LSD Derivatives, Synthesis, and Methods for Treating Diseases and Disorders

Abstract

Described herein are LSD derivative compounds and polymorphs thereof, methods for their synthesis, compositions, and treatment of diseases and disorders. The compounds have the structure of Formula I, including pharma- ceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof; [Formula 1] TIFF2024545931000105.tif54170 (wherein R1 to R14 are each independently selected from H or a substituted or unsubstituted hydrocarbon group, and X is selected from a halo group).

Description

[Technical field]

[0001] (Field) This application relates generally to novel LSD derivatives and polymorphs thereof, their compositions, methods for their synthesis, and their therapeutic uses. [Background technology]

[0002] BACKGROUND OF THEINVENTION LSD, commonly known as acid, scientifically known as lysergic acid diethylamide, is a semi-synthetic, powerful hallucinogen that produces a variety of effects ranging from intense sensory distortion and intense eye-opening hallucinations to feelings of spirituality and connectedness to everything. LSD can induce dissociative states in users, sometimes causing them to have full-blown panic attacks.

[0003] LSD is classified as a substance that is strictly controlled by regulatory agencies and is therefore illegal in most parts of the world. However, LSD does have its upsides as it is not addictive and has been shown to promote neuronal proliferation.

[0004] It would be beneficial to provide a non-hallucinogenic form of LSD that retains at least one of its beneficial properties. Summary of the Invention

[0005] (Summary of the invention) This disclosure describes lysergic acid diethylamide (LSD) derivatives and crystalline polymorphs thereof for general and pharmaceutical use. The present disclosure generally relates to a compound of formula I: [ka] (In the formula: R 1 ~R 14are each independently selected from H or a substituted or unsubstituted hydrocarbon group, and X is selected from a halo group. or a pharma- ceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, diastereomer, racemate, polymorph, or combination thereof.

[0006] According to an embodiment of the present invention are novel compounds of formula I. In an embodiment, they are substantially non-hallucinogenic and in a further embodiment, surprisingly, they do not induce tolerance, as is known to be the case with LSD.

[0007] According to an embodiment of the present invention are novel polymorphic compounds of formula I. In an embodiment, they are substantially non-hallucinogenic, and in a further embodiment, surprisingly, they do not induce tolerance, as is known to be the case with LSD.

[0008] The LSD derivative compound of formula I and its polymorph(s) include crystalline forms, optionally isolated crystalline forms. In an embodiment, the invention includes polymorphs, optionally isolated polymorphs. In an embodiment, the invention includes substantially one crystalline form. In an embodiment, the invention includes substantially one polymorph. In an embodiment, the invention includes one or more polymorphs thereof that are substantially free of solvates. In a currently preferred embodiment, the polymorph is substantially free of water. In an embodiment, the compound is (5R,8R) 2-bromo-LSD hemi-D-tartrate.

[0009] In an embodiment, the compound is an isolated polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate. In a further embodiment, the isolated polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate (E559) is formulated as a composition or formulation.

[0010] Another embodiment of the present invention encompasses a pharmaceutical composition comprising a compound of formula I substantially free of solvates, and a pharma- ceutically acceptable carrier, diluent, or excipient therefor. In another embodiment, the pharmaceutical compositions contemplated herein further comprise additional forms of formula I in crystalline, solvated, or amorphous form.

[0011] According to a further aspect are compositions and formulations of the non-hallucinogenic LSD derivative(s), including its polymorph(s).

[0012] The compositions and formulations include LSD derivative(s) represented by formula I; formula I'; formula Ia, formula Ib, formula Ic, formula Id; formula Ia', formula Ib', formula Ic', formula Id'; formula Ia'', formula Ib'', formula Ic'', formula Id''; formula IA, formula IB, formula Ic, formula Id; formula IAA, formula IBB, formula ICC, formula IDD; formula IAA', formula IBB', formula ICC', formula IDD'; formula IAA'', formula IBB'', formula ICC'', formula IDD''; formula IAA''', formula IBB''', formula ICC'', formula IDD''; formula IAA''', formula IBB''', formula ICC''', formula IDD'' and polymorph(s) thereof; and any mixtures thereof.

[0013] According to a further aspect is the use of the compounds / compositions / formulations of the LSD derivatives and polymorphs disclosed herein to treat one or more of the following: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma and stressor-related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating behavior and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; neurological-viral infections; countering the side effects of other medications; and general well-being.

[0014] In embodiments, the novel LSD derivative and polymorphic compounds / compositions / formulations disclosed herein are for reducing one or more signs or symptoms of any one or more of the following: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma and stressor related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating behavior and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; and neurological-viral infections.

[0015] In some embodiments, the compounds of the invention are not alternatively used for the treatment of recurrent cluster headache disorder, where the subject has a recurrent cluster headache disorder, which in embodiments is refractory to one or more preventive therapies. In embodiments, the compounds of the invention are not alternatively used for the treatment of a disorder that is a trigeminal autonomic headache, by enteral, sublingual, or parenteral administration.

[0016] It will be understood that the compounds of the present disclosure can be described as embodiments in any of the following listed items: Any embodiment described herein can be used with any other embodiment described herein, unless the aspects are mutually inconsistent.

