WO2024259250A2 - Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation - Google Patents

Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation Download PDF

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WO2024259250A2
WO2024259250A2 PCT/US2024/034032 US2024034032W WO2024259250A2 WO 2024259250 A2 WO2024259250 A2 WO 2024259250A2 US 2024034032 W US2024034032 W US 2024034032W WO 2024259250 A2 WO2024259250 A2 WO 2024259250A2
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compound
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hydrogen
independently selected
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WO2024259250A3 (fr
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Paul Galatsis
Urjita H. SHAH
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Transneural Therapeutics Inc
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Transneural Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Modulators of the 5-hydroxytryptamine 2A receptor are sought after as potential pharmaceuticals for a variety of psychiatric and neurological diseases and disorders including, but not limited to, depression, anxiety, post-traumatic stress disorder, obsessive compulsive disorder, substance abuse, eating disorders, migraine headaches, and/or cluster headaches, Alzheimer’s Disease, Parkinson’s Disease, and various somatic illnesses including, but not limited to, various inflammatory, cardiovascular, and/or pain disorders.
  • 5- HT2AR modulators have been developed, few are selective for this receptor over related subtypes, for example, the 5-HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.
  • the disclosure is directed, in part, to modulators of the 5 -hydroxy tryptamine 2A (5- HT2A) receptor.
  • pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.
  • a compound represented by Formula I or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein single bond, X is CR X , and Y is C(R ⁇ )2; or double bond, X is C, and Y is C(R Y ); W is selected from the group consisting of O, and S;
  • R x and R' are each independently selected from the group consisting of hydrogen and -Ci. C3 alkyl; or R x and R Y are joined together to form -CH2-;
  • R A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R h , -Ci-Cs alkyl, -Cs-C cycloalkyl, Ci-Cg alkoxy, phenyl.
  • Ci-Cg alkyl, -C3-C6 cycloalkyl, Ci-Cg alkoxy, phenyl, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , -C(O)-NR a R b , and C1-C3 alkoxy;
  • R 1 is selected from the group consisting of hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1.C3 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -NR a R b ; -NR a -C(O)-NR a R b , -CO2H, Ci-Cg alkyl, Ci-Cg alkoxy, and phenyl; wherein Ci- Cg alkyl, Ci.Cg alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , and C1-C3 alkoxy;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl
  • R a and R b are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; and m is 0, 1, 2, or 3.
  • X is O or S
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH 3 )2, -CF 3 , -CHF 2 , -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH 2 OH, and -NH-C(O)-N(CH 2 CH 3 )2;
  • R 1 is selected from the group consisting of hydrogen, -CH3, , and m is 0, 1, 2, or 3.
  • compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise at least one additional therapeutic agent that treats, ameliorates, and/or prevents a neurological disease and/or disorder.
  • a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of any of the compounds described herein, or a pharmaceutical composition thereof.
  • the neurological disease or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.
  • a compound disclosed herein or a pharmaceutical composition thereof.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci.4alkyl, and Ci-salkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1-butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5 alkenyl, C2-C6 alkenyl, and C3-C4 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6 alkynyl, and C3-6 alkynyl, respectively.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (alkyl-O-).
  • alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5 alkoxy, Ci-Ce alkoxy, and C2-C6 alkoxy, respectively.
  • alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • aryl refers to a radical 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 in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”).
  • an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci 4 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate 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, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Examples of representative substituted aryls include the following wherein one of R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryl oxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR ?8 SOR 59 NR ⁇ SCER 59 , COO-alkyl, COO-aryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SO-alkyl, SCE-alkyl, S-aryl, SO-aryl, S
  • R 60 and R 61 are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cg-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
  • carbonyl refers to the radical -C(O)-.
  • cyano refers to the radical -CN.
  • cycloalkyl or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10 cycloalkyl, C3-6 cycloalkyl or C4-6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.
  • halo or halogen as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl radical in which the 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, di chloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.
  • haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br, and I), referred to herein as C1-6 haloalkyl, C1.4 haloalkyl, and C1-3 haloalkyl, respectively.
  • a halogen i.e., Cl, F, Br, and I
  • hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • alkyl e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • heteroaryl or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • the term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen.
  • heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.
  • heterocyclyl “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.
  • the term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc.
  • the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane).
  • the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole).
