5-HT2A receptor modulators and methods of use thereof

Abstract

The present disclosure provides compounds, such as compounds of Formula I, and their use in the treatment of medical diseases or disorders, such as psychiatric and nervous system diseases. Pharmaceutical compositions and methods of making various benzisoxazole and benzisothiazole compounds are provided. These compounds are considered to be modulators of the serotonin 2A (5-HT2A) receptor.

Description

Cross-references to related applications

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

[0002] Modulators of the serotonin 2A receptor (5-HT2AR) are widely sought as potential medicines for a variety 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 physical disorders, including but not limited to various inflammatory, cardiovascular, and / or pain disorders. Although many 5-HT2AR modulators have been developed, few are selective for this receptor rather than for related subtypes, such as the 5-HT2B receptor, a toxicological anti-target closely associated with serious side effects, including drug-induced valvular heart disease.

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

[0004] This disclosure relates to modulators of the 5-hydroxytryptamine 2A (5-HT2AR) receptor. Pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier are also disclosed herein.

[0005] For example, this paper discloses a compound represented by formula I: (I); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is selected from the group consisting of 8-10 fused bicyclic heteroaryl, 12-14 fused tricyclic heteroaryl, 8-10 fused bicyclic heterocyclic group, and phenyl; wherein ring A can be selected from one or more of R A The substituents are substituted; R A Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NRa 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or one R X And an R Y They connect 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-membered heteroaryl); wherein the C1-C6 alkyl, phenyl and heteroaryl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy groups; R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 and R 5 Each is independently selected from 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 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups, and C1-C3 alkoxy groups; and R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens.

[0006] This article also discloses compounds represented by formula IIA, IIB or IIC: (IIA) (IIB) (IIC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , , , and , R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R dThe group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl and C1-C3 alkoxy; wherein the -C1-C3 alkyl group may be optionally substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; R 1 Choose free hydrogen, -CH3, and A group that is formed.

[0007] R 2 and R 3 Each is independently selected from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m can be 0, 1, 2, or 3.

[0008] This article also discloses compounds represented by Formula III: (III); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is , or ; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or R X and R Y They connect together to form -CH2-; R W The group is selected from the group consisting of hydrogen, C1-C6 alkyl and -SO2-phenyl; wherein the C1-C6 alkyl and phenyl may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl and C1-C3 alkoxy. R A Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, and -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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogens, hydroxyl groups, -NR groups, etc. a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R 1 The group 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-membered heteroaryl), and -CH2-(5-10-membered heterocyclic). Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclic may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 Choose from 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)-ORb -OC(O)-NR a R b 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 5 Choose from halogens, hydroxyl groups, cyano groups, 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 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups 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; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens; and m can be 0, 1, 2, or 3.

[0009] For example, this article discloses compounds represented by the formula IVA, IVB, or IVC: (IVA) (IVB) (IVC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , ,and ; R W Select from the group consisting of hydrogen and C1-C3 alkyl groups; R Y It is hydrogen or -CH3; R A Each time it appears, it is independently selected from fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazinyl, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; among which tetrahydropyrrolithyl, piperidinyl, piperazinyl, and aziridine can be optionally substituted with -CH3; R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , and The group formed; R 2 Choose the group consisting of free hydrogen, -CH3, and -CH2OH; R 3 Choose 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; and m can be 0, 1, 2, or 3.

[0010] This document also discloses pharmaceutical compositions comprising at least one compound of this disclosure and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises at least one additional therapeutic agent for treating, improving, and / or preventing neurological diseases and / or disorders.

[0011] In another embodiment, this document provides methods for improving and / or preventing neurological disorders or disturbances in patients in need, including administering to the patient a therapeutically effective amount of any of the compounds or pharmaceutical compositions thereof described herein. In some embodiments, the neurological disorder or disturbance is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.

[0012] This article also discloses a method for selectively modulating 5-hydroxytryptamine 2A (5-HT2A) receptors in patients in need, comprising administering to the patient a therapeutically effective amount of the compound disclosed herein or a pharmaceutical composition thereof. Detailed Implementation

[0013] The features and other details of this disclosure will now be described in more detail. Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be read in light of the remainder of this disclosure and as will be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0014] definition The term "treatment" includes any effect that produces improvements such as alleviating, reducing, regulating, or eliminating symptoms, diseases, or disorders.

[0015] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C14, 14 ... 1-6 Alkyl, C 1-4 Alkyl and C 1-3 Alkyl groups. 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, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

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

[0017] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups with 2-6 or 3-6 carbon atoms, referred to herein as C14-C2 ... 2-6 alkynyl group and C 3-6 Alkyne group. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, methylpropynyl, etc.

[0018] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group (alkyl-O-) bonded to an oxygen atom. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1-6 or 2-6 carbon atoms, referred to 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, etc.

[0019] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 p electrons in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has a six-ring carbon atom (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has a ten-ring carbon atom (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has a fourteen-ring carbon atom ("C"). 14"Aryl"; for example, anthracene. "Aryl" also includes cyclic systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or connecting point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from the following groups: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indene, naphthalene, octacene, octaphene, octalene, penta-2,4-diene. 2,4-Diene, pentalene, pentalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyridine, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Representative examples of substituted aryl groups include the following:

[0020] Where R 56 and R 57 One of them can be hydrogen, and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO-alkyl, COO-aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR 58 R 59 S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl; or R56 and R 57 They can be linked to form cyclic rings of 5-8 atoms (saturated or unsaturated), optionally containing one or more heteroatoms selected from N, O, or S. R 60 and R 61 Each of these can be independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 heteroaryl or substituted 5-10 heteroaryl.

[0021] The term "carbonyl" as used in this article refers to the group C(O)-.

[0022] The term "cyano" used in this article refers to the -CN group.

[0023] As used herein, the terms "cycloalkyl" or "carbocyclic group" refer to, for example, a saturated or partially unsaturated hydrocarbon group with 3-6 or 4-6 carbon atoms, referred to herein as C3-C4, respectively. 10 cycloalkyl, C 3-6 cycloalkyl or C 4-6 Cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0024] The term “halo” or “halogen” as used in this article refers to F, Cl, Br, or I.

[0025] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more halogens are substituted. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc. Exemplary haloalkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), referred to herein as C14, C24, C34, C44, C54, C64, C74, C64, C74, C74, C75 ... 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups and C 1-3 Halogenated alkyl groups.

[0026] When used to describe a compound or a group present on a compound, the term "hetero" refers to one or more carbon atoms in the compound or group that are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the aforementioned hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheterenyl), and analogs having 1 to 5, particularly 1 to 3, heteroatoms.

[0027] As used herein, the term "heteroaryl" or "heteroaromatic group" refers to an aromatic 5-10 membered ring system containing one or more heteroatoms (e.g., 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur). The term may also refer to 5-7 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl. Where possible, the heteroaryl ring may be linked to an adjacent group via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furans, thiophenes, pyrroles, pyrrolopyridines, indoles, thiazoles, oxazoles, isothiazoles, isoxazoles, imidazoles, benzimidazoles, imidazopyridines, pyrazoles, triazoles, pyridines, or pyrimidines.

[0028] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic radical” are generally accepted in the art to refer to saturated or partially unsaturated 4-10 membered ring structures whose ring structure includes 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclic ring may be linked to an adjacent group via carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused, or spirocyclic structures whose ring structure includes 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclic 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 spirocyclic heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7-bridged methyleneisoindole). A “spiroheterocyclic group” or “spiroheterocycle” refers to a polycyclic heterocyclic group having rings linked by a common atom (called the spiro atom), wherein the ring has one or more elements selected from N, O, and S(O). m The heteroatoms of the group (where m is an integer from 0 to 2) are used as ring atoms.

[0029] The term “hydroxyl” or “hydroxyl group” as used in this article refers to the -OH group.

[0030] The term “oxo” as used in this article refers to the =O group.

[0031] "Pharmaceutical or pharmacologically acceptable" molecular entities and compositions that, when administered to animals or humans (as the case may be), will not produce adverse reactions, allergic reactions, or other adverse effects. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA's Office of Biologics Standards.

[0032] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0033] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein and one or more pharmaceutically acceptable carriers.

[0034] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds disclosed herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as livestock (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). “Regulation” includes antagonism (e.g., inhibition), inverse activating, activating, biased activating, biased signal transduction, functionally selective activating, partial antagonism, and / or partial activating.

[0035] In this specification, the term "therapeuticly effective amount" refers to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) as sought by a researcher, veterinarian, physician, or other clinician. The compounds of this disclosure are administered at a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing an acidic or basic group that may be present in the compound used in the composition. Basic compounds included in the compositions of this invention are capable of forming various salts with a variety of inorganic and organic acids. Pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, glucuronides, glucuronates, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and papoate (i.e., 1,1'-methylenebis-(2-hydroxy-3-naphthylcarbamate)). The acidic compounds contained in the compositions of this invention are capable of forming basic salts with a variety of pharmacologically 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 the compositions of this invention, including basic or acidic moieties, can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein can contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compounds can exist as acid addition salts, zwitterions, or basic salts.

[0037] The compounds disclosed herein may contain one or more chiral centers and thus exist as stereoisomers. The term "stereoisomer" as used herein comprises all enantiomers or diastereomers. These compounds may be represented by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of the substituents surrounding the stereocarbon atom; however, those skilled in the art will recognize that a structure can implicitly represent a chiral center. This disclosure includes various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be referred to as "(±)" in nomenclature; however, those skilled in the art will recognize that a structure can implicitly represent a chiral center.

[0038] The compounds disclosed herein may contain one or more double bonds, and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bonds. (Symbols) The term "bond" indicates a single, double, or triple bond, as described herein. Substituents surrounding a carbon-carbon double bond are designated as "Z" or "E" configurations, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise stated, the structure describing a double bond includes both "E" and "Z" isomers. Substituents surrounding a carbon-carbon double bond may also 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.

[0039] The compounds disclosed herein may comprise a carbocyclic or heterocyclic ring, and thus exist as geometric isomers due to the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is designated as a “Z” or “E” configuration, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the description of the structure of the carbocyclic or heterocyclic ring includes both “Z” and “E” isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, wherein the term “cis” indicates a substituent on the same side of the ring plane, and the term “trans” indicates a substituent on the opposite side of the ring plane. A mixture of compounds with substituents located on the same and opposite sides of the ring plane is called a “cis / trans” compound.

[0040] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared from commercially available raw materials containing asymmetric or stereocenters, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. Examples of such resolution methods include: (1) linking an enantiomer mixture with a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating the optically enantiomer mixture on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis is a chemical or enzymatic reaction well known in the art in which a single reactant forms an unequal mixture of stereoisomers in the process of generating a new stereocenter or transforming an existing stereocenter. Stereoselective synthesis includes enantiomeric and diastereomeric transformations and may involve the use of chiral auxiliaries. For example, see Carreira and Kvaerno. Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.

[0041] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and this disclosure is intended to include both solvated and non-solvated 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.

[0042] This disclosure also includes isotopically labeled compounds of the same type as those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally measured in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 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. For example, compounds disclosed herein may have one or more deuterium-substituted H atoms.

[0043] Certain isotope-labeled public compounds (e.g., using) 3 H and 14 Those labeled with C can be used for the determination of the tissue distribution of compounds and / or substrates. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure can generally be prepared by following a procedure similar to that disclosed in the embodiments herein, replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0044] 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. This conversion can occur at various locations (e.g., in the intestinal lumen or transported in the intestine, blood, or liver) through various mechanisms such as esterases, amidases, phosphatases, oxidative and / or reductive metabolism. Prodrugs are well known in the art (see, for example, Rautio, Kumpulainen, et al., Nature Reviews DrugDiscovery 2008, 7, 255). For example, if the compound of this disclosure or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise an ester formed by substituting a hydrogen atom of an acid group with a group, such as (C... 1-8 )alkyl, (C 2-12 Alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4-9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5-10 carbon atoms, alkoxycarbonyloxymethyl having 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5-8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3-9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4-10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 )alkyl (e.g., β-dimethylaminoethyl), carbamoyl-(C 1-2 )alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidinyl-(C 2-3 )alkyl (piperidino-(C 2-3 )alkyl), pyrrolidine-(C 2-3 )alkyl(pyrrolidino-(C 2-3 alkyl), or morpholine (C) 2-3 )alkyl.

[0045] Similarly, if the compounds of this disclosure contain an alcohol functional group, they can be expressed by using groups such as (C) 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkylcarbonyloxy)ethyl(C 1-6 )alkoxycarbonyloxymethyl, N-(C1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkyl carbonyl, α-amino (C 1-4 Alkyl carbonyl, aryl alkyl carbonyl, and α-aminoalkyl carbonyl, or α-aminoalkyl carbonyl-α-aminoalkyl carbonyl substituted with hydrogen atoms of an alcohol group to form a prodrug, wherein each α-aminoalkyl carbonyl is independently selected from naturally occurring L-amino acids, P(O)(OH)2, P(O)(O(C 1-6 Alkyl group or glycosyl group (a group obtained by removing the hydroxyl group from a carbohydrate in hemiacetal form).

[0046] If the compounds of this disclosure introduce an amine functional group, they can be formed as prodrugs, for example, by generating amides or carbamates, N-alkylcarbonyloxyalkyl derivatives, (oxodioxanepentenyl)methyl derivatives, N-Mannich bases, imines, or enamines. Furthermore, secondary amines can be metabolically cleaved to produce bioactive primary amines, or tertiary amines can be metabolically cleaved to produce bioactive primary or secondary amines. See, for example, Simplício, et al. Molecules 2008, 13, 519 and its references.

[0047] compound This disclosure relates in part to compounds that act as modulators of the serotonin 2A (5-HT2A) receptor. In some embodiments, the modulators of this disclosure exhibit selective function and / or binding to the 5-HT2A receptor relative to 5-HT2B and / or 5-HT2C receptors. In some 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 disorders, substance abuse, migraines, and / or cluster headaches.

[0048] For example, this paper discloses compounds represented by formula I: (I); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is selected from the group consisting of 8-10 fused bicyclic heteroaryl, 12-14 fused tricyclic heteroaryl, 8-10 fused bicyclic heterocyclic group, and phenyl; wherein ring A can be selected from one or more of R A The substituents are substituted; R AEach time it appears, it is independently selected from 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or one R X And an R Y They connect 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-membered heteroaryl); wherein the C1-C6 alkyl, phenyl and heteroaryl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy groups; R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 and R 5 Each is independently selected from hydrogen, halogen, hydroxyl, cyano, and -NR. a Rb -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 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6aC6 alkenyl, C2-C6aC6 alkynyl, C1-C6aC6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups, and C1-C3 alkoxy groups; and R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens.

[0049] In some embodiments, the compounds disclosed herein are represented by the following formula: (IA) (IB), or (IC).

[0050] In some implementation schemes, R 6 and R 7 It is hydrogen. In other embodiments, R 2 and R 3 It is hydrogen. In some embodiments, the compounds disclosed herein are represented by the following formula: (ID) (IE), or (IF).

[0051] For example, in some implementations, A is selected from the group consisting of:

[0052] , ,and ;in: R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R d The group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, -C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl; wherein -C1-C3 alkyl can be optionally substituted by one, two or three substituents, and each substituent is independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; and m can be 0, 1, 2, or 3.

[0053] In some implementations, for example, R c Choose the group consisting of hydrogen and -CH3; R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; R e Choose from the group consisting of hydrogen, fluorine, chlorine, -CH3, and cyano groups.

[0054] In other implementations, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazineyl, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazineyl, and aziridine may optionally be substituted with -CH3. For example, in some embodiments, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3.

[0055] In some implementations, A is selected from the group consisting of, for example:

[0056]

[0057] , , , , , , ,and .

[0058] In other implementations, 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 other embodiments, R 4 It is hydrogen. In other embodiments, R 5 The group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2 is selected. In some other embodiments, R 5 It is hydrogen or -CH3. In some implementations, R 1 It is hydrogen. In another embodiment, R 1 Choose free hydrogen, -CH3, and A group that is formed.

[0059] This article also discloses compounds represented by formula IIA, IIB or IIC: (IIA) (IIB) (IIC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , , , ,and ; R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R dThe group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl and C1-C3 alkoxy; wherein the -C1-C3 alkyl group may be optionally substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; R 1 Choose free hydrogen, -CH3, and A group that is formed.

[0060] R 2 and R 3 Each is independently selected from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m can be 0, 1, 2, or 3.

[0061] In some implementation schemes, R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; R e The group is selected from hydrogen, fluorine, chlorine, -CH3, and cyano groups. In other embodiments, R 4 It is hydrogen. In other embodiments, R 5 The group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2 is selected. In some embodiments, R 5 It is hydrogen or -CH3. In some implementations, R 1 It is hydrogen.

[0062] In some embodiments, the compound is one of the compounds identified in Table 1 below or a pharmaceutically acceptable salt thereof.

[0063] Table 1: Exemplary Compounds

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] This article also discloses compounds represented by Formula III: (III); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is , ,or ; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or R X and R Y They connect together to form -CH2-; R W The group is selected from the group consisting of hydrogen, C1-C6 alkyl and -SO2-phenyl; wherein the C1-C6 alkyl and phenyl may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl and C1-C3 alkoxy. R A Each time it appears, it is independently selected from 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)-ORb -OC(O)-NR a R b 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R 1 The group 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-membered heteroaryl), and -CH2-(5-10-membered heterocyclic). Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclic may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 Choose from 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 bThe 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 5 Choose from halogens, hydroxyl groups, cyano groups, 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 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups 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; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens; and m can be 0, 1, 2, or 3.

[0077] In some embodiments, the compounds disclosed herein are represented by the following formula: (IIIA) (IIIB), or (IIIC).

[0078] In some implementation schemes, R 6 and R 7 It is hydrogen. For example, in some embodiments, the compounds disclosed herein are represented by the following formula: (IIID) (IIIE), or (IIIF).

[0079] In some embodiments, R Y It is hydrogen or -CH3. In other embodiments, R W The group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2 is selected. In other embodiments, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazineyl, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazineyl, and aziridine may optionally be substituted with -CH3. For example, in some embodiments, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH and -OCH2CH3.

[0080] In some implementation schemes, R 2 It is hydrogen. In other embodiments, R 3 The group consisting of hydrogen, -CH3, and -CH2OH is selected. In other embodiments, R... 4 It is hydrogen. In other embodiments, R 5 Choose 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.

[0081] In some implementation schemes, R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , and In some implementations, R 1 It is hydrogen.

[0082] This article also discloses compounds represented by the formula IVA, IVB, or IVC: (IVA) (IVB) (IVC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , ,and ; R W Select from the group consisting of hydrogen and C1-C3 alkyl groups; R Y It is hydrogen or -CH3; R A Each time it appears, it is independently selected from fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazinyl, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; among which tetrahydropyrrolithyl, piperidinyl, piperazinyl, and aziridine can be optionally substituted with -CH3; R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , and The group formed; R 2Choose the group consisting of free hydrogen, -CH3, and -CH2OH; R 3 Choose 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; and m can be 0, 1, 2, or 3.

[0083] In some embodiments, the compound is one of the compounds identified in Table 2 below or a pharmaceutically acceptable salt thereof.

[0084] Table 2: Exemplary Compounds

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] In some embodiments, the compound is one of the compounds identified in Table 3 below or a pharmaceutically acceptable salt thereof.

[0097] Table 3: Exemplary Compounds

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] The following examples provide methods for preparing the compounds described herein. In the reactions described below, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino, thio, or carboxyl groups) to prevent them from unnecessarily participating in the reaction. The introduction of these groups and the methods required for their introduction and removal are known to those skilled in the art (e.g., see Greene, Wuts, ...). Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis, thereby removing the protecting group to obtain the compound disclosed herein. The starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature or by modifications thereof, using methods known to those skilled in the art. The order of the steps may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0107] The compounds disclosed herein or any intermediates described in the above schemes can be further derivatized using one or more standard synthetic methods known to those skilled in the art. These methods may include substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify the disclosed compounds or any of the preceding intermediates by modifying, introducing, or removing suitable functional groups.

[0108] When a specific enantiomer of the disclosed compound is required, it can be prepared from the corresponding enantiomer mixture using any suitable conventional method for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (e.g., salts) can be prepared by reacting a mixture of enantiomers of the disclosed compound (e.g., racemic mixtures) with a suitable chiral compound (e.g., a chiral base). The diastereomers can then be separated by any conventional method such as crystallization or chromatography, and the desired enantiomers can be recovered (e.g., by acid treatment if the diastereomer is a salt). Alternatively, racemic mixtures of esters can be resolved by kinetic hydrolysis using various biocatalysts (e.g., see Patel). Stereoselective Biocatalysts , Marcel Decker; New York 2000).

[0109] In another separation method, the racemic derivatives 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 methods described above. When a specific geometric isomer of this disclosure is required, chromatography, recrystallization, and other conventional separation methods can also be used for the intermediates or final products.

