (1.50 g, 1.30 mmol). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 110 °C under N2 atmosphere for 16 h. Saturated potassium fluoride solution was added to the reaction mixture and stirred at 15 °C for 30 min. The organic layer was separated and concentrated under reduced pressure to give the crude compound. HCl (0.5 M, 90.0 mL) was added to the crude, the mixture was stirred for 30 min, and solid Na2CO3 (~5 g) was added until pH = ~7. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give compound I-15c (5.50 g, 88% yield) as a yellow solid. (Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15)) To a solution of compound I-15c (0.50 g, 1.05 mmol) in DCM (3.00 mL) and IPA (7.50 mL) was added trimethylphenylammonium tribromide (413 mg, 1.10 mmol). The mixture was stirred at 50° C. for 2 h. The reaction mixture was quenched with 10.0 mL of H2O at 25° C., then extracted with 15.0 mL of EtOAc (5.00 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound I-15 (0.90 g, 46% yield, 30% purity) as a white solid.

[0244] (Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-hydroxypyrrolidin-2-one (I-16) by Method 4 (Scheme 4):) [ka]

[0245] (Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(2-(thiophen-2-yl)ethyl)pyrrolidin-2-one (I-16a)) To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (10.8 g, 31.8 mmol) in THF (70.0 mL) was added LiHMDS (1 M, 47.7 mL) dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (10.8 g, 38.2 mmol) in THF (30.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 60 °C for 7 h. The reaction mixture was quenched by the addition of H2O (100 mL) at 25 °C, and then extracted with 150 mL of EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give compound I-16a (7.00 g, 49% yield) as a white solid. (Synthesis of (S)-1-(2-(5-bromothiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16b) To a solution of compound I-16a (7.00 g, 15.6 mmol) in DMF (56.0 mL) was added NBS (3.05 g, 17.1 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of H2O (50.0 mL) at 25 °C, and then extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give compound I-16b (4.60 g, 56% yield) as a colorless oil. (Synthesis of 1-(2-(5-acetylthiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16c)) To a solution of compound I-16b (4.60 g, 8.70 mmol) in toluene (Tol.) (32.0 mL) was added tributyl(1-ethoxyvinyl)stannane (4.40 g, 12.1 mmol, 4.11 mL) and Pd(PPh3)4 (1.01 g, 870 umol). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 110°C under N2 atmosphere for 16 h. Saturated potassium fluoride solution was added to the reaction mixture and stirred at 15°C for 30 min. The organic layer was separated and concentrated under reduced pressure to give the crude compound. HCl (0.5 M, 90.0 mL) was added to the crude reaction mixture and stirred for 30 min, and solid Na2CO3 (~15.0 g) was added until pH = ~7. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (10.0 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give compound I-16c (3.49 g, 82% yield) as a yellow oil. (Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16)) To a solution of compound I-16c (1.00 g, 2.03 mmol) in MeOH (5.00 mL) and DCM (1.50 mL) was added TBATB (1.03 g, 2.14 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by the addition of H2O (10.0 mL) at 25° C., and then extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give compound I-16 (0.80 g, 69% yield) as a yellow oil.

[0246] (Formula Y 1 -SH(wherein, R 2 Purification of the intermediate compound (=H):

[0247] (Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1)) [ka]

[0248] (Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (J-1-1)) A solution mixture of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10 g, 59.1 mmol) in formamide (40 mL) was stirred at 180° C. for 4 h. The reaction mixture was cooled to rt, after which a precipitate formed. The resulting precipitate was filtered in vacuum, washed with hexane, and dried in vacuum to give J-1-1 (7.2 g, yield: 79%) as an off-white solid. (Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1)) To a solution of compound J-1-1 (3.4 g, 22.6 mmol) in toluene (50.0 mL) was added Lawesson's reagent (5.4 g, 13.5 mmol) at 0 °C. The reaction mixture was stirred at 120 °C for 2 h. Then, the mixture was concentrated in vacuum, and the residue was purified by column chromatography on silica gel (60-120 mesh) eluted with 10% EtOAc in hexane to give J-1 (3.0 g, yield: 81%) as a pale yellow solid.

[0249] (Synthesis of 1,7-naphthyridine-8-thiol (J-5)) [ka] (Synthesis of 1,7-naphthyridine-8-thiol (J-5)) To a solution of 8-chloro-1,7-naphthyridine (500 mg, 3.04 mmol) in DMF (3.00 mL) was added NaSH (681 mg, 12.2 mmol). The mixture was stirred at 80° C. for 2 h. The reaction mixture was used directly in the next step without workup.

[0250] The following compounds can be prepared by vulcanization with P2S5 or Lawesson's reagent using the experimental conditions described above, either commercially available or of the formula Y 1 From the hydroxy-substituted heteroaryl of —OH, or alternatively, by thiol displacement using NaSH or NaS, compounds of the formula Y 1 Alternatively, some of the following compounds were commercially available: [Table 14]

[0251] (Formula Y 1 -SH(wherein, R 2 = haloalkyl, CF3, or CHF2)

[0252] (Synthesis of 2-(trifluoromethyl)quinazoline-4-thiol (K-1)) [ka]

[0253] (Synthesis of 2-(trifluoromethyl)quinazolin-4-ol (K-1-1)) To a stirred solution of 2-aminobenzamide (1.0 g, 7.344 mmol) in anhydrous DCM was added trifluoroacetic anhydride (1.7 g, 8.022 mmol), pyridine (1.0 mL), and DMAP (0.018 mg, 0.147 mmol) at room temperature. The reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC consumption of starting material. After consumption of starting material, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100:200 mesh, solvent: 10% EtOAc in hexane) to give K-1-1 (1.0 g, 63% yield). (Synthesis of 2-(trifluoromethyl)quinazoline-4-thiol (K-1)) To a stirred solution of 2-(trifluoromethyl)quinazolin-4(1H)-one (K-1-1) (0.5 g, 7.344 mmol) in anhydrous toluene, Lawesson's reagent (1.01 g, 7.344 mmol) was added under an atmosphere of anhydrous argon. The reaction was then heated under reflux for 16 h until no more starting material could be detected by TLC. A solution of 3N NaOH was then added to the mixture. After neutralization with 1N HCl, the solid formed was filtered and dried in vacuum to give K-1 (0.28 g, 52% yield) as an off-white solid.

[0254] (Synthesis of 3-(trifluoromethyl)isoquinoline-1-thiol (K-22)) [ka]

[0255] (Synthesis of 3-(trifluoromethyl)-1H-isochromen-1-one (K-22-1)) To a stirred solution of 2-(carboxymethyl)benzoic acid (2.0 g, 11.10 mmol), trifluoroacetic anhydride (2.1 mL) was added at room temperature, and the reaction mixture was stirred for 48 h at 100° C. The reaction mixture was concentrated under reduced pressure to give K-22-1 (2.5 g, crude), which was carried on to the next step without further purification. (Synthesis of 3-(trifluoromethyl)isoquinolin-1(2H)-one (K-22-2):) 3-(Trifluoromethyl)-1H-isochromen-1-one K-22-1 (2.5 g (crude), 11.62 mmol) was added to NHOH (37.0 mL) at rt. The resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give crude compound K-22-2 (160 mg, yield: 7%) as a white solid. (Synthesis of 3-(trifluoromethyl)isoquinoline-1-thiol (K-22):) To a stirred solution of 3-(trifluoromethyl)isoquinolin-1(2H)-one K-22-2 (160 mg, 0.751 mmol) in anhydrous toluene (6.0 mL) under nitrogen atmosphere was added Lawesson's reagent (303 g, 0.751 mmol). The reaction mixture was stirred at 120° C. for 4 h and then concentrated under vacuum. The residue was purified using combi-flash reverse phase purification (eluent: ACN and 0.001% TFA in water) to give compound K-22 (50 mg, 29% yield) as an off-white solid.

