5-HT2A receptor modulator and method of use thereof

Abstract

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

Description

[Background technology]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 508,569, filed on 16 June 2023, the disclosure of which is incorporated herein by reference.

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

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

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

[0005] For example, a compound represented by formula I: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, [Chemical formula] is a single bond, X is CR X where Y is C(R Y )2, or [Chemical formula] is a double bond, X is C, and Y is C(R Y ), W is selected from the group consisting of O and S, R X and R Y are each independently selected from the group consisting of hydrogen and -C1-C3 alkyl, or R X and R Y are joined together to form -CH2-, R A is hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -C1-C6 alkyl, -C3-C,6 cycloalkyl, C1-C6 alkoxy, phenyl, 4-7 member heterocyclyl, and 5-6 member heteroaryl, where C1-C6 alkyl, -C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl, heterocyclyl, and heteroaryl may each independently be substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, -NR a R b , -C(O)-NR a R b and C1-C3 alkoxy, R 1This is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 member heteroaryl), and -CH2-(5-10 member heterocyclyl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 and R 5 These are, independently, hydrogen, halogen, hydroxyl, and -NR. a R b , -NR a -C(O)-NR a R b Selected from the group consisting of -CO2H, C1-C6 alkyl, C1-C6 alkoxy, and phenyl, where C1-C6 alkyl, C1-C6 alkoxy, and phenyl are halogens, hydroxyls, -NR a R b and may be optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkoxys. R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. m is 0, 1, 2, or 3. Compounds represented by formula I or pharmaceutically acceptable salts and / or stereoisomers thereof are disclosed herein.

[0006] Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, X is either O or S, R A For each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, and tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are optionally substituted with -CH3. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, m is 0, 1, 2, or 3. Compounds represented by formulas IIA, IIB, or IIC, or their pharmaceutically acceptable salts and / or stereoisomers, are also disclosed herein.

[0007] Further disclosure herein are pharmaceutical compositions comprising at least one compound of the present disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises at least one additional therapeutic agent for treating, alleviating, and / or preventing neurological disorders and / or disabilities.

[0008] In another embodiment, a method for reducing and / or preventing a neurological disorder or disorder in a patient requiring reduction and / or prevention of such disorder is provided herein, comprising administering to the patient a therapeutically effective amount of any compound or pharmaceutical composition thereof described herein. In a particular embodiment, the neurological disorder or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.

[0009] Also disclosed herein is a method for selectively modulating the 5-hydroxytryptamine 2A (5-HT2A) receptor in patients requiring selective modulation of the 5-hydroxytryptamine 2A (5-HT2A) receptor, comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition thereof disclosed herein. [Modes for carrying out the invention]

[0010] Herein, we will describe in more detail the features and other details of this disclosure. Before further description of this disclosure, we hereby compile the specific terms used herein, in the examples and in the appended claims. These definitions should be read so as to be understood by those skilled in the art in light of the remainder of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] definition

[0012] The term "treat" includes any effect that results in improvement of a condition, disease, disorder, etc., such as reduction, mitigation, regulation, or elimination.

[0013] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbons. Exemplary alkyl groups are defined herein by the respective C 1~6 Alkyl, C 1~4 Alkyl and C 1~3 Alkyl hydrocarbons include, but are not limited to, linear or branched hydrocarbons with 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0014] As used herein, the term “alkenyl” refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, linear or branched groups of 2 to 6 or 3 to 4 carbon atoms, referred herein to as C1-C5 alkenyls, C2-C6 alkenyls, and C3-C4 alkenyls, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl.

[0015] As used herein, the term "alkynyl" refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups are defined herein by the following terms: C 2~6 Alkinyl and C 3~6 This includes, but is not limited to, linear or branched groups of 2 to 6 or 3 to 6 carbon atoms, called alkynyl groups. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl.

[0016] As used herein, the term "alkoxy" refers to a linear or branched alkyl group (alkyl-O-) bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1 to 6 or 2 to 6 carbon atoms, referred herein as C1-C5 alkoxy, C1-C6 alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0017] The term "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared within a cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system. 6~14 This refers to an aryl group ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring defined above is condensed with one or more carbocyrillic or heterocyclyl groups, and the radical or bond site is on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafen, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Typical examples of substituted aryls include: [ka] These include, In the formula, R 56 and R 57 One of them could be hydrogen, R 56 and R 57 At least one of these is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59. NR 58 SO2R 59 COO-alkyl, COO-aryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59Selected from S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl, or R 56 and R 57 The atoms may be linked together to form a cyclic ring (saturated or unsaturated) consisting of 5 to 8 atoms, and may contain one or more heteroatoms selected from the groups N, O, or S. 60 and R 61 These are, independently, hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 The aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl is used.

[0018] As used herein, the term "carbonyl" refers to the radical -C(O)-.

[0019] As used herein, the term "cyano" refers to the radical-CN.

[0020] As used herein, the terms "cycloalkyl" or "carbocyclic group" refer to saturated or partially unsaturated hydrocarbon groups of, for example, 3 to 6 or 4 to 6 carbon atoms, respectively, C3 to C6. 10 Cycloalkyl, C 3~6 Cycloalkyl or C 4~6 These are called cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0021] As used herein, the terms "halo" or "halogen" refer to F, Cl, Br, or I.

[0022] As used herein, the term “haloalkyl” refers to an alkyl radical in which an alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl. Exemplary haloalkyl groups are, as used herein, C 1~6 Haloalkyl, C 1~4 Haloalkyl and C 1~3 This includes, but is not limited to, linear or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), known as haloalkyls.

[0023] When the term "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the above hydrocarbyl groups, such as alkyls, e.g., heteroalkyls, cycloalkyls, e.g., heterocyclyls, aryls, e.g., heteroaryls, cycloalkenyls, e.g., cycloheteralkenyls, etc., which have 1 to 5 heteroatoms, particularly 1 to 3 heteroatoms.

[0024] As used herein, the terms “heteroaryl” or “heteroaromatic group” refer to aromatic 5- to 10-membered ring systems containing one or more heteroatoms, such as 1 to 3 heteroatoms, including nitrogen, oxygen, and sulfur. These terms may also be used to refer to 5- to 7-membered monocyclic heteroaryls or 8- to 10-membered bicyclic heteroaryls. Where possible, the heteroaryl ring may be linked to adjacent radicals via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzimidazole, imidazopyridine, pyrazole, triazole, pyridine, or pyrimidine.

[0025] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are recognized in the art and refer to a saturated or partially unsaturated 4- to 10-membered ring structure, the ring structure containing 1 to 3 heteroatoms such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be linked to adjacent radicals via carbon or nitrogen. The term may also be used to refer to a bridged, condensed, or spirocycle structure, the ring structure containing 1 to 3 heteroatoms, e.g., nitrogen, oxygen, and sulfur, a 4- to 10-membered saturated or partially unsaturated ring structure. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiroheterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridging heterocycle (e.g., octahydro-1H-4,7-methanoisoindole). A “spiroheterocyclyl” or “spiroheterocycle” refers to a polycyclic heterocyclyl having rings linked via one common atom (called a spiro atom), where the rings consist of N, O, and S(O) as ring atoms. m It has one or more heteroatoms selected from the group consisting of (wherein m is an integer from 0 to 2).

[0026] As used herein, the terms "hydroxy" and "hydroxyl" refer to the radical -OH.

[0027] As used herein, the term "oxo" refers to the radical = O.

[0028] "Pharmacologically or pharmacologically acceptable" includes molecular entities and compositions that, if administered to animals or humans as necessary, do not produce adverse reactions, allergic reactions, or other undesirable reactions. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by FDA Office of Biologics standards.

[0029] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refer to any solvent, dispersion medium, coating, isotonic agent, absorption retarder, etc., that is suitable for pharmaceutically active administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

[0030] As used herein, the term “pharmaceutical composition” refers to a composition comprising at least one compound disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0031] The terms “individual,” “patient,” or “subject” are used interchangeably and include all animals, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans. The compounds of this disclosure can be administered to mammals such as humans, but can also be administered to other mammals such as livestock (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.) that require veterinary treatment. “Modification” includes antagonistism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signaling, functionally selective agonism, partial antagonistism, and / or partial agonism.

[0032] In this specification, the term “therapeutic dose” means the amount of a compound of interest that elicits a biological or medical response in a tissue, system, or animal (e.g., mammal or human), as determined by researchers, veterinarians, physicians, or other clinicians. The compounds of this disclosure are administered in therapeutic doses to treat a disease. Alternatively, the therapeutic dose of a compound is the amount required to achieve the desired therapeutic and / or preventive effect.

[0033] As used herein, the term “pharmaceutically acceptable salts” refers to salts of any acidic or basic groups that may be present in the compounds used in the composition. The inherently basic compounds contained in this composition can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The essentially acidic compounds contained in this composition can form base salts with a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in this composition, including basic or acidic moieties, can also form pharmaceutically acceptable salts with a variety of amino acids. The compounds of this disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds can exist as acid addition salts, zwitterions, or base salts.

[0034] The compounds of this disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term “stereoisomer” encompasses all enantiomers or diastereomers. These compounds may be denoted by the symbols “(+)”, “(-)”, “R” or “S” depending on the arrangement of substituents around the stereogenic carbon atom, but those skilled in the art will recognize that the structure may imply a chiral center. This disclosure encompasses various stereoisomers and mixtures thereof of these compounds. Mixtures of enantiomers or diastereomers may be nominally designated as “(±)”, but those skilled in the art will recognize that the structure may imply a chiral center.

[0035] The compounds of this disclosure may contain one or more double bonds and therefore may exist as geometric isomers arising from the arrangement of substituents around a carbon-carbon double bond. [ka] This indicates a bond that may be a single, double, or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both "E" and "Z" isomers. Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" represents a substituent on the same side of the double bond and "trans" represents a substituent on the opposite side of the double bond.

[0036] The compounds of this disclosure may contain carbocyclic or heterocyclic rings and therefore may exist as geometric isomers arising from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in a "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a carbocyclic or heterocyclic ring encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be called "cis" or "trans," the term "cis" refers to substituents on the same side of the ring plane, and the term "trans" refers to substituents on opposite sides of the ring plane. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring plane is called "cis / trans."

[0037] The individual enantiomers and diastereomers of the compounds of this disclosure can be prepared synthetically from commercially available starting materials containing chiral or stereocenters, or by the preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation using an optically active resolving agent, (3) direct separation of the optical enantiomer mixture on a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture can also be separated into its component enantiomers by well known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms a heterogeneous mixture of stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may include the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0038] The compounds disclosed herein can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and the present disclosure is intended to encompass 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 another embodiment, the compound is in crystalline form.

[0039] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those recited herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, <0000x87>F and 36 Cl. For example, a compound of the present disclosure can have one or more H atoms substituted with deuterium.

[0040] Certain isotopically labeled disclosed compounds (e.g., those labeled with 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of the ease of their preparation and detectability. Further, deuterium (i.e., 2Substitution with heavier isotopes such as H) can confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or decreased required dosage) and may thus be preferred in some situations. The isotopically labeled compounds of the present disclosure can generally be prepared by procedures similar to those disclosed in the examples herein by using an isotopically labeled reagent in place of the non-isotopically labeled reagent.