[0110] In an alternative embodiment, the disclosed compound may also contain one or more isotopic substitutions. For example, hydrogen may be... 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example... 13 C or 14 C; oxygen can be, for example 18 O; nitrogen can be, for example 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H, 13 C 14 C 18 O or 15 N) can represent 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 specific position in the compound.

[0111] method Another aspect of this disclosure provides methods for treating patients suffering from neurological disorders or disorders. Specifically, in some embodiments, this disclosure provides methods for treating the following medical indications, including administering a therapeutically effective amount of the compound described herein to a patient in need.

[0112] For example, this document provides methods for treating neurological disorders or impairments in patients in need, including administering a therapeutically effective amount of a compound disclosed herein, such as a compound of formula I or II, to the patient. This document also provides methods for treating neurological disorders or impairments in patients in need, including administering a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, such as a compound of formula I or II, and a pharmaceutically acceptable excipient.

[0113] Non-limiting examples of neurological disorders or disturbances include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods described in this article include, but are not limited to, migraines and cluster headaches.

[0114] For example, in some embodiments, the methods described herein may include treating depression in a patient in need, including administering to the patient an effective amount of the disclosed compound or pharmaceutical composition thereof. In some embodiments, the depression may be major depressive disorder. In other embodiments, the depression may include treatment for antidepressants.

[0115] In some embodiments, the methods described herein may include treating an anxiety disorder in a patient in need, including administering to the patient an effective amount of the disclosed compound 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.

[0116] In other embodiments, the methods described herein may include treating trauma and / or stress disorders in patients in need, including administering to the patient an effective amount of the disclosed compound or a pharmaceutical composition thereof. In some embodiments, such disorder may be post-traumatic stress disorder. In other embodiments, such disorder may be a regulatory disorder.

[0117] In some embodiments, the methods described herein may include treating obsessive-compulsive disorder, such as body dysmorphic disorder, in patients in need, including administering to the patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof.

[0118] In other embodiments, the methods described herein may include treating an eating disorder in a patient in need, including administering to the patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof. In some embodiments, the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.

[0119] In other embodiments, the methods described herein may include treating sleep-wake disorders, such as insomnia, in patients in need, including administering to the patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof.

[0120] In some embodiments, the methods described herein may include treating a psychotic disorder, such as insomnia, in a patient in need, including administering to the patient an effective amount of the disclosed compound or a pharmaceutical composition thereof. In some embodiments, the psychotic disorder may be schizophrenia. In other embodiments, the psychotic disorder may be schizoaffective disorder. In other embodiments, the psychotic disorder may be schizotypal personality disorder.

[0121] In some embodiments, the methods described herein may include treating substance-related disorders and / or addiction disorders in patients in need, including administering to the patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof. In some embodiments, such disorders may be alcohol abuse disorders. In other embodiments, such disorders may be opioid abuse disorders. In other embodiments, such disorders may be tobacco abuse disorders. For example, in some embodiments, the compounds disclosed herein may be used to promote smoking cessation.

[0122] In some other embodiments, the methods described herein may include treating neurocognitive impairment in patients in need, including administering to a patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof. In some embodiments, neurocognitive impairment may include impairment caused by a primary neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0123] In some embodiments, the methods described herein may include treating a personality disorder in a patient in need, including administering an effective amount of the disclosed compound or a pharmaceutical composition thereof to the patient. In other embodiments, the methods described herein may include treating autism spectrum disorder in a patient in need, including administering an effective amount of the disclosed compound or a pharmaceutical composition thereof to the patient.

[0124] In other embodiments, the methods described herein may include treating bipolar disorder in a patient in need, including administering to the patient an effective amount of the disclosed compound 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.

[0125] In other embodiments, the methods described herein may include treating a pain disorder in a patient in need, including administering to the patient an effective amount of the compounds disclosed herein or pharmaceutical compositions thereof. In some embodiments, the pain disorder may be neuropathic pain. In other embodiments, the pain disorder may be migraine. In other embodiments, the pain disorder may be cluster headache. In other embodiments, the pain disorder may be trigeminal neuralgia. In other embodiments, the pain disorder may be cancer pain. In some embodiments, the pain disorder may be a regional pain disorder. In other embodiments, the pain disorder may be phantom limb pain. In some embodiments, the anticipated pain disorder may be chronic pain.

[0126] In some embodiments, the compounds disclosed herein, such as those of Formula I or II, may exhibit anxiolytic, antidepressant, and anti-drug abuse effects without exhibiting significant hallucinogenic effects. For example, the intended (5-HT2A) receptor modulators of this disclosure may confer antidepressant-like activity without causing hallucinogenic effects. For example, in some embodiments, the compounds disclosed herein may be safe and effective when used in the methods described herein, but lack the hallucinogenic effects of known hallucinogens such as DMT and psilocybin.

[0127] This disclosure also provides a method for selectively modulating the serotonin 2A (5-HT2A) receptor. The method includes administering to a patient a compound disclosed herein, such as a compound of formula I or II, a pharmaceutically acceptable salt thereof, and / or a stereoisomer thereof, wherein the compound selectively modulates the 5-HT2A receptor but not the 5-HT2B and / or 5-HT2C receptor. The method of selectively modulating the 5-HT2A receptor can be used to treat, improve, and / or prevent diseases or disorders affected by, associated with, or benefiting from selective modulation of the 5-HT2A receptor. When selectively modulating the 5-HT2A receptor relative to the 5-HT2B and / or 5-HT2C receptors, the method provides, for example, reduced side effects, such as, but not limited to, drug-induced valvular heart disease associated with modulation of the 5-HT2B receptor.

[0128] In some embodiments, the methods described herein also include administering additional therapeutic agents to a patient that treat neurological diseases or disorders, or diseases or disorders that are affected by, related to, or will benefit from selective modulation of the 5-HT2A receptor.

[0129] The anticipated 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).

[0130] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein. For clarity, this document considers fixed compositions comprising a disclosed compound and another therapeutic agent (such as those disclosed herein), and methods of administering the disclosed compound and the disclosed therapeutic agent separately. For example, this disclosure provides pharmaceutical compositions comprising a compound described herein, one or more additional therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, the disclosed compound and one additional therapeutic agent are administered. In some embodiments, the disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, the disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each formulated and administered separately. For example, the disclosed compound and the additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising a disclosed compound as a therapeutic agent and one or more additional therapeutic agents. For example, the disclosed compound and the additional therapeutic agent can be administered in a single formulation. Other combinations are also included in combination therapy. While the two or more agents in combination therapy can be administered simultaneously, they are not mandatory. For example, the administration of the first drug (or combination of drugs) may precede the administration of the second drug (or combination of drugs) by minutes, hours, days, or weeks. Therefore, two or more drugs may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 10 weeks of each other. In some cases, even longer intervals are possible. While it is desirable in many cases for two or more drugs used for combination therapy to be present in the patient simultaneously, this is not mandatory.

[0131] Combination therapy can also include administering one or more agents used in combination therapy twice or more using component agents in different orders. For example, if agent X and agent Y are used in combination, they can be administered once or more in any combined order, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0132] For example, the methods described herein include administering to a patient a therapeutically effective amount of at least one compound of formula I or II as described herein, optionally formulated in a pharmaceutical composition. In various embodiments, the at least one compound described herein, such as the compound of formula I or II, present in the pharmaceutical composition in a therapeutically effective amount is the only therapeutically active compound in the pharmaceutical composition. In some embodiments, the method further includes administering to a patient an additional therapeutic agent that treats a neurological disease or disorder, or a disease or disorder that is affected by, associated with, or will benefit from selective modulation of the 5-HT2A receptor.

[0133] For example, in some embodiments, the methods described herein may include administering to a patient a combination of one or more additional therapeutic agents with the compounds disclosed herein. In some 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, selective serotonin reuptake inhibitors may be selected from, for example, the group consisting of fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. In other embodiments, one or more additional therapeutic agents may be serotonin and norepinephrine reuptake inhibitors (SNRIs). For example, serotonin and norepinephrine reuptake inhibitors may be selected from, for example, the group consisting of duloxetine, venlafaxine, norvenlafaxine, and levomilnacipran. In other embodiments, one or more additional therapeutic agents may be selected from, for example, the group consisting of trazodone, mirtazapine, vortioxetine, vilazorone, and bupropion. In some 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 MAOI may be selected from the group consisting of, for example, tranylcypromine, phenelzine, and isocarboxazid. 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 some 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.

[0134] In some embodiments, administration of the compound described herein to a patient allows for the administration of a lower dose of the additional therapeutic agent compared to the dose of a separate additional therapeutic agent, the dose required to achieve similar results in the treatment, improvement, and / or prevention of neurological disorders or impairments, or in the treatment, improvement, and / or prevention of disorders or impairments that are selectively modulated by, associated with, or would benefit from the patient's 5-HT2A receptor. For example, in some embodiments, the compound described herein enhances the activity of the additional therapeutic compound, thereby allowing a lower dose of the additional therapeutic compound to provide the same effect.

[0135] Specifically, in some embodiments, this disclosure provides a method for treating the above-mentioned medical indications, the method comprising administering to a subject in need a therapeutically effective amount of the compound described herein, such as a compound of formula I or II.

[0136] Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable carriers. Specifically, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, oral, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration; however, the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated into unit doses and / or may be formulated for oral or subcutaneous administration.

[0137] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more compounds of this disclosure as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for topical, enteral, or parenteral application. The active ingredient can be mixed with commonly used, non-toxic, pharmaceutically acceptable carriers, such as those used in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The amount of the active target compound contained in the pharmaceutical composition is sufficient to produce the desired effect on the course or condition of a disease.

[0138] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic, pharmaceutically acceptable salt thereof. When it is said that these preformulation compositions are homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0139] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or dicalcium phosphate), and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicate; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retarders. (6) absorption enhancers, such as quaternary ammonium compounds; (7) humectants, such as acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the composition may also contain a buffer. Similar types of solid compositions can also be used as fillers for soft and hard filled gelatin capsules using such excipients as lactose or milk sugars, and high molecular weight polyethylene glycol, etc.

[0140] Tablets can be made by compression or molding, optionally containing one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch-hydroxyacetate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be molded in a suitable machine by molding a mixture of a subject composition wetted with an inert liquid diluent. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, can optionally be engraved or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations.

[0141] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable water 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 the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0142] In addition to the main composition, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0143] Formulations for rectal or vaginal administration can be in the form of suppositories, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but liquid at body temperature, and thus will melt and release the active agent in the body cavity.

[0144] The dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0145] In addition to the main composition, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0146] In addition to the main composition, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures of these substances. Aerosols may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0147] The compositions and compounds disclosed herein can also be administered via aerosols. This is achieved by preparing aqueous aerosols, liposomal formulations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic aerosols can be used because they minimize the possibility of the drug being exposed to shear, which could lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are formulated by combining an aqueous solution or suspension of the subject composition with conventionally pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tweens®, Pluronics®, or polyethylene glycol), nontoxic proteins (e.g., serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0148] The pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition combined with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile powders, wherein the sterile powders may be reformed into sterile injectable solutions or dispersions prior to use and may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0149] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate and cyclodextrin). For example, by using coating materials such as lecithin, the desired particle size can be maintained in the case of dispersions, and by using surfactants, appropriate flowability can be maintained.

[0150] On the other hand, this disclosure provides an enteric pharmaceutical formulation comprising the disclosed compound and an enteric-coated material, as well as a pharmaceutically acceptable carrier or excipient thereof. An enteric-coated material is a polymer that is substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is part of the gastrointestinal 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 materials are insoluble, for example, until they dissolve at a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0.Exemplary enteric-coated materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, and copolymers of methyl vinyl ether and maleic anhydride (Gantrez). The following are examples of enteric dispersions: ES series, ethyl methacrylate-methyl methacrylate-trimethylammonium chloride copolymer, natural resins (e.g., zein), shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above substances is either known or readily measurable in vitro. The possible materials listed above are not exhaustive, but those skilled in the art who benefit from this disclosure will recognize that there are other enteric materials that may satisfy the purposes of this disclosure.

[0151] This disclosure also provides a kit for use by consumers, for example, who require treatment for the diseases or disorders described herein. Such a kit includes a suitable dosage form as described above and instructions for use describing the method of mediating, reducing, or preventing inflammation using this dosage form. The instructions will instruct the consumer or healthcare professional to administer the dosage form according to methods of administration known to those skilled in the art. Such a kit can advantageously be packaged and sold in single or multiple kit units. One example of such a kit is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of material covered with a foil, preferably of a transparent plastic material. During the packaging process, grooves are formed in the plastic foil. The grooves have the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed into the groove, and the relatively rigid sheet of material is sealed onto the plastic foil on the foil side opposite to the direction in which the groove is formed. As a result, the tablet or capsule is sealed in the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough that tablets or capsules can be removed from the blister pack by manually applying pressure to the groove, thereby creating an opening in the groove of the sheet. The tablet or capsule can then be removed through said opening.

[0152] Memory aids may need to be provided on the kit, for example, in the form of numbers next to the tablets or capsules, whereby the numbers correspond to the number of days in the prescribed regimen in which the tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, such as “Week 1, Monday, Tuesday, … etc. Week 2, Monday, Tuesday, … etc.” Other variations of the memory aid will be readily apparent. A “daily dose” could be one tablet or capsule or several pills or capsules to be taken on a given day. Furthermore, the daily dose of the first compound could consist of one tablet or capsule, while the daily dose of the second compound could consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0153] Exemplary embodiments of the present invention E1. A compound represented by formula I: (I); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is selected from the group consisting of 8-10 fused bicyclic heteroaryl, 12-14 fused tricyclic heteroaryl, 8-10 fused bicyclic heterocyclic group, and phenyl; wherein ring A can be selected from one or more of R A The substituents are substituted; R A Each time it appears, it is independently selected from 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or one R X And an R Y They connect 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-membered heteroaryl); wherein the C1-C6 alkyl, phenyl and heteroaryl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy groups; R 2 and R 3Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 and R 5 Each is independently selected from 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 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups, and C1-C3 alkoxy groups; and R a and R b Each time it appears, it is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens.

[0154] E2. The compound according to E1, wherein the compound is represented by the following formula: (IA) (IB), or (IC).

[0155] E3. Based on compounds from E1 or E2, where R 6 and R 7 It is hydrogen.

[0156] E4. Based on any one of E1-E3, where R 2 and R 3 It is hydrogen.

[0157] E5. A compound according to any one of E1-E4, wherein the compound is represented by the following formula: (ID) (IE), or (IF).

[0158] E6. A compound based on any one of E1-E5, wherein A is selected from the group consisting of the following:

[0159]

[0160] , ,and ; in R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R d The group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl; wherein -C1-C3 alkyl can be optionally substituted by one, two or three substituents, and each substituent is independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; and m can be 0, 1, 2, or 3.

[0161] E7. A compound from any one of E1-E6, wherein: R c Choose the group consisting of hydrogen and -CH3; R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and R e Choose from the group consisting of hydrogen, fluorine, chlorine, -CH3, and cyano groups.

[0162] E8. Based on any one of E1-E5, where R AEach time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazine, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazine, and aziridine may be optionally substituted with -CH3.

[0163] E9. Based on any one of E1-E5 and E7, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3.

[0164] E10. Based on any one of the compounds in E1-E9, where A is selected from the group consisting of the following:

[0165]

[0166]

[0167]

[0168] , , , ,and .

[0169] E11. Based on any one of E1-E10, the compound, where 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.

[0170] E12. Based on any one of E1-E11, the compound, where R 4 It is hydrogen.

[0171] E13. Based on any one of E1-E12, where R 5Choose the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2 and -NH-C(O)-N(CH2CH3)2.

[0172] E14. Based on any one of E1-E13, where R 5 It is hydrogen or -CH3.

[0173] E15. Based on any one of E1-E14, where R 1 Choose free hydrogen, -CH3, and A group that is formed.

[0174] E16. Based on any one of E1-E15, where R 1 It is hydrogen.

[0175] E17. Based on compounds represented by formula IIA, IIB or IIC, (IIA) (IIB) (IIC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , , , ,and ; R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R d The group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl and C1-C3 alkoxy; wherein the -C1-C3 alkyl group may be optionally substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; R 1 Choose free hydrogen, -CH3, and A group that is formed.

[0176] R 2 and R 3 Each is independently selected from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m can be 0, 1, 2, or 3.

[0177] E18. A compound from any one of E1-E6, wherein: R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and R e Choose from the group consisting of hydrogen, fluorine, chlorine, -CH3, and cyano groups.

[0178] E19. Compounds based on E17 or E18, where R 4 It is hydrogen.

[0179] E20. A compound based on any one of E17-E19, where R 5 Choose from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2 and -NH-C(O)-N(CH2CH3)2.

[0180] E21. Based on any one of E17-E20, the compound, where R 5 It is hydrogen or -CH3.

[0181] E22. Based on any one of E17-E21, the compound, where R 1 It is hydrogen.

[0182] E23. A compound selected from the group consisting of:

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

[0190] E24. A compound represented by formula III, (III); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is , ,or ; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or R X and R Y They connect together to form -CH2-; R W The group is selected from the group consisting of hydrogen, C1-C6 alkyl and -SO2-phenyl; wherein the C1-C6 alkyl and phenyl may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl and C1-C3 alkoxy. R A Each time it appears, it is independently selected from 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R bThe group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R 1 The group 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-membered heteroaryl), and -CH2-(5-10-membered heterocyclic). Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclic may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 Choose from 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 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 5 Choose from halogens, hydroxyl groups, cyano groups, and -NR. a R b -C(O)-NR a R b -NR a -C(O)-R b -NRa -C(O)-NR a R b -NR a -(CO)-OR b -OC(O)-NR a R b 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups 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; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens; and m can be 0, 1, 2, or 3.

[0191] E25. The compound according to E24, wherein the compound is represented by the following formula: (IIIA) (IIIB), or (IIIC).

[0192] E26. According to compounds from E24 or E25, where R 6 and R 7 It is hydrogen.

[0193] E27. A compound according to any one of E24-E26, wherein said compound is represented by the following formula: (IIID) (IIIE), or (IIIF).

[0194] E28. A compound based on any one of E24-E27, where R Y It is hydrogen or -CH3.

[0195] E29. Based on any one of E24-E28, where R W Choose the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

[0196] E30. A compound based on any one of E24-E29, where R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazine, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazine, and aziridine may be optionally substituted with -CH3.

[0197] E31. Based on any one of E24-E30, a compound in which R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH and -OCH2CH3.

[0198] E32. Based on any one of E24-E31, a compound in which R 2 It is hydrogen.

[0199] E33. Based on any one of E24-E32, a compound in which R 3 Choose the group consisting of hydrogen, -CH3, and -CH2OH.

[0200] E34. A compound based on any one of E24-E33, where R 4 It is hydrogen.

[0201] E35. Based on any one of E24-E34, where R 5 Choose 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.

[0202] E36. A compound based on any one of E24-E35, where R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , ,and A group that is formed.

[0203] E37. A compound represented by the formula IVA, IVB, or IVC: (IVA) (IVB) (IVC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , ,and ; R W Select from the group consisting of hydrogen and C1-C3 alkyl groups; R Y It is hydrogen or -CH3; R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazine, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazine, and aziridine may be optionally substituted with -CH3; R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , ,and The group formed; R 2Choose the group consisting of free hydrogen, -CH3, and -CH2OH; R 3 Choose 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; and m can be 0, 1, 2, or 3.

[0204] E38. A compound selected from the group consisting of:

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

[0214] E39. A compound selected from the group consisting of:

[0215]

[0216]

[0217]

[0218]

[0219] , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

[0220] E40. A pharmaceutical composition comprising a compound from any one of E1-E39 and a pharmaceutically acceptable excipient.

[0221] E41. A method of treating mental or neurological disorders or disorders in patients in need, comprising administering to the patient a therapeutically effective amount of any one of E1-E39 compounds.

[0222] E42. A method of treating a mental or neurological disorder or psychiatric ailment in a patient in need, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of E1-E39 and a pharmaceutically acceptable excipient.

[0223] E43. According to the method of E41 or E42, the mental or neurological illness or disorder is selected from the group consisting of depression, anxiety, substance abuse and headache.

[0224] Example The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic methods known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment methods, can be selected as standard conditions for the reaction. Those skilled in the art of organic synthesis should understand that functional groups present on different parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods are indicated. The starting materials used in the examples are either commercially available or readily prepared from known materials by standard methods.

[0225] General information Unless otherwise specified or prepared by methods described in the literature, reagents and solvents are obtained from commercial sources without further purification. 1 H NMR and 13 C10 NMR spectra were recorded on a 300 or 400 MHz Bruker spectrometer using DMSO-d6, CDCl3, or CD3OD as solvents and tetramethylsilane (TMS) as an internal standard, at room temperature. Chemical shifts are given as δ relative to TMS, and coupling constants are also provided. J Values ​​are given in Hz. One of the following methods was used to generate the LCMS analysis method and instrumentation. All methods were detected by UV (254 nm) and ELSD.