  • “Spiro heterocyclyl,” or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) m (wherein m is an integer of 0 to 2) as ring atoms.
  • hydroxy and “hydroxyl” as used herein refer to the radical -OH.
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and/or partial agonism.
  • the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may 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 pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-m
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol — denotes 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 the “Z” or “E” configuration wherein the terms “Z” and “£” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a preexisting one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • isotopically labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2- i2)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl- 1 -(alkylcarbonyl oxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl- 1 -(alkoxy carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminom ethyl having from 3 to 9 carbon atoms, l-(N-
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxymethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l-((Ci- 6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci.e)alkoxy carbonylaminomethyl, succinoyl, (Ci-6)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a- aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a- aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(0)(0
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine.
  • the disclosure is directed to, in part, to compounds that are modulators of the 5- hydroxytryptamine 2A (5-HT2A) receptor.
  • the modulators of the disclosure exhibit selective functionality for, and/or binding to, the 5-HT2A receptor over the 5- HT2B and/or 5-HT2C receptor.
  • compounds of the disclosure can be used to treat a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and/or cluster headaches.
  • a compound represented by Formula I or a pharmaceutically acceptable salt and/or a stereoisomer thereof, wherein single bond, X is CR X , and Y is C(R )2; or double bond, X is C, and Y is C(R Y );
  • W is selected from the group consisting of O, and S;
  • R x and R Y are each independently selected from the group consisting of hydrogen and -Ci- C3 alkyl; or R x and R Y are joined together to form -CH2-;
  • R A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -Ci-Cs alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl.
  • Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , -C(O)-NR a R b , and C1-C3 alkoxy;
  • R 1 is selected from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Cg alkyl, C2-C6 alkenyl, C2 G5 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -NR a R b ; -NR a -C(O)-NR a R b , -CO2H, Ci-Cg alkyl, Ci-Cg alkoxy, and phenyl; wherein Ci. Cg alkyl, Ci-Ce alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , and C1-C3 alkoxy;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl
  • R a and R b are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; and m is 0, 1, 2, or 3.
  • a compound disclosed herein is represented by, for example,
  • R A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH 3 ) 2 , -OCH 3 , -OCH2CH3, -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -0CF3, -OCHF 2 , - CH 2 OH, -CH 2 NH 2 , -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxirany
  • m is 3.
  • A is selected from the group consisting of wherein X is O or S.
  • m is 2.
  • A is selected from the group consisting of wherein X is O or S.
  • m is 1.
  • A is selected from the group consisting of wherein X is O or S.
  • R 2 and R 3 are hydrogen.
  • R 6 and R 7 are hydrogen.
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH 2 OH, and -NH-C(O)-N(CH 2 CH3) 2 .
  • R 4 is hydrogen.
  • R ? is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.
  • R 5 is hydrogen or -CH3.
  • R 1 is hydrogen. In other embodiments, R 1 is selected from the group consisting of, for example, hydrogen, -CH3,
  • X is O or S
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3) 2 , -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -0CF3, -OCHF 2 , -CH 2 OH, -CH 2 NH 2 , - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH 2 CH 3 )2;
  • R 1 is selected from the group consisting of hydrogen, -CH3, , and m is 0, 1, 2, or 3.
  • R A is independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, iodo, cyano, and -CH3.
  • m is 3.
  • m is 2.
  • m is 1.
  • R 4 is hydrogen.
  • R ? is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH.3)2.
  • R 5 is hydrogen or -CH3.
  • R 1 is hydrogen.
  • the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.
  • enantiomer of a disclosed compound this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art.
  • diastereomeric derivatives such as salts
  • the diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt).
  • a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).
  • a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.
  • disclosed compounds may also comprise one or more isotopic substitutions.
  • hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like.
  • a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.
  • Another aspect of the disclosure provides methods of treating patients suffering from a neurological disease or disorder.
  • the disclosure provides a method of treating the below medical indications comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.
  • a method of treating a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II.
  • a method of treating a neurological disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I or Formula II, and a pharmaceutically acceptable excipient.
  • Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.
  • the methods described herein may include treating an anxiety disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.
  • the methods described herein may include treating a trauma and/or stress disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a disorder may be post-traumatic stress disorder.
  • such a disorder may be an adjustment disorder.
  • the methods described herein may include treating obsessive compulsive disorder, for example, body dysmorphic disorder, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the methods described herein may include treating an eating disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.
