5-HT2A receptor modulator and method of use thereof

Abstract

This disclosure provides compounds, such as those of formula I, and their use in the treatment of medical diseases or disorders such as mental and neurological disorders. Pharmaceutical compositions and methods for producing various benzisoxazole and benzoisothiazole compounds are provided. The compounds are thought to be modulators of the 5-hydroxytryptamine 2A (5-HT2A) receptor.

Description

[Background technology]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 508,570, filed on 16 June 2023, the disclosure of which is incorporated herein by reference.

[0002] Modulators of the 5-hydroxytryptamine 2A receptor (5-HT2AR) are sought after as potential medicines for a wide range of mental and neurological disorders and conditions, including but not limited to depression, anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder, substance abuse, eating disorders, migraines and / or cluster headaches, Alzheimer's disease, Parkinson's disease, and various inflammatory disorders, cardiovascular disorders, and / or pain disorders. While many 5-HT2AR modulators have been developed, few are more selective for this receptor than the 5-HT2B receptor, a toxicological antitarget strongly associated with related subtypes, such as drug-induced valvular heart disease.

[0003] Therefore, there is a need to develop safe and effective compounds that are 5-HT2A receptor modulators, for example, modulators that exhibit selective functionality of the 5-HT2A receptor and / or binding to the 5-HT2A receptor relative to the 5-HT2B receptor. [Overview of the project]

[0004] This disclosure relates in part to modulators of the 5-hydroxytryptamine 2A (5-HT2A) receptor. Pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier are also disclosed herein.

[0005] For example, a compound represented by formula I: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, [Chemical formula] is a single bond, X is CR b , b , a , a and Y is C(R Y )2, or [Chemical formula] is a double bond, X is C, and Y is C(R Y ), A is selected from the group consisting of 8- to 10-member fused bicyclic heteroaryl, 12- to 14-member fused tricyclic heteroaryl, 8- to 10-member fused bicyclic heterocyclyl, and phenyl, and ring A is optionally substituted with one or more substituents selected from R A ; R A is, for each occurrence independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C1-C6 alkyl, -C(O)-C1-C6 alkyl, C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, 4- to 7-member heterocyclyl, and 5- to 6-member heteroaryl, and C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are optionally substituted with halogen, hydroxyl, -(NR a R b , -C(O)NR a [[ID=SI]] b ​, optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or one R X and one R Y They bond together to form -CH2-, R 1 The group is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R bSelected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups may optionally be substituted with one or more halogens. Compounds represented by formula I or pharmaceutically acceptable salts and / or stereoisomers thereof are disclosed herein.

[0006] Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, A is [ka] [ka] Selected from the group consisting of, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d The substituent is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, and C1-C3 alkoxy, where the -C1-C3 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. m is 0, 1, 2, or 3. Compounds represented by formulas IIA, IIB, or IIC, or their pharmaceutically acceptable salts and / or stereoisomers, are also disclosed herein.

[0007] Compounds represented by formula III: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and A is [ka] or [ka] And, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or R X and R Y They bond together to form -CH2-, R W The molecule is selected from the group consisting of hydrogen, C1-C6 alkyl, and -SO2-phenyl, and the C1-C6 alkyl and phenyl molecules are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, C1-C3 alkyl, and C1-C3 alkoxy molecules. R A For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b, -O-(CO)-C1-C6 alkyl, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, 4-7 member heterocyclyl and 5-6 member heteroaryl, selected from the group consisting of, C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclyl and heteroaryl are halogen, hydroxyl, -NR a R b , -C(O)NR a R b , and are optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 member heteroaryl) and -CH2-(5-10 member heterocyclyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl and heterocyclyl are optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, deuterium and C1-C3 alkoxy, R 2 and R 3 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, C1-C6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy, R 4 is hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NRa R b 、 -NR a -(CO)-OR b 、 -O-C(O)-NR a R b 、 -O-(CO)-C1-C6 alkyl, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl and phenyl, wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl and phenyl are each independently selected from the group consisting of halogen, hydroxyl, -NR a R b and C1-C3 alkoxy and are optionally substituted with one or more substituents independently selected from the group consisting of, R 5 is halogen, hydroxyl, cyano, -NR a R b 、 -C(O)-NR a R b 、 -NR a -C(O)-R b 、 -NR a -C(O)-NR a R b 、 -NR a -(CO)-OR b 、 -O-C(O)-NR a R b 、 -O-(CO)-C1-C6 alkyl, -CO2H, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl and phenyl, wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl and phenyl are each independently selected from the group consisting of halogen, hydroxyl, -NR a R b and C1-C3 alkoxy and are optionally substituted with one or more substituents independently selected from the group consisting of, R 6 and R 7Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups are optionally substituted with one or more halogens. m is 0, 1, 2, or 3. Compounds represented by formula III or pharmaceutically acceptable salts and / or stereoisomers thereof are further disclosed herein.

[0008] For example, compounds represented by formulas IVA, IVB, or IVC: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, where, A is [ka] and [ka] Selected from the group consisting of, R W It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R Y is hydrogen or -CH3, R AFor each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl. Here, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. R 1 These are hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, [ka] and [ka] Selected from the group consisting of, R 2 It is selected from the group consisting of hydrogen, -CH3, and -CH2OH. R 3 This is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl. m is 0, 1, 2, or 3. Compounds represented by formulas IVA, IVB, or IVC, or their pharmaceutically acceptable salts and / or stereoisomers, are disclosed herein.

[0009] Further disclosure herein are pharmaceutical compositions comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises at least one additional therapeutic agent for treating, alleviating, and / or preventing neurological disorders and / or disabilities.

[0010] In another embodiment, a method for reducing and / or preventing a neurological disorder or disorder in a patient requiring reduction and / or prevention of such disorder is provided herein, comprising administering to the patient a therapeutically effective amount of any compound or pharmaceutical composition thereof described herein. In a particular embodiment, the neurological disorder or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.

[0011] Also disclosed herein is a method for selectively modulating the 5-hydroxytryptamine 2A (5-HT2A) receptor in patients requiring selective modulation of the 5-hydroxytryptamine 2A (5-HT2A) receptor, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition thereof disclosed herein. [Modes for carrying out the invention]

[0012] Herein, we will describe in more detail the features and other details of this disclosure. Before further description of this disclosure, we hereby compile the specific terms used herein, in the examples and in the appended claims. These definitions should be read so as to be understood by those skilled in the art in light of the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] definition

[0014] The term "treat" includes any effect that results in improvement of a condition, disease, disorder, etc., such as reduction, mitigation, regulation, or elimination.

[0015] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbons. Exemplary alkyl groups are defined herein by the respective C 1~6 Alkyl, C 1~4 Alkyl and C 1~3 Alkyl hydrocarbons include, but are not limited to, linear or branched hydrocarbons with 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0016] As used herein, the term “alkenyl” refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, linear or branched groups of 2 to 6 or 3 to 4 carbon atoms, referred herein to as C1-C5 alkenyls, C2-C6 alkenyls, and C3-C4 alkenyls, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0017] As used herein, the term "alkynyl" refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups are defined herein by the following terms: C 2~6 Alkinyl and C 3~6 This includes, but is not limited to, linear or branched groups of 2 to 6 or 3 to 6 carbon atoms, called alkynyl groups. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0018] As used herein, the term "alkoxy" refers to a linear or branched alkyl group (alkyl-O-) bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1 to 6 or 2 to 6 carbon atoms, referred herein as C1-C5 alkoxy, C1-C6 alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0019] The term "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared within a cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system. 6~14 This refers to an aryl group ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring defined above is condensed with one or more carbocyrillic or heterocyclyl groups, and the radical or bond site is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafen, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Typical examples of substituted aryls include: [ka] and These include, In the formula, R 56 and R 57 One of them could be hydrogen, R 56 and R 57 At least one of these is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COO-alkyl, COO-aryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R59 Selected from S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl, or R 56 and R 57 The atoms may be linked together to form a cyclic ring (saturated or unsaturated) consisting of 5 to 8 atoms, and may contain one or more heteroatoms selected from the groups N, O, or S. 60 and R 61 These are, independently, hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 The aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl is used.

[0020] As used herein, the term "carbonyl" refers to the radical -C(O)-.

[0021] As used herein, the term "cyano" refers to the radical-CN.

[0022] As used herein, the terms "cycloalkyl" or "carbocyclic group" refer to saturated or partially unsaturated hydrocarbon groups of, for example, 3 to 6 or 4 to 6 carbon atoms, respectively, C3 to C6. 10 Cycloalkyl, C 3~6 Cycloalkyl or C 4~6 These are called cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0023] As used herein, the terms "halo" or "halogen" refer to F, Cl, Br, or I.

[0024] As used herein, the term “haloalkyl” refers to an alkyl radical in which an alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl. Exemplary haloalkyl groups are, as used herein, C 1~6 Haloalkyl, C 1~4 Haloalkyl and C 1~3 This includes, but is not limited to, linear or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), known as haloalkyls.

[0025] When the term "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the above hydrocarbyl groups, such as alkyls, e.g., heteroalkyls, cycloalkyls, e.g., heterocyclyls, aryls, e.g., heteroaryls, cycloalkenyls, e.g., cycloheteralkenyls, etc., which have 1 to 5 heteroatoms, particularly 1 to 3 heteroatoms.

[0026] As used herein, the terms “heteroaryl” or “heteroaromatic group” refer to aromatic 5- to 10-membered ring systems containing one or more heteroatoms, such as 1 to 3 heteroatoms, including nitrogen, oxygen, and sulfur. These terms may also be used to refer to 5- to 7-membered monocyclic heteroaryls or 8- to 10-membered bicyclic heteroaryls. Where possible, the heteroaryl ring may be linked to adjacent radicals via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzimidazole, imidazopyridine, pyrazole, triazole, pyridine, or pyrimidine.

[0027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are recognized in the art and refer to a saturated or partially unsaturated 4- to 10-membered ring structure, the ring structure containing 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be linked to adjacent radicals via carbon or nitrogen. The term may also be used to refer to a bridged, condensed, or spirocycle structure, the ring structure containing 1 to 3 heteroatoms, e.g., nitrogen, oxygen, and sulfur, a 4- to 10-membered saturated or partially unsaturated ring structure. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiroheterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridging heterocycle (e.g., octahydro-1H-4,7-methanoisoindole). A “spiroheterocyclyl” or “spiroheterocycle” refers to a polycyclic heterocyclyl having rings linked via one common atom (called a spiro atom), where the rings consist of N, O, and S(O) as ring atoms. m It has one or more heteroatoms selected from the group consisting of (wherein m is an integer from 0 to 2).

[0028] As used herein, the terms "hydroxy" and "hydroxyl" refer to the radical -OH.

[0029] As used herein, the term "oxo" refers to the radical = O.

[0030] "Pharmacologically or pharmacologically acceptable" includes molecular entities and compositions that, if administered to animals or humans as necessary, do not produce adverse reactions, allergic reactions, or other undesirable reactions. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by FDA Office of Biologics standards.

[0031] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to any solvent, dispersion medium, coating, isotonic agent, absorption retarder, etc., that is suitable for pharmaceutically active administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0032] As used herein, the term “pharmaceutical composition” refers to a composition comprising at least one compound disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0033] The terms “individual,” “patient,” or “subject” are used interchangeably and include all animals, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds of this disclosure can be administered to mammals such as humans, but can also be administered to other mammals such as livestock (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.) that require veterinary treatment. “Modification” includes antagonistism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signaling, functionally selective agonism, partial antagonistism, and / or partial agonism.

[0034] In this specification, the term “therapeutic dose” means the amount of a compound of interest that elicits a biological or medical response in a tissue, system, or animal (e.g., mammal or human), as determined by researchers, veterinarians, physicians, or other clinicians. The compounds of this disclosure are administered in therapeutic doses to treat a disease. Alternatively, the therapeutic dose of a compound is the amount required to achieve the desired therapeutic and / or preventive effect.

[0035] As used herein, the term “pharmaceutically acceptable salts” refers to salts of any acidic or basic groups that may be present in the compounds used in the composition. The inherently basic compounds contained in this composition can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The essentially acidic compounds contained in this composition can form base salts with a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in this composition, including basic or acidic moieties, can also form pharmaceutically acceptable salts with a variety of amino acids. The compounds of this disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0036] The compounds of this disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term “stereoisomer” encompasses all enantiomers or diastereomers. These compounds may be denoted by the symbols “(+)”, “(-)”, “R” or “S” depending on the arrangement of substituents around the stereogenic carbon atom, but those skilled in the art will recognize that the structure may imply a chiral center. This disclosure encompasses various stereoisomers and mixtures thereof of these compounds. Mixtures of enantiomers or diastereomers may be nominally designated as “(±)”, but those skilled in the art will recognize that the structure may imply a chiral center.

[0037] The compounds of this disclosure may contain one or more double bonds and therefore may exist as geometric isomers arising from the arrangement of substituents around a carbon-carbon double bond. [ka] This indicates a bond that may be a single, double, or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" represents a substituent on the same side of the double bond and "trans" represents a substituent on the opposite side of the double bond.

[0038] The compounds of this disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers arising from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a carbocyclic or heterocyclic ring encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be called "cis" or "trans," the term "cis" refers to substituents on the same side of the ring plane, and the term "trans" refers to substituents on opposite sides of the ring plane. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring plane is called "cis / trans."

[0039] The individual enantiomers and diastereomers of the compounds of this disclosure can be prepared synthetically from commercially available starting materials containing chiral or stereocenters, or by the preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, (3) direct separation of the optical enantiomer mixture on a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture can also be separated into its component enantiomers by well known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms a heterogeneous mixture of stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may include the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0040] The compounds disclosed herein can exist in solvated and unsolvated forms with pharmaceutically acceptable solvents such as water and ethanol, and this disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is in crystalline form.

[0041] This disclosure also includes isotope-labeled compounds of this disclosure that are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is an example. For instance, the compounds of this disclosure may have one or more H atoms substituted with deuterium.

[0042] Specific isotope-labeled disclosed compounds (e.g., 3 H and 14 Those labeled with 1C are useful in compound and / or substrate tissue distribution assays. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2Substitution with heavier isotopes, such as H), may provide certain therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure can generally be prepared by procedures similar to those disclosed in the examples herein, by using an isotope-labeled reagent instead of a non-isotopically labeled reagent.

[0043] The term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur at various locations (e.g., in the intestinal lumen, or during passage through the intestines, blood, or liver) by various mechanisms (e.g., esterases, amidases, phosphatases, oxidative and / or reductive metabolism). Prodrugs are well known in the art (see, for example, Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, the prodrug is a compound of the hydrogen atoms of the acid group, (C 1~8 ) alkyl, (C 2~12 )alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C 1~2 ) Alkylamino(C 2~3 ) Alkyl (β-dimethylaminoethyl, etc.), carbamoyl-(C 1~2) alkyl, N,N-di(C 1~2 ) Alkylcarbamoyl-(C 1~2 ) Alkyl and piperidino-, pyrrolidino-, or morpholino (C 2~3 ) May include esters formed by substitution with groups such as alkyl groups.

[0044] Similarly, if the compound disclosed herein contains an alcohol functional group, the hydrogen atoms of the alcohol group, (C 1~6 ) Alkylcarbonyloxymethyl, 1-((C 1~6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1~6 )alkylcarbonyloxy)ethyl(C 1~6 ) Alkoxycarbonyloxymethyl, N-(C 1~6 ) Alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) Alkylcarbonyl, α-amino(C 1~4 Prodrugs can be formed by substitution with groups such as alkylcarbonyl, arylalkylcarbonyl, and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is a naturally occurring L-amino acid, P(O)(OH)2, -P(O)(O(C) 1~6 A radical independently selected from alkyl-2 or glycosyl (a radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0045] When the compounds of this disclosure incorporate amine functional groups, prodrugs can be formed, for example, by the production of amides or carbamates, N-alkylcarbonyloxyalkyl derivatives, (oxodioxolenyl)methyl derivatives, N-Mannich bases, imines, or enamines. Furthermore, secondary amines can be metabolically cleaved to produce biologically active primary amines, or tertiary amines can be metabolically cleaved to produce biologically active primary or secondary amines. See, for example, Simplicio, et al., Molecules 2008, 13, 519 and the references therein.

[0046] compound

[0047] This disclosure relates in part to compounds that are modulators of the 5-hydroxytryptamine 2A (5-HT2A) receptor. In some embodiments, the modulators of this disclosure exhibit selective functionality to the 5-HT2A receptor and / or binding to the 5-HT2A receptor more than the 5-HT2B receptor and / or the 5-HT2C receptor. In certain embodiments, the compounds of this disclosure can be used to treat a variety of neurological disorders and conditions, including, but not limited to, depression, anxiety, substance abuse, migraines, and / or cluster headaches.

[0048] For example, a compound represented by formula I: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and A is selected from the group consisting of 8-10 member condensed bicyclic heteroaryls, 12-14 member condensed tricyclic heteroaryls, 8-10 member condensed bicyclic heterocyclils, and phenyl, and ring A is R A Optionally substituted with one or more substituents selected from, R A For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NRa -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~7 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR a R b , optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or one R X and one R Y They bond together to form -CH2-, R 1 The group is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 2 and R 3Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6aC6 alkenyl, C2~C6aC6 alkynyl, C1~C6aC6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups may optionally be substituted with one or more halogens. Compounds represented by formula I or pharmaceutically acceptable salts and / or stereoisomers thereof are disclosed herein.

[0049] In some embodiments, the compounds disclosed herein are [ka] or [ka] It is represented by [this].

[0050] In some embodiments, R 6 and R 7 is hydrogen. In other embodiments, R 2 and R 3 is hydrogen. In certain embodiments, the compounds disclosed herein are [ka] or [ka] It is represented by [this].

[0051] For example, in some embodiments, A is [ka] and [ka] Selected from the group consisting of, in the formula, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R dThis is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, -C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, where -C1-C3 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, m is 0, 1, 2, or 3.

[0052] In some embodiments, for example, R c R is selected from the group consisting of hydrogen and -CH3. d R is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3, e The group is selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

[0053] In further embodiments, R A For each occurrence, is independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, where tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. For example, in a particular embodiment, R AThese are independently selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3.

[0054] In some embodiments, A is, for example, [ka] [ka] and [ka] It is selected from the group consisting of the following.

[0055] In other embodiments, R 4 and R 5 Each is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In yet another embodiment, R 4 is hydrogen. In further embodiments, R 5 R is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In certain other embodiments, R 5 is hydrogen or -CH3. In some embodiments, R 1 R is hydrogen. In further embodiments, R 1 is hydrogen, -CH3, [ka] and [ka] It is selected from the group consisting of the following.

[0056] Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, During the ceremony, A is [ka] and [ka] Selected from the group consisting of, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d The substituent is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, and C1-C3 alkoxy, where the -C1-C3 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. m is 0, 1, 2, or 3. Compounds represented by formulas IIA, IIB, or IIC, or their pharmaceutically acceptable salts and / or stereoisomers, are also disclosed herein.

[0057] In some embodiments, R d R is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3, e R is selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano. In other embodiments, R 4 is hydrogen. In further embodiments, R 5 R is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In certain embodiments, R 5 is hydrogen or -CH3. In some embodiments, R 1 It is hydrogen.

[0058] In some embodiments, the compound is one of the compounds specified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0059] Compounds represented by formula III: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and A is [ka] or [ka] And, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or R X and R Y They bond together to form -CH2-, R W The molecule is selected from the group consisting of hydrogen, C1-C6 alkyl, and -SO2-phenyl, and the C1-C6 alkyl and phenyl molecules are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, C1-C3 alkyl, and C1-C3 alkoxy molecules. R A For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~7 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR aR b , optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R 1 The substituents are selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 member heteroaryl), and -CH2-(5-10 member heterocyclyl), and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 These are hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R bSelected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 5 These are halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -CO2H, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 6 and R 7Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups are optionally substituted with one or more halogens. m is 0, 1, 2, or 3. Compounds represented by formula III or pharmaceutically acceptable salts and / or stereoisomers thereof are further disclosed herein.

[0060] In some embodiments, the compounds disclosed herein are [ka] or [ka] It is represented by [this].

[0061] In some embodiments, R 6 and R 7 is hydrogen. For example, in some embodiments, the compounds disclosed herein are [ka] or [ka] It is represented by [this].

[0062] In some embodiments, R Y is hydrogen or -CH3. In other embodiments, R WR is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In further embodiments, R A For each occurrence, is independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, where tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. For example, in a particular embodiment, R A These are independently selected from the appearances of the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH, and -OCH2CH3.

[0063] In some embodiments, R 2 is hydrogen. In other embodiments, R 3 R is selected from the group consisting of hydrogen, -CH3, and -CH2OH. In yet another embodiment, R 4 is hydrogen. In further embodiments, R 5 The group is selected from hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl.

[0064] In some embodiments, R 1 These are hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, [ka] and [ka] Selected from the group consisting of R 1 It is hydrogen.

[0065] Compounds represented by formulas IVA, IVB, or IVC: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein A is [ka] and [ka] Selected from the group consisting of, R W It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R Y is hydrogen or -CH3, R AFor each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl. Here, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. R 1 These are hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, [ka] and [ka] Selected from the group consisting of, R 2 It is selected from the group consisting of hydrogen, -CH3, and -CH2OH. R 3 This is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl. m is 0, 1, 2, or 3. Compounds represented by formulas IVA, IVB, or IVC, or their pharmaceutically acceptable salts and / or stereoisomers, are also disclosed herein.

[0066] In some embodiments, the compound is one of the compounds specified in Table 2 below or a pharmaceutically acceptable salt thereof. Table 2. Exemplary compounds. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

[0067] In some embodiments, the compound is one of the compounds specified in Table 3 below or a pharmaceutically acceptable salt thereof. Table 3. Exemplary compounds. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9]

[0068] Procedures for preparing the compounds described herein are provided in the following examples. In the reactions described below, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino, thio, or carboxyl groups) to avoid their undesirable involvement in the reaction. The incorporation of such groups, and the methods required for their introduction and removal, are known to those skilled in the art (see, for example, Greene, Wuts, Protective Groups in Organic Synthesis, 2nd Ed. (1999)). The deprotection step may be the final step of the synthesis such that the removal of the protecting group yields the compounds disclosed herein. The starting materials used in the following schemes can be purchased or prepared by methods known to those skilled in the art, by methods described in the chemical literature, or by adaptation thereof. The order in which the steps are carried out may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0069] The compounds disclosed herein, or any intermediates described in the scheme above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods may include substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify the disclosed compounds or any preceding intermediates by modifying, introducing, or removing appropriate functional groups.

[0070] If it is desired to obtain a specific enantiomer of the disclosed compound, this can be produced from the corresponding mixture of enantiomers by using any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, a diastereomer derivative (e.g., a salt) can be produced by reacting a mixture of enantiomers of the disclosed compound (e.g., a racemate) with a suitable chiral compound (e.g., a chiral base). The diastereomer can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer can be recovered (e.g., by treatment with acid if the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0071] Alternatively, the racemic mixture of the disclosed compound can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the above methods. Chromatography, recrystallization, and other conventional separation procedures may also be used in conjunction with intermediates or final products from which specific geometric isomers of the disclosure are desired.

[0072] In alternative embodiments, the disclosed compound may also include one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 It can be H (T or tritium), and carbon is, for example, 13 C or 14 It can be C, and oxygen is, for example, 18 It can be O, and nitrogen is, for example, 15 In other embodiments, it may be N, etc. 3 H, 13 C, 14 C, 18 O, or 15N) may account for at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0073] method

[0074] Another aspect of this disclosure provides a method for treating patients suffering from neurological disorders or conditions. In particular, in certain embodiments, this disclosure provides a method for treating the following medical indications, comprising administering a therapeutically effective amount of a compound described herein to a patient in need of treatment.

[0075] For example, a method for treating a neurological disorder or condition in a patient requiring treatment is provided herein, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, for example, a compound of formula I or formula II. A method for treating a neurological disorder or condition in a patient requiring treatment is also provided herein, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein (for example, a compound of formula I or formula II) and a pharmaceutically acceptable excipient.

[0076] Non-exclusive examples of neurological disorders or conditions include depression, anxiety, substance abuse, and headaches. Headaches that can be treated by the methods described herein include, but are not limited to, migraines and cluster headaches.

[0077] For example, in some embodiments, the methods described herein may include treating a depressive disorder in a patient requiring treatment for the depressive disorder, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the depressive disorder may be major depressive disorder. In other embodiments, the depressive disorder may include treatment-resistant depression.

[0078] In certain embodiments, the methods described herein may include treating an anxiety disorder in a patient requiring treatment for the anxiety disorder, and include administering to the patient an effective amount of the compound disclosed herein or a pharmaceutical composition thereof. In some embodiments, the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.

[0079] In further embodiments, the methods described herein may include treating trauma and / or stress disorders in patients requiring such treatment, which involves administering an effective amount of the compounds disclosed herein or their pharmaceutical compositions to the patient. In some embodiments, such disorders may be post-traumatic stress disorders. In other embodiments, such disorders may be adjustment disorders.

[0080] In certain embodiments, the methods described herein may include treating a patient in need of treatment for obsessive-compulsive disorder (e.g., body dysmorphic disorder), which involves administering to the patient an effective amount of the compound or pharmaceutical composition thereof disclosed herein.

[0081] In other embodiments, the methods described herein may include treating an eating disorder in a patient in need thereof, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.

[0082] In further embodiments, the methods described herein may include treating a sleep-wake disorder, such as insomnia, in a patient in need thereof, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient.

[0083] In some embodiments, the methods described herein may include treating a psychotic disorder, such as insomnia, in a patient in need thereof, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the psychotic disorder may be schizophrenia. In other embodiments, the psychotic disorder may be schizoaffective disorder. In yet another embodiment, the psychotic disorder may be schizotypal personality disorder.

[0084] In certain embodiments, the methods described herein may include treating a substance-related disorder and / or addiction disorder in a patient in need, comprising administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, such disorder may be alcohol use disorder. In other embodiments, such disorder may be opioid use disorder. In yet another embodiment, such disorder may be tobacco use disorder. For example, in some embodiments, the compounds disclosed herein may be useful in promoting smoking cessation.

[0085] In certain other embodiments, the methods described herein may include treating a neurocognitive disorder in a patient requiring treatment for the disorder, and include administering to the patient an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof. In some embodiments, the neurocognitive disorder may include those resulting from primary neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease.

[0086] In some embodiments, the methods described herein may include treating a personality disorder in a patient requiring such treatment, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In other embodiments, the methods described herein may include treating autism spectrum disorder in a patient requiring such treatment, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient.

[0087] In further embodiments, the methods described herein may include treating bipolar disorder in a patient requiring treatment for bipolar disorder, and include administering to the patient an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof. In some embodiments, the bipolar disorder may be bipolar I disorder. In other embodiments, the bipolar disorder may be bipolar II disorder.

[0088] In other embodiments, the methods described herein may include treating a pain disorder in a patient requiring treatment of the pain disorder, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the pain disorder may be neuropathic pain. In other embodiments, the pain disorder may be migraine. In yet another embodiment, the pain disorder may be cluster headache. In yet another embodiment, the pain disorder may be trigeminal neuralgia. In yet another embodiment, the pain disorder may be cancer pain. In certain embodiments, the pain disorder may be focal pain disorder. In yet another embodiment, the pain disorder may be phantom limb pain. In some embodiments, the pain disorder to be treated may be chronic pain.

[0089] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula I or formula II) may exhibit anxiolytic, antidepressant, and anti-drug abuse effects without substantially exhibiting psychedelic effects (e.g., hallucinogenic effects). For example, the (5-HT2A) receptor modulator intended in this disclosure may confer antidepressant-like activity without inducing psychedelic-like effects. For example, in some embodiments, the compounds disclosed herein may be safe and effective for use in the manner described herein, without exhibiting the hallucinogenic effects of known psychedelics such as DMT and psilocybin.

[0090] This disclosure also provides a method for selectively modulating the 5-hydroxytryptamine 2A (5-HT2A) receptor. This method comprises administering to a patient a compound disclosed herein (e.g., a compound of formula I or formula II), a pharmaceutically acceptable salt thereof, and / or a stereoisomer thereof, the compound selectively modulates 5-HT2A more selectively than 5-HT2B and / or 5-HT2C receptors. The method for selectively modulating the 5-HT2A receptor can be used to treat, alleviate, and / or prevent diseases or disorders that are affected, related to, or benefit from selective modulation of the 5-HT2A receptor. By selectively modulating the 5-HT2A receptor more selectively than 5-HT2B and / or 5-HT2C receptors, this method provides a reduction in side effects, such as, but not limited to, drug-induced valvular heart disease associated with modulation of the 5-HT2B receptor.