[0256] The following intermediate compounds (K-2) to (K-21) were prepared from the reaction of substituted aminocarboxamido aryl and heteroaryl and trifluoroacetic anhydride or CHF2-based reagents using the experimental conditions described above. Alternatively, they can be converted to compounds of formula Y, which are known in the art or commercially available, by vulcanization with P2S5 or Lawesson's reagent. 1 The compounds were prepared from -OH hydroxy-substituted heteroaryls. Alternatively, some of the following compounds were commercially available: [Table 15] TIFF2025503502000110.tif220170TIFF2025503502000111.tif128170

[0257] (Formula Y 1 -SH(wherein, R 2 Preparation of intermediate compounds of

[0258] (Synthesis of 7-chloro-2-methylquinazoline-4-thiol (M-1)) [ka]

[0259] (Synthesis of 7-chloro-2-methylquinazolin-4-ol (M-1-1)) To a solution of 2-amino-4-chlorobenzamide (1.5 g, 8.823 mmol) in dioxane (10 mL) was added DIPEA (1.61 mL, 9.264 mmol) followed by acetyl chloride (0.63 mL, 8.823 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was heated to reflux for 16 h after which it was concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude 7-chloro-2-methylquinazolin-4-ol (M-1-1) was carried forward to the next step without further purification. (Synthesis of 7-chloro-2-methylquinazoline-4-thiol (M-1)) To a solution of compound M-1-1 (400 mg, 2.061 mmol) in toluene (6.0 mL) was added P2S5 (457.7 mg, 2.061 mmol) at 0° C. The reaction mixture was stirred at 120° C. for 2 h, after which it was concentrated in vacuum. The residue was diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuum. The residual compound was washed with hexane and dried in vacuum to give 7-chloro-2-methylquinazoline-4-thiol (M-1) (190 mg, crude).

[0260] (Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11)) [ka]

[0261] (Synthesis of 6-methoxy-2-methylquinazolin-4-ol (M-11-1)) To EtOH (500 mL) was added NaH (42.1 g, 1.05 mol, 60% purity) in small portions at 0° C., followed by 2-amino-5-methoxybenzamide (25.0 g, 150 mmol), followed by EtOAc (53.0 g, 601 mmol, 58.91 mL). The resulting mixture was stirred at 90° C. for 12 h. The reaction mixture was quenched with 1M HCl (500 mL) and filtered. The filter cake was collected. The collected filter cake was dissolved in EtOAc / MeOH (V / V=1 / 1, 200 mL) and filtered. The filtrate was concentrated in vacuo to give compound M-11-1 (34.0 g, crude) as an off-white solid. [ka] (Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11)) To a solution of compound M-11-1 (20.0 g, 105 mmol) in toluene (140 mL) was added Lawesson's reagent (46.8 g, 115 mmol) and the mixture was stirred at 120° C. for 12 h under N2 atmosphere. Two additional runs of this reaction were performed with 18.0 g and 7.20 g scales of M-11-1, and the crude mixtures of all three runs were combined for workup. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was triturated with EtOAc / MeOH (V / V=10 / 1, 10 V, 3 times) at 25° C. for 6 h to give compound M-11 (25.5 g, 72% yield, 85.3% purity) as a yellow solid. [ka]

[0262] The following intermediate compounds M-2 to M-48 were prepared from the reaction of substituted aminocarboxamido aryl and heteroaryl and trifluoroacetic anhydride or CHF2-based reagents using the experimental conditions described above. Alternatively, they can be converted to compounds of formula Y, which are known in the art or commercially available, by vulcanization with P2S5 or Lawesson's reagent. 1 The compounds were prepared from -OH hydroxy-substituted heteroaryls. Alternatively, some of the following compounds were commercially available: [Table 16] TIFF2025503502000117.tif231170TIFF2025503502000118.tif227170TIFF2025503502000119.tif144170

[0263] (R 2 = NR2 Formula Y 1 Preparation of intermediate compound -SH:)

[0264] (Synthesis of 2-(dimethylamino)quinazoline-4-thiol (N-1)) [ka]

[0265] (Synthesis of 2-(dimethylamino)quinazolin-4-ol (N-1-1)) To a solution mixture of 2-iodobenzoic acid (1.0 g, 4.00 mmol) and compound-2 (743 mg, 6.0 mmol) in ACN (10 mL) was added K2CO3 (2.2 g, 16.1 mmol) and copper chloride hydrate (13 mg, 0.08 mmol) at rt. The reaction mixture was heated at 90 °C for 16 h. After cooling to rt, water (100 mL) was added and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give compound N-1-1 (700 mg, yield: 91%) as an off-white solid, which was carried on to the next step without further purification. (Synthesis of 2-(dimethylamino)quinazoline-4-thiol (N-1)) To a stirred solution of compound N-1-1 (300 mg, 1.67 mmol) in anhydrous toluene (4.0 mL) was added Lawesson's reagent (677 g, 1.675 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 4 h and then concentrated under vacuum. The crude compound was purified by column chromatography on silica gel (100-200 mesh) to give compound N-1 (150 mg, yield: 46%) as a yellow solid.

[0266] (G 1 =N 1 -SH intermediate compound regulation:)

[0267] (Synthesis of 4-methylphthalazine-1-thiol (O-1)) [ka]

[0268] To a solution mixture of 4-methylphthalazin-1(2H)-one (300 mg, 1.875 mmol) in toluene (5.0 mL) was added Lawesson's reagent (757.5 mg, 1.875 mmol) at 0° C. The reaction mixture was stirred at 110° C. for 2 h, after which it was concentrated in vacuo. The residue (O-1) was carried on to the next step without further purification.

[0269] (Synthesis of 4-(trifluoromethyl)phthalazine-1-thiol (O-2)) [ka]

[0270] (Synthesis of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (O-2-1):) To a stirred solution of isobenzofuran-1,3-dione (0.5 g, 3.378 mmol) in THF, cuprous iodide (0.062 g, 0.337 mmol), PPh3 (0.086 g, 0.338 mmol), and anhydrous KF (0.38 g, 6.551 mmol) were added under argon atmosphere. TMSCF3 (0.5 g, 3.378 mmol) was added to the reaction mixture and stirring was continued at 50 °C for 6 h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography by using silica gel to give O-2-1 (0.25 g, 35% yield) as an off-white solid. (Synthesis of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2):) To a stirred solution of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (O-2-1) (0.2 g, 0.917 mmol) in NMP, bromoethane (0.1 g, 0.929 mmol) and K2CO3 (0.15 g, 1.086 mmol) were added at 0 °C, and the resulting mixture was stirred at 70 °C for 6 h. The reaction progress was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography using silica gel to give O-2-2 (0.18 g, 48% pure by LCMS) as a white solid. (Synthesis of 4-(trifluoromethyl)phthalazin-1(2H)-one (O-2-3):) To a stirred solution of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2) (0.2 g, 0.81 mmol) in EtOH (2.0 mL) was added hydrazine hydrate (0.052 g, 1.60 mmol) at 0° C. and slowly warmed to 90° C. for 16 h. The reaction was monitored by TLC. After consumption of the starting material, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography by using silica gel to give O-2-3 (0.18 g, 78% yield) as a white solid. (Synthesis of 4-(trifluoromethyl)phthalazine-1-thiol (O-2)) To a stirred solution of 4-(trifluoromethyl)phthalazin-1(2H)-one (O-2-3) (0.2 g, 0.934 mmol, 1.0 equiv.) in anhydrous toluene was added Lawesson's reagent (0.37 g, 0.936 mmol, 1.0 equiv.) under an atmosphere of anhydrous argon. The reaction mixture was then heated at 110° C. for 1 h under microwave (μw) conditions. The crude material was purified by column chromatography on silica gel to give compound (O-2) (0.07 g, 10% pure by LCMS) as a yellow solid.

