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 piperidine compounds are provided. The compounds are considered 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 / 508,574, filed on 16 June 2023, the disclosure of which is incorporated herein by reference.

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

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

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

[0005] For example, compounds represented by formula IA or formula IB: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, Y is -CR , 1 R 11 -, -O-, -NR a , -S-, -S(O)- and -S(O)2-, and is selected from the group consisting of A is selected from the group consisting of 8- to 10-member fused bicyclic heteroaryl, 8- to 10-member fused bicyclic heterocyclyl, and 6- to 10-member aryl, and ring A may optionally be substituted by one or more substituents selected from A R R A is, for each occurrence, independently hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C1-C6 alkyl, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, 4- to 6-member heterocyclyl and 5- to 6-member heteroaryl, and C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, phenyl, heterocyclyl and heteroaryl may each independently be optionally substituted by one or more substituents selected from halogen, hydroxyl, -NR a R b , -C(O)NR a R b , C1-C3 alkyl and C1-C3 alkoxy, and may each independently be optionally substituted by one or more substituents selected from the group consisting of R 1The substituent is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, phenyl, and C1-C6 alkyl, where phenyl and C1-C6 alkyl may optionally be substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b And may optionally be substituted by one or more substituents independently selected from the group consisting of C1-C3 alkoxys, or Or, R 4 and R 5These may bond together with the carbon atoms to which they are bonded to form a C3-C4 alkyl group. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 8 and R 9 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 10 and R 11 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R 10 and R 11 These may also form C3-C4 cycloalkyl groups together with the carbon atoms to which they are bonded. R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more halogens. Compounds represented by formula IA or formula IB, or pharmaceutically acceptable salts and / or stereoisomers thereof, are disclosed herein.

[0006] Compounds represented by formula IIA or formula IIB: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, A is [ka] and [ka] Selected from the group consisting of, X, Y, and Z are NR c Selected from the group consisting of O and S, R a , R b , R d Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and -C1~C3 alkyl, R c It is selected from the group consisting of hydrogen and -C1~C3 alkyl groups, R e It is selected from the group consisting of hydrogen and halogens, R 1 This is selected from the group consisting of hydrogen, -C1~C3 alkyl, and -CH2-phenyl, where phenyl may optionally be substituted with hydroxyl. 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 9 and R 10 Each is independently selected from the group consisting of hydrogen and -CH3. Compounds represented by formula IIA or formula IIB, or pharmaceutically acceptable salts and / or stereoisomers thereof, 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 1~3Alkyl 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"; for example, anthracyl). "Aryl" also includes a ring system in which the aryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such cases, 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 aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include [Chemical formula] including wherein one of R 56 and R 57 can be hydrogen, and at least one of R 56 and R 57 is, independently of each other, C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO-alkyl, COO-aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR<000009{0}>R 59, selected from S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl, or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) consisting of 5 to 8 atoms and may contain one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 are each independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, substituted C6-C 10 aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[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 term "cycloalkyl" or "carbocyclic group" refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3 to 6 or 4 to 6 carbons, and is herein referred to as C3-C 10 cycloalkyl, C 3~6 cycloalkyl or C 4~6 cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0021] As used herein, the term "halo" or "halogen" refers 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 unsolvated forms with pharmaceutically acceptable solvents such as water and ethanol, and this disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is in crystalline form.

[0039] This disclosure also includes isotope-labeled compounds of this disclosure that are identical to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is an example. For instance, the compounds of this disclosure may have one or more H atoms substituted with deuterium.

[0040] Specific isotope-labeled disclosed compounds (e.g., 3 H and 14 Those labeled with 1C are useful in compound and / or substrate tissue distribution assays. Tritiation (i.e., 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2Substitution with heavier isotopes, such as H), may provide certain therapeutic benefits resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced required dose), and may therefore be preferable in some situations. The isotope-labeled compounds of this disclosure can generally be prepared by procedures similar to those disclosed in the examples herein, by using an isotope-labeled reagent instead of a non-isotopically labeled reagent.

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

[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 binding to the 5-HT2A receptor rather than to the 5-HT2B and / or 5-HT2C receptors. 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, compounds represented by formula IA or formula IB [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, Y is -CR 10 R 11 -, -O-, -NR a Selected from the group consisting of -S-, -S(O)-, and -S(O)2-, A is selected from the group consisting of 8-10 member fused bicyclic heteroaryls, 8-10 member fused bicyclic heterocyclyls, and 6-10 member aryls, where ring A is R A It may be optionally substituted by one or more substituents selected from R A For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b -OC(O)-NR a R bSelected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~6 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR a R b , it may be optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy. R 1 The substituent is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, phenyl, and C1-C6 alkyl, where phenyl and C1-C6 alkyl may optionally be substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a R b , -NR a -(CO)-ORb -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl and phenyl are halogens, hydroxyls, -NR a R b and may be optionally substituted by one or more substituents independently selected from the group consisting of C1-C3 alkoxys. Or, R 4 and R 5 These may bond together with the carbon atoms to which they are bonded to form a C3-C4 alkyl group. R 6 and R 7 Each of these is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, and the C1-C6 alkyl groups may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy groups. R 8 and R 9 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 10 and R 11 Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R 10 and R 11 These may also form C3-C4 cycloalkyl groups together with the carbon atoms to which they are bonded. R a and R bEach occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more halogens. Compounds represented by formula IA or formula IB, or pharmaceutically acceptable salts and / or stereoisomers thereof, are disclosed herein.

[0047] In some embodiments, R 2 and R 3 is hydrogen. In other embodiments, R 6 and R 7 is hydrogen. In a particular embodiment, R 8 and R 9 is hydrogen. In some embodiments, for example, the compounds of the present disclosure are of formula IC or formula ID: [ka] It is represented by [this].

[0048] In further embodiments, R A For each occurrence, for example, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b The C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy atoms are independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy atoms, and the C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy atoms may be optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyls, and C1-C3 alkoxy atoms.

[0049] For example, in some embodiments, A is [ka] and [ka] Selected from the group consisting of, R c It is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d This is selected from the group consisting of halogens, hydroxyls, cyanos, -C1-C3 alkyls, C1-C3 alkoxys, -C3-C4 cycloalkyls, 4-6 membered heterocyclines, and 5-6 membered heteroaryls, where -C1-C3 alkyls may optionally be substituted with one, two, or three substituents independently selected from the group consisting of halogens, hydroxyls, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, m is 0, 1, 2, or 3.

[0050] In a particular embodiment, for example, R c R is selected from the group consisting of hydrogen and C1-C3 alkyl groups. d These include halogens, hydroxyls, cyanos, -C1~C3 alkyls, -CH2OH and C1~C e Selected from the group consisting of alkoxys, R e This is selected from the group consisting of hydrogen, halogens, cyano, and C1-C3 alkyl groups.

[0051] In other embodiments, A is, for example, [ka] and [ka] It is selected from the group consisting of the following.

[0052] In some embodiments, R 10 and R 11 Each is independently selected from the group consisting of hydrogen and -CH3. In other embodiments, R 10 and R 11Each of these is hydrogen. In yet another embodiment, R 10 and R 11 These are each -CH3. In further embodiments, R 10 is hydrogen, R 11 It is -CH3.