[0091] In certain embodiments, the methods described herein further include administering to a patient an additional therapeutic agent for treating a neurological disorder or a disorder that is affected by, related to, or benefits from selective modulation of the 5-HT2A receptor.

[0092] The intended patients include not only humans, but also other animals such as companion animals (e.g., dogs, cats), livestock (e.g., cattle, pigs), and wild animals (e.g., monkeys, bats, snakes).

[0093] The compounds described herein may be administered in combination with one or more additional therapeutic agents to treat the disorders described herein. For clarity, both methods are considered herein, including a fixed composition comprising the disclosed compounds and another therapeutic agent, such as those disclosed herein, and a method of administering the disclosed compounds and the disclosed therapeutic agents separately. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein, one or more additional therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, the disclosed compounds and one additional therapeutic agent are administered. In some embodiments, the disclosed compounds as defined herein and two additional therapeutic agents are administered. In some embodiments, the disclosed compounds as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, the disclosed compounds and additional therapeutic agents may be formulated and administered separately. Combination therapy can also be achieved by administering a pharmaceutical composition comprising two or more therapeutic agents in a single formulation, for example, the disclosed compounds as one therapeutic agent and one or more additional therapeutic agents. For example, the disclosed compounds and additional therapeutic agents can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more drugs in combination therapy can be administered simultaneously, but are not necessarily required. For example, the first drug (or combination of drugs) can be administered a few minutes, hours, days, or weeks before the second drug (or combination of drugs) is administered. Thus, two or more drugs can be administered within a few minutes of each other, or within 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, or 24 hours of each other, or within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, or 14 days of each other, or within 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of each other. In some cases, longer intervals are possible.In many cases, it is desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, but this is not always the case.

[0094] Combination therapy may also involve administering one or more drugs used in combination, using different administration sequences of the component drugs. For example, when drugs X and Y are used in combination, they can be administered one or more times in any combination, in a sequence such as XYX, XXY, YXY, YYX, XXYY, etc.

[0095] For example, the method described herein comprises administering to a patient a therapeutically effective amount of at least one compound of formula I or formula II described herein, which may be formulated into a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein, e.g., a compound of formula I or formula II, present in the pharmaceutical composition is the sole therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further comprises administering to a patient an additional therapeutic agent that treats a neurological disorder or a disorder that is affected by, related to, or benefits from selective modulation at the 5-HT2A receptor.

[0096] For example, in some embodiments, the methods described herein may include administering one or more additional therapeutic agents to a patient in combination with the compounds disclosed herein. In certain embodiments, the one or more additional therapeutic agents that may be administered in combination with the compounds disclosed herein may be selective serotonin reuptake inhibitors (SSRIs). In some embodiments, the selective serotonin reuptake inhibitors may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. In other embodiments, the one or more additional therapeutic agents may be serotonin and norepinephrine reuptake inhibitors (SNRIs). For example, the serotonin and norepinephrine reuptake inhibitors may be selected from the group consisting of, for example, duloxetine, venlafaxine, desvenlafaxine, and levomirunacipran. In yet another embodiment, the one or more additional therapeutic agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, virazodone, and bupropion. In certain embodiments, one or more additional therapeutic agents may be tricyclic antidepressants. For example, in some embodiments, the tricyclic antidepressant may be selected from the group consisting of, for example, imipramine, nortriptyline, amitriptyline, doxepin, and desipramine. In further embodiments, one or more additional therapeutic agents may be monoamine oxidase inhibitors (MAOIs). For example, in some embodiments, the monoamine oxidase inhibitor may be selected from the group consisting of, for example, tranylcypromine, phenelzine, and isocarboxazide. In other embodiments, one or more additional therapeutic agents may be, for example, lithium compounds, such as lithium salts, such as lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate. In some embodiments, one or more additional therapeutic agents may be, for example, ketamine or esketamine. In certain embodiments, one or more additional therapeutic agents may be, for example, dextromethorphan. In other embodiments, one or more additional therapeutic agents may be, for example, D-methadone.

[0097] In some embodiments, administering the compound(s) described herein to a patient makes it possible to administer a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve similar results in treating, alleviating, and / or preventing a neurological disorder or impairment, or in treating, alleviating, and / or preventing a disorder or impairment that is affected by, associated with, or benefits from, selective modulation of the 5-HT2A receptor in the patient. For example, in certain embodiments, the compound(s) described herein enhance the activity of the additional therapeutic agent, thereby enabling a lower dose of the additional therapeutic agent to provide the same effect.

[0098] In particular, in certain embodiments, the present disclosure provides a method for treating the above-mentioned medical indications, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I or formula II, to a subject requiring treatment for the above-mentioned medical indications.

[0099] Pharmaceutical compositions and kits

[0100] Another aspect of the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but the most suitable mode of administration in any given case depends on the degree and severity of the condition being treated and the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0101] The exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical formulation containing one or more of the compounds of this disclosure as an active ingredient, for example, in solid, semi-solid, or liquid form, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient may be formulated with, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use that is normally non-toxic and pharmaceutically acceptable. The compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on a method or condition of disease.

[0102] To prepare solid compositions such as tablets, a main active ingredient can be mixed with a pharmaceutical carrier, such as conventional tableting components like corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid pre-formulation composition containing a homogeneous mixture of the compound of this disclosure or its non-toxic, pharmaceutically acceptable salt. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0103] For solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), this composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) water-retaining agents such as glycerol; (4 (1) Disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (2) Solution retarders such as paraffin; (3) Absorption enhancers such as quaternary ammonium compounds; (4) Wetting agents such as acetyl alcohol and glycerol monostearate; (5) Absorbents such as kaolin and bentonite clay; (6) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (7) Colorants. In the case of capsules, tablets and pills, the composition may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0104] Tablets may be prepared by compression or molding, sometimes with one or more auxiliary components. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of the composition moistened with an inert liquid diluent using appropriate machinery. Tablets, as well as other solid dosage forms such as sugar-coated tablets, capsules, pills, and granules, may be perforated or prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0105] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to these compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0106] In addition to the subject composition, the suspension may contain, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and suspending agents as mixtures thereof.

[0107] Formulations for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the body cavity and release the activator.

[0108] Dosage forms for transdermal administration of this composition include powder, spray, ointment, paste, cream, lotion, gel, solution, patch, and inhalant. The active ingredient may be mixed with a pharmaceutically acceptable carrier under sterile conditions and any preservatives, buffers, or propellants that may be required.

[0109] Ointments, pastes, creams, and gels may contain, in addition to the composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0110] The powder and spray may contain, in addition to the composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The spray may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0111] Alternatively, the compositions and compounds of this disclosure may be administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Although the compounds in the compositions may degrade when exposed to shear, ultrasonic nebulizers can be used to minimize exposure of the drugs to shear. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition, but typically include nonionic surfactants (Tween®, Pluronics®, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0112] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may include antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners.

[0113] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0114] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising the disclosed compounds and enteric coatings, and their pharmaceutically acceptable carriers or excipients. Enteric coatings refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, enteric-coated substances are not soluble up to pH levels of, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate acetate (PVAP), hydroxypropyl methylcellulose succinate acetate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate acetate, cellulose propionate phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionate acetate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal colloids, and several commercially available enteric-coated dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit Examples include L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be easily determined in vitro.The above is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not exhaustive and that there are other enteric-coated materials that serve the purposes of this disclosure.

[0115] This disclosure also provides, for example, kits for use by consumers requiring treatment of diseases or disorders described herein. Such kits include appropriate dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, alleviate, or prevent inflammation. The instructions will instruct consumers or healthcare professionals to administer the dosage forms according to dosage forms known to those skilled in the art. Such kits may be advantageously packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively rigid material covered with a foil, preferably made of clear plastic material. During the packaging method, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and the sheet of relatively rigid material is sealed against the plastic foil with the foil side opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the sheet has sufficient strength so that a tablet or capsule can be removed from the blister pack by manually applying pressure to the recess, thereby forming an opening in the sheet at the location of the recess. The tablet or capsule can then be removed through this opening.

[0116] For example, it may be desirable to provide a memory aid in the kit in the form of a number next to a tablet or capsule, where the number corresponds to the day of the regimen in which the designated tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, etc., Week 2, Monday, Tuesday, etc." Other variations of the memory aid will readily become apparent. The "daily dose" may be a single tablet or capsule or several pills or capsules taken on a given day. Also, the daily dose of a first compound may consist of one tablet or capsule, and the daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0117] Exemplary embodiments of the present invention

[0118] E1. Compound represented by formula I: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and A is selected from the group consisting of 8-10 member condensed bicyclic heteroaryls, 12-14 member condensed tricyclic heteroaryls, 8-10 member condensed bicyclic heterocyclils, and phenyl, and ring A is R A Optionally substituted with one or more substituents selected from, R AFor each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~7 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR a R b , optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or one R X and one R Y They bond together to form -CH2-, R 1 The group is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R bEach occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups may optionally be substituted with one or more halogens. A compound represented by formula I, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0119] E2. Compound, [ka] or [ka] The compound described in E1, represented by [the specified symbol].

[0120] E3.R 6 and R 7 A compound according to E1 or E2, wherein the compound is hydrogen.

[0121] E4.R 2 and R 3 A compound listed in any one of E1 to E3, wherein the hydrogen atom is hydrogen.

[0122] E5. Compound [ka] or [ka] A compound represented by one of the following: E1 to E4.

[0123] E6.A is [ka] and [ka] Selected from the group consisting of, in the formula, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d This is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, where -C1-C3 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, m is 0, 1, 2, or 3. A compound listed in any one of E1 to E5.

[0124] E7.R c However, selected from the group consisting of hydrogen and -CH3, R d However, it is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3, R e However, the compound is one of the compounds described in E1 to E6, selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

[0125] E8.R AHowever, for each occurrence, the compound is independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, wherein in the formula, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3, as described in any one of E1 to E5.

[0126] E9.R A However, for each occurrence, the compound is independently selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3, and is one of the compounds described in E1 to E5 and E7.

[0127] E10.A is [ka] [ka] and [ka] A compound selected from the group consisting of, one of E1 to E9.

[0128] E11.R 4 and R 5A compound according to any one of E1 to E10, wherein each of the elements is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

[0129] E12.R 4 A compound listed in any one of E1 to E11, wherein the hydrogen atom is hydrogen.

[0130] E13.R 5 The compound is one of the compounds described in E1 to E12, selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

[0131] E14.R 5 A compound according to any one of E1 to E13, wherein the compound is hydrogen or -CH3.

[0132] E15.R 1 However, hydrogen, -CH3, [ka] and [ka] A compound selected from the group consisting of, one of E1 to E14.

[0133] E16.R 1 A compound listed in any one of E1 to E15, wherein the hydrogen atom is hydrogen.

[0134] E17. Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, A is [ka] and [ka] Selected from the group consisting of, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d The substituent is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, and C1-C3 alkoxy, where the -C1-C3 alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. m is 0, 1, 2, or 3.

[0135] E18.R d This is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3. R e This is selected from the group consisting of hydrogen, fluoro, chloro, -CH3 and cyano. A compound listed in any one of E1 to E6.

[0136] E19.R 4 A compound of type E17 or E18 in which hydrogen is present.

[0137] E20.R 5 The compound is one of those described in E17 to E19, selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

[0138] E21.R 5 A compound according to any one of E17 to E20, wherein the compound is hydrogen or -CH3.

[0139] E22.R 1 A compound listed in any one of E17 to E21, wherein the hydrogen atom is hydrogen.

[0140] E23. [ka] [ka] [ka] [ka] [ka] [ka] and [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0141] E24. Compound represented by formula III: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and A is [ka] or [ka] And, R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or R X and R Y They bond together to form -CH2-, R W The molecule is selected from the group consisting of hydrogen, C1-C6 alkyl, and -SO2-phenyl, and the C1-C6 alkyl and phenyl molecules are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, C1-C3 alkyl, and C1-C3 alkoxy molecules. R AFor each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~7 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR a R b , optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy, R 1 The substituents are selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 member heteroaryl), and -CH2-(5-10 member heterocyclyl), and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 These are hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 5 These are halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R bSelected from the group consisting of -O-(CO)-C1~C6 alkyl, -CO2H, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may be substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxy compounds. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl groups are optionally substituted with one or more halogens. m is 0, 1, 2, or 3. A compound represented by formula III, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0142] E25. Compound [ka] or [ka] The compound described in E24, represented by [the specified symbol].

[0143] E26.R 6 and R 7 A compound of type E24 or E25 in which hydrogen is present.

[0144] E27. Compound, [ka] or [ka] A compound represented by one of the E24-E26 categories.

[0145] E28.R Y A compound according to any one of E24 to E27, wherein the compound is hydrogen or -CH3.

[0146] E29.R W However, the compound is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2, as described in any one of E24 to E28.

[0147] E30.R A However, for each appearance, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cy A compound independently selected from the group consisting of clobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxyranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, wherein tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3, as described in any one of E24 to E29.

[0148] E31.R AHowever, for each occurrence, the compound is one of those described in E24 to E30, independently selected from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH, and -OCH2CH3.

[0149] E32.R 2 A compound listed in any one of E24 to E31, wherein the hydrogen atom is hydrogen.

[0150] E33.R 3 A compound according to any one of E24 to E32, wherein is selected from the group consisting of hydrogen, -CH3, and -CH2OH.

[0151] E34.R 4 A compound listed in any one of E24 to E33, wherein the hydrogen atom is hydrogen.

[0152] E35.R 5 The compound is one of the compounds described in E24 to E34, selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl.

[0153] E36.R 1 However, hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, [ka] and [ka] A compound selected from the group consisting of any one of E24 to E35.

[0154] E37. Compounds represented by formulas IVA, IVA, or IVA: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein A is [ka] and [ka] Selected from the group consisting of, R W It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R Y is hydrogen or -CH3, R A For each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl. Here, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. R 1 These are hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, [ka] and [ka] Selected from the group consisting of, R 2 It is selected from the group consisting of hydrogen, -CH3, and -CH2OH. R 3 This is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl. m is 0, 1, 2, or 3. Compounds represented by formulas IVA, IVB, or IVC, or their pharmaceutically acceptable salts and / or stereoisomers.

[0155] E38. [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0156] E39. [ka] [ka] [ka] [ka] and [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0157] A pharmaceutical composition comprising one compound from E40.E1 to E39 and a pharmaceutically acceptable excipient.

[0158] E41. A method for treating a mental or neurological disorder or condition in a patient requiring the treatment thereof, comprising administering to the patient a therapeutically effective amount of one of the compounds E1 to E39.

[0159] E42. A method for treating a mental or neurological disorder or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising one compound from E1 to E39 and a pharmaceutically acceptable excipient.

[0160] E43. The method according to E41 or E42, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache. [Examples]

[0161] The compounds described herein can be prepared in numerous ways based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected to be standard conditions for the reaction unless otherwise indicated. Those skilled in the art of organic synthesis will understand that functional groups present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be obvious to those skilled in the art, and alternative methods will therefore be shown. The starting materials in the examples are commercially available or readily prepared from known materials by standard methods.

[0162] General information

[0163] Unless otherwise specified, reagents and solvents were obtained from commercial sources without further purification or prepared according to literature methods. 1 1H NMR and 13 13C NMR spectra were recorded at room temperature using a 300 or 400 MHz Bruker spectrometer with tetramethylsilane (TMS) as the internal standard and DMSO-d6, CDCl3, or CD3OD as the solvent. Chemical shifts were given in δ relative to TMS, and coupling constants J were given in Hz. LCMS analysis methods and apparatus were generated using one of the following methods. Detection was performed by UV (254 nm) and ELSD for all methods.

[0164] Method A (LCMS17, 41, 42, 50, 52)

[0165] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 4]

[0166] Method B (LCMS17, 41, 42, 47, 50, 52)

[0167] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 5]

[0168] Method C (LCMS25)

[0169] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO C18, particle size 2.6 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3 and solvent B: acetonitrile. [Table 6]

[0170] Method D (LCMS25)

[0171] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO C18, particle size 2.6 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3 and solvent B: acetonitrile. [Table 7]

[0172] Method E (LCMS40 )

[0173] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 8]

[0174] Method F (LCMS45)

[0175] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile. [Table 9]

[0176] Method G (LCMS45)

[0177] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile. [Table 10]

[0178] Method H (LCMS46, 48)

[0179] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 4.0 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 11]

[0180] Method I (LCMS46, 48)

[0181] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 4.0 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 12]

[0182] Method J (LCMS49)

[0183] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 2.0 mm Poroshell 120 EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 13]

[0184] Method K (LCMS49)

[0185] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 2.0 mm Poroshell 120 EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 14]

[0186] Method L (LCMS51, 53)

[0187] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO-C18, particle size 2.6 μm). Elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile / acetonitrile. [Table 15]

[0188] Method M (LCMS51, 53)

[0189] Experiments were performed using a SHIMADZU® 20A HPLC with a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVO-C18, particle size 2.6 μm). Elution was performed with solvent A: 5 mM water NH4HCO3; solvent B: acetonitrile / acetonitrile. [Table 16]

[0190] Method N (LCMS60)

[0191] Experiments were performed using a SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Agilent® EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 17]

[0192] Method O (LCMS61)

[0193] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (30 × 2.0 mm Gemini NX-C18, particle size 3.0 μm), and elution was performed with solvent A: (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 18]

[0194] Method P (LCMS63)

[0195] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, particle size 2.0 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 19]

[0196] Method Q (LCMS63)

[0197] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, particle size 2.0 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 20]

[0198] Example 1: Synthesis of 3-[(3R)-piperidine-3-yl]-2,1-benzoxazole and 3-[(3S)-piperidine-3-yl]-2,1-benzoxazole (compounds 109 and 110) [ka]

[0199] tert-butyl 3-{2-[(tert-butoxycarbonyl)amino]benzoyl}piperidine-1-carboxylate. To a solution of tert-butyl N-(2-bromophenyl)carbamate (8.00 g, 29.4 mmol) in THF (2 mL), CH3Li (1.29 g, 58.8 mmol, 1.6 M in Et2O) and n-BuLi (30 mL, 318 mmol, 2.5 M in n-hexane) were added dropwise at -78°C under an N2 atmosphere. After stirring the reaction mixture at -78°C for 30 minutes, a solution of tert-butyl 3-(2-methoxypropanoyl)piperidine-1-carboxylate (11.97 g, 44.1 mmol) in THF (2 mL) was added dropwise. 30 minutes after addition, the reaction mixture was quenched with NH4Cl (aqueous solution) and then extracted with ELISA (5 × 100 ml). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO₂) eluting with petroleum ether:ethyl acetate (9:1) to obtain the desired product as a yellow solid (1.30 g, yield 11%). LCMS 53 (Method M) (ESI)C 22 H 32 N2O5, calculated value 404.23; measured value [M+H] + :405.

[0200] 2-(piperidine-3-carbonyl)aniline. A solution of tert-butyl 3-{2-[(tert-butoxycarbonyl)amino]-benzoyl}piperidine-1-carboxylate (1.30 g, 3.21 mmol) in HCl / dioxane (2 mL) was stirred at room temperature for 12 hours, and then concentrated under reduced pressure to obtain the desired product as a yellow solid (600 mg, 91% yield). LCMS 47(ESI)C 12 H 16 N2O, calculated value 204.13; measured value [M+H] + 205. The product was used directly in the next step.

[0201] tert-butyl 3-(2-aminobenzoyl)piperidine-1-carboxylate. Di-tert-butyl dicarbonate (705 mg, 3.23 mmol) and trimethylamine (892 mg, 8.81 mmol) were added to a stirred solution of 2-(piperidine-3-carbonyl)aniline (600 mg, 2.93 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 0.5 hours and then concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with petroleum ether:ethyl acetate (3:1) to obtain the desired product as a yellow solid (600 mg, yield 67%). LCMS 50 (Method B) (ESI)C 17 H 24 N2O3, calculated value 304.18; measured value [M+H] + :305.

[0202] tert-butyl 3-(2,1-benzoxazole-3-yl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 3-(2-aminobenzoyl)piperidine-1-carboxylate (600 mg, 1.97 mmol) in acetonitrile (15 mL), iodosobenzene (2.60 g, 11.8 mmol) was added. The reaction mixture was stirred at 40°C for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with petroleum ether:ethyl acetate (3:1) to obtain the desired product as a yellow solid (300 mg, 50% yield). LCMS 47(ESI)C 17 H 22 N2O3, calculated value 302.16; measured value [M+H] + :303.

[0203] 3-(piperidine-3-yl)-2,1-benzoxazole. A solution of tert-butyl 3-(2,1-benzoxazole-3-yl)piperidine-1-carboxylate (300 mg, 0.99 mmol) in dichloromethane (2.5 mL) was mixed with trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 0.5 hours, then concentrated under reduced pressure. The residue was adjusted to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by chromatography (column, C18; mobile phase, water in acetonitrile (NH4HCO3 0.1%), gradient from 0% to 20% over 30 minutes; detector, UV 220 nm) to obtain the desired product as a yellow solid (100 mg, yield 50%). LCMS 40(ESI)C 12 H 14 N2O, calculated value 202.11; measured value [M+H] + :203.

[0204] 3-[(3R)-piperidine-3-yl]-2,1-benzoxazole and 3-[(3S)-piperidine-3-yl]-2,1-benzoxazole. 100 mg of 3-(piperidine-3-yl)-2,1-benzoxazole was separated by preparative chiral HPLC (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (10 mM NH3-MeOH), mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: isocratic 30; wavelength: 317 / 320 nm; RT1 (min): 9; RT2 (min): 13; sample solvent: methanol:dichloromethane = 4:1; sample concentration: mg / mL; injection volume: 0.2 mL; runs: 13) to obtain the following:

[0205] 3-[(3R)-piperidine-3-yl]-2,1-benzoxazole. Yellow solid (16.7 mg, yield 17%). LC-MS 63 (Method P) (ESI)C 12 H 14 N2O, calculated value 202.11; measured value [M+H] + :203.05. 1H NMR(300 MHz, DMSO-d6)δ 7.77(d,J=8.8 Hz,1H),7.53(d,J=8.9 Hz,1H),7.41-7.30(m,1H),6.99(t,J=7.5 Hz,1H),3.47(s,1H),3.19(d,J=11.9 Hz,1H),3.03-2.79(m,2H),2.60(d,J=10.8 Hz,1H),2.11(d,J=12.6 Hz,1H),1.96-1.80(m,J=12.4 Hz,1H),1.69(s,1H),1.54(d,J=12.8 Hz,1H).

[0206] 3-[(3S)-ピペリジン-3-イル]-2,1-ベンゾオキサゾール. White oil (18.1 mg, yield 18%). LCMS 51(Method L)(ESI)C 12 H 14 N2O, calculated value 202.11; measured value [M+H] + 202.95. 1 H NMR(400 MHz, DMSO-d6)δ 7.78-7.73(m,J=8.9,1.1 Hz,1H),7.55-7.50(m,J=9.1,1.0 Hz,1H),7.39-7.34(m,J=9.1,6.3,1.0 Hz,1H),7.03-6.98(m,J=8.8,6.3,0.7 Hz,1H),3.52-3.43(m,J=14.4,7.6,3.8 Hz,1H),3.17(dd,J=11.9,3.6 Hz,1H),2.95(dd,J=13.0,3.4 Hz,1H),2.83(dd,J=12.1,10.6 Hz,1H),2.58(dd,J=12.0,3.0 Hz,1H),2.15-2.07(m,J=10.9,3.8,1.9 Hz,1H),1.94-1.82(m,J=12.2,3.9 Hz,1H),1.74-1.67(m,J=13.2,3.4 Hz,1H),1.61-1.49(m,J=15.9,13.1,7.9,4.0 Hz,1H).

[0207] Example 2: Synthesis of 3-(1,2,5,6-Torotron-3-イル)-2,1-ベンゾオキサゾール (Compound 111)

change

[0208] 1-tert-butyl3-methyl5,6-dihydro-2H-pyridine-1,3-dicarboxylate. 1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridine-3-carboxylic acid (4.00 g, 17.60 mmol) was stirred in DCM (20 mL) and MeOH (20 mL). TMSCHN2 (17.6 mL, 35.20 mmol) was added dropwise at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours under an N2 atmosphere. The reaction was quenched with AcOH at room temperature, and the resulting mixture was concentrated under vacuum. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 60% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow liquid (3.60 g, yield 84.7%). LCMS 53 (Method L) (ESI)C 12 H 19 NO4, calculated value 241.13; measured value [M+H] + :242. 1 H NMR(400 MHz,DMSO-d6)δ 7.01(d,J=4.3,2.0 Hz,1H),4.00(d,J=2.6 Hz,2H),3.69(s,3H),3.39(d,J=5.7 Hz,2H),2.27(d,J=2.9 Hz,2H),1.41(s,9H).

[0209] tert-butyl 3-(hydroxymethyl)-5,6-dihydro-2H-pyridine-1,3-carboxylate. 1-tert-butyl 3-methyl 5,6-dihydro-2H-pyridine-1,3-dicarboxylate (3.60 g, 14.92 mmol) was stirred in toluene (40 mL) to which DIBAL-H (25.6 mL, 64.00 mmol, under an N2 atmosphere at 0°C) was added dropwise. The resulting mixture was stirred under an N2 atmosphere at room temperature for 30 minutes. The reaction was quenched with MeOH at 0°C. The resulting mixture was filtered, and the residue was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was filtered under the following conditions: column, C 18Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes; purified by reverse-phase flash chromatography using UV254nm to obtain the desired product as yellow oil (1.60 g, yield 50.2%). LCMS 53 (Method L) (ESI)C 11 H 19 NO3, calculated value 213.14; measured value [M+H] + :214. 1 H NMR(400 MHz,DMSO-d6)δ 5.69(s,1H),4.78(s,1H),3.81(d,J=23.0 Hz,4H),3.35(d,J=5.8 Hz,2H),2.10-1.95(m,2H),1.41(s,9H).

[0210] tert-butyl3-formyl-5,6-dihydro-2H-pyridine-1-carboxylate. A solution of tert-butyl3-(hydroxymethyl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.60 g, 7.50 mmol) and MnO2 (9.78 g, 112.60 mmol) in DCM (20 mL) was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with DCM (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (1.20 g, yield 75.9%). LCMS 48 (Method H) (ESI)C 11 H 17 NO3, calculated value 211.12; measured value [M+H] + :212. 1 H NMR(400 MHz,DMSO-d6)δ 9.43(d,J=1.2 Hz,1H),7.13(d,J=2.6 Hz,1H),4.00-3.89(m,2H),3.44(d,J=5.7 Hz,2H),2.41(d,J=2.9 Hz,2H),1.41(d,J=1.3 Hz,9H).

[0211] tert-butyl 3-[hydroxy(2-nitrophenyl)methyl]-5,6-dihydro-2H-pyridine-1-carboxylate. Phenylmagnesium bromide (514.9 mg, 2.83 mmol) was added dropwise to a stirred solution of 1-iodo-2-nitrobenzene (282.8 mg, 1.13 mmol) in tetrahydrofuran (6 mL) under an N2 atmosphere at -40°C, and the mixture was stirred for 5 minutes under an N2 atmosphere at -40°C. To the above mixture, tert-butyl 3-formyl-5,6-dihydro-2H-pyridine-1-carboxylate (200.0 mg, 0.94 mmol) was added dropwise at -40°C. The resulting mixture was stirred for a further 1 hour at -40°C. The reaction product was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with water (3 × 5 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA5:1) to obtain the desired product as yellow oil (150.0 mg, yield 47.3%). LCMS 52 (Method B) (ESI)C 17 H 22 N2O5, calculated value 334.15; measured value [M+H] + :335. 1 H NMR(400 MHz,CDCl3)δ 7.92(d,J=8.1 Hz,1H),7.86-7.81(m,1H),7.66(d,J=7.7 Hz,1H),7.46(d,J=7.8 Hz,1H),5.77(s,1H),5.73(s,1H),3.84(d,J=16.7 Hz,2H),3.42(d,J=5.8 Hz,2H),2.12(d,J=3.1 Hz,2H),1.43(s,9H).