[0017] Aspects disclosed herein include the following: 1. Formula I: [ka] (In the formula: R 1 ~R 14 are each independently selected from H or a substituted or unsubstituted hydrocarbon group, and X is selected from a halo group. A compound having the structure: Figure imgf000023_0001 or a pharma- ceutically acceptable salt, hydrate, solvate, tautomer, enantiomer, diastereomer, racemate, polymorph, or combination thereof. 2. The compound of claim 1, which is crystalline. 3. The compound of claim 1 or 2 in isolated crystalline form. 4. The compound of any one of claims 1 to 3, including its polymorph(s). 5. The compound of any one of claims 1 to 4, including a single polymorph thereof. 6. The compound of any one of claims 1 to 5, including isolated polymorphs thereof. 7. A compound according to any one of claims 1 to 6, comprising: (i) the compound is one or more of its polymorphs; (ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; (iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; (iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters which are 5R,8R; vi) the compound has two stereocenters which are 5R,8S; and vii) Any one or more of (i) to (vi); The compound. 8. A compound according to claim 1 or 2 having the stereocenters 5S,8R; 5R,8R; 5R,8S; or 5S,8S. 9. The compound according to claim 8, having the stereocenters 5S,8R; 5R,8R; or 5R,8S. 10. The compound of claim 9 having a stereocenter selected from 5R,8S or 5R,8R. 11. The compound according to any one of claims 1 to 10, which is a pharma- ceutical acceptable salt, hydrate, and / or solvate thereof. 12. The compound according to any one of claims 1 to 5, which is an acid salt. 13. The acid of the acid salt is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid 13. The compound of claim 12, wherein the compound is selected from the group consisting of succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 14. The compound of claim 13, wherein the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 15. The compound of claim 14, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 16. R 1 ~R 14are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 17. R 1 ~R 14 17. The compound of claim 16, wherein each is independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 18. R 1 ~R 14 18. The compound of claim 17, wherein each is independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. 19. R 1 ~R 14 20. The compound of claim 18, wherein each is independently selected from H, a methyl group, or an ethyl group. 20. R 1 and R 2 are each independently selected from H, a methyl group, or an ethyl group; R 3 , R 4 , and R 6 ~R 14 are H and R 5 The compound according to any one of claims 1 to 19, wherein is a methyl group. 21. R 1 and R 2 are each independently selected from a methyl group or an ethyl group; R 3 , R 4 , and R 6 ~R 14 are each H; and R 5 The compound according to any one of claims 1 to 20, wherein is a methyl group. 22. R 1 and R 2 are each an ethyl group; R 3 , R 4 , and R 6 ~R 14 are each H; and R 5 The compound according to any one of claims 1 to 21, wherein is a methyl group. 23. The compound of any one of claims 1-22, wherein X is selected from bromo, chloro, fluoro, or iodo. 24. The compound of claim 23, wherein X is selected from bromo, chloro, or fluoro. 25. The compound of claim 24, wherein X is selected from bromo or chloro. 26. The compound of claim 23, wherein X is bromo. 27. Formula I': [ka] (In the formula: R 1 and R 2 are each independently selected from H or a substituted or unsubstituted hydrocarbon group. 2. The compound of claim 1 having the structure: 28. The compound of claim 27, which is crystalline. 29. The compound of claim 27 or 28, in isolated crystalline form. 30. The compound of any one of claims 27-29, including its polymorph(s). 31. The compound of any one of claims 27-30, including a single polymorph thereof. 32. The compound of any one of claims 27-31, including an isolated polymorph thereof. 33. The compound according to any one of claims 27 to 32, wherein i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters which are 5R,8R; or vi) the compound has two stereocenters which are 5R,8S. 34. The compound of claim 27 or 28, wherein the compound has a stereocenter selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S. 35. The compound of claim 34 having a stereocenter selected from 5S,8R; 5R,8R; or 5R,8S. 36. The compound of claim 35 having a stereocenter selected from 5R,8S or 5R,8R. 37. The compound according to any one of claims 27 to 36, which is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. 38. The compound of any one of claims 27 to 37, which is an acid salt. 39. The acid of the acid salt is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid 39. The compound of claim 38, wherein the compound is selected from succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 40. The compound of claim 39, wherein the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 41. The compound of claim 40, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 42. R 1 and R 242. The compound according to any one of claims 27 to 41, wherein each is independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 43. R 1 and R 2 43. The compound of claim 42, wherein each is independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 44. R 1 and R 2 44. The compound of claim 43, wherein each is independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. 45. R 1 and R 2 45. The compound of claim 44, wherein each is independently selected from H, a methyl group, or an ethyl group. 46. ​​R 1 and R 2 46. ​​The compound of claim 45, wherein each is independently selected from a methyl group or an ethyl group. 47. R 1 and R 2 47. The compound of claim 46, wherein each is an ethyl group. 48. The following: [ka] TIFF2024545931000006.tif203170 (in the formula: R 1 and R 2 are each independently selected from H or a substituted or unsubstituted hydrocarbon group. 28. The compound of claim 27, having a structure of Formula I' selected from: 49. The compound of claim 48, which is crystalline. 50. The compound of claim 48 or 49, in isolated crystalline form. 51. The compound of any one of claims 48-50, including its polymorph(s). 52. The compound of any one of claims 48-51, including a single polymorph thereof. 53. The compound of any one of claims 48-52, including an isolated polymorph thereof. 54. The compound of any one of claims 48-53, wherein i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters which are 5R,8R; or vi) the compound has two stereocenters which are 5R,8S. 55. The compound of claim 48 or 49, wherein formula I' is selected from formula Ia; formula Ib; or formula Id. 56. The compound of claim 55, wherein formula I' is formula Ib or formula Id. 57. The compound according to any one of claims 48 to 56, which is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. 