[0053] In a particular embodiment, R 1 is hydrogen, -CH3, [ka] and [ka] Selected from the group consisting of R 4 is hydrogen. In some embodiments, R 5 This is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[0054] Compounds represented by formula IIA or formula IIB: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, A is [ka] and [ka] Selected from the group consisting of, X, Y, and Z are NR c Selected from the group consisting of O and S, R a , R b , R dEach of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and -C1~C3 alkyl, R c It is selected from the group consisting of hydrogen and -C1~C3 alkyl groups, R e It is selected from the group consisting of hydrogen and halogens, R 1 This is selected from the group consisting of hydrogen, -C1~C3 alkyl, and -CH2-phenyl, where phenyl may optionally be substituted with hydroxyl. 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 9 and R 10 Each is independently selected from the group consisting of hydrogen and -CH3. Compounds represented by formula IIA or formula IIB, or pharmaceutically acceptable salts and / or stereoisomers thereof, are also disclosed herein.

[0055] In some embodiments, the compound is one of the compounds specified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0056] 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.

[0057] 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.

[0058] 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).

[0059] 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.

[0060] 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.

[0061] method

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] The intended patients include not only humans, but also other animals such as companion animals (e.g., dogs, cats), livestock (e.g., cattle, pigs), and wild animals (e.g., monkeys, bats, snakes).

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] In some embodiments, administering a compound(s) described herein to a patient serves to treat, alleviate, and / or prevent a neurological disease or disorder, or to treat, alleviate, and / or prevent a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor in a patient, such that a lower dose of an additional therapeutic agent can be administered compared to the dose of the additional therapeutic agent alone that would be required to achieve a similar result. For example, in certain embodiments, a compound(s) described herein potentiates the activity of a further therapeutic compound, thereby enabling a lower dose of the further therapeutic compound to provide the same effect.

[0086] In particular, in certain embodiments, the present disclosure provides a method of treating a medical condition as described above, comprising administering to a subject in need of treatment for said medical condition a therapeutically effective amount of a compound described herein, such as a compound of formula I or formula II.

[0087] Pharmaceutical Compositions and Kits

[0088] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides a pharmaceutical composition comprising a compound 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, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as unit dosages and / or may be formulated for oral or subcutaneous administration.

[0089] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations containing one or more of the compounds of the present disclosure as active ingredients, for example, in solid, semi-solid or liquid forms, after being mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral applications. The active ingredients can be formulated, for example, with conventional tablet-forming ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other pharmaceutical diluents such as water, for tablets and other solid compositions. The active compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease method or condition.

[0090] [[ID=用於製備錠劑等固體組成物時,可將主要活性成分與藥用載體(例如玉米澱粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸、硬脂酸鎂、磷酸二鈣或膠等常規造粒成分)以及其他藥用稀釋劑(例如水)混合,以形成含有本公開化合物或其非毒性藥用可接受鹽的均勻混合物的固體預製劑組成物。若將這些預製劑組成物稱為均質的,則意味著活性成分在整個組成物中均勻分散,使得組成物可容易地細分成等效力的單位劑型,如錠劑、丸劑和膠囊劑等。

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising the disclosed compounds and enteric coatings, and their pharmaceutically acceptable carriers or excipients. Enteric coatings refer to polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Therefore, enteric-coated substances are not soluble up to pH levels of, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl phthalate acetate (PVAP), hydroxypropyl methylcellulose succinate acetate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose hexahydrophthalate acetate, cellulose propionate phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionate acetate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal colloids, and several commercially available enteric-coated dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit Examples include L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or can be easily determined in vitro.The above is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not exhaustive and that there are other enteric-coated materials that serve the purposes of this disclosure.

[0103] This disclosure also provides, for example, kits for use by consumers requiring treatment of diseases or disorders described herein. Such kits include appropriate dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, alleviate, or prevent inflammation. The instructions will instruct consumers or healthcare professionals to administer the dosage forms according to dosage forms known to those skilled in the art. Such kits may be advantageously packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively rigid material covered with a foil, preferably made of clear plastic material. During the packaging method, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the recess, and the sheet of relatively rigid material is sealed against the plastic foil with the foil side opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the sheet has sufficient strength so that a tablet or capsule can be removed from the blister pack by manually applying pressure to the recess, thereby forming an opening in the sheet at the location of the recess. The tablet or capsule can then be removed through this opening.

[0104] For example, it may be desirable to provide a memory aid in the kit in the form of a number next to a tablet or capsule, where the number corresponds to the day of the regimen in which the designated tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, etc., Week 2, Monday, Tuesday, etc." Other variations of the memory aid will readily become apparent. The "daily dose" may be a single tablet or capsule or several pills or capsules taken on a given day. Also, the daily dose of a first compound may consist of one tablet or capsule, and the daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0105] Exemplary embodiments of the present invention

[0106] E1. Compounds represented by formula IA or formula IB: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, Y is -CR 10 R 11 -, -O-, -NR a Selected from the group consisting of -S-, -S(O)-, and -S(O)2-, A is selected from the group consisting of 8-10 member fused bicyclic heteroaryls, 8-10 member fused bicyclic heterocyclyls, and 6-10 member aryls, and ring A is R A It may be optionally substituted by one or more substituents selected from R A For each occurrence, independently, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b , -NR a -C(O)-R b , -NR a -C(O)-NR a Rb , -NR a -(CO)-OR b -OC(O)-NR a R b Selected from the group consisting of -O-(CO)-C1~C6 alkyl, -C(O)-C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, 4~6 membered heterocyclyl, and 5~6 membered heteroaryl, where C1~C6 alkyl, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C3~C6 cycloalkyl, phenyl, heterocyclyl, and heteroaryl are halogens, hydroxyls, -NR a R b -C(O)NR a R b , it may be optionally substituted with one or more substituents independently selected from the group consisting of C1-C3 alkyl and C1-C3 alkoxy. R 1 The substituent is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 member heteroaryl), and the C1-C6 alkyl, phenyl, and heteroaryl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 2 and R 3 Each of these is independently selected from the group consisting of hydrogen, phenyl, and C1-C6 alkyl, where phenyl and C1-C6 alkyl may optionally be substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy. R 4 and R 5 These are independently hydrogen, halogen, hydroxyl, cyano, and -NR. a R b -C(O)-NR a R b , -NR a -C(O)-Rb , -NR a -C(O)-NR a R b , -NR a -(CO)-OR b , -O-C(O)-NR a R b , -O-(CO)-C1-C6 alkyl, -C(O)-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl, where C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -C3-C6 cycloalkyl, and phenyl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, -NR a R b and C1-C3 alkoxy, or R 4 and R 5 may together with the carbon atom to which they are attached form a C3-C4 alkyl, R 6 and R 7 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, and C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy, R 8 and R 9 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, and C1-C6 alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy, R 10 and R 11 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or, R 10 and R 11 may together with the carbon atom to which they are attached form a C3-C4 cycloalkyl, Ra and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more halogens. Compounds represented by formula IA or formula IB, or pharmaceutically acceptable salts and / or stereoisomers thereof.

[0107] E2.R 2 and R 3 A compound described in E1, in which hydrogen is present.

[0108] E3.R 6 and R 7 A compound according to E1 or E2, wherein the compound is hydrogen.

[0109] E4.R 8 and R 9 A compound listed in any one of E1 to E3, wherein the hydrogen atom is hydrogen.

[0110] E5. Compounds with formula IC or formula ID: [ka] A compound represented by one of the following: E1 to E4.

[0111] E6.R A However, for each occurrence, hydrogen, halogen, hydroxyl, cyano, -NR a R b -C(O)-NR a R b A compound according to any one of E1 to E5, independently selected from the group consisting of -C1-C6 alkyl, -C3-C6 cycloalkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl, -C3-C6 cycloalkyl, and C1-C6 alkoxy may optionally be substituted by one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy.