[0212] tert-butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylate. MnO2 (390.3 mg, 4.48 mmol) was added to a stirred solution of tert-butyl 3-[hydroxy(2-nitrophenyl)methyl]-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.44 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The resulting mixture was filtered, the residue was washed with CH2Cl2 (3 × 4 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA5:1) to obtain the desired product as yellow oil (80.0 mg, yield 53.6%). LCMS 49 (Method J) (ESI)C 17 H 20 N2O5, calculated value 332.14; measured value [M+H] + :333. 1 H NMR(400 MHz,CDCl3)δ 8.18(d,J=1.1 Hz,1H),7.74(d,J=1.2 Hz,1H),7.67-7.59(m,1H),7.43(d,J=1.5 Hz,1H),6.35(d,J=2.1 Hz,1H),4.34(d,J=2.4 Hz,2H),3.52(d,J=5.7 Hz,2H),2.28(d,J=4.1 Hz,2H),1.51(s,9H).

[0213] tert-butyl 3-(2,1-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. A mixture of tert-butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylate (80.0 mg, 0.24 mmol) in MeOH (0.5 mL) and siRNA (0.5 mL) was stirred, and SnCl2.2H2O (163.0 mg, 0.72 mmol) was added. The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction product was quenched at room temperature with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with siRNA (3 × 10 mL). The combined organic extract was washed with water (3 × 4 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA5:1) to obtain the desired product as a white solid (30.0 mg, yield 41.5%). LCMS 54(ESI)C 17 H 20 N2O3, calculated value 300.15; measured value [M+H] + :301. 1 H NMR(400 MHz,CDCl3)δ 7.64(d,J=8.9 Hz,1H),7.56(d,J=9.1 Hz,1H),7.29(d,J=6.1 Hz,1H),7.00(d,J=7.6 Hz,1H),6.94-6.87(m,1H),4.56(s,2H),3.63(d,J=5.7 Hz,2H),2.48(s,2H),1.52(s,9H).

[0214] 3-(1,2,5,6-tetrahydropyridine-3-yl)-2,1-benzoxazole. HCl (gas) in 1,4-dioxane (1 mL, 4 M) was added to a stirred solution of tert-butyl 3-(2,1-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (45.0 mg, 0.15 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 10% to 50% over 20 minutes; detector: reverse-phase flash chromatography using UV254nm to purify the product, obtaining the desired product as a white solid (18.1 mg, yield 60.3%). LCMS 51(Method L)(ESI)C 12 H 12 N2O, calculated value 200.24; measured value [M+H] + :201.15. 1 H NMR(400 MHz,CDCl3)δ 7.61(d,J=1.1 Hz,1H),7.58-7.51(m,1H),7.33-7.27(m,1H),7.01-6.94(m,1H),6.88(d,J=1.9 Hz,1H),3.99(d,J=1.8 Hz,2H),3.09(d,J=5.7 Hz,2H),2.46-2.33(m,2H).

[0215] Example 3: Synthesis of 7-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-2,1-benzoxazole (compound 112) [ka]

[0216] tert-butyl 3-[(3-fluoro-2-nitrophenyl)(hydroxy)methyl]-5,6-dihydro-2H-pyridine-1-carboxylate. To a stirred solution of 1-fluoro-3-iodo-2-nitrobenzene (909.9 mg, 3.40 mmol) in THF (10 mL), phenylmagnesium chloride (4.2 mL, 2 M in THF) was added dropwise at -40°C, and the mixture was stirred at -40°C for 5 minutes under an N2 atmosphere. To the above mixture, tert-butyl 3-formyl-5,6-dihydro-2H-pyridine-1-carboxylate (600.0 mg, 2.84 mmol) was added dropwise at -40°C, and the resulting mixture was stirred further at -40°C for 1 hour under an N2 atmosphere. The reaction product was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic extracts (3 × 50 mL) were washed with water (3 × 10 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (300 mg, yield 29.9%). LCMS 54(ESI)C 17 H 21 FN2O5, calculated value 352.14; measured value [M+H] + :353. 1 H NMR(400 MHz,DMSO-d6)δ 7.77-7.64(m,1H),7.60-7.42(m,2H),6.15(d,J=4.8 Hz,1H),5.69(s,1H),5.28(s,1H),3.75(d,J=17.8 Hz,1H),3.60(s,1H),3.30(s,2H),2.12-1.95(m,2H),1.35(s,9H).

[0217] tert-butyl 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylate. MnO2 (715.5 mg, 8.23 ​​mmol) was added to a stirred solution of tert-butyl 3-[(3-fluoro-2-nitrophenyl)(hydroxy)methyl]-5,6-dihydro-2H-pyridine-1-carboxylate (290.0 mg, 0.82 mmol) in DCM (3 mL). The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with CH2Cl2 (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (200 mg, yield 69.3%). LCMS 50 (Method B) (ESI)C 17 H 19 FN2O5, calculated value 350.13; measured value [M+H] + :351. 1 H NMR(400 MHz,DMSO-d6)δ 7.92-7.72(m,2H),7.51(d,J=7.5 Hz,1H),6.75(d,J=1.8 Hz,1H),4.11(d,J=2.3 Hz,2H),3.43(d,J=5.7 Hz,2H),2.33(d,J=2.7 Hz,2H),1.43(s,9H).

[0218] tert-butyl 3-(7-fluoro-2,1-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. A mixture of tert-butyl 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylate (190.0 mg, 0.54 mmol) in MeOH (1 mL) and siRNA (1 mL) was stirred, to which SnCl2.2H2O (370.3 mg, 1.62 mmol) was added. The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction product was quenched at room temperature with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic extract was washed with water (3 × 5 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA5:1) to obtain the desired product as a white solid (110 mg, yield 63.7%). LCMS 50 (Method B) (ESI)C 17 H 19 FN2O3, calculated value 318.14; measured value [M+H] + :319. 1 H NMR(300 MHz,CDCl3)δ 7.47-7.39(m,1H),6.98-6.87(m,3H),4.56(s,2H),3.64(d,J=5.7 Hz,2H),2.49(s,2H),1.51(s,9H).

[0219] 7-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-2,1-benzoxazole. HCl (gas) in 1 mL of dioxane was added to a stirred solution of tert-butyl 3-(7-fluoro-2,1-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.31 mmol) in dioxane. The resulting mixture was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV254nm to purify the product, obtaining the desired product as a white solid (30.4 mg, yield 44.1%). LCMS 51(Method L)(ESI)C 12 H 11 FN2O, calculated value 218.09; measured value [M+H] + :219.15. 1 H NMR(300 MHz,DMSO-d6)δ 7.70(d,J=8.8 Hz,1H),7.25(d,J=7.3 Hz,1H),7.11-6.98(m,2H),3.80(s,2H),2.89(d,J=5.7 Hz,2H),2.33(s,2H).

[0220] Example 4: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile (compound 121) [ka]

[0221] 1-(2,2-diethoxyethoxy)-2-iodobenzene. 2-bromo-1,1-diethoxyethane (12.54 g, 63.63 mmol) was added to a stirred solution of 2-iodophenol (7.00 g, 31.81 mmol) and K2CO3 (13.19 g, 95.45 mmol) in DMF (70 mL) at room temperature, and the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ELISA (100 mL). The organic extract was washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (5.4 g, yield 50.4%). LCMS 49 (Method J) (ESI)C 12 H 17 IO3, calculated value 336.02; measured value [M+H] + :337.

[0222] 7-Iodo-1-benzofuran. A solution of 1-(2,2-diethoxyethoxy)-2-iodobenzene (5.40 g, 16.06 mmol) and PPA (3.70 g, 32.12 mmol) in toluene (50 mL) was stirred at 100°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with Depositphotos (500 mL). The organic extract was washed with water (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a white solid (3.5 g, yield 89.2%). LCMS 17 (Method B) (ESI) C₂H₅IO, calculated value 243.94; measured value [M+H] + :245.

[0223] 2,3-Dibromo-7-iodo-2,3-dihydro-1-benzofuran. A solution of 7-iodo-1-benzofuran (1.00 g, 4.09 mmol) and Br2 (0.65 g, 4.09 mmol) in CHCl3 (10 mL) was stirred at room temperature under an N2 atmosphere for 1 hour. The resulting mixture was extracted with siRNA (200 mL). The organic extract was washed with water (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (1 g, yield 60.4%).

[0224] 3-Bromo-7-iodo-1-benzofuran. A solution of 2,3-dibromo-7-iodo-2,3-dihydro-1-benzofuran (1.00 g, 2.47 mmol) and KOH (0.42 g, 7.42 mmol) in EtOH (10 mL) was stirred at 80°C for 1 hour under an N2 atmosphere and concentrated under vacuum. The resulting mixture was extracted with siRNA (200 mL). The organic extract was washed with water (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a white solid (600 mg, yield 75.0%). 1H NMR(300 MHz,CDCl3)δ 7.78-7.70(m,2H),7.57-7.47(m,1H),7.14-7.04(m,1H).

[0225] 3-Bromo-1-benzofuran-7-carbonitrile. 3-Bromo-7-iodo-1-benzofuran (400.0 mg, 1.23 mmol) and Zn(CN)2 (174.5 mg, 1.48 mmol) were stirred in DMF (6 mL). Pd(PPh3)4 (143.1 mg, 0.12 mmol, 0.1 equivalent) was added at room temperature under an N2 atmosphere. The resulting mixture was stirred at 110°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with RINKAN (150 mL). The organic extract was washed with water (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (140 mg, yield 51%). 1 H NMR(300 MHz,CDCl3)δ 7.84-7.78(m,2H),7.72-7.66(m,1H),7.47-7.39(m,1H).

[0226] To a stirred solution of tert-butyl 3-(7-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-1-benzofuran-7-carbonitride (130.0 mg, 0.58 mmol), Pd(dppf)Cl2 (42.8 mg, 0.05 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (217.2 mg, 0.70 mmol) in 1,4-dioxane (2 mL) and H2O (1 mL), K2CO3 (242.7 mg, 1.75 mmol) was added at room temperature. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with siRNA (50 mL). The organic extract was washed with water (3 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (65 mg, yield 34.2%). LCMS 52 (Method B) (ESI)C 19 H 20 N2O3, calculated value 324.15; measured value [M+H] + :325.

[0227] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitride. A solution of tert-butyl 3-(7-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (65.0 mg, 0.20 mmol) and HCl (gas) in 1,4-dioxane (2 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 9 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (0.1% FA), gradient from 0% to 40% over 20 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as yellow oil (18.7 mg, yield 41.6%). LCMS 46 (Method I) (ESI)C 14 H 12N2O, calculated value 224.09; measured value [M+H] + :225.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.36-8.18(m,3H),7.86-7.75(m,1H),7.51-7.36(m,1H),6.55-6.40(m,1H),3.72-3.69(m,2H),3.09-2.97(m,2H),2.40-2.29(m,2H).

[0228] Example 5: Synthesis of 4-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile (compound 122) [ka]

[0229] 4-Fluoro-1-benzofuran-7-carbonitrile. A solution of 7-bromo-4-fluoro-1-benzofuran (2.00 g, 9.30 mmol), zinc cyanide (1.09 g, 9.30 mmol), and Pd(PPh3)4 (1.07 g, 0.93 mmol) in DMF (20.0 mL) was stirred overnight at 100°C under an N2 atmosphere. The resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic extract was washed with water and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (1.00 g, yield 66.7%). LCMS 52 (Method A) (ESI) C9H4FNO, calculated value 161.03; measured value [M+H] + :162. 1 H NMR(400 MHz,CDCl3)δ 7.75(d,J=2.3 Hz,1H),7.64-7.59(m,1H),7.04(d,J=8.6 Hz,1H),6.99-6.95(m,1H).

[0230] 2,3-Dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-carbonitride. To a stirred solution of 4-fluoro-1-benzofuran-7-carbonitride (1.00 g, 6.21 mmol) in CH2Cl2 (10.0 mL), Br2 (0.1 mL, 18.62 mmol) was added dropwise at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours under an N2 atmosphere. The reaction product was quenched with Na2S2O3 (aqueous solution). The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (700.0 mg, yield 35.1%). 1 H NMR(400 MHz,CDCl3)δ 7.68-7.63(m,1H),7.00-6.89(m,2H),5.79-5.75(m,1H).

[0231] 3-Bromo-4-fluoro-1-benzofuran-7-carbonitrile. A solution of 2,3-dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-carbonitrile (700.0 mg, 2.18 mmol) in DCM (10.0 mL) was treated with DBU (498.1 mg, 3.27 mmol), and the resulting mixture was stirred at 50°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (6:1) to obtain the desired product as a yellow solid (300.0 mg, yield 57.3%). 1 H NMR(400 MHz,DMSO-d6)δ 8.55(s,1H),8.10-7.99(m,1H),7.46-7.38(m,1H).

[0232] 3-(7-cyano-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. A solution of 3-bromo-4-fluoro-1-benzofuran-7-carbonitrile (300.0 mg, 1.25 mmol), Pd(dppf)Cl2 (45.7 mg, 0.06 mmol), K2CO3 (518.2 mg, 3.75 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (579.7 mg, 1.88 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with Â(3 × 10 mL). The combined organic extracts were washed with water (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (400.0 mg, yield 46.7%). LCMS 52 (Method A) (ESI)C 19 H 19 FN2O3, calculated value 342.14; measured value [M+H] + :343. 1 H NMR(400 MHz,DMSO-d6)δ 8.43(s,1H),8.10-7.99(m,1H),7.46-7.38(m,1H),6.40-6.34(s,1H),4.24(d,J=3.2 Hz,2H),3.55(d,J=5.8 Hz,2H),2.34(d,J=2.8 Hz,2H),1.49(s,9H).

[0233] A solution of 4-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitride, tert-butyl 3-(7-cyano-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol) in dioxane (0.5 mL) and a solution of HCl (gas) in 1,4-dioxane (0.5 mL) were stirred at room temperature for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was purified by this method to obtain a white solid (63.3 mg, yield 89.5%). LCMS 51 (Method L) (ESI)C 14 H 11 FN2O, calculated value 242.09; measured value [M+H] + :242.95. 1 H NMR(400 MHz,DMSO-d6)δ 8.34(d,J=1.9 Hz,2H),8.02-7.95(m,1H),7.40-7.32(m,1H),6.34-6.29(m,1H),3.68-3.59(m,2H),3.00-2.92(m,2H),2.31-2.23(m,2H).

[0234] Example 6: Synthesis of 3-(6,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 126) [ka]

[0235] 2,3-Difluorophenyl acetate. Acetyl chloride (2.90 g, 36.90 mmol) was added dropwise at 0°C to a stirred solution of 2,3-difluorophenol (4 g, 30.75 mmol) and TEA (9.33 g, 92.24 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10 / 1) to obtain the desired product as a grayish-white liquid (3.4 g, yield 64.2%).

[0236] 1-(3,4-difluoro-2-hydroxyphenyl)ethanone. 2,3-difluorophenyl acetate (3.4 g, 19.75 mmol) was stirred in DCE (20 mL), to which AlCl3 (3.95 g, 29.63 mmol) was added in fractions at room temperature. The resulting mixture was stirred overnight at 90°C under an N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with RINKAN (3 × 100 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5 / 1) to obtain the desired product as a yellow solid (2.3 g, yield 67.6%). 1 H NMR(400 MHz,DMSO-d6)δ 11.37(s,1H),7.54(m,1H),6.87(m,1H),2.50(d,J=1.8 Hz,3H).

[0237] 2-Chloro-1-(3,4-difluoro-2-hydroxyphenyl)ethanone. 1-(3,4-difluoro-2-hydroxyphenyl)ethanone (1 g, 5.81 mmol) was stirred in DCE (7 mL) and MeOH (3 mL), to which BnMe3NCl2I (4.04 g, 11.62 mmol) was added in fractions at room temperature. The resulting mixture was stirred at 65°C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with ELISA (3 × 30 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow solid (1.1 g, yield 91.6%). 1 H NMR(400 MHz,DMSO-d6)δ 11.77(s,1H),7.67(m,1H),7.04(td,J=9.5,6.9 Hz,1H),5.10(s,2H).

[0238] 6,7-Difluoro-2H-1-benzofuran-3-one. AcONa (0.87 g, 10.65 mmol) was added in a stirred solution of 2-chloro-1-(3,4-difluoro-2-hydroxyphenyl)ethanone (1.1 g, 5.33 mmol) in MeOH (15 mL) at room temperature. The resulting mixture was stirred at 65 °C for 2 hours and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow solid (374 mg, yield 41.2%). 1 H NMR(400 MHz,DMSO-d6)δ 7.55(m,1H),7.30-7.19(m,1H),4.98(s,2H).

[0239] 6,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonate. 6,7-Difluoro-2H-1-benzofuran-3-one (370 mg, 2.18 mmol) and DIEA (843.3 mg, 6.53 mmol) were stirred in DCM (15 mL), to which Tf2O (920.5 mg, 3.26 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction product was quenched with water (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow solid (310 mg, yield 47.1%). 1 H NMR(300 MHz,DMSO-d6)δ 8.89(s,1H),7.57(d,J=4.6 Hz,1H),7.56-7.52(m,1H).

[0240] To a stirred solution of tert-butyl 3-(6,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 6,7-difluoro-1-benzofuran-3-yltrifluoromethanesulfonate (310 mg, 1.03 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (475.8 mg, 1.54 mmol) in dioxane (2 mL) and H2O (10 mL), Pd(dppf)Cl2 (150.1 mg, 0.21 mmol) and K2CO3 (425.4 mg, 3.08 mmol) were added at room temperature. The resulting mixture was stirred at 80°C for 30 minutes under an N2 atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a pale yellow oil (312 mg, yield 90.6%). LCMS 60(ESI)C 18 H 19 F2NO3, calculated value 335.13; measured value [M+H] + :336.

[0241] 3-(6,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. A stirred solution of tert-butyl 3-(6,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150 mg, 0.45 mmol, 1.0 equivalent) in DCM (2 mL) was mixed with TFA (2 mL) and stirred at room temperature for 20 minutes. The resulting mixture was concentrated under vacuum and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5%B to 5%B at 1 min, 5%B to 26%B at 2 min, 26% to 44%B at 10 min) to obtain the desired product as a white solid, 28.6 mg, with a yield of 27.1%. LCMS 40(ESI)C 13 H 11 F2NO, calculated value 235.08; measured value [M+H] + :236. 1 H NMR(400 MHz,DMSO-d6)δ 8.19(s,1H),7.69(m,1H),7.37(m,1H),6.43(d,J=5.2 Hz,1H),3.50(s,2H),2.85(s,2H),2.21(s,2H).

[0242] Example 7: Synthesis of 3-(5,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 127) [ka]

[0243] 3,5-Difluoro-2-[(trimethylsilyl)methoxy]benzaldehyde. A solution of 3,5-difluoro-2-hydroxybenzaldehyde (1.50 g, 9.48 mmol), (chloromethyl)trimethylsilane (1.28 g, 10.43 mmol), NaI (1.56 g, 10.43 mmol), and K2CO3 (3.93 g, 28.46 mmol) in DMF (20 mL) was stirred at 60°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with water and extracted with siRNA (3 × 10 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (1.00 g, yield 43.1%).

[0244] 5,7-Difluoro-2,3-Dihydro-1-benzofuran-3-ol. A solution of 3,5-difluoro-2-[(trimethylsilyl)methoxy]benzaldehyde (1.00 g, 4.09 mmol) and CsF (5.60 g, 36.83 mmol, 9.0 equivalents) in DMF (20 mL) was stirred overnight at 110 °C under an N2 atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with  (3 × 30 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a colorless oil (600.0 mg, yield 85.1%). 1 H NMR(400 MHz,CDCl3)δ 6.98-6.91(m,1H),6.88-6.78(m,1H),5.54-5.32(m,1H),4.72-4.60(m,1H),4.59-4.49(m,1H).

[0245] 5,7-Difluoro-2H-1-benzofuran-3-one. 5,7-Difluoro-2,3-dihydro-1-benzofuran-3-ol (800.0 mg, 4.64 mmol) was dissolved in 20 mL of DCM, to which Dess-Martin reagent (1971.2 mg, 4.64 mmol) was added in fractions at 0°C and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with siRNA (3 × 30 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (300.0 mg, yield 37.9%). 1 H NMR(400 MHz,DMSO-d6)δ 7.87-7.78(m,1H),7.42-7.37(m,1H),4.96(s,2H).

[0246] 5,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonate. 5,7-Difluoro-2H-1-benzofuran-3-one (300.0 mg, 1.76 mmol, 1.0 equivalent) was stirred in DCM (5 mL), to which DIEA (682.38 mg, 5.28 mmol) and Tf2O (746.3 mg, 2.64 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 1 hour and diluted with water (10 mL). The resulting mixture was extracted with Âx (3 × 10 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5:1) to obtain the desired product as a pale yellow oil (crude product 200.0 mg, yield 37.5%).

[0247] To a solution of tert-butyl 3-(5,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 5,7-difluoro-1-benzofuran-3-yltrifluoromethanesulfonate (210.0 mg, 0.69 mmol, 1.0 equivalent) and K2CO3 (288.1 mg, 2.08 mmol, 3.0 equivalents) in dioxane (3 mL) and H2O (0.6 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (322.3 mg, 1.04 mmol, 1.5 equivalents) and Pd(dppf)Cl2 (101.7 mg, 0.13 mmol, 0.2 equivalents) were added. This was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with ₹ (3 × 20 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (200.0 mg, yield 85.8%). LCMS 54(ESI)C 18 H 19 F2NO3, calculated value 335.13; measured value [M+H] + :336. 1 H NMR(400 MHz,DMSO-d6)δ 8.32(s,1H),7.67-7.52(m,1H),7.45-7.31(m,1H),6.55-6.38(m,1H), 4.28-4.11(m,2H),3.61-3.46(m,2H),2.36-2.24(m,2H),1.44(s,9H).

[0248] 3-(5,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(5,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol, 1.0 equivalent) in DCM (3 mL), TFA (3 mL) was added in fractions at room temperature. The mixture was basicized to pH 8 with Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 25 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (35.6 mg, yield 50.4%). LCMS 51(Method M)(ESI)C 13 H 11 F2NO, calculated value 235.08; [M+H] + :236.10. 1 H NMR(400 MHz,CD3OD)δ 7.89(s,1H),7.56-7.19(m,1H),7.12-6.71(m,1H),6.48-6.25(m,1H),3.72-3.49(m,2H),3.07-2.83(m,2H),2.42-2.24(m,2H).

[0249] Example 8: Synthesis of 3-(4,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 128) [ka]

[0250] 4,7-Difluoro-2,3-Dihydro-1-benzofuran-3-ol. To a solution of trimethylsulfoxonium iodide (5.35 g, 24.35 mmol) in DMSO (30 mL), NaOtBu (2.34 g, 24.35 mmol) was added, and the resulting mixture was stirred at 0°C for 0.5 hours. 3,6-Difluoro-2-hydroxybenzaldehyde (3.50 g, 22.13 mmol) was added to the reaction product, and the mixture was stirred at room temperature for a further 2 hours. The resulting mixture was filtered, and the residue was washed with ethyl acetate (2 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (1.50 g, yield 39.3%).

[0251] 4,7-Difluoro-2H-1-benzofuran-3-one. A solution of 4,7-difluoro-2,3-dihydro-1-benzofuran-3-ol (700.0 mg, 4.06 mmol) in dichloromethane (8 mL) was mixed with Dess-Martin reagent (1.72 g, 40.67 mmol) and stirred at room temperature for 0.5 hours. The resulting mixture was filtered, and the residue was washed with ethyl acetate (2 × 100 ml). The filtrate was concentrated under reduced pressure to obtain the desired crude product as dark yellow oil (250.0 mg, yield 36.1%). The crude product was used directly in the next step without further purification.

[0252] 4,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonate. DIEA (524.2 mg, 4.05 mmol) was added at room temperature to a solution of 4,7-difluoro-2H-1-benzofuran-3-one (230.0 mg, 1.35 mmol) in dichloromethane (3 mL). Tf2O (572.1 mg, 2.02 mmol, 1.5 equivalents) was added dropwise to the mixture at 0°C for 1 hour. The resulting mixture was filtered, and the residue was washed with ethyl acetate (5 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 100% PE to obtain the desired product as a yellow solid (200.0 mg, yield 48.9%).

[0253] To a solution of 4,7-difluoro-1-benzofuran-3-yltrifluoromethanesulfonate (350.0 mg, 1.15 mmol) and K2CO3 (320.1 mg, 2.31 mmol) in dioxane (4 mL) and H2O (1 mL), Pd(dppf)Cl2 (169.5 mg, 0.23 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (429.7 mg, 1.39 mmol) were added. The mixture was stirred at 90°C for 2 hours under an N2 atmosphere, and then the reaction was quenched with ice at room temperature. The resulting mixture was filtered, and the residue was washed with ethyl acetate (5 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow solid (150.0 mg, yield 38.6). LCMS 49 (Method J) (ESI)C 18 H 19 F2NO3, Calculated value: 335.13, Measured value [M+H] + :336.

[0254] 3-(4,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. A stirred solution of tert-butyl 3-(4,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.44 mmol) in dioxane (1 mL) was mixed with HCl (gas) in dioxane (1 mL). After stirring at room temperature for 2 hours, the mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The crude product (70.0 mg) was purified by Prep-HPLC under the following conditions: Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 42% B over 7 mins; Wavelength: 254 nm / 220 nm; RT1 (min): 7.18 to obtain the desired product as a white solid (51.8 mg, yield 49.2%). LCMS 51 (Method M) (ESI)C 13 H 11 F2NO, calculated value 235.08; measured value [M+H] + :236.10. 1 H NMR(400 MHz,DMSO-d6)δ 8.14(s,1H),7.33-7.26(m,J=9.5,3.6 Hz,1H),7.14-7.07(m,J=10.4,8.9,3.3 Hz,1H),6.28-6.23(m,J=4.2,2.1 Hz,1H),3.49(d,J=3.0 Hz,2H),2.83(t,J=5.6 Hz,2H),2.2-2.12(m,J=5.7,2.6 Hz,2H).

[0255] Example 9: Synthesis of 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 130) [ka]

[0256] A solution of 7-chloro-5-fluoro-2,3-dihydro-1-benzofuran-3-ol in DMSO (20.0 mL) was treated with t-BuONa (1.21 g, 12.60 mmol) at 0°C under an N2 atmosphere for 30 minutes. Subsequently, 3-chloro-5-fluoro-2-hydroxybenzaldehyde (2.00 g, 11.46 mmol) was added at room temperature under an N2 atmosphere, and the mixture was stirred for a further 2 hours. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (1.20 g, 55.5% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.35-7.26(m,1H),7.23-7.17(m,1H),5.86(d,J=5.9 Hz,1H),5.38-5.28(m,1H),4.68-4.59(m,1H),4.38-4.30(m,1H).

[0257] 7-Chloro-5-fluoro-2H-1-benzofuran-3-one. 7-Chloro-5-fluoro-2,3-dihydro-1-benzofuran-3-ol (500.0 mg, 2.65 mmol) was stirred in DCM (5.0 mL), to which Dess-Martin reagent (1124.6 mg, 2.65 mmol) was added in fractions at 0°C, and the mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with  (3 × 30 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (300.0 mg, yield 60.7%).

[0258] 7-Chloro-5-fluoro-1-benzofuran-3-yltrifluoromethanesulfonate. A solution of 7-chloro-5-fluoro-2H-1-benzofuran-3-one (300.0 mg, 1.61 mmol) in DCM (3.0 mL) was treated with DIEA (623.5 mg, 4.83 mmol), followed by dropwise addition of Tf2O (680.5 mg, 2.41 mmol) at 0°C. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with Âx (3 × 30 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (8:1) to obtain the desired product as a yellow solid (200.0 mg, yield 39.0%).

[0259] A solution of tert-butyl 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 7-chloro-5-fluoro-1-benzofuran-3-yltrifluoromethanesulfonate (200.0 mg, 0.63 mmol), Pd(dppf)Cl2 (25.8 mg, 0.03 mmol), K2CO3 (260.3 mg, 1.88 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (291.1 mg, 0.94 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with dimethylammonium phosphate (3 × 20 mL). The combined organic extract was washed with water (2 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow solid (100.0 mg, yield 45.3%). 1H NMR(400 MHz,DMSO-d6)δ 8.34(s,1H),7.78-7.73(m,1H),7.57-7.49(m,1H),6.51(d,J=20.0 Hz,1H),4.20-4.15(m,1H),3.85-3.80(m,1H),3.53-3.47(m,1H),3.39-3.34(m,1H),2.35-2.28(m,1H),2.16-2.09(m,1H),1.42(d,J=15.7 Hz,9H).