  • the methods described herein may include treating a sleep-wake disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a sleep-wake disorder for example, insomnia
  • the methods described herein may include treating substance-related disorders and/or addictive disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • a disorder may be alcohol use disorder.
  • such a disorder may be opioid use disorder.
  • such a disorder may be tobacco use disorder.
  • a compound disclosed herein may be useful in facilitating smoking cessation.
  • the methods described herein may include treating a personality disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the methods described herein may include treating an autism spectrum disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the methods described herein may include treating a bipolar disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the bipolar disorder may be bipolar I disorder.
  • the bipolar disorder may be bipolar II disorder.
  • the methods described herein may include treating a pain disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.
  • the pain disorder may be neuropathic pain.
  • the pain disorder may be migraine.
  • the pain disorder may be cluster headache.
  • the pain disorder may be trigeminal neuralgia.
  • the pain disorder may be cancer pain.
  • the pain disorder may be regional pain disorder.
  • the pain disorder may be phantom limb pain.
  • a contemplated pain disorder may be a chronic pain.
  • a compound disclosed herein may exhibit anxiolytic, anti -depressive, and anti-drug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions.
  • a contemplated (5-HT2A) receptor modulator of the present disclosure may confer anti-depressant like activities without incurring psychedelic drug-like actions.
  • a compound disclosed herein may be safe an effective for use in a method described herein yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin.
  • This disclosure also provides a method of selectively modulating the 5- hydroxytryptamine 2A (5-HT2A) receptor.
  • the method includes administering to a patient a compound disclosed herein, e.g., a compound of Formula I or Formula II, a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein the compound selectively modulates the 5- HT2A over the 5-HT2B and/or 5-HT2C receptor.
  • the method of selectively modulating the 5- HT2A receptor can be used to treat, ameliorate, and/or prevent diseases or disorders that are affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.
  • the method provides, for example, reduced side effects such as, but not limited to, drug-induced valvular heart disease associated with modulating the 5-HT2B receptor.
  • a method described herein further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder, or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.
  • Contemplated patients include not only humans, but other animals such as companion animals (e.g., dogs, cats), domestic animals (e.g., cow, swine), and wild animals (e.g., monkeys, bats, snakes).
  • companion animals e.g., dogs, cats
  • domestic animals e.g., cow, swine
  • wild animals e.g., monkeys, bats, snakes.
  • Compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein.
  • contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic.
  • a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
  • a disclosed compound and one additional therapeutic agent is administered.
  • a disclosed compound as defined herein and two additional therapeutic agents are administered.
  • a disclosed compound as defined herein and three additional therapeutic agents are administered.
  • Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.
  • a disclosed compound and an additional therapeutic agent can be formulated and administered separately.
  • Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents.
  • a disclosed compound and an additional therapeutic agent can be administered in a single formulation.
  • Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y- Y, etc.
  • the methods described herein include administering to the patient a therapeutically effective amount of at least one compound of Formula I or Formula II, as described herein, which is optionally formulated in a pharmaceutical composition.
  • a therapeutically effective amount of at least one compound described herein, e.g., a compound of Formula I or Formula II, present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition.
  • the method further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.
  • the methods described herein can include administering to the patient one or more additional therapeutic agents in combination with a compound disclosed herein.
  • the one or more additional therapeutics agents that may be administered in combination with a compound disclosed herein may be a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the selective serotonin reuptake inhibitor may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram, and escitalopram.
  • the one or more additional therapeutics agents may be a serotonin and norepinephrine reuptake inhibitor (SNRI).
  • the serotonin and norepinephrine reuptake inhibitor may be selected from the group consisting of, e.g., duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran.
  • the one or more additional therapeutics agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, vilazodone and bupropion.
  • the one or more additional therapeutics agents may be a tricyclic antidepressant.
  • the tricyclic antidepressant may be selected from the group consisting of, e.g., imipramine, nortriptyline, amitriptyline, doxepin and desipramine.
  • the one or more additional therapeutics agents may be a monoamine oxidase inhibitor (MAOI).
  • MAOI monoamine oxidase inhibitor
  • the monoamine oxidase inhibitor may be selected from the group consisting of, e.g., tranylcypromine, phenelzine and isocarboxazid.
  • the one or more additional therapeutics agents may be, for example, a lithium compound, e.g., a lithium salt, e.g., lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate.
