CHYTIL MILAN (US)
| WO1995029907A1 | 1995-11-09 | |||
| WO2022170268A1 | 2022-08-11 |
| JP2017100953A | 2017-06-08 |
| CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein: - one of A, B and D is NR5 and the remaining two of A, B and D are CH2; - X is O or S(=O)x; - x is 0, 1, or 2; - each of R1, R2, R3 and R4 is independently hydrogen, halogen, -ORa, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl, wherein each alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl is optionally substituted; or any of R1 and R2, R2 and R3, or R3 and R4 are taken together with the carbon atoms to which they are attached to form an optionally substituted 5- or 6-membered ring; - R5 is hydrogen, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted; and - Ra is hydrogen, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, or heterocycloalkyl is optionally substituted; provided that when R5 is hydrogen or methyl, then at least one of R2-R4 is not hydrogen; when X is O or S, A and D are each CH2, B is NR5 wherein R5 is hydrogen or C1-C3 alkyl, and R2-R4 are each hydrogen, then R1 is not hydrogen, bromo, or methoxy; when X is O, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R1, R3, and R4 are each hydrogen, then R2 is not hydrogen, hydroxyl, fluoro, bromo, or methoxy; when X is O, R5 is -C(O)CF3, and R1, R3, and R4 are each hydrogen, then R2 is not hydrogen, hydroxy, fluoro, or bromo; when X is S, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R1, R3, and R4 are each hydrogen, then R2 is not hydrogen, hydroxyl, methoxy, fluoro, or trifluoromethyl; when X is O, B and D are each CH2, A is NR5 wherein R5 is hydrogen or methyl, and R1, R3, and R4 are each hydrogen, then R2 is not hydrogen, hydroxyl, or fluoro; when X is O, A and B are each CH2, D is NR5 wherein R5 is hydrogen or methyl, and R1, R3, and R4 are each hydrogen, then R2 is not hydrogen, hydroxyl, or methoxy; when X is O or S, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R2, and R4 are each hydrogen, then R1 and R3 are not hydroxyl or fluoro; when X is O, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R1, R2, and R4 are each hydrogen, then R3 is not hydrogen, bromo, or methoxy; when X is S, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R1, R2, and R4 are each hydrogen, then R3 is not hydrogen, fluoro, hydroxyl, or methoxy; and when X is O, A and D are each CH2, B is NR5 wherein R5 is hydrogen or methyl, and R1, R2, and R3 are each hydrogen, then R4 is not hydrogen, bromo, or methoxy. 2. The compound of claim 1, wherein X is O. 3. The compound of claim 1, wherein X is S. 4. The compound of claim 1, wherein X is S(=O). 5. The compound of claim 1, wherein X is S(=O)2. 6. The compound of claim 1, wherein A and D are each CH2 and B is NR5, and wherein the compound of Formula (I) has the structure of Formula (IA): or a pharmaceutically acceptable salt or solvate thereof. 7. The compound of claim 1, wherein A is NR5 and B and D are each CH2, and wherein the compound of Formula (I) has the structure of Formula (IB): or a pharmaceutically acceptable salt or solvate thereof. 8. The compound of claim 1, wherein D is NR5 and A and B are each CH2, and wherein the compound of Formula (I) has the structure of Formula (IC): or a pharmaceutically acceptable salt or solvate thereof. 9. The compound of claim 1, wherein A and D are each CH2, B is NR5 and X is O, and wherein the compound of Formula (I) has the structure of Formula (IIA): or a pharmaceutically acceptable salt or solvate thereof. 10. The compound of claim 1, wherein A is NR5, B and D are each CH2 and X is O, and the compound of Formula (I) has the structure of Formula (IIB): or a pharmaceutically acceptable salt or solvate thereof. 11. The compound of claim 1, wherein D is NR5, A and B are each CH2 and X is O, and wherein the compound of Formula (I) has the structure of Formula (IIC): or a pharmaceutically acceptable salt or solvate thereof. 12. The compound of claim 1, wherein A and D are each CH2, B is NR5 and X is S, and wherein the compound of Formula (I) has the structure of Formula (IIIA): or a pharmaceutically acceptable salt or solvate thereof. 13. The compound of claim 1, wherein A is NR5, B and D are each CH2 and X is S, and the compound of Formula (I) has the structure of Formula (IIIB): or a pharmaceutically acceptable salt or solvate thereof. 14. The compound of claim 1, wherein D is NR5, A and B are each CH2 and X is S, and wherein the compound of Formula (I) has the structure of Formula (IIIC): or a pharmaceutically acceptable salt or solvate thereof. 15. The compound of any one of claims 1-14, wherein each of R1, R2, R3 and R4 is independently hydrogen, halogen, -ORa, or haloalkyl. 16. The compound of any one of claims 1-14, wherein each of R1, R2, R3 and R4 is hydrogen. 17. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is halogen. 18. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is haloalkyl. 19. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is haloalkyl. 20. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is arylalkyl. 21. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is alkyl. 22. The compound of any one of claims 1-14, wherein at least one of R1, R2, R3 and R4 is hydrogen, benzyloxy, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 23. The compound of any one of claims 1-22, wherein R5 is alkyl, haloalkyl, or cycloalkyl, each of which is optionally substituted. 24. The compound of any one of claims 1-23, wherein R5 is methyl. 25. The compound of any one of claims 1-23, wherein R5 is cyclobutyl. 26. The compound of any one of claims 1-23, wherein R5 is -CH2CF3. 27. The compound of claim 1, wherein - X is O; - A is CH2; - B is NR5; - D is CH2; - each of R1, R2, R3 and R4 is independently hydrogen, halogen, -ORa, or haloalkyl; and - R5 is alkyl, haloalkyl, or cycloalkyl, each of which is optionally substituted. 28. The compound of claim 1, wherein - X is O; - A is NR5; - B is CH2; - D is CH2; - each of R1, R2, R3 and R4 is independently hydrogen, halogen, -ORa, or haloalkyl; and - R5 is alkyl, haloalkyl, or cycloalkyl, each of which is optionally substituted. 29. The compound of claim 1, wherein - X is O; - A is CH2; - B is CH2; - D is NR5; - each of R1, R2, R3 and R4 is independently hydrogen, halogen, -ORa, or haloalkyl; and - R5 is alkyl, haloalkyl, or cycloalkyl, each of which is optionally substituted. 30. The compound of any one of claims 27-29, wherein each of R1, R2, R3 and R4 is hydrogen. 31. The compound of any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is halogen. 32. The compound of claim any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is haloalkyl. 33. The compound of claim any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is haloalkyl. 34. The compound of claim any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is arylalkyl. 35. The compound of claim any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is alkyl. 36. The compound of claim any one of claims 27-29, wherein at least one of R1, R2, R3 and R4 is hydrogen, benzyloxy, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 37. The compound of any one of claims 27-36, wherein R5 is methyl. 38. The compound of any one of claims 27-36, wherein R5 is cyclobutyl. 39. The compound of any one of claims 27-36, wherein R5 is -CH2CF3. 40. The compound of claim 1, wherein - X is O; - A is CH2; - B is NR5; - D is CH2; - R5 is C1-C3 alkyl; - R1 is hydrogen, halogen, alkyl, heteroalkyl, aryl, arylalkyl, arylalkoxy, aryloxy, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl, wherein each alkyl, heteroalkyl, aryl, arylalkyl, arylalkoxy, aryloxy, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl is optionally substituted; and - each of R2, R3 and R4 is independently hydrogen, halogen, -ORa, alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl, wherein each alkyl, heteroalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or cycloalkyl is optionally substituted. 41. The compound of claim 40, wherein or a pharmaceutically acceptable salt or solvate thereof, wherein each of R1, R2, R3 and R4 is hydrogen. 42. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R3 and R4 is halogen. 43. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R3 and R4 is haloalkyl. 44. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is haloalkyl. 45. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R3 and R4 is ORa, wherein Ra is arylalkyl. 46. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R2, R3 and R4 is ORa, wherein Ra is alkyl. 47. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, benzyloxy, fluoro, trifluoromethyl, or trifluoromethoxy. 48. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, benzyloxy, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 49. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, benzyloxy, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 50. The compound of claim 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, benzyloxy, methoxy, fluoro, trifluoromethyl, or trifluoromethoxy. 51. A compound that is: or a pharmaceutically acceptable salt or solvate thereof. 52. A compound that is: or a pharmaceutically acceptable salt or solvate thereof. 53. A compound that is: or a pharmaceutically acceptable salt or solvate thereof. 54. A pharmaceutical composition comprising a compound of any one of claims 1-53, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. 55. A method of promoting neuronal growth in a mammal comprising administering to the mammal a compound of any one of claims 1-53, or any pharmaceutically acceptable salt or solvate thereof. 56. A method of improving neuronal structure in a mammal comprising administering to the mammal a compound of any one of claims 1-53, or any pharmaceutically acceptable salt or solvate thereof. 57. A method of modulating the activity of 5-hydroxytryptamine receptor 2A (5-HT2A) receptor in a mammal comprising administering to the mammal a compound of any one of claims 1- 53, or any pharmaceutically acceptable salt or solvate thereof. 58. A method of treating a disease or disorder in a mammal that is mediated by the action of 5- hydroxytryptamine (5-HT) at 5-hydroxytryptamine receptor 2A (5-HT2A) comprising administering to the mammal a compound of any one of claims 1-53, or any pharmaceutically acceptable salt or solvate thereof. 59. A method of treating a disease or disorder in a mammal that is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering to the mammal a compound of any one of claims 1-53, or any pharmaceutically acceptable salt or solvate thereof. 60. A method for treating a neurological disease or disorder in a mammal, the method comprising administering to the mammal a compound of any one of claims 1-53, or any pharmaceutically acceptable salt or solvate thereof. 61. The method of claim 60, wherein the neurological disease or disorder is a neurodegenerative, a neuropsychiatric, or a substance use disease or disorder. 62. The method of claim 60, wherein the neurological disease or disorder is an injury. 63. The method of claim 60, wherein the neurological disease or disorder is selected from the group consisting of an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, and a factitious disorder. 64. The method of any one of claims 55-63, wherein the mammal is a human. |
or a pharmaceutically acceptable salt or solvate thereof. [00133] In some embodiments, representative compounds of Formula (I) include, but are not limited to:
or a pharmaceutically acceptable salt or solvate thereof. [00134] In some embodiments, representative compounds of Formula (I) include, but are not limited to:
or a pharmaceutically acceptable salt or solvate thereof. [00135] Provided in some embodiments herein is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer, having a structure provided in Table 1.