58. The compound of any one of claims 48 to 57, which is an acid salt. 59. The acid of the acid salt is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid 59. The compound of claim 58, wherein the compound is selected from succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 60. The compound of claim 59, wherein the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 61. The compound of claim 60, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 62. R 1 and R 2are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 63. R 1 and R 2 63. The compound of claim 62, wherein each is independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 64. R 1 and R 2 64. The compound of claim 63, wherein each is independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. 65. R 1 and R 2 65. The compound of claim 64, wherein each is independently selected from H, a methyl group, or an ethyl group. 66. R 1 and R 2 66. The compound of claim 65, wherein each is independently selected from a methyl group or an ethyl group. 67. R 1 and R 2 67. The compound of claim 66, wherein each is an ethyl group. 68. Below: [ka] 28. The compound of claim 27, having a structure of Formula I' selected from TIFF2024545931000008.tif64170, a pharma- ceutically acceptable salt, hydrate, solvate, tautomer, polymorph, or combination thereof. 69. The compound of claim 68, which is crystalline. 70. The compound of claim 68 or 69, in isolated crystalline form. 71. The compound of any one of claims 68-70, including its polymorph(s). 72. The compound of any one of claims 68-71, including a single polymorph thereof. 73. The compound of any one of claims 68-72, including an isolated polymorph thereof. 74. The compound of any one of claims 68-73, wherein i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters which are 5R,8R; or vi) the compound has two stereocenters which are 5R,8S. 75. The compound of claim 73 or 74, wherein formula I' is selected from formula Ia'; formula Ib'; or formula Id'. 76. The compound of claim 75, wherein formula I' is formula Ib' or formula Id'. 77. The compound of any one of claims 68-76, a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. 78. The compound of any one of claims 68-77, which is an acid salt. 79. The acid of the acid salt is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid 80. The compound of claim 78, wherein the compound is selected from succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 80. The compound of claim 79, wherein the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 81. The compound of claim 80, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 82. The following: [ka] 28. The compound of claim 27, having a structure of formula I' selected from TIFF2024545931000010.tif56170, or a combination thereof. 83. The compound of claim 82, which is crystalline. 84. The compound of claim 82 or 83, in isolated crystalline form. 85. The compound of any one of claims 82-84, including its polymorph(s). 86. The compound of any one of claims 82-85, including an isolated polymorph thereof. 87. The compound of any one of claims 82-86, wherein i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. 88. The compound of claim 82 or 83, wherein formula I' is selected from formula Ia''; formula Ib''; or formula Id''. 89. The compound of claim 88, wherein formula I' is formula Ib' or formula Id'. 90. The compound of any one of claims 82-89, a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. 91. The compound of any one of claims 82-90, which is an acid salt. 92. The acid of the acid salt is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid 92. The compound of claim 91, wherein the compound is selected from succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 93. The compound of claim 92, wherein the acid of the acid salt is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. 94. The compound of claim 93, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 95. The following: [ka] 95. The compound of any one of claims 1 to 94, selected from TIFF2024545931000012.tif134170TIFF2024545931000013.tif135170TIFF2024545931000014.tif130170 or a combination thereof. 96. The compound of claim 95, which is crystalline. 97. The compound of claim 95 or 96, in isolated crystalline form. 98. The compound of any one of claims 95-97, including its polymorph(s). 99. The compound of any one of claims 95-98, including a single polymorph thereof. 100. The compound of any one of claims 95-99, including an isolated polymorph thereof. 101. The compound of any one of claims 95-100, wherein i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. 102. The compound of any one of claims 95-101, wherein the compound comprises 2-bromo LSD tartrate (about 1:about 0.5) and / or (about 1:about 1), i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. 103. The compound of any one of claims 1-102, wherein the ratio of the compound of formula I, I', Ia, Ib, Ic, Id, Ia', Ib', Ic', or Id' to the acid is from about 0.5:1 to about 2:1. 104. The compound of any one of claims 1-103, wherein the compound is (5R,8R) 2-bromo-LSD hemi-D-tartrate. 105. The compound of any one of claims 1-104, wherein the compound is an isolated polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate. 106. The compound of any one of claims 1 to 105, having a powder X-ray diffraction (PXRD) pattern including a peak at about 10.3° (2θ). 107. The compound of any one of claims 1-105, having an X-ray powder diffraction (PXRD) pattern including peaks at about 4.7° (2θ), about 9.4° (2θ), and about 10.3° (2θ). 108. The compound of any one of claims 1 to 105, having an X-ray powder diffraction (PXRD) pattern including peaks at about 4.7° (2θ), about 9.4° (2θ), about 10.3° (2θ), and about 20.1° (2θ). 109. The compound of any one of claims 1-105, having a powder X-ray diffraction (PXRD) pattern including a peak at about 10.3° (2θ) with a d value of about 8.6 Å. 110. The compound of any one of claims 1-105, having an X-ray powder diffraction (PXRD) pattern including peaks at about 4.7° (2θ) with a d value of about 18.8 Å, at about 9.4° (2θ) with a d value of about 9.4 Å, and at about 10.3° (2θ) with a d value of about 8.6 Å. 111. The compound of any one of claims 1-105, having an X-ray powder diffraction (PXRD) pattern including peaks at about 4.7° (2θ) with a d value of about 18.8 Å, at about 9.4° (2θ) with a d value of about 9.4 Å, at about 10.3° (2θ) with a d value of about 8.6 Å, and at about 20.1° (2θ) with a d value of about 4.4 Å. 112. The compound of any one of claims 1 to 105, having a powder X-ray diffraction (PXRD) pattern including a peak at 10.3°±0.2° (2θ). 113. The compound of any one of claims 1 to 105, having an X-ray powder diffraction (PXRD) pattern including peaks at 4.7°±0.2° (2θ), 9.4°±0.2° (2θ), and 10.3°±0.2° (2θ). 114. The compound of any one of claims 1 to 105, having an X-ray powder diffraction (PXRD) pattern including peaks at 4.7°±0.2° (2θ), 9.4°±0.2° (2θ), 10.3°±0.2° (2θ), and 20.1°±0.2° (2θ). 