[0260] 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.28 mmol) in dioxane (0.5 mL), HCl (gas) (0.5 mL, 4 M in 1,4-dioxane) was added at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL), and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30%B to 50%B in 30 mins; Wavelength: 254 nm / 220 nm; RT1 (min): 7.19) to obtain the desired product as a yellow solid (27.8 mg, 38.9%). LCMS 48 (Method H) (ESI)C 13 H 11 ClFNO, calculated value 251.05; measured value [M+H] + :252.10. 1 H NMR(400 MHz,DMSO-d6)δ 8.22(s,1H),7.76-7.69(m,1H),7.53-7.46(m,1H),6.40(d,J=4.4 Hz,1H),3.52-3.46(m,2H),2.88-2.79(m,2H),2.23-2.15(m,2H).

[0261] Example 10: Synthesis of 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 131) [ka]

[0262] 1-Chloro-2-(2,2-diethoxyethoxy)-4-fluorobenzene. 2-Chloro-5-fluorophenol (1.00 g, 6.82 mmol) was stirred in DMF (10 mL) to which [bromo(ethoxy),methoxy]ethane (1.87 g, 10.23 mmol) and Cs2CO3 (6.69 g, 20.47 mmol) were added, and the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with Depositphotos (3 × 30 mL). The combined organic extract was washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white liquid (1.50 g, yield 83.6%). 1 H NMR(400 MHz,CDCl3)δ 7.32-7.27(m,1H),6.74-6.66(m,1H),6.66-6.58(m,1H),4.87(d,J=5.2 Hz,1H),4.03(d,J=5.2 Hz,2H),3.85-3.76(m,2H),3.72-3.65(m,2H),1.28-1.24(m,6H).

[0263] 7-Chloro-4-fluoro-1-benzofuran. 1.50 g, 5.71 mmol of 1-chloro-2-(2,2-diethoxyethoxy)-4-fluorobenzene (1.50 g, 5.71 mmol) in toluene (50 mL) was mixed with PPA (1.68 g, 17.13 mmol) and stirred overnight at 110 °C under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with Depositphotos (3 × 50 mL). The combined organic extracts were washed with water (5 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (12:1) to obtain the desired product as a white solid (150.0 mg, yield 15.4%). 1 H NMR(400 MHz,DMSO-d6)δ 8.20(d,J=2.2 Hz,1H),7.51-7.42(m,1H),7.21(d,J=2.3 Hz,1H),7.17(d,J=9.0 Hz,1H).

[0264] 2,3-Dibromo-7-chloro-4-fluoro-2,3-dihydro-1-benzofuran. To a stirred mixture of 7-chloro-4-fluoro-1-benzofuran (150.0 mg, 0.87 mmol) in DCM (5 mL), Br2 (168.6 mg, 1.05 mmol) was added dropwise, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction product was quenched with saturated Na2S2O3 (aqueous solution), and the resulting mixture was extracted with siRNA (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow oil (220.0 mg, yield 75.7%). 1 H NMR(400 MHz,CD3OD)δ 7.52-7.45(m,1H),7.29(s,1H),6.95(d,J=8.6 Hz,1H),6.13(s,1H).

[0265] 3-Bromo-7-chloro-4-fluoro-1-benzofuran. 2,3-dibromo-7-chloro-4-fluoro-2,3-dihydro-1-benzofuran (220.0 mg, 0.66 mmol) was stirred in DCM (5 mL) and DBU (304.1 mg, 1.99 mmol) was added. The resulting mixture was stirred at 50°C for 2 hours under an N2 atmosphere. The residue was purified by chromatography (SiO2) eluting with PE / EA (12:1) to obtain the desired product as a white solid (140.0 mg, yield 84.2%). 1 H NMR(400 MHz,DMSO-d6)δ 8.46(d,J=1.7 Hz,1H),7.67-7.44(m,1H),7.34-7.09(m,1H).

[0266] tert-butyl 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. 3-bromo-7-chloro-4-fluoro-1-benzofuran (140.0 mg, 0.56 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (260.3 mg, 0.84 mmol) were stirred in dioxane (4 mL) and H2O (2 mL). K2CO3 (232.7 mg, 1.68 mmol) and Pd(dppf)Cl2 (41.0 mg, 0.05 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ELISA (3 × 10 mL). The combined organic extracts were washed with water (3 × 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (12:1) to obtain the desired product as a white solid (100.0 mg, yield 50.6%). LCMS 54(ESI)C 18 H 19 ClFNO3, calculated value 351.10; measured value [M+H] + :352. 1H NMR(400 MHz,DMSO-d6)δ 8.27(s,1H),7.56-7.48(m,1H),7.25-7.13(m,1H),6.29(s,1H),4.18(d,J=3.1 Hz,2H),3.49(d,J=5.7 Hz,2H),2.27(d,J=5.5 Hz,2H),1.44(s,9H).

[0267] 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. 1,4-dioxane (1 mL, 4 M) and tert-butyl 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.28 mmol) in HCl (gas) in dioxane (1 mL) were stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 60% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (31.1 mg, yield 42.9%). LCMS 40(ESI)C 13 H 11 ClFNO, calculated value 251.05; measured value [M+H] + :252.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.18(s,1H),7.60-7.46(m,1H),7.24-7.07(m,1H),6.26(s,1H),3.51(s,2H),2.85(d,J=5.7 Hz,2H),2.27-2.15(m,2H).

[0268] Example 11: Synthesis of 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 134) [ka]

[0269] 2-Chloro-3,5-difluorophenol. 5.13 g of NCS (38.43 mmol) was added to a stirred solution of 3,5-difluorophenol (5.00 g, 38.43 mmol) in TFA (250 mL) and ACN (50 mL), and the mixture was stirred at room temperature under an N2 atmosphere for 3 days. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as yellow oil (2.00 g, yield 31.6%).

[0270] 2-Chloro-1-(2,2-diethoxyethoxy)-3,5-difluorobenzene. 2-Chloro-3,5-difluorophenol (1.70 g, 10.33 mmol) and 2-bromo-1,1-diethoxyethane (3.05 g, 15.49 mmol) were stirred in DMF (20 mL) and Cs2CO3 (10.10 g, 30.99 mmol) was added. The mixture was stirred overnight at 120°C under an N2 atmosphere. The resulting mixture was quenched with 10 mL of water and extracted with Depositphotos (3 × 10 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a colorless oil (1.80 g, yield 62.0%).

[0271] 7-Chloro-4,6-difluoro-1-benzofuran. 2-Chloro-1-(2,2-diethoxyethoxy)-3,5-difluorobenzene (2.00 g, 7.12 mmol) was stirred in toluene (30 mL) and PPA (2.46 g, 21.37 mmol) was added. The mixture was stirred overnight at 110°C under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with 30 mL of water and extracted with RINKAN (3 × 30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by PE elution chromatography (SiO₂) to obtain the desired product as a white solid (450.0 mg, yield 33.4%). 1H NMR(300 MHz,DMSO-d6)δ 8.23(d,J=2.3 Hz,1H),7.49(dd,J=10.4,9.6 Hz,1H),7.23(d,J=2.2 Hz,1H).

[0272] 2,3-Dibromo-7-chloro-4,6-difluoro-2,3-dihydro-1-benzofuran. To a stirred solution of 7-chloro-4,6-difluoro-1-benzofuran (430.0 mg, 2.28 mmol) in DCM (5 mL), Br2 (0.21 mL, 4.19 mmol, 1.8 equivalents) was added. The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was diluted with 50 mL of CH2Cl2, washed with Na2CO3 (aqueous solution) (3 × 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow oil (600.0 mg, yield 75.5%). 1 H NMR(400 MHz,DMSO-d6)δ 8.14(d,J=2.1 Hz,1H),7.46-7.33(m,1H),7.14(d,J=2.1 Hz,1H).

[0273] 3-Bromo-7-chloro-4,6-difluoro-1-benzofuran. 2,3-dibromo-7-chloro-4,6-difluoro-2,3-dihydro-1-benzofuran (400.0 mg, 1.14 mmol) was stirred in DCM (5 mL), to which DBU (524.4 mg, 3.44 mmol) was added, and the mixture was stirred at 50°C for 1 hour under an N2 atmosphere. After concentration, the residue was purified by PE elution chromatography (SiO2) to obtain the desired product as a white solid (250.0 mg, yield 81.4%). 1 H NMR(400 MHz,CDCl3)δ 7.67(s,1H),6.96-6.85(m,1H).

[0274] A mixture of tert-butyl 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-7-chloro-4,6-difluoro-1-benzofuran (130.0 mg, 0.48 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (225.4 mg, 0.72 mmol), K2CO3 (201.5 mg, 1.45 mmol), and Pd(dppf)Cl2 (17.7 mg, 0.02 mmol) in dioxane (2 mL) and H2O (1 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with ₹ (3 × 5 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (100.0 mg, yield 55.6%). LCMS 60(ESI)C 18 H 18 ClF2NO3, calculated value 369.09; measured value [M+H] + :370. 1 H NMR(400 MHz,CDCl3)δ 7.61(s,1H),6.92-6.84(m,1H),6.29(s,1H),4.23-4.17(m,2H),3.63-3.50(m,2H),2.36-2.29(m,2H),1.50(s,9H).

[0275] 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. A solution of tert-butyl 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 0.27 mmol) in dioxane (2 mL) was stirred, to which HCl (gas) in 1,4-dioxane (2 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60% B to 87% B in 7 mins; wavelength: 254 nm / 220 nm; RT1 (min): 6.8) to obtain the desired product as a white solid (13.9 mg, yield 19.0%). LCMS 63(ESI)C 13 H 10 ClF2NO, calculated value 269.04; measured value [M+H] + :269.95. 1 H NMR(300 MHz,CD3OD)δ 7.88(s,1H),7.18-7.01(m,1H),6.30(s,1H),3.68-3.52(m,2H),3.08-2.93(m,2H),2.43-2.23(m,2H).

[0276] Example 12: Synthesis of 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 135) [ka]

[0277] 2,5-Dichloro-4-fluorophenol. 3-Chloro-4-fluorophenol (6.00 g, 41.09 mmol, 1.0 equivalent) and NCS (5.48 g, 41.09 mmol) were stirred in ACN (60 mL), to which TFA (300 mL) was added at room temperature under an N2 atmosphere. The reaction mixture was stirred for 2 hours. The resulting mixture was concentrated under vacuum to obtain the desired crude product as yellow oil (3.00 g, yield 67.6%). LCMS 50 (Method B) (ESI) C6H3Cl2FO, calculated value 179.95; measured value [M+H] + :181.

[0278] 1,4-Dichloro-2-(2,2-diethoxyethoxy)-5-fluorobenzene. 2,5-Dichloro-4-fluorophenol (3.00 g, 11.05 mmol) and 2-bromo-1,1-diethoxyethane (3.27 g, 16.57 mmol) were stirred in DMF (50 mL) and Cs2CO3 (10.80 g, 33.15 mmol) was added. The mixture was stirred overnight at 120°C under an N2 atmosphere. The resulting mixture was diluted with H2O (50 mL) and extracted with Depositphotos (3 × 50 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12:1) to obtain the desired product as a white liquid (3.00 g, yield 60.7%). LCMS 51 (Method L) (ESI)C 12 H 15 Cl2FO3, calculated value 296.04; measured value [M+H] + :297. 1 H NMR(400 MHz,CDCl3)δ 7.19(d,J=8.3 Hz,1H),7.00(d,J=6.6 Hz,1H),4.84(d,J=5.2 Hz,1H),4.01(d,J=5.2 Hz,2H),3.86-3.73(m,2H),3.71-3.62(m,2H),1.25(d,7.1Hz,6H).

[0279] 4,7-Dichloro-5-fluoro-1-benzofuran. Toluene (30 mL) containing 1,4-dichloro-2-(2,2-diethoxyethoxy)-5-fluorobenzene (3.00 g, 10.13 mmol) and PPA (1.16 g, 10.13 mmol) was stirred at 110°C for 1 hour under an N2 atmosphere and concentrated under high pressure. The residue was diluted with H2O (50 mL) and extracted with ELISA (3 × 30 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12:1) to obtain the desired product as a white solid (600.0 mg, yield 29.1%). 1 H NMR(400 MHz,CDCl3)δ 7.75(d,J=2.2 Hz,1H),7.18(d,J=9.1 Hz,1H),6.93(d,J=2.1 Hz,1H).

[0280] 2,3-Dibromo-4,7-Dichloro-5-Fluoro-2,3-Dihydro-1-Benzofuran. To a stirred solution of 4,7-dichloro-5-fluoro-1-benzofuran (600.0 mg, 2.92 mmol) in DCM (10 mL), Br2 (0.18 mL, 3.51 mmol) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction product was quenched with saturated Na2SO3 (aqueous solution) and extracted with CH2Cl2 (3 × 15 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow oil (750.0 mg, yield 70.2%). 1 H NMR(400 MHz,CDCl3)δ 7.24(d,J=8.6 Hz,1H),6.93(s,1H),5.71(s,1H).

[0281] 3-Bromo-4,7-dichloro-5-fluoro-1-benzofuran. 2,3-dibromo-4,7-dichloro-5-fluoro-2,3-dihydro-1-benzofuran (750.0 mg, 2.07 mmol) was stirred in DCM (10 mL), to which DBU (946.7 mg, 6.21 mmol) was added, and the mixture was stirred at 50°C for 1 hour under an N2 atmosphere. The mixture was purified by chromatography (SiO2) eluting with PE / EA (12:1) to obtain the desired product as a white solid (530.0 mg, yield 90.5%). 1 H NMR(400 MHz,DMSO-d6)δ 8.64-8.43(m,1H),7.93-7.69(m,1H).

[0282] A mixture of tert-butyl 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-4,7-dichloro-5-fluoro-1-benzofuran (300.0 mg, 1.05 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (490.1 mg, 1.58 mmol), K2CO3 (438.1 mg, 3.15 mmol), and Pd(dppf)Cl2 (77.3 mg, 0.10 mmol) in dioxane (4 mL) and H2O (2 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with ₹ (3 × 5 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (9:1) to obtain the desired product as a white solid (250.0 mg, yield 61.2%). LCMS 49 (Method K) (ESI)C 18 H 18 Cl2FNO3, calculated value 385.06; measured value [M+H] + :386. 1H NMR(300 MHz,DMSO-d6)δ 8.26(s,1H),7.78(d,J=9.6 Hz,1H),6.04-5.92(m,1H),4.12(s,2H),3.51(d,J=5.7 Hz,2H),2.31-2.14(m,2H),1.42(s,9H).

[0283] 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. A stirred solution of tert-butyl 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.38 mmol) in dioxane (1 mL) was mixed with HCl (gas) (1 mL, 4 M in 1,4-dioxane) under an N2 atmosphere and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL), and then basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was then processed as follows: column, C 18 The silica gel was used as the mobile phase, an aqueous MeCN solution (10 mmol / L NH4HCO3), and the mixture was purified by reverse-phase flash chromatography under conditions of 0% to 70% gradient over 30 minutes and UV 254 nm to obtain the desired product as a white solid (59.1 mg, yield 52.8%). LCMS 48 (Method H) (ESI)C 13 H 10 Cl2FNO, calculated value 285.01; measured value [M+H] + :286. 1 H NMR(300 MHz,DMSO-d6)δ 8.17(d,J=1.8 Hz,1H),7.81-7.64(m,1H),5.92(d,J=4.7 Hz,1H),3.43(s,2H),2.97-2.81(m,2H),2.22-2.06(m,2H).

[0284] Example 13: Synthesis of 4-ethoxy-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile (compound 140) [ka]

[0285] 4-Fluoro-1-benzofuran-7-carbonitrile. Pd(PPh3)4 (2.15 g, 1.86 mmol) was added to a stirred solution of 7-bromo-4-fluoro-1-benzofuran (4.00 g, 18.60 mmol) and zinc cyanide (2.18 g, 18.60 mmol) in DMA (40 mL). The resulting mixture was stirred overnight at 100 °C under an N2 atmosphere. The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic extract was washed with water (3 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (2.00 g, yield 66.7%). LCMS 52 (Method B) (ESI) C9H4FNO, calculated value 161.03; measured value [M+H] + :162. 1 H NMR(400 MHz,DMSO-d6)δ 8.30(d,J=2.0 Hz,1H),7.96(d,J=8.2,5.0,2.5 Hz,1H),7.38-7.32(m,1H),7.30(d,J=2.4 Hz,1H).

[0286] 2,3-Dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-carbonitrile. Br2 (0.95 mL, 18.61 mmol) was added to a stirred solution of 4-fluoro-1-benzofuran-7-carbonitrile (2.50 g, 15.51 mmol) in DCM (25 mL). The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction product was quenched at room temperature with saturated Na2SO3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 30 mL). The combined organic extracts were washed with water (3 × 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 20 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (3.00 g, yield 60.2%). LCMS 46 (Method I) (ESI) C9H4Br2FNO, calculated value 318.86; measured value [M+H] + :320. 1 H NMR(400 MHz,CDCl3)δ 7.66(d,J=8.8,5.0 Hz,1H),7.00-6.91(m,2H),5.76(s,1H).

[0287] 3-Bromo-4-ethoxy-1-benzofuran-7-carbonitrile. A solution of 2,3-dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-carbonitrile (1.00 g, 3.11 mmol) and KOH (349.7 mg, 6.23 mmol) in EtOH (10 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with  (3 × 3 mL). The combined organic extract was washed with water (3 × 3 mL) and dried on anhydrous Na₂SO₄. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a white solid (550.0 mg, yield 66.3%). LCMS 46 (Method I) (ESI)C 11 H8BrNO2, calculated value 264.97; measured value [M+H] + :266. 1 H NMR(400 MHz,CDCl3)δ 7.56(s,1H),7.50(d,J=8.5 Hz,1H),6.64(d,J=8.5 Hz,1H),4.16(d,J=7.0 Hz,2H),1.47(d,J=7.0 Hz,3H).

[0288] To a stirred solution of tert-butyl 3-(7-cyano-4-ethoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate and 3-bromo-4-ethoxy-1-benzofuran-7-carbonitride (550.0 mg, 2.06 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (958.6 mg, 3.10 mmol) in H2O (5 mL) and dioxane (10 mL), Pd(dppf)Cl2 (75.6 mg, 0.13 mmol) and K2CO3 (856.9 mg, 6.20 mmol) were added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 15 mL). The combined organic extract was washed with water (3 × 10 mL) and dried on anhydrous sodium ₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (4:1) to obtain the desired product as a white solid (650.0 mg, yield 85.3%). LCMS 47(ESI)C 21 H 24 N2O4, calculated value 368.17; measured value [M+H] + :369. 1 H NMR(400 MHz,CDCl3)δ 7.57-7.50(m,2H),6.69(d,J=8.5 Hz,1H),6.10(d,J=4.1,2.0 Hz,1H),4.28-4.09(m,4H),3.57(d,J=5.8 Hz,2H),2.33-2.23(m,2H),1.50(d,J=7.0 Hz,3H),1.49(s,9H).

[0289] 4-Ethoxy-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile. HCl (gas) in 1,4-dioxane (3 mL) was added to a stirred solution of tert-butyl 3-(7-cyano-4-ethoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.27 mmol) in dioxane (3 mL). The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The resulting mixture was concentrated under vacuum, and the residue was dissolved in MeOH (0.5 mL). This was then basicized to pH 10 with saturated Na2CO3 (aqueous solution). The mixture was analyzed under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 70% over 20 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (34.5 mg, yield 47.3%). LCMS 51(Method L)(ESI)C 16 H 16 N2O2, calculated value 268.12; measured value [M+H] + :269.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.03(s,1H),7.80(d,J=8.5 Hz,1H),6.97(d,J=8.6 Hz,1H),6.17(d,J=3.9,1.7 Hz,1H),4.25(d,J=6.9 Hz,2H),3.55(d,J=2.3 Hz,2H),2.88(d,J=5.8 Hz,2H),2.16(d,J=5.4,2.6 Hz,2H),1.42(d,J=6.9 Hz,3H).

[0290] Example 14: Synthesis of 4-hydroxy-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile (compound 141) [ka]

[0291] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate. KOH (0.35 g, 6.23 mmol) was added to a stirred solution of 2,3-dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-carbonitride (1.00 g, 3.11 mmol) in MeOH (15 mL). The resulting mixture was stirred at 80°C for 6 hours under an N2 atmosphere. The resulting mixture was extracted with  (3 × 20 mL). The combined organic extracts were washed with water (3 × 20 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (550.0 mg, yield 70.0%). LCMS 54(ESI)C 10 H6BrNO2, calculated value 250.96; measured value [M+H] + :252. 1 H NMR(400 MHz,CDCl3)δ 7.64(s,1H),7.59(d,J=8.5 Hz,1H),6.75(d,J=8.5 Hz,1H),4.01(s,3H).

[0292] To a stirred solution of tert-butyl 3-(7-cyano-4-methoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-4-methoxy-1-benzofuran-7-carbonitrile (300.0 mg, 1.19 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (552.0 mg, 1.78 mmol) in H2O (3 mL) and dioxane (6 mL), K2CO3 (493.4 mg, 3.57 mmol) and Pd(dppf)Cl2 (43.5 mg, 0.05 mmol) were added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 50 mL). The combined organic extract was washed with water (3 × 50 mL) and dried on anhydrous sodium ₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (380.0 mg, yield 90.0%). LCMS 53 (Method L) (ESI)C 20 H 22 N2O4, calculated value 354.16; measured value [M+H] + :355. 1 H NMR(400 MHz,CDCl3)δ 7.58(d,J=8.4 Hz,1H),7.55(s,1H),6.73(d,J=8.5 Hz,1H),6.06(d,J=4.1,2.0 Hz,1H),4.00(s,3H),3.58(d,J=5.8 Hz,2H),2.30(d,J=5.7,2.8 Hz,2H),2.05(s,2H),1.50(s,9H).

[0293] 4-Hydroxy-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-7-carbonitrile. 200.0 mg, 0.56 mmol of tert-butyl 3-(7-cyano-4-methoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (200.0 mg, 0.56 mmol) was stirred in 1 mL of DCM, to which BBr3 (2 mL) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 48 hours. The reaction product was quenched with MeOH at 0°C. The mixture was basicized to pH 10 with saturated Na2CO3 (aqueous solution) and concentrated under vacuum. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 60% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (37.5 mg, yield 27.6%). LCMS 63(Method Q)(ESI)C 14 H 12 N2O2, calculated value 240.09; measured value [M+H] + :241.10. 1 H NMR(400 MHz,DMSO-d6)δ 7.80(s,1H),7.36(d,J=8.5 Hz,1H),6.48-6.34(m,2H),3.93(s,2H),3.03(d,J=5.9 Hz,2H),2.28(s,2H).

[0294] Example 15: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-6-carbonitrile (compound 143) [ka]

[0295] 1-Benzofran-6-carbonitrile. Pd(PPh3)4 was added to a stirred mixture of 6-bromo-1-benzofuran (2.00 g, 10.15 mmol) and Zn(CN)2 (11.92 g, 101.51 mmol) in DMA (30 mL). The resulting mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic extract was washed with water (3 × 50 mL) and dried on anhydrous Na2SO4. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white semi-solid (1.03 g, yield 68.8%). 1 H NMR(400 MHz,CDCl3)δ 7.85-7.77(m,2H),7.71-7.66(m,1H),7.54-7.48(m,1H),6.90-6.84(m,1H).

[0296] 2,3-Dibromo-2,3-dihydro-1-benzofuran-6-carbonitrile. Br2 (0.5 mL, 8.63 mmol) was added to a stirred mixture of 1-benzofuran-6-carbonitrile (1.03 g, 7.19 mmol) in DCM (10 mL) at room temperature under an N2 atmosphere. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1.5 hours. The reaction product was quenched with saturated Na2SO3 (aqueous solution) at room temperature. The resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic extract was washed with water (3 × 20 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired crude product as yellow oil (1.90 g, yield 87.9%). The crude product was used directly in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ 7.62(d,J=7.8 Hz,1H),7.50-7.43(m,1H),7.36-7.31(m,1H),6.91(s,1H),5.72(s,1H).

[0297] 3-Bromo-1-benzofuran-6-carbonitride. A mixture of 2,3-dibromo-2,3-dihydro-1-benzofuran-6-carbonitride (1.90 g, 6.27 mmol) and DBU (2.86 g, 18.81 mmol) in DCM (20 mL) was stirred at 50°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with Â150 mL (3 × 50 mL). The combined organic extract was washed with water (3 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 The silica gel was used as the mobile phase, and an aqueous MeCN solution (10 mmol / L NH4HCO3) was used as the mobile phase. The mixture was purified by reverse-phase flash chromatography using UV254nm with a gradient from 0% to 60% over 30 minutes to obtain the desired product as a white semi-solid (800.0 mg, yield 57.4%). 1 H NMR(300 MHz,DMSO-d6)δ 8.60(s,1H),8.37(d,J=1.1 Hz,1H),7.83-7.72(m,2H).

[0298] To a mixture of tert-butyl 3-(6-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-1-benzofuran-6-carbonitrile (800.0 mg, 3.15 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.46 g, 4.72 mmol) stirred in dioxane (20 mL) and H2O (10 mL), K2CO3 (1.31 g, 9.45 mmol) and Pd(dppf)Cl2 (230.6 mg, 0.31 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic extracts were washed with water (3 × 50 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (12:1) to obtain the desired product as a white solid (300.0 mg, yield 25.5%). 1H NMR(300 MHz,CDCl3)δ 7.90(d,J=8.2 Hz,1H),7.86-7.82(m,1H),7.79(s,1H),7.60-7.54(m,1H),6.44-6.39(m,1H),4.25(d,J=2.4 Hz,2H),3.63(d,J=5.7 Hz,2H),2.41(d,J=3.9 Hz,2H),1.53(s,9H).

[0299] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-6-carbonitride. To a stirred mixture of tert-butyl 3-(6-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150 mg, 0.46 mmol) in dioxane (1 mL), HCl (gas) in 1,4-dioxane (1 mL) was added. The resulting mixture was stirred under an N2 atmosphere at room temperature for 1 hour and concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD Column 30*150mm, 5m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18%B to 37%B in 7 mins; wavelength: 254 nm / 220 nm; RT1 (min): 7.07) to obtain the desired product as a white solid (66.6 mg, yield 63.7%). LCMS 40(ESI)C 14 H 12 N2O, calculated value 224.09; measured value [M+H] + :225.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.31(s,1H),8.24(s,1H),8.07(d,J=8.2 Hz,1H),7.70(d,J=8.2 Hz,1H),6.45(d,J=4.6 Hz,1H),3.52(s,2H),2.85(d,J=5.7 Hz,2H),2.20(d,J=5.9 Hz,2H).

[0300] Example 16: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-5-carbonitrile (compound 144) [ka]

[0301] 2,3-Dibromo-2,3-Dihydro-1-Benzofuran-5-Carbonitrile. A mixture of 1-benzofuran-5-carbonitride (200.0 mg, 1.397 mmol) in DCM (2 mL) was stirred, to which Br2 (0.09 mL, 1.676 mmol) was added in fractions. The mixture was stirred at room temperature under an N2 atmosphere for 1.5 hours. The reaction product was quenched at room temperature with saturated Na2SO3 (aqueous solution). The resulting mixture was extracted with Âr (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired crude product as a white oil (250.0 mg, yield 59.0%). The crude product was used directly in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ 7.82(d,J=1.7 Hz,1H),7.71-7.67(m,1H),7.19-7.14(m,1H),6.92(s,1H),5.72(s,1H).

[0302] 3-Bromo-1-benzofuran-5-carbonitride. A mixture of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbonitride (250 mg, 0.825 mmol) and DBU (376.8 mg, 2.475 mmol) in DCM (5 mL) was stirred at 50°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (150.0 mg, yield 81.8%). 1 H NMR(400 MHz,CDCl3)δ 7.94-7.90(m,1H),7.78(s,1H),7.68-7.63(m,1H),7.62-7.58(m,1H).