[0226] Method A (LCMS17, 41, 42, 50, 52) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Express C18, 2.7 μm particle size) and eluted with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA.

[0227] Method B (LCMS17, 41, 42, 47, 50, 52) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Express C18, 2.7 μm particle size) and eluted with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA.

[0228] Method C (LCMS25) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVOC18, 2.6 μm particle size), eluted with solvent A: water / (5 mmol / L) NH4HCO3; solvent B: acetonitrile.

[0229] Method D (LCMS25) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVOC18, 2.6 μm particle size), eluted with solvent A: water / (5 mmol / L) NH4HCO3; solvent B: acetonitrile.

[0230] Method E (LCMS40) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Express C18, 2.7 μm particle size) and eluted with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA.

[0231] Method F (LCMS45) The experiment was performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Poroshell HPH-C18, 2.7 μm particle size) and eluted with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile.

[0232] Method G (LCMS45) The experiment was performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Poroshell HPH-C18, 2.7 μm particle size) and eluted with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile.

[0233] Method H (LCMS46, 48) The experiment was performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Poroshell HPH-C18, 4.0 μm particle size), eluted with solvent A: water / (5 mmol / L) NH4HCO3; solvent B: acetonitrile.

[0234] Method I (LCMS46, 48) The experiment was performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Poroshell HPH-C18, 4.0 μm particle size), eluted with solvent A: water / (5 mmol / L) NH4HCO3; solvent B: acetonitrile.

[0235] Method J (LCMS49) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 2.0 mm Poroshell 120EC‐C18, 1.9 μm particle size) eluted with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA.

[0236] Method K (LCMS49) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 2.0 mm Poroshell 120EC‐C18, 1.9 μm particle size) eluted with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA.

[0237] Method L (LCMS51, 53) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVO-C18, 2.6 μm particle size), eluted with solvent A: water / (5 mmol / L) NH4HCO3; solvent B: acetonitrile / acetonitrile.

[0238] Method M (LCMS51, 53) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVO-C18, 2.6 μm particle size), eluted with solvent A: water 5 mM NH4HCO3; solvent B: acetonitrile / acetonitrile.

[0239] Method N (LCMS60) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Agilent® EC-C18, 1.9 μm particle size) and eluted with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA.

[0240] Method O (LCMS61) The experiment was performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 2.0 mm Gemini NX-C18, 3.0 μm particle size), eluted with solvent A: (5 mmol / L) NH4HCO3; solvent B: acetonitrile.

[0241] Method P (LCMS63) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, 2.0 μm particle size) and eluted with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA.

[0242] Method Q (LCMS63) The experiments were performed on a SHIMADZU® 20A HPLC system using a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, 2.0 μm particle size) and eluted with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA.

[0243] Example 1: Synthesis of 3-[(3R)-piperidin-3-yl]-2,1-benzoxazole and 3-[(3S)-piperidin-3-yl]-2,1-benzoxazole (compounds 109 and 110)

[0244] 3-{2-[(tert-butoxycarbonyl)amino]benzoyl}piperidine-1-carboxylic acid tert-butyl ester At -78°C and under a N2 atmosphere, CH3Li (1.29 g, 58.8 mmol, 1.6 M in Et2O) was added dropwise to a THF (2 mL) solution of N-(2-bromophenyl)carbamate (8.00 g, 29.4 mmol) and... n -BuLi (30 mL, 318 mmol 2.5 M in n-hexane). The reaction mixture was stirred at -78 °C for 30 min, and then a solution of tert-butyl 3-(2-methoxypropionyl)piperidine-1-carboxylic acid (11.97 g, 44.1 mmol) in 2 mL THF was added dropwise. After 30 min of addition, the reaction mixture was quenched with NH4Cl (aqueous solution) and then extracted with EtOAc (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) by elution with petroleum ether:ethyl acetate (9:1) to give the desired product as a yellow solid (1.30 g, yield 11%). LCMS 53 (Method M) (ESI) C 22 H 32 Calculated N₂O₅: 404.23; Measured value [M+H] + :405.

[0245] 2-(piperidine-3-carbonyl)aniline A solution of tert-butyl 3-{2-[(tert-butoxycarbonyl)amino]-benzoyl}-piperidine-1-carboxylic acid (1.30 g, 3.21 mmol) in HCl / dioxane (2 mL) was stirred at room temperature for 12 hours, then concentrated under reduced pressure to give the desired product as a yellow solid (600 mg, 91% yield). LCMS 47 (ESI) C 12 H 16 Calculated N₂O: 204.13; Measured value [M+H] + 205. The product is used directly in the next step.

[0246] 3-(2-aminobenzoyl)piperidine-1-carboxylic acid tert-butyl esterTo a stirred solution of 2-(piperidin-3-carbonyl)aniline (600 mg, 2.93 mmol) in dichloromethane (6 mL), di-tert-butyl dicarbonate (705 mg, 3.23 mmol) and trimethylamine (892 mg, 8.81 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 h, and then concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with petroleum ether:ethyl acetate (3:1) to give the desired product as a yellow solid (600 mg, 67% yield). LCMS 50 (Method B) (ESI) C 17 H 24 Calculated N₂O₃: 304.18; Measured value [M+H] + 305.

[0247] 3-(2,1-benzoxazole-3-yl)piperidine-1-carboxylic acid tert-butyl ester To a stirred solution of tert-butyl 3-(2-aminobenzoyl)piperidine-1-carboxylic acid (600 mg, 1.97 mmol) in acetonitrile (15 mL), iodobenzene (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) by elution with petroleum ether:ethyl acetate (3:1) to give the desired product as a yellow solid (300 mg, 50% yield). LCMS 47 (ESI) C 17 H 22 Calculated N₂O₃: 302.16; Measured value [M+H] + :303.

[0248] 3-(piperidin-3-yl)-2,1-benzoxazole Trifluoroacetic acid (0.5 mL) was added to a solution of 3-(2,1-benzoxazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.99 mmol) in dichloromethane (2.5 mL). The reaction mixture was stirred at room temperature for 0.5 h, 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: 0% to 20% over 30 min; detector, UV 220 nm) to give the desired product as a yellow solid (100 mg, 50% yield). LCMS 40 (ESI) C 12 H 14 Calculated N₂O: 202.11; Measured value [M+H] + :203.

[0249] 3-[(3R)-piperidin-3-yl]-2,1-benzoxazole and 3-[(3S)-piperidin-3-yl]-2,1-benzoxazole3-(piperidin-3-yl)-2,1-benzoxazole (100 mg) was subjected to 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; number of runs: 13) to obtain: 3-[(3R)-piperidin-3-yl]-2,1-benzoxazole Yellow solid (16.7 mg, yield 17%). LCMS 63 (Method P) (ESI) C 12 H 14 Calculated N₂O: 202.11; Measured value [M+H] + : 203.05. 1 H NMR (300 MHz, DMSO-d6) δ7.77 (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).

[0250] 3-[(3S)-piperidin-3-yl]-2,1-benzoxazole White oily substance (18.1 mg, yield 18%). LCMS 51 (Method L) (ESI) C 12 H 14 Calculated N₂O: 202.11; Measured value [M+H] + : 202.95. 1H NMR (400 MHz, DMSO-d6)δ7.78 – 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, 0.7Hz, 1H), 3.52 – 3.43 (m, J = 14.4, 7.6, 3.8 Hz, 1H), 3.17 (dd, J = 11.9, 3.6Hz, 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).

[0251] Example 2: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-2,1-benzoxazole (compound 111)

[0252] 5,6-Dihydro-2H-pyridine-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester TMSCHN2 (17.6 mL, 35.20 mmol) was added dropwise to a stirred mixture of 1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridine-3-carboxylic acid (4.00 g, 17.60 mmol) in DCM (20 mL) and MeOH (20 mL) under a N2 atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The reaction was quenched with AcOH at room temperature, and the resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 60% over 30 minutes; UV 254 nm, yielding the desired product as a yellow liquid (3.60 g, yield 84.7%). LCMS 53 (Method L) (ESI) C 12 H19 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).

[0253] 3-(hydroxymethyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester DIBAL-H (25.6 mL, 64.00 mmol) was added dropwise to a stirred mixture of 3-methyl-1-tert-butyl 5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 3-methyl-1-tert-butyl ester (3.60 g, 14.92 mmol) in toluene (40 mL) under a N2 atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 30 min under a N2 atmosphere. 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 purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 50% over 30 minutes; UV 254 nm, yielding the desired product as a 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 (400MHz, 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).

[0254] 3-Formyl-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterA solution of tert-butyl 3-(hydroxymethyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (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 a 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) by elution with PE / EA (5:1) to give the desired product as a 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).

[0255] 3-[hydroxy(2-nitrophenyl)methyl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester At -40°C and under a N2 atmosphere, magnesium phenyl 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), and the mixture was stirred for 5 minutes at -40°C and under a N2 atmosphere. tert-butyl 3-formyl-5,6-dihydro-2H-pyridine-1-carboxylic acid (200.0 mg, 0.94 mmol) was added dropwise to the mixture at -40°C. The resulting mixture was stirred for another 1 hour at -40°C. The reaction 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 over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to obtain the desired product, a yellow oil (150.0 mg, yield 47.3%). LCMS 52 (Method B) (ESI) C 17 H 22 Calculated N₂O₅: 334.15; Measured value [M+H] + :335. 1H 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).

[0256] 3-(2-Nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 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-carboxylic acid (150.0 mg, 0.44 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The mixture was filtered, and the residue was washed with CH2Cl2 (3 × 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give the desired product as a yellow oil (80.0 mg, yield 53.6%). LCMS 49 (Method J) (ESI) C 17 H 20 Calculated N₂O₅: 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).

[0257] 3-(2,1-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterSnCl₂·2H₂O (163.0 mg, 0.72 mmol) was added to a stirred solution of tert-butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (80.0 mg, 0.24 mmol) in MeOH (0.5 mL) and EtOAc (0.5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with saturated NaHCO₃ (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with water (3 × 4 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give the desired product as a white solid (30.0 mg, 41.5% yield). LCMS 54 (ESI) C 17 H 20 Calculated N₂O₃: 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 = 6.1Hz, 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).

[0258] 3-(1,2,5,6-tetrahydropyridin-3-yl)-2,1-benzoxazole A solution of 1,4-dioxane (1 mL, 4 M) in HCl (gas) was added to a stirred solution of tert-butyl 3-(2,1-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (45.0 mg, 0.15 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase, aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 10% to 50% over 20 minutes; detector, UV 254 nm; yielded the desired product as a white solid (18.1 mg, yield 60.3%). LCMS51 (Method L) (ESI) C 12 H 12 Calculated N₂O: 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).

[0259] Example 3: Synthesis of 7-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-2,1-benzoxazole (compound 112)

[0260] 3-[(3-fluoro-2-nitrophenyl)(hydroxy)methyl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester At -40°C, magnesium phenyl chloride (4.2 mL, 2 M, in THF) was added dropwise to a stirred THF solution of 1-fluoro-3-iodo-2-nitrobenzene (909.9 mg, 3.40 mmol) in 10 mL of THF, and the mixture was stirred for 5 minutes at -40°C under a N2 atmosphere. 3-Formyl-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (600.0 mg, 2.84 mmol) was added dropwise to the mixture at -40°C, and the resulting mixture was stirred for another 1 hour at -40°C under a N2 atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 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 give the desired product as a yellow oil (300 mg, yield 29.9%). LCMS 54 (ESI) C 17 H 21 Calculated FN₂O₅: 352.14; Measured value [M+H] + :353. 1H 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).

[0261] 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 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-carboxylic acid (290.0 mg, 0.82 mmol) in DCM (3 mL). The resulting mixture was stirred overnight at room temperature under a N2 atmosphere. The 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) by elution with PE / EA (5:1) to give the desired product as a yellow oil (200 mg, yield 69.3%). LCMS 50 (Method B) (ESI) C 17 H 19 Calculated FN₂O₅: 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 = 1.8Hz, 1H), 4.11 (d, J = 2.3 Hz, 2H), 3.43 (d, J = 5.7 Hz, 2H), 2.33 (d, J = 2.7Hz, 2H), 1.43 (s, 9H).

[0262] 3-(7-fluoro-2,1-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterSnCl₂·2H₂O (370.3 mg, 1.62 mmol) was added to a stirred solution of tert-butyl 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (190.0 mg, 0.54 mmol) in MeOH (1 mL) and EtOAc (1 mL). The resulting mixture was stirred overnight at room temperature under a N₂ atmosphere. The reaction was quenched with saturated NaHCO₃ (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 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 preparative TLC (PE / EA 5:1) to give the desired product as a white solid (110 mg, yield 63.7%). LCMS 50 (Method B) (ESI) C 17 H 19 Calculated FN₂O₃: 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).

[0263] 7-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-2,1-benzoxazole A solution of 1 mL of dioxane in HCl (gaseous) was added to a stirred solution of tert-butyl 3-(7-fluoro-2,1-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.31 mmol) in dioxane. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was then concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 10% to 50% over 30 minutes; detector: UV 254 nm; yielded the desired product as a white solid (30.4 mg, yield 44.1%). LCMS 51 (Method L) (ESI) C 12 H 11 Calculated FN2O value: 218.09; Measured value [M+H] + : 219.15. 1H 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).

[0264] Example 4: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile (compound 121)

[0265] 1-(2,2-diethoxyethoxy)-2-iodobenzene At room temperature, 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), and the mixture was stirred at 100 °C for 1 hour under a N₂ atmosphere. The resulting mixture was extracted with EtOAc (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) by elution with PE / EA (5:1) to give the desired product as a yellow oil (5.4 g, yield 50.4%). LCMS 49 (Method J) (ESI) C 12 H 17 Calculated IO3 value: 336.02; Measured value [M+H]+: 337.

[0266] 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 a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (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) by elution with PE / EA (5:1) to give the desired product as a white solid (3.5 g, yield 89.2%). LCMS 17 (Method B) (ESI) C8H5IO Calculated value 243.94; Found value [M+H] + :245.

[0267] 2,3-Dibromo-7-iodo-2,3-dihydro-1-benzofuranUnder a nitrogen atmosphere, 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 for 1 hour. The resulting mixture was extracted with EtOAc (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) by elution with PE / EA (5:1) to give the desired product as a white solid (1 g, yield 60.4%).

[0268] 3-Bromo-7-iodo-1-benzofuran Under a nitrogen atmosphere, 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 and concentrated under vacuum. The resulting mixture was extracted with EtOAc (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) by elution with PE / EA (5:1) to give the desired product as a white solid (600 mg, yield 75.0%). 1 H NMR (300 MHz, CDCl3) δ 7.78 –7.70 (m, 2H), 7.57 – 7.47 (m, 1H), 7.14 – 7.04 (m, 1H).

[0269] 3-Bromo-1-benzofuran-7-onitrile Pd(PPh3)4 (143.1 mg, 0.12 mmol, 0.1 equivalent) was added to a stirred DMF (6 mL) solution of 3-bromo-7-iodo-1-benzofuran (400.0 mg, 1.23 mmol) and Zn(CN)2 (174.5 mg, 1.48 mmol) under a N2 atmosphere and at 110 °C for 1 hour. The resulting mixture was extracted with EtOAc (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) by elution with PE / EA (3:1) to give the desired product as a yellow oil (140 mg, 51% yield). 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).

[0270] 3-(7-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester At room temperature, K₂CO₃ (242.7 mg, 1.75 mmol) was added to a stirred solution of 3-bromo-1-benzofuran-7-onitrile (130.0 mg, 0.58 mmol), Pd(dppf)Cl₂ (42.8 mg, 0.05 mmol), and 1,4-dioxane (2 mL) and H₂O (1 mL) of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (217.2 mg, 0.70 mmol). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (50 mL). The organic extract was washed with water EtOAc (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 give the desired product as a yellow oil (65 mg, yield 34.2%). LCMS 52 (Method B) (ESI) C 19 H 20 Calculated N₂O₃: 324.15; Measured value [M+H] + 325.

[0271] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile Under a nitrogen atmosphere, a solution of tert-butyl 3-(7-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (65.0 mg, 0.20 mmol) and HCl (gas) in 1,4-dioxane (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was alkalized to pH 9 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase, aqueous solution of MeCN (0.1% FA), gradient: 0% to 40% over 20 minutes; UV 254 nm, yielding the desired product as a yellow oil (18.7 mg, yield 41.6%). LCMS 46 (Method I) (ESI) C 14 H 12 Calculated N₂O: 224.09; Measured value [M+H] + 225.05. 1H 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).

[0272] Example 5: Synthesis of 4-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile (compound 122)

[0273] 4-Fluoro-1-benzofuran-7-nitrile Under a nitrogen atmosphere, a DMF (20 mL) 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) was stirred overnight at 100 °C. The resulting mixture was extracted with EtOAc (3 × 20 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) by elution with PE / EA (5:1) to give the desired product as a yellow solid (1.00 g, yield 66.7%). LCMS 52 (Method A) (ESI) C9H4FNO calculated value 161.03; found 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).

[0274] 2,3-Dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-nitrileBr2 (0.1 mL, 18.62 mmol) was added dropwise to a stirred solution of 4-fluoro-1-benzofuran-7-onitrile (1.00 g, 6.21 mmol) in CH2Cl2 (10.0 mL) under a N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The reaction 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) by elution with PE / EA (5:1) to give 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).

[0275] 3-Bromo-4-fluoro-1-benzofuran-7-onitrile A solution of 2,3-dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-onitrile (700.0 mg, 2.18 mmol) in DCM (10.0 mL) was treated with DBU (498.1 mg, 3.27 mmol). The resulting mixture was stirred at 50 °C for 2 hours under a nitrogen 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) by elution with PE / EA (6:1) to give 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).

[0276] 3-(7-cyano-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid esterUnder a nitrogen atmosphere, a solution of 3-bromo-4-fluoro-1-benzofuran-7-onitrile (300.0 mg, 1.25 mmol), Pd(dppf)Cl2 (45.7 mg, 0.06 mmol), K2CO3 (518.2 mg, 3.75 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (579.7 mg, 1.88 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80 °C for 2 hours. The resulting mixture was extracted with EtOAc (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) and eluted with PE / EA (5:1) to give the desired product as a yellow solid (400.0 mg, yield 46.7%). LCMS 52 (Method A) (ESI) C 19 H 19 Calculated FN₂O₃: 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).

[0277] 4-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-onitrile Under a nitrogen atmosphere, a solution of tert-butyl 3-(7-cyano-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol) in dioxane (0.5 mL) and a solution of 1,4-dioxane in HCl (gas) were stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, aqueous solution of MeCN (0.1% FA), gradient: 0% to 50% over 30 minutes; detector, UV 254 nm, yielding the desired product as a white solid (63.3 mg, yield 89.5%). LCMS 51 (Method L) (ESI) C 14 H 11 Calculated FN2O 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).

[0278] Example 6: Synthesis of 3-(6,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 126)

[0279] 2 3-Difluorophenylacetic acid ester Acetyl chloride (2.90 g, 36.90 mmol) was added dropwise 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) at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10 / 1) to give the desired product as a grayish-white liquid (3.4 g, yield 64.2%).

[0280] 1-(3,4-Difluoro-2-hydroxyphenyl)ethyl ketone At room temperature, AlCl3 (3.95 g, 29.63 mmol) was added in portions to a stirred solution of 2,3-difluorophenylacetate (3.4 g, 19.75 mmol) in 20 mL of DCE. The resulting mixture was stirred overnight at 90 °C under a N2 atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with PE / EA (5 / 1) to give the desired product as a yellow solid (2.3 g, 67.6% yield). 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).

[0281] 2-Chloro-1-(3,4-difluoro-2-hydroxyphenyl) ethyl ketoneAt room temperature, BnMe3NCl2I (4.04 g, 11.62 mmol) was added fractionally to a stirred solution of 1-(3,4-difluoro-2-hydroxyphenyl)ethyl ketone (1 g, 5.81 mmol) in DCE (7 mL) and MeOH (3 mL). The resulting mixture was stirred at 65 °C for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give the desired product as a yellow solid (1.1 g, 91.6% yield). 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).

[0282] 6,7-Difluoro-2H-1-benzofuran-3-one At room temperature, AcONa (0.87 g, 10.65 mmol) was added in portions to a stirred solution of 1.1 g (5.33 mmol) of 2-chloro-1-(3,4-difluoro-2-hydroxyphenyl)ethyl ketone in MeOH (15 mL). The resulting mixture was stirred at 65 °C for 2 hours and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0283] 6,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonate At 0 °C, Tf₂O (920.5 mg, 3.26 mmol) was added dropwise to a stirred solution of 6,7-difluoro-2H-1-benzofuran-3-one (370 mg, 2.18 mmol) and DIEA (843.3 mg, 6.53 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) and eluted with PE / EA (10:1) to give the desired product as a yellow solid (310 mg, yield 47.1%). 1H NMR (300 MHz, DMSO-d6)δ 8.89 (s, 1H), 7.57 (d, J = 4.6 Hz, 1H), 7.56 – 7.52 (m, 1H).