  • the one or more additional therapeutics agents may be, for example, ketamine or esketamine.
  • the one or more additional therapeutics agents may be, for example, dextromethorphan.
  • the one or more additional therapeutics agents may be, for example, D-methadone.
  • administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and/or preventing a neurological disease or disorder or in treating, ameliorating, and/or preventing a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor in the patient.
  • the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.
  • the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or Formula II.
  • a compound described herein e.g., a compound of Formula I or Formula II.
  • compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e ., 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 on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens®, Pluronics®, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • non-ionic surfactants Teweens®, Pluronics®, or polyethylene glycol
  • innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • enteral pharmaceutical formulations including a disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate- methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resin
  • kits for use by, e.g., a consumer in need of treatment of a disease or disorder described herein.
  • kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be 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 being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • S' is a single bond, X is CR X , and Y is C(R Y )2; or
  • S' is a double bond, X is C, and Y is C(R Y );
  • W is selected from the group consisting of O, and S;
  • R x and R y are each independently selected from the group consisting of hydrogen and -Ci- C3 alkyl; or R x and R Y are joined together to form -CH2-;
  • R A is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , -C(O)-NR a R b , -Ci-Cg alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl.
  • Ci-Ce alkyl, -C3-C6 cycloalkyl, Ci-Ce alkoxy, phenyl, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , -C(O)-NR a R b , and C1-C3 alkoxy;
  • R 1 is selected from the group consisting of hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C6 cycloalkyl, -CH2-phenyl, -CFE-CEb-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3- Cg cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3 alkoxy;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci- Cg alkyl; wherein Ci-Cg alkyl, may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1.C3 alkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -NR a R b ; -NR a -C(O)-NR a R b , -CO2H, Ci-Ce alkyl, Ci-Ce alkoxy, and phenyl; wherein Ci.
  • Ci-Ce alkoxy and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NR a R b , and C1-C3 alkoxy;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and Ci- Ce alkyl
  • R a and R b are each independently selected from the group consisting of hydrogen and Ci- G> alkyl; and m is 0, 1, 2, or 3.
  • E3 The compound of El or E2, wherein R A is independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH 3 ) 2 , -OCH 3 , -OCH2CH3, -OCH2CH2CH3, -OCH(CH 3 ) 2 , -CF 3 , - CHF 2 , -OCF3, -0CHF2, -CH2OH, -CH2NH2, -CH 2 C(O)NH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 NH 2 , cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl
  • E4 The compound of any one of E1-E3, wherein R A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3
  • E5. The compound of any one of E1-E4, wherein m is 3.
  • E6 The compound of any one of E1-E5, wherein A is selected from the group consisting of wherein X is O or S.
  • E7 The compound of any one of E1-E4, wherein m is 2.
  • E8 The compound of any one of E1-E4 and E7, wherein A is selected from the group consisting of wherein X is O or S.
  • E10 The compound of any one of E1-E4 and E9, wherein A is selected from the group consisting of wherein X is O or S.
  • El l The compound of any one of El -El 0, wherein R 2 and R 3 are hydrogen.
  • E12 The compound of any one ofEl-El 1 , wherein R 6 and R 7 are hydrogen.
  • E13 The compound of any one of El -El 2, wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)- N(CH 2 CH 3 ) 2
  • E14 The compound of any one of E1-E13, wherein R 4 is hydrogen.
  • E15 The compound of any one of E1-E14, wherein R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH 2 OH, and -NH-C(O)-N(CH 2 CH3) 2 .
  • E16 The compound of any one of E1-E15, wherein R 5 is hydrogen or -CH 3
  • E17 The compound of any one of E1-E16, wherein R 1 is selected from the group consisting of hydrogen,
  • X is O or S
  • R A is independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH 3 ) 2 , -CF 3 , -CHF 2 , -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazoly
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxyl, -CH 3 , -CH 2 OH, and -NH-C(O)-N(CH 2 CH3) 2 ;
  • R 1 is selected from the group consisting of hydrogen, -CH3, , and m is 0, 1, 2, or 3.
  • E20 The compound of E19, wherein R A is independently selected for each occurrence from the group consisting of fluoro, chloro, iodo, cyano, and -CH3.
  • E22 The compound of E19 or E20, wherein m is 2.