[0112] E7.A is, [ka] and [ka] Selected from the group consisting of, R c However, it is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d However, the substituent is selected from the group consisting of halogens, hydroxyls, cyanos, -C1-C3 alkyls, C1-C3 alkoxys, -C3-C4 cycloalkyls, 4-6 membered heterocyclines, and 5-6 membered heteroaryls, where the -C1-C3 alkyls may optionally be substituted by one, two, or three substituents independently selected from the group consisting of halogens, hydroxyls, -NH2, -C(O)-NH2, and -OCH3. R e It is selected from the group consisting of hydrogen, halogen, cyano, and -C1~C3 alkyl, m is 0, 1, 2, or 3. A compound listed in any one of E1 to E6.

[0113] E8.R c However, it is selected from the group consisting of hydrogen and C1-C3 alkyl groups, R d However, halogens, hydroxyl, cyano, -C1~C3 alkyl, -CH2OH and C1~C e Selected from the group consisting of alkoxys, R e However, selected from the group consisting of hydrogen, halogen, cyano and -C1~C3 alkyl, The compound described in E7.

[0114] E9.A is, [ka] and [ka] A compound selected from the group consisting of, one of E1 to E8.

[0115] E10.R 10 and R 11 A compound according to any one of E1 to E9, wherein each of the members is independently selected from the group consisting of hydrogen and -CH3.

[0116] E11.R 10 and R 11 A compound listed in any one of E1 to E10, wherein each of the atoms is a hydrogen atom.

[0117] E12.R 10 and R 11 A compound described in any one of E1 to E10, wherein each of the groups is -CH3.

[0118] E13.R 10 is hydrogen, R 11 A compound listed in any one of E1 to E10, wherein the parent molecule is -CH3.

[0119] E14.R 1 However, hydrogen, -CH3, [ka] and [ka] A compound selected from the group consisting of, one of E1 to E13.

[0120] E15.R 4 A compound listed in any one of E1 to E14, wherein the hydrogen atom is hydrogen.

[0121] E16.R 5 The compound is one of the compounds described in E1 to E15, selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.

[0122] E17. Compounds represented by formula IIA or formula IIB: [ka] or a pharmaceutically acceptable salt and / or stereoisomer thereof, A is [ka] and [ka] Selected from the group consisting of, X, Y, and Z are NR c Selected from the group consisting of O and S, R a , R b , R d Each of these is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and -C1~C3 alkyl, R c It is selected from the group consisting of hydrogen and -C1~C3 alkyl groups, R e It is selected from the group consisting of hydrogen and halogens, R 1 This is selected from the group consisting of hydrogen, -C1~C3 alkyl, and -CH2-phenyl, where phenyl may optionally be substituted with hydroxyl. 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 9 and R 10 Each is independently selected from the group consisting of hydrogen and -CH3. Compounds represented by formula IIA or formula IIB, or pharmaceutically acceptable salts and / or stereoisomers thereof.

[0123] E18. [ka] [ka] [ka] [ka] and [ka] A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0124] A pharmaceutical composition comprising one compound from E1 to E18 and a pharmaceutically acceptable excipient.

[0125] E20. 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 E18.

[0126] E21. 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 E18 and a pharmaceutically acceptable excipient.

[0127] E22. The method according to E20 or E21, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache. [Examples]

[0128] 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.

[0129] General information

[0130] Unless otherwise specified, reagents and solvents were obtained from commercial sources without further purification or prepared according to literature methods. 1 1H NMR and 13 13C NMR spectra were recorded at room temperature using a 300 or 400 MHz Bruker spectrometer with tetramethylsilane (TMS) as the internal standard and DMSO-d6, CDCl3, or CD3OD as the solvent. Chemical shifts were given in δ relative to TMS, and coupling constants J were given in Hz. LCMS analysis methods and apparatus were generated using one of the following methods. Detection was performed by UV (254 nm) and ELSD for all methods.

[0131] Method A (LCMS17, 41, 42, 50, 52)

[0132] 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]

[0133] Method B (LCMS17, 41, 42, 47, 50, 52)

[0134] 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]

[0135] Method C (LCMS25)

[0136] 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]

[0137] Method D (LCMS25)

[0138] 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]

[0139] Method E (LCMS40)

[0140] 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]

[0141] Method F (LCMS45)

[0142] 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]

[0143] Method G (LCMS45)

[0144] 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]

[0145] Method H (LCMS46, 48)

[0146] 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]

[0147] Method I (LCMS46, 48)

[0148] 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]

[0149] Method J (LCMS49)

[0150] 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]

[0151] Method K (LCMS49)

[0152] 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]

[0153] Method L (LCMS51, 53)

[0154] 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]

[0155] Method M (LCMS51, 53)

[0156] 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]

[0157] Method N (LCMS60)

[0158] Experiments were performed using 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]

[0159] Method O (LCMS61)

[0160] 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]

[0161] Method P (LCMS63)

[0162] 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]

[0163] Method Q (LCMS63)

[0164] 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]

[0165] Example 1: Synthesis of ((3R,5R)-5-((1H-indole-3-yl)methyl)piperidine-3-yl)methanol (Compound 101) [ka]

[0166] tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate. A solution of 1-(tert-butoxycarbonyl)piperidine-3,5-dicarboxylic acid (8.0 g, 29.3 mmol) in acetic anhydride (30 mL) was stirred at 120 °C for 3 hours. The resulting mixture was concentrated under reduced pressure to obtain a crude product as a brown solid (7.30 g), which was used directly in the next step. LCMS 49 (Method K) (ESI)C 12 H17 NO5 Calculated value 255.11; Measured value [M+H] + :256.

[0167] (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid. To a stirred solution of tert-butyl 2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (7.30 g, 28.6 mmol) and 1,4-bis[(S)-[(2R,4S,5S)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl](6-methoxyquinoline-4-yl)methoxy]-9,10-dihydroanthracene-9,10-dione (2.61 g, 3.03 mmol) in THF (20 mL) and Et2O (56 mL), MeOH (13 mL) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 1 hour, then the solution was acidified and extracted with toluene (3 × 100 mL). The combined organic extracts were washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was examined by flash chromatography (C). 18 The sample was purified by column chromatography (mobile phase: acetonitrile in water (0.1% formic acid), gradient from 2% to 60% over 10 minutes; detector: UV 220 nm) to obtain the desired product as a pale yellow solid (2.21 g, yield 27%). LCMS 49 (Method K) (ESI)C 13 H 21 NO6 Calculated value 287.14; Measured value [M+H] + :288. 1 H NMR(400 MHz,CDCl3)δ 4.38(s,2H),3.71(s,3H),2.82-2.62(m,2H),2.58-2.42(m,3H),1.80-1.65(m,1H),1.47(s,9H).

[0168] 1-tert-butyl 3-methyl(3R,5S)-5-(hydroxymethyl)piperidine-1,3-dicarboxylate. (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.01 g, 6.96 mmol) was stirred in tetrahydrofuran (20 mL), to which 4-methylmorpholine (1.41 g, 13.9 mmol) and isobutyl carbonochloride (1.43 g, 10.4 mmol) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours, after which sodium borohydride (2.63 g, 69.6 mmol) was added in portions at 0°C. The reaction mixture was stirred further at room temperature for 15 minutes, then cooled to 0°C and quenched with 30 mL of saturated NH4Cl. The resulting mixture was extracted with RINKAN (50 mL), the organic extract was washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (column: C18; mobile phase: aqueous acetonitrile solution (10 mmol / L ammonium bicarbonate), gradient from 5% to 70% over 8 mins; detector: UV 200 nm) to obtain the desired product as light brown oil (1.31 g, yield 68%). LCMS 49 (Method K) (ESI)C 13 H 23 NO5 Calculated value 273.16; Measured value [M+H] + :274. 1 H NMR(400 MHz,DMSO-d6)δ 4.62-4.55(m,1H),4.22-3.97(m,2H),3.62(s,3H),3.31-3.27(m,1H),3.26-3.15(m,1H),2.77-2.54(m,1H), 2.47-2.37(m,1H),2.37-2.16(m,1H),2.01-1.92(m,1H),1.58-1.45(m,1H),1.40(s,9H),1.22-1.08(m,1H).