115. The compound of any one of claims 1-105, having an optical rotation of from about 0.30° to about 0.40°; optionally, from about 0.30° to about 0.35°. 116. The compound of any one of claims 1-115, wherein the compound or a polymorph thereof is non-hallucinogenic. 117. The compound of any one of claims 1-116, wherein the compound or a polymorph thereof is substantially non-hallucinogenic. 118. A compound according to any one of claims 1 to 117, which does not induce resistance in a subject. 119. A compound according to any one of claims 1 to 118 which is a moderate to potent pan agonist across all 5-HT1 receptor subtypes. 120. A compound of any one of claims 1-119 that is a potent 5-HT6 receptor partial agonist. 121. A compound of any one of claims 1-120 that is a partial agonist at the 5-HT2A and 5-HT1A receptor subtypes. 122. A compound according to any one of claims 1 to 121, which exhibits receptor activating activity at D2-like receptors, including D2 and D4. 123. A compound according to any one of claims 122, which enhances neuroplasticity in neurons, e.g., in cortical neurons. 124. A composition comprising a compound according to any one of claims 1-123. 125. The composition of claim 124, further comprising a pharma- ceutically acceptable carrier, adjuvant, or vehicle. 126. The composition of claim 124 or 125, further comprising a second therapeutic agent. 127. The composition of any one of claims 124 to 126, which is a pharmaceutical composition. 128. A formulation comprising the composition of any one of claims 124-126 and / or the pharmaceutical composition of claim 127. 129. The formulation of claim 128, which is a liquid or solid, optionally wherein the solid is a powder, tablet, or pill. 130. The formulation of claim 128 or 129, comprising an established amount of said compound, optionally for oral or parenteral administration. 131. The formulation of any one of claims 128-130, wherein the formulation is for making a medicament for the treatment of one or more of: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma- and stress-related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; neurological-viral infections; countering side effects of other medications; and general well-being. 132. The formulation of any one of claims 128-130, wherein the formulation is for the treatment of one or more of: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma and stressor-related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; neurological-viral infections; combating side effects of other medications; and general well-being. 133. The formulation of any one of claims 128 to 130, wherein the formulation is for reducing one or more signs or symptoms of any one or more of the following: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma and stressor-related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; and neurological-viral infections. 134. a) Hydrolyzing a compound of formula IA to produce an intermediate of formula IB. [ka] b) reacting said intermediate of formula IB with R 1 -NH-R 2 to form a compound of formula IC. [ka] c) converting the compound of formula IC to a salt or hydrate with an organic or inorganic acid, 77. A method of making a compound according to any one of claims 1 to 76, wherein R is selected from -OR1 or -NR1R2, and R1 and R2 are each independently selected from H, halo, hydroxyl, amino, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted hybrid group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group, and optionally R1 and R2 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted hybrid group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group. 135. The method of claim 134, wherein the method of making does not use LSD and / or other Schedule I substances as substrates. 136. The method of claim 134 or 135, wherein the hydrolysis is acid or base hydrolysis, and optionally the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid, or the base is selected from potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and / or tetrabutylammonium hydroxide. 137. The method of claim 134, 135, or 136, further comprising using a water-miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, or a combination thereof. 138. The method of any one of claims 134-137, comprising heating to about 50°C to about 95°C in a), b), and / or c). 139. The method of any one of claims 134-137, wherein b) further comprises converting the hydroxyl group of the carboxylic acid to a better leaving group (LG) such as a halide (e.g., Cl, Br, I), tosylate, mesylate, or perfluoroalkylsulfonate, optionally converting to an acid chloride using phosphoryl chloride or thionyl chloride. 140. The method of any one of claims 134-139, wherein b) further comprises base-catalyzed amide bond formation (optionally using a base and a coupling agent). 141. The coupling agent is selected from the group consisting of carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl 141. The method of claim 140, wherein the aryl group is selected from cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof. 142. The method of claim 141, wherein the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate azabenzotriazole tetramethylnium (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof. 143. The method of any one of claims 134-142, wherein b) further comprises base-catalyzed amide bond formation, optionally using N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI). 144. The method of any one of claims 134 to 143, wherein in a) and / or b) the acidity of the intermediates of formula IB and formula IC is adjusted to cause precipitation; optionally by adjusting the pH to about 6 to about 8 with an acid. 145. The process of any one of claims 134-144, wherein in c) the compound of formula IC is converted to its salt or hydrate using an organic or inorganic acid, either in situ together with (b) or in a separate, independent step. 146. The acid is hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, cobalt acid, butyl ... 146. The method of claim 145, wherein the acid is selected from citrate, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or a combination thereof. 147. The method of any one of claims 134-146, wherein c) comprises heating the compound of formula IC with the organic or inorganic acid in a water immiscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc., or a combination thereof. 148. The method of any one of claims 134-147, wherein c) comprises heating at a temperature of about 60°C to about 80°C, optionally about 60°C to about 70°C. 149. The method of any one of claims 134-148, wherein the water-miscible solvent is selected from methanol, ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, the water-miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA). 