[0041] The term "prodrug" refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The conversion can occur by various mechanisms (e.g., esterases, amidases, phosphatases, oxidative and / or reductive metabolism) at various sites (e.g., within the intestinal lumen or upon passage through the intestine, blood or liver). Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, when the compound of the present disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug is a hydrogen atom of the acid group that is replaced by (C 1~8 ) alkyl, (C 2~12 ) alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C 1~2 ) alkylamino(C 2~3 ) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1~2) alkyl, N,N-di(C 1~2 ) Alkylcarbamoyl-(C 1~2 ) Alkyl and piperidino-, pyrrolidino-, or morpholino (C 2~3 ) May include esters formed by substitution with groups such as alkyl groups.

[0042] Similarly, if the compound disclosed herein contains an alcohol functional group, the hydrogen atoms of the alcohol group, (C 1~6 ) Alkylcarbonyloxymethyl, 1-((C 1~6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1~6 )alkylcarbonyloxy)ethyl(C 1~6 ) Alkoxycarbonyloxymethyl, N-(C 1~6 ) Alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) Alkylcarbonyl, α-amino(C 1~4 Prodrugs can be formed by substitution with groups such as alkylcarbonyl, arylalkylcarbonyl, and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is a naturally occurring L-amino acid, P(O)(OH)2, -P(O)(O(C) 1~6 A radical independently selected from alkyl-2 or glycosyl (a radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate).

[0043] When the compounds of this disclosure incorporate amine functional groups, prodrugs can be formed, for example, by the production of amides or carbamates, N-alkylcarbonyloxyalkyl derivatives, (oxodioxolenyl)methyl derivatives, N-Mannich bases, imines, or enamines. Furthermore, secondary amines can be metabolically cleaved to produce biologically active primary amines, or tertiary amines can be metabolically cleaved to produce biologically active primary or secondary amines. See, for example, Simplicio, et al., Molecules 2008, 13, 519 and the references therein.

[0044] compound

[0045] This disclosure relates in part to compounds that are modulators of the 5-hydroxytryptamine 2A (5-HT2A) receptor. In some embodiments, the modulators of this disclosure exhibit selective functionality to the 5-HT2A receptor and / or binding to the 5-HT2A receptor more than the 5-HT2B receptor and / or the 5-HT2C receptor. In certain embodiments, the compounds of this disclosure can be used to treat a variety of neurological disorders and conditions, including, but not limited to, depression, anxiety, substance abuse, migraines, and / or cluster headaches.

[0046] For example, a compound represented by formula I: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, [ka] It is a single bond, and X is a CR bond. X And Y is C(R Y )2, or [ka] It is a double bond, X is C, and Y is C(R Y ) and W is selected from the group consisting of O and S. R X and R Y Each is independently selected from the group consisting of hydrogen and -C1~C3 alkyl, or R X and R Y They bond together to form -CH2-, R A These are hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R bSelected from the group consisting of -C1~C6 alkyl, -C3~C6 cycloalkyl, C1~C6 alkoxy, phenyl, 4~7 membered heterocyclil and 5~6 membered heteroaryl, where C1~C6 alkyl, -C3~C6 cycloalkyl, C1~C6 alkoxy, phenyl, heterocyclil and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)-NR a R b and may be optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkoxys. R 1 This is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 member heteroaryl), and -CH2-(5-10 member heterocyclyl), and C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 4 and R 5 These are, independently, hydrogen, halogen, hydroxyl, and -NR. a R b , -NR a -C(O)-NR a R b Selected from the group consisting of -CO2H, C1-C6 alkyl, C1-C6 alkoxy, and phenyl, where C1-C6 alkyl, C1-C6 alkoxy, and phenyl are halogens, hydroxyls, -NR a R band may be optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkoxys. R 6 and R 7 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. R a and R b Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. m is 0, 1, 2, or 3. Compounds represented by formula I or pharmaceutically acceptable salts and / or stereoisomers thereof are disclosed herein.

[0047] In some embodiments, the compounds disclosed herein are, for example, [ka] or [ka] It is represented by [this].

[0048] In some embodiments, R A is independently selected from each occurrence of the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, where tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil may optionally be substituted with -CH3. For example, in a particular embodiment, R AFor each occurrence, the group consisting of fluoro, chloro, iodo, cyano, and -CH3 is independently selected.

[0049] In some embodiments, m is 3.

[0050] For example, in a particular embodiment, A is [ka] and [ka] Selected from the group consisting of, X is either O or S.

[0051] In other embodiments, m is 2. For example, in some embodiments, A is [ka] and [ka] Selected from the group consisting of, X is either O or S.

[0052] In further embodiments, m is 1. For example, in some embodiments, A is [ka] and [ka] Selected from the group consisting of, X is either O or S.

[0053] In some embodiments, R 2 and R 3is hydrogen. In other embodiments, R 6 and R 7 R is hydrogen. In other embodiments, R 4 and R 5 Each is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. In further embodiments, R 4 is hydrogen. In some embodiments, for example, R 5 R is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. For example, in a particular embodiment, R 5 It is either hydrogen or -CH3.

[0054] In other embodiments, R 1 is hydrogen. In other embodiments, R 1 For example, hydrogen, -CH3, [ka] and [ka] It is selected from the group consisting of the following.

[0055] Compounds represented by formula IIA, formula IIB, or formula IIC: Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, X is either O or S, R AFor each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, where tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil may optionally be substituted with -CH3. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, m is 0, 1, 2, or 3. Compounds represented by formulas IIA, IIB, or IIC: Compounds represented by formulas IIA, IIB, or IIC, or their pharmaceutically acceptable salts and / or stereoisomers are also disclosed herein.

[0056] In some embodiments, R A For each occurrence, m is independently selected from the group consisting of, for example, fluoro, chloro, iodo, cyano, and -CH3. In other embodiments, m is 3. In yet another embodiment, m is 2. In yet another embodiment, m is 1. In some embodiments, R 4is hydrogen. In a particular embodiment, R 5 R is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. In further embodiments, R 5 is hydrogen or -CH3. In other embodiments, R 1 It is hydrogen.

[0057] In some embodiments, the compound is one of the compounds specified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0058] Procedures for preparing the compounds described herein are provided in the following examples. In the reactions described below, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amino, thio, or carboxyl groups) to avoid their undesirable involvement in the reaction. The incorporation of such groups, and the methods required for their introduction and removal, are known to those skilled in the art (see, for example, Greene, Wuts, Protective Groups in Organic Synthesis, 2nd Ed. (1999)). The deprotection step may be the final step of the synthesis such that the removal of the protecting group yields the compounds disclosed herein. The starting materials used in the following schemes can be purchased or prepared by methods known to those skilled in the art, by methods described in the chemical literature, or by adaptation thereof. The order in which the steps are carried out may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

[0059] The compounds disclosed herein, or any intermediates described in the scheme above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods may include substitution, oxidation, or reduction reactions. These methods can also be used to obtain or modify the disclosed compounds or any preceding intermediates by modifying, introducing, or removing appropriate functional groups.

[0060] If it is desired to obtain a specific enantiomer of the disclosed compound, this can be produced from the corresponding mixture of enantiomers by using any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, a diastereomer derivative (e.g., a salt) can be produced by reacting a mixture of enantiomers of the disclosed compound (e.g., a racemate) with a suitable chiral compound (e.g., a chiral base). The diastereomer can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer can be recovered (e.g., by treatment with acid if the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0061] Alternatively, the racemic mixture of the disclosed compound can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the above methods. Chromatography, recrystallization, and other conventional separation procedures may also be used in conjunction with intermediates or final products from which specific geometric isomers of the disclosure are desired.

[0062] In alternative embodiments, the disclosed compound may also include one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 It can be H (T or tritium), and carbon is, for example, 13 C or 14 It can be C, and oxygen is, for example, 18 It can be O, and nitrogen is, for example, 15 In other embodiments, it may be N, etc. 3 H, 13 C, 14 C, 18 O, or 15N) may account for at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound.

[0063] method

[0064] Another aspect of this disclosure provides a method for treating patients suffering from neurological disorders or conditions. In particular, in certain embodiments, this disclosure provides a method for treating the following medical indications, comprising administering a therapeutically effective amount of a compound described herein to a patient in need of treatment.

[0065] For example, a method for treating a neurological disorder or condition in a patient requiring treatment is provided herein, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, for example, a compound of formula I or formula II. A method for treating a neurological disorder or condition in a patient requiring treatment is also provided herein, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein (for example, a compound of formula I or formula II) and a pharmaceutically acceptable excipient.

[0066] Non-exclusive examples of neurological disorders or conditions include depression, anxiety, substance abuse, and headaches. Headaches that can be treated by the methods described herein include, but are not limited to, migraines and cluster headaches.

[0067] For example, in some embodiments, the methods described herein may include treating a depressive disorder in a patient requiring treatment for the depressive disorder, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the depressive disorder may be major depressive disorder. In other embodiments, the depressive disorder may include treatment-resistant depression.

[0068] In certain embodiments, the methods described herein may include treating an anxiety disorder in a patient requiring treatment for the anxiety disorder, and include administering to the patient an effective amount of the compound disclosed herein or a pharmaceutical composition thereof. In some embodiments, the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.

[0069] In further embodiments, the methods described herein may include treating trauma and / or stress disorders in patients requiring such treatment, which involves administering an effective amount of the compounds disclosed herein or their pharmaceutical compositions to the patient. In some embodiments, such disorders may be post-traumatic stress disorders. In other embodiments, such disorders may be adjustment disorders.

[0070] In certain embodiments, the methods described herein may include treating a patient in need of treatment for obsessive-compulsive disorder (e.g., body dysmorphic disorder), which involves administering to the patient an effective amount of the compound or pharmaceutical composition thereof disclosed herein.

[0071] In other embodiments, the methods described herein may include treating an eating disorder in a patient in need thereof, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.

[0072] In further embodiments, the methods described herein may include treating a sleep-wake disorder, such as insomnia, in a patient in need thereof, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient.

[0073] In some embodiments, the methods described herein may include treating a psychotic disorder, such as insomnia, in a patient in need thereof, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the psychotic disorder may be schizophrenia. In other embodiments, the psychotic disorder may be schizoaffective disorder. In yet another embodiment, the psychotic disorder may be schizotypal personality disorder.

[0074] In certain embodiments, the methods described herein may include treating a substance-related disorder and / or addiction disorder in a patient in need, comprising administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, such disorder may be alcohol use disorder. In other embodiments, such disorder may be opioid use disorder. In yet another embodiment, such disorder may be tobacco use disorder. For example, in some embodiments, the compounds disclosed herein may be useful in promoting smoking cessation.

[0075] In certain other embodiments, the methods described herein may include treating a neurocognitive disorder in a patient requiring treatment for the disorder, and include administering to the patient an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof. In some embodiments, the neurocognitive disorder may include those resulting from primary neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease.

[0076] In some embodiments, the methods described herein may include treating a personality disorder in a patient requiring such treatment, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient. In other embodiments, the methods described herein may include treating autism spectrum disorder in a patient requiring such treatment, and include administering an effective amount of the compound disclosed herein or a pharmaceutical composition thereof to the patient.