[0169] 1-tert-butyl3-methyl(3R,5S)-5-(iodomethyl)piperidine-1,3-dicarboxylate. To a stirred solution of 1-tert-butyl3-methyl(3R,5S)-5-(hydroxymethyl)piperidine-1,3-dicarboxylate (1.45 g, 5.30 mmol) in CH2Cl2 (20 mL), imidazole (0.83 g, 12.2 mmol), iodine (2.69 g, 10.6 mmol), and triphenylphosphine (3.20 g, 12.2 mmol) were added at 0°C. After stirring at room temperature for 30 minutes, the resulting mixture was diluted with CH2Cl2 (10 mL) and washed with 10 mL of saturated sodium thiosulfate. The organic layer was concentrated under reduced pressure, and the crude product was chromatographed (column, C). 18 The product was purified by chromatography (SiO2) with elution in 25% ethyl acetate in petroleum ether to obtain the desired product as a white solid (1.2 g, yield 59%). (Mobile phase: acetonitrile in water (0.1% formic acid), gradient from 10% to 70% over 8 minutes; detector: UV 200 nm). The product was then re-purified by chromatography (SiO2) with elution in 25% ethyl acetate in petroleum ether to obtain the desired product as a white solid (1.2 g, yield 59%). LCMS 49 (Method K) (ESI)C 13 H 22 NO4 Calculated value: 383.06; Measured value: [M+H] + :384. 1 H NMR(400 MHz,DMSO-d6)δ 4.11(d,J=12.5 Hz,2H),3.63(s,3H),3.27-3.20(m,1H),3.19-3.10(m,1H),2.77-2.55(m,1H),2.47-2.43(m, 1H),2.43-2.21(m,1H),2.19-2.09(m,1H),1.62-1.69(m,1H),1.40(s,9H),1.29-1.15(m,1H).

[0170] 1-tert-butyl3-methyl(3R,5R)-5-{[1-(tert-butoxycarbonyl)indole-3-yl]methyl}piperidine-1,3-dicarboxylate. 1-tert-butyl3-methyl(3R,5S)-5-(iodomethyl)piperidine-1,3-dicarboxylate (1.01 g, 2.63 mmol) and tert-butyl3-bromoindole-1-carboxylate (600 mg, 2.02 mmol) were dissolved in DMA (4 mL) under an N2 atmosphere. Manganese (334 mg, 6.08 mmol), dtbpy (109 mg, 0.41 mmol), pyridine (160 mg, 2.02 mmol), and Ni(OAc)2 (72.0 mg, 0.41 mmol) were added. The reaction mixture was stirred at 65°C for 1 hour and then diluted with ELISA (10 mL). Next, wash with brine (3 × 10 mL), concentrate under reduced pressure, and chromatograph (column, C 18 The solution was purified by mobile phase (acetonitrile in water (0.1% formic acid), gradient from 5% to 90% over 10 minutes, and detector (UV 254 nm). The desired product was obtained as a white solid (550 mg, yield 57%). LCMS 49 (Method J) (ESI)C 26 H 36 N2O6 calculated value: 472.26; measured value: [M+H] + :473. 1 H NMR(400 MHz,CDCl3)δ 8.11(d,J=7.6 Hz,1H),7.49(d,J=7.7 Hz,1H),7.38(s,1H),7.34-7.28(m,1H),7.26-7.21(m,1H),4.41-4.07(m,2H),3.6 6(s,3H),2.75-2.62(m,2H),2.60-2.51(m,1H),2.50-2.29(m,2H),2.15(d,J=13.2 Hz,1H),1.97-1.81(m,1H),1.68(s,9H),1.41(s,9H),1.34-1.21(m,1H).

[0171] tert-butyl 3-{[(3R,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)piperidine-3-yl]methyl}indole-1-carboxylate. 1-tert-butyl 3-methyl(3R,5R)-5-{[1-(tert-butoxycarbonyl)indole-3-yl]methyl}piperidine-1,3-dicarboxylate (550 mg, 1.16 mmol) was stirred in THF (8 mL), to which LiAlH4 (177 mg, 4.66 mmol) was added in fractions at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 20 minutes, then quenched with water (10 mL) at 0°C. The resulting mixture was filtered through Celite, the cake was washed with methanol (3 × 10 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (1:1) to obtain the desired product as a white semi-solid (200 mg, yield 39%). LCMS 49 (Method J) (ESI)C 25 H 36 N2O5 calculated value: 444.26; measured value: [M+H] + :445.

[0172] [(3R,5R)-5-(1H-indole-3-ylmethyl)piperidine-3-yl]methanol. A solution of tert-butyl 3-{[(3R,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)piperidine-3-yl]methyl}indole-1-carboxylate (200 mg, 0.45 mmol) in HCl (3 mL) and methanol (3 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was chromatographed (column, C 18 The solution was purified by mobile phase (acetonitrile in water (0.1% formic acid), with a gradient of 1% to 15% over 10 minutes; and a detector (UV 254 nm). The desired product was obtained as a brown solid (69.1 mg, yield 61%). LCMS 63(Method Q)(ESI)C 15 H 20 N2O calculated value: 244.16; measured value [M+H] + :245.25. 1H NMR(400 MHz,DMSO-d6)δ 10.88(d,J=3.2 Hz,1H),8.40(d,J=2.2 Hz,1H),7.50(d,J=7.8 Hz,1H),7.42-7.26(m,1H),7.12(d,J=2.3 Hz,1H),7.07-7.05(m,1H),6.98-6.96(m,1H),3.32-3.04(m,4H),2.69-2.56(m, 2H),2.36-2.34(m,2H),2.06-1.92(m,1H),1.81-1.62(m,2H),0.89-0.87(m,1H).

[0173] Example 2: Synthesis of (R)-3-(piperidine-3-ylmethyl)-1H-indole (compound 102) [ka]

[0174] A mixture of tert-butyl(R)-3-((1-(tert-butoxycarbonyl)piperidine-3-yl)methyl)-1H-indole-1-carboxylate. tert-butyl 3-bromoindole-1-carboxylate (2.00 g, 6.75 mmol), tert-butyl(3S)-3-(bromomethyl)piperidine-1-carboxylate (2.82 g, 10.13 mmol), Mn (0.74 g, 13.5 mmol), dtbpy (0.18 g, 0.68 mmol), and Ni(OAc)2 (0.17 g, 0.68 mmol) in DMA (10 mL) and pyridine (0.1 mL) was stirred at 50°C for 4 hours under an N2 atmosphere. The resulting mixture was extracted with ELISA (3 × 500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with 20% siRNA in petroleum ether to obtain the desired product as a grayish-white solid (1.65 g; yield 59%). LCMS 49 (Method J) (ESI)C 24 H 34 N2O4 calculated value: 414.25; measured value: [M+H] + :415

[0175] (R)-3-(piperidine-3-ylmethyl)-1H-indole. To a 5 mL stirred solution of tert-butyl 3-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}indole-1-carboxylate (1.00 g, 2.41 mmol) in MeOH, HCl (12 M in water) / MeOH (v:v=1:2, 10 mL) was added at 0°C. The reaction mixture was stirred at room temperature under an N2 atmosphere for 4 hours and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was chromatographed (column, C). 18 The sample was purified by column chromatography (mobile phase: acetonitrile in water (0.1% FA), gradient 2% to 30% over 20 minutes; detector: UV 200 nm) to obtain the desired product as a white solid (293 mg, yield 57%). LCMS 40(ESI)C 14 H 18 N2 Calculated value 214.15; Measured value [M+H] + :215.20. 1 H NMR(400 MHz,DMSO-d6)δ 10.77(s,1H),7.48(d,J=7.9 Hz,1H),7.32(d,J=8.1 Hz,1H),7.09-6.98(m,2H),6.95(m,1H),2.86(m,2H),2.60-2.47(m,2H),2.40(m,1H),2.19(m,1H),1.78-1.60(m,2H),1.54(m,3.5 Hz,1H),1.29(m,1H),1.06(m,1H).