Table 1
[00136] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. Further Forms of Compounds [00137] In some embodiments, compounds described herein (e.g., a compound of Formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), or (IIIC)) are in the form of pharmaceutically acceptable salts. In some embodiments, any compound provided herein is a pharmaceutically acceptable salt, such as, for example, any salt described herein (such as, e.g., a fumarate salt of the compound provided herein or maleate salt of the compound provided herein). In some embodiments, any compound provided herein is a fumarate salt of the compound provided herein. In some embodiments, any compound provided herein is a maleate salt of the compound provided herein. [00138] As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00139] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, with an acid. In some embodiments, the compound of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. [00140] In some embodiments, the compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, (i.e. free base form) is basic and is reacted with maleic acid. [00141] In some embodiments, the compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, (i.e. free base form) is basic and is reacted with fumaric acid. [00142] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, with a base. In some embodiments, the compound of represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, is acidic and is reacted with a base. In such situations, an acidic proton of the compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. [00143] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. [00144] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, as well as active metabolites of these compounds having the same type of activity. [00145] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group. [00146] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00147] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact 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. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P and 33 P. In some embodiments, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. In some embodiments, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens of the compounds of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, are replaced with deuterium. [00148] In some embodiments, a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, exists in the R configuration. In some embodiments, a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. [00149] In some embodiments, a composition provided herein comprises a racemic mixture of a compound represented by a structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1. In some embodiments, a compound provided herein is a racemate of a compound represented by a structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1. [00150] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, is prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. [00151] In some embodiments, compounds described herein are prepared as prodrugs. In some embodiments, a prodrug is an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. [00152] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs. [00153] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1, as set forth herein are included within the scope of the claims. [00154] In some embodiments, any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above. [00155] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect. [00156] In some embodiments, a metabolite of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. In some embodiments, an “active metabolite” of a compound provided herein is a biologically active derivative of the compound provided herein that is formed when the compound is metabolized. In some embodiments, metabolism is the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. In some embodiments, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. In some embodiments, a metabolite of a compound disclosed herein is optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Synthesis of Compounds [00157] Compounds of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or compounds of Table 1, described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. [00158] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. [00159] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6 th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. [00160] In some embodiments, compounds described herein are synthesized as outlined in the Examples. Pharmaceutical compositions [00161] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound having a structure represented by formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1), and a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient. [00162] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00163] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ. [00164] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste. [00165] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses. [00166] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00167] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [00168] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Methods of Treatment, Dosing and Treatment Regimens [00169] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for promoting neuronal growth and/or improving neuronal structure. [00170] Provided herein are non-hallucinogenic psychoplastogens that useful for treating one or more diseases or disorders associated with loss of synaptic connectivity and/or plasticity. [00171] In some embodiments, provided herein is a method of promoting neural plasticity (e.g., cortical structural plasticity) in an individual by administering a compound described herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1), to the individual. In some embodiments, provided herein are methods of modulating 5-HT 2A in an individual by administering a compound described herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1), to the individual. In some embodiments, provided herein are methods of agonizing 5-HT 2A in an individual by administering a compound described herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1), to the individual. In some embodiments, the individual has or is diagnosed with a brain disorder or other conditions described herein. [00172] In some embodiments, provided herein is a method of promoting neuronal growth in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00173] In some embodiments, provided herein is a method of improving neuronal structure in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00174] In some embodiments, provided herein is a method of modulating the activity of 5- hydroxytryptamine receptor 2A (5-HT 2A ) receptor in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00175] In some embodiments, provided herein is a method of treating a disease or disorder in an individual in need thereof that is mediated by the action of 5-hydroxytryptamine (5-HT) at 5- hydroxytryptamine receptor 2A (5-HT 2A ), comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00176] In some embodiments, provided herein is a method of treating a disease or disorder in an individual in need thereof that is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00177] In some embodiments, provided herein is a method of treating a neurological disease or disorder in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1). [00178] In some embodiments, an individual administered a compound provided herein has a hallucinogenic event. In some embodiments, an individual administered a compound provided herein does not have a hallucinogenic event. In some embodiments, an individual administered a compound provided herein has a hallucinogenic event after the compound provided herein reaches a particular maximum concentration (C max ) in the individual. In some embodiments, the particular maximum concentration (C max ) in the individual is the hallucinogenic threshold of the compound provided herein. In some embodiments, a compound provided herein is administered to an individual in need thereof below the hallucinogenic threshold of the compound provided herein. [00179] In some embodiments, described herein are methods for treating a disease or disorder, wherein the disease or disorder is a neurological diseases and disorder. [00180] In some embodiments, a compound of the present disclosure is used to treat neurological diseases. In some embodiments, a compound provided herein has, for example, anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. [00181] In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia. [00182] In some embodiments, a compound disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, is useful for the modulation of a 5-hydroxytryptamine (5-HT) receptor. In some embodiments, the 5-HT receptor modulated by the compounds and methods is 5- hydroxytryptamine receptor 2A (5-HT 2A ). [00183] Provided in some embodiments herein are modulators of 5-hydroxytryptamine receptor 2A (5-HT 2A ) that are useful for treating one or more diseases or disorders associated with 5-HT 2A activity. [00184] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from inhibition or reduction of 5-HT 2A activity. [00185] In some embodiments, a compound described herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from promoting neuronal growth and/or improving neuronal structure. [00186] Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein (e.g., a compound represented by the structure of formula (I), (IA), (IB), (IC), (I`), (I``), (I```), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), or a compound of Table 1) or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal. [00187] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a mammal already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the mammal’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [00188] In prophylactic applications, compositions containing the compounds described herein are administered to a mammal susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the mammal’s state of health, weight, and the like. When used in mammals, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the mammal’s health status and response to the drugs, and the judgment of a healthcare professional. In some embodiments, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition. [00189] In certain embodiments wherein the mammal’s condition does not improve, upon the discretion of a healthcare professional the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the mammal’s life in order to ameliorate or otherwise control or limit the symptoms of the mammal’s disease or condition. [00190] In certain embodiments wherein a mammal’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. [00191] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the mammal requires intermittent treatment on a long-term basis upon any recurrence of symptoms. [00192] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [00193] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [00194] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [00195] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and ED 50 . The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 . In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. [00196] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal. [00197] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day. [00198] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. [00199] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00200] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [00201] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some embodiments, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein. EXAMPLES [00202] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. General [00203] All reagents are obtained commercially and used without purification unless otherwise noted. DMSO is purified by passage under 12 psi N2 through activated alumina columns. Reactions are performed using glassware that is flame-dried under reduced pressure (~1 Torr). Compounds purified by chromatography are adsorbed to the silica gel before loading. Thin layer chromatography is performed on Millipore silica gel 60 F254 Silica Gel plates. Visualization of the developed chromatogram is accomplished by fluorescence quenching or by staining with ninhydrin or aqueous ceric ammonium molybdate (CAM). [00204] Nuclear magnetic resonance (NMR) spectra are acquired on either a Bruker 400 operating at 400 and 100 MHz, a Varian 400 operating at 400 and 100 MHz, or a Varian 500 operating at 500 and 125 MHz for 1 H and 13 C, respectively, and are referenced internally according to residual solvent signals. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), and integration. Data for 13 C NMR are reported in terms of chemical shift (δ, ppm). Liquid chromatography-mass spectrometry (LC-MS) is performed using a Agilent LC-MS with Ion Trap or ELSD detector, or a Waters LC-MS with an UPLC detector. [00205] General HPCL conditions: HPLC separation method: Chiral HPLC Column Chiralpak IG 30mm ID x 250mm L 5µ Mobile Phase A 0.1%DEA in n –HEXANE Mobile Phase B DCM:MEOH (1:1) Flow rate 35.0 mL/min Chemistry General synthetic scheme for benzofurans: [00206] In some embodiments, benzofuran compounds provided herein are prepared as outlined in Scheme 1.