[0303] tert-butyl 3-(5-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. 3-bromo-1-benzofuran-5-carbonitride (140.0 mg, 0.631 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (292.4 mg, 0.947 mmol) were stirred in dioxane (2 mL) and H2O (2 mL). K2CO3 (261.4 mg, 1.893 mmol) and Pd(dppf)Cl2 (23.1 mg, 0.032 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with  (3 × 10 mL). The combined organic extracts were washed with water (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow solid (180.0 mg, yield 88.0%). LCMS 54(ESI)C 19 H 20 N2O3, calculated value 324.15; measured value [M+H] + :325. 1 H NMR(400 MHz,CDCl3)δ 8.14(d,J=1.1 Hz,1H),7.71(s,1H),7.62-7.56(m,2H),6.42-6.37(m,1H),4.22(s,2H),3.61(d,J=5.7 Hz,2H),2.40(d,J=7.0 Hz,2H),1.51(s,9H).

[0304] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzofuran-5-carbonitrile. HCl (gas) in 1 mL of 1,4-dioxane was added to a stirred mixture of tert-butyl 3-(5-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (180.0 mg, 0.555 mmol, 1.0 equivalent) in 2 mL of dioxane at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was basicized to pH 7 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD Column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18%B to 37%B in 7 mins; wavelength: 254 nm / 220 nm; RT1 (min): 7.07) to obtain the desired product as a white solid (30.8 mg, yield 34.6%). LCMS 63 (Method P) (ESI)C 14 H 12 N2O, calculated value 224.09; measured value [M+H] + :225.10 1 H NMR(400 MHz,DMSO-d6)δ 8.46(d,J=1.4 Hz,1H),8.23(s,1H),7.86-7.75(m,2H),6.56-6.48(m,1H),3.51(d,J=2.3 Hz,2H),2.85(d,J=5.7 Hz,2H),2.25-2.21(m,2H).

[0305] Example 17: Synthesis of tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (compound 146) [ka]

[0306] tert-butyl(E)-3-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate. Under an N2 atmosphere, a stirred solution of NaH (2.41 g, 100.37 mmol) in THF (20 mL) was treated with triethyl phosphonoacetate (11.25 g, 50.19 mmol) at 0°C for 30 minutes. Then, while maintaining the temperature at 0°C, tert-butyl 3-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol) was added dropwise. The final reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 16% ethyl in petroleum ether to obtain the desired product as yellow oil (3.00 g, yield 44%, (E):(Z)=9:5). LCMS(ESI)C 14 H 23 NO4, calculated value 269.16; measured value [M+H] + :270.(E) 1 H NMR(400 MHz,CDCl3)δ 5.74(s,1H),4.19-4.11(m,2H),4.00-3.90(m,2H),3.54-3.44(m,2H),3.00-2.87(m,2H),1.76-1.66(m,2H),1.46(s,9H),1.28(t,J=7.1 Hz,3H).LCMS 50(Method B)(ESI)C 14 H 23 NO4, calculated value 269.16; measured value [M+H] + :270(Z) 1 H NMR(400 MHz,CDCl3)δ 5.70-5.64(m,1H),4.62(d,J=1.3 Hz,2H),4.22-4.13(m,2H),3.49(t,J=5.9 Hz,2H),2.38-2.30(m,2H),1.77-1.67(m,2H),1.45(s,9H),1.28(d,J=7.1 Hz,3H).

[0307] Isopropyl(3Z)-3-(2-hydroxyethylidene)piperidine-1-carboxylate. To a stirred solution of tert-butyl(3Z)-3-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (2.70 g, 10.02 mmol) in ether (10.0 mL), DIBAL-H (13.4 mL, 20.06 mmol, 1.5 M in toluene) was added dropwise at -78°C under an N2 atmosphere. The final reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding ice water. The reaction mixture was extracted with dichloromethane (3 × 50 mL), the combined organic extract was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with dichloromethane containing 50% MeOH to obtain the desired product as a yellow liquid (1.70 g, 80% yield). LCMS 54(ESI)C 12 H 21 NO3, calculated value 227.15; measured value [M+H] + :228. 1 H NMR(400 MHz,CDCl3)δ 5.55(s,1H),4.17(d,J=6.9 Hz,2H),3.96(s,1H),3.86(s,1H),3.46(s,2H),2.36-2.23(m,2H),2.05(s,1H),1.61(s,2H),1.45(s,9H).

[0308] 5-Fluoro-2-iodophenol. To a stirred solution of 4-fluoro-1-iodo-2-methoxybenzene (2.80 g, 11.11 mmol) in dichloromethane (30.0 mL), boron tribromide (13.92 g, 55.55 mmol) was added dropwise at 0°C under an N2 atmosphere. The final reaction mixture was stirred at room temperature for 30 minutes and then quenched with water at 0°C. The reaction mixture was extracted with dichloromethane (3 × 100 mL), the combined organic extract was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO₂) eluting with 16% siRNA in petroleum ether to obtain the desired product as a yellow liquid (2.10 g, yield 79%). 1H NMR(400 MHz,DMSO-d6)δ 10.81(s,1H),7.73-7.63(m,1H),6.74-6.60(m,1H),6.61-6.45(m,1H).

[0309] tert-butyl(3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-1-carboxylate. A solution of tert-butyl(3Z)-3-(2-hydroxyethylidene)piperidine-1-carboxylate (600.0 mg, 2.64 mmol), 5-fluoro-2-iodophenol (628.2 mg, 2.64 mmol), and triphenylphosphine (1.04 g, 3.96 mmol) in THF (10.0 mL) was stirred at room temperature for 10 minutes under an N2 atmosphere, and then diisopropyl azodicarboxylate (1.60 g, 7.92 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for a further 30 minutes and then concentrated under reduced pressure. The residue was purified by preparative TLC (20 × 20 cm², 16% ethyl acetate solution in petroleum ether) to obtain the desired product as yellow oil (900 mg, yield 53%). LCMS 50(Method B)(ESI)C 18 H 23 FINO3, calculated value 447.07; measured value [M+H] + :448. 1 H NMR(400 MHz,DMSO-d6)δ 7.86-7.68(m,1H),7.00-6.91(m,1H),6.69-6.61(m,1H),5.54(t,J=6.4 Hz,1H),4.67(d,J=6.4 Hz,2H),3.83(s,1H),3.44-3.33(m,2H),3.33(s,1H),2.38(t,J=6.0 Hz,1H),2.34-2.24(m,1H),1.56(d,J=8.3 Hz,2H),1.37(s,9H).

[0310] tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. CoCl2 (29.0 mg, 0.22 mmol) was added to a 10 mL Schlenk tube at room temperature, and then heated with a hairdryer for 2 minutes. DPPB (57.2 mg, 0.13 mmol, 0.1 equivalent) and tetrahydrofuran (5.0 mL) were added to the tube. The resulting mixture was stirred at room temperature for a further 5 minutes. [(chloromagnesio)methyl]trimethylsilane (492.9 mg, 3.35 mmol, 3.0 equivalent) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 0°C for a further 5 minutes. To the above mixture, tert-butyl(3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-1-carboxylate (500.0 mg, 1.12 mmol, 1.0 equivalent) was added dropwise at room temperature. The resulting mixture was stirred at 80°C for a further 30 minutes. The reaction was quenched by adding saturated NH4Cl (aqueous solution) at 0°C. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by chromatography (SiO2) eluting with dichloromethane containing 50% MeOH to obtain the desired product as a brown solid (300.0 mg, yield 84%). LCMS 50 (Method A) (ESI)C 18 H 22 FNO3, calculated value 319.16; measured value [M+H] + :320.

[0311] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (300.0 mg, 0.94 mmol) in 1,4-dioxane (1.0 mL), HCl (gas) (2 mL, 4 M) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in methanol (5.0 mL), neutralized to pH 7 with saturated ammonium bicarbonate solution, and then concentrated again under reduced pressure. The crude product was purified by chromatography (column, C18; mobile phase, acetonitrile in water (0.1% formic acid), gradient from 5% to 95% over 10 minutes; detector, UV 254 nm) to obtain the desired product as a pale yellow oil (20.7 mg, yield 10%). LCMS 40(ESI)C 13 H 14 FNO, calculated value 219.11; measured value [M+H] + :220.10. 1 H NMR(400 MHz,DMSO-d6)δ 8.33(s,1H),7.17-7.08(m,1H),6.78-6.66(m,2H),5.64(d,J=3.9 Hz,1H),4.69(t,J=9.3 Hz,1H),4.45-4.35(m,1H),4.20-4.09(m,1H),3.43(d,J=16.7 Hz,1H),3.15(d,J=16.3 Hz,1H),2.97(d,J=6.1 Hz,2H),2.16(d,J=6.2 Hz,2H).

[0312] Example 18: Synthesis of 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine (compound 147) [ka]

[0313] 6-Fluoro-1-benzofuran-3-yltrifluoromethanesulfonate. Tf2O (2.80 g, 9.90 mmol) was added dropwise at 0°C to a stirred solution of 6-fluoro-2H-1-benzofuran-3-one (1.00 g, 6.60 mmol) and TEA (2.00 g, 19.70 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 1 hour and then diluted with water. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (420 mg, yield 22%). LCMS 50 (Method A) (ESI) C9H4F4O4S, calculated value 283.98; measured value [M+H] + :285.

[0314] To a stirred solution of tert-butyl 3-(6-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 6-fluoro-1-benzofuran-3-yltrifluoromethanesulfonate (320.0 mg, 1.13 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (522.3 mg, 1.69 mmol) in H2O (2 mL) and dioxane (10 mL), Pd(dppf)Cl2 (165 mg, 0.23 mmol) and K2CO3 (467 mg, 3.40 mmol) were gradually added at room temperature. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere, and then diluted with water. The resulting mixture was extracted with Â(3 × 50 mL), and the combined organic extract was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA(1:1) to obtain the desired product as yellow oil (210 mg, yield 59%). LCMS 50 (Method A) (ESI)C 18 H 20 FNO3, calculated value 317.14; measured value [M+H] + :318.

[0315] tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 3-(6-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (210.0 mg, 0.67 mmol) in MeOH (5 mL), PtO2 (0.08 g, 0.33 mmol) was added in fractions at room temperature. The resulting mixture was stirred overnight at room temperature under an H2 atmosphere, and then filtered through Celite. The filtrate cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as yellow oil (130 mg, yield 61%). LCMS 54(ESI)C 18 H 24 FNO3, calculated value 321.17; measured value [M+H] + :322.

[0316] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine. A solution of tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine-1-carboxylate (150 mg, 0.47 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The crude product (65 mg) was purified by HPLC (column: XBridge Prep OBD C18 Column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: MEOH; flow rate: 60 mL / min; gradient: 33% B to 47% B in 9 min; wavelength: 254 nm / 220 nm) to obtain the desired product as a white solid (34.9 mg, yield 33%). LCMS 63 (Method Q) (ESI)C 13 H 16 FNO, calculated value 221.12; measured value [M+H] + :222.00. 1H NMR(400 MHz,DMSO-d6)δ 7.22(t,J=7.0 Hz,1H),6.65(t,J=8.6 Hz,2H),4.62-4.41(m,2H),3.90-3.67(m,1H).3.29(d,J=8.5 Hz,1H),2.82(d,J=61.8 Hz,1H),2.41(s,2H),1.82-1.45(m,3H),1.43-1.02(m,2H).

[0317] Example 19: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitrile (compound 159) [ka]

[0318] 1-Benzothiophene-7-Carbonitrile. Pd(PPh3)4 (1.08 g, 0.93 mmol) was added to a stirred solution of 7-bromo-1-benzothiophene (1.00 g, 4.69 mmol) and Zn(CN)2 (1.65 g, 14.03 mmol) in DMA (10 mL). The resulting mixture was stirred at 90°C for 3 hours under an N2 atmosphere. The resulting mixture was extracted with RINKAN (3 × 10 mL). The combined organic extract was washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (400.0 mg, yield 53.5%).

[0319] 3-Bromo-1-benzothiophene-7-carbonitride. Br2 (0.12 mL, 2.32 mmol) was added to a stirred solution of 1-benzothiophene-7-carbonitride (330.0 mg, 2.07 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic extract was washed with Na2SO3 (aqueous solution) (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18The silica gel was used as the mobile phase, an aqueous MeCN solution (0.1% FA), with a gradient from 0% to 55% over 15 minutes. The product was purified by reverse-phase flash chromatography using UV254nm to obtain the desired product as a white solid (220.0 mg, yield 44.5%). 1 H NMR(400 MHz,CDCl3)δ 8.05(d,J=8.2,1.1 Hz,1H),7.78(d,J=7.4,1.1 Hz,1H),7.60(s,1H),7.59-7.53(m,1H).

[0320] 3-Methyl-1-benzothiophene-7-carbonitride. 3-bromo-1-benzothiophene-7-carbonitride (160.0 mg, 0.67 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (313.9 mg, 1.01 mmol) were stirred in H2O (1.5 mL) and dioxane (3 mL). Pd(dppf)Cl2 (24.5 mg, 0.03 mmol) and K2CO3 (278.6 mg, 2.01 mmol) were added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with  (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as a colorless oil (200.0 mg, yield 87.4%). LCMS 52 (Method B) (ESI)C 19 H 20 N2O2S, calculated value 340.12; measured value [M+H] + :341. 1 H NMR(300 MHz,CDCl3)δ 8.13(d,J=8.2 Hz,1H),7.72(d,J=7.3 Hz,1H),7.51-7.40(m,2H),6.14(d,J=3.3,2.6 Hz,1H),4.23(s,2H),3.63(d,J=5.8 Hz,2H),2.39(d,J=6.2 Hz,2H),1.51(s,9H).

[0321] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitride. 100.0 mg, 0.29 mmol, 1.0 equivalent of tert-butyl 3-(7-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol, 1.0 equivalent) was stirred in 5 mL of DCM, to which 1 mL of TFA was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 30 minutes. The mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 21% B over 9 min; wavelength: 254 nm / 220 nm) to obtain the desired product as a white solid (55.4 mg, yield 78.4%). LCMS 63 (Method Q) (ESI)C 14 H 12 N2S, calculated value 240.17; measured value [M+H+ACN] + :282.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.30(d,J=8.2 Hz,1H),8.00(d,J=7.3 Hz,1H),7.90(d,J=3.6 Hz,1H),7.63(t,J=7.8 Hz,1H),6.22(s,1H),3.73(s,2H),3.06(s,2H),2.35(s,2H).

[0322] Example 20: Synthesis of 5-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitrile (compound 168) [ka]

[0323] Ethyl [(2-bromo-4-fluorophenyl)sulfanyl]methanethioate. 2-bromo-4-fluoroaniline (3 g, 15.79 mmol) and NaNO2 (1.20 g, 17.37 mmol) were stirred in HCl (10 mL) and H2O (10 mL). Ethyl xanthopotassium (3.04 g, 18.95 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with ELISA (5 × 100 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (1.6 g, yield 34.3%). 1 H NMR(400 MHz,CDCl3)δ 7.60(s,1H),7.47(s,1H),7.10(s,1H),4.65-4.57(m,2H),1.37-1.31(m,3H).

[0324] 2-Bromo-1-[(2,2-dimethoxyethyl)sulfanyl]-4-fluorobenzene. Ethyl[(2-bromo-4-fluorophenyl)sulfanyl]methanethioate (1.6 g, 5.42 mmol) and ethane, 2-bromo-1,1-dimethoxy-(1.10 g, 6.50 mmol) were stirred in EtOH (15 mL). KOH (0.91 g, 16.26 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure, diluted with H2O (20 mL), extracted with ELISA (3 × 20 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (1.2 g, yield 75.0%). 1 H NMR(400 MHz,CDCl3)δ 7.43(s,1H),7.34(s,1H),7.01(s,1H),4.58-4.50(m,1H),3.36(s,6H),3.08(d,J=5.6 Hz,2H).

[0325] 7-Bromo-5-fluoro-1-benzothiophene. 2-Bromo-1-[(2,2-dimethoxyethyl)sulfanyl]-4-fluorobenzene (1.2 g, 4.07 mmol) was stirred in chlorobenzene (20 mL) and PPA (1.40 g, 12.20 mmol) was added at room temperature. The mixture was stirred at 110 °C for 2 hours under an N2 atmosphere. The resulting mixture was diluted with water and extracted with RINKAN (3 × 50 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (385 mg, yield 40.9%). 1 H NMR(400 MHz,CDCl3)δ 7.59(d,J=5.4 Hz,1H),7.46(s,1H),7.40(d,J=5.4 Hz,1H),7.32(s,1H).

[0326] 5-Fluoro-1-benzothiophene-7-carbonitrile. A mixture of 7-bromo-5-fluoro-1-benzothiophene (350 mg, 1.52 mmol), Pd(PPh3)4 (350.1 mg, 0.30 mmol), and Zn(CN)2 (533.5 mg, 4.55 mmol) in DMA (10 mL) was stirred at 100 °C for 2 hours under an N2 atmosphere. The resulting mixture was diluted with water, quenched with FeSO4 aqueous solution, and extracted with  (3 × 20 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (175 mg, yield 65.2%). 1 H NMR(400 MHz,CDCl3)δ 7.69-7.57(m,2H),7.40(s,1H),7.32(d,J=5.5 Hz,1H).

[0327] 5-Fluoro-1-benzothiophene-7-carbonitrile. To a stirred solution of 7-bromo-5-fluoro-1-benzothiophene (170 mg, 0.736 mmol) in DCM (5 mL), Br2 (176.4 mg, 1.10 mmol) was added dropwise at 0°C and the mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with 10 mL of Na2S2O3 at 0°C and extracted with siRNA (3 × 10 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (60 mg, yield 46.0%). 1 H NMR(400 MHz,DMSO-d6)δ 8.36(s,1H),8.21(s,1H),7.96(s,1H).

[0328] A mixture of tert-butyl 3-(7-cyano-5-fluoro-1-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-5-fluoro-1-benzothiophen-7-carbonitrile (60 mg, 0.20 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (90.6 mg, 0.29 mmol), Pd(dppf)Cl2 (28.6 mg, 0.04 mmol), and K2CO3 (81.0 mg, 0.59 mmol) in dioxane (2.5 mL) and H2O (0.5 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with 20 mL of water and extracted with ₹(3 × 20 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA(5:1) to obtain the desired product as a white solid (52 mg, yield 74.3%). LCMS 60(ESI)C 19 H 19 FN2O2S, calculated value 358.12; measured value [M+H] + :359.

[0329] 5-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitride. To a stirred solution of tert-butyl 3-(7-cyano-5-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (52 mg, 0.17 mmol) in DCM (2 mL), TFA (2 mL) was added at room temperature and stirred for 15 minutes at room temperature. The mixture was concentrated under reduced pressure, and the residue was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD Column 19*250mm, 5m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MEOH; flow rate: 60 mL / min; gradient: 5%B to 5%B at 1 min, 5%B to 37%B at 2 min, 37% to 55%B at 10 min) to obtain the desired product as a white solid (22.8 mg, yield 59.4%). LCMS 52(ESI)C 14 H 11 FN2S, calculated value 258.06; measured value [M+H] + :258.90. 1 H NMR(400 MHz,CD3OD)δ 8.00(s,1H),7.80(s,1H),7.73(s,1H),6.26-6.20(m,1H),3.85-3.78(m,2H),3.23(s,2H),2.55-2.46(m,2H).

[0330] Example 21: Synthesis of 4-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitrile (compound 169) [ka]

[0331] 4-Fluoro-1-benzothiophene-7-carbonitrile. A solution of 7-bromo-4-fluoro-1-benzothiophene (700 mg, 3.029 mmol), zinc cyanide (1067.1 mg, 9.087 mmol), and Pd(PPh3)4 (700.1 mg, 0.606 mmol) in DMA (10 mL) was stirred at 110 °C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ethyl acetate. The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (320 mg, yield 59.6%). 1 H NMR(400 MHz,DMSO-d6)δ 7.42-7.39(m,2H),7.31-7.13(m,2H).

[0332] 3-Bromo-4-fluoro-1-benzothiophene-7-carbonitride. To a stirred mixture of 4-fluoro-1-benzothiophene-7-carbonitride (300 mg, 1.693 mmol) in DCM (5 mL), Br2 (1352.8 mg, 8.465 mmol) was added in fractions at 0°C and stirred overnight at room temperature. The reaction was quenched by adding Na2S2O3 at 0°C. The resulting mixture was extracted with RINKAN (3 × 20 mL), and the combined organic extract was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 10% to 50% over 20 minutes; detector: reverse-phase flash chromatography using UV254nm to purify the product, obtaining the desired product as a white solid (70 mg, yield 16.1%). 1 H NMR(400 MHz,DMSO-d6)δ 8.24-8.17(m,1H),8.12(m,1H),7.51(m,1H).

[0333] A mixture of tert-butyl 3-(7-cyano-4-fluoro-1-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-4-fluoro-1-benzothiophen-7-carbonitrile (20 mg, 0.078 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (36.2 mg, 0.117 mmol), Pd(dppf)Cl2 (5.7 mg, 0.008 mmol), and K2CO3 (32.4 mg, 0.234 mmol) in dioxane (2 mL) and H2O (0.4 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 5 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (15 mg, yield 53.5%). LCMS51(Method L)(ESI)C 19 H 19 FN2O2S, calculated value 358.12; measured value [M+H] + :359.

[0334] 4-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-7-carbonitride. A solution of tert-butyl 3-(7-cyano-4-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (20 mg, 0.056 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 10 minutes. After concentration under reduced pressure, the residue was diluted with MeOH (0.5 mL) and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was subjected to the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 10% to 50% over 20 minutes; detector: reverse-phase flash chromatography using UV254nm to obtain the desired product as a white solid (11.9 mg, yield 82.5%). LCMS 63(Method P)(ESI)C 14 H 11FN2S, calculated value 258.06; measured value [M+H] + :259.10. 1 H NMR(400 MHz,CD3OD)δ 7.84(dd,J=8.3,4.3 Hz,1H),7.58(s,1H),7.27(dd,J=11.2,8.3 Hz,1H),5.99(m,1H),3.59(m,2H),3.03(t,J=5.9 Hz,2H),2.40-2.22(m,2H).

[0335] Example 22: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-6-carbonitrile (compound 176) [ka]

[0336] 1-Benzothiophene-6-Carbonitrile. A solution of 6-bromo-1-benzothiophene (1.00 g, 4.69 mmol), Pd(PPh3)4 (0.54 g, 0.47 mmol), and Zn(CN)2 (0.55 g, 4.69 mmol) in DMA (10.0 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. The aqueous layer was extracted with ELISA (3 × 50 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (600.0 mg, yield 80.3%). 1 H NMR(400 MHz,DMSO-d6)δ 8.69-8.63(m,1H),8.14(d,J=5.4 Hz,1H),8.08(d,J=8.3 Hz,1H),7.79-7.74(m,1H),7.63(d,J=5.4 Hz,1H).

[0337] 3-Bromo-1-benzothiophene-6-carbonitride. 1-benzothiophene-6-carbonitride (600.0 mg, 3.77 mmol) was stirred in DCM (6.0 mL), to which Br2 (0.5 mL) was added dropwise at room temperature under an N2 atmosphere, and the mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction was quenched by the addition of Na2S2O3. The aqueous layer was extracted with RINKAN (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (300.0 mg, yield 33.4%). 1 H NMR(400 MHz,CD3OD)δ 8.46-8.42(m,1H),8.03(s,1H),7.96(d,J=8.4 Hz,1H),7.80-7.75(m,1H).

[0338] A mixture of tert-butyl 3-(6-cyano-1-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-1-benzothiophen-6-carbonitrile (300.0 mg, 1.26 mmol), Pd(dppf)Cl2 (44.2 mg, 0.06 mmol), K2CO3 (522.4 mg, 3.78 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (584.4 mg, 1.89 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extract was dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (200.0 mg, yield 46.6%). 1H NMR(400 MHz,CDCl3)δ 8.19(d,J=1.4 Hz,1H),8.00(d,J=8.5 Hz,1H),7.63-7.58(m,1H),7.53(s,1H),6.17-6.12(m,1H),4.23(s,2H),3.646-3.60(m,2H),2.43-2.35(m,2H),1.51(s,9H).

[0339] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-6-carbonitride. A solution of tert-butyl 3-(6-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol) in HCl (2.0 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 hour under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL), and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5m; Mobile phase A: Water (NH4HCO3 at 10 mmol / L), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2%B to 2%B at 5 min, 2%B to 20%B at 20 min, 20%B to 41%B at 30 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.9) to obtain the desired product as a yellow solid (25.0 mg, yield 35.4%). LCMS 51 (Method L) (ESI)C 14 H 12 N2S, calculated value 240.07; measured value [M+H] + :241.15. 1 H NMR(400 MHz,CD3OD)δ 8.38-8.27(m,1H),8.09-8.00(m,1H),7.75-7.67(m,1H),7.66-7.57(m,1H), 6.17-6.08(m,1H),3.67-3.56(m,2H),3.09-2.98(m,2H),2.41-2.28(m,2H).

[0340] Example 23: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-5-carbonitrile (compound 177) [ka]

[0341] 1-Benzothiophene-5-Carbonitrile. 5-Bromo-1-benzothiophene (2.00 g, 9.38 mmol) and Zn(CN)2 (1.32 g, 11.26 mmol) were stirred in DMA (15 mL). Pd(PPh3)4 (1.08 g, 0.93 mmol) was added at room temperature under an N2 atmosphere. The resulting mixture was stirred at 100°C for 1 hour under an N2 atmosphere, diluted with H2O (200 mL), and extracted with siRNA (3 × 200 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (1 g, yield 66.9%). LCMS 49 (Method K) (ESI) C9H5NS, calculated value 159.01[M+H] + :160. 1 H NMR(400 MHz,DMSO-d6)δ 8.44(d,J=1.6 Hz,1H),8.29-8.24(m,1H),8.00(d,J=5.4 Hz,1H),7.76-7.70(m,1H),7.61-7.56(m,1H).

[0342] 3-Bromo-1-benzothiophene-5-carbonitride. Br2 (1.00 g, 6.28 mmol) was added to a stirred solution of 1-benzothiophene-5-carbonitride (1.00 g, 6.28 mmol) in DCM (10 mL) under an N2 atmosphere at 0°C. The resulting mixture was stirred under an N2 atmosphere at 0°C for 1 hour. The resulting mixture was diluted with RINKAN (100 mL), washed with saturated sodium thiosulfate (3 × 100 mL), and the combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (800 mg, yield 53.4%). LCMS 49 (Method K) (ESI) C9H4BrNS, calculated value 236.92; measured value [M+H] + :238.

[0343] The solutions of tert-butyl 3-(5-cyano-1-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-bromo-1-benzothiophen-5-carbonitrile (200.0 mg, 0.84 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (311.6 mg, 1.00 mmol), K2CO3 (348.2 mg, 2.52 mmol), and Pd(dppf)Cl2 (61.4 mg, 0.08 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL) were stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL). The combined organic extract was dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (130 mg, yield 45.6%). LCMS49 (Method K) (ESI)C 19 H 20 N2O2S, calculated value 340.12; measured value [M+H] + :341.

[0344] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1-benzothiophene-5-carbonitride. To a stirred solution of tert-butyl 3-(5-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol) in 1,4-dioxane (0.5 mL), HCl (gas) (0.5 mL, 4 M in 1,4-dioxane) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 3 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL), and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 47% B in 9 mins; wavelength: 254 nm / 220 nm; RT1 (min): 9.3) to obtain the desired product as a white solid (49.6 mg, yield 70.1%). LCMS 41 (Method B) (ESI)C 14 H 12 N2S, calculated value: 240.07; measured value [M+H] + :241. 1 H NMR(300 MHz,CD3OD)δ 8.35-8.30(m,1H),8.13-8.05(m,1H),7.67-7.59(m,2H),6.22-6.11(m,1H),3.74-3.63(m,2H),3.16-3.06(m,2H),2.49-2.34(m,2H).

[0345] Example 24: Synthesis of {1-[(3R)-piperidine-3-yl]imidazo[4,5-b]pyridine-5-yl}methanol (compound 193) [ka]

[0346] 6-Bromo-3-methoxy-2-nitropyridine. A solution of 6-bromo-2-nitropyridine-3-ol (6.00 g, 27.5 mmol), iodomethane (11.72 g, 82.6 mmol), and cesium carbonate (26.9 g, 82.6 mmol) in acetone (50 mL) was stirred overnight at 60°C under an N2 atmosphere. The reaction mixture was filtered through Celite, the filter cake was washed with dichloromethane (4 × 20 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with dichloromethane containing 40% siRNA to obtain the desired product as a pale yellow solid (5.3 g, yield 83%). LCMS 54(ESI)C6H5BrN2O3, calculated value 231.95; measured value [M+H] + :233.