[0284] 3-(6,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester At room temperature, Pd(dppf)Cl2 (150.1 mg, 0.21 mmol) and K2CO3 (425.4 mg, 3.08 mmol) were added to a stirred solution of 6,7-difluoro-1-benzofuran-3-yltrifluoromethanesulfonate (310 mg, 1.03 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborheopyran-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (475.8 mg, 1.54 mmol) in dioxane (2 mL) and H2O (10 mL). The resulting mixture was stirred at 80 °C for 30 min under a N2 atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) and eluted with PE / EA (10:1) to give the desired product as a pale yellow oil (312 mg, yield 90.6%). LCMS 60 (ESI) C 18 H 19 Calculated F₂NO₃ value: 335.13; Measured value [M+H] + :336.

[0285] 3-(6,7-Difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine TFA (2 mL) was added to a stirred solution of tert-butyl 3-(6,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (150 mg, 0.45 mmol, 1.0 equivalent) in DCM (2 mL), and the mixture was stirred at room temperature for 20 min. The resulting mixture was concentrated under vacuum and alkalized to pH 8 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge preparative 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 within 1 min, 5% B to 26% B within 2 min, 26% B to 44% B within 10 min), yielding the desired product as a white solid, 28.6 mg, yield 27.1%. LCMS 40 (ESI)C 13 H 11 Calculated F2NO value: 235.08; Measured value [M+H] + :236. 1H 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).

[0286] Example 7: Synthesis of 3-(5,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 127)

[0287] 3,5-Difluoro-2-[(trimethsilyl)methoxy]benzaldehyde Under a nitrogen atmosphere, a DMF (20 mL) 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) was stirred at 60 °C for 1 hour. The resulting mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) elution with PE / EA (5:1) to give the desired product as a white solid (1.00 g, yield 43.1%).

[0288] 5,7-Difluoro-2,3-dihydro-1-benzofuran-3-ol Under a nitrogen atmosphere, a DMF (20 mL) 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) was stirred overnight at 110 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with PE / EA (1:1) to give 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).

[0289] 5,7-Difluoro-2H-1-benzofuran-3-oneAt 0 °C, Dess-Martin reagent (1971.2 mg, 4.64 mmol) was added fractionally to a DCM (20 mL) solution of 5,7-difluoro-2,3-dihydro-1-benzofuran-3-ol (800.0 mg, 4.64 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (5:1) to give the desired product as a white solid (300.0 mg, yield 37.9%). 1 H NMR (400 MHz, DMSO-d6) δ7.87 – 7.78 (m, 1H), 7.42 – 7.37 (m, 1H), 4.96 (s, 2H).

[0290] 5,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonate At 0 °C, DIEA (682.38 mg, 5.28 mmol) and Tf₂O (746.3 mg, 2.64 mmol) were added to a stirred solution of 5,7-difluoro-2H-1-benzofuran-3-one (300.0 mg, 1.76 mmol, 1.0 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour and diluted with water (10 mL). The mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give the desired product as a pale yellow oil (200.0 mg crude product, yield 37.5%).

[0291] 3-(5,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterTo a solution of 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 equivalent) in dioxane (3 mL) and H₂O (6 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (322.3 mg, 1.04 mmol, 1.5 equivalent) and Pd(dppf)Cl₂ (101.7 mg, 0.13 mmol, 0.2 equivalent) were added. The mixture was stirred at 80 °C for 1 hour under a N₂ atmosphere. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) with PE / EA (5:1) elution to give the desired product as a white solid (200.0 mg, yield 85.8%). LCMS 54 (ESI) C 18 H 19 Calculated F₂NO₃ value: 335.13; Measured value [M+H] + :336. 1 H NMR (400MHz, 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).

[0292] 3-(5,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine At room temperature, TFA (3 mL) was added fractionally to a stirred solution of tert-butyl 3-(5,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol, 1.0 equivalent) in DCM (3 mL). The mixture was alkalized to pH 8 with Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 50% over 25 minutes; UV 254 nm, yielding the desired product as a white solid (35.6 mg, yield 50.4%). LCMS 51 (Method M) (ESI) C 13 H 11 Calculated F2NO 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).

[0293] Example 8: Synthesis of 3-(4,7-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 128)

[0294] 4,7-Difluoro-2,3-dihydro-1-benzofuran-3-ol To a DMSO (30 mL) solution of trimethylsulfonium iodide (5.35 g, 24.35 mmol), NaOtBu (2.34 g, 24.35 mmol) was added, and the resulting mixture was stirred at 0 °C for 0.5 h. 3,6-Difluoro-2-hydroxybenzaldehyde (3.50 g, 22.13 mmol) was added to the reactants, and the mixture was stirred again at room temperature for 2 h. 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) by elution with PE / EA (5:1) to give the desired product as a yellow solid (1.50 g, yield 39.3%).

[0295] 4,7-Difluoro-2H-1-benzofuran-3-one Add Dys-Martin reagent (1.72 g, 40.67 mmol) to a solution of 4,7-difluoro-2,3-dihydro-1-benzofuran-3-ol (700.0 mg, 4.06 mmol) in dichloromethane (8 mL), and stir at room temperature for 0.5 h. Filter the resulting mixture and wash the residue with ethyl acetate (2 × 100 mL). Concentrate the filtrate under reduced pressure to give the desired crude product as a dark yellow oil (250.0 mg, yield 36.1%). The crude product was used directly in the next step without further purification.

[0296] 4,7-Difluoro-1-benzofuran-3-yltrifluoromethanesulfonateAt room temperature, DIEA (524.2 mg, 4.05 mmol) was added 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 equivalence) 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 × 10⁻⁶ mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) elution with 100% PE to give the desired product as a yellow solid (200.0 mg, yield 48.9%).

[0297] 3-(4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 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 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (429.7 mg, 1.39 mmol) were added. The mixture was stirred at 90 °C for 2 hours under N₂ atmosphere, and 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) and eluted with PE / EA (10:1) to give the desired product as a yellow solid (150.0 mg, yield 38.6%). LCMS 49 (Method J) (ESI) C 18 H 19 Calculated F2NO3 value: 335.13; Measured value [M+H] + :336.

[0298] 3-(4,7-Difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridineA solution of 1 mL of dioxane containing HCl (gaseous) was added to a stirred solution of tert-butyl 3-(4,7-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (150.0 mg, 0.44 mmol). After stirring for 2 hours at room temperature, the mixture was alkalized to pH 8 with saturated Na₂CO₃ (aqueous solution). The resulting mixture was then concentrated under reduced pressure. The crude product (70.0 mg) was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; 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 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 7.18. The desired product was obtained as a white solid (51.8 mg, yield 49.2%). LCMS 51 (Method M) (ESI) C 13 H 11 Calculated F2NO 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).

[0299] Example 9: Synthesis of 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 130)

[0300] 7-Chloro-5-fluoro-2,3-dihydro-1-benzofuran-3-olAt 0 °C and under a N2 atmosphere, a solution of Me3SOI (2.77 g, 12.60 mmol) in DMSO (20.0 mL) was treated with t-BuONa (1.21 g, 12.60 mmol) for 30 min. Then, at room temperature and under a N2 atmosphere, 3-chloro-5-fluoro-2-hydroxybenzaldehyde (2.00 g, 11.46 mmol) was added and stirred for another 2 h. The resulting mixture was diluted with water (40 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with PE / EA (5:1) to give the desired product as a yellow solid, 1.20 g, yield 55.5%. 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).

[0301] 7-Chloro-5-fluoro-2H-1-benzofuran-3-one At 0 °C, Dysmart reagent (1124.6 mg, 2.65 mmol) was added fractionally to a stirred solution of 7-chloro-5-fluoro-2,3-dihydro-1-benzofuran-3-ol (500.0 mg, 2.65 mmol) in DCM (5.0 mL), and the mixture was stirred at room temperature under N2 atmosphere for 2 hours. The resulting mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (5:1) to give the desired product as a yellow solid (300.0 mg, yield 60.7%).

[0302] 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 mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) elution with PE / EA (8:1) to give the desired product as a yellow solid (200.0 mg, 39.0% yield).

[0303] 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution of 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 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (291.1 mg, 0.94 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80 °C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (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) and eluted with PE / EA (10:1) to give the desired product as a yellow solid (100.0 mg, yield 45.3%). 1 H 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).

[0304] 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridineUnder a nitrogen atmosphere, HCl (gas) (0.5 mL, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl 3-(7-chloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.28 mmol) in dioxane (0.5 mL). The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (1 mL) and alkalized to pH 9 with saturated Na₂CO₃ (aqueous solution). The mixture was purified by preparative HPLC under the following conditions: (Column: XBridge Shield RP18 OBD column 30*150mm, 5m; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30% B to 50% B over 30 minutes; Wavelength: 254 nm / 220 nm; RT1 (min): 7.19). The desired product was obtained as a yellow solid (27.8 mg, yield 38.9%). LCMS 48 (Method H) (ESI) C 13 H 11 Calculated ClFNO 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).

[0305] Example 10: Synthesis of 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 131)

[0306] 1-Chloro-2-(2,2-diethoxyethoxy)-4-fluorobenzeneAdd [bromo(ethoxy)methoxy]ethane (1.87 g, 10.23 mmol) and Cs₂CO₃ (6.69 g, 20.47 mmol) to a stirred mixture of 2-chloro-5-fluorophenol (1.00 g, 6.82 mmol) and DMF (10 mL), and stir at 100 °C for 1 hour under N₂ atmosphere. Extract the resulting mixture with EtOAc (3 × 30 mL). Wash the combined organic extracts with water (3 × 50 mL) and dry with anhydrous Na₂SO₄. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by chromatography (SiO₂) with PE / EA (5:1) to give 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).

[0307] 7-Chloro-4-fluoro-1-benzofuran PPA (1.68 g, 17.13 mmol) was added to a stirred mixture of 1-chloro-2-(2,2-diethoxyethoxy)-4-fluorobenzene (1.50 g, 5.71 mmol) and toluene (50 mL), and the mixture was stirred overnight at 110 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was extracted with EtOAc (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) by elution with PE / EA (12:1) to give 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).

[0308] 2,3-Dibromo-7-chloro-4-fluoro-2,3-dihydro-1-benzofuranBr2 (168.6 mg, 1.05 mmol) was added dropwise to a stirred mixture of 7-chloro-4-fluoro-1-benzofuran (150.0 mg, 0.87 mmol) and DCM (5 mL), and the mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction was quenched with saturated Na2S2O3 (aqueous solution), and the resulting mixture was extracted with EtOAc (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 to give the desired product as a yellow oil (220.0 mg, yield 75.7%). 1 H NMR (400 MHz, CD3OD) δ7.52 – 7.45 (m, 1H), 7.29 (s, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.13 (s, 1H).

[0309] 3-Bromo-7-chloro-4-fluoro-1-benzofuran DBU (304.1 mg, 1.99 mmol) was added to a stirred mixture of 2,3-dibromo-7-chloro-4-fluoro-2,3-dihydro-1-benzofuran (220.0 mg, 0.66 mmol) and DCM (5 mL). The resulting mixture was stirred at 50 °C for 2 hours under a nitrogen atmosphere. The residue was purified by chromatography (SiO2) by elution with PE / EA (12:1) to give 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).

[0310] 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterTo a stirred mixture of 3-bromo-7-chloro-4-fluoro-1-benzofuran (140.0 mg, 0.56 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (260.3 mg, 0.84 mmol) 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 a nitrogen atmosphere. The mixture was extracted with EtOAc (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 give the desired product as a white solid (100.0 mg, yield 50.6%). LCMS 54 (ESI) C 18 H 19 Calculated value of ClFNO3: 351.10; Measured value [M+H] + :352. 1 H NMR (400MHz, 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 = 5.5Hz, 2H), 1.44 (s, 9H).

[0311] 3-(7-chloro-4-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine Under a nitrogen atmosphere, a solution of 1 mL (4 M) of 1,4-dioxane and a solution of 1 mL of dioxane in HCl (gaseous solution) were stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum and alkalized to pH 9 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 60% over 30 minutes; UV 254 nm, yielding the desired product as a white solid (31.1 mg, yield 42.9%). LCMS 40 (ESI) C 13 H 11Calculated ClFNO 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).

[0312] Example 11: Synthesis of 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 134)

[0313] 2-Chloro-3,5-Difluorophenol NCS (5.13 g, 38.43 mmol) was added to a stirred solution of 3,5-difluorophenol (5.00 g, 38.43 mmol) in TFA (250 mL) and CAN (50 mL), and stirred for 3 days at room temperature under a N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give the desired product as a yellow oil (2.00 g, yield 31.6%).

[0314] 2-Chloro-1-(2,2-diethoxyethoxy)-3,5-difluorobenzene Cs₂CO₃ (10.10 g, 30.99 mmol) was added to a stirred DMF (20 mL) solution of 2-chloro-3,5-difluorophenol (1.70 g, 10.33 mmol) and 2-bromo-1,1-diethoxyethane (3.05 g, 15.49 mmol), and the mixture was stirred overnight at 120 °C under N₂ atmosphere. The resulting mixture was quenched with 10 mL of water and extracted with EtOAc (3 × 10 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) by elution with PE / EA (10:1) to give the desired product as a colorless oil (1.80 g, yield 62.0%).

[0315] 7-Chloro-4,6-Difluoro-1-benzofuranPPA (2.46 g, 21.37 mmol) was added to a stirred solution of 2-chloro-1-(2,2-diethoxyethoxy)-3,5-difluorobenzene (2.00 g, 7.12 mmol) in toluene (30 mL), and the mixture was stirred overnight at 110 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was diluted with 30 mL of water and extracted with EtOAc (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) and eluted with PE to give the desired product as a white solid (450.0 mg, yield 33.4%). 1 H 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).

[0316] 2,3-Dibromo-7-chloro-4,6-difluoro-2,3-dihydro-1-benzofuran Br2 (0.21 mL, 4.19 mmol, 1.8 equivalents) was added to a stirred solution of 7-chloro-4,6-difluoro-1-benzofuran (430.0 mg, 2.28 mmol) in DCM (5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The 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 give the desired product as a 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).

[0317] 3-Bromo-7-chloro-4,6-difluoro-1-benzofuran DBU (524.4 mg, 3.44 mmol) was added to a stirred solution of 2,3-dibromo-7-chloro-4,6-difluoro-2,3-dihydro-1-benzofuran (400.0 mg, 1.14 mmol) in DCM (5 mL), and the mixture was stirred at 50 °C for 1 hour under a N2 atmosphere. After concentration, the residue was purified by chromatography (SiO2) and eluted with PE to give 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).

[0318] 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of 3-bromo-7-chloro-4,6-difluoro-1-benzofuran (130.0 mg, 0.48 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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. The resulting mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 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) and eluted with PE / EA (10:1) to give the desired product as a white solid (100.0 mg, yield 55.6%). LCMS60(ESI)C 18 H 18 Calculated value of ClF2NO3: 369.09; Measured value of [M + H]+: 370. 1 H NMR (400 MHz, CDCl3) δ7.61 (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).

[0319] 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridineA solution of 1,4-dioxane (2 mL, 4 M) containing HCl (gaseous) was added to a stirred solution of tert-butyl 3-(7-chloro-4,6-difluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100 mg, 0.27 mmol) in dioxane (2 mL), and the mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The mixture was then alkalized to pH 8 with saturated Na₂CO₃ (aqueous solution). The mixture was purified by preparative HPLC under the following conditions: (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 60% B to 87% B over 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.8). The desired product was obtained as a white solid (13.9 mg, yield 19.0%). LCMS 63 (ESI) C 13 H 10 Calculated value of ClF2NO: 269.04; Measured value [M + H] + 269.95. 1 H NMR (300 MHz, CD3OD) δ7.88 (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).

[0320] Example 12: Synthesis of 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine (compound 135)

[0321] 2,5-Dichloro-4-fluorophenol TFA (300 mL) was added to a stirred mixture of 3-chloro-4-fluorophenol (6.00 g, 41.09 mmol, 1.0 equivalent) and NCS (5.48 g, 41.09 mmol) in ACN (60 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 2 hours. The resulting mixture was concentrated under vacuum to give the desired crude product as a yellow oil (3.00 g, yield 67.6%). LCMS 50 (Method B) (ESI) C6H3Cl2FO calculated value 179.95; found value [M+H]+: 181.

[0322] 1,4-Dichloro-2-(2,2-diethoxyethoxy)-5-fluorobenzeneCs₂CO₃ (10.80 g, 33.15 mmol) was added to a mixture of 2,5-dichloro-4-fluorophenol (3.00 g, 11.05 mmol) and 2-bromo-1,1-diethoxyethane (3.27 g, 16.57 mmol) in DMF (50 mL) under stirring, and the mixture was stirred overnight at 120 °C under N₂ atmosphere. The resulting mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3 × 50 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) by elution with PE / EA (12:1) to give the desired product as a white liquid (3.00 g, yield 60.7%). LCMS 51 (Method L) (ESI) C 12 H 15 Calculated value of Cl2FO3: 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 = 6.6Hz, 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).

[0323] 4,7-Dichloro-5-fluoro-1-benzofuran A solution of 1,4-dichloro-2-(2,2-diethoxyethoxy)-5-fluorobenzene (3.00 g, 10.13 mmol) and PPA (1.16 g, 10.13 mmol) in toluene (30 mL) was stirred at 110 °C for 1 hour under a nitrogen atmosphere and concentrated under vacuum. The residue was diluted with H₂O (50 mL) and extracted with EtOAc (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) by elution with PE / EA (12:1) to give the desired product as a white solid (600.0 mg, yield 29.1%). 1 H NMR (400MHz, 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).

[0324] 2,3-Dibromo-4,7-dichloro-5-fluoro-2,3-dihydro-1-benzofuranBr2 (0.18 mL, 3.51 mmol) was added dropwise to a stirred solution of 4,7-dichloro-5-fluoro-1-benzofuran (600.0 mg, 2.92 mmol) in 10 mL of DCM at 0 °C, and the mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction was quenched with saturated Na2SO3 (aqueous solution) and extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product as a 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).

[0325] 3-Bromo-4,7-dichloro-5-fluoro-1-benzofuran DBU (946.7 mg, 6.21 mmol) was added to a stirred solution of 2,3-dibromo-4,7-dichloro-5-fluoro-2,3-dihydro-1-benzofuran (750.0 mg, 2.07 mmol) in DCM (10 mL), and the mixture was stirred at 50 °C for 1 hour under N2 atmosphere. The mixture was purified by chromatography (SiO2) by elution with PE / EA (12:1) to give 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).

[0326] 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of 3-bromo-4,7-dichloro-5-fluoro-1-benzofuran (300.0 mg, 1.05 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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. The resulting mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) and eluted with PE / EA (9:1) to give the desired product as a white solid (250.0 mg, yield 61.2%). LCMS49 (Method K) (ESI) C 18 H18 Calculated value of Cl2FNO3: 385.06; Measured value [M+H] + 386. 1 H 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).

[0327] 3-(4,7-Dichloro-5-fluoro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine Under a nitrogen atmosphere, HCl (gas) (1 mL, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl 3-(4,7-dichloro-5-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (150.0 mg, 0.38 mmol) in dioxane (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (1 mL), then alkalized to pH 9 with saturated Na₂CO₃ (aqueous solution). The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3), gradient: 0% to 70% over 30 minutes; UV 254 nm, yielding the desired product as a white solid (59.1 mg, yield 52.8%). LCMS 48 (Method H) (ESI) C 13 H 10 Calculated value of Cl2FNO: 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).

[0328] Example 13: Synthesis of 4-ethoxy-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile (compound 140)

[0329] 4-Fluoro-1-benzofuran-7-nitrilePd(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 a N2 atmosphere. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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) by elution with PE / EA (5:1) to give the desired product as a white solid (2.00 g, yield 66.7%). LCMS 52 (Method B) (ESI) C9H4FNO Calculated value 161.03; Found value [M+H] + :162. 1 H NMR (400MHz, 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).

[0330] 2,3-Dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-nitrile Br2 (0.95 mL, 18.61 mmol) was added to a stirred solution of 4-fluoro-1-benzofuran-7-onitrile (2.50 g, 15.51 mmol) in 25 mL of DCM. The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The reaction was quenched with saturated Na2SO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (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 reversed-phase rapid chromatography under the following conditions: column, C2000. 18 Silica gel; mobile phase, aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 50% over 20 minutes; UV 254 nm, yielding 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).

[0331] 3-Bromo-4-ethoxy-1-benzofuran-7-nitrile Under a nitrogen atmosphere, a solution of 2,3-dibromo-4-fluoro-2,3-dihydro-1-benzofuran-7-onitrile (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. 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. The residue was purified by chromatography (SiO₂) by elution with PE / EA (5:1) to give the desired product as a white solid (550.0 mg, yield 66.3%). LCMS 46 (Method I) (ESI) C 11 Calculated value of H8BrNO2: 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).