Scheme 1 [00207] In Scheme 1, R 1 -R 5 are as defined herein. R and R’ are each independently hydrogen, alkyl, or R and R’ are taken together to form a cycloalkyl ring. The leaving group X can be, by way of example, a halogen, a sulfonate (OSO2)R’’ wherein R’’ is alkyl or aryl, e.g., OMs (mesylate), OTs (tosylate), imidazole, phenoxy or a substituted phenoxy (e.g., nitrophenoxy, C 6 F 5 O), and the like. [00208] Representative procedure 1: Preparation of intermediate I-3: [00209] To a stirred solution of commercially available intermediate I-1 (1.0 eq) in 1,2- dichloroethane (0.2M) were added freshly pre-activated 4A molecular sieves (250 mg/mmol) followed by commercially available intermediate I-2 (2.0 eq) and Copper (I) chloride (1.0 eq) at room temperature. To this reaction mixture was added pyridine (1.1 eq) and the reaction mixture was stirred for 24 hours while exposed to ambient atmosphere. Solids were removed by filtration, the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with a brine solution, the combined organic layer was dried over anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was concentrated in vacuo to provide a crude reaction residue that was purified by silica gel chromatography (30% EtOAc in hexane) to afford intermediate I-3. [00210] Representative procedure 2: Preparation of intermediate I-4 [00211] To a stirred solution of intermediate I-3 (1.0 eq) in a mixture of 10% MeOH in CHCl 3 (0.1M) was added hydrazine monohydrate (3.0 eq) at 0°C, the reaction mixture was allowed to slowly warm to room temperature and stirred for 16 hours. Solids were removed by filtration, the filtrate was diluted with water and extracted with CH 2 Cl 2 . The combined organic layers were washed with a brine solution, the combined organic layer was dried over anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was concentrated in vacuo to provide a crude reaction product that was purified by silica gel chromatography (10% EtOAc in hexane) to afford intermediate I-4. [00212] Representative procedure 3: Preparation of compounds A and B: [00213] To a stirred solution of intermediate I-4 (1.0 eq) in EtOH (0.1M) were added intermediate I-5 (1.0 eq) followed by HCl (6.0 eq, 37% aqueous solution) and the resulting reaction mixture was heated under reflux for 24 hours. The reaction mixture was concentrated in vacuo and the crude residue was diluted with CH 2 Cl 2 , basified with NaOH (1M aqueous solution) and extracted with 10% MeOH in CH 2 Cl 2 . The combined organic layers were washed with a brine solution, the combined organic layer was dried over anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was concentrated in vacuo to provide a crude reaction product as a mixture of regioisomers that were separated by multiple chiral preparative HPLC runs to afford regioisomers A and B. Chemical structures of each regioisomer were determined by 2D-NMR spectroscopy techniques. [00214] Representative procedure 4: Preparation of substituted N-alkyl-benzofurans and N- cycloalkyl-benzofurans C, D: [00215] To a stirred solution of compound A (1.0 eq) in a mixture of MeOH/THF (1:1, 10 vol, for reactions with aldehyde using NaCNBH 3 ) or CH 2 Cl 2 (10 vol, for reactions with ketone using STAB) was added a carbonyl starting material (2.0 eq) (e.g., paraformaldehyde, cyclobutanone, or the like) at room temperature and the reaction mixture was stirred for 0.5 to 2h (e.g., 1 hour). The reaction mixture was cooled to 0°C and NaCNBH 3 (2 equiv, for aldehydes) or STAB (4 equiv, for ketones) was added portion-wise. The reaction mixture was allowed to slowly warm to room temperature and stirred for additional 16 hours. Volatiles were removed in vacuo, the crude reaction residue was washed with water and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl. The separated organic layer was dried over anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was concentrated in vacuo to provide a crude residue that was purified by silica gel chromatography to afford compound C. The regioisomeric compound D was prepared using the same procedure but using the corresponding compound B as the starting material. [00216] Representative procedure 5: Preparation of compounds E, F [00217] To a stirred solution of substituted compound A (1.0 eq) in CH 2 Cl 2 (20 vol) were added Et3N (2.0 eq) followed by CF 3 CH 2 OTf (1.5 eq) at room temperature and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with water (2 mL) and extracted with CH 2 Cl 2 (2 X 2 mL). The combined organic layers were washed with an aqueous solution of NaCl, the organic layer was dried over anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was concentrated in vacuo to provide a crude residue that was purified by silica gel chromatography to afford compound E. The regioisomeric compound F was prepared using the same procedure but using the regioisomeric compound B as the starting materials. [00218] Preparation of exemplary benzofuran analogs following Scheme 1: [00219] Example 1: Preparation of 2-(3-methoxyphenoxy)isoindoline-1,3-dione (I-3b): According to representative procedure 1, using intermediate I-1 (10 g, 61.3 mmol), 4A molecular sieves (15.3 g), (3-methoxyphenyl)boronic acid (I-2b, 18.65 g, 122.6 mmol), copper (I) chloride (6.06 g, 61.3 mmol), and pyridine (5.33 g, 67.4 mmol), the title compound was obtained and purified to afford intermediate I-3b (11 g, 66%); ESI-MS m/z=270.0 [M+H]+; 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.95 - 7.89 (m, 2H), 7.86 - 7.77 (m, 2H), 7.25 - 7.20 (m, 1H), 6.76 - 6.67 (m, 3H), 3.80 (s, 3H). [00220] Example 2: Preparation of 2-(3-fluorophenoxy)isoindoline-1,3-dione (I-3c): According to representative procedure 1, using intermediate I-1 (5 g, 30.6 mmol), 4A molecular sieves (7.6 g), (3-fluorophenyl)boronic acid (I-2c, 8.56 g, 61.2 mmol), copper (I) chloride (3 g, 30.6 mmol), and pyridine (2.65 g, 33.6 mmol), the title compound was obtained and purified to afford intermediate I-3c (3.4 g, 43%); ESI-MS m/z=258.1 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.07 - 7.84 (m, 4H), 7.45 (br d, J = 8.3 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.16 (br d, J = 8.3 Hz, 2H), 7.09 - 6.96 (m, 2H). [00221] Example 3: Preparation of 2-(3-fluorophenoxy)isoindoline-1,3-dione (I-3d): According to representative procedure 1, using intermediate I-1 (5 g, 30.6 mmol), 4A molecular sieves (7.6 g), (3-(trifluoromethyl)phenyl)boronic acid (I-2d, 11.65 g, 61.2 mmol), copper (I) chloride (3 g, 30.6 mmol) and pyridine (2.65 g, 33.6 mmol), the title compound was obtained and purified to afford intermediate I-3d (3 g, 31%); ESI-MS m/z=308.0 [M+H]+. [00222] Example 4: Preparation of 2-(3-(trifluoromethoxy)phenoxy)isoindoline-1,3-dione (I- 3e): According to representative procedure 1, using intermediate I-1 (5 g, 30.6 mmol), 4A molecular sieves (7.6 g), (3-(trifluoromethyl)phenyl)boronic acid (I-2e, 11.65 g, 61.2 mmol), copper (I) chloride (3 g, 30.6 mmol), and pyridine (2.65 g, 33.6 mmol), the title compound was obtained and purified to afford I-3e (3.5 g, 35%); ESI-MS m/z=324.1 [M+H]+. [00223] Example 5: Preparation of O-(3-methoxyphenyl)hydroxylamine (I-4b): According to representative procedure 2, using intermediate I-3b (11 g, 40.8 mmol) and hydrazine monohydrate (6.1 g, 122 mmol), the title compound was obtained and purified to afford intermediate I-4b (4.4 g, 77%); ESI-MS m/z=140.1 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 7.12 (t, J = 8.2 Hz, 1H), 6.85 (s, 2H), 6.67 (t, J = 2.3 Hz, 1H), 6.66 - 6.58 (m, 1H), 6.44 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H), 3.71 (s, 3H). [00224] Example 6: Preparation of O-(3-fluorophenyl)hydroxylamine (I-4c): According to representative procedure 2, using intermediate I-3c (3.4 g, 13.2 mmol) and hydrazine monohydrate (1.98 g, 39.6 mmol), the title compound was obtained and purified to afford I-4c (1.5 g, 89%); ESI-MS m/z=128.1 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.23 (m, 1H), 7.03 - 6.87 (m, 2H), 6.87 - 6.74 (m, 1H), 2.03 (s, 3H), 2.01 - 1.97 (m, 3H) [00225] Example 7: Preparation of O-(3-(trifluoromethyl)phenyl)hydroxylamine (I-4d): According to representative procedure 2, using intermediate I-3d (3 g, 9.77 mmol) and hydrazine monohydrate (1.48 g, 29.3 mmol), the title compound was obtained and purified to afford I-4d (1.3 g, 75%); ESI-MS m/z=175.9 [M-H]+. [00226] Example 8: Preparation of O-(3-(trifluoromethoxy)phenyl)hydroxylamine (I-4e): According to representative procedure 2, using Intermediate I-3e (3.5 g, 10.8 mmol) and hydrazine monohydrate (1.64 g, 32.5 mmol), the title compound was obtained and purified to afford I-4e (750 mg, 36%); ESI-MS m/z=194.1 [M+H]+. [00227] Example 9: Preparation of compounds 31 and 22: According to representative procedure 3, using intermediate I-4a, I-5b (N-Boc azepan-4-one), and Conc. HCl, the title compounds were obtained and purified to afford compound 31 and compound 22. Following representative procedure 9, compound 31 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 11.77 - 8.25 (m, 1H), 7.53 - 7.43 (m, 2H), 7.26 - 7.18 (m, 2H), 6.51 (s, 2H), 3.19 - 3.12 (m, 4H), 3.12 - 3.04 (m, 2H), 2.90 - 2.79 (m, 3H). Following representative procedure 9, compound 22 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 11.01 - 8.27 (m, 1H), 7.58 - 7.53 (m, 1H), 7.50 - 7.44 (m, 1H), 7.26 - 7.19 (m, 2H), 6.48 (s, 2H), 4.08 (s, 2H), 3.24 - 3.19 (m, 2H), 3.01 (br s, 2H), 1.92 (br d, J = 4.6 Hz, 2H). [00228] Example 10: Preparation of compounds 30 and 21: According to representative procedure 3, using Intermediate I-4a, I-5c (N-methyl azepan-4-one hydrochloride) and Conc. HCl, the title compounds were obtained and purified to isolate 30 and 21. Following representative procedure 9, compound 30 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 13.76 - 11.85 (m, 1H), 7.51 - 7.47 (m, 1H), 7.45 - 7.41 (m, 1H), 7.24 - 7.17 (m, 2H), 3.00 (br d, J = 5.5 Hz, 2H), 2.93 - 2.84 (m, 5H), 2.79 - 2.74 (m, 2H), 2.47 - 2.46 (m, 3H) Following representative procedure 9, compound 21produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.41 (m, 2H), 7.24 - 7.17 (m, 2H), 6.58 (s, 1H), 3.77 (s, 2H), 2.97 - 2.88 (m, 4H), 2.43 (s, 3H), 1.91 - 1.85 (m, 2H) [00229] Example 11: Preparation of compounds 27, 19, 18 and 16: According to representative procedure 3, using Intermediate I-4b, I-5a (azepan-4-one hydrochloride), and Conc. HCl, the title compounds were obtained as a regioisomeric mixture of four compounds to afford 27, 19, 18, and 16. Following representative procedure 9, compound 27 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 8.93 - 8.82 (m, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 6.90 - 6.85 (m, 1H), 6.01 (s, 2H), 3.78 (s, 3H), 3.41 - 3.36 (m, 4H), 3.21 - 3.16 (m, 2H), 2.99 - 2.94 (m, 2H) Following representative procedure 9, compound 19produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.5, 2.3 Hz, 1H), 6.02 (s, 2H), 4.35 (s, 2H), 3.79 (s, 3H), 3.47 - 3.43 (m, 2H), 3.04 (br s, 2H), 2.04 (br s, 2H). Following representative procedure 9, compound 18 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 7.08 (s, 1H), 6.79 - 6.73 (m, 1H), 6.50 (s, 2H), 4.27 (s, 2H), 3.86 (s, 3H), 3.21 (br d, J = 5.4 Hz, 2H), 2.97 (br s, 2H), 1.90 (br d, J = 3.6 Hz, 2H). Following representative procedure 9, compound 16 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 7.07 (s, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.54 (s, 3H), 3.85 (s, 4H), 3.15 (br s, 6H), 3.07 - 3.03 (m, 2H). [00230] Example 12: Preparation of compounds 26 and 17: According to representative procedure 3, using Intermediate I-4b, I-5c (N-methyl azepan-4-one) and Conc. HCl, the title compounds were obtained as a regioisomeric mixture of two compounds that was purified to afford compounds 26 (40 mg) and 17 (200 mg). Following representative procedure 9, compound 26produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 10.11 - 9.76 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.88 (dd, J = 8.6, 2.2 Hz, 1H), 6.04 - 6.00 (m, 2H), 3.78 (s, 3H), 3.24 - 3.16 (m, 3H), 3.08 - 2.86 (m, 6H). Following representative procedure 9, compound 17 produced the corresponding fumarate salt. 1 H NMR (400 MHz, METHANOL-d4) δ 6.61 (d, J = 8.6 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 6.10 (dd, J = 8.6, 2.1 Hz, 1H), 5.43 (s, 2H), 3.73 (s, 2H), 3.02 (s, 3H), 2.94 - 2.78 (m, 2H), 2.33 - 2.28 (m, 2H), 2.28 - 2.21 (m, 3H), 1.50 - 1.34 (m, 2H). [00231] Example 13: Preparation of compounds 24, 10, 7 and 6: According to representative procedure 3, using I-4c, I-5a (azepan-4-one hydrochloride) and Conc. HCl, the title compounds were obtained as a regioisomeric mixture of four compoundsthat was purified to afford 24, 10, 7, and 