[0271] The following intermediate compound O-3 can be prepared by vulcanization with P2S5 reagent or Lawesson's reagent using the experimental conditions described above to give the compound of formula Y 1 It was prepared from commercially available hydroxy-substituted heteroaryls with -OH: [Table 17]

[0272] ([5,6] Bicyclic heteroaryl of formula Y 1 -SH intermediate compound (wherein G 2 =O or NR 4 Preparation of

[0273] (Synthesis of 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol (P-1)) [ka]

[0274] (Synthesis of 3-amino-6-(trifluoromethyl)pyridin-2-ol (P-1-1)) To a stirred solution of 3-nitro-6-(trifluoromethyl)pyridin-2-ol (200 mg, 0.961 mmol) in MeOH (1 mL) was added 15% Pd-C (30 mg). H2 gas was then bubbled at 60 psi for 3 h, and the mixture was then heated to 50° C. for 3 h. The reaction mixture was filtered through a bed of Celite under vacuum. The solvent was evaporated under reduced pressure to give the title compound P-1-1 (142 mg, 75% yield). (Synthesis of 5-(trifluoromethyl)oxazole[5,4-b]pyridine-2-thiol (P-1)) To a solution of 3-amino-6-(trifluoromethyl)pyridin-2-ol P-1-1 (1.8 g, 0.010 mol) in EtOH (18 mL) was added KOH (1.13 g, 0.0202 mol) followed by CS2 (1.13 mL, 0.0202 mol) at 0° C. The resulting reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure and purified by C18-reverse phase combi-flash chromatography (eluent: 0.1% formic acid in ACN) to give the title compound P-1 (1.8 g, 81% yield) as an off-white solid.

[0275] (Synthesis of 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6)) [ka]

[0276] (Synthesis of 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1)) To a solution of 2-(trifluoromethyl)pyridin-4-ol (7.50 g, 45.9 mmol) in H2SO4 (40.0 mL) was added fuming nitric acid (68.6 g, 980 mmol) and H2SO4 (82.8 g, 844 mmol) at 0 °C. The mixture was stirred at 120 °C for 8 h. The reaction mixture was quenched at 0 °C by addition of ice-cold water (300 mL) and extracted with EtOAc (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 = 100 / 1 to 0 / 1) to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1) (3.62 g, 38% yield) as a yellow solid. (Synthesis of 5-amino-2-(trifluoromethyl)pyridin-4-ol (P-6-2)) Compound P-6-1 (13.5 g, 64.8 mmol) was added to a solution of Pd / C (2.00 g, 64.8 mmol, 10% purity) in MeOH (100 mL) under Ar. The suspension was degassed under vacuum and purged with H2 several times, then the mixture was stirred under H2 (15 psi) at 25 °C for 5 h. The suspension was filtered and the filter cake was washed with MeOH (100 mL × 3). The combined filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 5-amino-2-(trifluoromethyl)pyridin-4-ol (P-6-2) (9.10 g, 67% yield) as a brown solid. (Synthesis of 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6)) To a solution of compound P-6-2 (1.00 g, 5.61 mmol) in Py (10.0 mL), potassium ethyl xanthate (1.08 g, 6.74 mmol) was added dropwise at 25 °C. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was poured into 1N HCl until pH = 4-5, then extracted with EtOAc (30.0 mL × 3), and the combined organic layer was 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 = 100 / 1-0 / 1, petroleum ether / ethyl acetate = 2 / 1, R f =0.2) to afford 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6) (400 mg, 32% yield) as a brown solid.

[0277] (Synthesis of 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7)) [ka]

[0278] (Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (P-7-1)) To a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (8.00 g, 33.2 mmol) in dioxane (40.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.27 g, 36.5 mmol), KOAc (9.77 g, 99.6 mmol), and Pd(dppf)Cl2 (729 mg, 996 umol). The mixture was stirred at 90 °C for 6 h. The reaction mixture was quenched at 25 °C by the addition of H2O (20.0 mL) and then extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine P-7-1 (9.00 g, 94% yield) as a white solid. (Synthesis of 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2)) To a solution of compound P-7-1 (9.00 g, 31.2 mmol) in THF (90.0 mL) was added H2O2 (43.4 g, 383 mmol, 36.8 mL, 30% purity). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched at 5 °C by the addition of aqueous saturated NH4Cl (80.0 mL) and then extracted with EtOAc (40.0 mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (40.0 mL) and then extracted with 1 M HCl (40 mL). The aqueous phase was adjusted to pH = 8 with NaHCO3, then extracted with EtOAc (40.0 mL × 3) to give 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2) (5.00 g, 79% yield, 87.5% purity) as a light yellow solid. (Synthesis of 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7)) To a solution of compound P-7-2 (3.00 g, 16.8 mmol) in EtOH (30.0 mL) was added CS2 (3.85 g, 50.5 mmol, 3.05 mL) and KOH (2.84 g, 50.5 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched at 25 °C by the addition of 2 M HCl (30.0 mL) and then extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with 2 M HCl (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7) (2.47 g, 67% yield) as a yellow solid.

[0279] The following intermediate thiols (P-2) to (P-15) were prepared from the reaction of substituted bicyclic oxazole 2-hydroxyls and Lawesson's reagent using the experimental conditions described above for K-1. Alternatively, some of the following compounds were commercially available: [Table 18]

[0280] (Preparation of Example Compounds) Example 1: N-((5-(2-((2-isopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide [ka]

[0281] According to step 4 of method 2 (scheme 2): To a solution mixture of intermediate M-3 (100 mg, 0.49 mmol, 1 eq) in DMF (3.0 mL), NaOMe (29.12 mg, 0.539 mmol) was added at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min, and compound I-4 (171 mg, 0.539 mmol) was added. The reaction mixture was stirred at rt for 16 h. After completion of the reaction, cold water was added to the reaction mixture, extracted with EtOAc (2×50 mL), and the entire organic layer was dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by Combi-Flash chromatography to give Example 1 (70 mg, 30% yield).