[0332] 3-(7-cyano-4-ethoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester To a stirred solution of 3-bromo-4-ethoxy-1-benzofuran-7-onitrile (550.0 mg, 2.06 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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 a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 15 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) with PE / EA (4:1) elution to give the desired product as a white solid (650.0 mg, yield 85.3%). LCMS 47 (ESI)C 21 H 24 Calculated N₂O₄ value: 368.17; Measured value [M+H] + 369. 1H 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).

[0333] 4-Ethoxy-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile A solution of 1,4-dioxane in HCl (gas) (3 mL) was added to a stirred solution of 3-(7-cyano-4-ethoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100.0 mg, 0.27 mmol) in dioxane (3 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The mixture was concentrated under vacuum, and the residue was dissolved in MeOH (0.5 mL). It was then alkalized to pH 10 with saturated Na2CO3 (aqueous solution). The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 70% over 20 minutes; UV 254 nm, yielding the desired product as a white solid (34.5 mg, yield 47.3%). LCMS 51 (Method L) (ESI) C 16 H 16 Calculated N2O2 value: 268.12; Measured [M+H]+ value: 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).

[0334] Example 14: Synthesis of 4-hydroxy-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile (compound 141)

[0335] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylic acid ester 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-onitrile (1.00 g, 3.11 mmol) in 15 mL of MeOH. The resulting mixture was stirred at 80 °C for 6 hours under a N2 atmosphere. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were 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) by elution with PE / EA (5:1) to give the desired product as a white solid (550.0 mg, yield 70.0%). LCMS 54 (ESI) C 10 Calculated value of H6BrNO2: 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).

[0336] 3-(7-cyano-4-methoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester To a stirred solution of 3-bromo-4-methoxy-1-benzofuran-7-onitrile (300.0 mg, 1.19 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (552.0 mg, 1.78 mmol) in H2O (10 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 a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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) and eluted with PE / EA (5:1) to give the desired product as a yellow oil (380.0 mg, yield 90.0%). LCMS 53 (Method L) (ESI) C 20 H 22 Calculated N₂O₄ value: 354.16; Measured value [M+H] + 355. 1H 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).

[0337] 4-Hydroxy-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-7-nitrile BBr3 (2 mL) was added to a stirred solution of tert-butyl 3-(7-cyano-4-methoxy-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (200.0 mg, 0.56 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 48 hours under a N2 atmosphere. The reaction was quenched with MeOH at 0 °C. The mixture was alkalized to pH 10 with saturated Na2CO3 (aqueous solution) and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3), gradient: 0% to 60% over 30 minutes; UV 254 nm, yielding the desired product as a white solid (37.5 mg, yield 27.6%). LCMS 63 (Method Q) (ESI) C 14 H 12 Calculated N₂O₂: 240.09; Measured value [M+H] + :241.10. 1 H NMR (400MHz, 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).

[0338] Example 15: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-6-nitrile (compound 143)

[0339] 1-Benzofuran-6-nitrilePd(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 a N2 atmosphere. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give the desired product as a white semi-solid (1.03 g, 68.8% yield). 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).

[0340] 2,3-Dibromo-2,3-dihydro-1-benzofuran-6-nitrile Br2 (0.5 mL, 8.63 mmol) was added to a stirred mixture of 1-benzofuran-6-onitrile (1.03 g, 7.19 mmol) in DCM (10 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. The reaction was quenched with saturated Na2SO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with water (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired crude product as a 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).

[0341] 3-Bromo-1-benzofuran-6-onitrileUnder a nitrogen atmosphere, a mixture of 2,3-dibromo-2,3-dihydro-1-benzofuran-6-onitrile (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. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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 reversed-phase rapid chromatography under the following conditions: column, C₂. 18 Silica gel; mobile phase, MeCN aqueous solution (10 mmol / L NH4HCO3), gradient: 0% to 60% over 30 minutes; UV 254 nm, 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).

[0342] 3-(6-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester To a stirred mixture of 3-bromo-1-benzofuran-6-onitrile (800.0 mg, 3.15 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.46 g, 4.72 mmol) 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 a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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) and eluted with PE / EA (12:1) to give 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 = 2.4Hz, 2H), 3.63 (d, J = 5.7 Hz, 2H), 2.41 (d, J = 3.9 Hz, 2H), 1.53 (s, 9H).

[0343] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-6-nitrile A solution of 1,4-dioxane (1 mL) in HCl (gaseous) was added to a stirred mixture of 150 mg (0.46 mmol) of 3-(6-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 mL) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere 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 (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 18% B to 37% B over 7 minutes; Wavelength: 254nm / 220nm; RT1 (min): 7.07). The desired product was obtained as a white solid (66.6 mg, yield 63.7%). LCMS 40 (ESI) C 14 H 12 Calculated N₂O: 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 = 5.9Hz, 2H).

[0344] Example 16: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-5-nitrile (compound 144)

[0345] 2,3-Dibromo-2,3-dihydro-1-benzofuran-5-nitrile Br2 (0.09 mL, 1.676 mmol) was added fractionally to a mixture of 1-benzofuran-5-onitrile (200.0 mg, 1.397 mmol) in DCM (2 mL), and the mixture was stirred for 1.5 h at room temperature under a N2 atmosphere. The reaction was quenched with saturated Na2SO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (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 to give 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).

[0346] 3-Bromo-1-benzofuran-5-nitrile Under a nitrogen atmosphere, a mixture of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-onitrile (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. The resulting mixture was extracted with CH2Cl2 (3 × 5 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) by elution with PE / EA (5:1) to give 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).

[0347] 3-(5-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterTo a stirred mixture of 3-bromo-1-benzofuran-5-onitrile (140.0 mg, 0.631 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (292.4 mg, 0.947 mmol) 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 a N₂ atmosphere. The mixture was extracted with EtOAc (3 × 10⁻⁶ mL). The combined organic extracts were washed with water (3 × 10⁻⁶ mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 50% over 30 minutes; UV 254 nm, yielding the desired product as a yellow solid (180.0 mg, yield 88.0%). LCMS 54 (ESI) C 19 H 20 Calculated N₂O₃: 324.15; Measured value [M+H] + 325. 1 H NMR (400MHz, 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 = 7.0Hz, 2H), 1.51 (s, 9H).

[0348] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzofuran-5-nitrileAt room temperature and under a N2 atmosphere, a 1 mL solution of HCl (gaseous) in 1,4-dioxane was added to a stirred mixture of 3-(5-cyano-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (180.0 mg, 0.555 mmol, 1.0 equivalent) in dioxane (2 mL). The resulting mixture was concentrated under vacuum. The mixture was alkalized 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 (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 18% B to 37% B over 7 minutes; Wavelength: 254nm / 220nm; RT1 (min): 7.07). The desired product was obtained as a white solid (30.8 mg, yield 34.6%). LCMS 63 (Method P) (ESI) C 14 H 12 Calculated N₂O: 224.09; Measured value [M+H] + :225.10. 1 H NMR (400 MHz, DMSO-d6) δ8.46 (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).

[0349] Example 17: Synthesis of tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (compound 146)

[0350] (E)-3-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylic acid tert-butyl esterUnder a nitrogen atmosphere, a stirred solution of NaH (2.41 g, 100.37 mmol) in 20 mL of THF was treated with triethyl phosphonoacetate (11.25 g, 50.19 mmol) at 0 °C for 30 min. Then, tert-butyl 3-oxopiperidinium-1-carboxylate (5.00 g, 25.1 mmol) was added dropwise while maintaining the temperature at 0 °C. The final reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with 16% EtOAc in petroleum ether to give the desired product as a yellow oil (3.00 g, yield 44%, (E):(Z) = 9:5). LCMS (ESI) C 14 H 23 Calculated NO4 value: 269.16; Measured value [M+H]+: 270. (E) 1 ¹H 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 Calculated NO4 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).

[0351] (3Z)-3-(2-hydroxyethylidene)piperidine-1-carboxylic acid isopropyl esterAt -78 °C and under a N2 atmosphere, DIBAL-H (13.4 mL, 20.06 mmol, 1.5 M in toluene) was added dropwise to a stirred solution of (3Z)-3-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 10.02 mmol) in diethyl ether (10 mL). The final reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding ice water. The reaction mixture was extracted with dichloromethane (3 × 50 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with a solution of 50% MeOH in dichloromethane to give the desired product as a yellow liquid (1.70 g, 80% yield). LCMS 54 (ESI) C 12 H 21 Calculated NO3 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).

[0352] 5-Fluoro-2-iodophenol Boron tribromide (13.92 g, 55.55 mmol) was added dropwise to a stirred solution of 4-fluoro-1-iodo-2-methoxybenzene (2.80 g, 11.11 mmol) in dichloromethane (30 mL) under a N2 atmosphere at 0 °C. The final reaction mixture was stirred at room temperature for 30 min and then quenched with water at 0 °C. The reaction mixture was extracted with dichloromethane (3 × 100 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with 16% EtOAc in petroleum ether to give the desired product as a yellow liquid (2.10 g, 79% yield). 1 H 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).

[0353] (3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-1-carboxylic acid tert-butyl esterUnder a nitrogen atmosphere, a solution of (3Z)-3-(2-hydroxyethylidene)piperidin-1-carboxylic acid tert-butyl ester (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 mL) was stirred at room temperature for 10 minutes, followed by dropwise addition of diisopropyl azodicarboxylic acid (1.60 g, 7.92 mmol) at room temperature. The reaction mixture was stirred at room temperature for another 30 minutes, followed by concentration under reduced pressure. The residue was purified by preparative TLC (20 × 20 cm, 16% ethyl acetate in petroleum ether) to give the desired product as a yellow oil (900 mg, 53% yield). 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).

[0354] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterAdd CoCl2 (29.0 mg, 0.22 mmol) to a 10 mL Schlenk tube at room temperature and heat with a hairdryer for 2 minutes. Add DPPB (57.2 mg, 0.13 mmol, 0.1 equivalent) and tetrahydrofuran (5.0 mL) to the tube. Stir the resulting mixture at room temperature for another 5 minutes. Add [(chloromagnesiumoxy)methyl]trimethylsilane (492.9 mg, 3.35 mmol, 3.0 equivalent) dropwise to the mixture at 0°C. Stir the resulting mixture at 0°C for another 5 minutes. Add (3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.12 mmol, 1.0 equivalent) dropwise to the mixture at room temperature. Stir the resulting mixture at 80°C for another 30 minutes. Quench the reaction 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) by elution with a 50% MeOH solution in dichloromethane to give the desired product as a brown solid (300.0 mg, 84% yield). LCMS 50 (Method A) (ESI) C 18 H 22 Calculated FNO3 value: 319.16; Measured value [M+H] + 320.

[0355] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-1,2,5,6-tetrahydropyridine At 0 °C, a solution of 1,4-dioxane (2 mL, 4 M) in HCl (gas) was added dropwise to a stirred solution of 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (300.0 mg, 0.94 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 30 min, 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 desired product was obtained by chromatography (column, C18; mobile phase, aqueous acetonitrile (0.1% formic acid), gradient: 5% to 95% over 10 min; detector, UV 254 nm), as a pale yellow oil (20.7 mg, yield 10%). LCMS 40 (ESI) C 13 H 14 Calculated FNO value: 219.11; Measured value [M+H] + :220.10. 1H 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).

[0356] Example 18: Synthesis of 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine (compound 147)

[0357] 6-Fluoro-1-benzofuran-3-yltrifluoromethanesulfonate At 0 °C, Tf₂O (2.80 g, 9.90 mmol) was added dropwise 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 extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) by elution with PE / EA (5:1) to give the desired product as a yellow oil (420 mg, yield 22%). LCMS 50 (Method A) (ESI) C₁₈H₄F₄O₄S Calculated value 283.98; Found value [M+H] + :285.

[0358] 3-(6-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterAt room temperature, Pd(dppf)Cl2 (165 mg, 0.23 mmol) and K2CO3 (467 mg, 3.40 mmol) were added fractionally to a stirred solution of 6-fluoro-1-benzofuran-3-yltrifluoromethanesulfonate (320.0 mg, 1.13 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (522.3 mg, 1.69 mmol) in H2O (2 mL) and dioxane (10 mL). The resulting mixture was stirred at 80 °C for 1 hour under a N2 atmosphere and then diluted with water. The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) and eluted with PE / EA (1:1) to obtain the desired product as a yellow oil (210 mg, yield 59%). LCMS 50 (Method A) (ESI) C 18 H 20 Calculated FNO3 value: 317.14; Measured value [M+H] + :318.

[0359] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidine-1-carboxylic acid tert-butyl ester At room temperature, PtO2 (0.08 g, 0.33 mmol) was added fractionally to a stirred solution of tert-butyl 3-(6-fluoro-1-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (210.0 mg, 0.67 mmol) in MeOH (5 mL). The resulting mixture was stirred overnight at room temperature under H2 atmosphere, and then filtered through diatomaceous earth. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with PE / EA (1:1) to give the desired product as a yellow oil (130 mg, 61% yield). LCMS 54 (ESI) C 18 H 24 Calculated FNO3 value: 321.17; Measured value [M+H] + :322.

[0360] 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidineA solution of tert-butyl 3-(6-fluoro-2,3-dihydro-1-benzofuran-3-yl)piperidin-1-carboxylic acid (150 mg, 0.47 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 20 min, then concentrated under reduced pressure. The desired product was obtained by HPLC (column: XBridge preparative 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 over 9 min; wavelength: 254 nm / 220 nm), as a white solid (34.9 mg, yield 33%). LCMS 63 (Method Q) (ESI) C 13 H 16 Calculated FNO value: 221.12; Measured value [M+H] + 222.00. 1 H NMR (400 MHz, DMSO-d6) δ7.22 (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).

[0361] Example 19: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-nitrile (compound 159)

[0362] 1-Benzothiophene-7-nitrile 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 a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were 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) by elution with PE / EA (10:1) to give the desired product as a white solid (400.0 mg, yield 53.5%).

[0363] 3-Bromo-1-benzothiophene-7-onitrile Br2 (0.12 mL, 2.32 mmol) was added to a stirred solution of 1-benzothiophene-7-onitrile (330.0 mg, 2.07 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were 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 purified by reversed-phase rapid chromatography under the following conditions: column, C20 ... 18 Silica gel; mobile phase, aqueous solution of MeCN (0.1% FA), gradient: 0% to 55% over 15 minutes; UV 254 nm, 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).

[0364] 3-Methyl-1-benzothiophene-7-nitrile To a stirred solution of 3-bromo-1-benzothiophene-7-onitrile (160.0 mg, 0.67 mmol) and 3-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (313.9 mg, 1.01 mmol) 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 a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 10⁻⁶ mL). The combined organic extracts were washed with water (3 × 10⁻⁶ mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product, a colorless oil (200.0 mg, yield 87.4%). LCMS 52 (Method B) (ESI) C 19 H 20 Calculated N₂O₂S: 340.12; Measured value [M+H] + :341. 1H NMR (300MHz, 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).

[0365] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-onitrile TFA (1 mL) was added to a stirred solution of tert-butyl 3-(7-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol, 1.0 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The mixture was alkalized 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 preparative C18 column, 30*150mm, 5m; Mobile phase A: water (0.1% FA), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 2% B to 21% B over 9 minutes; Wavelength: 254 nm / 220 nm). The desired product was obtained as a white solid (55.4 mg, yield 78.4%). LCMS 63 (Method Q) (ESI) C 14 H 12 Calculated N2S 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 = 7.3Hz, 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).

[0366] Example 20: Synthesis of 5-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-onitrile (compound 168)

[0367] Ethyl[(2-bromo-4-fluorophenyl)thioalkyl]methanethiol saltPotassium ethyl xanthate (3.04 g, 18.95 mmol) was added dropwise to a stirred solution of 2-bromo-4-fluoroaniline (3 g, 15.79 mmol) and NaNO2 (1.20 g, 17.37 mmol) in HCl (10 mL) and H2O (10 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with EtOAc (5 × 100 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0368] 2-Bromo-1-[(2,2-dimethoxyethyl)thioalkyl]-4-fluorobenzene At room temperature, KOH (0.91 g, 16.26 mmol) was added to a stirred EtOH (15 mL) solution of [(2-bromo-4-fluorophenyl)thioalkyl]methanethiol ethyl ester (1.6 g, 5.42 mmol) and 2-bromo-1,1-dimethoxy-ethane (1.10 g, 6.50 mmol), and the mixture was stirred at 80 °C for 1 hour under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure, diluted with H2O (20 mL), extracted with EtOAc (3 × 20 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0369] 7-Bromo-5-fluoro-1-benzothiopheneAt room temperature, PPA (1.40 g, 12.20 mmol) was added to a stirred solution of 2-bromo-1-[(2,2-dimethoxyethyl)thioalkyl]-4-fluorobenzene (1.2 g, 4.07 mmol) in 20 mL of chlorobenzene, and the mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3 × 50 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0370] 5-Fluoro-1-benzothiophene-7-onitrile Under a nitrogen atmosphere, 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. The resulting mixture was diluted with water, quenched with an aqueous FeSO4 solution, and extracted with EtOAc (3 × 20 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0371] 5-Fluoro-1-benzothiophene-7-onitrile Br2 (176.4 mg, 1.10 mmol) was added dropwise to a stirred solution of 7-bromo-5-fluoro-1-benzothiophene (170 mg, 0.736 mmol) in DCM (5 mL) at 0 °C, and the mixture was stirred at room temperature for 2 days. The reaction was quenched with 10 mL of Na2S2O3 at 0 °C, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) and eluted with PE / EA (10:1) to give the desired product as a white solid (60 mg, yield 46.0%). 1HNMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H).

[0372] 3-(7-cyano-5-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, 3-bromo-5-fluoro-1-benzothiophene-7-onitrile (60 mg, 0.20 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (90.6 mg, 0.29 mmol), Pd(dppf)Cl2 (28.6 mg, 0.04 mmol), and K2CO3 (81.0 mg, 0.59 mmol) were stirred at 80 °C for 1 hour in a mixture of dioxane (2.5 mL) and H2O (0.5 mL). The resulting mixture was diluted with 20 mL of water, extracted with EtOAc (3 × 20 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2), eluting with PE / EA (5:1) to give the desired product as a white solid (52 mg, yield 74.3%). LCMS 60 (ESI) C 19 H 19 Calculated FN₂O₂S: 358.12; Measured value [M + H] + :359.

[0373] 5-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-onitrile At room temperature, TFA (2 mL) was added to a stirred solution of tert-butyl 3-(7-cyano-5-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (52 mg, 0.17 mmol) in DCM (2 mL), and the mixture was stirred for 15 min at room temperature. The mixture was concentrated under reduced pressure, and the residue was alkalized 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 preparative phenyl OBD column 19*250 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MEOH; flow rate: 60 mL / min; gradient: 5% B to 5% B within 1 min, 5% B to 37% B within 2 min, 37% B to 55% B within 10 min) to obtain the desired product as a white solid (22.8 mg, yield 59.4%). LCMS 52 (ESI) C 14 H 11 Calculated FN2S value: 258.06; Measured value [M + H] + : 258.90. 1H 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).

[0374] Example 21: Synthesis of 4-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-onitrile (compound 169)

[0375] 4-Fluoro-1-benzothiophene-7-onitrile Under a nitrogen atmosphere, a DMA (10 mL) 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) was stirred at 110 °C for 1 hour. The resulting mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with PE / EA (5:1) to give the desired product as a white solid (320 mg, 59.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.39 (m, 2H), 7.31 – 7.13 (m, 2H).

[0376] 3-Bromo-4-fluoro-1-benzothiophene-7-onitrile At 0 °C, Br2 (1352.8 mg, 8.465 mmol) was added fractionally to a stirred mixture of 4-fluoro-1-benzothiophene-7-onitrile (300 mg, 1.693 mmol) in DCM (5 mL), and the mixture was stirred overnight at room temperature. The reaction was quenched by adding Na2S2O3 at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 10% to 50% over 20 minutes; detector, UV 254 nm, yielded 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).

[0377] 3-(7-cyano-4-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of 3-bromo-4-fluoro-1-benzothiophene-7-onitrile (20 mg, 0.078 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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. The mixture was extracted with EtOAc (3 × 5 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with PE / EA (5:1) to give the desired product as a white solid (15 mg, 53.5% yield). LCMS 51 (Method L) (ESI) C 19 H 19 Calculated FN₂O₂S: 358.12; Measured value [M+H] + :359.

[0378] 4-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-7-onitrile A solution of tert-butyl 3-(7-cyano-4-fluoro-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (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 alkalized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 10% to 50% over 20 minutes; detector: UV 254 nm; yielded the desired product as a white solid (11.9 mg, yield 82.5%). LCMS 63 (Method P) (ESI) C 14 H 11 Calculated FN2S value: 258.06; Measured value [M+H] + :259.10. 1H NMR (400 MHz, CD3OD) δ 7.84 (dd, J = 8.3, 4.3Hz, 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).