6. Following representative procedure 9, compound 24 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 8.1 Hz, 1H), 7.23 (br d, J = 5.4 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.55 (s, 3H), 3.13 - 3.06 (m, 6H), 3.05 - 3.00 (m, 3H), 2.97 - 2.93 (m, 2H) Following representative procedure 9, compound 10 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (dd, J = 8.6, 5.5 Hz, 1H), 7.44 (dd, J = 9.5, 2.2 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.57 (s, 3H), 3.17 (br d, J = 5.5 Hz, 4H), 3.10 - 3.06 (m, 2H), 2.87 - 2.83 (m, 2H). Following representative procedure 9, compound 7 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.58 - 7.51 (m, 1H), 7.46 - 7.39 (m, 1H), 7.10 (s, 1H), 6.50 (s, 2H), 5.75 (s, 1H), 4.04 (s, 2H), 3.17 (br t, J = 5.2 Hz, 4H), 3.01 - 2.96 (m, 2H), 1.93 - 1.85 (m, 2H). Compound 6: ESI-MS m/z=206.1 [M+H]+; Following representative procedure 9, compound 6 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.37 - 7.33 (m, 1H), 7.26 - 7.19 (m, 1H), 7.05 - 6.98 (m, 1H), 6.51 (s, 1H), 4.09 (s, 2H), 3.14 - 3.10 (m, 2H), 2.98 (br s, 2H), 1.87 (br s, 2H). [00232] Example 14: Preparation of compounds 43 and 48: According to representative procedure 3, using I-4d and I-5a (azepan-4-one hydrochloride), the title compounds were obtained as a regioisomeric mixture of two compounds that was purified by chiral HPLC to afford compounds 43 and 48. Following representative procedure 9, compound 43 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.52 (s, 2H), 2.99 - 2.92 (m, 8H), 1.89 (s, 1H). Following representative procedure 9, compound 48 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.55 (br d, J = 7.8 Hz, 1H), 6.59 (s, 2H), 3.81 (s, 2H), 3.00 - 2.96 (m, 2H), 2.95 - 2.92 (m, 2H), 2.42 (s, 1H), 1.93 - 1.79 (m, 2H). [00233] Example 15: Preparation of compounds of 44 and 49: According to representative procedure 3, using I-4e, I-5a (azepan-4-one hydrochloride) and Conc. HCl (840 mg, 23.28 mmol), the title compounds were obtained and purified by HPLC to afford 44 and 49. Following representative procedure 9, compound 44 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.59 (m, 2H), 7.26 - 7.22 (m, 1H), 6.57 (s, 3H), 3.18 - 3.12 (m, 4H), 3.10 - 3.06 (m, 2H), 2.87 - 2.82 (m, 2H). Following representative procedure 9, compound 49 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.70 - 7.59 (m, 2H), 7.25 (dd, J = 8.4, 0.8 Hz, 1H), 6.50 (s, 2H), 4.10 (s, 2H), 3.27 - 3.16 (m, 3H), 3.05 - 3.00 (m, 2H), 1.93 (br d, J = 4.1 Hz, 2H). [00234] Example 16: Preparation of compounds 45, 47, 50 and 51: According to representative procedure 3, using I-4f, I-5a (azepan-4-one hydrochloride) and Conc. HCl, the title compounds were obtained as a regioisomeric mixture of four compounds that was purified by chiral HPLC to afford compounds 45, 47, 50, and 51. Following representative procedure 9, compound 45 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.29 (m, 6H), 7.16 (s, 1H), 6.92 (br d, J = 8.5 Hz, 1H), 6.51 (s, 2H), 5.13 (s, 2H), 3.17 - 3.10 (m, 4H), 3.03 (br d, J = 4.9 Hz, 2H), 2.80 (br t, J = 4.8 Hz, 2H). Following representative procedure 9, compound 47 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.48 (br d, J = 7.8 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.17 (t, J = 8.1 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.68 (s, 2H), 5.19 (s, 2H), 3.50 - 3.38 (m, 6H), 3.29 - 3.25 (m, 3H) Following representative procedure 9, compound 50 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 10.74 - 9.87 (m, 1H), 7.48 - 7.29 (m, 6H), 7.19 (s, 1H), 6.93 (br d, J = 8.5 Hz, 1H), 6.48 (s, 2H), 5.13 (s, 2H), 4.09 (s, 2H), 3.27 - 3.21 (m, 2H), 2.97 (br t, J = 5.6 Hz, 2H), 1.93 (br s, 2H) Following representative procedure 9, compound 51 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (br d, J = 7.1 Hz, 2H), 7.44 - 7.31 (m, 3H), 7.19 - 7.08 (m, 2H), 6.87 (d, J = 7.9 Hz, 1H), 6.48 (s, 2H), 5.22 (s, 2H), 4.36 (s, 2H), 3.27 - 3.21 (m, 3H), 3.03 - 2.95 (m, 2H), 1.95 (br s, 2H). [00235] The compounds in Table 2 were prepared according to Representative procedure 3 using the appropriately substituted 2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine, or 2,3,4,5-tetrahydro- 1H-benzofuro[2,3-d]azepine. Table 2
[00236] Example 17: Preparation of compound 28: According to representative procedure 4, using compound 31, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 28 Following representative procedure 9, compound 28 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 7.50 - 7.41 (m, 2H), 7.24 - 7.17 (m, 2H), 6.61 (s, 2H), 3.20 (s, 4H), 3.03 - 2.89 (m, 3H), 2.79 - 2.70 (m, 6H), 2.08 (br t, J = 3.7 Hz, 3H), 1.83 (br dd, J = 8.9, 2.4 Hz, 2H), 1.63 (br d, J = 10.8 Hz, 2H). [00237] Example 18: Preparation of compound 25: According to representative procedure 4, using compound 27, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 25. Following representative procedure 9, compound 25 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.83 (dd, J = 8.5, 2.3 Hz, 1H), 6.63 (s, 2H), 3.78 (s, 3H), 3.23 - 3.16 (m, 2H), 2.95 - 2.89 (m, 4H), 2.79 - 2.73 (m, 4H), 2.69 (br s, 3H), 2.10 (br s, 2H), 1.87 - 1.79 (m, 2H), 1.65 (br d, J = 10.8 Hz, 2H). [00238] Example 19: Preparation of compound 23: According to representative procedure 4, using compound 24, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 23. Following representative procedure 9, compound 23 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 8.2 Hz, 1H), 7.21 (dt, J = 8.2, 5.4 Hz, 1H), 6.99 (dd, J = 10.7, 8.0 Hz, 1H), 6.61 (s, 3H), 3.03 - 2.99 (m, 2H), 2.94 - 2.85 (m, 7H), 2.46 (s, 3H). [00239] Example 20: Preparation of compound 20: According to representative procedure 4, using compound 22, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 20. Following representative procedure 9, compound 20 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 14.13 - 11.58 (m, 1H), 7.50 - 7.43 (m, 2H), 7.24 - 7.17 (m, 2H), 6.60 (s, 2H), 3.68 (s, 2H), 3.15 (br t, J = 7.6 Hz, 1H), 2.96 - 2.91 (m, 2H), 2.89 - 2.83 (m, 2H), 2.08 (s, 2H), 2.07 - 1.98 (m, 2H), 1.88 - 1.77 (m, 4H), 1.67 - 1.50 (m, 3H). [00240] Example 21: Preparation of compound 15: According to representative procedure 4, using compound 16, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 15. Following representative procedure 9, compound 15 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.17 (s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.73 - 6.68 (m, 4H), 3.91 - 3.83 (m, 4H), 3.38 (br s, 6H), 3.25 - 3.21 (m, 2H), 2.45 - 2.36 (m, 2H), 2.23 (dt, J =9.8, 2.4 Hz, 2H), 1.93 - 1.80 (m, 2H). [00241] Example 22: Preparation of compound 14: According to representative procedure 4, using compound 18, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 14. Following representative procedure 9, compound 14 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.25 - 7.19 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.69 (s, 2H), 4.62 (s, 2H), 3.94 (s, 3H), 3.89 - 3.80 (m, 1H), 3.52 - 3.43 (m, 2H), 3.15 - 3.09 (m, 2H), 2.44 - 2.33 (m, 2H), 2.28 - 2.20 (m, 2H), 2.19 - 2.12 (m, 3H), 1.92 - 1.76 (m, 2H). [00242] Example 23: Preparation of compound 12: According to representative procedure 4, using compound 19, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 12. Following representative procedure 9, compound 12 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.42 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.72 (s, 2H), 4.26 (s, 2H), 3.87 - 3.80 (m, 4H), 3.47 - 3.41 (m, 2H), 3.16 - 3.10 (m, 2H), 2.44 - 2.35 (m, 2H), 2.27 - 2.12 (m, 4H), 1.92 - 1.77 (m, 2H). [00243] Example 24: Preparation of compound 9: According to representative procedure 4, using compound 6, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 9. Following representative procedure 9, compound 9 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 8.2 Hz, 1H), 7.21 (dt, J = 8.1, 5.5 Hz, 1H), 7.01 (dd, J = 10.6, 8.3 Hz, 1H), 6.61 (s, 3H), 3.90 (s, 3H), 2.99 - 2.89 (m, 5H), 2.43 (s, 4H), 1.91 - 1.82 (m, 2H). [00244] Example 25: Preparation of compound 4: According to representative procedure 4, using compound 7 , formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 4. Following representative procedure 9, compound 4 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 14.03 - 11.50 (m, 1H), 7.54 - 7.49 (m, 1H), 7.41 (dd, J = 9.4, 2.3 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.60 (s, 2H), 3.78 (s, 3H), 2.95 - 2.89 (m, 4H), 2.43 (s, 3H), 1.90 - 1.83 (m, 2H). [00245] Example 26: Preparation of compound 3: According to representative procedure 4, using compound 10, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 3. Following representative procedure 9, compound 3 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J = 8.5, 5.6 Hz, 1H), 7.40 (dd, J = 9.4, 2.3 Hz, 1H), 7.08 (dt, J = 9.2, 2.3 Hz, 1H), 6.60 (s, 3H), 3.00 (br d, J = 5.4 Hz, 2H), 2.90 (br d, J = 5.3 Hz, 4H), 2.78 - 2.74 (m, 2H), 2.47 (s, 3H). [00246] Example 27: Preparation of compound 2: According to representative procedure 4, using compound 10, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 2. Following representative procedure 9, compound 2 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 8.5, 5.4 Hz, 1H), 7.39 (dd, J = 9.4, 2.2 Hz, 1H), 7.07 (ddd, J = 9.9, 8.5, 2.3 Hz, 1H), 6.61 (s, 2H), 3.17 - 3.13 (m, 1H), 2.97 - 2.91 (m, 2H), 2.72 (br d, J = 8.1 Hz, 6H), 2.10 - 2.03 (m, 2H), 1.81 (br t, J = 8.8 Hz, 2H), 1.69 - 1.57 (m, 2H). [00247] Example 28: Preparation of compound 1: According to representative procedure 4, using compound 7, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 1. Following representative procedure 9, compound 1 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J = 8.6, 5.6 Hz, 1H), 7.41 (dd, J = 9.4, 2.3 Hz, 1H), 7.07 (ddd, J = 9.8, 8.6, 2.4 Hz, 1H), 6.61 (s, 2H), 3.65 (s, 2H), 3.14 - 3.11 (m, 1H), 2.94 - 2.89 (m, 2H), 2.85 - 2.81 (m, 2H), 2.07 - 1.98 (m, 2H), 1.81 (br s, 4H), 1.65 - 1.50 (m, 2H). [00248] Example 29: Preparation of compound 39: According to representative procedure 4, using 43, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide 39. Following representative procedure 9, compound 39 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.71 (br d, J = 8.3 Hz, 1H), 7.54 (br d, J = 8.3 Hz, 1H), 6.59 (s, 2H), 3.04 - 3.01 (m, 2H), 2.85 - 2.75 (m, 6H), 2.42 (s, 3H). [00249] Example 30: Preparation of compound 52: According to representative procedure 4, using compound 48, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide 52. Following representative procedure 9, compound 52 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.74 (br d, J = 8.3 Hz, 1H), 7.55 (br d, J = 7.8 Hz, 1H), 6.59 (s, 2H), 3.81 (s, 2H), 3.01 - 2.91 (m, 6H), 2.42 (s, 3H). [00250] Example 31: Preparation of compound 40: According to representative procedure 4, using compound 44, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 40. Following representative procedure 9, compound 40produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.56 (m, 2H), 7.22 (br d, J = 8.3 Hz, 1H), 6.60 (s, 2H), 3.05 - 2.99 (m, 2H), 2.93 - 2.86 (m, 4H), 2.80 - 2.76 (m, 2H), 2.47 (s, 3H). [00251] Example 32: Preparation of compound 53: According to representative procedure 4, using compound 49, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 53. Following representative procedure 9, compound 53 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.60 (m, 2H), 7.23 (br d, J = 8.8 Hz, 1H), 6.59 (s, 2H), 3.82 (s, 2H), 2.99 - 2.92 (m, 4H), 2.44 (s, 3H), 1.92 - 1.83 (m, 2H). [00252] Example 33: Preparation of compound 41: According to representative procedure 4, using 45, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide 41. Following representative procedure 9, compound 41 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.42 (m, 2H), 7.39 - 7.28 (m, 4H), 7.14 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.6, 2.2 Hz, 1H), 6.56 (s, 2H), 5.11 (s, 2H), 3.02 - 2.92 (m, 6H), 2.77 - 2.73 (m, 2H), 2.50 (br s, 3H). [00253] Example 34: Preparation of compound 54: According to representative procedure 4, using 50, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide 54. Following representative procedure 9, compound 54 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.42 (m, 2H), 7.40 - 7.34 (m, 3H), 7.33 - 7.28 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.6, 2.2 Hz, 1H), 6.55 (s, 2H), 5.11 (s, 2H), 3.84 (s, 2H), 3.02 - 2.97 (m, 2H), 2.91 - 2.85 (m, 2H), 2.47 (d, J = 2.0 Hz, 3H), 1.91 - 1.84 (m, 2H). [00254] Example 35: Preparation of compound 55: According to representative procedure 4, using compound 51, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 55. Following representative procedure 9, compound 55 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.47 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.14 - 7.10 (m, 1H), 7.09 - 7.05 (m, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.60 (s, 2H), 5.22 (s, 2H), 4.09 (s, 2H), 3.00 - 2.97 (m, 2H), 2.94 - 2.89 (m, 2H), 2.40 (s, 3H), 1.90 - 1.82 (m, 2H). [00255] The compounds in Table 3 were prepared according to Representative procedure 4 using the appropriately substituted 2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine, or 2,3,4,5-tetrahydro- 1H-benzofuro[2,3-d]azepine. Table 3