[0282] Example 60: 2-Hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide [ka]

[0283] To a solution of M-11 (10.0 g, 48.5 mmol) in DMF (108 mL) was added NaOMe (2.62 g, 48.5 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. Then, compound I-13 was added to the mixture (15.6 g, 53.3 mmol), and the mixture was stirred at 25° C. for 2 h. Three additional runs of this reaction were performed with M-11 on a 5.0 g scale, a 10 g scale, and a 10 g scale, and the crude mixtures of all four runs were combined for workup. The combined reaction mixture was poured into H2O (651 mL) and filtered to collect the solid. The solid was triturated with MTBE (10V×2) at 25° C. for 2 h to give Example 60 (16.25 g, 31.7% yield, 98.9% purity) as a light yellow solid. [ka]

[0284] The following examples are based on the compound of formula Y 1The compounds were prepared using similar experimental conditions as described above for the synthesis of Example 1 (General Method 2, Scheme 2, Step 4) obtained from the reaction of -SHM, N, O, or P intermediates with compound I-4: [Table 19]

[0285] The following examples are based on the compound of formula Y 1 -SH was prepared using similar experimental conditions as described above for the synthesis of Example 1 (Method 2, Scheme 2, Step 4), which was obtained from the reaction of intermediate K with compound I-4: [Table 20]

[0286] The following examples are based on the compound of formula Y 1 -SH was prepared using the experimental conditions described above for the synthesis of compound (1) obtained from the reaction of J, M or K intermediate compound with the applicable intermediate compound In (by method 4, scheme 4, step 4): [Table 21]

[0287] The following examples are based on the compound of formula Y 1 -SH was prepared using the experimental conditions described above for the synthesis of compound (1) obtained from the reaction of J, M or K intermediate compound with the applicable intermediate compound In (by method 2, scheme 2, step 4): [Table 22] TIFF2025503502000135.tif150170

[0288] The following examples are based on the compound of formula Y 1 Reaction of intermediate compound I-15 with intermediate compound I-15 in -SH K-11, followed by chiral SFC (Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IH (250 mm *The compound (1) was prepared using the experimental conditions described above for the synthesis of compound (1) (according to method 2, scheme 2, step 4) obtained from the separation of enantiomers using: 30 mm, 10 um; mobile phase: A for CO2 and B for MeOH; gradient: B%=40% isocratic elution mode; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar): [Table 23]

[0289] (Synthesis of 1-(5-(2-aminoethyl)thiophen-2-yl)-2-((2-(trifluoromethyl)quinazolin-4-yl)thio)ethan-1-one (Q-1)) [ka]

[0290] To a solution mixture of compound K-1 (390 mg, 130 mmol) in DMF (5 mL) was added NaOMe (77 mg, 1.43 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 min and compound I-2 (549 mg, 156 mmol) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with cold water and extracted with EtOAc (2 × 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude compound was purified by column chromatography on silica gel (60-120 mesh). The compound was eluted with 30% EtOAc in hexane to give compound (Q-1-1). To a solution mixture of compound (Q-1-1) in dioxane (3.0 mL) was added 4 M HCl in dioxane (6.0 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuum. The crude compound was washed with n-pentane and dried in vacuum to give the hydrochloride salt of compound (Q-1) as a white solid.

[0291] The following intermediate compound Q can be prepared using the above experimental conditions (General Method 1) to obtain a compound of formula Y 1The -SH compounds J, K, and M were prepared from reaction of bromo-ketones I-1, I-2, I-3, or I-5, followed by deprotection of the Boc protecting group to provide a terminal amino group. [Table 24] TIFF2025503502000139.tif232170TIFF2025503502000140.tif232170TIFF2025503502000141.t if212170TIFF2025503502000142.tif222170TIFF2025503502000143.tif213170TIFF2025503502 000144.tif207170TIFF2025503502000145.tif231170TIFF2025503502000146.tif227170TIFF20 25503502000147.tif221170TIFF2025503502000148.tif222170TIFF2025503502000149.tif99170

[0292] Example 190: tert-Butyl ((5-(2-((6-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)carbamate [ka]

[0293] Example 190 was prepared from the reaction of intermediate M-39 with intermediate I-1 using the experimental conditions described above for intermediate Q-1-1.

[0294] Example 189: Synthesis of 3-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-1,1-dimethylurea [ka]

[0295] To a solution of compound Q-11 (100 mg, 278 μmol) in THF (2.00 mL) was added DIEA (108 mg, 835 μmol, 145 μL) and dimethylcarbamic chloride (32.9 mg, 306 μmol, 28.1 μL). The mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (column: waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30% to 60% B over 8 min) to give Example 189 (32 mg, 27% yield, 100% purity) as a light yellow solid.

[0296] Example 29: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)pivalamide [ka]

[0297] To a solution mixture of compound Q-1 (190 mg, 25 mmol) in DCM (2.0 mL) was added Et3N (2 eq.) and (CH3)3CCOCl (29 mg, 1.5 eq.) at 0° C. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×20 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residual compound was purified using column chromatography to give example compound (29) as a white solid (60 mg, 50% yield).

[0298] The following examples are carried out by combining compound Q and compound of formula R using the experimental conditions described in Example 29 above. 9 -COCl with acyl chloride: [Table 25] TIFF2025503502000154.tif216170

[0299] (Example 63: 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide) [ka]

[0300] (Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholino-quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1)) To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid I-13a (699 mg, 2.22 mmol) in DMF (4.00 mL) was added HATU (699 mg, 2.02 mmol) at 0° C. After the addition, the mixture was stirred at 0° C. and a mixture of compound Q-37 (837 mg, 2.02 mmol) and DIEA (1.41 mL, 8.08 mmol) in DMF (4.00 mL) was added dropwise to the above mixture at 0° C. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholino-quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1), which was used without further purification. (Synthesis of 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (63)) To a solution of compound R-1-1 (0.60 g, 862 umol) in THF (6.00 mL), TBAF (1 M, 905 uL) was added. The mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched by the addition of H2O (10.0 mL) at 25° C., and then extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 5 / 1) TLC (petroleum ether / ethyl acetate=1 / 1, product RT=0.2) to give compound 63 (200 mg, 57.4% yield).

[0301] The following examples were prepared from the reaction of compound Q with protected hydroxy acid derivatives of formula HO2C-CH2-OTBDPS and HO2C-CH2-OTBS using the experimental conditions described in Example 63 above: [Table 26] TIFF2025503502000157.tif233170TIFF2025503502000158.tif224170TIFF2025503502000159.tif233170TIFF2025503502000160.tif70170

[0302] The following examples are carried out using the experimental conditions described above, by reacting compound Q with carboxylic acid R 9 In some cases, R 9 The group contained an alcohol group, which was protected with a suitable protecting group, e.g., TBS or TBDPS, and later removed in the same manner as described above for the conversion of R-1-1 to Example compound 63. 9 The group contains an amino group, which is protected with a suitable protecting group known in the art, for example Boc, and later removed using conditions known in the art, for example TFA / DCM. [Table 27] TIFF2025503502000162.tif228170TIFF2025503502000163.tif187170

[0303] Example 87: N-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)methanesulfonamide [ka]

[0304] To a solution mixture of compound Q-2 (100 mg, 0.281 mmol, 1 equiv.) in DCM (3.0 mL), E t3 N (0.075 mL, 2 equiv.) was added at 0° C. The resulting reaction mixture was stirred at 0° C. for 10 min and methanesulfonyl chloride (0.032 mL, 0.422 mmol) was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo. Cold water (10 mL) was added to the crude compound and extracted with EtOAc to give the crude compound, which after final purification gave compound (87) as a white solid (40 mg, 31% yield).