[0379] Example 22: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-6-onitrile (compound 176)

[0380] 1-Benzothiophene-6-nitrile 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 for 2 hours under a nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 × 50 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) by elution with PE / EA (5:1) to give 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).

[0381] 3-Bromo-1-benzothiophene-6-onitrile Br2 (0.5 mL) was added dropwise to a stirred solution of 1-benzothiophene-6-onitrile (600.0 mg, 3.77 mmol) in DCM (6.0 mL) at room temperature and under a N2 atmosphere, and the mixture was stirred for 2 hours at room temperature and under a N2 atmosphere. The reaction was quenched by adding Na2S2O3. The aqueous layer was extracted with EtOAc (3 × 30 mL), and 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) by elution with PE / EA (5:1) to give the desired product as a white solid (300.0 mg, yield 33.4%). 1H 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).

[0382] 3-(6-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of 3-bromo-1-benzothiophene-6-onitrile (300.0 mg, 1.26 mmol), Pd(dppf)Cl2 (44.2 mg, 0.06 mmol), K2CO3 (522.4 mg, 3.78 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (584.4 mg, 1.89 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80 °C for 2 hours. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 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) and eluted with PE / EA (5:1) to give the desired product as a yellow solid (200.0 mg, yield 46.6%). 1 H NMR (400MHz, 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).

[0383] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-6-onitrileUnder a nitrogen atmosphere, a solution of tert-butyl 3-(6-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (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. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (1 mL) and alkalized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture 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: 5 min 2% B to 2% B, 20 min 2% B to 20% B, 30 min 20% B to 41% B; Wavelength: 254 nm / 220 nm; RT1 (min): 8.9). The desired product was obtained as a yellow solid (25.0 mg, yield 35.4%). LCMS 51 (Method L) (ESI) C 14 H 12 Calculated N2S value: 240.07; Measured value [M+H] + :241.15. 1 H NMR (400MHz, 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).

[0384] Example 23: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-5-nitrile (compound 177)

[0385] 1-Benzothiophene-5-nitrilePd(PPh3)4 (1.08 g, 0.93 mmol) was added to a stirred solution of 5-bromo-1-benzothiophene (2.00 g, 9.38 mmol) and Zn(CN)2 (1.32 g, 11.26 mmol) in DMA (15 mL) at room temperature and under a N2 atmosphere. The resulting mixture was stirred at 100 °C for 1 hour under a N2 atmosphere, diluted with H2O (200 mL), and extracted with EtOAc (3 × 200 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) by elution with PE / EA (10:1) to give 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) δ8.44 (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).

[0386] 3-Bromo-1-benzothiophene-5-nitrile Br2 (1.00 g, 6.28 mmol) was added to a stirred solution of 1-benzothiophene-5-onitrile (1.00 g, 6.28 mmol) in DCM (10 mL) under a N2 atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour under a N2 atmosphere. The resulting mixture was diluted with EtOAc (100 mL), washed with saturated sodium thiosulfate (3 × 100 mL), and 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) by elution with PE / EA (10:1) to give the desired product as a white solid (800 mg, yield 53.4%). LCMS 49 (Method K) (ESI) C9H4BrNS Calculated value 236.92; Found value [M+H] + :238.

[0387] 3-(5-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterUnder a nitrogen atmosphere, a solution of tert-butyl 3-bromo-1-benzothiophene-5-onitrile (200.0 mg, 0.84 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (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) was stirred at 80 °C for 1 hour. The resulting mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 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) and eluted with PE / EA (3:1) to give the desired product as a yellow oil (130 mg, yield 45.6%). LCMS 49 (Method K) (ESI) C 19 H 20 Calculated N₂O₂S: 340.12; Measured value [M+H] + :341.

[0388] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1-benzothiophene-5-nitrile HCl (gas) (0.5 mL, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl 3-(5-cyano-1-benzothiophene-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (tert-butyl ester) (100.0 mg, 0.29 mmol). The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (1 mL) and alkalized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by preparative HPLC under the following conditions: (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 47% B over 9 minutes; Wavelength: 254 nm / 220 nm; RT1 (min): 9.3). The desired product was obtained as a white solid (49.6 mg, yield 70.1%). LCMS 41 (Method B) (ESI) C 14 H 12 Calculated N2S value: 240.07; Measured value [M+H] + :241. 1H NMR (300MHz, 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).

[0389] Example 24: Synthesis of {1-[(3R)-piperidin-3-yl]imidazo[4,5-b]pyridin-5-yl}methanol (compound 193)

[0390] 6-Bromo-3-methoxy-2-nitropyridine Under a nitrogen atmosphere, 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. The reaction mixture was filtered through diatomaceous earth, 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 a 40% EtOAc solution in dichloromethane to give the desired product as a pale yellow solid (5.3 g, yield 83%). LCMS 54 (ESI) C6H5BrN2O3 Calculated value 231.95; Found value [M+H] + :233.

[0391] 5-Methoxy-6-nitropyridine-2-carboxylic acid methyl ester Under a CO atmosphere, 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. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol (5 × 10 mL). The resulting mixture was diluted with brine (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO₂) by elution with 50% EtOAc in petroleum ether to give the desired product as a light brown solid (1.5 g, 66% yield). LCMS 49 (Method J) (ESI) C8H8N2O5 calculated value: 212.04; measured value [M+H] + :213. 1H 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).

[0392] 5-{[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-6-nitropyridine-2-carboxylic acid methyl ester A DMF (10 mL) 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) was stirred at 70 °C for 20 h, followed by concentration under reduced pressure. The residue was purified by chromatography (SiO2) and eluted with 40% EtOAc in petroleum ether to give the desired product as a yellow solid (700 mg, yield 39%). LCMS 49 (Method J) (ESI) C 17 H 24 Calculated N4O6 value: 380.17; Measured value [M+H] + :381.

[0393] 6-Amino-5-{[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}pyridine-2-carboxylic acid methyl ester A mixture of methyl 5-{[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-6-nitropyridine-2-carboxylic acid (700 mg, 1.84 mmol) and Pd / C (140 mg, 1.32 mmol) in MeOH (10 mL) was stirred at room temperature for 15 minutes at room temperature under a H2 atmosphere. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with a 3% MeOH solution in dichloromethane to give the desired product as a yellow solid (400 mg, 62% yield). LCMS 47 (ESI) C 17 H 26 Calculated N4O4 value: 350.20; Measured value [M+H] + :351.

[0394] (3R)-3-[5-(methoxycarbonyl)imidazo[4,5-b]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester A solution of methyl 6-amino-5-{[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}pyridine-2-carboxylic acid (400 mg, 1.14 mmol) and triethyl orthoformate (5 mL) of AcOH (0.05 mL, 0.873 mmol) was stirred overnight at 110 °C and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) and eluted with 5% MeOH in dichloromethane to give the desired product as a yellow solid (300 mg, 73% yield). LCMS 45 (Method F) (ESI) C 18 H 24Calculated N4O4 value: 360.18; Measured value [M+H] + :361.

[0395] (3R)-3-[5-(hydroxymethyl)imidazo[4,5-b]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester At room temperature, lithium aluminum hydride (158 mg, 4.16 mmol) was added to a stirred THF (10 mL) solution of (3R)-3-[5-(methoxycarbonyl)imidazo[4,5-b]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester (300 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then quenched with methanol (5 mL). The resulting mixture was filtered through diatomaceous earth, the filter cake was washed with MeOH (5 × 10 mL), and the filtrate was concentrated under reduced pressure to give the desired product as an orange solid (200 mg, 72% yield). LCMS 49 (Method K) (ESI) C 17 H 24 Calculated N4O3: 332.18; Measured value [M+H] + 333. Use directly for the next step.

[0396] {1-[(3R)-piperidin-3-yl]imidazo[4,5-b]pyridin-5-yl}methanol At room temperature, 5 mL of TFA was added dropwise to a stirred solution of (3R)-3-[5-(hydroxymethyl)imidazo[4,5-b]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 0.60 mmol) in 10 mL of dichloromethane. The resulting mixture was stirred for 30 min, 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), gradient: 1% to 20% over 10 min) to give the desired product as a yellow solid (54.8 mg, 39% yield). LCMS 49 (Method K) (ESI) C 12 H 16 Calculated N4O 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, 2H), 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).

[0397] Example 25: Synthesis of 1-(piperidin-3-yl)-1H-imidazo[4,5-b]pyridine (compound 195)

[0398] 3-((2-nitropyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester Under N2, a stirred solution of tert-butyl 3-aminopiperidine-1-carboxylic acid (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 at 90 °C for 2 hours. The resulting mixture was extracted with EtOAc (3 × 50 mL), and the combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with 20% ethyl acetate in petroleum ether to give the desired product as a white solid (1.10 g, 68% yield). LCMS 61 (ESI) C 15 H 22 Calculated N4O4 value: 322.16; Measured value [M+H] + :323.

[0399] 3-((2-aminopyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, Zn (1.12 g, 17.06 mmol) and NH4Cl (0.55 g, 10.23 mmol, 3.0 equivalence) were added to a stirred solution of 3-[(2-nitropyridin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.10 g, 3.41 mmol) in 15 mL MeOH. After 2 hours at room temperature, the reaction mixture was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) by elution with 30% ethyl acetate in petroleum ether to give the desired product as a purple solid (400 mg, 40% yield). LCMS 60 (ESI) C 15 H 24 Calculated N4O2 value: 292.19; Measured value [M+H] + :293.

[0400] 3-(1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-carboxylic acid tert-butyl esterUnder a nitrogen atmosphere, a solution of tert-butyl 3-[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylic acid (430.0 mg, 1.47 mmol) in 10 mL of triethyl orthoformate was stirred at 110 °C. After 2 hours, the reaction mixture was extracted with EtOAc (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO₂) and eluted with 50% ethyl acetate in petroleum ether to give the desired product as a brown solid (180 mg, 40% yield). LCMS 61 (ESI) C 16 H 22 Calculated N4O2 value: 302.17; Measured value [M+H] + :303.

[0401] 1-(piperidin-3-yl)-1H-imidazo[4,5-b]pyridine Under a nitrogen atmosphere, a solution of tert-butyl 3-{imidazo[4,5-b]pyridin-1-yl}piperidine-1-carboxylic acid (180.0 mg, 0.59 mmol) in 2 mL of HCl / 1,4-dioxane was stirred at room temperature for 1 hour, followed by concentration under reduced pressure. The desired product was obtained by preparative HPLC (column: XBridge preparative 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 minutes; wavelength: 254 nm / 220 nm), as a pale yellow solid (37.5 mg, yield 31%). LCMS 48 (Method H) (ESI) C 11 H 14 Calculated N4 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).

[0402] Example 26: Synthesis of 5-(2,5-dimethoxy-4-methylphenyl)-1,2,3,6-tetrahydropyridine (compound 250)

[0403] 3-(2,5-Dimethoxy-4-methylphenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution of 1-bromo-2,5-dimethoxy-4-methylbenzene (300.0 mg, 1.29 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (4 × 100 mL). The combined organic phases were concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (6:1) to give the desired product as a white solid, 150.0 mg, yield 34.6%. LCMS 53 (Method M) (ESI) [M+H] + : 218. 1HNMR (400MHz, 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).

[0404] 3-(2,5-Dimethoxy-4-methylphenyl)-1,2,5,6-tetrahydropyridine Under a nitrogen atmosphere, a solution of tert-butyl 3-(2,5-dimethoxy-4-methylphenyl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (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. The mixture was concentrated under reduced pressure; the residue was dissolved in MeOH (2 mL) and alkalized to pH 8 with saturated Na₂CO₃ (aqueous solution). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18; mobile phase, aqueous acetonitrile (10 mmol / L NH₄HCO₃), gradient: 10% to 50% over 30 minutes; detector, UV 254 nm. The desired product was given 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).

[0405] Example 27: Synthesis of 7-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 305)

[0406] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylic acid esterAt 0 °C, SEM-Cl (3.90 g, 23.52 mmol) was added to a stirred solution of methyl 3-bromo-1H-indazole-7-carboxylic acid (2.00 g, 7.84 mmol) and NaH (0.30 g, 12.54 mmol) in dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The reaction was quenched at 0 °C by adding NH4Cl (aqueous solution) (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 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) by elution with PE / EA (5:1) to give the desired product as a colorless oil (2.60 g, yield 86.0%). LCMS 52 (Method A) (ESI) C 15 H 21 Calculated value of BrN2O3Si: 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).

[0407] 3-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbazide Under a nitrogen atmosphere, a solution of methyl 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylic acid (2.60 g, 6.74 mmol) in hydrazine hydrate (30 mL) and ethanol (30 mL) was stirred overnight at 100 °C. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 61% over 20 minutes; UV 254 nm, yielding the desired product as a white solid (2.00 g, yield 76.9%). LCMS 53 (Method M) (ESI) C 14 H 21 The calculated value of BrN4O2Si is 384.06 [M+H]. + 385. 1H 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).

[0408] 3-Bromo-7-(5-methyl-1,3,4-oxadiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl} Indazole Under a nitrogen atmosphere, a solution of 10 mL of triethyl orthoacetate of 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbazide (1.00 g, 2.59 mmol) and 4-methylbenzene-1-sulfonic acid hydrate (197.4 mg, 1.03 mmol) was stirred overnight at 120 °C. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: MeCN aqueous solution (10 mmol / L NH4HCO3), gradient: 0% to 75% over 30 minutes; UV 254 nm, yielding the desired product as a white solid (300.0 mg, yield 28.2%). LCMS 53 (Method M) (ESI) C 16 H 21 Calculated value of BrN4O2Si: 408.06; Measured value [M+H] + :409.

[0409] 3-[7-(5-methyl-1,3,4-oxadiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indyl [[3-yl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester]To 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 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (339.9 mg, 1.09 mmol) in dioxane (5 mL) and H₂O (5 mL), K₂CO₃ (303.8 mg, 2.19 mmol) and Pd(dppf)Cl₂ (26.8 mg, 0.03 mmol) were added. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The 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 preparative TLC (PE / EA 4:1) to obtain the desired product as a colorless oil (350.0 mg, yield 93.3%). LCMS 52 (Method A) (ESI) C 26 H 37 Calculated value of N5O4Si: 511.26; Measured value [M+H] + :512. 1 HNMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.2, 1.0 Hz, 1H), 7.99 (d, J = 7.3, 1.0Hz, 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).

[0410] 7-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazoleA solution of 1,4-dioxane (5 mL, 4 M) in HCl (gas) was added dropwise to a stirred solution of 3-[7-(5-methyl-1,3,4-oxadiazol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}indazol-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.39 mmol) in dioxane (5 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The mixture was concentrated under reduced pressure and diluted with DCM (5 mL). It was then alkalized to pH 10 with saturated Na2CO3 (aqueous solution). After concentration, the residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 60% over 30 minutes; UV 254 nm, yielding the desired product as a yellow solid (37.3 mg, yield 33.9%). LCMS 63 (Method P) (ESI) C 15 H 15 Calculated N5O value: 281.13; Measured value [M+H] + :282.10. 1 NMR (300MHz, 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).

[0411] Example 28: Synthesis of 7-(1-methyl-1,2,3-triazol-4-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole; formic acid (compound 309)

[0412] 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-[2-(trimethylsilyl)ethynyl]indazoleCuI (203.5 mg, 1.068 mmol) was added to a stirred TEA (20 mL) 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). The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The mixture was filtered, and the residue was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure to give a crude product as a yellow oil (2.37 g, 94.4% yield). The crude product was used directly in the next step without further purification. LCMS 54 (ESI) C 18 H 28 Calculated N2OSi2: 344.17; Measured value [M+H] + 345.

[0413] 7-Ethynyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole Under a nitrogen atmosphere, 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. 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) with PE / EA (10:1) as elution. The desired product was given as a yellow oil (650.0 mg, yield 34.6%). LCMS 61 (ESI) C 15 H 20 Calculated N2OSi value: 272.13; Measured value [M+H] + :273. 1 H 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), 6.31 (s, 2H), 3.89 – 3.74(m, 2H), 3.66 (s, 1H), 1.15 – 1.00 (m, 2H), 0.11 (s, 9H).

[0414] 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-{1-[(trimethylsilyl)methyl]-1,2,3-triazole-4- IndazoleAt room temperature and under a nitrogen atmosphere, a solution of CuBr (349.1 mg, 2.434 mmol) in DMF (2 mL) was treated for 20 minutes with (2-{[2-(dimethylamino)ethyl](methyl)amino}ethyl)dimethylamine (454.8 mg, 2.625 mmol) in DMF (5 mL) in portions at room temperature. The resulting mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere. A solution of (azidomethyl)trimethylsilane (259.0 mg, 2.004 mmol) in DMF (3 mL) was added to the mixture. The resulting mixture was stirred at room temperature for another 1 hour. The mixture was extracted with EtOAc (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 resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2), eluting with PE / EA (5:1) to give the desired product as a yellow oil (750.0 mg, yield 78.2%). LCMS 54 (ESI) C 19 H 31 Calculated N5OSi2 value: 401.21; Measured value [M+H] + :402. 1 H NMR (400MHz, 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).

[0415] 7-(1-((trimethyl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole Under a nitrogen atmosphere, a solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-7-{1-[(trimethylsilyl)methyl]-1,2,3-triazol-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. The resulting mixture was concentrated under vacuum to give a crude product as a yellow oil (476.7 mg, yield 94.1%). The crude product was used directly in the next step without further purification. LCMS 52 (Method B) (ESI) C 13 H17 Calculated value for N5Si: 271.13; Measured value [M+H] + :272.

[0416] 7-(1-Methyl-1,2,3-triazol-4-yl)-1H-indazole At 0°C, TBAF (3.73 mL, 3.734 mmol) was added in portions to a mixture of 7-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (476.7 mg, 1.867 mmol) in 10 mL of THF. The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The mixture was then concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C1000000 ppm. 18 Silica gel; mobile phase, aqueous solution of MeCN (0.1% FA), gradient: 0% to 50% over 30 minutes; UV 254 nm, yielding the desired product as a yellow oil (300.0 mg, yield 85.7%). LCMS 50 (Method B) (ESI) C 10 Calculated value of H9N5: 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).

[0417] 3-Iodo-7-(1-Methyl-1,2,3-triazol-4-yl)-1H-indazole K₂CO₃ (208.1 mg, 1.506 mmol) was added to a stirred mixture of 7-(1-methyl-1,2,3-triazol-4-yl)-1H-indazole (300.0 mg, 1.506 mmol) and NIS (406.5 mg, 1.807 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 1 hour under a N₂ atmosphere. The mixture was extracted with CH₂Cl₂ (3 × 5 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 reversed-phase rapid chromatography under the following conditions: column, C₂. 18 Silica gel; mobile phase: aqueous solution of MeCN (0.1% FA), gradient: 0% to 50% over 30 minutes; UV 254 nm, yielding the desired product as a yellow solid (280.0 mg, yield 57.1%). LCMS 54 (ESI) C 10Calculated value of H8IN5: 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).

[0418] 3-[7-(1-methyl-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl acetate Under a nitrogen atmosphere, a mixture of 3-iodo-7-(1-methyl-1,2,3-triazol-4-yl)-1H-indazole (200.0 mg, 0.615 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient: 0% to 60% over 30 minutes; UV 254 nm, yielding the desired product as a yellow solid (100.0 mg, yield 42.7%). LCMS 50 (Method B) (ESI) C 20 H 24 Calculated N₆O₂: 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).

[0419] 7-(1-Methyl-1,2,3-triazol-4-yl)-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole; formic acidA solution of 1,4-dioxane (1 mL) in HCl (gas) was added to a stirred mixture of 3-[7-(1-methyl-1,2,3-triazol-4-yl)-1H-indazol-3-yl]-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (120.0 mg, 0.315 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere and then concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: (Column: Sunfire preparative C18 column, 30*150mm, 5m; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 15% B over 9 minutes; Wavelength: 254 nm / 220 nm; RT1 (min): 8.68 / 9.42). The desired product was obtained as a white solid (14.8 mg, yield 14.3%). LCMS 51 (Method L) (ESI) C 15 H 16 Calculated N6 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).

[0420] Example 29: Synthesis of 7-cyclopropyl-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 314)

[0421] 7-Cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazoleUnder a nitrogen atmosphere, a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (3.00 g, 9.16 mmol), potassium cyclopropyltrifluoro-4-borane (1.63 g, 10.99 mmol), Pd(dppf)Cl2 (670.6 mg, 0.91 mmol), and K2CO3 (3.80 g, 27.49 mmol) in 1,4-dioxane (60 mL) and H2O (30 mL) was stirred at 100 °C for 3 hours. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 × 200 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) and eluted with PE / EA (3:1) to give the desired product as a yellow oil (600 mg, yield 22.6%). LCMS 42 (Method A) (ESI) C 16 H 24 Calculated N2OSi: 288.17; Measured value [M+H] + :289.