[0347] Methyl 5-methoxy-6-nitropyridine-2-carboxylate. A mixture of 6-bromo-3-methoxy-2-nitropyridine (2.50 g, 10.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.36 g, 3.22 mmol), and triethylamine (4.4 mL, 32.2 mmol) in MeOH (30 mL) and DMSO (90 mL) was stirred at 100°C for 4 hours under a CO atmosphere. The resulting mixture was filtered through Celite, and the filtrate was washed with methanol (5 × 10 mL). The resulting mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic extract was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) elution with petroleum ether containing 50% SiO2 to obtain the desired product as a light brown solid (1.5 g, yield 66%). LCMS 49 (Method J) (ESI) C8H8N2O5, calculated value 212.04; measured value [M+H] + :213. 1 H NMR(300 MHz,CDCl3)δ 8.37(d,J=8.6 Hz,1H),7.60(d,J=8.6 Hz,1H),4.05(s,3H),4.00(s,3H).

[0348] Methyl 5-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]amino}-6-nitropyridine-2-carboxylate. A solution of methyl 5-methoxy-6-nitropyridine-2-carboxylate (1.00 g, 4.71 mmol) and tert-butyl(3R)-3-aminopiperidine-1-carboxylate (1.04 g, 5.18 mmol) in DMF (5 mL) was stirred at 70°C for 20 hours and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 40% siRNA in petroleum ether to obtain the desired product as a yellow solid (700 mg, yield 39%). LCMS 49 (Method J) (ESI)C 17 H 24 N4O6, calculated value 380.17; measured value [M+H] + :381

[0349] Methyl 6-amino-5-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]amino}pyridine-2-carboxylate. A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]amino}-6-nitropyridine-2-carboxylate (700 mg, 1.84 mmol) and Pd / C (140 mg, 1.32 mmol) in MeOH (10 mL) was stirred at room temperature under an H2 atmosphere for 15 minutes. The resulting mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with dichloromethane containing 3% MeOH to obtain the desired product as a yellow solid (400 mg, yield 62%). LCMS47(ESI)C 17 H 26 N4O4, calculated value 350.20; measured value [M+H] + :351

[0350] tert-butyl(3R)-3-[5-(methoxycarbonyl)imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate. A solution of methyl 6-amino-5-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]amino}pyridine-2-carboxylate (400 mg, 1.14 mmol) and AcOH (0.05 mL, 0.873 mmol) in triethyl orthoformate (5 mL) was stirred overnight at 110 °C and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with dichloromethane containing 5% MeOH to obtain the desired product as a yellow solid (300 mg, yield 73%). LCMS 45 (Method F) (ESI)C 18 H 24 N4O4, calculated value 360.18; measured value [M+H] + :361

[0351] tert-butyl(3R)-3-[5-(hydroxymethyl)imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate. To a stirred solution of tert-butyl(3R)-3-[5-(methoxycarbonyl)imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (300 mg, 0.83 mmol) in THF (10 mL), lithium aluminum hydride (158 mg, 4.16 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then quenched with methanol (5 mL). The resulting mixture was filtered through Celite, the filter cake was washed with MeOH (5 × 10 mL), and the filtrate was concentrated under reduced pressure to obtain the desired product as an orange solid (200 mg, yield 72%). LCMS 49 (Method K) (ESI)C 17 H 24 N4O3, calculated value 332.18; measured value [M+H] + 333. It was used directly in the next step.

[0352] {1-[(3R)-piperidine-3-yl]imidazo[4,5-b]pyridine-5-yl}methanol. 5 mL of TFA was added dropwise to 10 mL of a stirred solution of tert-butyl(3R)-3-[5-(hydroxymethyl)imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (200 mg, 0.60 mmol) in dichloromethane at room temperature. The resulting mixture was stirred for 30 minutes, then adjusted to pH 8 with ammonium bicarbonate (aqueous solution) and concentrated under reduced pressure. The residue was purified by chromatography (column, C18; mobile phase, aqueous acetonitrile solution (10 mmol / L ammonium bicarbonate), 1% to 20% gradient over 10 minutes) to obtain the desired product as a yellow solid (54.8 mg, yield 39%). LCMS 49 (Method K) (ESI)C 12 H 16 N4O, calculated value 232.13; measured value [M+H] + :233.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.55(s,1H),8.12(d,J=8.4 Hz,1H),7.42(d,J=8.3 Hz,1H),5.40(s,1H),4.66-4.55(m,3H),3.49-3.41(m,1H),3.26-3.18(m,2 H),2.86-2.84(m,1H),2.17-2.15(m,2H),1.95-1.93(m,1H),1.79(d,J=20.2 Hz,1H).

[0353] Example 25: Synthesis of 1-(piperidine-3-yl)-1H-imidazo[4,5-b]pyridine (compound 195) [ka]

[0354] tert-butyl 3-((2-nitropyridine-3-yl)amino)piperidine-1-carboxylate. A mixture of tert-butyl 3-aminopiperidine-1-carboxylate (1.00 g, 4.99 mmol), 3-fluoro-2-nitropyridine (1.06 g, 7.49 mmol), and DIEA (1.94 g, 14.97 mmol) in 10 mL of DMF was stirred and stirred at 90°C for 2 hours under N2. The resulting mixture was extracted with siRNA (3 × 50 mL), the combined extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with a 20% ethyl acetate petroleum ether solution to obtain the desired product as a white solid (1.10 g, yield 68%). LCMS 61(ESI)C 15 H 22 N4O4, calculated value 322.16; measured value [M+H] + :323.

[0355] tert-butyl 3-((2-aminopyridine-3-yl)amino)piperidine-1-carboxylate. Under an N2 atmosphere, 15 mL of tert-butyl 3-[(2-nitropyridine-3-yl)amino]piperidine-1-carboxylate (1.10 g, 3.41 mmol) was stirred in MeOH, to which Zn (1.12 g, 17.06 mmol) and NH4Cl (0.55 g, 10.23 mmol, 3.0 equivalents) were added. After 2 hours at room temperature, the reaction mixture was extracted with siRNA (3 × 50 mL), the combined organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with a 30% ethyl acetate petroleum ether solution to obtain the desired product as a purple solid (400 mg, yield 40%). LCMS 60(ESI)C 15 H 24 N4O2, calculated value 292.19; measured value [M+H] + :293.

[0356] tert-butyl 3-(1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate. A 10 mL solution of tert-butyl 3-[(2-aminopyridine-3-yl)amino]piperidine-1-carboxylate (430.0 mg, 1.47 mmol) in triethyl orthoformate was stirred at 110°C under a N2 atmosphere. After 2 hours, the reaction mixture was extracted with siRNA (3 × 50 mL), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 50% ethyl acetate in petroleum ether to obtain the desired product as a brown solid (180 mg, yield 40%). LCMS 61(ESI)C 16 H 22 N4O2, calculated value 302.17; measured value [M+H] + :303.

[0357] 1-(piperidine-3-yl)-1H-imidazo[4,5-b]pyridine. A 2 mL solution of tert-butyl 3-{imidazo[4,5-b]pyridine-1-yl}piperidine-1-carboxylate (180.0 mg, 0.59 mmol) in HCl / 1,4-dioxane was stirred at room temperature for 1 hour under a N2 atmosphere and then concentrated under reduced pressure. The crude product (75 mg) was purified by preparative HPLC (column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; mobile phase A: 10 mmol / L NH4HCO3 + 0.05% NH3H2O, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 1% B to 15% B over 8 mins; wavelength: 254 nm / 220 nm) to obtain the desired product as a pale yellow solid (37.5 mg, yield 31%). LCMS 48(Method H)(ESI)C 11 H 14 N4, calculated value 202.12; measured value [M+H] + :203. 1H NMR(300 MHz,CDCl3)δ 8.60(dd,J=4.7,1.5 Hz,1H),8.38(s,1H),7.82(dd,J=8.1,1.5 Hz,1H),7.27-7.23(m,1H),4.43(ddd,J=14.3,10.0,3.9 Hz,1H),3.55-3.39(m,1H),3.16(dd,J=12.1,4.0 Hz,1H),3.04(dd,J=11.6,9.8 Hz,1H),2.80(td,J=11.4,3.0 Hz,1H),2.30(dd,J=12.5,4.5 Hz,1H),2.16-1.93(m,2H),1.86-1.67(m,1H).

[0358] Example 26: Synthesis of 5-(2,5-dimethoxy-4-methylphenyl)-1,2,3,6-tetrahydropyridine (compound 250) [ka]

[0359] A solution of tert-butyl 3-(2,5-dimethoxy-4-methylphenyl)-5,6-dihydro-2H-pyridine-1-carboxylate, 1-bromo-2,5-dimethoxy-4-methylbenzene (300.0 mg, 1.29 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (602.1 mg, 1.94 mmol), Pd(dppf)Cl2 (94.9 mg, 0.13 mmol), K2CO3 (538.2 mg, 3.89 mmol), and H2O (3 mL) in dioxane (6 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (4 × 100 mL). The combined organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (6:1) to obtain the desired product as a white solid (150.0 mg, yield 34.6%). LCMS 53(MethodM)(ESI)[M+H] + :218. 1HNMR(400 MHz,DMSO-d6)δ 6.83(s,1H),6.67(s,1H),5.83(s,1H),4.11(s,1H),3.71(d,J=12.5 Hz,5H),3.45(t,J=5.8 Hz,2H),2.21-2.08(m,2H),2.14(s,3H),1.41(d,J=5.4 Hz,9H),1.21(s,2H).

[0360] 3-(2,5-dimethoxy-4-methylphenyl)-1,2,5,6-tetrahydropyridine. A solution of tert-butyl 3-(2,5-dimethoxy-4-methylphenyl)-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.45 mmol, 1.0 equivalent) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (2 mL), and the pH was basicized to 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes; detector, UV 254 nm, to obtain the desired product as a white solid (52.7 mg, yield 50.2%). LCMS 40(ESI)[M+H] + :234. 1 H NMR(400 MHz,DMSO-d6)δ 6.78(s,1H),6.62(s,1H),5.88-5.66(m,1H),3.72(s,3H),3.67(s,3H),3.42(s,2H),2.80-2.67(m,2H),2.12(s,3H),2.10-1.98(m,2H).

[0361] Example 27: Synthesis of 7-(5-methyl-1,3,4-oxadiazole-2-yl)-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 305) [ka]

[0362] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate. Methyl 3-bromo-1H-indazole-7-carboxylate (2.00 g, 7.84 mmol) and NaH (0.30 g, 12.54 mmol) were stirred in dimethylformamide (20 mL), to which SEM-Cl (3.90 g, 23.52 mmol) was added at 0°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The reaction was quenched by adding NH4Cl (aqueous solution) (20 mL) at 0°C. The resulting mixture was extracted with Âx (3 × 20 mL). The combined organic extract was washed with water (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a colorless oil (2.60 g, yield 86.0%). LCMS 52 (Method A) (ESI)C 15 H 21 BrN2O3Si, calculated value 384.05; measured value [M+H] + :385. 1 H NMR(400 MHz,CDCl3)δ 8.11(d,J=7.4,1.2 Hz,1H),7.94(d,J=8.0,1.2 Hz,1H),7.40(d,J=7.7 Hz,1H),6.15(s,2H),4.11(s,3H),3.48-3.37(m,2H),0.93-0.82(m,2H),0.06(s,9H).

[0363] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbozide. A solution of methyl 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate (2.60 g, 6.74 mmol) in hydrazine hydrate (30 mL) and ethyl alcohol (30 mL) was stirred overnight at 100°C under an N2 atmosphere. The residue was collected under the following conditions: column, C 18Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 61% over 20 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (2.00 g, yield 76.9%). LCMS 53 (Method M) (ESI)C 14 H 21 BrN4O2Si, calculated value 384.06[M+H] + :385. 1 H NMR(400 MHz,CDCl3)δ 7.83(d,J=8.1,1.1 Hz,1H),7.64(d,J=7.2,1.1 Hz,1H),7.34(d,J=6.6,1.5 Hz,1H),5.90(s,2H),3.53-3.47(m,2H),0.91-0.83(m,2H),0.06(s,9H).

[0364] 3-bromo-7-(5-methyl-1,3,4-oxadiazole-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole. A solution of 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbohydrazide (1.00 g, 2.59 mmol) and 4-methylbenzene-1-sulfonic acid hydrate (197.4 mg, 1.03 mmol) in triethyl orthoacetate (10 mL) was stirred overnight at 120°C under an N2 atmosphere. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 75% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (300.0 mg, yield 28.2%). LCMS 53 (Method M) (ESI)C 16 H 21 BrN4O2Si, calculated value 408.06; measured value [M+H] + :409.

[0365] tert-Butyl 3-[7-(5-methyl-1,3,4-oxadiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazol-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylate. A stirred solution of 3-bromo-7-(5-methyl-1,3,4-oxadiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (300.0 mg, 0.73 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (339.9 mg, 1.09 mmol) in dioxane (5 mL) and H2O (5 mL) was added with K2CO3 (303.8 mg, 2.19 mmol) and Pd(dppf)Cl2 (26.8 mg, 0.03 mmol). The resulting mixture was stirred at 80 °C for 1 h under a N2 atmosphere. The resulting mixture was extracted with EtOAc (3 × 3 mL). The combined organic extracts were washed with water (3 × 3 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 4:1) to give the desired product as a colorless oil (350.0 mg, yield 93.3%). LCMS 52 (Method A) (ESI) C 26 H 37 N5O4Si, calculated 511.26; found [M+H] + : 512. 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.2, 1.0 Hz, 1H), 7.99 (d, J = 7.3, 1.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 4.2, 1.9 Hz, 1H), 6.27 (s, 2H), 4.67 (s, 2H), 3.82 (d, J = 5.7 Hz, 2H), 3.40 (d, J = 8.1 Hz, 2H), 2.82 (s, 3H), 2.65 - 2.56 (m, 2H), 1.69 (s, 9H), 0.81 (d, J = 8.0 Hz, 2H), 0.06 (s, 9H).

[0366] 7-(5-methyl-1,3,4-oxadiazole-2-yl)-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. A solution of tert-butyl3-[7-(5-methyl-1,3,4-oxadiazole-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylate (200.0 mg, 0.39 mmol) was stirred in dioxane (5 mL), to which HCl (gas) (5 mL, 4 M) was added dropwise. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The mixture was concentrated under reduced pressure and diluted with DCM (5 mL). This was then basicized to pH 10 with saturated Na2CO3 (aqueous solution). After concentration, the residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 60% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow solid (37.3 mg, yield 33.9%). LCMS 63(Method P)(ESI)C 15 H 15 N5O, calculated value 281.13; measured value [M+H] + :282.10. 1 NMR(300 MHz,DMSO-d6)δ 13.17(s,1H),δ 8.24(d,J=8.3,1.0 Hz,1H),7.97(dd,J=7.3,0.9 Hz,1H),7.34(d,J=8.2,7.3 Hz,1H),6.68(s,1H),3.75(d,J=2.9 Hz,2H),2.90(t,J=5.7 Hz,2H),2.65(s,3H),2.26(s,2H).

[0367] Example 28: Synthesis of 7-(1-methyl-1,2,3-triazol-4-yl)-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole; formic acid (compound 309) [ka]

[0368] 1-{[2-(Trimethylsilyl)ethoxy]methyl}-7-[2-(trimethylsilyl)ethynyl]indazole. A solution of 7-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (2.00 g, 5.343 mmol), Pd(PPh3)2Cl2 (375.1 mg, 0.534 mmol) and trimethylsilylacetylene (787.2 mg, 8.015 mmol) in TEA (20 mL) was stirred, and CuI (203.5 mg, 1.068 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The resulting mixture was filtered, and the residue was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain a crude product as a yellow oil (2.37 g, yield 94.4%). The crude product was used directly in the next step without further purification. LCMS 54 (ESI)C 18 H 28 N2OSi2, calculated value 344.17; measured value [M + H] + : 345.

[0369] 7-Ethynyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole. A solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-[2-(trimethylsilyl)ethynyl]indazole (2.37 g, 6.877 mmol) and K2CO3 (1.91 g, 13.754 mmol) in MeOH and DCM (10 mL) was stirred at room temperature for 2 hours under a N2 atmosphere. The resulting mixture was concentrated under vacuum and extracted with CH2Cl2 (3 × 30 mL). The combined organic extracts were washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a yellow oil (650.0 mg, yield 34.6%). LCMS 61 (ESI)C 15 H 20 N2OSi, calculated value 272.13; measured value [M + H] + : 273. 1H NMR(400 MHz,CDCl3)δ 8.25(s,1H),7.96-7.94(m,1H),7.81-7.77(m,1H),7.37-7.31(m,1H),6.3 1(s,2H),3.89-3.74(m,2H),3.66(s,1H),1.15-1.00(m,2H),0.11(s,9H).

[0370] 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-{1-[(trimethylsilyl)methyl]-1,2,3-triazole-4-yl}indazole. A solution of CuBr (349.1 mg, 2.434 mmol) in DMF (2 mL) was treated with (2-{[2-(dimethylamino)ethyl](methyl)amino}ethyl)dimethylamine (454.8 mg, 2.625 mmol) under an N2 atmosphere at room temperature for 20 minutes, and then 7-ethynyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (650.0 mg, 2.386 mmol) from DMF (5 mL) was added in fractions at room temperature. The resulting mixture was stirred under an N2 atmosphere at room temperature for 5 minutes. (azidomethyl)trimethylsilane (259.0 mg, 2.004 mmol) from DMF (3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for a further 1 hour. The resulting mixture was extracted with dimethylethanol (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (750.0 mg, yield 78.2%). LCMS 54(ESI)C 19 H 31 N5OSi2, calculated value 401.21; measured value [M+H] + :402. 1H NMR(400 MHz,CDCl3)δ 8.38(s,1H),8.19(s,1H),8.08(d,J=8.0,1.2 Hz,1H),7.79-7.75(m,1H),7.53(d,J=7.6 Hz,1H),5.79(s,2H),4.33(s,2H),3.76-3.68(m,2H),1.05-0.94(m,2H),0.51(s,9H),0.20(s,9H).

[0371] 7-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazole-4-yl)-1H-indazole. A solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-{1-[(trimethylsilyl)methyl]-1,2,3-triazole-4-yl}indazole (750.0 mg, 1.867 mmol) in HCl (5 mL) and dioxane (5 mL) was stirred at 60°C for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum to obtain the crude product as yellow oil (476.7 mg, yield 94.1%). The crude product was used directly in the next step without further purification. LCMS52 (Method B) (ESI)C 13 H 17 N5Si, calculated value 271.13; measured value [M+H] + :272.

[0372] 7-(1-methyl-1,2,3-triazole-4-yl)-1H-indazole. 7-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazole-4-yl)-1H-indazole (476.7 mg, 1.867 mmol) was stirred in THF (10 mL), to which TBAF (3.73 mL, 3.734 mmol) was added in fractions at 0°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 30 minutes. The resulting mixture was concentrated under vacuum. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as yellow oil (300.0 mg, yield 85.7%). LCMS 50 (Method B) (ESI)C 10H9N5, calculated value 199.09; measured value [M+H] + :200. 1 H NMR(400 MHz,CDCl3)δ 11.76(s,1H),8.14(s,1H),7.96(s,1H),7.75(d,J=8.0 Hz,1H),7.55(d,J=7.1 Hz,1H),7.20(d,J=7.6 Hz,1H),4.21(s,3H).

[0373] 3-iodo-7-(1-methyl-1,2,3-triazole-4-yl)-1H-indazole. 300.0 mg, 1.506 mmol of 7-(1-methyl-1,2,3-triazole-4-yl)-1H-indazole and NIS (406.5 mg, 1.807 mmol) were stirred in THF (5 mL), to which K2CO3 (208.1 mg, 1.506 mmol) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic extract was washed with water (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV 254 nm yielded the desired product as a yellow solid (280.0 mg, yield 57.1%). LCMS 54(ESI)C 10 H8IN5, calculated value 324.98; measured value [M+H] + :326. 1 H NMR(400 MHz,DMSO-d6)δ 13.47(s,1H),8.77(s,1H),7.89(d,J=7.2 Hz,1H),7.44(d,J=8.1 Hz,1H),7.31(d,J=7.6 Hz,1H),4.17(s,3H).

[0374] tert-butyl3-[7-(1-methyl-1,2,3-triazol-4-yl)-1H-indazole-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylate. A mixture of 3-iodo-7-(1-methyl-1,2,3-triazole-4-yl)-1H-indazole (200.0 mg, 0.615 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (190.2 mg, 0.615 mmol), Pd(dppf)Cl2 (45.7 mg, 0.06 mmol), and K2CO3 (255.1 mg, 1.845 mmol) in dioxane (1.2 mL) and H2O (0.6 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (0.1% FA), gradient from 0% to 60% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow solid (100.0 mg, yield 42.7%). LCMS 50 (Method B) (ESI)C 20 H 24 N6O2, calculated value 380.20; measured value [M+H] + :381. 1 H NMR(400 MHz,DMSO-d6)δ 12.98(s,1H),8.75(s,1H),7.99(d,J=8.2 Hz,1H),7.82(d,J=7.2 Hz,1H),7.26(d,J=7.7 Hz,1H),6.73(s,1H),4.44(s,2H),4.17(s,3H),3.56(d,J=5.8 Hz,2H),2.38(d,J=6.1 Hz,2H),1.45(s,9H).

[0375] 7-(1-methyl-1,2,3-triazole-4-yl)-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole; formic acid. To a stirred mixture of tert-butyl 3-[7-(1-methyl-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylate (120.0 mg, 0.315 mmol) in dioxane (1 mL), HCl (gas) in 1,4-dioxane (1 mL) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 15% B in 9 mins; wavelength: 254 nm / 220 nm; RT1 (min): 8.68 / 9.42) to obtain the desired product as a white solid (14.8 mg, yield 14.3%). LCMS 51 (Method L) (ESI)C 15 H 16 N6, calculated value 280.14; measured value [M+H] + :281.20. 1 H NMR(400 MHz,DMSO-d6)δ 8.74(s,1H),7.96(d,J=8.2 Hz,1H),7.81(d,J=7.1 Hz,1H),7.23(d,J=7.7 Hz,1H),6.65(d,J=4.0 Hz,1H),4.17(s,3H),3.76(d,J=2.3 Hz,2H),2.90(d,J=5.6 Hz,2H),2.30-2.24(m,2H).

[0376] Example 29: Synthesis of 7-cyclopropyl-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 314) [ka]

[0377] 7-Cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole. 7-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (3.00 g, 9.16 mmol), cyclopropyltrifluoro-λ4-borane potassium (1.63 g, 10.99 mmol), Pd(dppf)Cl2 (670.6 mg, 0.91 mmol), and K2CO3 (3.80 g, 27.49 mmol) were mixed in 1,4-dioxane (60 mL) and H2O (30 mL) and stirred at 100°C for 3 hours under an N2 atmosphere. The resulting mixture was diluted with H2O (200 mL) and extracted with siRNA (3 × 200 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (600 mg, yield 22.6%). LCMS 42 (Method A) (ESI)C 16 H 24 N2OSi, calculated value 288.17; measured value [M+H] + :289.

[0378] 7-Cyclopropyl-1H-Indazole. A stirred solution of 7-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (600.0 mg, 2.08 mmol) in 1,4-dioxane (6 mL) was prepared by adding HCl (6 mL, 4 M in 1,4-dioxane) at room temperature. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The mixture was concentrated under reduced pressure, dissolved in MeOH (2 mL), and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was then analyzed under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 20 minutes; purified by reverse-phase flash chromatography using UV254nm to obtain the desired product as yellow oil (200 mg, yield 60.7%). LCMS 42 (Method A) (ESI)C 10 H 10 N2, calculated value 158.08; measured value [M+H] + :159.

[0379] 7-Cyclopropyl-3-iodo-1H-indazole. 7-Cyclopropyl-1H-indazole (200.0 mg, 1.26 mmol) was stirred in DMF (3 mL), to which NIS (341.3 mg, 1.51 mmol) was added at room temperature. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour and extracted with siRNA (20 mL). The combined organic extract was washed with water (3 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (160 mg, yield 44.5%). LCMS 42 (Method A) (ESI)C 10 H9IN2, calculated value 283.98; measured value [M+H] + :285.

[0380] tert-butyl 3-(7-cyclopropyl-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. 7-cyclopropyl-3-iodo-1H-indazole (150.0 mg, 0.52 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (195.9 mg, 0.63 mmol), Pd(dppf)Cl2 (38.6 mg, 0.05 mmol), and K2CO3 (218.9 mg, 1.58 mmol) were mixed in 1,4-dioxane (4 mL) and H2O (2 mL) and stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was diluted with H2O (20 mL) and extracted with SiO2 (3 × 20 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as yellow oil (140 mg, yield 78.1%). LCMS49 (Method J) (ESI)C 20 H 25 N3O2, calculated value 339.19; measured value [M+H] + :340.

[0381] 7-Cyclopropyl-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. A stirred solution of tert-butyl 3-(7-cyclopropyl-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol) in 1,4-dioxane (0.5 mL) was mixed with HCl (0.5 mL, 4 M in 1,4-dioxane) at room temperature under an N2 atmosphere, and the mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL), and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3%B to 3%B at 1 min, 3%B to 20%B at 2 min, 20% to 38%B at 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.52) to obtain the desired product as a white solid (43.4 mg, yield 61.5%). LCMS 41 (Method B) (ESI)C 15 H 17 N3, calculated value 239.14; measured value [M+H] + :240. 1 H NMR(300 MHz,CD3OD)δ 7.81-7.71(m,1H),7.15-7.04(m,1H),7.03-6.92(m,1H),6.73-6.62(m,1H),4.04-3.93(m,2H), 3.18-3.07(m,2H),2.53-2.40(m,2H),2.28-2.14(m,1H),1.12-0.99(m,2H),0.85-0.70(m,2H).

[0382] Example 30: Synthesis of 7-chloro-6-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 513) [ka]

[0383] (E)-[(3-chloro-2,4-difluorophenyl)methylidene]hydrazine. Hydrazine hydrate (5.67 g, 113.28 mmol) was added in fractions to a stirred solution of 3-chloro-2,4-difluorobenzaldehyde (2 g, 11.33 mmol) in EtOH (10 mL), and the mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (1.3 g, yield 60.2%). LCMS 60(ESI)C7H5ClF2N2, calculated value 190.01; measured value [M+H] + :191.

[0384] A solution of 7-bromo-6-fluoro-1H-indazole (E)-[(3-chloro-2,4-difluorophenyl)methylidene]hydrazine (1.3 g, 6.82 mmol) in ethylene glycol (10 mL) was stirred at 120 °C for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (800 mg, yield 54.5%). LCMS 60(ESI)C7H4ClFN2, calculated value 170; measured value [M+H] + :171. 1 HNMR(400 MHz,DMSO-d6)δ 13.74(s,1H),8.27-8.16(m,1H),7.81(dd,J=8.8,4.6 Hz,1H),7.25-7.13(m,1H).

[0385] 7-Chloro-6-fluoro-3-iodo-1H-indazole. 7-Chloro-6-fluoro-1H-indazole (800 mg, 4.69 mmol) and KOH (526.3 mg, 9.38 mmol) were stirred in DMF (10 mL), to which I2 (1428.5 mg, 5.63 mmol) was added in fractions at 0°C. The resulting mixture was stirred at room temperature for 20 minutes. The resulting mixture was diluted with water (10 mL), extracted with  (3 × 20 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (550 mg, yield 39.5%). 1 HNMR(400 MHz,DMSO-d6)δ 14.19(s,1H),7.47(dd,J=8.8,4.5 Hz,1H),7.33-7.21(m,1H).

[0386] tert-butyl 3-(7-chloro-6-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. 7-chloro-6-fluoro-3-iodo-1H-indazole (550 mg, 1.86 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (860.5 mg, 2.78 mmol) were stirred in H2O (2 mL) and dioxane (10 mL). K2CO3 (769.2 mg, 5.57 mmol) and Pd(dppf)Cl2 (271.5 mg, 0.37 mmol) were added at room temperature. The resulting mixture was stirred at 80°C for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with ₹ (3 × 20 mL). The combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (380 mg, yield 58.2%). LCMS 60(ESI)C 17 H 19 ClFN3O2, calculated value 351.11; measured value [M+H] + :352.