[0077] In further embodiments, the methods described herein may include treating bipolar disorder in a patient requiring treatment for bipolar disorder, and include administering to the patient an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof. In some embodiments, the bipolar disorder may be bipolar I disorder. In other embodiments, the bipolar disorder may be bipolar II disorder.

[0078] In other embodiments, the methods described herein may include treating a pain disorder in a patient requiring treatment of the pain disorder, and include administering an effective amount of the compounds disclosed herein or a pharmaceutical composition thereof to the patient. In some embodiments, the pain disorder may be neuropathic pain. In other embodiments, the pain disorder may be migraine. In yet another embodiment, the pain disorder may be cluster headache. In yet another embodiment, the pain disorder may be trigeminal neuralgia. In yet another embodiment, the pain disorder may be cancer pain. In certain embodiments, the pain disorder may be focal pain disorder. In yet another embodiment, the pain disorder may be phantom limb pain. In some embodiments, the pain disorder to be treated may be chronic pain.

[0079] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula I or formula II) may exhibit anxiolytic, antidepressant, and anti-drug abuse effects without substantial psychedelic effects (e.g., hallucinogenic effects). For example, the (5-HT2A) receptor modulator intended in this disclosure may confer antidepressant-like activity without inducing psychedelic-like effects. For example, in some embodiments, the compounds disclosed herein may be safe and effective for use in the manner described herein, without the hallucinogenic effects of known psychiatrists such as DMT and psilocybin.

[0080] This disclosure also provides a method for selectively modulating the 5-hydroxytryptamine 2A (5-HT2A) receptor. This method comprises administering to a patient a compound disclosed herein (e.g., a compound of formula I or formula II), a pharmaceutically acceptable salt thereof, and / or a stereoisomer thereof, the compound selectively modulates 5-HT2A more selectively than 5-HT2B and / or 5-HT2C receptors. The method for selectively modulating the 5-HT2A receptor can be used to treat, alleviate, and / or prevent diseases or disorders that are affected, related to, or benefit from selective modulation of the 5-HT2A receptor. By selectively modulating the 5-HT2A receptor more selectively than 5-HT2B and / or 5-HT2C receptors, this method provides a reduction in side effects, such as, but not limited to, drug-induced valvular heart disease associated with modulation of the 5-HT2B receptor.

[0081] In certain embodiments, the methods described herein further include administering to a patient an additional therapeutic agent for treating a neurological disorder or a disorder that is affected by, related to, or benefits from selective modulation of the 5-HT2A receptor.

[0082] The patients targeted 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).

[0083] The compounds described herein may be administered in combination with one or more additional therapeutic agents to treat the disorders described herein. For clarity, both methods are considered herein, including a fixed composition comprising the disclosed compounds and another therapeutic agent, such as those disclosed herein, and a method of administering the disclosed compounds and the disclosed therapeutic agents separately. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein, one or more additional therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, the disclosed compounds and one additional therapeutic agent are administered. In some embodiments, the disclosed compounds as defined herein and two additional therapeutic agents are administered. In some embodiments, the disclosed compounds as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, the disclosed compounds and additional therapeutic agents may be formulated and administered separately. Combination therapy can also be achieved by administering a pharmaceutical composition comprising two or more therapeutic agents in a single formulation, for example, the disclosed compounds as one therapeutic agent and one or more additional therapeutic agents. For example, the disclosed compounds and additional therapeutic agents can be administered in a single formulation. Other combinations are also included in combination therapy. Two or more drugs in combination therapy can be administered simultaneously, but are not necessarily required. For example, the first drug (or combination of drugs) can be administered a few minutes, hours, days, or weeks before the second drug (or combination of drugs) is administered. Thus, two or more drugs can be administered within a few minutes of each other, or within 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, or 24 hours of each other, or within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, or 14 days of each other, or within 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks of each other. In some cases, longer intervals are possible.In many cases, it is desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, but this is not always the case.

[0084] Combination therapy may also involve administering one or more drugs used in combination, using different administration sequences of the component drugs. For example, when drugs X and Y are used in combination, they can be administered one or more times in any combination, in a sequence such as XYX, XXY, YXY, YYX, XXYY, etc.

[0085] For example, the method described herein comprises administering to a patient a therapeutically effective amount of at least one compound of formula I or formula II described herein, which may be formulated into a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein, e.g., a compound of formula I or formula II, present in the pharmaceutical composition is the sole therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further comprises administering to a patient an additional therapeutic agent that treats a neurological disorder or a disorder that is affected by, related to, or benefits from selective modulation at the 5-HT2A receptor.

[0086] For example, in some embodiments, the methods described herein may include administering one or more additional therapeutic agents to a patient in combination with the compounds disclosed herein. In certain embodiments, the one or more additional therapeutic agents that may be administered in combination with the compounds disclosed herein may be selective serotonin reuptake inhibitors (SSRIs). In some embodiments, the selective serotonin reuptake inhibitors may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. In other embodiments, the one or more additional therapeutic agents may be serotonin and norepinephrine reuptake inhibitors (SNRIs). For example, the serotonin and norepinephrine reuptake inhibitors may be selected from the group consisting of, for example, duloxetine, venlafaxine, desvenlafaxine, and levomirunacipran. In yet another embodiment, the one or more additional therapeutic agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, virazodone, and bupropion. In certain embodiments, one or more additional therapeutic agents may be tricyclic antidepressants. For example, in some embodiments, the tricyclic antidepressant may be selected from the group consisting of, for example, imipramine, nortriptyline, amitriptyline, doxepin, and desipramine. In further embodiments, one or more additional therapeutic agents may be monoamine oxidase inhibitors (MAOIs). For example, in some embodiments, the monoamine oxidase inhibitor may be selected from the group consisting of, for example, tranylcypromine, phenelzine, and isocarboxazide. In other embodiments, one or more additional therapeutic agents may be, for example, lithium compounds, such as lithium salts, such as lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate. In some embodiments, one or more additional therapeutic agents may be, for example, ketamine or esketamine. In certain embodiments, one or more additional therapeutic agents may be, for example, dextromethorphan. In other embodiments, one or more additional therapeutic agents may be, for example, D-methadone.

[0087] In some embodiments, administering the compound(s) described herein to a patient makes it possible to administer a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve similar results in treating, alleviating, and / or preventing a neurological disorder or impairment, or in treating, alleviating, and / or preventing a disorder or impairment that is affected by, associated with, or benefits from, selective modulation of the 5-HT2A receptor in the patient. For example, in certain embodiments, the compound(s) described herein enhance the activity of the additional therapeutic agent, thereby enabling a lower dose of the additional therapeutic agent to provide the same effect.

[0088] In particular, in certain embodiments, the present disclosure provides a method for treating the above-mentioned medical indications, comprising administering a therapeutically effective amount of a compound described herein, for example, a compound of formula I or formula II, to a subject requiring treatment for the above-mentioned medical indications.

[0089] Pharmaceutical compositions and kits

[0090] Another aspect of the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, the Disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, but the most suitable mode of administration in any given case depends on the degree and severity of the condition being treated and the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0091] The exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical formulation containing one or more of the compounds of this disclosure as an active ingredient, for example, in solid, semi-solid, or liquid form, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. The active ingredient may be formulated with, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use that is normally non-toxic and pharmaceutically acceptable. The compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on a method or condition of disease.

[0092] To prepare solid compositions such as tablets, a main active ingredient can be mixed with a pharmaceutical carrier, such as conventional tableting components like corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid pre-formulation composition containing a homogeneous mixture of the compound of this disclosure or its non-toxic, pharmaceutically acceptable salt. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0093] For solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), this composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) water-retaining agents such as glycerol; (4 (1) Disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (2) Solution retarders such as paraffin; (3) Absorption enhancers such as quaternary ammonium compounds; (4) Wetting agents such as acetyl alcohol and glycerol monostearate; (5) Absorbents such as kaolin and bentonite clay; (6) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (7) Colorants. In the case of capsules, tablets and pills, the composition may also include buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose and high molecular weight polyethylene glycol.

[0094] Tablets may be prepared by compression or molding, sometimes with one or more auxiliary components. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of the composition moistened with an inert liquid diluent using appropriate machinery. Tablets, as well as other solid dosage forms such as sugar-coated tablets, capsules, pills, and granules, may be perforated or prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0095] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to these compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0096] In addition to the subject composition, the suspension may contain, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and suspending agents as mixtures thereof.

[0097] Formulations for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the body cavity and release the activator.

[0098] Dosage forms for transdermal administration of this composition include powder, spray, ointment, paste, cream, lotion, gel, solution, patch, and inhalant. The active ingredient may be mixed with a pharmaceutically acceptable carrier under sterile conditions and any preservatives, buffers, or propellants that may be required.

[0099] Ointments, pastes, creams, and gels may contain, in addition to the composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0100] The powder and spray may contain, in addition to the composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The spray may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0101] Alternatively, the compositions and compounds of this disclosure may be administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Although the compounds in the compositions may degrade when exposed to shear, ultrasonic nebulizers can be used to minimize exposure of the drugs to shear. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition, but typically include nonionic surfactants (Tween®, Pluronics®, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, and glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0102] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may include antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient to whom the formulation is intended, or suspending agents or thickeners.

[0103] Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0104] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising the disclosed compounds and enteric coatings, and their pharmaceutically acceptable carriers or excipients. Enteric coatings refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, enteric-coated substances are not soluble up to pH levels of, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate acetate (PVAP), hydroxypropyl methylcellulose succinate acetate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate acetate, cellulose propionate phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionate acetate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal colloids, and several commercially available enteric-coated dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit Examples include L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be easily determined in vitro.The foregoing is a list of possible materials, but those skilled in the art who benefit from the present disclosure will recognize that it is not comprehensive and that there are other enteric substances that meet the objectives of the present disclosure.

[0105] The present disclosure also provides, for example, a kit for use by a consumer who needs treatment of a disease or disorder described herein. Such a kit includes a suitable dosage form such as those described above, and instructions describing a method of using such a dosage form to mediate, reduce or prevent inflammation. The instructions will instruct the consumer or healthcare provider to administer the dosage form according to a mode of administration known to those skilled in the art. Such a kit can advantageously be packaged and sold in single or multiple kit units. An 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 pharmaceutical unit dosage forms (tablets, capsules, etc.). A blister pack generally consists of a sheet of a relatively rigid material, preferably covered with a foil of a transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the recesses, and the sheet of relatively rigid material is sealed to the plastic foil on the side of the foil opposite the side in which the recesses are formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming an opening in the sheet at the location of the recesses. The tablets or capsules can then be removed through the opening.

[0106] For example, it may be desirable to provide a memory aid in the form of a number next to a tablet or capsule, the number corresponding to the day of the regimen on which the tablet or capsule so designated is to be taken. Another example of such a memory aid is, for example, 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 readily become apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules taken on a given day. Also, the daily dose of the first compound can consist of one tablet or capsule, and the daily dose of the second compound can consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0107] Exemplary embodiments of the present invention

[0108] E1. A compound represented by formula I:

Chemical formula

Chemical formula

Chemical formula

[0109] E2. Compound [ka] or [ka] The compound described in E1, which can be represented by...