[0305] The following examples are carried out by combining compound Q and formula R using the experimental conditions described in Example 87 above. 9 -SO2Cl with sulfonyl chloride derivatives: [Table 28]

[0306] (Characteristics of Example Compounds) The properties of the synthesized example compounds are shown in Table 4 below. [Table 29] TIFF2025503502000167.tif232170TIFF2025503502000168.tif221170TIFF20255035020001 69.tif231170TIFF2025503502000170.tif231170TIFF2025503502000171.tif231170TIFF202 5503502000172.tif227170TIFF2025503502000173.tif231170TIFF2025503502000174.tif2 28170TIFF2025503502000175.tif221170TIFF2025503502000176.tif226170TIFF2025503502 000177.tif230170TIFF2025503502000178.tif233170TIFF2025503502000179.tif232170TI FF2025503502000180.tif232170TIFF2025503502000181.tif231170TIFF2025503502000182. tif232170TIFF2025503502000183.tif230170TIFF2025503502000184.tif232170TIFF202550 3502000185.tif230170TIFF2025503502000186.tif232170TIFF2025503502000187.tif89170

[0307] Example 2: Cellular Target Engagement Assay - NanoBRET Materials and Methods NanoBRET target engagement was performed against the catalytic domain 2 (CD2) of HDAC6 using the kit manufacturer's protocol (Promega) with minor modifications. Expression of exogenous NanoLuc-HDAC6(CD2) fusions in HEK293T was achieved following transient transfection with FuGENE HD Transfection Reagent (Promega). Intracellular target engagement assays against HDAC6(CD2) were performed in a 384-well plate format using 8,000 cells per well and a tracer concentration of 0.125 μM or 0.600 μM for HDAC6(CD2). Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were either manually diluted in culture medium to 8x the final assay concentration and then 5 μL was added to the assay plate or, in an automated manner, 160 nL of compound was added to 5 μL of OptiMEM (Gibco) without phenol red using an Echo650 (Labcyte). After adding the tracer solution to the cells, 35 μL of the cell / tracer mixture was seeded into the assay plate. The final reaction volume was 40 μL and the final DMSO concentration was 1.4% (manual compound addition) or 1.25% (automated compound addition). The assay plate was incubated for 2 hours at 37°C in a humidified atmosphere containing 5% CO2. NanoBRET Nano-glo substrate / inhibitors were prepared by diluting NanoBRET Nano-Glo substrate (1:332) and extracellular inhibitor (1:1000) in assay medium (Promega). NanoBRET TE Nano-glo substrate / inhibitors were added to cells and measurements of NanoBRET donor and acceptor signals (460–80 and 647–75, respectively) were performed at room temperature 1–2 min after addition of NanoLuc substrate using either an EnVision Xcite (PerkinElmer) plate reader or a CLARIOstar (BMG Labtech) plate reader. BRET ratios were calculated as the acceptor / donor signal ratio (mBRET=acceptor / donor signal ratio). *1000) and normalized for each plate. Percentage inhibition was calculated by setting the mBRET obtained with cells without tracer to 100%, while the mBRET obtained with uninhibited cells with tracer was set to 0%. IC50 values ​​were calculated from the percentage inhibition using log(inhibitor) vs. response-variable slope (4 parameter) nonlinear regression in GraphPad Prism software.

[0308] (result) The results of this assay are presented in Table 5 below, where "+" means: 1000nM <IC 50 ≦10000nM, "++" means: 500nM <IC 50 ≦1000nM, "+++" means: 100nM <IC 50 ≦500nM and "++++" means: IC 50 <100nM means [Table 30] TIFF2025503502000189.tif207170

[0309] These results clearly demonstrate that the compounds of formula (I) effectively inhibit the interaction between HDAC6 catalytic domain 2 and its substrates, thereby inhibiting its deacetylation activity. Therefore, this assay indicates that the compounds of formula (I) can be used for the treatment and / or prevention of HDAC6-related diseases.

[0310] Example 3: In vitro measurement of acetylated α-tubulin Materials and Methods HeLa cells were cultured in UltraCulture serum-free medium (Lonza) supplemented with 2 mM glutamine (Lonza). The assay was performed in 96-well or 384-well format. The differences in the assay protocols are detailed in Table 6. Cells were plated per well and incubated overnight at 37°C in a humidified atmosphere containing 5% CO2. Cell density and seeding volume are detailed in Table 6. Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were added manually by diluting to 10x the final assay concentration in culture medium and adding 10 μL to the cells (96-well protocol). Alternatively, 50 nL of compound was added directly to the cell culture using an Echo650 (Labcyte) (384-well protocol). In this assay, the final assay concentration of DMSO is 0.1%-0.4%. Trichostatin A (TSA) was used as a positive control. Cells were incubated with compounds for 6 hours at 37°C in a humidified atmosphere containing 5% CO2. The levels of acetylated tubulin (Lys40) were assessed by immunocytochemistry using target-specific antibodies. Cells were fixed with 4% PFA at RT as detailed in Table 6. After 2-3 washing steps with PBS, cells were permeabilized with 0.5% Triton in PBS for 10 minutes at RT and then washed 1-2 times with PBS. To avoid non-specific antibody staining, cells were blocked with 3% BSA in PBS for 1 hour at room temperature. Afterwards, cells were incubated with anti-acetylated tubulin (mouse monoclonal antibody, acetylated tubulin Lys40, clone 6-11B, Sigma) at 1:3000 and anti-α-tubulin (rabbit monoclonal, abcam) at 1:1000 diluted in 1% BSA for 1 hour at RT. Cells were washed 2–3 times with PBS and labeled with Alexa 647-conjugated goat anti-mouse secondary antibodies (Thermofisher) and Alexa 555-conjugated goat anti-rabbit secondary antibodies (Thermofisher) diluted to a final concentration of 1:1000 in 1% BSA for 1 h at RT.At the same time, nuclei were stained with Hoechst (Thermofisher) at 1:10000-1:15000. Primary antibody incubation times and temperatures are detailed in Table 6. Cells were washed 2-3 times with PBS and imaged on an Operetta CLS or Opera Phenix (PerkinElmer). Imaging is further detailed in Table 6. For imaging analysis, Harmony analysis software (PerkinElmer) was used. Cytoplasmic (defined by total α-tubulin staining) intensity per well was used for quantification of α-tubulin (acetylated and total). Intensity was measured per cell and then averaged per well. The mean intensity level of acetylated tubulin was normalized to the mean intensity level of total tubulin. Changes in acetylated tubulin were normalized for each plate using GraphPad Prism software: acetylated tubulin in vehicle (DMSO) treated cells was set to 0%, while acetylated tubulin in TSA cells was set to 100%. EC50 values ​​were calculated using log(inhibitor) vs. response-variable slope (4 parameters) nonlinear regression in GraphPad Prism software. [Table 31]

[0311] (result) The results of this assay are presented in Table 7 below, where "+" means: 1000nM <IC 50 ≦3333nM, "++" means: 500nM <IC 50 ≦1000nM, "+++" means: 100nM <IC 50 ≦500nM, "++++" means: IC 50 <100nM and "-" means: IC 50 >3333nM. [Table 32] TIFF2025503502000192.tif118170

[0312] These results clearly demonstrate that the compound of formula (I) increases the ratio of acetylated α-tubulin to total α-tubulin in HeLa cells, indicating HDAC6 inhibition (HDAC6 is the only HDAC enzyme capable of deacetylating α-tubulin). Therefore, this assay indicates that the compound of formula (I) can be used for the treatment and / or prevention of HDAC6-related diseases.