[0422] 7-Cyclopropyl-1H-Indazole At room temperature, HCl (6 mL, 4 M in 1,4-dioxane) was added to a stirred solution of 7-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole (600.0 mg, 2.08 mmol) in 1,4-dioxane (6 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The mixture was concentrated under reduced pressure, dissolved in MeOH (2 mL), and alkalized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by reversed-phase rapid chromatography under the following conditions: column, C20 ... 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient: 0% to 50% over 20 minutes; UV 254 nm, yielding the desired product as a yellow oil (200 mg, yield 60.7%). LCMS 42 (Method A) (ESI) C 10 H 10 Calculated N2 value: 158.08; Measured value [M+H] + :159.

[0423] 7-Cyclopropyl-3-iodo-1H-indazoleAt room temperature, NIS (341.3 mg, 1.51 mmol) was added to a stirred solution of 7-cyclopropyl-1H-indazole (200.0 mg, 1.26 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere and extracted with EtOAc (20 mL). The combined organic extracts were 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) by elution with PE / EA (3:1) to give the desired product as a yellow oil (160 mg, yield 44.5%). LCMS 42 (Method A) (ESI) C 10 Calculated H9IN2 value: 283.98; Measured value [M+H] + :285.

[0424] 3-(7-cyclopropyl-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution of 7-cyclopropyl-3-iodo-1H-indazole (150.0 mg, 0.52 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (195.9 mg, 0.63 mmol), Pd(dppf)Cl2 (38.6 mg, 0.05 mmol), and K2CO3 (218.9 mg, 1.58 mmol) in 1,4-dioxane (4 mL) and H2O (2 mL) was stirred at 80 °C for 1 hour. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 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) and eluted with PE / EA (3:1) to give the desired product as a yellow oil (140 mg, yield 78.1%). LCMS 49 (Method J) (ESI) C 20 H 25 Calculated N3O2 value: 339.19; Measured value [M+H] + :340.

[0425] 7-Cyclopropyl-3-(1,2,5,6-Tetrahydropyridin-3-yl)-1H-indazoleAt room temperature and under a N2 atmosphere, HCl (0.5 mL, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl 3-(7-cyclopropyl-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol) in 1,4-dioxane (0.5 mL), and the mixture was stirred for 1 hour at room temperature and under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (1 mL) and alkalized to pH 9 with saturated Na2CO3 (aqueous solution). The mixture was purified by preparative HPLC under the following conditions: (Column: XBridge preparative phenyl OBD column 19*250mm, 5m; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 1 min 3% B to 3% B, 2 min 3% B to 20% B, 10 min 20% B to 38% B; Wavelength: 254nm / 220nm; RT1 (min): 8.52), yielding the desired product as a white solid (43.4 mg, yield 61.5%). LCMS 41 (Method B) (ESI) C 15 H 17 Calculated N3 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).

[0426] Example 30: Synthesis of 7-chloro-6-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 513)

[0427] (E)-[(3-chloro-2,4-difluorophenyl)methylene]hydrazineHydrazine hydrate (5.67 g, 113.28 mmol) was added fractionally to a stirred solution of 3-chloro-2,4-difluorobenzaldehyde (2 g, 11.33 mmol) in 10 mL of EtOH, and the mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (1:1) to give the desired product as a white solid (1.3 g, 60.2% yield). LCMS 60 (ESI) C7H5ClF2N2 Calculated value 190.01; Found value [M+H] + :191.

[0428] 7-Bromo-6-fluoro-1H-indazole Under an N2 atmosphere, ( E A solution of 1.3 g (6.82 mmol) of 3-chloro-2,4-difluorophenyl)methylene]hydrazine in ethylene glycol (10 mL) was stirred at 120 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) with PE / EA (1:1) to give the desired product as a white solid (800 mg, yield 54.5%). LCMS 60 (ESI) C7H4ClFN2 Calculated value 170; Found 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).

[0429] 7-Chloro-6-fluoro-3-iodo-1H-indazole At 0 °C, I₂ (1428.5 mg, 5.63 mmol) was added in portions to a stirred solution of 7-chloro-6-fluoro-1H-indazole (800 mg, 4.69 mmol) and KOH (526.3 mg, 9.38 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 20 minutes. The mixture was diluted with water (10 mL), extracted with EtOAc (3 × 20 mL), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) with elution using PE / EA (1:1) to give the desired product as a white solid (550 mg, 39.5% yield). 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).

[0430] 3-(7-chloro-6-fluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterAt room temperature, K₂CO₃ (769.2 mg, 5.57 mmol) and Pd(dppf)Cl₂ (271.5 mg, 0.37 mmol) were added to a stirred solution of 7-chloro-6-fluoro-3-iodo-1H-indazole (550 mg, 1.86 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (860.5 mg, 2.78 mmol) in H₂O (2 mL) and dioxane (10 mL). The resulting mixture was stirred at 80 °C for 1 hour. The mixture was diluted with water (10 mL), extracted with EtOAc (3 × 20 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 give the desired product as a white solid (380 mg, yield 58.2%). LCMS 60 (ESI) C 17 H 19 Calculated value of ClFN3O2: 351.11; Measured value [M+H] + :352.

[0431] 7-Chloro-6-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole TFA (2 mL) was added in portions to a stirred solution of tert-butyl 3-(7-chloro-6-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (360 mg, 1.02 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 20 min. The resulting mixture was concentrated under reduced pressure. The crude product (180 mg) was purified by preparative HPLC under the following conditions: (column: XBridge preparative 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 in 1 min, 5% B to 20% B in 2 min, 20% B to 38% B in 10 min) to provide the desired product as a white solid (156.7 mg, yield 48.6%). LCMS63 (Method Q) (ESI) C 12 H 11 Calculated ClFN3 value: 251.06; Measured value [M+H] + 251.95. 1HNMR (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).

[0432] Example 31: Synthesis of 6-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-nitrile (compound 514)

[0433] (E)-[(3-bromo-2,4-difluorophenyl)methylene]hydrazine At room temperature, hydrazine hydrate (3.4 g, 67.87 mmol) was added fractionally to a stirred solution of 3-bromo-2,4-difluorobenzaldehyde (1.5 g, 6.79 mmol) in 20 mL of EtOH. The resulting mixture was stirred overnight at room temperature under a N2 atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) by elution with PE / EA (1:1) to give the desired product as a white solid (1.2 g, 75.2% yield). LCMS 60 (ESI) C7H5BrF2N2 Calculated value 233.96; Measured value [M+H] + :235.

[0434] 7-Bromo-6-fluoro-1H-indazole Under a nitrogen atmosphere, a solution of (E)-(3-bromo-2,4-difluorophenyl)methylene]hydrazine (1.2 g, 5.11 mmol) in ethylene glycol dimethyl ether (20 mL) was stirred overnight at 120 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) with PE / EA (1:1) elution to give the desired product as a white solid (800 mg, yield 72.8%). LCMS 60 (ESI) C7H4BrFN2 calculated value 213.95; found value [M+H] + :215.

[0435] 6-Fluoro-1H-indazole-7-nitrileAt room temperature, Zn(CN)₂ (0.87 g, 7.44 mmol) and Pd(PPh₃)₄ (0.86 g, 0.74 mmol) were added to a stirred solution of 7-bromo-6-fluoro-1H-indazole (800 mg, 3.72 mmol) in DMF (10 mL). The resulting mixture was stirred at 60 °C for 1 hour under a N₂ atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) with PE / EA (1:1) elution to give the desired product as a white solid (350 mg, yield 58.3%). LCMS 60 (ESI) C₈H₄FN₃ calculated value 161.04; found value [M+H] + :162.

[0436] 6-Fluoro-3-iodo-1H-indazole-7-nitrile At 0 °C, KOH (365.6 mg, 6.52 mmol) and I₂ (826.9 mg, 3.26 mmol) were added in portions to a stirred solution of 6-fluoro-1H-indazole-7-onitrile (350 mg, 2.17 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 1 hour, diluted with water (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) with PE / EA (1:1) to give the desired product as a white solid (300 mg, yield 48.1%). LCMS 60 (ESI) C₈H₃FIN₃ calculated value 286.94; found value [M+H] + :288.

[0437] 3-(7-cyano-6-fluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester At room temperature, Pd(dppf)Cl2 (148 mg, 0.20 mmol) and K2CO3 (419 mg, 3.03 mmol) were added to a stirred solution of 6-fluoro-3-iodo-1H-indazole-7-onitrile (290 mg, 1.01 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (468.6 mg, 1.52 mmol) in dioxane (10 mL) and H2O (2 mL). The resulting mixture was stirred at 80 °C for 1 hour under a N2 atmosphere. The 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 give the desired product as a white solid (190 mg, yield 54.9%). LCMS 53 (Method L) (ESI) C 18 H 19 Calculated FN4O2 value: 342.15; Measured value [M+H]+ :343.

[0438] 6-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-nitriles; Formic acid At room temperature, TFA (2 mL) was added fractionally to a stirred solution of tert-butyl 3-(7-cyano-6-fluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100 mg, 0.29 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 30 minutes. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C10). 18 Silica gel; mobile phase, aqueous ACN solution (0.1% FA), gradient: 5% to 100% over 30 minutes, yielding the desired product as a white solid (39.3 mg, yield 46.6%). LCMS 40 (ESI) C 13 H 11 Calculated FN4 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 = 6.4Hz, 2H).

[0439] Example 32: Synthesis of 6,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 517)

[0440] 6,7-Difluoro-3-iodo-1H-indazoleI₂ (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 for 30 minutes at room temperature, the resulting mixture was quenched with saturated Na₂S₂O₃ (aqueous solution) at room temperature. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with water (4 × 10 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) and eluted with 20% ethyl acetate in petroleum ether to give the desired product as a white solid (213.0 mg, yield 13.4%). LCMS 54 (ESI) C₇H₃F₂IN₂ Calculated value 279.93; Found value [M+H] + :280.

[0441] 5-(6,7-difluoro-1H-indazol-3-yl)-3,6-dihydropyridine-2H-pyridine-1-carboxylic acid tert-butyl ester 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), 5-(4,4,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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 min under N₂ atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase, aqueous acetonitrile solution (0.1% FA), gradient: 1% to 99% over 20 minutes; detector, UV 254 nm, yielding the desired product as a brown solid (230.0 mg, yield 92.3%). LCMS 54 (ESI) C 17 H 19 Calculated value of F2N3O2: 335.14; Measured value [M+H] + :336.

[0442] 6,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole A solution of 1,4-dioxane (13 mL, 4 M) in HCl (gaseous) was added to a stirred solid 5-(6,7-difluoro-1H-indazol-3-yl)-3,6-dihydropyridine-2H-pyridine-1-carboxylic acid tert-butyl ester (220.0 mg, 0.66 mmol). The mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was alkalized to pH 10 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂...18 Silica gel; mobile phase, aqueous acetonitrile solution (0.1% FA), gradient: 1% to 50% over 25 minutes; detector, UV 220 nm. The desired product was obtained as a white solid (58.9 mg, yield 38.1%). LCMS 40 (ESI) C 12 H 11 Calculated F2N3 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).

[0443] Example 33: Synthesis of 5,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 518)

[0444] 5,7-Difluoro-1H-indazole-3-amine At room temperature, hydrazine hydrate (5 mL, 102.87 mmol, 16.1 equivalents) was added 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 a N2 atmosphere. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 20 mL). After filtration, 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%. LCMS 49 (Method J) (ESI) [M+H] + :170.

[0445] 5,7-Difluoro-3-iodo-1H-indazoleAt -10 °C and under a N2 atmosphere, a solution of BF3·Et2O (0.5 mL, 3.94 mmol, 2.2 equivalents) and a solution of 3-methylbutyl nitrite (0.4 mL) in THF (4 mL) were added dropwise and in portions to a stirred solution of 5,7-difluoro-1H-indazole-3-amine (300.0 mg, 1.77 mmol, 1.0 equivalents) in THF (4 mL). The resulting mixture was stirred at room temperature for 30 minutes. The residue was purified by preparation with diethyl ether (20 mL) to give a dark brown solid. The solid dissolved in acetone (4 mL) and NaI (120.0 mg, 0.80 mmol, 0.5 equivalents) were then added under ice bath conditions. The resulting mixture was stirred at room temperature for 10 minutes under a 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.

[0446] 3-(5,7-difluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a mixture of 5,7-difluoro-3-iodo-1H-indazole (200.0 mg, 0.71 mmol, 1.0 equivalent), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (450.0 mg, 1.45 mmol, 2.0 equivalent), Pd(dppf)Cl2 (55.0 mg, 0.07 mmol, 0.1 equivalent), and K2CO3 (300.0 mg, 2.17 mmol, 3.0 equivalent) in dioxane (5 mL) and H2O (1 mL) was stirred at 80 °C for 1 hour. 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.

[0447] 5,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazoleAt room temperature, TFA (1 mL) was added dropwise to a stirred solution of tert-butyl 3-(5,7-difluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol, 1.0 equivalent) in DCM (3 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was concentrated under vacuum. The mixture was alkalized to pH 8 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18; mobile phase, water in acetonitrile (0.1% NH₄HCO₃), gradient: 0% to 50% over 30 min; UV 254 nm. White solid, 35.5 mg, yield 50.4%. LCMS 40 (ESI) [M+H] + :236.10. 1 H NMR (400 MHz, CD3OD) δ7.47 (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).

[0448] Example 34: Synthesis of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 519)

[0449] 4,7-Difluoro-1H-indazole At room temperature, DIEA (2.42 g, 18.73 mmol, 3.0 equivalent) and hydrazine hydrate (0.63 g, 12.49 mmol, 2.0 equivalent) were added to a stirred solution of 2,3,6-trifluorobenzaldehyde (1.00 g, 6.24 mmol, 1.0 equivalent) in DME (5 mL). The resulting mixture was stirred at 80 °C for 2 hours under a N2 atmosphere. The 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). A pale yellow oil, 500.0 mg, yield 51.9%. LCMS 52 (Method B) (ESI) [M+H] + :155.

[0450] 4,7-Difluoro-3-iodo-1H-indazoleAt room temperature, I₂ (700.0 mg, 2.75 mmol, 1.0 equivalent) was slowly added to a mixture of stirred 4,7-difluoro-1H-indazole (400.0 mg, 2.59 mmol, 1.0 equivalent) and KOH (500.0 mg, 8.91 mmol, 3.4 equivalent) in DMF (10 mL). The resulting mixture was stirred at room temperature for 2 hours under a N₂ atmosphere. 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. A pale yellow oil, 400.0 mg, yield 55.0%. LCMS 49 (Method K) (ESI) [M+H] + :281.

[0451] 3-(4,7-difluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, 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 fractionally to a stirred solution of 4,7-difluoro-3-iodo-1H-indazole (300.0 mg, 1.07 mmol, 1.0 equivalent) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (662.5 mg, 2.14 mmol, 2.0 equivalent) in dioxane (5 mL) at room temperature and a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The residue was purified by chromatography (SiO2) with elution using PE / EA (5:1). White solid, 320.0 mg, yield 89.0%. LCMS 49 (Method K) (ESI) [M+H] + :336.

[0452] 4,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole At room temperature, TFA (0.5 mL) was added dropwise to a stirred solution of tert-butyl 3-(4,7-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (150.0 mg, 0.44 mmol, 1.0 equivalent) in DCM (1 mL). The resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated under reduced pressure. The mixture was alkalized to pH 8 with a saturated aqueous solution of Na₂CO₃. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18; mobile phase, ACN solution of (0.1% NH₄HCO₃) water, gradient: 0% to 50% over 30 min; UV 254 nm. 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).

[0453] Example 35: Synthesis of 5-fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-nitrile (compound 520)

[0454] 5-Fluoro-1H-indazole-7-nitrile 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 mL) was stirred at 120 °C for 2 hours under a N₂ atmosphere. The aqueous layer was extracted with EtOAc (3 × 10⁻⁶ 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) by elution with PE / EA (5:1) to give the desired product as a yellow solid (300.0 mg, yield 80.1%). LCMS 60 (ESI) C₈H₄FN₃ calculated value 161.04; found value [M+H] + :162. 1 HNMR (400 MHz, DMSO-d6) δ 14.15 (s, 1H), 8.32 (s, 1H), 8.08 – 7.98 (m, 2H).

[0455] 5-Fluoro-3-iodo-1H-indazole-7-nitrile A solution of 5-fluoro-1H-indazole-7-nitrile (400.0 mg, 2.48 mmol) and NIS (558.5 mg, 2.48 mmol) in DMF (5.0 mL) was stirred at room temperature for 2 hours under a N2 atmosphere. The aqueous layer was extracted with EtOAc (3 × 20 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) by elution with PE / EA (5:1) to give the desired product as a yellow solid (300.0 mg, yield 42.1%). LCMS 60 (ESI) C8H3FIN3 calculated value 286.94; found value [M+H] + :288. 1HNMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 8.17 – 8.13 (m, 1H), 7.74 – 7.69 (m,1H).

[0456] 3-(7-cyano-5-fluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere and at 80 °C, Pd(dppf)Cl2·CH2Cl2 (42.6 mg, 0.05 mmol) and K2CO3 (433.3 mg, 3.14 mmol) were added to a stirred solution of 5-fluoro-3-iodo-1H-indazole-7-onitrile (300.0 mg, 1.05 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (484.8 mg, 1.57 mmol) in dioxane (4.0 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers 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) and eluted with PE / EA (5:1) to give the desired product as a yellow solid (200.0 mg, yield 55.9%). LCMS 60 (ESI) C 18 H 19 Calculated value of FN4O2; measured value 342.15[M–H]-: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).

[0457] 5-Fluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole-7-nitrilesUnder a nitrogen atmosphere, a solution of tert-butyl 3-(7-cyano-5-fluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.29 mmol, 1.0 equivalent) in dioxane (0.5 mL) and a solution of HCl (gas) in 1,4-dioxane (0.5 mL) were stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was alkalized 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 preparative 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 over 30 minutes; Wavelength: 254 nm / 220 nm; RT1 (min): 9.68). The desired product was obtained as a yellow solid (23.2 mg, yield 32.8%). LCMS48 (Method I) (ESI) C 13 H 11 FN4 calculated value: 242.10; measured value [M–H]-: 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).

[0458] Example 36: Synthesis of 7-chloro-1-isopropyl-3-(1,2,5,6-tetrahydropyridin-3-yl)indole (compound 525)

[0459] 7-Chloro-1-isopropylindoleUnder a nitrogen atmosphere and at 0 °C, a solution of indole-7-chloro (3.00 g, 19.79 mmol) in N,N-dimethylformamide (10 mL) was added dropwise 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 mixture. The resulting mixture was stirred for another 2 hours at room temperature. The resulting mixture was diluted with EtOAc (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) and eluted with petroleum ether / ethyl acetate (17:3) to give the desired product as a colorless liquid (1.05 g, yield 27.4%). LCMS 54 (ESI) C 11 H 12 Calculated ClN 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).

[0460] 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) for 25 min at 0 °C and under a N2 atmosphere. The resulting mixture was diluted with EtOAc (20 mL). The reaction 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) by elution with a petroleum ether solution of 3% ethyl acetate to give the desired product as a colorless liquid (1.02 g, yield 69.0%). LCMS 54 (ESI) C 11 H 11 Calculated value of BrClN: 270.98; Measured value [M+H] + :272. 1H NMR (400MHz, 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).

[0461] 3-(7-chloro-1-isopropylindol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution of 3-bromo-7-chloro-1-isopropylindole (1.00 g, 3.67 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.70 g, 5.50 mmol) in water (1.5 mL) and dioxane (7.5 mL) was treated with [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (0.54 g, 0.73 mmol) and potassium carbonate (1.01 g, 7.34 mmol) at 90 °C for 3 h. The resulting mixture was extracted with EtOAc (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 purified by reversed-phase rapid chromatography under the following conditions: column, C 18 Silica gel; mobile phase: aqueous acetonitrile (0.1% formic acid), gradient: 10% to 95% over 10 minutes; detector: UV 254 nm, yielding the desired product as a brown oil (750.0 mg, yield 54.5%). LCMS 54 (ESI) C 21 H 27 Calculated value of ClN2O2: 374.18; Measured value [M+H] + :375.

[0462] 7-Chloro-1-isopropyl-3-(1,2,5,6-tetrahydropyridin-3-yl)indoleAt room temperature, a solution of 1,4-dioxane (0.43 mL, 1.74 mmol) containing hydrochloric acid (gaseous) was added dropwise to a stirred solution of tert-butyl 3-(7-chloro-1-isopropylindol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (130.0 mg, 0.34 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated under reduced pressure. The residue was rapidly purified by reverse-phase chromatography under the following conditions (column: Sunfire preparative 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: 9 min 10% B to 30% B; wavelength: 254 nm / 220 nm) to obtain the desired product as a white solid (66.0 mg, yield 59.3%). LCMS 40 (ESI) C 16 H 19 Calculated ClN2 value: 274.12; Measured value [M+H] + :275.10. 1 H NMR (400MHz, 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).