[0110] E3.R Ais independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, 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, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl and oxadiazolyl, wherein tetrahydropyrrolyl, piperidinyl, piperazinyl and azetidinyl are optionally substituted by -CH3, a compound according to E1 or E2.

[0111] E4.R A is, for each occurrence, independently selected from the group consisting of fluoro, chloro, iodo, cyano and -CH3, a compound according to any one of E1 to E3.

[0112] E5. A compound according to any one of E1 to E4, wherein m is 3.

[0113] E6. A is

Chemical formula

Chemical formula

[0114] E7. A compound according to any one of E1 to E4, wherein m is 2.

[0115] E8. A is

Chemical formula

[0116] A compound listed in any one of E1 to E4, where E9.m is 1.

[0117] E10.A is [ka] and [ka] Selected from the group consisting of, X is either O or S. A compound listed in any one of E1-E4 and E9.

[0118] E11.R 2 and R 3 A compound listed in any one of E1 to E10, wherein the hydrogen atom is hydrogen.

[0119] E12.R 6 and R 7 A compound listed in any one of E1 to E11, wherein the hydrogen atom is hydrogen.

[0120] E13.R 4 and R 5 A compound according to any one of E1 to E12, wherein each of the elements is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[0121] E14.R 4 A compound listed in any one of E1 to E13, wherein the hydrogen atom is hydrogen.

[0122] E15.R 5 The compound is one of the compounds described in E1 to E14, selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[0123] E16.R 5 A compound according to any one of E1 to E15, wherein the compound is hydrogen or -CH3.

[0124] E17.R 1 However, hydrogen, -CH3, [ka] and [ka] A compound selected from the group consisting of, one of E1 to E16.

[0125] E18.R 1 A compound listed in any one of E1 to E17, wherein the hydrogen atom is hydrogen.

[0126] E19. Compounds represented by formula IIA, formula IIB, or formula IIC: [ka] or its pharmaceutically acceptable salts and / or stereoisomers, X is either O or S, R AFor each occurrence, the following are independently selected from the group consisting of fluoro, chloro, bromo, iodine, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxiranil, azetidinil, phenyl, triazolyl, and oxadiazolyl, where tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil may optionally be substituted with -CH3. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2. R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of, m is 0, 1, 2, or 3. Compounds represented by formula IIA, formula IIB, or formula IIC, or their pharmaceutically acceptable salts and / or stereoisomers.

[0127] E20.R A However, for each occurrence, the compound described in E19 is independently selected from the group consisting of fluoro, chloro, iodo, cyano, and -CH3.

[0128] A compound of E19 or E20 in which E21.m is 3.

[0129] A compound of E19 or E20 in which E22.m is 2.

[0130] A compound of E19 or E20 in which E23.m is 1.

[0131] E24.R 4 A compound listed in any one of E1 to E23, wherein the hydrogen atom is hydrogen.

[0132] E25.R 5 The compound is one of the compounds described in E1 to E24, selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[0133] E26.R 5 A compound according to any one of E1 to E25, wherein the compound is hydrogen or -CH3.

[0134] E27.R 1 A compound listed in any one of E1 to E26, wherein the hydrogen atom is hydrogen.

[0135] E28. [ka] [ka] and [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0136] A pharmaceutical composition comprising one compound from E29.E1 to E28 and a pharmaceutically acceptable excipient.

[0137] E30. A method for treating a mental or neurological disorder in a patient who requires treatment for a mental or neurological disorder, comprising administering to the patient a therapeutically effective amount of any one of the compounds described in E1 to E28.

[0138] E31. A method for treating a mental or neurological disorder or disorder in a patient who requires treatment of such disorder or disorder, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described in E1 to E28 and a pharmaceutically acceptable excipient.

[0139] E32. The method according to E30 or E31, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache. [Examples]

[0140] The compounds described herein can be prepared in numerous ways based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected to be standard conditions for the reaction unless otherwise indicated. Those skilled in the art of organic synthesis will understand that functional groups present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be obvious to those skilled in the art, and alternative methods will therefore be shown. The starting materials in the examples are commercially available or readily prepared from known materials by standard methods.

[0141] General information

[0142] Unless otherwise specified, reagents and solvents were obtained from commercial sources without further purification or prepared according to literature methods. 1 1H NMR and 1313C NMR spectra were recorded at room temperature using a 300 or 400 MHz Bruker spectrometer with tetramethylsilane (TMS) as the internal standard and DMSO-d6, CDCl3, or CD3OD as the solvent. Chemical shifts were given in δ relative to TMS, and coupling constants J were given in Hz. LCMS analysis methods and apparatus were generated using one of the following methods. Detection was performed by UV (254 nm) and ELSD for all methods.

[0143] Method A (LCMS17, 41, 42, 50, 52)

[0144] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 2]

[0145] Method B (LCMS17, 41, 42, 47, 50, 52)

[0146] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 3]

[0147] Method C (LCMS25)

[0148] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO C18, particle size 2.6 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3 and solvent B: acetonitrile. [Table 4]

[0149] Method D (LCMS25)

[0150] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO C18, particle size 2.6 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3 and solvent B: acetonitrile. [Table 5]

[0151] Method E (LCMS40)

[0152] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (30 × 3.0 mm Express C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 6]

[0153] Method F (LCMS45)

[0154] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile. [Table 7]

[0155] Method G (LCMS45)

[0156] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 2.7 μm), and elution was performed with solvent A: water / 0.04% NH4H2O; solvent B: acetonitrile. [Table 8]

[0157] Method H (LCMS46, 48)

[0158] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 4.0 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 9]

[0159] Method I (LCMS46, 48)

[0160] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Poroshell HPH-C18, particle size 4.0 μm), and elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 10]

[0161] Method J (LCMS49)

[0162] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 2.0 mm Poroshell 120 EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 11]

[0163] Method K (LCMS49)

[0164] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 2.0 mm Poroshell 120 EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 12]

[0165] Method L (LCMS51, 53)

[0166] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (50 × 3.0 mm Kinetex® EVO-C18, particle size 2.6 μm). Elution was performed with solvent A: water / (5 mmol / L)NH4HCO3; solvent B: acetonitrile / acetonitrile. [Table 13]

[0167] Method M (LCMS51, 53)

[0168] Experiments were performed using a SHIMADZU® 20A HPLC with a C18 reversed-phase column (50 × 3.0 mm Kinetex® EVO-C18, particle size 2.6 μm). Elution was performed with solvent A: 5 mM water NH4HCO3; solvent B: acetonitrile / acetonitrile. [Table 14]

[0169] Method N (LCMS60)

[0170] Experiments were performed using a SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Agilent® EC-C18, particle size 1.9 μm), and elution was performed with solvent A: water / 0.1% FA; solvent B: acetonitrile / 0.07% FA. [Table 15]

[0171] Method O (LCMS61)

[0172] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reverse-phase column (30 × 2.0 mm Gemini NX-C18, particle size 3.0 μm), and elution was performed with solvent A: (5 mmol / L)NH4HCO3; solvent B: acetonitrile. [Table 16]

[0173] Method P (LCMS63)

[0174] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, particle size 2.0 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 17]

[0175] Method Q (LCMS63)

[0176] Experiments were performed using SHIMADZU® 20A HPLC with a C18 reversed-phase column (30 × 3.0 mm Halo C18, 100A, particle size 2.0 μm), and elution was performed with solvent A: water / 0.05% TFA; solvent B: acetonitrile / 0.05% TFA. [Table 18]

[0177] Example 1: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole-7-carbonitrile (compound 104) [ka]

[0178] Methyl 2-bromo-3-iodobenzoate. 2-bromo-3-iodobenzoic acid (5.00 g, 15.29 mmol) was stirred in MeOH (50.0 mL), to which SOCl2 (2.00 g, 16.82 mmol) was added dropwise at 0°C, and the mixture was stirred overnight at 60°C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with Depositphotos (3 × 50 mL). The combined organic extracts were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (4.00 g, yield 76.7%). 1 H NMR(400 MHz,CDCl3)δ 8.15-8.10(m,1H),7.83-7.79(m,1H),7.56-7.50(m,1H),3.51(s,3H).

[0179] Methyl 2-bromo-3-cyanobenzoate. A solution of methyl 2-bromo-3-iodobenzoate (4.00 g, 11.73 mmol), Pd(PPh3)4 (1.36 g, 1.17 mmol), and Zn(CN)2 (4.13 g, 35.20 mmol) in DMA (40.0 mL) was stirred at 100°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with siRNA (3 × 50 mL). The combined organic extract was washed with water (20 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (2.00 g, yield 71.0%). 1H NMR(400 MHz,DMSO-d6)δ 8.14-8.10(m,1H),8.06-8.02(m,1H),7.74-7.68(m,1H),3.90(s,3H).

[0180] 2-Bromo-3-cyanobenzoic acid. A solution of methyl 2-bromo-3-cyanobenzoate (2.00 g, 8.33 mmol) and LiOH (0.70 g, 16.66 mmol) in THF (20.0 mL) and H2O (10.0 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 00% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was obtained as a yellow solid (1.50 g, yield 79.7%). LCMS 52 (Method A) (ESI) C8H4BrNO2 Calculated value: 224.94; Measured value: [MH] - :224. 1 H NMR(400 MHz,CDCl3)δ 8.17-8.12(m,1H),7.85-7.81(m,1H),7.55-7.53(m,1H).

[0181] 2-Bromo-3-cyanobenzamide. 2-Bromo-3-cyanobenzoic acid (1.50 g, 6.64 mmol) was stirred in DMF (20.0 mL), to which NH4Cl (3.55 g, 66.36 mmol), DIEA (2.57 g, 19.91 mmol), and HATU (3.79 g, 9.95 mmol) were added in fractions at room temperature. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was obtained as a yellow solid (1.00 g, yield 67.0%). LCMS 46 (Method H) (ESI) C8H5BrN2O Calculated value 223.96; Measured value [MH] - :223. 1H NMR(400 MHz,CDCl3)δ 7.81-7.77(m,1H),7.76-7.21(m,1H),7.55-7.49(m,1H).

[0182] 3-Oxo-2H-1,2-Benzothiazole-7-Carbonitrile. A solution of 1,10-phenanthroline (0.24 g, 1.33 mmol) and CuI (0.25 g, 1.33 mmol) in DMF (10.0 mL) was stirred at room temperature under an N2 atmosphere for 15 minutes. Subsequently, 2-bromo-3-cyanobenzamide (1.00 g, 4.44 mmol), octathiocane (1.48 g, 5.78 mmol), and K2CO3 (0.80 g, 5.78 mmol) were added in fractions at room temperature. The resulting mixture was stirred at room temperature under an N2 atmosphere for 15 minutes, and then stirred at 110°C under a nitrogen atmosphere for 2 hours. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was obtained as a yellow solid (600.0 mg, yield 76.6%). LCMS 49 (Method K) (ESI) C8H4N2OS Calculated value 176; Measured value [MH] - :175. 1 H NMR(400 MHz,DMSO-d6)δ 8.10-8.04(m,1H),7.98-7.93(m,1H),7.46-7.40(m,1H).