[00256] Example 36: Preparation of compound 29: According to representative procedure 5, using compound 31, Et 3 N, and CF 3 CH 2 OTf , the title compound was obtained and purified to afford compound 29. [00257] Example 37: Preparation of compound 13: According to representative procedure 5, using compound 22, Et 3 N, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 13. [00258] Example 38: Preparation of compound 11: According to representative procedure 5, using compound 19 , Et 3 N, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 11. [00259] Example 39: Preparation of compound 8: According to representative procedure 5, using compound 10, Et3N,, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 8. [00260] Example 40: Preparation of compound 5: According to representative procedure 5, using compound 7, Et3N, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 5. [00261] The compounds in Table 4 were prepared according to Representative procedure 5 using the appropriately substituted 2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine, or 2,3,4,5-tetrahydro- 1H-benzofuro[2,3-d]azepine. Table 4 [00262] General synthetic scheme for Benzothiophenes: [00263] In some embodiments, benzothiophene compounds provided herein are prepared as outlined in Scheme 2. Scheme 2 [00264] In Scheme 2, R 1 -R 5 are as defined herein. R and R’ are each independently hydrogen, alkyl, or R and R’ are taken together to form a cycloalkyl ring. The leaving group X can be, by way of example, a halogen, a sulfonate (OSO 2 )R’’ wherein R’’ is alkyl or aryl, e.g., OMs (mesylate), OTs (tosylate), imidazole, phenoxy or a substituted phenoxy (e.g., nitrophenoxy, C 6 F 5 O), and the like. [00265] Representative procedure 6: Preparation of a mixture of intermediates I-7a and I-7b: [00266] To a solution intermediate I-6 (1.0 eq) in chloroform at 0°C was added dropwise solution of Br 2 (1.5 eq) in chloroform and the reaction mixture was stirred at room temperature for 16 hours. Solids were collected by filtration, dissolved in dichloromethane and Et 3 N (2.0 eq) was added followed by (Boc) 2 O (2.0 eq) at 0°C the reaction mixture was stirred at room temperature for 3 hours. Volatiles were removed in vacuo and the crude reaction residue was purified by silica gel chromatography to provide a mixture of intermediates I-7a and I-7b as a yellow oil. [00267] Representative procedure 7: Preparation of a mixture of intermediates I-9 and I-10: [00268] To a stirred solution of a mixture of intermediates I-7a and I-7b (1.0 eq) in 2-propanol was added sodium bicarbonate (3.0 eq) followed by 3-methoxybenzene-1-thiol at room temperature and the reaction mixture was stirred for 80°C for 90 hours in a sealed tube. Volatiles were removed in vacuo, the crude reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried with anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was evaporated in vacuo to provide a crude reaction product that was purified by silica gel chromatography to provide a mixture of intermediates I-9 and I-10 as pale-yellow oil. [00269] Representative procedure 8: Preparation of compounds M and N: [00270] To a mixture of intermediates I-9 and I-10 (1.0 eq) was added H 2 SO 4 (7% solution in dioxane) or polyphosphoric acid (PPA, 10 vol) and the reaction mixture was stirred at 80-90°C for 16 hours. The crude reaction mixture was cooled (e.g., to 0°C), basified with NaOH (1-2M aqueous solution) and extracted with ethyl acetate. The combined organic layer dried with anhydrous Na 2 SO 4 , solids were removed by filtration and the filtrate was evaporated in vacuo to provide a crude reaction product that was purified by silica gel chromatography to provide compound M and compound N as two individual peaks. [00271] Preparation of compounds O and P: [00272] Compound O and compound P were prepared as described for compounds C and D, (representative procedure 4)but using compounds M or compound N as the starting materials. [00273] Representative procedure 9: Preparation of fumarate salts: [00274] Fumaric acid is added to a sealed tube containing acetone. The suspension is heated to 40 °C until all of the fumaric acid dissolved. A solution of a compound described herein as a free base in acetone is added drop-wise at the same temperature, and the mixture is stirred for 1h. After cooling the solution to room temperature, the solid is filtered, washed with acetone, and dried under reduced pressure to yield the compound described herein as a fumarate salt. [00275] Preparation of exemplary benzothiophene analogs following Scheme 2. [00276] Example 41: Preparation of a mixture of intermediates I-7a and I-7b: According to representative procedure 6, using intermediate I-6 (10 g, 46.8 mmol) and Br 2 (11.2 g, 70.2 mmol), the title compounds were obtained and purified to provide the mixture of intermediates I-7a and I-7b (5 g, yellow oil). [00277] Example 42:Preparation of a mixture of intermediates I-9a and I-10a: According to representative procedure 7, using the mixture of intermediates I-7a and I-7b (2.5 g, 8.56 mmol), sodium bicarbonate (2.15 g, 25.6 mmol), and benzenethiol (I-8a, 0.94 g, 8.56 mmol), the title compounds were obtained and purified to provide mixture of I-9a and I-10a (2.5 g). [00278] Example 43: Preparation of a mixture of intermediates I-9b and I-10b: According to representative procedure 7, using mixture of I-7a and I-7b (3.5 g, 11.9 mmol), sodium bicarbonate (2.99 g, 35.7 mmol), and 3-methoxybenzenethiol (I-8b, 1.66 g, 11.9 mmol), the title compounds were obtained and purified to provide the intermediates I-9b and I-10b (3.2 g). [00279] Example 44: Preparation of a mixture of intermediates I-9c and I-10c: According to representative procedure 7, using mixture of I-7a and I-7b (1 g, 6.84 mmol), sodium bicarbonate (1.72 g, 20.5 mmol), and 3-fluorobenzenethiol (I-8c, 0.87 g, 6.84 mmol), the title compounds were obtained and purified to provide mixture of I-9c and I-10c (2.1 g). [00280] Example 45: Preparation of a mixture of intermediates I-9d and I-10d: According to representative procedure 7, using mixture of I-7a and I-7b (3 g, 10.3 mmol), sodium bicarbonate (2.6 g, 30.9 mmol), and 3-(trifluoromethoxy)benzenethiol (I-8d, 2 g, 10.3 mmol), the title compounds were obtained and purified to provide mixture of I-9d and I-10d (2.3 g). [00281] Example 46: Preparation of compound 65: According to representative procedure 8, using a solution of intermediates I-9a and I-10a (0.5 g, 1.55 mmol) in polyphosphoric acid (5 mL), the title compound was obtained and purified to provide compound 65. Following representative procedure 9, compound 65 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.41 - 7.28 (m, 2H), 6.50 (s, 2H), 3.19 - 3.09 (m, 9H). [00282] Example 47: Preparation of compound 35: According to representative procedure 8, using a solution of intermediates I-9b and I-10b (1 g, 2.84 mmol) in polyphosphoric acid (10 mL), the title compound was obtained and purifiedto provide compound 35. Following representative procedure 9, compound 35 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.53 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 9.0, 2.2 Hz, 1H), 6.49 (s, 3H), 3.93 - 3.83 (m, 1H), 3.80 (s, 3H), 3.35 - 2.98 (m, 10H). [00283] Example 48: Preparation of compound 46: According to representative procedure 8, using a solution of intermediates I-9c and I-10cin polyphosphoric acid, the title compound was obtained and purified to provide compound 46. Following representative procedure 9, compound 46 (100 mg) produced the corresponding fumarate salt (100 mg) as a white solid; 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J = 9.3, 2.4 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.25 (br d, J = 2.4 Hz, 1H), 6.49 (s, 2H), 3.20 - 3.10 (m, 9H). [00284] Example 49: Preparation of compound 66 and compound 67: According to representative procedure 8, using a solution of intermediates I-9d and I-10d in polyphosphoric acid, the title compound was obtained and purified to isolate compound 66 and compound 67. Compound 66; ESI-MS m/z=288.0 [M+H] + ; Following representative procedure 9, compound 66 (50 mg) produced the corresponding fumarate salt (60 mg); 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (br s, 1H), 7.78 (br d, J = 8.8 Hz, 1H), 7.33 (br d, J = 8.3 Hz, 1H), 6.49 (s, 2H), 3.10 - 2.91 (m, 8H), 2.09 (s, 1H). Compound 67; ESI-MS m/z=288.0 [M+H] + ; Following representative procedure 9, compound 67 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.8 Hz, 1H), 7.42 - 7.31 (m, 2H), 6.50 (s, 2H), 3.34 (br s, 1H), 3.33 - 3.31 (m, 1H), 3.20 - 3.10 (m, 7H). [00285] Example 50: Preparation of compound 72: According to representative procedure 4, using compound 65, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 72. Following representative procedure 9, compound 72 produced the corresponding fumarate salt. [00286] Example 51: Preparation of compound 73: According to representative procedure 4, using compound 65, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 73. Following representative procedure 9, compound 73 produced the corresponding fumarate salt. [00287] Example 52: Preparation of compound 34: According to representative procedure 4, using compound 35, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 34. Following representative procedure 9, compound 34produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.53 (m, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 6.64 - 6.46 (m, 2H), 3.80 - 3.78 (m, 3H), 2.98 (td, J = 10.4, 5.3 Hz, 4H), 2.80 (br s, 4H), 2.48 (br s, 3H). [00288] Example 53: Preparation of compound 74: According to representative procedure 4, using compound 35, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 74. Following representative procedure 9, compound 74 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.8 Hz, 1H), 7.46 - 7.41 (m, 1H), 6.99 - 6.94 (m, 1H), 6.60 (s, 2H), 3.81 - 3.77 (m, 3H), 3.12 - 3.05 (m, 1H), 2.92 (br s, 5H), 2.68 - 2.58 (m, 4H), 2.13 - 2.02 (m, 2H), 1.92 - 1.78 (m, 2H), 1.69 - 1.56 (m, 2H). [00289] Example 54: Preparation of compound 32: According to representative procedure 4, using compound 46, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 32. Following representative procedure 9, compound 32produced the corresponding fumarate salt (28 mg); 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J = 9.3, 2.4 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.60 (s, 2H), 3.12 - 3.05 (m, 1H), 2.97 (td, J = 10.3, 5.1 Hz, 4H), 2.65 - 2.60 (m, 4H), 2.06 (br s, 2H), 1.91 - 1.80 (m, 2H), 1.70 - 1.54 (m, 2H). [00290] Example 55: Preparation of compound 33: According to representative procedure 4, using compound 46, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 33. Following representative procedure 9, compound 33 produced the corresponding fumarate salt as a white solid; 1 H NMR (400 MHz, METHANOL-d4) δ 7.70 (dd, J = 8.9, 5.0 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.18 (dt, J = 9.0, 2.4 Hz, 1H), 6.70 (s, 2H), 3.54 - 3.40 (m, 5H), 3.36 - 3.32 (m, 2H), 3.30 - 3.25 (m, 2H), 3.00 - 2.96 (m, 4H). [00291] Example 56: Preparation of compound 75: According to representative procedure 4, using compound 66, formaldehyde, and NaCNBH 3 , the title compound was obtained and purified to provide compound 75. Following representative procedure 9, compound 75produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.35 (br d, J = 8.8 Hz, 1H), 6.60 (s, 2H), 3.00 (br dd, J =13.0, 4.6 Hz, 4H), 2.75 - 2.52 (m, 4H), 2.41 (s, 3H). [00292] Example 57: Preparation of compound 76: According to representative procedure 4, using compound 66, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 76. Following representative procedure 9, compound 76produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.79 (br d, J = 8.8 Hz, 1H), 7.35 (br d, J = 8.8 Hz, 1H), 6.61 (s, 2H), 3.13 - 3.05 (m, 1H), 3.00 (td, J = 4.8, 15.3 Hz, 4H), 2.66 - 2.61 (m, 4H), 2.08 (br d, J = 7.3 Hz, 2H), 1.93 - 1.79 (m, 2H), 1.69 - 1.55 (m, 2H). [00293] Example 58: Preparation of compound 68: According to representative procedure 4, using compound 67, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 68. Following representative procedure 9, compound 68 produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br d, J = 7.3 Hz, 1H), 7.38 - 7.31 (m, 2H), 6.61 (s, 2H), 3.27 - 3.13 (m, 4H), 3.07 - 2.96 (m, 4H), 2.94 - 2.89 (m, 1H), 2.09 - 2.02 (m, 2H), 1.84 - 1.75 (m, 2H), 1.65 - 1.56 (m, 2H). [00294] Example 59: Preparation of compound 69: According to representative procedure 5, using compound 65, Et 3 N followed by CF 3 CH 2 OTf, the title compound was obtained and purified to provide compound 69. [00295] Example 60: Preparation of compound 70: According to representative procedure 5, using compound 35, Et3N, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 70 [00296] Example 61: Preparation of compound 71: According to representative procedure 5, using compound 46,Et 3 N, and CF 3 CH 