[0176] Example 3: Synthesis of 3-[(3S)-piperidine-3-ylmethyl]-1H-indole (compound 103) [ka]

[0177] tert-butyl 3-{[(3S)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}indole-1-carboxylate. A mixture of tert-butyl 3-bromoindole-1-carboxylate (2.00 g, 6.75 mmol), tert-butyl(3R)-3-(bromomethyl)piperidine-1-carboxylate (2.82 g, 10.13 mmol), Mn (0.74 g, 13.5 mmol), dtbpy (0.18 g, 0.68 mmol), and Ni(OAc)2 (0.17 g, 0.68 mmol) in DMA (10 mL) and pyridine (0.1 mL) was stirred at 50°C for 4 hours under an N2 atmosphere. The resulting mixture was extracted with ELISA (3 × 500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) elution with 20% siRNA in petroleum ether to obtain the desired product as a grayish-white solid (1.65 g, 59%). LCMS 40(ESI)C 24 H 34 N2O4 calculated value: 414.25; measured value: [M+H] + :415.

[0178] 3-[(3S)-piperidine-3-ylmethyl]-1H-indole. To a 5 mL stirred solution of tert-butyl 3-{[(3S)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}indole-1-carboxylate (1.0 g, 2.41 mmol) in MeOH, HCl (12 M in water) / MeOH (v:v=1 / 2, 10 mL) was added at 0°C. The reaction mixture was stirred at room temperature under an N2 atmosphere for 4 hours and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was chromatographed (column, C). 18 The solution was purified by column chromatography (mobile phase: acetonitrile in water (0.1% FA), gradient from 2% to 30% over 20 minutes; detector: UV 200 nm). The desired product was obtained as a formate (66.3 mg of white solid, 47% yield). LCMS 40(ESI)C 14 H 18 N2 Calculated value 214.15; Measured value [M+H] + :215.20. 1H NMR(300 MHz,DMSO-d6)δ 10.87(s,1H),8.40(s,1H),7.50(d,J=8.0 Hz,1H),7.34(d,J=8.0 Hz,1H),7.12(d,J=2.3 Hz,1H),7.07(t,J=7.1 Hz,1H),6.97(t,J=7.1 Hz,1H),3.12-2.99(m,2H),2.61(d,J=7.0 Hz,2H),2.47-2.39(m,2H),2.02-1.85(m,1H),1.8-1.67(m,2H),1.5-1.43(m,1H),1.30-1.08(m,1H).

[0179] Example 4: Synthesis of 3-[(3R)-piperidine-3-ylmethyl]-1H-indazole-7-carbonitrile (compound 141) [ka]

[0180] 3-Iodo-1H-indazole-7-carbonitride. I2 (2.13 g, 8.38 mmol) was gradually added at 0°C to a stirred solution of 1H-indazole-7-carbonitride (1.00 g, 6.99 mmol) and KOH (1.18 g, 21.0 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, then quenched at 0°C with 100 mL of saturated Na2S2O3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 100 mL), and the combined organic layer was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2) eluting with PE / EA (5:1) to obtain the desired product as a pale yellow solid (1.0 g, yield 53%). LCMS 52 (Method B) (ESI) C8H4N3 Calculated value 268.94; Measured value [MH] + :270.

[0181] 3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbonitrile. 3-iodo-1H-indazole-7-carbonitrile (1.00 g, 3.72 mmol) was stirred in THF (10 mL), to which NaH (0.27 g, 11.2 mmol) was added in fractions at 0°C under an N2 atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, after which SEM-Cl (0.74 g, 4.46 mmol) was added. This reaction mixture was stirred for 30 minutes, and then quenched with water (100 mL) at 0°C. The mixture was extracted with Âx (3 × 100 mL), and the combined organic layer 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 (400 mg; yield 27%). LCMS 52 (Method B) (ESI) C14H18IN3OSi Calculated value 399.31; Measured value [MH] + :400.

[0182] A mixture of tert-butyl(3R)-3-[(7-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-3-yl)-methyl]piperidine-1-carboxylate. 3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carbonitrile (300 mg, 0.75 mmol), tert-butyl(3S)-3-(iodomethyl)piperidine-1-carboxylate (366.5 mg, 1.13 mmol), Mn (82.6 mg, 1.50 mmol), dtbpy (40.3 mg, 0.15 mmol), and Ni(OAc)2 (26.6 mg, 0.15 mmol) in DMA (10 mL) and pyridine (0.1 mL) was stirred at 50°C for 4 hours under an N2 atmosphere. The resulting reaction mixture was extracted with Depositphotos (3 × 20 mL), and the combined organic extract was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (100 mg, yield 28%). LCMS 52 (Method B) (ESI)C 25 H 38 N3O3Si calculated value: 470.27; measured value: [M+H] + :471.

[0183] 3-[(3R)-piperidine-3-ylmethyl]-1H-indazole-7-carbonitride. At room temperature, tert-butyl(3R)-3-[(7-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-3-yl)methyl]piperidine-1-carboxylate (80 mg, 0.17 mmol) was stirred in DCM (1 mL), to which TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC (column: XBridge Shield RP18 OBD Column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 26% B in 8 mins), UV 220 nm). The desired product was obtained as a white solid (9.5 mg, 22% yield). LC-MS 52 (Method B) (ESI)C 14 H 16 N4 Calculated value 240.14; Measured value [M+H] + :241.00. 1 H NMR(400 MHz,CD3OD)δ 8.12-8.07(m,1H),7.83-7.78(m,1H),7.30-7.23(m,1H),3.04-2.95(m,2H),2.91(d,J=7.2 Hz,2H),2.61-2.50(m,1H),2.44-2.32(m,1H),2.11-1.95(m,1H),1.87 -1.78(m,1H),1.74-1.65(m,1H),1.55-1.41(m,1H),1.30-1.17(m,1H).

[0184] Example 5: Synthesis of 6-fluoro-1-methyl-3-[(3S)-piperidine-3-ylmethyl]indole (compound 128) [ka]

[0185] tert-butyl(R)-3-(iodomethyl)piperidine-1-carboxylate. To a stirred solution of tert-butyl(3R)-3-(bromomethyl)piperidine-1-carboxylate (3.58 g, 12.9 mmol) in acetone (100 mL) at room temperature, NaI (1.93 g, 12.9 mmol) was added in fractional amounts. The reaction mixture was stirred at 80°C for 2 hours, then cooled to room temperature and concentrated under reduced pressure to obtain the crude product as a yellow solid (4 g; yield 96%). The crude product was used directly in the next step. LCMS 49 (Method J) (ESI)C 11 H 20 INO2 calculated value: 325.05; measured value: [M+H] + :326.