[0183] 3-Chloro-1,2-benzothiazole-7-carbonitride. 3-oxo-2H-1,2-benzothiazole-7-carbonitride (600.0 mg, 3.41 mmol) was stirred in POCl3 (6.0 mL), to which pyridine (404.1 mg, 5.11 mmol) was added dropwise at room temperature under an N2 atmosphere. The final reaction mixture was irradiated with microwaves at 120°C for 2 hours. The reaction product was quenched with water at 0°C. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as a yellow solid (300.0 mg, yield 45.3%). LCMS 49 (Method K) (ESI) C8H3ClN2S Calculated value 193.97; Measured value [MH] - :193. 1 H NMR(400 MHz,DMSO-d6)δ 8.48-8.43(m,1H),8.42-8.38(m,1H),7.89-7.83(m,1H).

[0184] tert-butyl 3-(7-cyano-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. Solutions of 3-chloro-1,2-benzothiazole-7-carbonitrile (300.0 mg, 1.54 mmol), Pd(dppf)Cl2.CH2Cl2 (62.8 mg, 0.08 mmol), K2CO3 (639.1 mg, 4.62 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (714.9 mg, 2.31 mmol) in dioxane (2.0 mL) and H2O (1.0 mL) were stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with Â(3 × 5 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) eluting with PE / EA (5:1) to obtain the desired product as a yellow solid (150.0 mg, yield 28.5%). 1H NMR(400 MHz,DMSO-d6)δ 8.66(d,J=8.3 Hz,1H),8.27(d,J=7.3 Hz,1H),7.78-7.70(m,1H),6.83-6.77(m,1H),4.41(d,J=3.0 Hz,2H),3.60-3.53(m,2H),2.46-2.37(m,2H),1.44(s,9H).

[0185] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole-7-carbonitride. A solution of tert-butyl 3-(7-cyano-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.29 mmol) in dioxane (0.5 mL) and HCl (gas) in dioxane (0.5 mL) was stirred at room temperature for 1 hour under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basicized to pH 9 with saturated Na2CO3 (aqueous solution). The crude product (100.0 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 18%B to 38%B in 30 mins; Wavelength: 254 / 220 nm; RT1 (min): 10.02) to obtain the desired product as a yellow solid (5.9 mg, yield 8.4%). LCMS 48 (Method I) (ESI)C 13 H 11 N3S calculated value: 241.07; measured value: [M+H] + :242.15. 1 H NMR(400 MHz,CD3OD)δ 8.59-8.52(m,1H),8.07-8.01(m,1H),7.71-7.63(m,1H),6.73-6.66(m,1H),3.94-3.83(m,2H),3.10-3.01(m,2H),2.50-2.39(m,2H).

[0186] Example 2: Synthesis of 7-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)benzo[d]isothiazole (compound 106) [ka]

[0187] 2-Bromo-3-fluorobenzamide. To a stirred mixture of 2-bromo-3-fluorobenzoic acid (6.00 g, 27.40 mmol) in DMF (50 mL), NH4Cl (14.60 g, 273.96 mmol), HATU (15.60 g, 41.09 mmol, 1.5 equivalents), and DIEA (10.60 g, 82.19 mmol) were gradually added at room temperature. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The residue was collected under the following conditions: column, C 18 The silica gel was used as the mobile phase, an aqueous MeCN solution (0.1% FA), with a gradient from 0% to 50% over 55 minutes. The mixture was purified by reverse-phase flash chromatography using a UV 254 nm detector. The resulting mixture was concentrated under vacuum to obtain the desired product as a white solid (1.4 g, yield 23.4%). 1 H NMR(400 MHz,DMSO-d6)δ 7.94(s,1H),7.67(s,1H),7.53-7.33(m,2H),7.24(d,J=1.7 Hz,1H).

[0188] 7-Fluoro-2H-1,2-benzothiazole-3-one. CuI (5.7 mg, 0.03 mmol) was added to a stirred solution of 1,10-phenanthroline (5.4 mg, 0.03 mmol) in DMF (5 mL), and the resulting mixture was stirred at room temperature under an N2 atmosphere for 15 minutes. Subsequently, 2-bromo-3-fluorobenzamide (20.0 mg, 0.09 mmol), K2CO3 (469.7 mg, 3.39 mmol), and S8 (108.7 mg, 3.39 mmol) were added in fractions at room temperature. The resulting mixture was stirred at 110°C for 2 hours under an N2 atmosphere. The residue was collected under the following conditions: column, C 18Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 55 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The resulting mixture was concentrated under vacuum to obtain the desired product as a white solid (400 mg, yield 90.4%). LCMS 60(ESI)C7H4FNOS Calculated value: 169; Measured value: [M+H] + :170. 1 H NMR(400 MHz,DMSO-d6)δ 12.42(s,1H),7.82-7.74(m,1H),7.52(d,J=6.2 Hz,2H).

[0189] 3-Chloro-7-fluoro-1,2-benzothiazole. Pyridine (504.9 mg, 6.38 mmol) was added to a stirred solution of 7-fluoro-2H-1,2-benzothiazole-3-one (540.0 mg, 3.19 mmol) in POCl3 (4 mL). The resulting mixture was stirred at 140°C for 1 hour under an N2 atmosphere. The reaction product was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 40 mL) and dried on anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (7:1) to obtain the desired product as a white solid (240.0 mg, yield 40.0%). LCMS 52 (Method A) (ESI) C7H3ClFNS Calculated value 186.97; Measured value [M+H] + :188. 1 H NMR(400 MHz,CDCl3)δ 7.87-7.80(m,1H),7.51(d,J=7.9,4.5 Hz,1H),7.29(d,J=9.3 Hz,1H).

[0190] To a stirred solution of tert-butyl 3-(7-fluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate and 3-chloro-7-fluoro-1,2-benzothiazole (290.9 mg, 1.54 mmol) in dioxane (3.0 mL) and H2O (1.0 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (716.9 mg, 2.31 mmol), Pd(dppf)Cl2 (113.1 mg, 0.15 mmol), and K2CO3 (640.8 mg, 4.63 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The aqueous layer was extracted with ₹ (3 × 40 mL), dried with anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by chromatography (SiO₂) eluting with PE / EA (6:1) to obtain the desired product as a white oil (400.0 mg, yield 77.3%). LCMS 52 (Method A) (ESI)C 17 H 19 FN2O2S calculated value: 334.12; measured value [M+H] + :335. 1 H NMR(400 MHz,CDCl3)δ 7.95(d,J=8.2 Hz,1H),7.42(d,J=8.0 Hz,1H),7.24-7.12(m,1H),6.61(s,1H),4.50(d,J=2.5 Hz,2H),3.65(d,J=5.8 Hz,2H),2.45(d,J=6.9 Hz,2H),1.51(s,9H).

[0191] 7-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)benzo[d]isothiazole. Bis(tert-butyl3-(7-fluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate) (200.0 mg, 0.29 mmol) in dioxane (2.0 mL) and a solution of HCl (gas) in 1,4-dioxane (2.0 mL) were stirred at room temperature under an N2 atmosphere for 1 hour. The mixture was basicized to pH 9 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD Column, 30 × 150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 25% B in 10 mins; wavelength: 254 nm / 220 nm; RT1 (min): 9.32) to obtain the desired product as a white solid (36.9 mg, yield 27.9%). LCMS 52 (Method A) (ESI)C 12 H 11 FN2S calculated value: 234.06; measured value: [M+H] + :234.95. 1 H NMR(400 MHz,DMSO-d6)δ 8.14(d,J=8.0 Hz,1H),7.64-7.48(m,2H),6.68(d,J=2.2 Hz,1H),3.72(d,J=2.5 Hz,2H),2.89(d,J=5.6 Hz,2H),2.28(d,J=2.8 Hz,2H).

[0192] Example 3: Synthesis of 7-methyl-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole (compound 108) [ka]

[0193] 2-(benzylsulfanyl)-3-methylbenzonitrile. 2-fluoro-3-methylbenzonitrile (1.00 g, 7.40 mmol) and benzyl mercaptan (1.08 g, 14.80 mmol) were stirred in 1,4-dioxane (10 mL). NaH (0.2 g, 11.10 mmol) was added in fractions at 0°C under an N2 atmosphere. The resulting mixture was stirred further at 80°C for 30 minutes. The reaction product was quenched with water at 0°C. The aqueous layer was extracted with ELISA (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 petroleum ether:ethyl acetate (5:1) to obtain the desired product as a white solid (1.20 g, yield 67.7%). LCMS 50 (Method A) (ESI)C 15 H 13 NS calculated value 239.08; measured value [M+H] + :240.

[0194] 3-Methyl-2-sulfanylbenzonitrile. 2-(benzylsulfanyl)-3-methylbenzonitrile (300.0 mg, 1.25 mmol) was stirred in toluene (3 mL), to which AlCl3 (501.3 mg, 3.75 mmol) was added in fractions at 0°C. The resulting mixture was stirred at room temperature for a further 1 hour. The reaction was quenched with water at 0°C, and the resulting mixture was extracted with  (2 × 100 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with petroleum ether:ethyl acetate (5:1) to obtain the desired product as a yellow liquid (120.0 mg, yield 64.1%). LCMS 50 (Method A) (ESI) C8H7NS Calculated value 149.03; Measured value [M+H] + :150.

[0195] 3-Bromo-7-methyl-1,2-benzothiazole. Br2 (200.2 mg, 1.25 mmol) was added dropwise at 0°C to a stirred solution of 3-methyl-2-sulfanylbenzonitrile (110.0 mg, 0.73 mmol) in ethyl acetate. The resulting mixture was stirred further at room temperature for 30 minutes. The reaction was quenched with a thiosulfate solution at 0°C. The aqueous layer was extracted with siRNA (2 × 100 mL). The residue was purified by chromatography (SiO2) eluting with petroleum ether:ethyl acetate (10:1) to obtain the desired product as a yellow liquid (124.0 mg, yield 73.7%). LCMS 47(ESI)C8H6BrNS Calculated value 226.94; Measured value [M+H] + :228.

[0196] A mixture of tert-butyl 3-(7-methyl-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate,3-bromo-7-methyl-1,2-benzothiazole (100.0 mg, 0.43 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (126.6 mg, 0.05 mmol), K2CO3 (181.7 mg, 1.31 mmol), and Pd(dppf)Cl2 (71.4 mg, 0.08 mmol) in dioxane (2 mL) and H2O (0.5 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with ELISA (2 × 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with petroleum ether:ethyl acetate (5:1) to obtain the desired product as yellow oil (140.0 mg, yield 96.6%). LCMS 49 (Method J) (ESI)C 18 H 22 N2O2S calculated value: 330.14; measured value [M+H] + :331.

[0197] A mixture of 7-methyl-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole and tert-butyl 3-(7-methyl-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.30 mmol) in 1,4-dioxane (5 mL, 4 M) containing HCl (gas) was stirred at room temperature for 30 minutes under an air atmosphere. The mixture was basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The crude product (55.8 mg) was purified by Prep-HPLC under the following conditions: Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 m; Mobile phase A: 10 mmol / L NH4HCO3 + 0.05% NH3H2O; Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5%B to 5%B at 1 min, 5%B to 30%B at 2 min, 30% to 45%B at 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.4. The desired product was obtained as a white solid (29.1 mg, yield 41.7%). LCMS 63 (Method P) (ESI)Cl3H 14 N2S calculated value: 230.09; measured value: [M+H] + :231.10. 1 H NMR(400 MHz,DMSO-d6)δ 8.10(d,J=7.8 Hz,1H),7.47(t,J=7.4 Hz,1H),7.43(d,J=6.9 Hz,1H),6.62(dd,J=5.2,2.8 Hz,1H),3.75-3.69(m,J=2.5 Hz,2H),2.90(t,J=5.7 Hz,2H),2.55(s,3H),2.33-2.23(m,J=5.9,3.0 Hz,2H).