2 OTf, the title compound was obtained and purified to afford compound 71. [00297] In some embodiments, benzothiophene compounds described herein are prepared as outlined in Scheme 3. Scheme 3 [00298] Preparation of exemplary Benzothiophene analogs following Scheme 3. [00299] Example 62: Preparation of tert-butyl 8-methoxy-1,2,4,5-tetrahydro-3H- benzo[4,5]thieno[2,3-d]azepine-3-carboxylate (I-11): To a solution of compound 35 (700 mg, 3.0 mmol, 1.0 equiv) in CH 2 Cl 2 (7 mL, 10 vol) was added Et 3 N (8.4 mL, 6.0 mmol, 2.0 equiv) followed by Boc2O (780 mg, 3.6 mmol, 1.2 equiv) at 0 °C. The resulting reaction mixture was stirred for 3h at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with CH 2 Cl 2 (2 X 10 mL). The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (30% EtOAc in hexane) to afford intermediate I-11 (500 mg, 50%); ESI-MS m/z: 334.1 [M+H]. [00300] Example 63: Preparation of 3,4,5-tetrahydro-1H-benzo[4,5]thieno[2,3-d]azepin-8-ol (I-12): To a solution of I-11 (500 mg, 1.5 mmol, 1.0 equiv) in CH 2 Cl 2 (5 mL, 10 vol) was added 1M BBr3 in CH 2 Cl 2 (4.5 mL, 4.5 mmol, 3.0 equiv) at 0 °C. Then the resulting solution was stirred for 12h at room temperature. The reaction mixture was quenched with MeOH (3 mL) at 0 °C and the volatiles were concentrated in vacuo to afford the crude I-12 (380 mg); ESI-MS m/z: 220.1 [M+H]. This was directly used in the next step without further purification. [00301] Example 64: Preparation of tert-butyl 8-((tert-butoxycarbonyl)oxy)-1,2,4,5- tetrahydro-3H-benzo[4,5]thieno[2,3-d]azepine-3-carboxylate (I-13): To a solution of I-12 (380 mg, 1.73 mmol, 1.0 equiv) in CH 2 Cl 2 (3.8 mL, 10 vol) was added Et 3 N (700 mg, 6.92 mmol, 4.0 equiv) followed by Boc 2 O (754 mg, 3.46 mmol, 2 equiv) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12h, diluted with water (10 mL) and extracted with CH 2 Cl 2 (2 X 10 mL). The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (10% EtOAc in hexane) to afford I-13 (370 mg, 59%). ESI-MS m/z:420.1 [M+H]. [00302] Example 65: Preparation of tert-butyl 8-hydroxy-1,2,4,5-tetrahydro-3H- benzo[4,5]thieno[2,3-d]azepine-3-carboxylate (I-14): To a solution of I-13 (370 mg, 0.88 mmol, 1.0 equiv) in THF (3.3 mL) and water (0.66 mL) was added LiOH (105 mg, 4.4 mmol, 5.0 equiv) followed by Boc 2 O (754 mg, 3.46 mmol, 2 equiv) at 0 °C. The resulting suspension was stirred for 12h at 60 °C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (10% EtOAc in hexane) to afford I-14 (200 mg, 71%), ESI-MS m/z: 320.2 [M+H]. [00303] Example 66: Preparation of compound 80: Intermediate I-14 (20 mg) was treated with 2M HCl in Et 2 O to isolate pure compound 80 as the HCl salt [00304] Example 67: Preparation of tert-butyl 8-(benzyloxy)-1,2,4,5-tetrahydro-3H- benzo[4,5]thieno[2,3-d]azepine-3-carboxylate (I-15): To a solution of I-14 (180 mg, 0.56 mmol, 1.0 equiv) in DMF (2 mL) was added Cs 2 CO 3 (547 mg, 1.68 mmol, 1.0 equiv) followed by BnBr (96 mg, 0.56 mmol, 1 equiv) at 0 °C. The resulting suspension was stirred for 12h at room temperature. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (10% EtOAc in hexane) to afford I-15 (200 mg, 86%); ESI-MS m/z: 410.2 [M+H]. [00305] Example 68: Preparation of compound 77: Intermediate I-15 (200 mg ) was treated with 2M HCl in Et2O to afford compound 77 as the HCl salt. [00306] Example 69: Preparation of compound 78: According to representative procedure 4, using compound 77, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 78. Following representative procedure 9, compound 78 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.53 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 7.1 Hz, 2H), 7.39 - 7.33 (m, 3H), 7.32 - 7.28 (m, 1H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 6.61 (s, 2H), 5.11 (s, 2H), 3.20 - 3.11 (m, 1H), 3.11 - 3.03 (m, 4H), 2.96 - 2.89 (m, 4H), 2.27 - 2.21 (m, 2H), 2.10 - 2.02 (m, 2H), 1.83 - 1.72 (m, 2H). [00307] Example 70: Preparation of compound 79: To a solution of I-15 (80 mg, 0.19 mmol, 1.0 equiv) in THF (1 mL) was added 2M LAH in THF (0.28 mL, 0.57 mmol, 3.0 equiv) at 0 °C and heated to reflux for 4h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc (2 X 5 mL). The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (1% MeOH in CH 2 Cl 2 ) to provide compound 79. Following representative procedure 9, compound 79 produced the corresponding fumarate salt; 1 H NMR (400 MHz, METHANOL-d4) δ 7.52 (d, J = 8.9 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.39 - 7.34 (m, 3H), 7.34 - 7.27 (m, 1H), 7.04 (dd, J = 8.9, 2.4 Hz, 1H), 6.70 (s, 2H), 5.11 (s, 2H), 3.08 - 2.96 (m, 4H), 2.87 - 2.80 (m, 4H), 2.52 (s, 3H). [00308] The compounds in Table 5 were prepared as described above for schemes 2 and 3, using the appropriate starting material. Table 5
[00309] In some embodiments, benzofuran compounds described herein are prepared as outlined in Scheme 4. Scheme 4 aReagents and conditions: (i) CH 3 I (1.1 equiv), K 2 CO 3 (1.5 equiv), DMF (10 vol), 80 °C, 2h; (ii) a) diethyl (cyanomethyl)phosphonate (5 equiv), Na 2 SO 4 (w/w), 45 °C, 30 min, b) NaH (5 equiv), THF, THF, 0 °C to RT, 4h; (iii) a) Boc 2 O (2 equiv), NiCl 2 .6H 2 O (1 equiv), MeOH (10 vol), RT, b) NaBH 4 , 0 °C to RT, 4h; (iv) NBS (1 equiv), DMF (38 vol), 0 °C to RT, 2h; (v) 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.5 equiv), K 2 CO 3 (3 equiv), Pd(Ph 3 ) 4 (0.05 equiv), THF/H 2 O (9:1), 80 °C, 16h; (vi) a) BH 3 (2 equiv), THF (10 vol), reflux, 2h, b) 3M NaOH, 30% H 2 O 2 , RT, 5h; (vii) TsCl (1.2 equiv), Et 3 N (2 equiv), CH 2 Cl 2 (10 vol), RT, 12 h; (viii) 2M HCl in Et 2 O, CH 2 Cl 2 ; (ix) K 2 CO 3 , IPA; (x) a) cyclobutanone (2 equiv), CH 2 Cl 2 , 2 h, b) STAB (2.5 equiv), RT, 16 h. [00310] Preparation of exemplary benzofuran analogs following Scheme 4: [00311] Example 71: Preparation of 6-methoxybenzofuran-3(2H)-one (I-28): To a solution of I-27 (10 g, 66.6 mmol, 1.0 equiv) in DMF (100 mL, 10 vol) was added K 2 CO 3 (13.8 g, 99.9 mmol, 1.5 equiv) and MeI (14.1 g, 99.9 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 2h. The crude reaction residue was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude reaction residue was purified using CombiFlash® chromatographic systems (50% EtOAc in heptane) to provide I-28 (8 g, 80%); ESI-MS m/z=164.8 [M+H]+. [00312] Example 72: Preparation of 2-(6-methoxybenzofuran-3-yl)acetonitrile (I-29): To a solution of I-28 (6 g, 36.5 mmol, 1.0 equiv) in THF (60 mL, 10 vol) was added NaH (60% mineral oil, 7.31 g, 182.9 mmol, 5 equiv) and cyanophosphonate I-28a (32.3 g, 182.9 mmol, 5 equiv) at 0°C and the resulting reaction mixture was warmed to room temperature and stirred for 4h. The crude reaction residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified using CombiFlash® chromatographic systems (10% EtOAc in heptane) to provide I-29 (6.3 g, 92%). ESI-MS m/z=188.1 [M+H]+. [00313] Example 73: Preparation of tert-butyl (2-(6-methoxybenzofuran-3- yl)ethyl)carbamate (I-30): To a solution of I-29 (6 g, 32 mmol, 1.0 equiv) in MeOH (60 mL, 10 vol) was added Boc 2 O (13.98 g, 64.1 mmol, 2 equiv) and NiCl 2 .6H 2 O (7.6 g, 32 mmol, 1 equiv) followed by NaBH 4 (6.05 g, 64.1, 5 equiv) at 0°C and the resulting reaction mixture was warmed to room temperature and stirred for 4h. The reaction mixture was diluted with water and filtered through celite pad and concentrated in vacuo, and the concentrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified using CombiFlash® chromatographic systems (10% EtOAc in heptane) to provide I-30 (7.1 g, 76%). ESI-MS m/z=292.1 [M+H]+. [00314] Example 74: Preparation of tert-butyl (2-(2-bromo-6-methoxybenzofuran-3- yl)ethyl)carbamate (I-31): To a solution of I-30 (7.1 g, 24.3 mmol, 1.0 equiv) in DMF (270 mL, 38 vol) was added N- bromosuccinimide (4.32 g, 24.3 mmol, 1 equiv) at 0 °C and the resulting suspension was warmed to room temperature and stirred for 2h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude residue was purified using CombiFlash® chromatographic systems (10% EtOAc in heptane) to provide intermediate I-31 (8 g, 88%); ESI-MS m/z=370.2 [M+H]+. [00315] Example 75: Preparation of tert-butyl (2-(6-methoxy-2-vinylbenzofuran-3- yl)ethyl)carbamate (I-32): To a solution of I-31 (4 g, 10.8 mmol, 1.0 equiv) in mixture of THF:water (9:1, 40 mL, 10 vol) was added compound-A I-31a (2.49 g, 16.2 mmol, 1.5 equiv) followed by K 2 CO 3 (1.49 g, 10.8 mmol, 1 equiv). The resulting suspension was degassed for 30 minutes, treated with Pd(PPh 3 ) 4 (624 mg, 0.54 mmol, 0.05 equiv) under N 2 atmosphere and stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo. The residue was purified using CombiFlash® chromatographic systems (10% EtOAc in heptane) to provide I-32 (2.3 g, 67%). ESI-MS m/z=318.1 [M+H]+. [00316] Example 76: Preparation of tert-butyl (2-(2-(2-hydroxyethyl)-6-methoxybenzofuran- 3-yl)ethyl)carbamate (I-33): To a solution of I-32 (2.2 g, 6.94 mmol, 1.0 equiv) in THF (22 mL) was added a solution of BH 3 (1M in THF, 13.8 mL, 13.8 mmol, 2.0 equiv) at 0 °C and stirred under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, quenched with aqueous NaOH (3M in water, 14 mL) and a solution of H 2 O 2 (30% in water, 10 mL) was added. After stirring an additional 5 hours at ambient temperature, the reaction mixture was quenched with ice-cold aqueous solution of NaCl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified using CombiFlash® chromatographic systems (5% ethyl acetate in hexane) to provide I-33 (1.2 g, 51%); ESI-MS m/z=336.2 [M+H]+. [00317] Example 77: Preparation of 2-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-6- methoxybenzofuran-2-yl)ethyl 4-methylbenzenesulfonate (I-34): To a solution of I-33 (1 g, 2.98 mmol, 1.0 equiv) in CH 2 Cl 2 (10 mL) was added Et 3 N (602 mg, 5.97 mmol, 2 equiv) and TsCl (681 mg, 3.57 mmol, 1.2 equiv) at 0°C and the reaction mixture was warmed to room temperature and stirred for 12h. The resulting reaction mixture was washed with water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated in vacuo. The residue was purified using CombiFlash® chromatographic systems (10% EtOAc in heptane) to provide I-34 (800 mg, 54%); ESI-MS m/z=490.1 [M+H]+. [00318] Example 78: Preparation of compound 27: To a solution of I-34 (800 mg, 1.63 mmol, 1.0 equiv) in CH 2 Cl 2 (8 mL) was added 2M HCl in Et 2 O (3.2 mL, 6.54 mmol, 4 equiv) at 0°C and the reaction mixture was warmed to room temperature and stirred for 4h. The volatiles were evaporated in vacuo to provide the corresponding Boc-deprotected amine as the HCl salt (700 mg). To a suspension of the HCl salt in IPA (7 mL) was added K 2 CO 3 (680 mg, 4.92 mmol, 3 equiv) at room temperature and heated to 80 °C with stirring for 12h. The reaction mixture was washed with water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of NaCl, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo to provide compound 27 (400 mg, 54%); ESI-MS m/z=218.1 [M+H]+. [00319] Example 79: Preparation of compound 25: According to representative procedure 4, using compound 27, cyclobutanone, and STAB, the title compound was obtained and purified to provide compound 25; ESI-MS m/z=272.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (br d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.79 (br d, J = 7.3 Hz, 1H), 3.74 (s, 3H), 3.15 - 3.06 (m, 1H), 2.88 - 2.78 (m, 2H), 2.73 - 2.60 (m, 6H), ), 2.10 - 2.04 (m, 2H), 1.83 - 1.69 (m, 2H), 1.68 - 1.52 (m, 2H). Following representative procedure 9, compound 25produced the corresponding fumarate salt; 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (br d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.79 (br d, J = 7.3 Hz, 1H), 6.58 (s, 2H), 3.75 (s, 3H), 3.28 - 3.17 (m, 1H), 2.93 (br t, J = 5.4 Hz, 2H), 2.80 - 2.76 (m, 4H), 2.70 - 2.66 (m, 2H), 2.10 - 2.04 (m, 2H), 1.89 - 1.80 (m, 2H), 1.68 - 1.56 (m, 2H). PHARMACEUTICAL COMPOSITIONS Example A-1: Parenteral Pharmaceutical Composition [00320] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a water-soluble salt of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection. Example A-2: Oral Solution [00321] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s),optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution. Example A-3: Oral Tablet [00322] A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg. Example A-4: Oral Capsule [00323] To prepare a pharmaceutical composition for oral delivery, 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. [00324] In another embodiment, 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed. BIOLOGICAL EXAMPLES [00325] Hallucinogenic Potential. Hallucinogenic compound 5-MeO-DMT produces a robust, dose-dependent head-twitch response (HTR) in mice. However, the isosteric compound 6-MeO- DMT is significantly less potent. As expected based on drug-discrimination data, 6-MeO-DMT does not produce a HTR. Finally, potent plasticity-promoting compounds do not produce a HTR, demonstrating that hallucinogenic potential and psychoplastogenicity can be decoupled. [00326] Hallucinogens (e.g., LSD and 5-MeO-DMT) can activate a 5HT 2A sensor assay in agonist mode, but their non-hallucinogenic congeners (lisuride (LIS) and 6-MeO-DMT) may not. Moreover, compounds, such as, for example, 5-MeO-DMT, LSD, DMT, DOI, which are hallucinogenic in animals (e.g., humans), activate the 5HT 2A sensor assay in agonist mode, whereas compounds, such as, for example, 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, Ketanserin, BOL148, which are non-hallucinogenic in animals (e.g., humans), do not activate the 5HT 2A sensor assay in agonist mode. In some embodiments, hallucinogenic potential of a compound provided herein is determined in vitro. In some embodiments, hallucinogenic potential of a compound provided herein is determined using a 5HT 2A sensor assay. In some embodiments, the 5HT 2A sensor assay is in an agonist mode or an antagonist mode. In some embodiments, the 5HT 2A sensor assay is in an agonist mode. In some embodiments, a compound provided herein does not activate the sensor in agonist mode and has non-hallucinogenic potential. In some embodiments, a compound provided herein does not activate the sensor in agonist mode and is a non-hallucinogenic compound. [00327] In some embodiments, the hallucinogenic potential of the compound provided herein are assessed in a 5HT 2A sensor assay in an agonist mode. [00328] Furthermore, in some embodiments, non-hallucinogenic compounds (e.g., lisuride and 6- MeO-DMT) compete off 5-HT when the 5HT 2A sensor assay is run in antagonist mode. Additionally, compounds, such as, for example, 6-F-DET, Ketanserin, BOL148, which are non-hallucinogenic in animals (e.g., humans), can compete with 5HT binding to 5HT 2A in the antagonist mode sensor assay. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT 2A . In some embodiments, the 5HT 2A sensor assay is in an antagonist mode. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT 2A and has non-hallucinogenic potential. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT 2A and is non- hallucinogenic. In some embodiments, a compound provided herein prevents binding of 5-HT to 5HT 2A in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound provided herein that prevents binding of 5-HT in antagonist mode is a non-hallucinogenic compound. In some embodiments, a compound provided herein that inhibits the response of the sensor assay in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound provided herein that inhibits the response of the sensor assay in antagonist mode is a non-hallucinogenic compound. [00329] In some embodiments, the results for the agonist mode sensor assay suggests a compound provided herein is a non-hallucinogenic ligand of the 5-HT 2A receptor. In some embodiments, the results for the antagonist mode sensor assay suggests a compound provided herein is a non- hallucinogenic ligand of the 5-HT 2A receptor. In some embodiments, the results for the agonist mode and antagonist mode sensor assay together suggest a compound provided herein is a non- hallucinogenic ligand of the 5-HT 2A receptor. [00330] In some embodiments, the hallucinogenic potential of the compounds are assessed in a 5HT 2A sensor assay in an antagonist mode. [00331] Forced Swim Test. As increased cortical structural plasticity in the anterior parts of the brain mediates the sustained (>24 h) antidepressant-like effects of ketamine and play a role in the therapeutic effects of 5-HT2A agonists, the impact of compounds on forced swim test (FST) behavior is used evaluate therapeutic potential of compounds provided herein. First, a pretest is used to induce a depressive phenotype. Compounds are administered 24 h after the pre-test, and the FST is performed 24 h and 7 d post drug administration. [00332] Neurite outgrowth assay. Changes in the pattern of neurite outgrowth have been implicated in neurodegenerative disorders as well as traumatic injuries. The discovery of compounds that can positively affect neuritogenesis are important for developing new therapeutics for neurological diseases. In some embodiments, measurement of neurite outgrowth of rat cortical neurons using an automated image-based assay is used to determine the neuroplastic effects of the compounds provided herein. In some embodiments, a compound provided herein increases the pattern of neurite outgrowth. In some embodiments, a compound provided herein increases neurite average length compared to a control. In some embodiments, a compound provided herein increases neurite branch points compared to a control. In some embodiments, a compound provided herein increases neurite average length and neurite branch points compared to a control. [00333] In some embodiments, the plastogenic potential of compounds provided herein is assessed by measuring the changes in neurite development. [00334] Dendritogenesis Assays. Phenotypic screening has historically proven more successful than target-based approaches for identifying drugs with novel mechanisms of action. Using a phenotypic assay, the compounds provided herein are tested for their ability to increase dendritic arbor complexity in cultures of cortical neurons. Following treatment, neurons are fixed and visualized using an antibody against MAP2—a cytoskeletal protein localized to the somatodendritic compartment of neurons. Sholl analysis is then performed, and the maximum number of crossings (N max ) is used as a quantitative metric of dendritic arbor complexity. For statistical comparisons between specific compounds, the raw Nmax values are compared. Percent efficacies are determined by setting the Nmax values for the vehicle (DMSO) and positive (ketamine) controls equal to 0% and 100%, respectively. [00335] Animals. For the dendritogenesis experiments, timed pregnant Sprague Dawley rats are obtained from Charles River Laboratories (Wilmington, MA). In some embodiments, male and female C57BL/6J mice are obtained from Jackson Laboratory (Sacramento, C.A.). In some instances, mice are housed in a temperature and humidity-controlled room maintained on a 12-h light/dark cycle in groups of 4–5 (same sex). [00336] Dendritogenesis – Sholl Analysis. Neurons are plated in 96-well format (200 ^L of media per well) at a density of approximately 15,000 cells/well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 h, the medium is replaced with Neurobasal containing 1x B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamate. After 3 days in vitro (DIV3), the cells are treated with compounds. Compounds tested in the dendritogenesis assays are treated at 10 μM unless noted otherwise. Stock solutions of the compounds in DMSO are first diluted 100-fold in Neurobasal before an additional 10-fold dilution into each well (total dilution = 1:1000; 0.1% DMSO concentration). Treatments are randomized. After 1 h, the media is removed and replaced with new Neurobasal media containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamate. The cells grow for an additional 71 h. At that time, neurons are fixed by removing 80% of the media and replacing it with a volume of 4% aqueous paraformaldehyde (Alfa Aesar) equal to 50% of the working volume of the well. Then, the cells are incubated at room temperature for 20 min before the fixative is aspirated and each well washed twice with DPBS. Cells are permeabilized using 0.2% Triton X-100 (ThermoFisher) in DPBS for 20 minutes at room temperature without shaking. Plates are blocked with antibody diluting buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Then, plates are incubated overnight at 4ºC with gentle shaking in ADB containing a chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2). The next day, plates are washed three times with DPBS and once with 2% ADB in DPBS. Plates are incubated for 1 h at room temperature in ADB containing an anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1:500) and washed five times with DPBS. After the final wash, 100 µL of DPBS is added per well and imaged on an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale,CA) with a 20x objective. [00337] Images are analyzed using ImageJ Fiji (version 1.51W). First, images corresponding to each treatment are sorted into individual folders that are then blinded for data analysis. Plate controls (both positive and negative) are used to ensure that the assay is working properly as well as to visually determine appropriate numerical values for brightness/contrast and thresholding to be applied universally to the remainder of the randomized images. Next, the brightness/contrast settings are applied, and approximately 1–2 individual pyramidal-like neurons per image (i.e., no bipolar neurons) are selected using the rectangular selection tool and saved as separate files. Neurons are selected that did not overlap extensively with other cells or extend far beyond the field of view. The threshold settings are then applied to the individual images. The paintbrush tool is used to eliminate artifacts and dendritic processes originating from adjacent neurons (cleanup phaseNext, the point tool is used to select the center of the neuron, and the images are saved and processed using the following Sholl analysis batch macro: run("Sholl Analysis...", "starting=0 ending=NaN radius_step=2 #_samples=1 integration=Mean enclosing=1 #_primary=4 infer fit linear polynomial=[Best fitting degree] most semi-log normalizer=Area create background=228 save do"); Sholl analysis circle radii = 2 pixel increments = 0.67 ^m. All images are taken and analyzed by an experimenter blinded to treatment conditions. The number of crossings for each neuron at each distinct radius is averaged to produce an average Sholl plot for each treatment. The N max values are simply determined by identifying the maximum of each plot. For each treatment, neurons are selected from at least 6 wells spread across 2 plates (9 sites/well x 3 wells/plate x 2 plates). Each plate is prepared using neurons obtained from independent pregnant dams). [00338] Spinogenesis Experiments. Spinogenesis experiments are performed as previously described with the exception that cells are treated on DIV19 and fixed 24 h after treatment on DIV20. (Ly, C. et al., 2018) The images are taken on a Nikon HCA Confocal microscope a with a 100x/NA 1.45 oil objective. DMSO and ketamine (10 μM) are used as vehicle and positive controls, respectively. [00339] Serotonin 5-HT2A In Vitro Radioligand Binding Competition Assay. The 5-HT2A radioligand binding competition assay was performed at Epics Therapeutics S.A. (Belgium, FAST- 0505B) using conventional methods. Briefly, competition binding was performed in duplicate in the wells of a 96 well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extracts (amount of protein/well optimized for each receptor), radiotracer [ 3 H]-DOI (final concentration optimized for each receptor) and test compound. Nonspecific binding was determined by co-incubation with 200-fold excess of cold competitor. The samples were incubated in a final volume of 0.1 ml at a temperature and for a duration optimized for each receptor and then filtered over filter plates. Filters were washed six times with 0.5 ml of ice-cold washing buffer (optimized for each receptor) and 50 μl of Microscint 20 (Packard) were added in each well. The plates were incubated 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well. [00340] Serotonin 5-HT2A In Vitro Cellular IPOne Agonism Assay. The 5-HT2A IPOne HTRF assay was performed at Epics Therapeutics S.A. (Belgium, FAST-0505I) using conventional methods. Briefly, CHO-K1 cells expressing human recombinant 5-HT2A receptor grown to mid-log phase in culture media without antibiotics were detached with PBS-EDTA, centrifuged, and resuspended in medium without antibiotics buffer.20,000 cells are distributed in a 96 well plate and incubated overnight at 37°C with 5% CO 2 . [00341] For agonist testing, the medium was removed and 20μl of assay buffer plus 20μl of test compound or reference agonist were added in each well. The plate was incubated for 60 min. at 37°C with 5% CO 2 . [00342] After addition of the lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. [00343] Serotonin 5-HT2C In Vitro Radioligand Binding Competition Assay. The 5- HT2Cedited (accession number AAF35842.1) radioligand binding competition assay was performed at Epics Therapeutics S.A. (Belgium, FAST-0507B) using conventional methods. Briefly, competition binding was performed in duplicate in the wells of a 96 well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extracts (amount of protein/well optimized for each receptor), radiotracer [ 3 H]-DOI (final concentration optimized for each receptor) and test compound. Nonspecific binding was determined by co- incubation with 200-fold excess of cold competitor. The samples were incubated in a final volume of 0.1 ml at a temperature and for a duration optimized for each receptor and then filtered over filter plates. Filters were washed six times with 0.5 ml of ice-cold washing buffer (optimized for each receptor) and 50 μl of Microscint 20 (Packard) were added in each well. The plates were incubated 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well. [00344] Serotonin 5-HT2C In Vitro Cellular