[0313] Example 4: HDAC6 enzyme activity assay Materials and Methods Dose response studies of HDAC6 and HDAC1 were performed at Reaction Biology Corporation (RBC). Inhibition of HDAC enzymes was performed using N-terminal GST-tagged human full-length recombinant HDAC6 (H88-30G, SignalChem) and C-terminal FLAG His-tagged human full-length recombinant HDAC1 produced in insect cells (KDA-21-365, RBC). Enzyme reactions were performed in 50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, freshly supplemented with 1 mg / ml BSA, 1% DMSO. 2x enzyme was delivered to each well of the reaction plate, except for the "no enzyme" control well, where buffer was added. Compounds in 100% DMSO were delivered into the enzyme mix by acoustic technology (Echo550). Plates were spun down and compounds were incubated with enzyme for 10 min at room temperature. The reaction was initiated by adding 2x fluorescent peptide (RHKKAc, 10 μM final concentration) derived from p53 residues 379-382 to all wells, followed by incubation at 30°C for 1 h. A color development solution containing trichostatin A was added to stop the reaction and develop the fluorescent color. Kinetic measurements were performed on an Envision plate reader (Perkin Elmer, Ex / Em=360 / 460) for 20 min at 5 min intervals. The end-point reading of the color reaction, i.e., the plateau, was used for analysis. Data were reported by RBC as percentage enzyme activity. Percentage inhibition was calculated by subtracting the percentage enzyme activity from 100. IC50 values ​​were calculated from the percentage inhibition using GraphPad Prism 9 based on the log(inhibitor) vs. response-variable slope (4-parameter) equation.

[0314] (result) The results of this assay are presented in Table 8 below, where "+" means: 1000nM <IC 50 ≦10000nM, "++" means: 500nM <IC 50 ≦1000nM, "+++" means: 100nM <IC 50 ≦500nM, "++++" means: IC50 <100nM, "-" means IC 50 >10000 nM and "NT" means "not tested." [Table 33] TIFF2025503502000194.tif56170

[0315] These results clearly demonstrate that compounds of formula (I) inhibit fluorescent substrate conversion by HDAC6, but not by HDAC1. Thus, this assay provides direct evidence that compounds of formula (I) specifically inhibit HDAC6 over HDAC1, and therefore may be used for the treatment and / or prevention of HDAC6-associated diseases, with no or reduced toxicity due to inhibition of other HDAC proteins.

[0316] Example 5: HDAC6 Enzyme Activity Assay (Alternative Protocol) Materials and Methods Inhibition of HDAC enzymes was performed in 384-well plate format using human full-length recombinant HDAC1 and HDAC6 isolated from a baculovirus expression system in Sf9 cells (BPS Bioscience). Reaction buffer for HDAC1 contained 50 mM Tris-HCl pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 0.1 mg / mL BSA, and reaction buffer for HDAC6 contained 50 mM Tris / HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 250 μM EDTA, 1 mM DTT, 0.1 mg / mL BSA. Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were diluted in assay buffer at 3× final assay concentration and then added to the assay plate. SAHA (10 μM) was used as a positive control. Recombinant enzyme at 3x final assay concentration (final assay concentrations are 4 nM and 5 nM for HDAC1 and HDAC6, respectively) was pre-incubated with test compounds for 10 min at room temperature. Then, acetylated fluorescent peptide (Ac-Gly-Ala-Lys(Ac)-AMC, Bachem; final assay concentrations are 12 μM and 40 μM for HDAC1 and HDAC6, respectively) at 3x final assay concentration was added to the assay plate and the deacetylase reaction was incubated for 60 min at room temperature. A color reagent containing 5 μM SAHA and 50 μM trypsin was added to stop the deacetylase reaction and develop AMC fluorescence. 15 min after addition of the color reagent, end-point measurements were taken using a CLARIOstar (BMG Labtech) plate reader (excitation / emission: 360 / 450). Fluorescence signals were normalized for each plate using GraphPad Prism software: reacted HDAC substrate in the presence of DMSO was set to 100%, while reacted HDAC substrate in the presence of 10 μM SAHA was set to 0%. IC50 values ​​were calculated from the normalized measurements using GraphPad Prism software and nonlinear regression with 0% lower and 100% upper constraints.

[0317] (result) The results of this assay are presented in Table 9 below, where "+" means: 1000nM <IC 50 ≦10000nM, "++" means: 500nM <IC 50 ≦1000nM, "+++" means: 100nM <IC 50 ≦500nM, "++++" means: IC 50 <100nM and "-" means IC 50 >10000nM. [Table 34] TIFF2025503502000196.tif58170

[0318] These results clearly demonstrate that compounds of formula (I) inhibit fluorescent substrate conversion by HDAC6, but not by HDAC1. Thus, this assay provides direct evidence that compounds of formula (I) specifically inhibit HDAC6 over HDAC1, and therefore may be used for the treatment and / or prevention of HDAC6-associated diseases, with no or reduced toxicity due to inhibition of other HDAC proteins.

[0319] Taken together, the above results demonstrate that the compounds of formula (I) act as specific HDAC6 inhibitors.