[0198] Example 4: Synthesis of 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole (compound 109) [ka]

[0199] 2-Bromo-3,4-difluorobenzamide. A solution of 2-bromo-3,4-difluorobenzoic acid (2.00 g, 8.43 mmol), HATU (4.80 g, 12.65 mmol), NH4Cl (4.51 g, 84.39 mmol), and DIEA (3.27 g, 25.31 mmol) in DMF (10 mL) was stirred at room temperature under an N2 atmosphere for 2 hours. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile water (0.1% formic acid), 10% to 50% gradient over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was purified as a white solid (1.50 g, yield 75.3%). LCMS 60(ESI)C7H4BrF2NO Calculated value: 234.94; Measured value: [MH] - :234. 1 H NMR(400 MHz,DMSO-d6)δ 7.95(s,1H),7.70(s,1H),7.54-7.44(m,1H),7.32-7.26(m,1H).

[0200] 6,7-Difluoro-2H-1,2-Benzothiazole-3-one. To a solution of 1,10-phenanthroline (343.5 mg, 1.90 mmol) in DMF (5 ml), CuI (363.1 mg, 1.90 mmol) was added at 25°C and the mixture was stirred for 15 minutes. Then, 2-bromo-3,4-difluorobenzamide (1.50 g, 6.35 mmol), K2CO3 (1.14 g, 8.26 mmol), and sulfur (264.39 mg, 8.26 mmol) were added and the mixture was stirred for 15 minutes, followed by stirring at 110°C for 2 hours. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: acetonitrile (0.1% formic acid) in water, gradient from 10% to 50% over 30 minutes; detector: reverse-phase flash chromatography using UV 254 nm. The desired product was purified as a white solid (1.00 g, yield 84.0%). LCMS 49 (Method K) (ESI) C7H3F2NOS Calculated value 186.99; Measured value [M+H] + :188. 1 H NMR(400 MHz,DMSO-d6)δ 12.57(s,1H),7.77-7.68(m,1H),7.57-7.48(m,1H).

[0201] 3-Chloro-6,7-difluoro-1,2-benzothiazole. A solution of 6,7-difluoro-2H-1,2-benzothiazole-3-one (1.00 g, 5.34 mmol) and pyridine (633.9 mg, 8.01 mmol) in POCl3 (8 mL) was stirred at 140°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched with water at 0°C and concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (6:1) to obtain the desired product as a white solid (600.0 mg, yield 54.6%). LCMS 49 (Method K) (ESI) C7H2ClF2NS Calculated value 204.96; Measured value [M+H] + :206. 1 H NMR(400 MHz,DMSO-d6)δ 8.06-7.98(m,1H),7.87-7.78(m,1H).

[0202] A solution of tert-butyl 3-(6,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-chloro-6,7-difluoro-1,2-benzothiazole (600.0 mg, 2.91 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.35 g, 4.37 mmol), Pd(dppf)Cl2 (213.52 mg, 0.29 mmol), K2CO3 (1.20 g, 8.75 mmol), and H2O (4 mL) in dioxane (8 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 30 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (7:1) to obtain the desired product as a white solid (200.0 mg, yield 19.4%). LCMS 72(ESI)C 17 H 18 F2N2O2S calculated value: 352.11; measured value: [M+H] + :353. 1H NMR(400 MHz,DMSO-d6)δ 8.18(dt,J=9.0,1.3 Hz,1H),7.69(q,J=8.8 Hz,1H),6.83-6.73(m,1H),4.38(q,J=2.4 Hz,2H),3.55(t,J=5.8 Hz,2H),2.39-2.43(m,2H),1.44(s,9H).

[0203] 6,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole. To a solution of tert-butyl 3-(6,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.28 mmol) in dioxane (2 mL), HCl (2 mL, 4 M in 1,4-dioxane) was added dropwise, and the resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (2 mL), and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The mixture was concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32%B to 58%B in 7 mins; wavelength: 254 nm / 220 nm; RT1 (min): 6.15) to obtain the desired product as a white solid (25.3 mg, 34.8%). LCMS 46 (Method I) (ESI)C 12 H 10 F2N2S Calculated value: 252.05; Measured value: M+H] + :253. 1 H NMR(400 MHz,DMSO-d6)δ 8.13-8.06(m,1H),7.74-7.62(m,1H),6.66(d,J=4.2 Hz,1H),3.70(s,2H),2.89-2.72(m,2H),2.28(d,J=5.1 Hz,2H).

[0204] Example 5: Synthesis of 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole (compound 110) [ka]

[0205] 2-Bromo-3,5-difluorobenzamide. 2-Bromo-3,5-difluorobenzoic acid (1.00 g, 4.21 mmol) was stirred in DMF (10 mL), to which NH4Cl (2.26 g, 42.19 mmol), DIEA (1.64 g, 12.65 mmol), and HATU (2.41 g, 6.32 mmol) were added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 30% over 20 minutes; purification by reverse-phase flash chromatography using UV 254 nm yielded the desired product as a yellow oily substance (750.0 mg, yield 75.3%). LCMS 42 (Method A) (ESI) C7H4BrF2NO Calculated value 234.94; Measured value [M+H] + :236. 1 H NMR(400 MHz,CDCl3)δ 7.25-7.19(m,1H),7.04-6.97(m,1H),6.09(s,2H).

[0206] 5,7-Difluoro-2H-1,2-Benzothiazole-3-one. A mixture of 1,10-phenanthroline (171.7 mg, 0.95 mmol) and CuI (181.5 mg, 0.95 mmol) in DMF (10 mL) was mixed with 2-bromo-3,5-difluorobenzamide (750.0 mg, 3.17 mmol), sulfur (132.1 mg, 4.13 mmol), and K2CO3 (570.9 mg, 4.13 mmol). The resulting mixture was stirred under an N2 atmosphere at room temperature for 15 minutes and at 110°C for 2 hours. The mixture was then analyzed under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV 254 nm yielded the desired product as a white solid (380.0 mg, yield 63.8%). LCMS 17 (Method A) (ESI) C7H3F2NOS Calculated value 186.99; Measured value [M+H]+ :188. 1 H NMR(300 MHz,DMSO-d6)δ 12.70(s,1H),7.77-7.66(m,1H),7.65-7.56(m,1H).

[0207] 3-Chloro-5,7-difluoro-1,2-benzothiazole. Pyridine (240.9 mg, 3.04 mmol) was added to a stirred mixture of 5,7-difluoro-2H-1,2-benzothiazole-3-one (380.0 mg, 2.03 mmol) in POCl3 (5 mL). The resulting mixture was stirred at 140°C for 2 hours under an N2 atmosphere. The reaction product was quenched at 0°C with ice water. The resulting mixture was extracted with RINKAN (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (9:1) to obtain the desired product as a white solid (200.0 mg, yield 47.9%). 1 H NMR(400 MHz,CDCl3)δ 7.56-7.50(m,1H),7.18-7.09(m,1H).

[0208] To a mixture of tert-butyl 3-(5,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate and 3-chloro-5,7-difluoro-1,2-benzothiazole (200.0 mg, 0.97 mmol) stirred in dioxane (4 mL) and H2O (2 mL), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (451.1 mg, 1.45 mmol), K2CO3 (403.3 mg, 2.91 mmol), and Pd(dppf)Cl2 (71.1 mg, 0.09 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The resulting mixture was extracted with ₹ (3 × 10 mL). The combined organic extract was washed with water (3 × 10 mL) and dried on anhydrous sodium ₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (9:1) to obtain the desired product as a white solid (270.0 mg, yield 78.7%). LCMS 52 (Method A) (ESI)C 17 H 18 F2N2O2S calculated value: 352.11; measured value: [M+H] + :353. 1 H NMR(300 MHz,DMSO-d6)δ 8.10-8.01(m,1H),7.80-7.70(m,1H),6.79(s,1H),4.39(d,J=2.8 Hz,2H),3.60-3.51(m,2H),2.40(d,J=5.5 Hz,2H),1.44(s,9H).

[0209] 5,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole. To a stirred mixture of tert-butyl 3-(5,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (150.0 mg, 0.42 mmol) in dioxane (1 mL), HCl (gas) in 1,4-dioxane (1 mL) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CO3 (aqueous solution). The crude product was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5m; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5%B to 5%B at 1.5 min, 5%B to 25%B at 2 min, 25%B to 43%B at 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.2) to obtain the desired product as a white solid (13.6 mg, yield 12.6%). LCMS 40(ESI)C 12 H 10 F2N2S calculated value: 252.05; measured value: [M+H] + :253.05. 1 H NMR(400 MHz,DMSO-d6)δ 8.08-7.90(m,1H),7.85-7.63(m,1H),6.67(d,J=4.2 Hz,1H),3.71-3.68(m,2H),2.96-2.83(m,2H),2.28(d,J=2.8 Hz,2H).

[0210] Example 6: Synthesis of 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole (compound 111) [ka]

[0211] 2-Bromo-3,6-difluorobenzamide. A solution of 2-bromo-3,6-difluorobenzoic acid (3.00 g, 12.65 mmol), NH4Cl (6.77 g, 126.58 mmol), DIEA (4.91 g, 37.97 mmol), and HATU (7.22 g, 18.98 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours under an N2 atmosphere. The mixture was analyzed under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 10% to 50% over 30 minutes; purified by reverse-phase flash chromatography using UV 254 nm. The resulting mixture was concentrated under vacuum to obtain the desired product as a white solid (1.00 g, yield 33.4%). LCMS 54(ESI)C7H4BrF2NO Calculated value: 234.94; Measured value: [M+H] + :236. 1 H NMR(400 MHz,DMSO-d6)δ 8.16(s,1H),7.92(s,1H),7.43-7.24(m,2H).

[0212] 4,7-Difluoro-2H-1,2-Benzothiazole-3-one. A solution of 1,10-phenanthroline (230.0 mg, 1.27 mmol) in DMF (1 mL) was treated with CuI (242.0 mg, 1.27 mmol) under an N2 atmosphere at room temperature for 15 minutes, followed by the dropwise addition of K2CO3 (761.2 mg, 5.50 mmol), S8 (176.2 mg, 5.50 mmol), and 2-bromo-3,6-difluorobenzamide (1.00 g, 4.23 mmol) at room temperature. The resulting mixture was stirred at 110°C for 1 hour under an N2 atmosphere. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 10% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV 254 nm yielded the desired product as a white solid (400.0 mg, yield 50.4%). LCMS 50 (Method B) (ESI) C7H3F2NOS Calculated value 186.99; Measured value [M+H] + :188. 1 H NMR(400 MHz,DMSO-d6)δ 7.15-7.06(m,1H),6.89-6.81(m,1H).