150. The method of any one of claims 134-149, wherein heating the compound of formula IC with the organic or inorganic acid is for about 30 minutes to about 1 hour. 151. The method of any one of claims 134 to 150, wherein the compound is cooled in solution to about 0 to about 10°C, optionally to about 3 to about 7°C, optionally to about 5°C, and optionally for about 30 minutes to about 2 hours. 152. The method of any one of claims 134-151, wherein the salt or hydrate of the compound of formula IC is recrystallized to produce a crystalline compound. 153. The method of claim 152, wherein the salt or hydrate of the compound of formula IC is in an isolated crystalline form. 154. The method of claim 153, wherein the salt or hydrate of the compound of formula IC includes polymorph(s) thereof. 155. The method of claim 154, wherein the salt or hydrate of the compound of formula IC includes a single polymorph thereof. 156. The method of claim 155, wherein the salt or hydrate of the compound of formula IC includes an isolated polymorph thereof. 157. The method of any one of claims 134-156, wherein the salt or hydrate of the compound of formula IC is recrystallized using a water-miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc., or a combination thereof. 158. The method of claim 157, wherein the water-miscible solvent is selected from methanol, ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, the water-miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA). 159. The process of any one of claims 134-158, wherein recrystallizing comprises heating the salt or hydrate of the compound of formula IC in the solvent to a suitable temperature for a suitable period of time, and cooling to yield the compound of any one of claims 27-123. 160. The method of any one of claims 134-158, wherein recrystallizing comprises heating the salt or hydrate of the compound of formula IC in the solvent at about 60°C to about 80°C, optionally about 60°C to about 70°C. 161. The method of any one of claims 134-158, wherein recrystallizing comprises heating the salt or hydrate of the compound of formula IC in the solvent at about 60°C to about 80°C, optionally about 60°C to about 70°C, for about 1 hour to about 2 hours. 162. The method of any one of claims 134-158, wherein recrystallizing comprises heating the salt or hydrate of the compound of formula IC in the solvent at about 60°C to about 80°C, optionally about 60°C to about 70°C, for about 1 hour to about 2 hours, and cooling the compound in solution to about 0 to about 10°C, optionally about 3 to about 7°C, optionally about 5°C, optionally for about 1 hour to about 2 hours. 163. The method of any one of claims 134-162, wherein the recrystallized compound is about 99% to about 99.9% pure, optionally about 99.5% to about 99.9% pure. 164. a) Hydrolysis of compound of formula IAA (5S,8R) to give intermediate of formula IBB. [ka] b) reacting said intermediate of formula IBB with R 1 -NH-R 2 to produce the formula ICC. [ka] 164. The process of any one of claims 134-163, comprising c) converting the compound of formula ICC to a salt or hydrate using an organic or inorganic acid. 165. a) Hydrolysis of a compound of formula IAA' (5R,8R) to give an intermediate of formula IBB'. [ka] b) reacting said intermediate of formula IBB′ with R 1 -NH-R 2 to produce a compound of formula ICC'. [ka] c) converting the compound of formula ICC' into a salt or hydrate using an organic or inorganic acid; The method of any one of claims 134 to 163, comprising: 166. a) Hydrolysis of a compound of formula IAA″ (5R,8S) to produce an intermediate of formula IBB″. [ka] b) reacting said intermediate of formula IBB″ with R 1 -NH-R 2 to produce a compound of formula ICC''. [ka] c) converting the compound of formula ICC″ into a salt or hydrate using an organic or inorganic acid; The method of any one of claims 134 to 163, comprising: 167. a) Hydrolysis of compound (5S,8S) of formula IAA''' to produce intermediate of formula IBB'''. [ka] b) reacting said intermediate of formula IBB''' with R 1 -NH-R 2 to produce a compound of formula ICC''' [ka] c) converting the compound of formula ICC'' into a salt or hydrate using an organic or inorganic acid; The method of any one of claims 134 to 163, comprising: 168. The method of any one of claims 134-167, wherein the compound of formula IA, formula IAA, formula IAA', formula IAA'', or formula IAA''' is a bromine-containing ergoline derivative, such as bromocriptine mesylate. 169. The compound of formula IA, formula IAA, formula IAA', formula IAA'', or formula IAA''', [ka] The method according to any one of claims 134 to 167, 170. Heating 2-bromolysergic diamide and IPA. combining D-tartaric acid and IPA with 2-bromolysergic diamide and IPA, the combined solution becoming clear; heating the combined solution for a period of time; allowing the mixture to cool to about room temperature; Further cooling provides a solid containing a major amount of (5R,8R) 2-bromo-LSD hemi-D-tartrate and a minor amount of (5R,8S) 2-bromo-LSD hemi-D-tartrate. The method of any one of claims 134 to 169, comprising: 171. Heating 2-bromolysergic acid diamide and IPA to about 65°C; combining D-tartaric acid and IPA with 2-bromolysergic diamide and IPA, the combined solution becoming clear; heating the combined solution to about 65° C. for a period of time; allowing the mixture to cool to about room temperature; Cooling to about 5° C. provides a solid containing a major amount of (5R,8R) 2-bromo-LSD hemi-D-tartrate and a minor amount of (5R,8S) 2-bromo-LSD hemi-D-tartrate. The method of any one of claims 134 to 170, comprising: 172. The method of claim 171, wherein the predetermined time is about 30 minutes. 173. The method of any one of claims 134-172, wherein the ratio of (5R,8R) 2-bromo-LSD hemi-D-tartrate to (5R,8S) 2-bromo-LSD hemi-D-tartrate is about 87 to about 13. 174. The method of any one of claims 134-172, wherein the solid is recrystallized to obtain (5R,8R) 2-bromo-LSD hemi-D-tartrate, optionally using ethanol. 175. The method of any one of claims 134-172, wherein the solid is recrystallized to obtain (5R,8R) 2-bromo-LSD hemi-D-tartrate having a purity of about 99% to about 99.9%, optionally about 99.5% to about 99.9%. 176. The method of any one of claims 134-135, wherein the solid is a polymorph. 177. A method for treating a depressive disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 178. The method of claim 177, wherein the depressive disorder is: depressive state, major depressive disorder (including major depressive episode), major mood dysregulation disorder, atypical depression, major psychotic depression, catatonic depression, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, substance / medication-induced depressive disorder, bilateral depression, depressive personality disorder, persistent depressive disorder (dysthymia), recurrent brief depression, minor depressive disorder, depressive disorder due to a medical condition, depressive disorder not otherwise specified, or treatment-resistant depressive disorder. 