Claims

1. A pharmaceutical composition for use in the treatment and / or prevention of an HDAC6-associated disease, comprising: Formula (I): 【Chemistry 1】 A compound of the formula ・Y 1 is expressed as follows: 【Chemistry 2】 is a 9- or 10-membered bicyclic heteroaryl selected from where: A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 are each independently, CR 7 and N; A 8 , A 9 , A 10 , and A 11 are each independently, CR 7 and N, with the proviso that A 8 , A 9 , A 10 , or A 11 at least one of is N; G 1 is CR 3 and N; G 2 O and NR 4 Selected from; B is O, S, and NR 5 is selected from However, A 5 , A 6 , and A 7 is CR 7 If B is not S; and R 2 is 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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 , -NR 16 -(C 1 -C 6 )Alkylene-C(O)OR 15 Selected from; R 3 is 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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 , -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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 15 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 )Alkylene-C(O)-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 15 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 )Alkylene-C(O)-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-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 are independently hydrogen, halogen, amino, hydroxy, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -SO-R 15 , -SO 2 -R 15 , -SO 2 NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 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 , or -NR 16 -C(O)-OR 15 Selected from; where: R 2 , R 3 , R 4 , R 5 , or R 7 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 2 , R 3 , R 4 , R 5 , or R 7 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , and R 18 are each independently hydrogen, -(C 1 -C 6 ) haloalkyl, -(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-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, and -(C 1 -C 6 ) alkylene-aryl; and / or R 15 , R 16 , R 17 , and R 18 Two groups selected from -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) together form a ring selected from heterocycloalkyl, aryl, and heteroaryl; where: R 15 , R 16 , R 17 , or R 18 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , or R 18 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from ・Y 2 is expressed as follows: 【Transformation 3】 is a 5-membered heteroaryl selected from where R 12 , R 13 , and R 14 are each independently hydrogen, halogen, cyano, hydroxy, 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 Selected from; where R 12 , R 13 , or R 14 In the -(C 1 -C 6 ) alkyl is selected from 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 optionally substituted with at least one group selected from ・L is -(CR 10 R 11 ) n , -(C 3 -C 7 ) cycloalkyl, and (C 3 -C 7 ) heterocycloalkyl; where: n is an integer selected from 1, 2, 3, and 4; R 10 and R 11 are independently hydrogen, halogen, hydroxy, 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 Selected from; The -(C 3 -C 7 ) cycloalkyl or (C 3 -C 7 ) heterocycloalkyl may be selected from 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 optionally substituted with at least one group selected from ・Z 1 is (C=O)-R 9 and S(O 2 )-R 9 Selected from; where R 9 is amino, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 21 , -(C 1 -C 6 ) Alkylene-NR 23 R 24 , -(C 1 -C 6 )Alkylene-C(O)-NR 23 R 24 , -(C 1 -C 6 )Alkylene-C(O)-NR 23 R 24 , -(C 1 -C 6 ) Alkylene-NR 22 -C(O)-R 21 , -(C 1 -C 6 )Alkylene-C(O)OR 21 , -OR 21 , -NR 23 R 24 , -NR 22 -(C 2 -C 6 ) Alkylene-OR 21 , -NR 22 -(C 2 -C 6 ) Alkylene-NR 23 R 24 , -NR 22 -(C 1 -C 6 )Alkylene-C(O)OR 21 Selected from; where: R 9 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 9 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from R 21 , R 22 , R 23 , and R 24 are each independently hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) halocycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, and -(C 1 -C 6 ) alkylene-aryl; and / or R 21 , R 22 , R 23 , and R 24 Two groups selected from -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) together form a ring selected from heterocycloalkyl, aryl, and heteroaryl; where: R 21 , R 22 , R 23 , or R 24 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 21 , R 22 , R 23 , or R 24 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 and ・R 1 is hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) Alkylene-OR 19 , and -(C 1 -C 6 ) Alkylene-NR 19 R 20 is selected from where: R 19 and R 20 are each independently hydrogen, -(C 1 -C 6 ) alkyl, and -(C 3 -C 7 ) cycloalkyl; or R 19 and R 20 is -(C 3 -C 7 )cycloalkyl and -(C 3 -C 7 ) heterocycloalkyl; R 1 , R 19 , and R 20 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , or R 18 In the -(C 3 -C 7 ) cycloalkyl or -(C 3 -C 7 ) heterocycloalkyl may be selected from 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 optionally substituted with at least one group selected from R 1 and R 10 or R 11 One of the groups contains at least one nitrogen atom (C 3 -C 7 ) together form a heterocycloalkyl; where R 1 and R 10 or R 11 In the (C 3 -C 7 )Heterocycloalkyl is a heterocyclic group selected from 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 or R 1 and R 9 contains at least one nitrogen atom (C 3 -C 7 ) together form a heterocycloalkyl; where R 1 and R 9 In the (C 3 -C 7 )Heterocycloalkyl is a heterocyclic group selected from 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 and optionally substituted with at least one group selected from or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

2. Formula (I): 【Chemistry 4】 A compound of the formula ・Y 1 is expressed as follows: 【Transformation 5】 is a 9- or 10-membered bicyclic heteroaryl selected from where: A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 are each independently, CR 7 and N; A 8 , A 9 , A 10 , and A 11 are each independently, CR 7 and N, with the proviso that A 8 , A 9 , A 10 , or A 11 at least one of is N; G 1 is CR 3 and N; G 2 O and NR 4 Selected from; B is O, S, and NR 5 is selected from However, A 5 , A 6 , and A 7 is CR 7 If B is not S; and R 2 is 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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 , -NR 16 -(C 1 -C 6 )Alkylene-C(O)OR 15 Selected from; R 3 is 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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 , -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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 15 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 )Alkylene-C(O)-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-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 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 15 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -(C 1 -C 6 )Alkylene-C(O)-NR 17 R 18 , -(C 1 -C 6 ) Alkylene-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 are independently hydrogen, halogen, amino, hydroxy, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 3 -C 7 ) Heterocycloalkyl, aryl, heteroaryl, -OR 15 , -(C 1 -C 6 ) Alkylene-OR 15 , -O-(C 2 -C 6 ) Alkylene-OR 15 , -NR 16 (C 2 -C 6 ) Alkylene-OR 15 , -NR 17 R 18 , -(C 1 -C 6 ) Alkylene-NR 17 R 18 , -O-(C 2 -C 6 ) Alkylene-NR 17 R 18 , -NR 16 -(C 2 -C 6 ) Alkylene-NR 17 R 18 , -SO-R 15 , -SO 2 -R 15 , -SO 2 NR 17 R 18 , -(C 1 -C 6 ) Alkylene-SO 2 -NR 17 R 18 , -NR 16 -SO 2 -R 15 , -(C 1 -C 6 ) Alkylene-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 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 , or -NR 16 -C(O)-OR 15 Selected from; where: R 2 , R 3 , R 4 , R 5 , or R 7 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 2 , R 3 , R 4 , R 5 , or R 7 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , and R 18 are each independently hydrogen, -(C 1 -C 6 ) haloalkyl, -(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-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, and -(C 1 -C 6 ) alkylene-aryl; and / or R 15 , R 16 , R 17 , and R 18 Two groups selected from -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) together form a ring selected from heterocycloalkyl, aryl, and heteroaryl; where: R 15 , R 16 , R 17 , or R 18 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , or R 18 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from ・Y 2 is expressed as follows: 【Transformation 6】 is a 5-membered heteroaryl selected from where R 12 , R 13 , and R 14 are each independently hydrogen, halogen, cyano, hydroxy, 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 Selected from; where R 12 , R 13 , or R 14 In the -(C 1 -C 6 ) alkyl is selected from 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 optionally substituted with at least one group selected from ・L is -(CR 10 R 11 ) n , -(C 4 -C 7 ) cycloalkyl, and (C 4 -C 7 ) heterocycloalkyl; where: n is an integer selected from 1 or 2; R 10 and R 11 are independently hydrogen, halogen, hydroxy, 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 Selected from; The -(C 3 -C 7 ) cycloalkyl or (C 3 -C 7 ) heterocycloalkyl may be selected from 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 optionally substituted with at least one group selected from ・Z 1 is -C(O)-R 9 and -SO 2 -R 9 Selected from; where R 9 is amino, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-aryl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) Alkylene-OR 21 , -(C 1 -C 6 ) Alkylene-NR 23 R 24 , -(C 1 -C 6 )Alkylene-C(O)-NR 23 R 24 , -(C 1 -C 6 )Alkylene-C(O)-NR 23 R 24 , -(C 1 -C 6 ) Alkylene-NR 22 -C(O)-R 21 , -(C 1 -C 6 )Alkylene-C(O)OR 21 , -OR 21 , -NR 23 R 24 , -NR 22 -(C 2 -C 6 ) Alkylene-OR 21 , -NR 22 -(C 2 -C 6 ) Alkylene-NR 23 R 24 , -NR 22 -(C 1 -C 6 )Alkylene-C(O)OR 21 Selected from; where: R 9 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 9 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 optionally substituted with at least one group selected from R 21 , R 22 , R 23 , and R 24 are each independently hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) halocycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, and -(C 1 -C 6 ) alkylene-aryl; and / or R 21 , R 22 , R 23 , and R 24 Two groups selected from -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) together form a ring selected from heterocycloalkyl, aryl, and heteroaryl; where: R 21 , R 22 , R 23 , or R 24 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 21 , R 22 , R 23 , or R 24 In the -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, aryl, or heteroaryl may each be 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 and ・R 1 is hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, -(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) heterocycloalkyl, -(C 1 -C 6 ) Alkylene-OR 19 , and -(C 1 -C 6 ) Alkylene-NR 19 R 20 is selected from where: R 19 and R 20 are each independently hydrogen, -(C 1 -C 6 ) alkyl, and -(C 3 -C 7 ) cycloalkyl; or R 19 and R 20 is -(C 3 -C 7 )cycloalkyl and -(C 3 -C 7 ) heterocycloalkyl; R 1 , R 19 , and R 20 In the -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) alkylene may be 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 optionally substituted with at least one group selected from R 15 , R 16 , R 17 , or R 18 In the -(C 3 -C 7 ) cycloalkyl or -(C 3 -C 7 ) heterocycloalkyl may be selected from 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 optionally substituted with at least one group selected from R 1 and R 10 or R 11 One of the groups contains at least one nitrogen atom (C 3 -C 7 ) together form a heterocycloalkyl; where R 1 and R 10 or R 11 In the (C 3 -C 7 )Heterocycloalkyl is a heterocyclic group selected from 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 or R 1 and R 9 contains at least one nitrogen atom (C 3 -C 7 ) together form a heterocycloalkyl; where R 1 and R 9 In the (C 3 -C 7 )Heterocycloalkyl is a heterocyclic group selected from 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 optionally substituted with at least one group selected from however, ・Y 1 is quinazolinyl and R 1 When is hydrogen, Z 1 -C(O)-methyl and -S(O) 2 - not selected from methyl; ・Y 1 is 1H-pyrazolo[3,4-d]pyrimidinyl and R 1 When is hydrogen, Z 1 is -C(O)-methyl, -C(O)-t-butyl, and -SO 2 - not selected from methyl; and The compound of formula (I) is not N-(2-(5-(2-((5-methyloxazolo[4,5-b]pyridin-2-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt and / or solvate thereof.