[0387] 7-Chloro-6-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. To a stirred solution of tert-butyl 3-(7-chloro-6-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (360 mg, 1.02 mmol) in DCM (2 mL), TFA (2 mL) was added in fractional amounts and stirred at room temperature for 20 minutes. The resulting mixture was concentrated under reduced pressure. The crude product (180 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5%B to 5%B at 1 min, 5%B to 20%B at 2 min, 20% to 38%B at 10 min) to obtain the desired product as a white solid (156.7 mg, yield 48.6%). LCMS 63 (Method Q) (ESI)C 12 H 11 ClFN3, calculated value 251.06; measured value [M+H] + :251.95. 1 HNMR(400 MHz,DMSO-d6+D2O)δ 8.10-8.02(m,1H),7.31-7.23(m,1H),6.88-6.81(m,1H),4.17-4.10(m,2H),3.38-3.27(m,2H),2.65-2.55(m,2H).

[0388] Example 31: Synthesis of 6-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole-7-carbonitrile (compound 514) [ka]

[0389] (E)-[(3-bromo-2,4-difluorophenyl)methylidene]hydrazine. Hydrazine hydrate (3.4 g, 67.87 mmol) was added in fractions to a stirred solution of 3-bromo-2,4-difluorobenzaldehyde (1.5 g, 6.79 mmol) in EtOH (20 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (1.2 g, yield 75.2%). LCMS60(ESI)C7H5BrF2N2, calculated value 233.96; measured value [M+H] + :235.

[0390] 7-Bromo-6-fluoro-1H-indazole. A solution of (E)-[(3-bromo-2,4-difluorophenyl)methylidene]hydrazine (1.2 g, 5.11 mmol) in ethylene glycol dimethyl ether (20 mL) was stirred overnight at 120 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (800 mg, yield 72.8%). LCMS 60(ESI)C7H4BrFN2, calculated value 213.95; measured value [M+H] + :215.

[0391] 6-Fluoro-1H-indazole-7-Carbonitrile. 7-Bromo-6-Fluoro-1H-indazole (800 mg, 3.72 mmol) was stirred in DMF (10 mL), to which Zn(CN)2 (0.87 g, 7.44 mmol) and Pd(PPh3)4 (0.86 g, 0.74 mmol) were added at room temperature. The resulting mixture was stirred at 60°C for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (350 mg, yield 58.3%). LCMS 60(ESI)C8H4FN3, calculated value 161.04; measured value [M+H] + :162.

[0392] 6-Fluoro-3-iodo-1H-indazole-7-carbonitrile. To a stirred solution of 6-fluoro-1H-indazole-7-carbonitrile (350 mg, 2.17 mmol) in DMF (10 mL) were added KOH (365.6 mg, 6.52 mmol) and I₂ (826.9 mg, 3.26 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h, diluted with water (5 mL), extracted with EtOAc (3 × 10 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (1:1) to afford the desired product as a white solid (300 mg, yield 48.1%). LCMS 60 (ESI) C₈H₃FIN₃, calcd 286.94; found [M+H] + : 288.

[0393] tert-Butyl 3-(7-cyano-6-fluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. To a stirred solution of 6-fluoro-3-iodo-1H-indazole-7-carbonitrile (290 mg, 1.01 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (468.6 mg, 1.52 mmol) in dioxane (10 mL) and H₂O (2 mL) were added Pd(dppf)Cl₂ (148 mg, 0.20 mmol) and K₂CO₃ (419 mg, 3.03 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under a N₂ atmosphere. The resulting mixture was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (1:1) to afford the desired product as a white solid (190 mg, yield 54.9%). LCMS 53 (method L) (ESI) C 18 H 19 FN₄O₂, calcd 342.15; found [M+H] + : 343.

[0394] 6-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole-7-carbonitrate; formic acid. To a stirred solution of tert-butyl 3-(7-cyano-6-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 0.29 mmol) in DCM (2 mL), TFA (2 mL) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The residue was collected under the following conditions (column: C 18 The desired product was purified by reverse-phase flash chromatography using silica gel (mobile phase, ACN (0.1% FA) in water, with a gradient of 5% to 100% over 30 minutes) to obtain a white solid (39.3 mg, yield 46.6%). LCMS 40(ESI)C 13 H 11 FN4, calculated value 242.10; measured value [M+H] + :243.25. 1 H NMR(400 MHz,DMSO-d6)δ 10.86-10.22(m,1H),8.05(dd,J=8.1,4.4 Hz,1H),7.16(dd,J=11.3,8.1 Hz,1H),6.68(m,1H),4.03(d,J=2.5 Hz,2H),3.20(d,J=12.0 Hz,2H),2.47(d,J=6.4 Hz,2H).

[0395] Example 32: Synthesis of 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 517) [ka]

[0396] 6,7-Difluoro-3-iodo-1H-indazole. I2 (1.72 g, 6.78 mmol) was added to a stirred solution of 6,7-difluoro-1H-indazole (870.9 mg, 5.65 mmol) and KOH (317.0 mg, 5.65 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 30 minutes, the resulting mixture was quenched at room temperature with saturated Na2S2O3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 10 mL). The combined organic extract was washed with water (4 × 10 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with a 20% ethyl acetate petroleum ether solution to obtain the desired product as a white solid (213.0 mg, yield 13.4%). LCMS 54(ESI)C7H3F2IN2, calculated value 279.93; measured value [M+H] + :280.

[0397] tert-butyl 5-(6,7-difluoro-1H-indazole-3-yl)-3,6-dihydropyridine-2H-pyridine-1-carboxylate. To a solution of 6,7-difluoro-3-iodo-1H-indazole (208.0 mg, 0.74 mmol) and K2CO3 (205.3 mg, 1.47 mmol) in H2O (1 mL) and 1,4-dioxane (4 mL), tert-butyl 5-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (367.5 mg, 1.19 mmol) and Pd(dppf)Cl2 (163.1 mg, 0.22 mmol) were added. After stirring at 85°C for 30 minutes under an N2 atmosphere, the resulting mixture was concentrated under reduced pressure. Residue, under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile in water (0.1% FA), gradient from 1% to 99% over 20 minutes; detector: reverse-phase flash chromatography using UV 254 nm to purify the product, yielding the desired product as a brown solid (230.0 mg, yield 92.3%). LCMS 54(ESI)C 17 H 19 F2N3O2, calculated value 335.14; measured value [M+H] + :336.

[0398] 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. To a stirred solid of tert-butyl 5-(6,7-difluoro-1H-indazole-3-yl)-3,6-dihydropyridine-2H-pyridine-1-carboxylate (220.0 mg, 0.66 mmol), HCl (gas) in 1,4-dioxane (13 mL, 4 M) was added. After stirring at room temperature under an N2 atmosphere for 15 minutes, the resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 10 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile in water (0.1% FA), gradient from 1% to 50% over 25 minutes; detector: reverse-phase flash chromatography using UV 220 nm to purify the product, obtaining the desired product as a white solid (58.9 mg, yield 38.1%). LCMS 40(ESI)C 12 H 11 F2N3, calculated value 235.09; measured value [M+H] + :236. 1 H NMR(400 MHz,DMSO-d6)δ 8.35(s,1H),7.84-7.82(m,1H),7.23-7.21(m,1H),6.75(d,J=4.1 Hz,1H),4.01-3.90(m,2H),3.14-3.12(m,2H),2.46-2.44(m,2H).

[0399] Example 33: Synthesis of 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 518) [ka]

[0400] 5,7-Difluoro-1H-Indazole-3-amine. Hydrazine hydrate (5 mL, 102.87 mmol, 16.1 equivalents) was added at room temperature to a stirred solution of 2,3,5-trifluorobenzonitrile (1.00 g, 6.36 mmol, 1.0 equivalent) in 1-butanol (15 mL). The resulting mixture was stirred at 150 °C for 4 hours under an N2 atmosphere. The resulting mixture was extracted with RINKAN (3 × 30 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 20 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with DCM / MeOH (10:1). Yellow solid, 750.0 mg, yield 69.6%. LCMS49 (Method J) (ESI) [M+H] + :170.

[0401] 5,7-difluoro-3-iodo-1H-indazole. To a stirred solution of 5,7-difluoro-1H-indazole-3-amine (300.0 mg, 1.77 mmol, 1.0 equivalent) in THF (4 mL), BF3.Et2O (0.5 mL, 3.94 mmol, 2.2 equivalents) and 3-methylbutylnitrite (0.4 mL) were added dropwise under an N2 atmosphere at -10°C. The resulting mixture was stirred at room temperature for 30 minutes. The residue was purified by rubbing with ethyl ether (20 mL) to obtain a dark brown solid. The solid was then dissolved in propan-2-one (4 mL) with NaI (120.0 mg, 0.80 mmol, 0.5 equivalents) and added under ice bath conditions. The resulting mixture was stirred at room temperature for 10 minutes under an N2 atmosphere. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 10 mL). After filtration, the filtrate was concentrated under reduced pressure. Black solid, 280.0 mg, yield 56.3%. LCMS 49 (Method J) (ESI) [M+H] + :281.

[0402] tert-butyl3-(5,7-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. A mixture of 5,7-difluoro-3-iodo-1H-indazole (200.0 mg, 0.71 mmol, 1.0 equivalent), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (450.0 mg, 1.45 mmol, 2.0 equivalents), Pd(dppf)Cl2 (55.0 mg, 0.07 mmol, 0.1 equivalent), and K2CO3 (300.0 mg, 2.17 mmol, 3.0 equivalents) in dioxane (5 mL) and H2O (1 mL) was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1). Pale yellow solid, 180.0 mg, yield 75.1%. LCMS 49 (Method J) (ESI) [M+H] + :336.

[0403] 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. To a stirred solution of tert-butyl 3-(5,7-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol, 1.0 equivalent) in DCM (3 mL), TFA (1 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under vacuum. The mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18; mobile phase, water in ACN (0.1% NH4HCO3), gradient from 0% to 50% over 30 minutes. White solid, 35.5 mg, yield 50.4%. LCMS 40(ESI)[M+H] + :236.10. 1H NMR(400 MHz,CD3OD)δ 7.47(d,J=9.1 Hz,1H),7.06(d,J=11.0 Hz,1H),6.60(d,J=4.1 Hz,1H),3.89(d,J=2.3 Hz,2H),3.07(d,J=5.9 Hz,2H),2.43(d,J=8.5 Hz,2H).

[0404] Example 34: Synthesis of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 519) [ka]

[0405] 4,7-Difluoro-1H-Indazole. To a stirred solution of 2,3,6-trifluorobenzaldehyde (1.00 g, 6.24 mmol, 1.0 equivalent) in DME (5 mL), DIEA (2.42 g, 18.73 mmol, 3.0 equivalents) and hydrazine hydrate (0.63 g, 12.49 mmol, 2.0 equivalents) were added at room temperature. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 100 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1). Pale yellow oil, 500.0 mg, yield 51.9%. LCMS 52 (Method B) (ESI) [M+H] + :155.

[0406] 4,7-Difluoro-3-iodo-1H-indazole. 4,7-Difluoro-1H-indazole (400.0 mg, 2.59 mmol, 1.0 equivalent) and KOH (500.0 mg, 8.91 mmol, 3.4 equivalents) were stirred in DMF (10 mL). I2 (700.0 mg, 2.75 mmol, 1.0 equivalent) was slowly added at room temperature. The resulting mixture was stirred under an N2 atmosphere at room temperature for 2 hours. The reaction was quenched by adding saturated Na2S2O3 aqueous solution (10 mL) under ice bath conditions. The aqueous layer was extracted with EA (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. Pale yellow oil, 400.0 mg, yield 55.0%. LCMS 49 (Method K) (ESI) [M+H] + :281.

[0407] tert-butyl3-(4,7-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. To a stirred solution of 4,7-difluoro-3-iodo-1H-indazole (300.0 mg, 1.07 mmol, 1.0 equivalent) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (662.5 mg, 2.14 mmol, 2.0 equivalent) in dioxane (5 mL), Pd(dppf)Cl2 (100.0 mg, 0.14 mmol, 0.1 equivalent), K2CO3 (450.0 mg, 3.25 mmol, 3.0 equivalent), and H2O (1 mL) were added in portions at room temperature under an N2 atmosphere. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1). White solid, 320.0 mg, yield 89.0%. LCMS49 (Method K) (ESI) [M+H] + :336.

[0408] 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. To a stirred solution of tert-butyl 3-(4,7-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.44 mmol, 1.0 equivalent) in DCM (1 mL), TFA (0.5 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 8 with saturated Na2CO3 aqueous solution. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using UV254 nm under the following conditions: column, C18; mobile phase, (0.1% NH4HCO3) water in ACN, gradient from 0% to 50% over 30 minutes. White solid, 30.2 mg, yield 28.5%. LCMS 40(ESI)[M+H] + :236.10. 1 H NMR(300 MHz,CDCl3)δ 7.00(s,1H),6.71(s,2H),3.97-3.90(m,2H),3.11(s,2H),2.37(s,2H).

[0409] Example 35: Synthesis of 5-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole-7-carbonitrile (compound 520) [ka]

[0410] 5-Fluoro-1H-indazole-7-Carbonitrile. A solution of 7-bromo-5-fluoro-1H-indazole (500.0 mg, 2.33 mmol, 1.0 equivalent) and Zn(CN)2 (273.0 mg, 2.33 mmol, 1.0 equivalent) in DMA (5.0 mL) was stirred at 120°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with  (3 × 10 mL). The combined organic extracts were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (300.0 mg, yield 80.1%). LCMS 60(ESI)C8H4FN3, calculated value 161.04; measured value [M+H] + :162. 1 H NMR(400 MHz,DMSO-d6)δ 14.15(s,1H),8.32(s,1H),8.08-7.98(m,2H).

[0411] 5-Fluoro-3-iodo-1H-indazole-7-carbonitride. A solution of 5-fluoro-1H-indazole-7-carbonitride (400.0 mg, 2.48 mmol) and NIS (558.5 mg, 2.48 mmol) in DMF (5.0 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. The aqueous layer was extracted with  (3 × 20 mL). The combined organic extract was washed with water (3 × 10 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (300.0 mg, yield 42.1%). LCMS 60(ESI)C₂H₃FIN₃, calculated value 286.94; measured value [M+H] + :288. 1 H NMR(400 MHz,DMSO-d6)δ 14.58(s,1H),8.17-8.13(m,1H),7.74-7.69(m,1H).

[0412] To a stirred solution of tert-butyl 3-(7-cyano-5-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 5-fluoro-3-iodo-1H-indazole-7-carbonitride (300.0 mg, 1.05 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (484.8 mg, 1.57 mmol) in dioxane (4.0 mL), Pd(dppf)Cl2·CH2Cl2 (42.6 mg, 0.05 mmol) and K2CO3 (433.3 mg, 3.14 mmol) were added at 80°C under an N2 atmosphere. The aqueous layer was extracted with  (3 × 20 mL). The combined organic layers were washed with water (3 × 10 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (200.0 mg, yield 55.9%). LCMS 60(ESI)C 18 H 19 FN4O2, calculated value; measured value 342.15 [MH] - :341. 1 H NMR(400 MHz,DMSO-d6)δ 14.06(s,1H),8.27-8.18(m,1H),8.03(m,1H),6.79-6.73(s,1H),4.40-4.35(m,2H),3.54(d,J=5.8 Hz,2H),2.42-2.28(m,2H),1.48-1.42(m,9H).

[0413] 5-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole-7-carbonitride. A solution of tert-butyl 3-(7-cyano-5-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol, 1.0 equivalent) in 0.5 mL of dioxane and 0.5 mL of HCl (gas) in 0.5 mL of 1,4-dioxane was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was basicized to pH 10 with saturated Na2CO3 (aqueous solution). The crude product (100.0 mg) was purified by preparative HPLC under the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 m; Mobile phase A: Water (0.1% NH4HCO3), Mobile phase B: ACN; Flow rate: 60.0 mL / min; Gradient: 5% B to 22% B in 30 mins; Wavelength: 254 nm / 220 nm; RT1 (min): 9.68) to obtain the desired product as a yellow solid (23.2 mg, yield 32.8%). LCMS 48 (Method I) (ESI)C 13 H 11 FN4 calculated value 242.10; measured value [MH]-: 241.20. 1 H NMR(400 MHz,DMSO-d6)δ 8.20(d,J=9.2 Hz,1H),8.05-7.98(m,1H),6.65(s,1H),3.71(s,2H),2.93-2.84(m,2H),2.24(s,2H).

[0414] Example 36: Synthesis of 7-chloro-1-isopropyl-3-(1,2,5,6-tetrahydropyridine-3-yl)indole (compound 525) [ka]

[0415] 7-Chloro-1-isopropylindole. Indole-7-chloro (3.00 g, 19.79 mmol) in N,N-dimethylformamide (10 mL) was added dropwise at 0°C under a N2 atmosphere to a stirred solution of sodium hydride (1.90 g, 79.16 mmol) in N,N-dimethylformamide (15 mL). The resulting mixture was stirred for 30 minutes. 2-bromopropane (3.65 g, 29.68 mmol) was added dropwise to the above mixture. The resulting mixture was stirred further at room temperature for 2 hours. The resulting mixture was diluted with toluene (50 mL). The reaction was quenched by adding 1 M hydrochloric acid at 0°C. The organic layer was washed with brine (3 × 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with petroleum ether / ethyl acetate (17:3) to obtain the desired product as a colorless liquid (1.05 g, yield 27.4%). LCMS 54(ESI)C 11 H 12 ClN, calculated value 193.07; measured value [M+H] + :194. 1 H NMR(300 MHz,CDCl3)δ 7.47-7.40(m,1H),7.26-7.20(m,1H),7.10-7.03(m,1H),6.95-6.85(m,1H),6.46(d,J=3.3 Hz,1H),5.71-5.55(m,1H),1.45(d,J=6.7 Hz,6H).

[0416] 3-Bromo-7-chloro-1-isopropylindole. A solution of 7-chloro-1-isopropylindole (1.05 g, 5.42 mmol) in dioxane (10 mL) was treated with 1,3-dibromo-5,5-dimethylhydantoin (1.01 g, 3.524 mmol) under an N2 atmosphere at 0°C for 25 minutes. The resulting mixture was diluted with  (20 mL). The reaction product was quenched by adding saturated sodium thiosulfate (aqueous solution) at 0°C. The organic layer was washed with water (3 × 10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with a 3% ethyl acetate petroleum ether solution to obtain the desired product as a colorless liquid (1.02 g, yield 69.0%). LCMS 54(ESI)C 11 H 11 BrClN, calculated value 270.98; measured value [M+H] + :272. 1 H NMR(400 MHz,CDCl3)δ 7.48-7.43(m,1H),7.32-7.28(s,1H),7.23-7.17(m,1H),7.11-7.03(m,1H),5.76-5.64(m,1H),1.51(d,J=6.7 Hz,6H).

[0417] tert-butyl 3-(7-chloro-1-isopropylindole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. Solutions of 3-bromo-7-chloro-1-isopropylindole (1.00 g, 3.67 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.70 g, 5.50 mmol) in water (1.5 mL) and dioxane (7.5 mL) were treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.54 g, 0.73 mmol) and potassium carbonate (1.01 g, 7.34 mmol) under an N2 atmosphere at 90°C for 3 hours. The resulting mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (2 × 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile (0.1% formic acid) in water, gradient from 10% to 95% over 10 minutes; detector: reverse-phase flash chromatography using UV254nm to purify the product, yielding the desired brown oil (750.0 mg, yield 54.5%). LCMS 54(ESI)C 21 H 27 ClN2O2, calculated value 374.18; measured value [M+H] + :375.

[0418] 7-Chloro-1-isopropyl-3-(1,2,5,6-tetrahydropyridine-3-yl)indole. To a stirred solution of tert-butyl 3-(7-chloro-1-isopropylindole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (130.0 mg, 0.34 mmol) in dichloromethane (10 mL), hydrochloric acid (gas) in 1,4-dioxane (0.43 mL, 1.74 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash under the following conditions: (Column: Sunfire prep C18 column 30*150 mm, 5 m; Mobile phase A: Water (0.1% formic acid), Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 10% B to 30% B over 9 minutes; Wavelength: 254 nm / 220 nm). The desired product was obtained as a white solid (66.0 mg, yield 59.3%). LCMS 40(ESI)C 16 H 19 ClN2, calculated value 274.12; measured value [M+H] + :275.10. 1 H NMR(400 MHz,CD3OD)δ 8.49(s,1H),7.75-7.73(m,1H),7.57(s,1H),7.19-7.17(m,1H),7.06-7.04(m,1H),6.33-6.31(m ,1H),5.76-7.54(m,1H),4.06-4.04(m,2H),3.41-3.39(m,2H),2.64-2.62(m,2H),1.53(d,J=6.7 Hz,6H).

[0419] Example 37: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-4-ol (compound 527) [ka]

[0420] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-4-ol. To a solution of tert-butyl3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridine-3-yl]-4-methoxyindole-1-carboxylate (150.0 mg, 0.35 mmol) in dichloromethane (5.0 mL), BBr3 (263.1 mg, 1.05 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The reaction product was quenched with water. The resulting mixture was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile in water (10 mmol / L NH4HCO3), gradient from 5% to 95% over 20 minutes; detector: reverse-phase flash chromatography using UV 254 nm to obtain the desired product as a black solid (32.3 mg, yield 41.2%). LCMS 41 (Method B) (ESI)C 13 H 14 N2O, calculated value 214.11; measured value [M+H] + :215.10. 1 H NMR(400 MHz,DMSO-d6)δ 10.89(s,1H),7.06(s,1H),6.92-6.68(m,2H),6.36(d,J=7.3 Hz,1H),5.99(s,1H),4.29(s,1H),3.60(s,1H),3.46(s,1H),2.83(s,1H),2.12(d,J=35.5 Hz,2H).

[0421] Example 38: Synthesis of 7-chloro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-5-ol (compound 529) [ka]

[0422] 7-Chloro-5-methoxy-1H-indole. To a stirred solution of 2-chloro-4-methoxy-1-nitrobenzene (2.00 g, 10.662 mmol) in THF (20 mL), bromo(ethenyl)magnesium (37.4 mL, 1 M in THF) was added dropwise at -40°C. The resulting mixture was stirred at -40°C for 0.5 hours under an N2 atmosphere. The reaction product was quenched with saturated NH4Cl (aqueous solution) at -40°C. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (678 mg, yield 35.0%). LCMS 52 (Method A) (ESI) C9H8ClNO Calculated value 181.03; Measured value [MH] - :180. 1 H NMR(400 MHz,CDCl3)δ 8.21(s,1H),7.17(m,1H),7.01(d,J=2.2 Hz,1H),6.90(d,J=2.2 Hz,1H),6.49(m,1H),3.82(s,3H).

[0423] 7-Chloro-3-iodo-5-methoxy-1H-indole. 7-Chloro-5-methoxy-1H-indole (660.0 mg, 3.634 mmol) was stirred in DMF (7 mL), to which NIS (817.5 mg, 3.634 mmol) was added in fractions at 0°C. The mixture was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was extracted with  (3 × 20 mL). The combined organic extract was washed with water (3 × 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (760 mg, yield 68.0%). LCMS 60(ESI)C₁H₂ClINO, calculated value 306.93; measured value [M+H] + :308.

[0424] tert-butyl 7-chloro-3-iodo-5-methoxyindole-1-carboxylate. 7-chloro-3-iodo-5-methoxy-1H-indole (750.0 mg, 2.439 mmol), TEA (740.3 mg, 7.317 mmol), and DMAP (29.8 mg, 0.244 mmol) were stirred in DCM (8 mL), to which Boc2O (1.60 g, 7.317 mmol) was added at 0°C. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The resulting mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic extract was washed with water (3 × 4 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as a yellow solid (367 mg, yield 36.9%). LCMS 54(ESI)C 14 H 15 ClINO3, calculated value 406.98; measured value [M+H] + :408. 1 H NMR(400 MHz,CDCl3)δ 7.65(s,1H),7.03(d,J=2.4 Hz,1H),6.78(d,J=2.4 Hz,1H),3.88(d,J=1.0 Hz,3H),1.64(s,9H).

[0425] To a stirred solution of tert-butyl 3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridine-3-yl]-7-chloro-5-methoxyindole-1-carboxylate, tert-butyl 7-chloro-3-iodo-5-methoxyindole-1-carboxylate (350.0 mg, 0.859 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (398.2 mg, 1.288 mmol), and K2CO3 (356.0 mg, 2.577 mmol) in dioxane (4 mL) and H2O (2 mL), Pd(dppf)Cl2 (62.8 mg, 0.086 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 20 mL). The combined organic extract was washed with water (3 × 5 mL) and dried over anhydrous sodium ₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow oil (200 mg, yield 50.3%). LCMS 49 (Method J) (ESI)C 24 H 31 ClN2O5, calculated value 462.19; measured value [M+H] + :463. 1 H NMR(400 MHz,DMSO-d6)δ 7.65(s,1H),7.23(s,1H),7.06(d,J=2.3 Hz,1H),6.30(s,1H),4.17(d,J=2.6 Hz,2H),3.82(s,3H),3.51(d,J=5.7 Hz,2H),2.35-2.26(m,2H),1.60(s,9H),1.44(s,9H).

[0426] Example 39: Synthesis of 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole (compound 533) [ka]

[0427] 2,3-Difluoro-6-[2-(trimethylsilyl)ethynyl]aniline. 2,3-Difluoro-6-iodoaniline (1.5 g, 5.882 mmol) and trimethylsilylacetylene (808.8 mg, 8.235 mmol) were stirred in TEA (15 mL), to which CuI (224.1 mg, 1.176 mmol) and Pd(PPh3)2Cl2 (412.9 mg, 0.588 mmol) were added. The resulting mixture was stirred under an N2 atmosphere at room temperature for 2 hours. The resulting mixture was extracted with RINKAN (3 × 20 mL). The combined organic extract was washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (9:1) to obtain the desired product as yellow oil (920.0 mg, yield 69.4%). LCMS 54(ESI)C 11 H 13 F2NSi, calculated value 225.08; measured value [M+H] + :226. 1 H NMR(400 MHz,DMSO-d6)δ 6.88(m,1H),6.36(m,1H),5.48(s,2H)0.10(s,9H).

[0428] 6,7-difluoro-1H-indole. CuI (1.56 g, 8.166 mmol) was added to a stirred mixture of 2,3-difluoro-6-[2-(trimethylsilyl)ethynyl]aniline (920.0 mg, 4.083 mmol) in DMF (20 mL). The resulting mixture was stirred at 100°C for 5 hours under an N2 atmosphere. The resulting mixture was extracted with  (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (550.0 mg, yield 87.9%). 1 H NMR(400 MHz,DMSO-d6)δ 11.75(s,1H),7.42(d,J=2.8 Hz,1H),7.34(d,J=8.7,4.3 Hz,1H),7.01(m,1H),6.52(d,J=2.8 Hz,1H).

[0429] 6,7-Difluoro-3-iodo-1H-indole. 6,7-Difluoro-1H-indole (540.0 mg, 3.526 mmol) was mixed in DMF (10 mL) with NIS (1.19 g, 5.289 mmol). The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction product was quenched at room temperature with saturated Na2SO3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 30 mL). The combined organic extracts were washed with water (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV 254 nm yielded the desired product as yellow oil (610.0 mg, yield 66.9%). LCMS 60(ESI)C8H4F2IN, calculated value 278.94; measured value [M+H] + :280. 1 H NMR(400 MHz,DMSO-d6)δ 12.24(s,1H),7.65(d,J=2.5 Hz,1H),7.22-7.06(m,2H).

[0430] tert-butyl 3-(6,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. 6,7-difluoro-3-iodo-1H-indole (600.0 mg, 2.150 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (997.3 mg, 3.225 mmol) were stirred in dioxane (6 mL) and H2O (3 mL). K2CO3 (891.5 mg, 6.450 mmol) and Pd(dppf)Cl2 (157.3 mg, 0.215 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous sodium ₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (9:1) to obtain the desired product as a yellow solid (400.0 mg, yield 55.6%). LCMS 54(ESI)C 18 H 20 F2N2O2, calculated value 334.15; measured value [M+H] + :335. 1 H NMR(400 MHz,CD3OD)δ 7.50(d,J=9.0,4.1 Hz,1H),7.29(s,1H),6.94-6.90(m,1H),6.25-6.23(m,1H),4.24(s,2H),3.59(d,J=6.0 Hz,2H),2.39-2.26(m,2H),1.50(s,9H).