IPOne Agonism Assay. The 5-HT2C IPOne HTRF assay was performed at Epics Therapeutics S.A. (Belgium, FAST-0507I) using conventional methods. Briefly, CHO-K1 cells expressing human recombinant 5-HT2Cedited receptor (accession number AAF35842.1) grown to mid-log phase in culture media without antibiotics were detached with PBS-EDTA, centrifuged, and resuspended in medium without antibiotics buffer.20,000 cells are distributed in a 96 well plate and incubated overnight at 37°C with 5% CO 2 . [00345] For agonist testing, the medium was removed and 20μl of assay buffer plus 20μl of test compound or reference agonist are added in each well. The plate was incubated for 60 min. at 37°C with 5% CO 2 . [00346] After addition of the lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. [00347] The compounds provided herein were tested in the Serotonin 5-HT2A and 5-HT2C in vitro radioligand binding and cellular IPOne agonism assays. The binding and agonism functional potencies of the compounds (as indicated by their IC50s or EC50s) are shown in Tables 6 (benzofurans) and Table 7 (benzothiophenes). Table 6. In vitro 5-HT2A and 5-HT2C Radioligand Binding and Cellular IPOne Agonism Activity A: IC50 or EC50 is <0.010 μM; B: IC50 or EC50 is 0.010 μM - 0.100 μM; C: IC50 or EC50 is 0.101 μM - 1 μM; D: IC50 or EC50 is 1.001 μM - 10 μM; E: IC50 or EC50 is >10 μM Table 7. In vitro 5-HT2A and 5-HT2C Radioligand Binding and Cellular IPOne Agonism Activity A: IC50 or EC50 is <0.010 μM; B: IC50 or EC50 is 0.010 μM - 0.100 μM ;C: IC50 or EC50 is 0.101 μM - 1 μM; D: IC50 or EC50 is 1.001 μM - 10 μM; E: IC50 or EC50 is >10 μM [00348] Serotonin 5-HT2A In Vitro Cellular IPOne Antagonism Assay. The 5-HT2A IPOne HTRF assay was performed at Epics Therapeutics S.A. (Belgium, FAST-0505I) in antagonism mode using conventional methods. Briefly, CHO-K1 cells expressing human recombinant 5-HT2A receptor grown to mid-log phase in culture media without antibiotics were detached with PBS- EDTA, centrifuged, and resuspended in medium without antibiotics buffer. 20,000 cells are distributed in a 96 well plate and incubated overnight at 37°C with 5% CO 2 . [00349] For antagonist testing, a reference agonist a-Me-5HT was added and fluorescence signal monitored for several minutes, followed by addition of 20μl of assay buffer plus 20μl of test compound or reference antagonist ketanserin, in each well. The plate was incubated for 60 min. at 37°C with 5% CO 2 . [00350] After addition of the lysis buffer containing IP1-d2 and anti-IP1 cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios are measured according to the manufacturer specification, with the HTRF kit. [00351] The compounds provided herein were tested in the Serotonin 5-HT2A antagonism assays. The results are shown in Table 8. Table 8 A: IC50 or EC50 is <0.010 μM; B: IC50 or EC50 is 0.010 μM - 0.100 μM ;C: IC50 or EC50 is 0.101 μM - 1 μM; D: IC50 or EC50 is 1.001 μM - 10 μM; E: IC50 or EC50 is >10 μM [00352] Neurite Outgrowth Assay. Neurite Outgrowth in Primary Neuronal Cultures Assay. Changes in the pattern of neurite outgrowth have been implicated in psychiatric and neurodegenerative disorders as well as traumatic injuries. The discovery of new compounds that can positively affect neuritogenesis are important for developing new therapeutics for neurological diseases. Measurement of neurite outgrowth of rat cortical neurons using an automated image-based assay was used to determine the neuroplastic effects of the compounds of the present disclosure. The neurite outgrowth assay was performed at Neurofit SAS (France) as described below. [00353] Pregnant Wistar rats (Janvier; France) were used for the study. They were delivered 6 days before their use. Upon arrival at Neurofit animal facility, they were housed one per cage and maintained in a room with controlled temperature (21-22°C) and a reversed light-dark cycle (12h/12h; lights on: 17:30 – 05:30; lights off: 05:30 – 17:30) with food and water available ad libitum. [00354] Female Wistar rats of 17 days gestation were killed by cervical dislocation and the fetuses were removed from the uterus. Their brains were placed in ice-cold medium of Leibovitz (L15, Gibco, Fisher bioblock, France). Cortices were dissected and meninges were carefully removed. The cortical neurons were dissociated by trypsinization for 30 min at 37°C (trypsin-EDTA, Gibco) in presence of 0.1 mg/ml DNAse I (Roche, France). The reaction was stopped by addition of Dulbecco’s Modified Eagle Medium (DMEM; Gibco) with 10% of fetal bovine serum (FBS; Gibco). The suspension was triturated with a 10-ml pipette and using a needle syringe 21G and centrifuged at 350 x g for 10 min at room temperature. The pellet of dissociated cells was resuspended in a medium consisting of Neurobasal (Gibco) supplemented with 2% B27 supplement (Gibco), 0.5mM L- Glutamine (Gibco), an antibiotic-antimicotic mixture. Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test (Sigma). Cells were seeded at a density of 10000 cells per well in 96-well plate (Costar) precoated with poly-L-lysine. Test compound at different concentrations were added to the cultures. Donepezil (positive control) was tested at 250 nM. [00355] After 72h (3 days) of plating, cultures were fixed with paraformaldehyde in PBS (4%, Sigma) for 30 min at 4°C. Then, cells were successively permeabilized with 0.1% Triton X100 for 30 min, saturated with PBS containing 3% of BSA and were incubated 1h with anti-beta III tubulin antibody (Sigma) at 1/10000 in PBS containing 0.5% of BSA. Cells were washed three times with PBS containing 0.5% of BSA, and they were incubated 1h with goat anti-mouse antibody coupled with AF488 (Invitrogen A11001) diluted at 1/1000 in PBS containing 0.5% of BSA. Finally, nuclei were staining with DAPI 1 mg/ml at 1/1000 in PBS containing 0.5% of BSA. After rinsing with PBS, the plate was filmed and neurite networks were examined and analyzed using High-Content Screening (CellInsight, Thermo Scientific). The average number of neurites per neuron and the average total length of neurites per neuron were the main parameters analyzed. Analysis of data was performed using analysis of variance (ANOVA). The Fisher’s Protected Least Significant Difference test was used for multiple comparisons. A p value ≤ 0.05 was considered significant. The software used is StatView 5.0 from SAS Institut. [00356] In some embodiments, a compound of the present disclosure increases the pattern of neurite outgrowth. In some embodiments, a compound of the present disclosure increases neurite average length compared to a control. In some embodiments, a compound of the present disclosure increases neurite branch points compared to a control. In some embodiments, a compound of the present disclosure significantly increases the number of new neurites and/or the average neurite length compared to a control. [00357] The plastogenic potential of the compounds ((as measured by the Neurite Outgrowth Procedure B) is shown in Table 9 (benzofurans) and Table 10 (benzothiophenes). Table 9. Neurite Outgrowth in Primary Rat Neuronal Cultures
A: Statistically significant mean increase as a percent of DMSO control at 10 μM or less B: No statistically significant mean increase as a percent of DMSO control at 10 μM or less Table 10. Neurite Outgrowth in Primary Rat Neuronal Cultures A: Statistically significant mean increase as a percent of DMSO control at 10 μM or less B: No statistically significant mean increase as a percent of DMSO control at 10 μM or less [00358] In some embodiments, a compound of the present disclosure increases the pattern of neurite outgrowth. In some embodiments, a compound of the present disclosure increases neurite average length compared to a control. In some embodiments, a compound of the present disclosure increases neurite branch points compared to a control. In some embodiments, a compound of the present disclosure significantly increases the number of new neurites and/or the average neurite length compared to a control. [00359] 5HT 2A Sensor Assays. HEK293T (ATCC) 5HT2A sensor stable line (sLight1.3s) is generated via lentiviral transduction of HIV-EF1α-sLight1.3 and propagated from a single colony. Lentivirus is produced using 2 nd generation lentiviral plasmids pHIV-EF1α -sLight1.3, pHCMV-G, and pCMV-deltaR8.2. [00360] For the screening, sLight1.3s cells are plated in 96-well plates at a density of 4000024- hours prior to imaging. On the day of imaging, compounds solubilized in DMSO are diluted from the 100mM stock solution to working concentrations of 1mM, 100μM and 1μM with a DMSO concentration of 1%. Immediately prior to imaging, cells growing in DMEM (Gibco) are washed 2x with HBSS (Gibco) and in agonist mode 180 μL of HBSS or in antagonist mode 160 μL of HBSS is added to each well after the final wash. For agonist mode, images are taken before and after the addition of the 20 μL compound working solution into the wells containing 180 μL HBSS. This produces final compound concentrations of 100μM, 10μM and 100nM with a DMSO concentration of 0.1%. For antagonist mode, images are taken before and after addition of 20 μL of 900nM 5-HT and again after 20 μL of the compound working solutions to produce final concentrations of 100nM for 5HT and 100μM, 10μM and 100nM for the compounds with a DMSO concentration of 0.1%. Compounds are tested in triplicates (3 wells) for each concentration (100μM, 10μM and 100nM). Additionally, within each plate, 100nM 5HT and 0.1% DMSO controls are also imaged. [00361] Imaging is performed using the Leica DMi8 inverted microscope with a 40x objective using the FITC preset with an excitation of 460nm and emission of 512-542nm. For each well, the cellular membrane where the 5HT2A sensor is targeted is autofocused using the adaptive focus controls and 5 images from different regions within the well are taken with each image processed from a 2x2 binning. [00362] For data processing, the membranes from each image are segmented and analyzed using a custom algorithm written in MATLAB producing a single raw fluorescence intensity value. For each well the 5 raw fluorescence intensity values generated from the 5 images are averaged and the change in fluorescence intensity (dFF) is calculated as: dFF = (F sat – F apo )/ F apo [00363] For both agonist and antagonist modes, the fluorescence intensity values before compound addition in HBSS only are used as the Fapo values while the fluorescence intensity values after compound addition are used as the F sat values. [00364] For agonist mode, data are as percent activation relative to 5HT, where 0 is the average of the DMSO wells and 100 is the average of the 100 uM 5HT wells. For antagonist mode, the inactivation score is calculated as: Inactivation score = (dFFF(Compound+5HT) – dFF(5HT))/dFF(5HT) [00365] Head twitch response (HTR) experiments. C57BL/6J Mice (9–10 weeks old) are housed following an IACUC approved protocol. The mice are habituated in the test cage for at least 30 min, injected intraperitoneally with compound (injection volume 5 ml/kg), returned to the empty test cage, and filmed for 20 minutes. Each video is scored for the number of head-twitches by a trained observer blinded to treatment condition. [00366] Forced Swim Test (FST). Male Sprague Dawley rats from Envigo (Indianapolis, IN) are obtained and housed 3 rats per cage following an IACUC approved protocol. All experiments are carried out at ambient temperatures (20 and 23°C) under artificial lighting during the light-on part of the light/dark cycle in a Forced Swim chamber constructed of clear acrylic (height = 40 cm; diameter = 20.3 cm). Only one rat is placed in the swim chamber at a time for each swim test. The water is changed and the chamber cleaned between each animal. All rats are exposed to two swim sessions. The water depth is 16 cm in the first swim session and 30 cm in the second swim session, and the water temperature is maintained at 23±1 °C for all swim sessions. During the FST, animals undergo a 15 min swim session (pre-swim), lasting for 15 minutes, dried with paper towels, and returned to the home cage. Rats are injected with either saline, ketamine (positive control), or test compound after the habituation session, returned to home cage, and then tested in a second FST lasting 5 minutes ~24 hours (second swim test) later. The second swim test is video recorded for scoring. Body weights are measured on both days. Scoring of the second swim test is performed by trained technicians using a time sampling technique in which the animal in the video recorded test is viewed every 5 seconds and the behavior seen is noted. The measures noted are immobility, climbing, and swimming behaviors. [00367] Statistical analysis. Treatments are randomized, and data are analyzed by experimenters blinded to treatment conditions. Statistical analyses are performed using GraphPad Prism (version 8.1.2). Comparisons are planned prior to performing each experiment. [00368] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.
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