[0186] 6-Fluoro-1-methylindole. A solution of NaH (0.71 g, 29.6 mmol) in DMF (20 mL) was treated with 6-fluoro-1H-indole (2 g, 14.8 mmol) under an N2 atmosphere at 0°C for 1 hour, and then CH3I (6.30 g, 44.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred for a further 1 hour at 0°C, and then quenched with water (10 mL) at 0°C. This solution was extracted with Depositphotos (3 × 100 mL), and the combined organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA (12:1) to obtain the desired product as a colorless oil (2.1 g; yield 95%). LCMS 49 (Method J) (ESI) C9H8FN Calculated value 149.06; Measured value [M+H] + :150.

[0187] 6-Fluoro-3-iodo-1-methylindole. At room temperature, 6-fluoro-1-methylindole (2.1 g, 14.1 mmol) and KOH (2.37 g, 42.2 mmol) were stirred in DMF (20 mL), to which I2 (3.93 g, 15.5 mmol) was added in fractions. The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated sodium thiosulfate (30 mL). The resulting mixture was extracted with siRNA (3 × 100 mL), the combined organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired product was obtained by chromatography (column, C). 18 Mobile phase: MeCN aqueous solution (0.1% FA), gradient from 10% to 50% over 30 minutes; Detector: UV 254 nm) yielded as a colorless oil (3.2 g; yield 83%). LCMS 49 (Method J) (ESI) C9H7FN Calculated value 274.96; Measured value [M+H] + :276.

[0188] tert-butyl(3S)-3-[(6-fluoro-1-methylindole-3-yl)methyl]piperidine-1-carboxylate. A solution of 6-fluoro-3-iodo-1-methylindole (750 mg, 2.73 mmol), tert-butyl(3R)-3-(iodomethyl)piperidine-1-carboxylate (1.33 g, 4.09 mmol), Ni(OAc)2 (96.4 mg, 0.55 mmol), Mn (300 mg, 5.45 mmol), and dtbpy (146 mg, 0.55 mmol) in pyridine (0.5 mL) and DMA (10 mL) was stirred overnight at 50°C under an N2 atmosphere. The reaction mixture was extracted with Â(3 × 100 mL), the combined organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The desired product was obtained as a yellow oil by chromatography (SiO2) eluting with PE / EA (10:1) (560 mg; yield 59%). LCMS 49 (Method J) (ESI)C 20 H 27 FN2O2 calculated value: 346.21; measured value: [M+H] + :347.

[0189] 6-Fluoro-1-methyl-3-[(3S)-piperidine-3-ylmethyl]indole. To a stirred solution of tert-butyl(3S)-3-[(6-fluoro-1-methylindole-3-yl)methyl]piperidine-1-carboxylate (200 mg, 0.58 mmol), TFA (5 mL) was added dropwise at room temperature under an N2 atmosphere. After stirring the reaction mixture for 1 hour, the pH was adjusted to 8.0 with saturated Na2CO3. After concentration, chromatography (column, C) was performed. 18 Silica gel; mobile phase, aqueous MeCN solution (10 mmol / L NH4HCO3), 10% to 50% gradient over 30 minutes; detector, UV 254 nm) yielded the desired product as yellow oil (51.9 mg, yield 36%). LCMS 48(ESI)C 15 H 19 FN2 Calculated value: 246.15; Measured value: [M+H] + :247.25. 1 H NMR(400 MHz,CD3OD)δ 7.45(dd,J=8.7,5.3 Hz,1H),7.02(dd,J=10.2,2.3 Hz,1H),6.92(s,1H),6.81-6.76(m,1H),3.69(s,3H),3.02-2.94(m,2H),2.60-2.58(m,2H),2.56-2.49 (m,1H),2.32-2.27(m,1H),1.90-1.75(m,2H),1.72-1.63(m,1H),1.54-1.38(m,1H),1.20-1.10(m,1H).

[0190] Example 6: Synthesis of 7-methyl-3-[(3R)-piperidine-3-ylmethyl]-1H-indole (compound 129) [ka]

[0191] 3-iodo-7-methyl-1H-indole. A solution of 7-methylindole (500 mg, 3.81 mmol) in DMF (20 mL) was stirred at 0°C. KOH (0.64 g, 11.4 mmol) and I2 (1.16 g, 4.57 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then quenched at 0°C with 50 mL of saturated Na2S2O3 (aqueous solution). The resulting mixture was extracted with RINKAN (3 × 50 mL), and the combined organic layer was concentrated under reduced pressure. The desired product was obtained by chromatography (SiO2) eluting with PE / EA (10:1), and the product was obtained as a grayish-white oil (430 mg; yield 44%). LCMS 53 (Method M) (ESI) C9H8IN Calculated value 256.97; Measured value [M+H] + :258.

[0192] tert-butyl 3-iodo-7-methylindole-1-carboxylate. 3-iodo-7-methyl-1H-indole (430 mg, 1.95 mmol) and Boc2O (0.44 g, 2.33 mmol) were stirred in DCM (20 mL) at room temperature. DMAP (0.02 g, 0.20 mmol) and TEA (0.51 g, 5.84 mmol) were added. The resulting mixture was stirred for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a pink solid (530 mg, 76% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.87(s,1H),7.30-7.24(m,1H),7.20(d,J=8.4,6.7,1.6 Hz,2H),2.55-2.53(m,3H),1.60(s,9H).

[0193] A mixture of tert-butyl 3-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}-7-methylindole-1-carboxylate. The mixture consisted of tert-butyl 3-iodo-7-methylindole-1-carboxylate (530 mg, 1.48 mmol)a, tert-butyl(3S)-3-(iodomethyl)piperidine-1-carboxylate (656 mg, 2.02 mmol), Ni(OAc)2 (52.5 mg, 0.30 mmol), dtbpy (79.7 mg, 0.30 mmol), and Mn (165.2 mg, 3.00 mmol) in DMA (10 mL) and pyridine (0.1 mL). This mixture was stirred at 60°C for 4 hours under an N2 atmosphere. The mixture was extracted with ELISA (3 × 50 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (195 mg; yield 31%). LCMS 53 (Method M) (ESI)C 25 H 36 N2O4 calculated value: 428.27; measured value: [M+H] + :429.

[0194] 7-methyl-3-[(3R)-piperidine-3-ylmethyl]-1H-indole. A 150 mg, 0.35 mmol solution of tert-butyl 3-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}-7-methylindole-1-carboxylate was stirred in 2 mL of DCM at room temperature, to which 2 mL of TFA was added. The resulting mixture was stirred for 15 minutes, then adjusted to pH 10 with saturated Na₂CO₃, and concentrated under reduced pressure. Preparative HPLC (column: XBridge Shield RP18 OBD Column 30*150mm, 5m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18%B to 41%B in 7 mins; wavelength: 220 nm) yielded the desired product as a white solid (15.8 mg; yield 20%). LCMS 40(ESI)C 15 H 20 N2 Calculated value 228.16; Measured value [M+H] + :229.15. 1H NMR(400 MHz,CD3OD)δ 7.36-7.31(m,1H),6.99(s,1H),6.93-6.84(m,2H),3.05-2.95(m,2H),2 .68-2.59(m,2H),2.58-2.50(m,1H),2.46(s,3H),2.32(dd,J=12.3,10.6 Hz,1H),1.94-1.80(m,2H),1.75-1.65(m,1H),1.56-1.40(m,1H),1.24-1.09(m,1H).