[0431] 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole.HCl (gas) in 1,4-dioxane (2 mL) was added to a stirred solution of tert-butyl 3-(6,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (200.0 mg, 0.598 mmol) in dioxane (2 mL). The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour and concentrated under vacuum. The mixture was dissolved in methanol and the pH was adjusted to 8 with saturated Na2CO3 (aqueous solution). After concentration under reduced pressure, the residue was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2%B to 2%B at 1.5 min, 2%B to 19%B at 2 min, 19%B to 38%B at 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.94) to obtain the desired product as a white solid (68.4 mg, yield 48.4%). LCMS 40(ESI)C 13 H 12 F2N2, calculated value 234.14; measured value [M+H] + :235.05. 1 H NMR(400 MHz,CD3OD)δ 7.53-7.48(m,1H),7.28(s,1H),6.98-6.90(m,1H),6.26-6.23(m,1H),3.71(d,J=2.3 Hz,2H),3.06(d,J=5.9 Hz,2H),2.42-2.35(m,2H).

[0432] Example 40: Synthesis of 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole (compound 534) [ka]

[0433] 5,7-Difluoro-3-iodo-1H-indole. A solution of 5,7-difluoro-1H-indole (500.0 mg, 3.27 mmol) and NIS (734.6 mg, 3.27 mmol) in DMF (5.0 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. The aqueous layer was extracted with RINKAN (3 × 50 mL). The combined organic extract was washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as a yellow solid (800.0 mg, yield 87.8%). LCMS 42 (Method B) (ESI) C8H4F2IN Calculated value 278.94; Measured value [MH]-: 278. 1 H NMR(400 MHz,DMSO-d6)δ 12.21(s,1H),7.72(d,J=2.6 Hz,1H),7.14-7.04(m,1H),6.96-6.86(m,1H).

[0434] tert-butyl 3-(5,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. Solutions of 5,7-difluoro-3-iodo-1H-indole (800.0 mg, 2.87 mmol), Pd(dppf)Cl2.CH2Cl2 (116.8 mg, 0.14 mmol), K2CO3 (1188.7 mg, 8.60 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1329.8 mg, 4.30 mmol) in dioxane (8.0 mL) and H2O (4.0 mL) were stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with Depositphotos (3 × 10 mL). The combined organic extracts were washed with water (10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (200.0 mg, yield 20.9%). LCMS 41 (Method B) (ESI)C 18 H 20 F2N2O2 calculated value: 334.15; measured value [MH]-: 333.1 H NMR(400 MHz,DMSO-d6)δ 11.83(s,1H),7.56(s,1H),7.45-7.38(m,1H),7.09-7.00(m,1H),6.25-6.18( m,1H),4.24-4.15(m,2H),3.55-3.46(m,2H),2.32-2.24(m,2H),1.44(s,9H).

[0435] 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole. A solution of tert-butyl 3-(5,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (200.0 mg, 0.60 mmol) in dioxane (0.5 mL) and HCl (gas) in 1,4-dioxane (1.0 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 10 with saturated Na2CO3 (aqueous solution). The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV254nm to purify the product, and the desired product was obtained as a yellow solid (78.9 mg, yield 56.3%). LCMS 52 (Method B) (ESI)C 13 H 12 F2N2, calculated value 234.10; measured value [M+H] + :234.95. 1 H NMR(400 MHz,DMSO-d6)δ 11.72(s,1H),7.49(s,1H),7.39-7.35(m,1H),7.03-6.97(m,1H),6.15(d,J=4.2 Hz,1H),3.53(s,2H),2.89-2.79(m,2H),2.25-2.12(m,2H).

[0436] Example 41: Synthesis of 7-chloro-4,6-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole (compound 521) [ka]

[0437] 3-Chloro-2,4,6-trifluorobenzaldehyde. To a stirred solution of 2-chloro-1,3,5-trifluorobenzene (2.50 g, 15.01 mmol) in THF (10 mL), LDA (2.4 mL, 18.01 mmol) was added dropwise at -78°C and the mixture was stirred at -78°C for 15 minutes under an N2 atmosphere. Then, DMF (13.9 mL, 180.14 mmol) was added at -78°C and the mixture was stirred at -78°C for 15 minutes under an N2 atmosphere, followed by the addition of H2SO4 (5 mL) at -78°C. The resulting mixture was stirred at -50°C for 30 minutes under an N2 atmosphere. The reaction product was quenched with 60 mL of water at room temperature. The aqueous layer was extracted with RINKAN (5 × 60 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (1.70 g, yield 58.2%). 1 H NMR(300 MHz,CDCl3)δ 10.41-10.16(m,1H),7.00-6.86(m,1H).

[0438] 7-Chloro-4,6-difluoro-1H-indazole. A solution of 3-chloro-2,4,6-trifluorobenzaldehyde (1.00 g, 5.14 mmol) and N2H4.H2O (385.5 mg, 7.71 mmol) in EtOH (10 mL) was stirred at 80°C for 3 hours under an N2 atmosphere. The resulting mixture was concentrated under vacuum and diluted with H2O (70 mL). The aqueous layer was extracted with RINKAN (5 × 70 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (400.0 mg, yield 41.2%). LCMS 60(ESI)C7H3ClF2N2, calculated value 188.56; measured value [M+H] + :189. 1 H NMR(300 MHz,CDCl3)δ 8.19(s,1H),6.90-6.72(m,1H).

[0439] 7-Chloro-4,6-difluoro-3-iodo-1H-indazole. A solution of 7-chloro-4,6-difluoro-1H-indazole (200.0 mg, 1.06 mmol) and NIS (357.9 mg, 1.59 mmol) in DMF (3 mL) was stirred at 50°C for 1 hour under an N2 atmosphere. The reaction mixture was quenched at room temperature with 40 mL of Na2S2O3 (aqueous solution). The aqueous layer was extracted with RINKAN (5 × 40 mL) ethyl acetate. The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (6:1) to obtain the desired product as a white solid (300.0 mg, yield 89.9%). LCMS 60(ESI)C7H2ClF2IN2, calculated value 313.89; measured value [M+H] + :315. 1 H NMR(300 MHz,CDCl3)δ 10.44(s,1H),6.90-6.69(m,1H).

[0440] A solution of tert-butyl 3-(7-chloro-4,6-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate was prepared by stirring the mixture in H2O (2 mL) and dioxane (4 mL) with 7-chloro-4,6-difluoro-3-iodo-1H-indazole (200.0 mg, 0.63 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (295 mg, 0.95 mmol), Pd(dppf)Cl2 (46.5 mg, 0.06 mmol), and K2CO3 (263.7 mg, 1.90 mmol). The mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction was quenched by adding water (50 mL) at room temperature. The aqueous layer was extracted with Depositphotos (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (6:1) to obtain the desired product as a white solid (200 mg, yield 85.0%). LCMS 52(ESI)C 17 H 18 ClF2N3O2, calculated value 369.11; measured value [M+H] + :370. 1H NMR(300 MHz,CDCl3)δ 6.83-6.64(m,2H),4.51(s,2H),3.70-3.54(m,2H),2.50-2.35(m,2H),1.54(s,9H).

[0441] 7-chloro-4,6-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indazole. To a stirred solution of tert-butyl 3-(7-chloro-4,6-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.27 mmol) in dioxane (2 mL), HCl (gas) (2 mL, 4 M) in 1,4-dioxane was added dropwise at room temperature under an N2 atmosphere, and the mixture was stirred for 3 hours. The resulting mixture was concentrated under vacuum. The mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The mixture was purified by Prep-HPLC under the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250mm, 5m; Mobile phase A: 10 mmol / L NH4HCO3 + 0.05% NH3H2O; Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5%B to 5%B at 1 min, 5%B to 47%B at 2 min, 47% to 60%B at 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.48) to obtain the desired product as a white solid (38.6 mg, yield 51.8%). LCMS 52(ESI)C 12 H 10 ClF2N3, calculated value 269.05; measured value [M+H] + :270.15. 1 H NMR(400 MHz,DMSO-d6)δ 7.20(d,J=3.3 Hz,1H),6.57-6.40(m,1H),3.77-3.61(m,2H),2.86(d,J=5.7 Hz,2H),2.29-2.14(m,2H).

[0442] Example 42: Synthesis of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole (compound 535) [ka]

[0443] 4,7-Difluoro-3-iodo-1H-indole. A solution of 4,7-difluoro-1H-indole (250.0 mg, 1.63 mmol) and NIS (551.0 mg, 2.45 mmol) in DMF (3.0 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. The aqueous layer was extracted with RINKAN (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as a yellow solid (400.0 mg, yield 87.8%). LCMS 41 (Method B) (ESI) C8H4F2IN Calculated value 278.94; Measured value [MH]-: 278. 1 H NMR(400 MHz,DMSO-d6)δ 12.29(s,1H),7.62(d,J=2.6 Hz,1H),6.99-6.90(m,1H),6.81-6.72(m,1H).

[0444] tert-butyl3-(4,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. Solutions of 4,7-difluoro-3-iodo-1H-indole (400.0 mg, 1.43 mmol), Pd(dppf)Cl2.CH2Cl2 (58.4 mg, 0.07 mmol), K2CO3 (594.4 mg, 4.30 mmol), and tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (664.9 mg, 2.15 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) were stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with Depositphotos (3 × 10 mL). The combined organic extracts were washed with water (3 × 10 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (100.0 mg, yield 20.9%). LCMS 42 (Method B) (ESI)C 18 H20 F2N2O2 calculated value: 334.15; measured value [MH]-: 333. 1 H NMR(400 MHz,DMSO-d6)δ 11.99(s,1H),7.45(s,1H),6.97-6.89(m,1H),6.79-6.71(m,1H),6.05( s,1H),4.19(s,2H),3.52-3.44(m,2H),2.27-3.20(m,2H),1.43(s,9H).

[0445] A solution of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole, tert-butyl 3-(4,7-difluoro-1H-indole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.30 mmol) in dioxane (0.5 mL) and HCl (gas) in 1,4-dioxane (0.5 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 10 with saturated Na2CO3 (aqueous solution). The crude product (100.0 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5%B to 5%B at 1 min, 5%B to 17%B at 15 min, 17% to 32%B at 30 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.03) to obtain the desired product as a yellow solid (27.1 mg, yield 38.7%). LCMS 52 (Method B) (ESI)C 13 H 12 F2N2, calculated value 234.10; measured value [M+H] + :234.95. 1 H NMR(400 MHz,DMSO-d6)δ 11.87(s,1H),7.38(s,1H),6.94-6.86(m,1H),6.74-6.66(m,1H),6.01(d,J=5.0 Hz,1H),3.51(d,J=2.6 Hz,2H),2.85-2.79(m,2H),2.16-2.09(m,2H).

[0446] 7-Chloro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1H-indole-5-ol. A 200.0 mg, 0.432 mmol solution of tert-butyl3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridine-3-yl]-7-chloro-5-methoxyindole-1-carboxylate (200.0 mg, 0.432 mmol) was stirred in 5 mL of DCM, to which BBr3 (324.6 mg, 1.296 mmol) was added under an N2 atmosphere. The resulting mixture was stirred under an N2 atmosphere at room temperature for 1 hour and concentrated under reduced pressure. The crude product was collected under the following conditions (column: XBridge Prep OBD C 18 The sample was purified by preparative HPLC using a 30*150mm, 5m column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10%B to 30%B over 20 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 21 minutes. The desired product was obtained as a white solid (15.8 mg, yield 14.7%). LCMS 63 (Method Q) (ESI)C 13 H 13 ClN2O, calculated value 248.07; measured value [M+H] + :249.0. 1 H NMR(400 MHz,DMSO-d6)δ 11.12(s,1H),9.07(s,1H),7.29(d,J=2.6 Hz,1H),7.10(d,J=2.1 Hz,1H),6.71(d,J=2.0 Hz,1H),6.07(d,J=4.0 Hz,1H),3.53(d,J=2.2 Hz,2H),2.86(d,J=5.7 Hz,2H),2.26-2.11(m,2H).

[0447] Example 43: Synthesis of 2-{[(3R)-3-(1H-indazole-3-yl)piperidine-1-yl]methylphenol and 2-{[(3S)-3-(1H-indazole-3-yl)piperidine-1-yl]methylphenol (compounds 523 and 524) [ka]

[0448] A solution of tert-butyl 3-(1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.90 g, 6.14 mmol), 3-iodo-1H-indazole (1.00 g, 4.09 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.90 g, 6.14 mmol), Pd(dppf)Cl2 (0.30 g, 0.41 mmol), K2CO3 (1.70 g, 12.29 mmol), and H2O (3 mL) in dioxane (6 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with ELISA (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (5:1) to obtain the desired product as a yellow solid (800.0 mg, yield 65.2%). LCMS 50 (Method B) (ESI)C 17 H 21 N3O2, calculated value 299.16; measured value [M+H] + :300. 1 H NMR(400 MHz,DMSO-d6)δ 13.01(s,1H),7.98(d,J=8.2 Hz,1H),7.54(d,J=8.4 Hz,1H),7.41-7.33(m,1H),7.16(d,J=7.6 Hz,1H),6.69(s,1H),4.40(s,2H),3.59-3.45(m,2H),2.35(d,J=4.5 Hz,2H),1.44(s,9H).

[0449] tert-butyl 3-(1H-indazole-3-yl)piperidine-1-carboxylate. A solution of tert-butyl 3-(1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (800.0 mg, 2.67 mmol) and Pd / C (142.1 mg, 1.33 mmol, 0.5 equivalents) in MeOH (10 mL) was hydrogenated at room temperature under a hydrogen atmosphere for 5 hours. After filtration, the filtrate was concentrated under vacuum. The residue was collected under the following conditions: column, C 18The silica gel was used as the mobile phas...

Claims

1. Compounds represented by formula I: 【Chemistry 1】 or its pharmaceutically acceptable salts and / or stereoisomers, 【Chemistry 2】 It is a single bond, and X is CR Ｘ And Y is C(R Ｙ ) ２ is; or 【Transformation 3】 It is a double bond, X is C, and Y is C(R Ｙ ) and; A is selected from the group consisting of 8-10 member condensed bicyclic heteroaryls, 12-14 member condensed tricyclic heteroaryls, 8-10 member condensed bicyclic heterocyclyls, and phenyl, and ring A is R Ａ It may be substituted with one or more substituents selected from; R Ａ is, for each occurrence independently, hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ -(CO)-OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ alkyl, -C(O)-C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R Ｘ and R Ｙ These are, independently, hydrogen and -C. １ ~C ３ Selected from the group consisting of alkyl groups; or one R Ｘ and one R Ｙ They bond together to form -CH ２ - forms, R １ is hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, -CH ２ -phenyl, -CH ２ CH ２ -phenyl and -CH ２ - Selected from the group consisting of (4-6 member heteroaryls); C １ ~C ６ Alkyl, phenyl, and heteroaryl compounds are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ２ and R ３ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; C １ ~C ６ Alkyls are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ４ and R ５ are each independently hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ -(CO)-OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ alkyl, -C(O)-C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ alkoxy, -C ３ ~C ６ cycloalkyl and phenyl selected from the group consisting of; C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C<00001​​​​​​​​​​​​​​​​​​​​​ R ６ and R ７ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; C １ ~C ６ Alkyls are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ａ and R ｂ For each appearance, independently, hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups, C １ ~C ３ The alkyl group may optionally be substituted with one or more halogens. A compound represented by formula I, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

2. The aforementioned compound, 【Chemistry 4】 or 【Transformation 5】 The compound according to claim 1, represented by [the given expression].

3. R ６ and R ７ The compound according to claim 1 or 2, wherein the compound is hydrogen.

4. R ２ and R ３ The compound according to claim 1 or 2, wherein the compound is hydrogen.

5. The aforementioned compound, 【Transformation 6】 or 【Transformation 7】 The compound according to claim 1 or 2, represented by...

6. A, 【Transformation 8】 and 【Chemistry 9】 Selected from the group consisting of; in the formula, R ｃ However, hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups, R ｄ However, hydrogen, halogen, hydroxyl, cyano, -C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -C ３ ~C ４ Selected from the group consisting of cycloalkyls, 4-6 membered heterocyclines, and 5-6 membered heteroaryls; where -C １ ~C ３ Alkyls are halogens, hydroxyls, and -NH ２ , -C(O)-NH ２ and -OCH ３ It may be optionally substituted with one, two, or three substituents independently selected from the group consisting of; R ｅ However, hydrogen, halogens, cyano and -C １ ~C ３ Selected from the group consisting of alkyl groups, m is 0, 1, 2, or 3. The compound according to claim 1 or 2.

7. R ｃ However, hydrogen and -CH ３ Selected from the group consisting of, R ｄ However, hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH ３ , -OCH ３ ien-CH ２ C(O)NH ２ and -OCH ２ CH ３ Selected from the group consisting of, R ｅ However, hydrogen, fluoro, chloro, -CH ３ A compound according to claim 1 or 2, selected from the group consisting of and cyano.

8. R Ａ However, for each appearance, fluoro, chloro, bromo, iod, hydroxyl, cyano, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ ,-CHF ２ , -OCF ３ , -OCHF ２ ien-CH ２ OH, -CH ２ NH ２ ien-CH ２ C(O)NH ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ NH ２ A compound independently selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxyranil, azetidinil, phenyl, triazolyl, and oxadiazolyl; in the formula, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are -CH ３ The compound according to claim 1 or 2, which may be substituted by

9. R Ａ However, for each appearance, fluoro, chloro, bromo, iod, hydroxyl, cyano, -CH ３ , -OCH ３ ien-CH ２ C(O)NH ２ and -OCH ２ CH ３ A compound according to claim 1 or 2, independently selected from the group consisting of the following.

10. A, 【Chemistry 10-1】 【Chemistry 10-2】 and 【Chemistry 11】 A compound according to claim 1 or 2, selected from the group consisting of the following.

11. R ４ and R ５ However, each is independent of hydrogen, hydroxyl, and -CH. ３ ien-CH ２ OH, -NH ２ , and -NH-C(O)-N(CH ２ CH ３ ) ２ A compound according to claim 1 or 2, selected from the group consisting of the following.

12. R ４ The compound according to claim 1 or 2, wherein the compound is hydrogen.

13. R ５ However, hydrogen, hydroxyl, -CH ３ ien-CH ２ OH, -NH ２ , and -NH-C(O)-N(CH ２ CH ３ ) ２ A compound according to claim 1 or 2, selected from the group consisting of the following.

14. R ５ is hydrogen or -CH ３ The compound according to claim 1 or 2.

15. R １ However, hydrogen, -CH ３ , 【Chemistry 12】 and 【Chemistry 13】 A compound according to claim 1 or 2, selected from the group consisting of the following.

16. R １ The compound according to claim 1 or 2, wherein the compound is hydrogen.

17. Compounds represented by formula IIA, formula IIB, or formula IIC: 【Chemistry 14】 or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, A is, 【Chemistry 15】 and 【Chemistry 16】 Selected from the group consisting of; R ｃ is hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups; R ｄ These are hydrogen, halogen, hydroxyl, cyano, and -C. １ ~C ３ Alkyl and C １ ~C ３ Selected from the group consisting of alkoxys; where -C １ ~C ３ Alkyls are halogens, hydroxyls, and -NH ２ , -C(O)-NH ２ and -OCH ３ It may be optionally substituted with one, two, or three substituents independently selected from the group consisting of; R ｅ These are hydrogen, halogens, cyano and -C １ ~C ３ Selected from the group consisting of alkyl groups; R １ is hydrogen, -CH ３ , 【Chemistry 17】 and [Chemistry 18] Selected from the group consisting of; R ２ and R ３ These are, independently, hydrogen, hydroxyl, and -CH₂. ３ ien-CH ２ OH, -NH ２ , and -NH-C(O)-N(CH ２ CH ３ ) ２ Selected from the group consisting of; m is 0, 1, 2, or 3. Compounds represented by formula IIA, formula IIB, or formula IIC, or pharmaceutically acceptable salts and / or stereoisomers thereof.

18. R ｄ These are hydrogen, fluoro, chloro, bromo, iodine, hydroxyl, cyano, and -CH ３ , -OCH ３ ien-CH ２ C(O)NH ２ and -OCH ２ CH ３ Selected from the group consisting of, R ｅ is hydrogen, fluoro, chloro, -CH ３ Selected from the group consisting of and cyano, The compound according to claim 1.

19. R ４ The compound according to claim 17 or 18, wherein is hydrogen.

20. R ５ However, hydrogen, hydroxyl, -CH ３ ien-CH ２ OH, -NH ２ , and -NH-C(O)-N(CH ２ CH ３ ) ２ A compound according to claim 17 or 18, selected from the group consisting of the following.

21. R ５ is hydrogen or -CH ３ The compound according to claim 17 or 18.

22. R １ The compound according to claim 17 or 18, wherein is hydrogen. 【Request Item 23】 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 and 【Chemistry 20】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

24. Compounds represented by formula III: 【Chemistry 21】 or its pharmaceutically acceptable salts and / or stereoisomers, During the ceremony, 【Chemistry 22】 It is a single bond, and X is CR Ｘ And Y is C(R Ｙ ) ２ is; or 【Chemistry 23】 It is a double bond, X is C, and Y is C(R Ｙ ) and; A is, 【Chemistry 24】 or 【Chemistry 25】 And; R Ｘ and R Ｙ These are, independently, hydrogen and -C. １ ~C ３ Selected from the group consisting of alkyl groups; or R Ｘ and R Ｙ They bond together to form -CH ２ - forms, R Ｗ is hydrogen, C １ ~C ６ Alkyl and -SO ２ - Selected from the group consisting of phenyl, C １ ~C ６ Alkyl and phenyl compounds are halogens, hydroxyls, and C １ ~C ３ Alkyl and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R Ａ For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ - (CO) - OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ Alkyl, -C(O)-C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Selected from the group consisting of cycloalkyl, phenyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl; C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyl, -NR ａ R ｂ , -C(O)NR ａ R ｂ , C １ ~C ３ Alkyl and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R １ is hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, -C ３ ~C ６ Cycloalkyl, -CH ２ -phenyl, -CH ２ -CH ２ -phenyl, -CH ２ - (5-10 member heteroaryl) and - CH ２ - Selected from the group consisting of (5-10 member heterocyclils); C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, -C ３ ~C ６ Cycloalkyl, phenyl, heteroaryl, and heterocyclyl compounds contain halogens, hydroxyls, deuterium, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ２ and R ３ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; C １ ~C ６ Alkyls are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ４ is hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ - (CO) - OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ Alkyl, -C(O)-C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Selected from the group consisting of cycloalkyl and phenyl; in the formula, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Cycloalkyls and phenyls are halogens, hydroxyls, and -NR ａ R ｂ and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ５ is halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ - (CO) - OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ Alkyl, -CO ２ H, -C(O)-C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Selected from the group consisting of cycloalkyl and phenyl; in the formula, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, -C ３ ~C ６ Cycloalkyls and phenyls are halogens, hydroxyls, and -NR ａ R ｂ and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ６ and R ７ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; C １ ~C ６ Alkyls are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys; R ａ and R ｂ For each appearance, independently, hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups; C １ ~C ３ Alkyl groups may be optionally substituted with one or more halogens; m is 0, 1, 2, or 3. A compound represented by formula III, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

25. The aforementioned compound, 【Chemistry 26】 or 【Chemistry 27】 The compound according to claim 24, represented by [the specified figure].

26. R ６ and R ７ The compound according to claim 24 or 25, wherein is hydrogen.

27. The aforementioned compound, 【Chemistry 28】 or 【Chemistry 29】 The compound according to claim 24 or 25, as represented by...

28. R Ｙ is hydrogen or -CH ３ The compound according to claim 24 or 25.

29. R Ｗ However, hydrogen, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ and -CH(CH ３ ) ２ A compound according to claim 24 or 25, selected from the group consisting of the following.

30. R Ａ However, for each appearance, fluoro, chloro, bromo, iod, hydroxyl, cyano, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ ,-CHF ２ , -OCF ３ , -OCHF ２ ien-CH ２ OH, -CH ２ NH ２ ien-CH ２ C(O)NH ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ NH ２ A compound independently selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxyranil, azetidinil, phenyl, triazolyl, and oxadiazolyl; in the formula, tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are -CH ３ The compound according to claim 24 or 25, which may be optionally substituted by the aforementioned means.

31. R Ａ However, for each appearance, fluoro, chloro, hydroxyl, cyano, phenyl, -CH ３ ,-CHF ２ ien-CH ２ OH, -CH ２ CH ３ , -OCH ３ ien-CH ２ C(O)NH ２ ien-CH ２ CH ２ OH and -OCH ２ CH ３ A compound according to claim 24 or 25, independently selected from the group consisting of the following.

32. R ２ The compound according to claim 24 or 25, wherein is hydrogen.

33. R ３ However, hydrogen, -CH ３ , and -CH ２ A compound according to claim 24 or 25, selected from the group consisting of OH.

34. R ４ The compound according to claim 24 or 25, wherein is hydrogen.

35. R ５ However, hydrogen, hydroxyl, -NH ２ ien-CH ３ ien-CH ２ OH, -CH ２ NH ２ , -CO ２ H, -NH-C(O)-N(CH ２ CH ３ ) ２ The compound according to claim 24 or 25, selected from the group consisting of phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl.

36. R １ However, hydrogen, -CH ３ , -CD ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH ２ - Phenyl, cyclopropyl, 【Transformation 30】 and 【Chemistry 31】 A compound according to claim 24 or 25, selected from the group consisting of the following.

37. Compounds represented by formulas IVA, IVB, or IVC: 【Chemistry 32】 or its pharmaceutically acceptable salts and / or stereoisomers, A is, 【Transformation 33】 and 【Transformation 34】 Selected from the group consisting of; R Ｗ is hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups; R Ｙ is hydrogen or -CH ３ And; R Ａ For each occurrence, the following are indicated: fluoro, chloro, bromo, iod, hydroxyl, cyano, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ ,-CHF ２ , -OCF ３ , -OCHF ２ ien-CH ２ OH, -CH ２ NH ２ ien-CH ２ C(O)NH ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ NH ２ A compound independently selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxyranil, azetidinil, phenyl, triazolyl, and oxadiazolyl; tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are -CH ３ In some cases, it is often replaced by; R １ is hydrogen, -CH ３ , -CD ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH ２ - Phenyl, cyclopropyl, 【Chemistry 35】 and 【Transformation 36】 Selected from the group consisting of; R ２ is hydrogen, -CH ３ , and -CH ２ Selected from the group consisting of OH; R ３ is hydrogen, hydroxyl, -NH ２ ien-CH ３ ien-CH ２ OH, -CH ２ NH ２ , -CO ２ H, -NH-C(O)-N(CH ２ CH ３ ) ２ Selected from the group consisting of phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl; m is 0, 1, 2, or 3. Compounds represented by formulas IVA, IVB, or IVC, or their pharmaceutically acceptable salts and / or stereoisomers. 【Request Item 38】 【Chemistry 37-1】 【Chemistry 37-2】 【Chemistry 37-3】 【Chemistry 37-4】 【Chemistry 37-5】 【Chemistry 37-6】 【Chemistry 37-7】 and 【Transformation 38】 A compound selected from the group consisting of, or its pharmaceutically acceptable salts and / or stereoisomers. 【Request Item 39】 【Chemistry 39-1】 【Chemistry 39-2】 【Chemistry 39-3】 【Chemistry 39-4】 and 【Chemistry 40】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

40. A compound comprising any one of claims 1, 17, 23, 24, 37, 38, and 39, and a pharmaceutically acceptable excipient, Pharmaceutical composition.

41. A method for treating a mental or neurological disorder or disorder in a patient who requires treatment for such disorder or disorder, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1, 17, 23, 24, 37, 38, and 39.

42. A method for treating a mental or neurological disorder or disorder in a patient who requires treatment for such disorder or disorder, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of claims 1, 17, 23, 24, 37, 38, and 39, and a pharmaceutically acceptable excipient.

43. The method according to claim 41, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache.

44. The method according to claim 42, wherein the mental or neurological disorder or illness is selected from the group consisting of depression, anxiety, substance abuse, and headache.

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