179. The method of claim 177 or 178, wherein the depressive disorder is major depressive disorder. 180. The method of claim 179, wherein the major depressive disorder is dysthymia. 181. The method of claim 178, wherein the depressive disorder is atypical depression. 182. The method of claim 178, wherein the depressive disorder is catatonic depression. 183. The method of claim 178, wherein the depressive disorder is caused by a medical condition. 184. The method of claim 177, wherein the depressive disorder is postpartum depression. 185. The method of claim 177, wherein the depressive disorder is premenstrual dysphoric disorder. 186. The method of claim 177, wherein the depressive disorder is seasonal affective disorder. 187. The method of any one of claims 177 to 186, wherein the amount of the compound for administration to the subject is in a range selected from about 25 to 500 μg / kg / body weight / day; or about 50 to about 2000 μg / kg / body weight / day; or about 10 to about 500 μg / kg / body weight / day. 199. A method for treating bipolar disorder and related disorders, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 200. The method of claim 199, wherein the bipolar disorder and related disorders are bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder not otherwise specified. 201. The method of claim 200, wherein the amount of the compound for administration to the subject is in a range selected from about 25 to about 1000 μg / kg / body weight / day. 202. A method for treating schizophrenia spectrum disorders and other psychotic disorders comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 203. The method of claim 202, wherein the schizophrenia spectrum disorder and other psychotic disorders are: delusional disorder, brief psychotic disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, substance / drug-induced psychotic disorder, schizotypal (personality) disorder, psychotic disorder caused by another medical condition, catatonia associated with another psychiatric disorder, and other specified or unspecified schizophrenia spectrum and other psychotric disorders. 204. The method of claim 203, wherein the amount of the compound for administration to the subject ranges from about 50 to about 2000 μg / kg / body weight / day. 205. A method for treating a personality disorder classified by DSM-5, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 206. The method of claim 205, wherein the personality disorder is: paranoid personality disorder; schizoid personality disorder; schizotypal personality disorder; antisocial personality disorder; borderline personality disorder; histrionic personality disorder; narcissistic personality disorder; avoidant personality disorder; dependent personality disorder; obsessive-compulsive personality disorder; personality change due to another medical condition; other specified personality disorder, and unspecified personality disorder. 207. A method for treating anxiety comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 208. The method of claim 207, wherein the anxiety disorder is: generalized anxiety disorder, separation anxiety disorder, panic disorder, selective mutism, specific phobias (fear of animals, natural environment, blood / injections / trauma, situational, other), social anxiety disorder, panic disorder, panic attack specific terms, agoraphobia, substance / drug induced anxiety, anxiety caused by other medical conditions, and other specified or unspecified anxiety disorders. 209. The method of claim 208, wherein the amount of the compound for administration to the subject ranges from about 10 to about 1000 μg / kg / body weight / day. 210. A method for treating trauma and stress-related disorders comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 211. The method of claim 210, wherein the trauma- and stress-related disorder comprises attachment disorder, disinhibited interpersonal disorder, post-traumatic stress disorder (PTSD), acute stress disorder, adjustment disorder, or other specified or unspecified trauma- and stress-related disorder. 212. The method of claim 211, wherein the amount of the compound for administration to the subject ranges from about 10 to about 1000 μg / kg / body weight / day. 213. A method for treating obsessive-compulsive disorder and related disorders, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 214. The method of claim 213, wherein said obsessive-compulsive disorder and related disorders include: obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking disorder), substance / drug-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders caused by another medical condition, and other specified and unspecified obsessive-compulsive disorder and related disorders (e.g., body-focused repetitive behavior disorder, obsessive jealousy). 215. The method of claim 214, wherein the amount of the compound for administration to the subject ranges from about 10 to about 1000 μg / kg / body weight / day. 216. A method for treating disruptive, impulse-control, and conduct disorders comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 217. The method of claim 216, wherein the disruptive, impulse control and conduct disorders include: oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, trichotillomania, and other specified and unspecified disruptive, impulse control and conduct disorders. 218. A method for treating eating disorders and eating disorders comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 219. The method of claim 218, wherein the eating disorders and alimentary disorders include: pica, rumination disorder, avoidant-restrictive food intake disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, polyphagia or over-eating disorder, diabetic bulimia, Prader-Willi syndrome, and hypothalamic obesity, body dysmorphic disorder, and other specified and unspecified eating disorders or alimentary disorders. 220. A method for treating a dissociative disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 221. The method of claim 220, wherein the dissociative disorder comprises dissociative identity disorder, dissociative amnesia, depersonalization-derealization disorder, and other specified and unspecified dissociative disorders. 222. A method for treating a neurodevelopmental disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 223. The method of claim 222, wherein the neurodevelopmental disorder comprises: intellectual disability (intellectual developmental disorder), global developmental delay, communication (language, speech, childhood-onset fluency or stuttering, social, non-specific) disorders, autism spectrum disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), specific learning disorder, movement disorders (developmental coordination, stereotypy, Tourette's disorder, persistent / chronic motor or vocal tic disorder, provisional tic disorder), and other specified or unspecified neurodevelopmental disorders. 