[0195] Example 7: Synthesis of (3R)-3-(1-benzofuran-3-ylmethyl)piperidine (compound 105) [ka]

[0196] A mixture of tert-butyl(3R)-3-(1-benzofuran-3-ylmethyl)piperidine-1-carboxylate, 3-bromo-1-benzofuran (400.0 mg, 2.03 mmol), tert-butyl(3S)-3-(iodomethyl)piperidine-1-carboxylate (990 mg, 3.04 mmol), Mn (223 mg, 4.06 mmol), dtbpy (109 mg, 0.40 mmol), and Ni(OAc)2 (71.7 mg, 0.40 mmol) in DMA (5 mL) and pyridine (0.5 mL) was stirred overnight at 60°C under an N2 atmosphere. The mixture was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a pale yellow oil (260 mg, yield 41%). LCMS 49 (Method K) (ESI)C 19 H 25 NO3 Calculated value 315.18; Measured value [M+H] + :316.

[0197] (3R)-3-(1-benzofuran-3-ylmethyl)piperidine. To a stirred solution of tert-butyl(3R)-3-(1-benzofuran-3-ylmethyl)piperidine-1-carboxylate (200 mg, 0.63 mmol) in DCM (3 mL), TFA (1 mL) was added at room temperature. The reaction mixture was stirred for 10 minutes and then concentrated under vacuum. The crude product was basicized to pH 8 with saturated Na2CO3 aqueous solution and then purified by chromatography (column, C18; mobile phase, water in ACN (0.1% NH4HCO3), gradient from 0% to 50% over 20 minutes; UV 254 nm). The desired product was obtained as a colorless oil (45.2 mg, yield 31%). LCMS 40(ESI)C 14 H 17 NO Calculated value 215.13; Measured value [M+H] + :216.15. 1 H NMR(400 MHz,DMSO-d6)δ 7.76(s,1H),7.62(d,J=7.5 Hz,1H),7.57-7.50(m,1H),7.34-7.16(m,2H),2.94-2.80(m,2H),2.53(d,J=6.8 Hz,2H),2.42(d,J=11.7 Hz,1H),2.28-2.18(m,1H),1.76(d,J=16.7 Hz,2H),1.56(d,J=13.1 Hz,1H),1.41-1.26(m,1H),1.16-1.01(m,1H).

[0198] Example 8: Synthesis of (R)-6-fluoro-1-isopropyl-3-(piperidine-3-ylmethyl)-1H-indole (compound 112) [ka]

[0199] tert-butyl(3R)-3-[(6-fluoro-1-isopropylindole-3-yl)methyl]piperidine-1-carboxylate. A mixture of 6-fluoro-3-iodo-1-isopropylindole (300 mg, 0.99 mmol), tert-butyl(3S)-3-(bromomethyl)piperidine-1-carboxylate (550 mg, 1.97 mmol), Mn (110 mg, 2.00 mmol), Ni(OAc)2 (50.0 mg, 0.20 mmol), and dtbpy (50.0 mg, 0.18 mmol) in DMA (4 mL) and pyridine (0.1 mL) was stirred at 50°C for 4 hours under an N2 atmosphere. This mixture was extracted with  (3 × 20 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a pale yellow oil (200 mg, yield 54%). LCMS 60(ESI)C 22 H 31 FN2O2 calculated value: 374.24; measured value: [M+H] + :375.

[0200] 6-Fluoro-1-isopropyl-3-[(3R)-piperidine-3-ylmethyl]indole. At room temperature, tert-butyl(3R)-3-[(6-fluoro-1-isopropylindole-3-yl)methyl]piperidine-1-carboxylate (150 mg, 0.40 mmol) was stirred in DCM (2 mL), to which TFA (2 mL) was added dropwise. The resulting mixture was stirred for 20 minutes, then adjusted to pH 8 with saturated Na2CO3 (aqueous solution), and concentrated under reduced pressure. The residue was purified by chromatography (column, C18; mobile phase, water in ACN, 0% to 50% gradient over 30 minutes; UV 254 nm) to obtain the desired product as a pale yellow oil (41.5 mg, yield 37%). LCMS 40(ESI)C 17 H 23 FN2 Calculated value: 274.18; Measured value: [M+H] + :275.20. 1 H NMR(400 MHz,CD3OD)δ 7.45(d,J=8.6 Hz,1H),7.12-7.05(m,2H),6.78(d,J=9.6 Hz,1H),4.59(d,J=6.7 Hz,1H),3.05-2.95(m,2H),2.62-2.50(m,3H),2.33(d,J=12.3 Hz,1H),1.93-1.77(m,2H),1.70(d,J=13.2 Hz,1H),1.47(d,J=6.7 Hz,7H),1.17(d,J=13.6 Hz,1H).

[0201] Example 9: Synthesis of 7-ethyl-3-[(3R)-piperidine-3-ylmethyl]-1H-indole (compound 130) [ka]

[0202] 7-Ethyl-3-iodo-1H-indole. 7-ethyl-1H-indole (600 mg, 4.13 mmol) and KOH (696 mg, 12.4 mmol) were stirred in DMF (10 mL), to which I2 (1,258 mg, 4.96 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, and then quenched at 0°C with 50 mL of Na2S2O3 aqueous solution. The resulting mixture was extracted with Âxy (3 × 50 mL), and the combined organic extract was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a white solid (510 mg, yield 46%). LCMS 53 (Method L) (ESI)C 10 H 10 IN calculated value 270.99; measured value [M+H] + :272.

[0203] tert-butyl 7-ethyl-3-iodoindole-1-carboxylate. 7-ethyl-3-iodo-1H-indole (490 mg, 1.81 mmol) and TEA (549 mg, 5.42 mmol) were stirred in DCM (10 mL) at room temperature. Boc2O (473 mg, 2.17 mmol) and DMAP (22.1 mg, 0.18 mmol) were added. The resulting mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to obtain the desired product as a pink solid (600 mg, yield 89%). LCMS 53 (Method L) (ESI)C 15 H 18 INO2 calculated value: 371.04; measured value: [M+H-56] + :316. 1 H NMR(400 MHz,DMSO-d6)δ 7.88(s,1H),7.33-7.20(m,3H),3.08-2.98(m,2H),1.61(s,9H),1.11(t,J=7.5 Hz,3H).

[0204] A mixture of tert-butyl 3-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}-7-ethylindole-1-carboxylate. The mixture of tert-butyl 7-ethyl-3-iodoindole-1-carboxylate (600 mg, 1.62 mmol), tert-butyl(3S)-3-(iodomethyl)piperidine-1-carboxylate (788 mg, 2.42 mmol), Mn (178 mg, 3.23 mmol), dtbpy (86.8 mg, 0.32 mmol), and Ni(OAc)2 (86.8 mg, 0.32 mmol) in DMA (5 mL) and pyridine (383.6 mg, 4.85 mmol) was stirred overnight at 60°C under an N2 atmosphere. The resulting mixture was diluted with water (20 mL), extracted with ₹ (3 × 50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO₂) eluting with PE / EA (10:1) to obtain the desired product as a grayish-white oil (260 mg, yield 36%). LCMS 53 (Method L) (ESI)C 26 H 38N2O4 calculated value: 442.28; measured value: [M+H] + :443. 1 H NMR(400 MHz,CDCl3)δ 7.36-7.32(m,1H),7.29(s,1H),7.21-7.13(m,2H),4.06-3.81(m,2H),3.12(s,2H),2.87-2. 73(m,1H),2.65-2.47(m,3H),1.91-1.76(m,3H),1.64(s,10H),1.40(s,10H),1.20(t,J=7.4 Hz,3H).