3. Y 1 But the following formula: 【Transformation 7】 (In the formula, A 1 ~A 4 , A 6 , A 7 , B, G 1 , and R 2 are independently as defined in claim 1 or 2); and Below formula: 【Transformation 8】 (In the formula, A 8 ~A 11 and G 2 are independently as defined in claim 1 or claim 2) 3. The pharmaceutical composition for use according to claim 1, or the compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R is a 9- or 10-membered bicyclic heteroaryl selected from the group consisting of:

4. Y 1 But the following formula: 【Chemistry 9】 (In the formula, R 2 , R 3 , and R 7 are independently as defined in claim 1 or claim 2) 3. The pharmaceutical composition for use according to claim 1, or the compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R is a 10-membered [6,6] bicyclic heteroaryl selected from the group consisting of:

5. Y 2 But the following formula: 【Chemistry 10】 (In the formula, R 12 , R 13 , and R 14 are independently as defined in claim 1 or 2) 3. A pharmaceutical composition for use according to claim 1, or a compound according to claim 2, selected from: or a pharmaceutically acceptable salt and / or solvate thereof.

6. R 12 and R 13 and R are each hydrogen, or a compound or a pharmaceutically acceptable salt and / or solvate thereof.

7. L is -(CR 10 R 11 ) n and R 10 , R 11 2. A pharmaceutical composition for use according to claim 1, or a compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 2, wherein n is as defined in claim 1 or 2.

8. R 10 and R 11 are independently hydrogen and (C 1 -C 3 2. A pharmaceutical composition for use according to claim 1, or a compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

9. R 10 and R 11 and each are hydrogen.

10. R 1 is hydrogen and (C 1 -C 3 2. A pharmaceutical composition for use according to claim 1, or a compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

11. R 1 11. The pharmaceutical composition for use according to claim 10, or the compound or a pharmaceutically acceptable salt and / or solvate thereof, wherein is hydrogen.

12. 3. A pharmaceutical composition for use according to claim 1, or a compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein n is 1.

13. R 9 are methyl, tert-butyl, cyclopropyl, O-tert-butyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, methoxymethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, phenylmethyl, phenyl, 2,2-difluorocyclopropyl, and 2,2,3,3,3-pentafluoropropyl, H 2 3. The pharmaceutical composition for use according to claim 1, or the compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, selected from N-methyl, N-methyl-NH-methyl, N-methylazetidinyl, 1-hydroxyethyl, and pyrrolidinyl.

14. R 9 is selected from cyclopropyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, 2,2-difluorocyclopropyl, and 2,2,3,3,3-pentafluoropropyl, or a pharmaceutically acceptable salt and / or solvate thereof.

15. n is an integer selected from 1 and 2, and R 10 and R 11 10. The pharmaceutical composition for use according to claim 1, wherein each of is hydrogen.

16. The compound: Table 1 or a pharmaceutically acceptable salt and / or solvate thereof.

17. 2. The pharmaceutical composition for use according to claim 1, wherein the HDAC6-associated disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases, neurodegenerative diseases, pain, neurological disorders, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, and metabolic or hormonal disorders.

18. 18. The pharmaceutical composition for use according to claim 17, wherein the HDAC6-associated disease is a neuropathy selected from Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using anticancer chemotherapy drugs, diabetic peripheral neuropathy (DPN), neuralgia, pain, and / or neuropathic pain.

19. The pharmaceutical composition for use according to claim 17, wherein the HDAC6-related disease is a cardiovascular disease selected from chronic or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, heart disease, tachycardia, and congestive heart failure.

20. 18. The pharmaceutical composition for use according to claim 17, wherein the HDAC6-related disease is an inflammatory disease selected from the group consisting of 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 posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, hidradenitis suppurativa, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

21. 18. The pharmaceutical composition for use according to claim 17, wherein the HDAC6-related disease is a metabolic or hormonal disorder selected from obesity, diabetes, acromegaly, infertility, and metabolic syndrome.

22. the below described: Table 2 Or a compound or a pharmaceutically acceptable salt and / or solvate thereof selected from any of these pharmaceutically acceptable salts and / or solvates.

23. The compound is Table 3 3. The compound according to claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, selected from any of these pharmaceutically acceptable salts and / or solvates.

24. 2-hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide: 【Chemistry 11】 3. The compound of claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

25. N-((5-(2-((6-chloro-7-fluoro-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide: 【Chemistry 12】 3. The compound of claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

26. 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide: 【Chemistry 13】 3. The compound of claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

27. N-((5-(2-((5-fluoro-6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide: 【Chemistry 14】 3. The compound of claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

28. (R)-2-hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)propanamide: 【Chemistry 15】 3. The compound of claim 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

29. 10. A process for preparing the compound of claim 2 or a pharmaceutically acceptable salt and / or solvate thereof, comprising: (i) Formula T-9: 【Chemistry 16】 a linear or cyclic amine of formula R 9 -COCl, acyl chloride, formula R 9 -COOH carboxylic acids, or 9 -SO 2 Cl with sulfonyl chloride; or (ii) Formula T-13: 【Chemistry 17】 The halo-ketone of formula Y 1 -SH thiol; reacting (In the formula, Y 1 , Y 2 , L, R 1 , R 9 , and Z 1 is as defined in claim 1 or 2 and X is halo.

30. 10. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

31. Formula T-9: [Chemistry 18] (In the formula, Y 1 , Y 2 , L, and R 1 is as defined in claim 1 or 2).

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