[0213] 3-Chloro-4,7-difluoro-1,2-benzothiazole. A solution of 4,7-difluoro-2H-1,2-benzothiazole-3-one (400.0 mg, 2.13 mmol) and pyridine (253.5 mg, 3.20 mmol) in POCl3 (3 mL) was stirred at 140°C for 2 hours under an N2 atmosphere. The reaction was quenched with water at 0°C. The mixture was extracted with CH2Cl2 (2 × 100 mL), and the combined organic phase was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (6:1) to obtain the desired product as a white solid (150.0 mg, yield 34.1%). LCMS 47(ESI)C7H2ClF2NS Calculated value 204.96; Measured value [M+H] + :206. 1 H NMR(400 MHz,DMSO-d6)δ 7.67-7.58(m,1H),7.49-7.41(m,1H).

[0214] A solution of tert-butyl 3-(4,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate, 3-chloro-4,7-difluoro-1,2-benzothiazole (150.0 mg, 0.73 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (338.3 mg, 1.09 mmol), Pd(dppf)Cl2 (53.3 mg, 0.07 mmol), and K2CO3 (302.4 mg, 2.19 mmol) in H2O (1 mL) and dioxane (2 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The aqueous layer was extracted with ELISA (4 × 100 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (7:1) to obtain the desired product as a white solid (100.0 mg, yield 38.9%). LCMS 47(ESI)C 17 H 18 F2N2O2S calculated value: 352.11 [M+H] + :353. 1H NMR(400 MHz,DMSO-d6)δ 7.58(d,J=3.0 Hz,1H),7.40(ddd,J=10.7,8.6,3.5 Hz,1H),6.44(dp,J=6.0,2.2 Hz,1H),4.44-4.27(m,2H),3.53(t,J=5.7 Hz,2H),2.34-2.22(m,2H),1.44(s,9H).

[0215] 4,7-difluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzothiazole. To a stirred solution of tert-butyl 3-(4,7-difluoro-1,2-benzothiazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (100.0 mg, 0.28 mmol, 1.0 equivalent) in dioxane (2 mL), HCl (2 mL, 4 M in 1,4-dioxane) was added dropwise, and the resulting mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (2 mL), and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35%B to 65%B in 7 mins; wavelength: 254 nm / 220 nm; RT1 (min): 4.62) to obtain the desired product as a white solid (55.2 mg, yield 76.5%). LCMS 48 (Method I) (ESI)C 12 H 10 F2N2S calculated value: 252.05; measured value: [M+H] + :253.15. 1 H NMR(400 MHz,DMSO-d6)δ 7.56(td,J=8.6,3.0 Hz,1H),7.37(ddd,J=10.9,8.6,3.5 Hz,1H),6.43-6.22(m,1H),3.65(s,2H),2.88(t,J=5.7 Hz,2H),2.21(dt,J=6.7,3.0 Hz,2H).

[0216] Example 7: Synthesis of 6-fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzoxazole (compound 121) [ka]

[0217] tert-butyl 3-(2,4-difluorobenzoyl)-4-oxopiperidine-1-carboxylate. To a stirred solution of LiHMDS (210.7 mL, 1 M in THF) in THF (400 mL), tert-butyl 4-oxopiperidine-1-carboxylate (40.00 g, 200.75 mmol) was added dropwise at 0°C and the mixture was stirred at 0°C for 20 minutes under an N2 atmosphere. To the above mixture, 2,4-difluorobenzoyl chloride (37.21 g, 210.78 mmol) was added dropwise at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction product was quenched at 0°C with 500 mL of saturated NH4Cl (aqueous solution) and extracted with CH2Cl2 (3 × 1000 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow crude oil (36.00 g, yield 53%). LCMS 54(ESI)C 17 H 19 F2NO4 calculated value 339.13; measured value [M+H] + :340.

[0218] tert-butyl 3-[(2,4-difluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl 3-(2,4-difluorobenzoyl)-4-oxopiperidine-1-carboxylate (36.00 g, 106.09 mmol) in MeOH (400 mL), NaBH4 (16.05 g, 424.35 mmol) was added in fractions at 0°C, and the mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction product was quenched with 100 mL of water at room temperature and extracted with CH2Cl2 (3 × 100 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a yellow crude oil (19.00 g, yield 52%). LCMS 54(ESI)C 17 H 23 F2NO4 calculated value 343.16; measured value [M+H] + :344.

[0219] tert-butyl 3-(2,4-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl 3-[(2,4-difluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-1-carboxylate (19.00 g, 55.33 mmol) in DCM (200 mL), MnO2 (72.16 g, 830.01 mmol) was added and stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with CH2Cl2 (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as yellow oil (8.40 g, yield 44%). LCMS 54(ESI)C 17 H 21 F2NO4 calculated value 341.14; measured value [M+H] + :342. 1H NMR(400 MHz,DMSO-d6)δ 7.92-7.80(m,1H),7.45-7.35(m,1H),7.26-7.19(m,1H),4.84(d,J=4.2 Hz,1H),4.17(d,J=4.1 Hz,1H),3.94-3.83(m,1H),3.72-3.64(m,1H),3.28(s,1H),2.50(s,1H),1.68-1.61(m,2H),1.40(d,J=4.0 Hz,9H).

[0220] tert-butyl 3-[(1E)-(2,4-difluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl 3-(2,4-difluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (8.40 g, 24.61 mmol) in MeOH (6 mL), hydroxylamine hydrochloride (2.05 g, 29.53 mmol) and AcONa (2.42 g, 29.53 mmol) were added, and the mixture was stirred overnight at 40°C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a white solid (5.90 g, yield 67%). LCMS 54(ESI)C 17 H 22 F2N2O4 calculated value: 356.15; measured value: [M+H] + :357. 1 H NMR(400 MHz,DMSO-d6)δ 10.99(s,1H),7.43-7.34(m,1H),7.29-7.21(m,1H),7.15-7.08(m,1H),4.64(d,J=3.9 Hz,1H),3.82-3.66(m,2H),3.09(d,J=72.2 Hz,2H),2.57(d,J=11.2 Hz,1H),1.63-1.44(m,2H),1.39(s,9H).

[0221] tert-butyl 3-(6-fluoro-1,2-benzoxazole-3-yl)-4-hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl 3-[(1E)-(2,4-difluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-1-carboxylate (5.90 g, 16.55 mmol) in THF (4 mL), t-BuOK (2.42 g, 21.52 mmol) was added and the mixture was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction mixture was quenched at room temperature with 100 mL of saturated NH4Cl (aqueous solution) and extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (0.1% FA), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow oily substance (3.30 g, yield 59%). LCMS 54(ESI)C 17 H 21 FN2O4 calculated value: 336.15; measured value: [M+H] + :337. 1 H NMR(400 MHz,DMSO-d6)δ 8.07-7.98(m,1H),7.72-7.64(m,1H),7.32-7.23(m,1H),4.93(s,1H), 3.85(s,2H),3.64(s,2H),3.47(s,1H),1.79(s,2H),1.46-1.34(m,9H).

[0222] To a stirred solution of tert-butyl 3-(6-fluoro-1,2-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3.30 g, 9.81 mmol) in DCE (2 mL), Burgess reagent (3.51 g, 14.72 mmol) was added, and the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was filtered under the following conditions: column, C 18The desired product was obtained as a yellow oily substance by reverse-phase flash chromatography using silica gel, mobile phase, and MeCN aqueous solution (0.1% FA) with a gradient from 0% to 70% over 30 minutes; UV 254 nm. (LCMS 54(ESI)C) 17 H 19 FN2O3 calculated value: 318.14; measured value [M+H] + :319. 1 H NMR(400 MHz,CDCl3)δ 7.84-7.76(m,1H),7.30-7.27(m,1H),7.15-7.05(m,1H),6.82(s,1H),4.47(s,2H),3.65(s,2H),2.46(d,J=6.1,2.8 Hz,2H),1.50(s,9H).

[0223] 6-Fluoro-3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzoxazole. A solution of tert-butyl 3-(6-fluoro-1,2-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.10 g, 3.45 mmol) in HCl (gas) and 1,4-dioxane (11 mL, 4 M) was stirred at room temperature for 1 hour under an N2 atmosphere and concentrated under vacuum. The residue was dissolved in 0.5 mL of MeOH and basicized to pH 9 with saturated Na2CO3 (aqueous solution). The resulting mixture was subjected to the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeOH solution (10 mmol / L NH4HCO3), gradient from 0% to 40% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (439 mg, 57% yield). LCMS 40(ESI)C 12 H 11 FN2O calculated value: 218.09; measured value: [M+H] + :219.00. 1 H NMR(400 MHz,DMSO-d6)δ 8.18-8.08(m,1H),7.77-7.67(m,1H),7.36-7.25(m,1H),6.97(d,J=4.3 Hz,1H),3.71-3.61(m,2H),2.89(s,2H),2.35-2.23(m,2H).

[0224] Example 8: Synthesis of 3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzoxazole (compound 122) [ka]

[0225] tert-butyl 3-(2-fluorobenzoyl)-4-oxopiperidine-1-carboxylate. To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol) in THF (50 mL), LiHMDS (26 mL, 1 M in THF) was added dropwise at 0°C, and the mixture was stirred at 0°C for 20 minutes under an N2 atmosphere. 2-fluorobenzoyl chloride (3.96 g, 25.09 mmol) was added dropwise to the above mixture at 0°C, and the resulting mixture was stirred for a further 30 minutes at 0°C. The reaction product was quenched with 50 mL of saturated NH4Cl (aqueous solution) at 0°C, and the resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as yellow crude oil (4.00 g, yield 49.7%). LCMS 50(ESI)C 17 H 20 FNO4 calculated value 321.14; measured value [M+H] + :322.

[0226] tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-1-carboxylate. To a stirred mixture of tert-butyl 3-(2-fluorobenzoyl)-4-oxopiperidine-1-carboxylate (4.00 g, 12.45 mmol) in MeOH (200 mL), NaBH4 (1.88 g, 49.82 mmol) was added in fractions at 0°C and stirred at room temperature for 1 hour. The reaction mixture was quenched with 40 mL of water at 0°C, and the resulting mixture was concentrated under vacuum and extracted with ELISA (3 × 40 mL). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to obtain the desired product as a white crude solid (1.90 g, yield 46.9%). LCMS 47(ESI)C 17 H 24 FNO4 calculated value 325.17; measured value [M+H] + :326.

[0227] tert-butyl 3-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate. A mixture of tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]-4-hydroxypiperidine-1-carboxylate (1.90 g, 5.84 mmol) in DCM (200 mL) was stirred, to which MnO2 (7.62 g, 87.64 mmol) was added and stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with CH2Cl2 (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to obtain the desired product as a white solid (1.40 g, yield 74.5%). LCMS 49(ESI)C 17 H 22 FNO4 calculated value: 323.15; measured value: [M+H] + :324. 1H NMR(300 MHz,DMSO-d6)δ 7.52(d,J=7.4 Hz,1H),7.36-7.33(m,1H),7.28-7.25(m,2H),4.85(d,J=4.1 Hz,1H),4.19(s,1H),3.93(s,1H),3.70(d,J=13.4 Hz,1H),3.28(s,1H),3.13-2.94(m,1H),1.65(s,2H),1.40(s,9H).