  • E24 The compound of any one of E1-E23, wherein R 4 is hydrogen.
  • E25 The compound of any one of E1-E24, wherein R 5 is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, and -NH-C(O)-N(CH2CH3)2.
  • E26 The compound of any one of E1-E25, wherein R 5 is hydrogen or -CH3
  • E27 The compound of any one of E1-E26, wherein R 1 is hydrogen.
  • E29 A pharmaceutical composition comprising a compound of any one of E1-E28 and a pharmaceutically acceptable excipient.
  • E30 A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of E1-E28.
  • E31 A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of E1-E28 and a pharmaceutically acceptable excipient.
  • E32 The method of E30 or E31, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.
  • tert-butyl 3-(7-cyano-l,2-benzothiazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate A solution of 3-chloro-l, 2-benzothiazole-7-carbonitrile (300.0 mg, 1.54 mmol), Pd(dppf)C12.CH2C12 (62.8 mg, 0.08 mmol), K2CO3 (639.1 mg, 4.62 mmol), and tert-butyl 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-27/-pyridine-l-carboxylate (714.9 mg, 2.31 mmol) in dioxane (2.0 mL) and H2O (1.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere.
  • CD 3 OD 5 8.59 - 8.52 (m, 1H), 8.07 - 8.01 (m, 1H), 7.71 - 7.63 (m, 1H), 6.73 - 6.66 (tn, 1H), 3.94 - 3.83 (m, 2H), 3.10 - 3.01 (m, 2H), 2.50 - 2.39 (m, 2H).
  • the crude product (55.8 mg) was purified by Prep-HPLC with the following conditions, Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: lOmmol/L NH4HC03+0.05%NH3H20, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 5% B to 5% B in 1 min, 5% B to 30% B in 2 min, 30% to 45% B in 10 min; Wave Length: 254nm/220nm nm; RTl(min): 7.4. to afford the desired product as a white solid (29.1 mg, 41.7% yield).
  • the mixture was neutralized to pH 7 with saturated Na2CO3 (aq.).
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 1.5 min, 5% B to 25% B in 2 min, 25% B to 43% B in 9 min; Wave Length: 254 nm/220 nm nm; RTl(min): 9.2) to afford the desired product as a white solid (13.6 mg, 12.6% yield).
  • tert-Butyl 3-(2,4-difluorobenzoyl)-4-oxopiperidine-l-carboxylate To a stirred solution of LiHMDS (210.7 mL, 1 M in THF) in THF (400 mL) was added tert-butyl 4- oxopiperidine-1 -carboxylate (40.00 g, 200.75 mmol) dropwise at 0 °C and stirred for 20 min at 0 °C under an N2 atmosphere. To the above mixture was added 2,4-difluorobenzoyl chloride (37.21 g, 210.78 mmol) dropwise at 0 °C and stirred for 30 min at 0 °C.
  • IP1 inositol monophosphate
  • HTRF Homogeneous Time Resolved Fluorescence
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés, par exemple, des composés de formule I, et leur utilisation dans le traitement de maladies ou de troubles médicaux, tels que des troubles psychiatriques et neurologiques. L'invention concerne des compositions pharmaceutiques et des procédés de fabrication de divers composés de benzisoxazole et de benzoisothiazole. Les composés sont envisagés pour être des modulateurs du récepteur de la 5-hydroxytryptamine 2A (5-HT2A).
PCT/US2024/034032 2023-06-16 2024-06-14 Modulateurs du récepteur 5-ht2a et leurs procédés d'utilisation Pending WO2024259250A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352811A (en) * 1981-11-12 1982-10-05 Hoechst-Roussel Pharmaceuticals Inc. 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles
US5140029A (en) * 1989-01-09 1992-08-18 Janssen Pharmaceutica N.V. 2-aminopyrimidinone derivatives
TWI357408B (en) * 2003-03-26 2012-02-01 Mitsubishi Tanabe Pharma Corp 3-substituted-4-pyrimidone derivatives
US20200262916A1 (en) * 2019-02-15 2020-08-20 Stc. Unm Mammalian Atg8 Proteins Control Autolysosomal Biogenesis Through SNARES
EP4466266A1 (fr) * 2022-01-19 2024-11-27 Transneural Therapeutics, Inc. Hétérocycles fusionnés utilisés en tant qu'agonistes du récepteur 5-ht2a

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