224. A method for treating a disorder comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130, wherein the disorder comprises: seizures (including generalized seizures, focal seizures, seizures of unknown onset, and bilateral seizures of focal onset) and epilepsy (including generalized epilepsy, focal epilepsy, generalized and focal epilepsy, Dravet syndrome, and epilepsy of unknown onset). 225. A method for treating a sleep-wake disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 226. The method of claim 225, wherein the sleep-wake disorder comprises: insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder (e.g., obstructive sleep apnea-hypopnea, central sleep apnea, idiopathic central sleep apnea, sleep-related hypoventilation), circadian rhythm sleep-wake disorder, non-rapid eye movement (NREM) sleep-wake disorder, nightmare disorder, rapid eye movement (REM) sleep behavior disorder, restless legs syndrome, substance / drug-induced sleep disorder, and other specified and unspecified sleep-wake disorders. 227. A method for treating substance-related disorders (SRD) and addictive disorders, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 226. The method of claim 227, wherein the substance-related disorders (SRDs) and addictive disorders include, but are not limited to, the following classes of drugs: alcohol, nicotine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (amphetamine-type substances, cocaine, and other stimulants), and pharmaceuticals, as well as other specified or unspecified substance-induced disorders. 227. A method for treating a non-substance related disorder comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 228. The method of claim 227, wherein the non-substance-related disorder is gambling disorder. 229. A method for treating a headache disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 230. The method of claim 229, wherein the headache disorder is classified by the Headache Classification Committee of the International Headache Society (IHS) to include the following: primary headache disorders, including migraine (including migraine without aura, migraine with aura, and chronic migraine), tension-type headache (including infrequent episodic, frequent episodic, and chronic tension-type headache), trigeminal-autonomic headaches (including cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua), and other primary headache disorders. 231. The method of claim 229, wherein the headache disorder is cluster headache (familial cluster headache, histaminergic headache, or vasculogenic facial pain), episodic cluster headache, recurrent or chronic cluster headache, trigeminal autonomic cephalopathy (TAC) such as short-lasting unilateral neuralgiform headache (SUNHA), short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms. 232. The method of claim 229, wherein the headache disorder is a secondary headache disorder such as headache due to trauma or injury to the head and / or neck, headache due to vascular disorder of the head and / or neck, headache due to nonvascular intracranial disorder, headache due to a substance or withdrawal, headache due to infection, headache due to a disorder of homeostasis, headache or facial pain due to a disorder of the skull, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structures, headache due to a psychiatric disorder, and headache categories of painful lesions of the cranial nerves and other facial pain, including pain due to lesions or disease of the trigeminal nerve. 233. A method for treating pain, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 234. The pain may be caused by any of a variety of causes, including inflammation (e.g., rheumatoid arthritis, lupus, Behcet's disease), genetic factors (e.g., erythromelalgia), diabetes, cancer, and conditions that cause nerve damage leading to pain, such as in cancer treatments, such as chemotherapy; neurological conditions, such as multiple sclerosis (MS); neurodegenerative conditions, such as Parkinson's disease; stroke, shingles, HIV, leprosy, Guillain-Barre syndrome, vascular disease, angiodysplasia, and autoimmune conditions; peripheral neuropathy, autonomic neuropathy, regional neuropathy, proximal neuropathy, diabetic neuropathy, and compressive mononeuropathy. 234. The method of claim 233, wherein the pain is caused by conditions such as all neuropathies, phantom limb pain, residual limb pain, and complex regional pain syndrome (CRPS), trigeminal neuralgia, postherpetic neuralgia, radicular pain, all radiculopathies including radiculitis and thoracic or lumbar radiculopathies, nociceptive pain (e.g., trauma-induced pain, cancer pain), high prevalence of somatization or nociceptive pain (e.g., chronic widespread pain, fibromyalgia, chronic temporomandibular joint disorder, chronic low back pain of unknown etiology, irritable bowel syndrome, chronic primary bladder pain syndrome, chronic primary pelvic pain syndrome), and various other forms of chronic pain regardless of etiology (e.g., chronic low back pain). 235. The pain is: chronic primary pain (such as fibromyalgia, chronic pelvic pain, nonspecific back pain, and chronic primary pain not otherwise specified); chronic cancer pain (such as pain due to cancer and metastases, chemotherapy-induced pain, pain due to radiation therapy, pain due to cancer surgery, and other chronic pain related to cancer); chronic post-operative and post-traumatic pain (including all post-operative and post-traumatic pain, and post-operative / post-traumatic pain not otherwise specified); chronic neuropathic pain (including peripheral neuropathic pain, central neuropathic pain, and other neuropathic pain, and neuropathic pain not otherwise specified); chronic headache and orofacial pain (including chronic primary headache, chronic secondary The method of claim 233, wherein the pain is chronic pain such as chronic pain, including headache, chronic orofacial pain, and headache and orofacial pain not otherwise specified; chronic visceral pain (including chronic visceral pain as a result of persistent inflammation, and / or vascular mechanisms, and / or obstruction / distention, and / or traction / compression, and / or combined mechanisms, or from other sites, referred chronic visceral pain from cancer, or chronic pain of functional or unknown etiology); and chronic musculoskeletal pain (including chronic musculoskeletal pain as a result of persistent inflammation and / or structural bone-joint changes, and / or chronic musculoskeletal pain originating from a disease of the nervous system such as spasmodic pain and chronic non-specific musculoskeletal pain, and referred pain syndromes). 236. The method of claim 233, wherein the pain is acute pain, including pain of any type including inflammatory, nociceptive, neuropathic, nociceptive, and other types of pain, lasting for a short period of time, from a few hours or days up to three months, including acute pain as a result of tissue injury, such as that resulting from any type of surgical procedure, dental procedure, labor and delivery, cuts, burns, fractures, and other accidents or trauma, acute pain due to any disease state, acute pain due to any type of trauma, and acute pain of unknown cause. 