[0228] tert-butyl 3-[(1E)-(2-fluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-1-carboxylate. To a stirred solution of tert-butyl 3-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate (1.40 g, 4.33 mmol) and hydroxylamine hydrochloride (361.3 mg, 5.19 mmol) in EtOH (100 mL), AcONa (426.4 mg, 5.19 mmol) was added, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure, the residue was diluted with H2O (20 mL), and the aqueous layer was extracted with ELISA (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) eluting with PE / EA (1:1) to obtain the desired product as a white solid (730.0 mg, yield 49.9%). LCMS 49(ESI)C 17 H 23 FN2O4 calculated value: 338.16; measured value: [M+H] + :339. 1 H NMR(400 MHz,DMSO-d6)δ 10.91(s,1H),7.44-7.36(m,1H),7.35-7.29(m,1H),7.24-7.17(m,2H),4.62(d,J=3.8 Hz,1H),3.74(d,J=30.7 Hz,2H),3.17(s,2H),2.56(d,J=11.1 Hz,1H),1.57(d,J=12.8 Hz,2H),1.39(s,9H).

[0229] tert-butyl 3-(1,2-benzoxazole-3-yl)-4-hydroxypiperidine-1-carboxylate. A mixture of tert-butyl 3-[(1E)-(2-fluorophenyl)(hydroxyimino)methyl]-4-hydroxypiperidine-1-carboxylate (730.0 mg, 2.16 mmol) in 10 mL of THF was stirred, to which t-BuOK (629.8 mg, 5.61 mmol) was added at 0°C and stirred at room temperature under an N2 atmosphere for 1 hour. The reaction mixture was quenched at room temperature with 50 mL of saturated NH4Cl (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was collected under the following conditions: column, C 18 Silica gel; mobile phase: aqueous MeCN solution (0.1% FA), gradient from 0% to 40% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow solid (300.0 mg, yield 43.65%). LCMS 50(ESI)C 17 H 22 N2O4 calculated value: 318.16; measured value: [M+H] + :319. 1 H NMR(300 MHz,DMSO-d6)δ 7.99(d,J=7.9 Hz,1H),7.72(d,J=8.4 Hz,1H),7.63(d,J=7.6 Hz,1H),7.37(d,J=7.4 Hz,1H),5.01-4.83(m,1H),4.32(s,1H),3.89(s,1H),3.67(s,2H),3.45(d,J=6.7 Hz,1H),1.82(d,J=8.7 Hz,2H),1.49-1.20(m,9H).

[0230] tert-butyl 3-(1,2-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate. A stirred solution of tert-butyl 3-(1,2-benzoxazole-3-yl)-4-hydroxypiperidine-1-carboxylate (300.0 mg, 0.94 mmol) in DCE (1 mL) was mixed with Burgess reagent (337.0 mg, 1.41 mmol) and stirred at 100°C for 30 minutes under an N2 atmosphere. The residue was collected under the following conditions: column, C18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 40% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a yellow oily substance (90.0 mg, yield 31.8%). LCMS 60(ESI)C 17 H 20 N2O3 calculated value: 300.15; measured value: [M+H] + :301. 1 H NMR(400 MHz,CDCl3)δ 7.86(d,J=8.0 Hz,1H),7.57(d,J=15.2 Hz,2H),7.34(d,J=7.4 Hz,1H),6.87(s,1H),4.50(s,2H),3.65(d,J=5.7 Hz,2H),2.55-2.35(m,2H),1.51(s,9H).

[0231] 3-(1,2,5,6-tetrahydropyridine-3-yl)-1,2-benzoxazole. HCl (gas) in 1,4-dioxane (1 mL, 4 M) was added to tert-butyl 3-(1,2-benzoxazole-3-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (90.0 mg, 0.29 mmol), and the mixture was stirred at room temperature for 30 minutes under an N2 atmosphere. The resulting mixture was concentrated under vacuum and basicized to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was then filtered under the following conditions: column, C 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), gradient from 0% to 50% over 30 minutes; purification by reverse-phase flash chromatography using UV254nm yielded the desired product as a white solid (10.9 mg, yield 18.3%). LCMS 51(ESI)C 12 H 12 N2O calculated value: 200.09; measured value: [M+H] + :201.05. 1 H NMR(400 MHz,CD3OD)δ 8.02(d,J=8.0 Hz,1H),7.68-7.58(m,2H),7.47-7.37(m,1H),7.02(s,1H),3.97-3.85(m,2H),3.14(s,2H),2.51(s,2H).

[0232] Example 9: IP1 accumulation assay

[0233] The functional activity of the disclosed compounds is measured using an IP1 (inositol monophosphate) accumulation assay. IP1 production (G q The effects of the disclosed compounds on activation surrogacy were measured in HEK293 cells expressing human serotonin 2A receptor (5-HT2AR) using a homogeneous time-resolved fluorescence (HTRF) assay. A standard protocol was followed. Briefly, the cell suspension and test compounds were incubated in standard buffer. After incubation, the cells were lysed and the fluorescent acceptor and donor were added. After incubation, fluorescence transfer was measured, and the data were analyzed using GraphPad Prism to create concentration-response curves. The results are shown in Table 2. Here, A=<100; B=100~1000; C=>1000~10000; D=>10000; E=inactive; and +++=>90; ++=75~90; +=50~<75%; -=<50%; NC=not calculated. Table 2. [Table 19]

[0234] Embedding by reference All publications and patents referenced herein, including those listed below, are incorporated herein by reference in their entirety for all purposes, as if each individual publication or patent were incorporated specifically and individually by reference. In case of any conflict, this application, including all definitions herein, shall prevail.

[0235] Equivalents and scope In patent claims, articles such as “a,” “an,” and “the” can mean one or more unless otherwise indicated or made clear from the context. A claim or statement containing “or” between one or more members of a group is considered satisfied if, unless otherwise indicated or made clear from the context, one, two or more, or all of the group members are present in, used in, or related to a given product or method. The present invention includes embodiments in which exactly one member of a group is present in, used in, or related to a given product or method. The present invention includes embodiments in which two or more, or all, group members are present in, used in, or related to a given product or method.

[0236] Furthermore, the present invention encompasses all variations, combinations, and substitutions in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim can be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in Markush group form, each subgroup of the elements is also disclosed, and any element can be removed from a group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or embodiments of the present invention consist of or essentially consist of such elements and / or features. For simplicity, these embodiments are not specifically shown herein. Note that the terms “comprising” and “containing” are intended to be open and also allow for the inclusion of additional elements or processes. Where a scope is given, the endpoints are included. Furthermore, unless otherwise indicated, or unless it is obvious from the context and the understanding of those skilled in the art, values ​​expressed as a range may, unless the context clearly indicates otherwise, assume any specific value or subrange within the range described in different embodiments of the present invention, up to one-tenth of the lower limit unit of the range.

[0237] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention contained in the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly stated herein, as they are considered to be known to those skilled in the art. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0238] Those skilled in the art will recognize, or can verify by routine experimentation alone, many equivalents to the specific embodiments described herein. The scope of these embodiments described herein is not limited to the above description but is set forth in the appended claims. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

Claims

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

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

3. R Ａ is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ , -CHF ２ , -OCF ３ , -OCHF ２ , -CH ２ OH, -CH ２ NH ２ , -CH ２ C(O)NH ２ , -CH ２ CH ２ , -CH ２ CH ２ NH ２ , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl and azetidinyl may optionally be substituted by -CH ３ , the compound according to claim 1 or 2.

4. R Ａ However, for each appearance, fluoro, chloro, iodine, cyano and -CH ３ A compound according to claim 1 or 2, independently selected from the group consisting of the following.

5. The compound according to claim 1 or 2, wherein m is 3.

6. A, 【Transformation 6】 and 【Transformation 7】 Selected from the group consisting of, The compound according to claim 1 or 2, wherein X is O or S.

7. The compound according to claim 1 or 2, wherein m is 2.

8. A, 【Transformation 8】 and 【Chemistry 9】 Selected from the group consisting of, The compound according to claim 1 or 2, wherein X is O or S.

9. The compound according to claim 1 or 2, wherein m is 1.

10. A, 【Chemistry 10】 and 【Chemistry 11】 Selected from the group consisting of, The compound according to claim 1 or 2, wherein X is O or S.

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

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

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

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

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

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

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

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

19. Compounds represented by formula IIA, formula IIB, or formula IIC: 【Chemistry 14】 or its pharmaceutically acceptable salts and / or stereoisomers, X is either O or S; R Ａ For each occurrence, the following are indicated: fluoro, chloro, bromo, iod, hydroxyl, cyano, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -CF ３ ,-CHF ２ , -OCF ３ , -OCHF ２ ien-CH ２ OH, -CH ２ NH ２ ien-CH ２ C(O)NH ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ NH ２ A compound independently selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranil, tetrahydropyranil, tetrahydropyrrolyl, piperidinil, piperazinil, morpholinil, oxyranil, azetidinil, phenyl, triazolyl, and oxadiazolyl; tetrahydropyrrolyl, piperidinil, piperazinil, and azetidinil are -CH ３ It may be replaced depending on the circumstances; R ２ and R ３ These are, independently, hydrogen, hydroxyl, and -CH₂. ３ ien-CH ２ OH and -NH-C(O)-N(CH ２ CH ３ ) ２ Selected from the group consisting of; R １ is hydrogen, -CH ３ , 【Chemistry 15】 and 【Chemistry 16】 Selected from the group consisting of; m is 0, 1, 2, or 3. Compounds represented by formula IIA, formula IIB, or formula IIC, or their pharmaceutically acceptable salts and / or stereoisomers.

20. R Ａ However, for each appearance, fluoro, chloro, iodine, cyano and -CH ３ A compound according to claim 19, independently selected from the group consisting of the following.

21. The compound according to claim 19 or 20, wherein m is 3.

22. The compound according to claim 19 or 20, wherein m is 2.

23. The compound according to claim 19 or 20, wherein m is 1.

24. R ４ The compound according to claim 1 or 19, wherein is hydrogen.

25. R ５ However, hydrogen, hydroxyl, -CH ３ ien-CH ２ OH and -NH-C(O)-N(CH ２ CH ３ ) ２ A compound according to claim 1 or 19, selected from the group consisting of the following.

26. R ５ is hydrogen or -CH ３ The compound according to claim 1 or 19.

27. R １ The compound according to claim 1 or 19, wherein is hydrogen. 【Request Item 28】 【Chemistry 17-1】 【Chemistry 17-2】 and [Chemistry 18] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

29. A pharmaceutical composition comprising a compound according to any one of claims 1, 19, and 28, and a pharmaceutically acceptable excipient.

30. A method for treating a mental or neurological disorder in a patient who requires treatment for a mental or neurological disorder, comprising administering to the patient a therapeutically effective amount of the compound described in any one of claims 1, 19, and 28.

31. A method for treating a mental or neurological disorder or disorder in a patient requiring treatment of such disorder or disorder, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of claims 1, 19, and 28 and a pharmaceutically acceptable excipient.

32. The method according to claim 30, wherein the mental or neurological disorder or illness is selected from the group consisting of depression, anxiety, substance abuse, and headache.

33. The method according to claim 31, wherein the mental or neurological disorder or illness is selected from the group consisting of depression, anxiety, substance abuse, and headache.

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