[0463] Example 37: Synthesis of 3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-4-ol (compound 527)

[0464] 3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indol-4-ol BBr3 (263.1 mg, 1.05 mmol) was added to a solution of 3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridin-3-yl]-4-methoxyindole-1-carboxylic acid tert-butyl ester (150.0 mg, 0.35 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C 18Silica gel; mobile phase: aqueous acetonitrile (10 mmol / L NH4HCO3), gradient: 5% to 95% over 20 minutes; detector: UV 254 nm; yielded the desired product as a black solid (32.3 mg, yield 41.2%). LCMS 41 (Method B) (ESI) C 13 H 14 Calculated N₂O: 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).

[0465] Example 38: Synthesis of 7-chloro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-5-ol (compound 529)

[0466] 7-Chloro-5-methoxy-1H-indole At -40°C, magnesium bromo(vinyl)magnesium (37.4 mL, 1 M in THF) was added dropwise to a stirred solution of 2-chloro-4-methoxy-1-nitrobenzene (2.00 g, 10.662 mmol) in 20 mL of THF. The resulting mixture was stirred at -40°C for 0.5 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at -40°C. The resulting mixture was extracted with CH2Cl2 (3 × 50 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) by elution with PE / EA (5:1) to give the desired product as a 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).

[0467] 7-Chloro-3-iodo-5-methoxy-1H-indole At 0 °C, NIS (817.5 mg, 3.634 mmol) was added fractionally to a stirred DMF (7 mL) solution of 7-chloro-5-methoxy-1H-indole (660.0 mg, 3.634 mmol) and stirred for 1 hour at room temperature under a N2 atmosphere. The resulting mixture was extracted with EtOAc (3 × 20 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) by elution with PE / EA (5:1) to give the desired product as a yellow solid (760 mg, yield 68.0%). LCMS 60 (ESI) C9H7ClINO calculated value 306.93; found value [M+H] + :308.

[0468] 7-Chloro-3-iodo-5-methoxyindole-1-carboxylic acid tert-butyl ester At 0 °C, Boc₂O (1.60 g, 7.317 mmol) was added to a stirred solution of 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) in DCM (8 mL). The resulting mixture was stirred at room temperature for 1 hour under a N₂ atmosphere. The mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were washed with water (3 × 4 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the desired product as a yellow solid (367 mg, yield 36.9%). LCMS 54 (ESI) C 14 H 15 Calculated ClINO3 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).

[0469] 3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridin-3-yl]-7-chloro-5-methoxyindole-1-carboxylic acid tert-butoxycarbonyl Butyl acetatePd(dppf)Cl2 (62.8 mg, 0.086 mmol) was added to a stirred solution of tert-butyl 7-chloro-3-iodo-5-methoxyindole-1-carboxylate (350.0 mg, 0.859 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was extracted with EtOAc (3 × 20 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 to obtain the desired product, a yellow oil (200 mg, yield 50.3%). LCMS 49 (Method J) (ESI) C 24 H 31 Calculated value of ClN2O5: 462.19; Measured value [M+H] + :463. 1 H NMR (400 MHz, DMSO-d6) δ7.65 (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).

[0470] Example 39: Synthesis of 6,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (compound 533)

[0471] 2,3-Difluoro-6-[2-(trimethylsilyl)ethynyl]anilineCuI (224.1 mg, 1.176 mmol) and Pd(PPh3)2Cl2 (412.9 mg, 0.588 mmol) were added to a stirred mixture of 2,3-difluoro-6-iodoaniline (1.5 g, 5.882 mmol) and trimethylsilylacetylene (808.8 mg, 8.235 mmol) in TEA (15 mL). The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic extracts were 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) by elution with PE / EA (9:1) to give the desired product as a yellow oil (920.0 mg, yield 69.4%). LCMS 54 (ESI)C 11 H 13 Calculated F2NSi 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).

[0472] 6,7-Difluoro-1H-indole CuI (1.56 g, 8.166 mmol) was added to a mixture of 2,3-difluoro-6-[2-(trimethylsilyl)ethynyl]aniline (920.0 mg, 4.083 mmol) in DMF (20 mL) under stirring. The resulting mixture was stirred at 100 °C for 5 hours under a N2 atmosphere. The mixture was extracted with EtOAc (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) by elution with PE / EA (5:1) to give the desired product as a 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).

[0473] 6,7-Difluoro-3-iodo-1H-indoleNIS (1.19 g, 5.289 mmol) was added to a stirred mixture of 6,7-difluoro-1H-indole (540.0 mg, 3.526 mmol) and DMF (10 mL). The resulting mixture was stirred at room temperature for 1 hour under a N2 atmosphere. The reaction was quenched with saturated Na2SO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (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 purified by reversed-phase rapid chromatography under the following conditions: column, C1000000 ppm. 18 Silica gel; mobile phase, aqueous solution of MeCN (0.1% FA), gradient: 0% to 50% over 30 minutes; UV 254 nm, yielding the desired product as a 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).

[0474] 3-(6,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester To a stirred mixture of 6,7-difluoro-3-iodo-1H-indole (600.0 mg, 2.150 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (997.3 mg, 3.225 mmol) 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 a N₂ atmosphere. The mixture was extracted with EtOAc (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 (9:1) to give the desired product as a yellow solid (400.0 mg, yield 55.6%). LCMS 54 (ESI) C 18 H 20 Calculated value of F₂N₂O₂: 334.15; Measured value [M+H] + :335. 1H NMR (400MHz, 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).

[0475] 6,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole A 2 mL solution of 1,4-dioxane in HCl (gas) was added to a stirred solution of 2 mL of dioxane in 3-(6,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.598 mmol). The resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere 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 (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 1.5min 2% B to 2% B, 2min 2% B to 19% B, 9min 19% B to 38% B; Wavelength: 254nm / 220nm; RT1 (min): 8.94), yielding the desired product as a white solid (68.4 mg, yield 48.4%). LCMS 40 (ESI) C 13 H 12 Calculated F2N2 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 = 5.9Hz, 2H), 2.42 – 2.35 (m, 2H).

[0476] Example 40: Synthesis of 5,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (compound 534)

[0477] 5,7-Difluoro-3-iodo-1H-indole A DMF (5.0 mL) solution of 5,7-difluoro-1H-indole (500.0 mg, 3.27 mmol) and NIS (734.6 mg, 3.27 mmol) was stirred at room temperature for 2 hours under a N2 atmosphere. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were 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) by elution with PE / EA (3:1) to give the desired product as a yellow solid (800.0 mg, yield 87.8%). LCMS 42 (Method B) (ESI) C8H4F2IN calculated value 278.94; found value [M–H]-: 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).

[0478] 3-(5,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution 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 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1329.8 mg, 4.30 mmol) in dioxane (8.0 mL) and H2O (4.0 mL) was stirred at 80 °C for 2 hours. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were 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) and eluted with PE / EA (5:1) to give the desired product as a yellow solid (200.0 mg, yield 20.9%). LCMS 41 (Method B) (ESI) C 18 H 20 Calculated value of F2N2O2: 334.15; Measured value [M - H]: 333. 1H NMR (400 MHz, DMSO-d6) δ11.83 (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).

[0479] 5,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole Under a nitrogen atmosphere, a solution of tert-butyl 3-(5,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (200.0 mg, 0.60 mmol) in dioxane (0.5 mL) and a solution of 1,4-dioxane in HCl (gas) were stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was alkalized to pH 10 with saturated Na₂CO₃ (aqueous solution). The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C₂... 18 Silica gel; mobile phase: aqueous solution of MeCN (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes; detector: UV 254 nm; yielded the desired product as a yellow solid (78.9 mg, yield 56.3%). LCMS 52 (Method B) (ESI) C 13 H 12 Calculated value of F2N2: 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 = 4.2Hz, 1H), 3.53 (s, 2H), 2.89 – 2.79 (m, 2H), 2.25 – 2.12 (m, 2H).

[0480] Example 41: Synthesis of 7-chloro-4,6-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazole (compound 521)

[0481] 3-Chloro-2,4,6-TrifluorobenzaldehydeLDA (2.4 mL, 18.01 mmol) was added dropwise to a stirred THF (10 mL) solution of 2-chloro-1,3,5-trifluorobenzene (2.50 g, 15.01 mmol) at -78 °C, and the mixture was stirred at -78 °C for 15 min under N2 atmosphere. DMF (13.9 mL, 180.14 mmol) was then added at -78 °C, and the mixture was stirred at -78 °C for 15 min under N2 atmosphere, followed by the addition of H2SO4 (5 mL) at -78 °C. The resulting mixture was stirred at -50 °C for 30 min under N2 atmosphere. The reaction was quenched with 60 mL of water at room temperature. The aqueous layer was extracted with EtOAc (5 × 60 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) by elution with PE / EA (10:1) to give 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).

[0482] 7-Chloro-4,6-Difluoro-1H-indazole Under a nitrogen atmosphere, 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. The resulting mixture was concentrated under vacuum and diluted with H2O (70 mL). The aqueous layer was extracted with EtOAc (5 × 70 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) with PE / EA (10:1) to give the desired product as a white solid (400.0 mg, yield 41.2%). LCMS 60 (ESI) C7H3ClF2N2 Calculated value 188.56; Found value [M + H] + :189. 1 H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 6.90 – 6.72 (m, 1H).

[0483] 7-Chloro-4,6-difluoro-3-iodo-1H-indazoleUnder a nitrogen atmosphere, a DMF (3 mL) solution of 7-chloro-4,6-difluoro-1H-indazole (200.0 mg, 1.06 mmol) and NIS (357.9 mg, 1.59 mmol) was stirred at 50 °C for 1 hour. The reaction was quenched with 40 mL of Na₂S₂O₃ (aqueous solution) at room temperature. The aqueous layer was extracted with EtOAc (5 × 40 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO₂) and eluted with PE / EA (6:1) to give the desired product as a white solid (300.0 mg, yield 89.9%). LCMS 60 (ESI) C₇H₂ClF₂IN₂ calculated value 313.89; found value [M + H] + :315. 1 H NMR (300 MHz, CDCl3) δ 10.44 (s, 1H), 6.90 – 6.69 (m, 1H).

[0484] 3-(7-chloro-4,6-difluoro-1H-indazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. Under a nitrogen atmosphere, a solution of 7-chloro-4,6-difluoro-3-iodo-1H-indazole (200.0 mg, 0.63 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (295 mg, 0.95 mmol), Pd(dppf)Cl2 (46.5 mg, 0.06 mmol), K2CO3 (263.7 mg, 1.90 mmol), H2O (2 mL), and dioxane (4 mL) was stirred at 80 °C for 2 hours. The reaction was quenched by adding water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) by elution with PE / EA (6:1) to give the desired product as a white solid (200 mg, yield 85.0%). LCMS 52 (ESI)C 17 H 18 Calculated value of ClF2N3O2: 369.11; Measured value [M + H] + :370. 1 H 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).

[0485] 7-Chloro-4,6-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indazoleAt room temperature and under a nitrogen atmosphere, a solution of 1,4-dioxane (2 mL) containing HCl (gas) was added dropwise to a stirred solution of tert-butyl 3-(7-chloro-4,6-difluoro-1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.27 mmol) in dioxane (2 mL), and the mixture was stirred for 3 hours. The resulting mixture was concentrated under vacuum. The mixture was then alkalized to pH 8 with saturated Na₂CO₃ (aqueous solution). The mixture was purified by preparative HPLC under the following conditions: column: XBridge preparative 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: 1 min 5% B to 5% B, 2 min 5% B to 47% B, 10 min 47% B to 60% B; wavelength: 254 nm / 220 nm; RT1 (min): 8.48. The desired product was obtained as a white solid (38.6 mg, yield 51.8%). LCMS 52 (ESI) C 12 H 10 Calculated value of ClF2N3: 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).

[0486] Example 42: Synthesis of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (compound 535)

[0487] 4,7-Difluoro-3-iodo-1H-indoleUnder a nitrogen atmosphere, a DMF (3 mL) solution of 4,7-difluoro-1H-indole (250.0 mg, 1.63 mmol) and NIS (551.0 mg, 2.45 mmol) was stirred at room temperature for 2 hours. The aqueous layer was extracted with EtOAc (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) by elution with PE / EA (3:1) to give the desired product as a yellow solid (400.0 mg, yield 87.8%). LCMS 41 (Method B) (ESI) C8H4F2IN calculated value 278.94; found value [M - H]-: 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).

[0488] 3-(4,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, a solution 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 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (664.9 mg, 2.15 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred at 80 °C for 2 hours. The aqueous layer was extracted with EtOAc (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) and eluted with PE / EA (5:1) to give the desired product as a yellow solid (100.0 mg, yield 20.9%). LCMS 42 (Method B) (ESI) C 18 H 20 Calculated value of F2N2O2: 334.15; Measured value [M - H]: 333. 1H NMR (400 MHz, DMSO-d6) δ11.99 (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).

[0489] 4,7-Difluoro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole Under a nitrogen atmosphere, a solution of tert-butyl 3-(4,7-difluoro-1H-indol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid (100.0 mg, 0.30 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. The resulting mixture was concentrated under reduced pressure. The mixture was then alkalized 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 preparative 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: 1 min 5% B to 5% B, 15 min 5% B to 17% B, 30 min 17% B to 32% B; wavelength: 254 nm / 220 nm; RT1 (min): 8.03. The desired product was obtained as a yellow solid (27.1 mg, yield 38.7%). LCMS 52 (Method B) (ESI) C 13 H 12 Calculated F2N2 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).

[0490] 7-Chloro-3-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indol-5-olUnder a nitrogen atmosphere, BBr3 (324.6 mg, 1.296 mmol) was added to a stirred solution of tert-butyl 3-[1-(tert-butoxycarbonyl)-5,6-dihydro-2H-pyridin-3-yl]-7-chloro-5-methoxyindole-1-carboxylic acid (tert-butyl ester) (200.0 mg, 0.432 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature and under a nitrogen atmosphere for 1 hour, and then concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge preparative OBD C18 column, 30*150mm, 5m; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 30% B for 20 min; Wavelength: 254 nm / 220 nm; RT1 (min): 21). The desired product was obtained as a white solid (15.8 mg, yield 14.7%). LCMS 63 (Method Q) (ESI) C 13 H 13 Calculated value of ClN2O: 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).

[0491] Example 43: Synthesis of 2-{[(3R)-3-(1H-indazol-3-yl)piperidin-1-yl]methyl}phenol and 2-{[(3S)-3-(1H-indazol-3-yl)piperidin-1-yl]methyl}phenol (Compounds 523 and 524)

[0492] 3-(1H-indazol-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylic ...

Claims

1. A compound represented by formula I: （I）； Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is selected from the group consisting of 8-10 fused bicyclic heteroaryl, 12-14 fused tricyclic heteroaryl, 8-10 fused bicyclic heterocyclic group, and phenyl; wherein ring A can be selected from one or more of R A The substituents are substituted; R A Each time it appears, it is independently selected from 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or one R X And an R Y They connect 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-membered heteroaryl); wherein the C1-C6 alkyl, phenyl and heteroaryl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy groups; R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 and R 5 Each is independently selected from 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 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups, and C1-C3 alkoxy groups; and R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens.

2. The compound according to claim 1, wherein the compound is represented by the following formula: (IA) (IB), or (IC).

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

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

5. The compound according to claim 1 or 2, wherein the compound is represented by the following formula: (ID), (IE), or (IF).

6. The compound according to claim 1 or 2, wherein A is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , ,and ;in: R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R d The group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl, C1-C3 alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl; wherein -C1-C3 alkyl can be optionally substituted by one, two or three substituents, and each substituent is independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; and m can be 0, 1, 2, or 3.

7. The compound according to claim 1 or 2, wherein: R c Choose the group consisting of hydrogen and -CH3; R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and R e Choose from the group consisting of hydrogen, fluorine, chlorine, -CH3, and cyano groups.

8. The compound according to claim 1 or 2, wherein R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazine, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazine, and aziridine may be optionally substituted with -CH3.

9. The compound according to claim 1 or 2, R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2 and -OCH2CH3.

10. The compound according to claim 1 or 2, wherein A is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

11. The compound according to claim 1 or 2, wherein 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.

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

13. The compound according to claim 1 or 2, wherein R 5 Choose from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2 and -NH-C(O)-N(CH2CH3)2.

14. The compound according to claim 1 or 2, wherein R 5 It is hydrogen or -CH3.

15. The compound according to claim 1 or 2, wherein R 1 Choose free hydrogen, -CH3, and A group that is formed.

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

17. A compound represented by formula IIA, IIB or IIC: (IIA), (IIB) (IIC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , , , ,and ; R c Select from the group consisting of hydrogen and C1-C3 alkyl groups; R d The group is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3 alkyl and C1-C3 alkoxy; wherein the -C1-C3 alkyl group may be optionally substituted by one, two or three substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2 and -OCH3; R e Choose from the group consisting of hydrogen, halogen, cyano, and -C1-C3 alkyl groups; R 1 Choose free hydrogen, -CH3, and The group formed; R 2 and R 3 Each is independently selected from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m can be 0, 1, 2, or 3.

18. The compound according to claim 1, wherein: R d Choose from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and R e Choose from the group consisting of hydrogen, fluorine, chlorine, -CH3, and cyano groups.

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

20. The compound according to claim 17 or 18, wherein R 5 Choose from the group consisting of hydrogen, hydroxyl group, -CH3, -CH2OH, -NH2 and -NH-C(O)-N(CH2CH3)2.

21. The compound according to claim 17 or 18, wherein R 5 It is hydrogen or -CH3.

22. The compound according to claim 17 or 18, wherein R 1 It is hydrogen.

23. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

24. A compound represented by formula III: (III); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein It's a single key, X is CR. X Y is C(R) Y )2; or It's a double bond; X is C, and Y is C(R) Y ); A is , ,or ; R X and R Y Each is independently selected from the group consisting of hydrogen and -C1-C3 alkyl groups; or R X and R Y They connect together to form -CH2-; R W The group is selected from the group consisting of hydrogen, C1-C6 alkyl and -SO2-phenyl; wherein the C1-C6 alkyl and phenyl may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, C1-C3 alkyl and C1-C3 alkoxy. R A Each time it appears, it is independently selected from 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 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 heterocyclic groups, and 5-6 membered heteroaryl groups; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclic, and heteroaryl groups may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b -C(O)NR a R b The group consisting of C1-C3 alkyl and C1-C3 alkoxy groups; R 1 The group 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-membered heteroaryl), and -CH2-(5-10-membered heterocyclic). Among them, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclic may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups and C1-C3 alkoxy groups; R 4 Choose from 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 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; wherein the C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 5 Choose from halogens, hydroxyl groups, cyano groups, 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 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; wherein C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl may optionally be substituted by one or more substituents, each substituent being independently selected from halogen, hydroxyl, -NR a R b The group consisting of C1-C3 alkoxy groups; R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups; wherein the C1-C6 alkyl groups may be optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of halogens, hydroxyl groups 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; wherein the C1-C3 alkyl groups may optionally be substituted by one or more halogens; and m can be 0, 1, 2, or 3.

25. The compound according to claim 24, wherein the compound is represented by the following formula: (IIIA) (IIIB), or (IIIC).

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

27. The compound according to claim 24 or 25, wherein the compound is represented by the following formula: (IIID), (IIIE), or (IIIF).

28. The compound according to claim 24 or 25, wherein R Y It is hydrogen or -CH3.

29. The compound according to claim 24 or 25, wherein R W Choose the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3 and -CH(CH3)2.

30. The compound according to claim 24 or 25, wherein R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazine, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolithyl, piperidinyl, piperazine, and aziridine may be optionally substituted with -CH3.

31. The compound according to claim 24 or 25, wherein R A Each time it appears, it is independently selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH and -OCH2CH3.

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

33. The compound according to claim 24 or 25, wherein R 3 Choose the group consisting of hydrogen, -CH3, and -CH2OH.

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

35. The compound according to claim 24 or 25, wherein R 5 Choose 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.

36. The compound according to claim 24 or 25, wherein R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , ,and A group that is formed.

37. A compound represented by the formula IVA, IVB, or IVC: (IVA)、 (IVB)、 (IVC); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein A. Choose from the following groups: , ,and ; R W Select from the group consisting of hydrogen and C1-C3 alkyl groups; R Y It is hydrogen or -CH3; R A Each time it appears, it is independently selected from fluorine, chlorine, bromine, 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, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazinyl, morpholinyl, ethylene oxide, aziridine, phenyl, triazolyl, and oxadiazolyl; among which tetrahydropyrrolithyl, piperidinyl, piperazinyl, and aziridine can be optionally substituted with -CH3; R 1 Choose from hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl, cyclopropyl, , , , , ,and The group formed; R 2 Choose the group consisting of free hydrogen, -CH3, and -CH2OH; R 3 Choose 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; and m can be 0, 1, 2, or 3.

38. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

39. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

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

41. A method of treating a mental or neurological disorder or psychiatric ailment in a patient in need, comprising administering to the patient a therapeutically effective amount of any one of claims 1, 17, 23, 24, 37, 38, and 39.

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

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

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

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