[0205] 7-ethyl-3-[(3R)-piperidine-3-ylmethyl]-1H-indole. At room temperature, tert-butyl 3-{[(3R)-1-(tert-butoxycarbonyl)piperidine-3-yl]methyl}-7-ethylindole-1-carboxylate (150 mg, 0.34 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. The resulting mixture was stirred for 15 minutes and then concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC (column: XBridge Shield RP18 OBD Column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 42% B over 7 mins, UV 220 nm) to obtain the desired product as a white solid (17.7 mg, yield 21.0%). LCMS 40(ESI)C 16 H 22 N2 Calculated value 242.18; Measured value [M+H] + :243.15. 1 H NMR(400 MHz,CD3OD)δ 7.37-7.32(m,1H),6.99(s,1H),6.96-6.88(m,2H),3.10-2.99(m,2H),2.89-2.82(m,2H),2.71-2.54(m,3H),2. 40-2.32(m,1H),1.97-1.84(m,2H),1.77-1.68(m,1H),1.58-1.46(m,1H),1.34-1.29(m,3H),1.25-1.14(m,1H).

[0206] Example 10: IP1 accumulation assay

[0207] 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]

[0208] Built-in 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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 IA or formula IB: 【Chemistry 1】 or its pharmaceutically acceptable salts and / or stereoisomers, Y is -CR １０ R １１ -, -O-, -NR ａ -S-, -S(O)-, and -S(O) ２ - Selected from the group consisting of, A is selected from the group consisting of 8-10 membered condensed bicyclic heteroaryls, 8-10 membered condensed bicyclic heterocyclyls, and 6-10 membered aryls, and ring A is R Ａ It may optionally be substituted by one or more substituents selected from R Ａ is, for each occurrence independently, hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ -(CO)-OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ alkyl, -C(O)-C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ alkoxy, -C ３ ~C ６ cycloalkyl, phenyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, selected from the group consisting of; C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ alkoxy, -C ３ ~C ６ cycloalkyl, phenyl, heterocyclyl and heteroaryl are halogen, hydroxyl, -NR ａ R ｂ , -C(O)NR ａ R ｂ , C １ ~C ３ alkyl and C １ ~C ３ They may optionally be substituted by 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, -CH ２ -phenyl, -CH ２ CH ２ -phenyl and -CH ２ - Selected from the group consisting of (4-6 member heteroaryls); C １ ~C ６ Alkyl, phenyl, and heteroaryl compounds are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted by one or more substituents independently selected from the group consisting of alkoxys. R ２ and R ３ These are, independently, hydrogen, phenyl, and C. １ ~C ６ Selected from the group consisting of alkyl groups; where phenyl and 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 are each independently hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -NR ａ -C(O)-R ｂ , -NR ａ -C(O)-NR ａ R ｂ , -NR ａ -(CO)-OR ｂ , -O-C(O)-NR ａ R ｂ , -O-(CO)-C １ ~C ６ alkyl, -C(O)-C １ ~C ６ alkyl, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ alkoxy, -C ３ ~C ６ cycloalkyl and phenyl, and are optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR １ ~C[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Or, R ４ and R ５ They bond together with the carbon atoms to which they are bonded, C ３ ~C ４ Alkyl groups may be formed. R ６ and R ７ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; C １ ~C ６ Alkyls are halogens, hydroxyls, and C １ ~C ３ They may optionally be substituted by one or more substituents independently selected from the group consisting of alkoxys. R ８ and R ９ 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 １０ and R １１ These are, independently, hydrogen and C １ ~C ６ Selected from the group consisting of alkyl groups; or R １０ and R １１ Together with the carbon atoms to which they are bonded, C ３ ~C ４ A cycloalkyl group may be formed. R ａ and R ｂ For each appearance, independently, hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups, C １ ~C ３ Alkyl can optionally be substituted with one or more halogens. Compounds represented by formula IA or formula IB, or pharmaceutically acceptable salts and / or stereoisomers thereof.

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

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

4. R ８ and R ９ The compound according to claim 1 or 2, wherein the compound is hydrogen.

5. The aforementioned compound is of formula IC or formula ID: 【Chemistry 2】 The compound according to claim 1 or 2, represented by...

6. R Ａ However, for each appearance, hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , -C(O)-NR ａ R ｂ , -C １ ~C ６ Alkyl, -C ３ ~C ６ Cycloalkyl and C １ ~C ６ Independently selected from the group consisting of alkoxys, C １ ~C ６ Alkyl, -C ３ ~C ６ Cycloalkyl, and C １ ~C ６ Alkoxy compounds include halogens, hydroxyls, and C. １ ~C ３ The compound according to claim 1 or 2, which may optionally be substituted with one or more substituents independently selected from the group consisting of alkoxys.

7. A, 【Transformation 3】 and 【Chemistry 4】 Selected from the group consisting of, R ｃ is hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups, R ｄ These are halogen, hydroxyl, cyano, and -C. １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -C ３ ~C ４ Selected from the group consisting of cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, where -C １ ~C ３ Alkyls are halogens, hydroxyls, and -NH ２ , -C(O)-NH ２ and -OCH ３ It may be optionally substituted by one, two, or three substituents independently selected from the group consisting of the following: R ｅ These are hydrogen, halogens, cyano and -C １ ~C ３ Selected from the group consisting of alkyl groups, m is 0, 1, 2, or 3. The compound according to claim 1 or 2.

8. R ｃ However, hydrogen and C １ ~C ３ Selected from the group consisting of alkyl groups, R ｄ However, halogen, hydroxyl, cyano, -C １ ~C ３ Alkyl, -CH ２ OH and C １ ~C ｅ Selected from the group consisting of alkoxys, R ｅ However, hydrogen, halogens, cyano and -C １ ~C ３ Selected from the group consisting of alkyl groups, The compound according to claim 7.

9. A, 【Transformation 5】 and 【Transformation 6】 A compound according to claim 1 or 2, selected from the group consisting of the following.

10. R １０ and R １１ However, each independently, hydrogen and -CH ３ A compound according to claim 1 or 2, selected from the group consisting of the following.

11. R １０ and R １１ The compound according to claim 1 or 2, wherein each of them is hydrogen.

12. R １０ and R １１ Each of them is -CH ３ The compound according to claim 1 or 2.

13. R １０ is hydrogen, R １１ ga-CH ３ The compound according to claim 1 or 2.

14. R １ However, hydrogen, -CH ３ , 【Transformation 7】 and 【Transformation 8】 A compound according to claim 1 or 2, selected from the group consisting of the following.

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

16. 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.

17. Compounds represented by formula IIA or formula IIB: 【Chemistry 9】 or its pharmaceutically acceptable salts and / or stereoisomers, A is, 【Chemistry 10】 and 【Chemistry 11】 Selected from the group consisting of, X, Y, and Z are NR ｃ Selected from the group consisting of O and S, R ａ , R ｂ , R ｄ These are, independently, hydrogen, halogen, hydroxyl, cyano, and -C. １ ~C ３ Selected from the group consisting of alkyl groups, R ｃ is hydrogen and -C １ ~C ３ Selected from the group consisting of alkyl groups, R ｅ It is selected from the group consisting of hydrogen and halogens, R １ is hydrogen, -C １ ~C ３ Alkyl and -CH ２ - Selected from the group consisting of phenyl, where phenyl may be optionally substituted with hydroxyl, 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 ９ and R １０ These are, independently, hydrogen and -CH ３ Selected from the group consisting of, Compounds represented by formula IIA or formula IIB, or pharmaceutically acceptable salts and / or stereoisomers thereof. 【Request Item 18】 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 and 【Chemistry 13】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt and / or stereoisomer thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1, 17, and 18, and a pharmaceutically acceptable excipient.

20. 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, 17, and 18.

21. 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, 17, and 18 and a pharmaceutically acceptable excipient.

22. The method according to claim 20, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache.

23. The method according to claim 21, wherein the mental or neurological disorder or condition is selected from the group consisting of depression, anxiety, substance abuse, and headache.

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