237. A method for treating spasticity, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 238. The method of claim 237, wherein the spasticity is with or without neuropathic pain and includes: cerebral palsy, stroke, multiple sclerosis (MS), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, adrenoleukodystrophy (ALD), phenylketonuria, Krabbe disease, and spinal cord injury. 239. A method for treating disorders and diseases associated with nerve injury or trauma, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 240. The method of claim 239, wherein the disorders and diseases are associated with nerve damage or trauma from: peripheral nerve damage or trauma regardless of cause and / or central nervous system (brain and spinal cord) nerve damage or trauma regardless of cause; disorders and diseases resulting from external physical causes, such as accidents, sports injuries, falls, gunshots, or explosive blaststrokes; or from internal causes, such as stroke, ruptured cerebral aneurysm, lack of oxygen, infections (viral, bacterial, prion, or other), autoimmune diseases; other nerve damage or trauma caused directly or indirectly by external causes, and / or nerve damage or trauma resulting directly or indirectly from a disease state. 241. A method for treating fatigue, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 242. The method of claim 241, wherein the fatigue is chronic fatigue (e.g., physical fatigue, psychological fatigue, or mental fatigue) due to traumatic brain injury (TBI), chronic fatigue syndrome (CFS), and related conditions, and other diseases and / or disorders that cause chronic fatigue. 243. A method for treating a neurodegenerative disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 244. The method of claim 243, wherein the neurodegenerative disorder comprises: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Batten disease, Friedreich's ataxia, Huntington's disease, Lewy body disease, motor neuron disease, multiple sclerosis, Parkinson's disease, prion diseases, spinal muscular atrophy, neurodegenerative conditions caused by viral (e.g., HIV) or bacterial infections, substance / drug caused neurodegenerative conditions, and other aging-related and non-aging-related neurodegenerative conditions. 245. A method for treating a disease and / or disorder selected from the group consisting of sexual dysfunction delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, substance / drug induced sexual dysfunction, other specified and unspecified sexual dysfunction, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 246. A method for treating gender dysphoria, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 247. A method for treating a neurodegenerative disorder, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 248. The method of claim 247, wherein the neurocognitive disorder (NCD) comprises delirium, NCD caused by Alzheimer's disease, vascular NCD, NCD with Lewy bodies, NCD caused by Parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance / drug induced NCD; NCD caused by Huntington's disease, NCD caused by prion disease; NCD caused by another medical condition, NCD caused by multiple etiologies, and unspecified NCD. 249. The method of claim 247, wherein the neurocognitive disorder is a neurocognitive / learning dysfunction such as memory problems, lack of mental clarity, poor concentration, and / or inability to concentrate due to infection (viral / bacterial / prion / other), or other identified or unidentified disorder, disease, or other unknown cause. 250. The method of claim 247, wherein the neurocognitive disorder is a decline in memory, cognition, and / or learning with or without overt signs of a neurodegenerative or neurodevelopmental disorder, and / or prevention of a decline in memory, cognition, and / or learning at any age with or without overt signs of a neurodegenerative or neurodevelopmental disorder. 251. The method of claim 247, wherein the neurocognitive disorder is a neurological and / or neuropsychiatric disorder and / or condition associated with normal aging and / or a progeria syndrome. 252. A method for treating a neurological disease caused by a viral infection comprising administering to a subject in need thereof a compound according to any one of claims 1-123, a composition according to any one of claims 124-127, or a formulation according to any one of claims 128-130, wherein the neurological disease is caused by a viral infection that utilizes neuronal cell surface receptors for entry, such as the serotonergic (5-HT) receptor (particularly the 5-HT2A receptor), such as progressive multifocal leukoencephalopathy (PML) caused by the JC virus. 253. A method for reducing and / or preventing hallucinogen side effects comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 254. A method for maintaining or improving well-being comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 255. A method for treating a disease and / or disorder having a therapeutic mechanism associated with 5-HT1 receptor activation, receptor activating activity at one or more 5-HT1 receptor subtypes, such as 5-HT1A, 1B, 1D, 1E, and 1F, comprising administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130. 256. A method for treating a disease and / or disorder associated with deficits or decline in cognition / learning / memory, the method comprising administering to a subject in need thereof a compound described in any one of claims 1 to 123, a composition described in any one of claims 124 to 127, or a formulation described in any one of claims 128 to 130, wherein the therapeutic mechanism is associated with 5-HT6 receptor activation (receptor activating action). 257. A method for treating a disease and / or disorder, the mechanism of treatment being associated with 5-HT2A receptor activation (receptor activating action), comprising administering to a subject in need thereof a compound described in any one of claims 1 to 123, a composition described in any one of claims 124 to 127, or a formulation described in any one of claims 128 to 130. 258. A method for treating a disease or disorder in which the therapeutic mechanism is associated with D2-like receptor activation (receptor agonism), such as the D2 and D4 receptor subtypes, comprising administering to a subject in need thereof a compound described in any one of claims 1-123, a composition described in any one of claims 124-127, or a formulation described in any one of claims 128-130. 259. The method of any one of claims 177-258, wherein the treatment eliminates hallucinogenic effects and does not induce tolerance to the compound of any one of claims 1-123, the composition of any one of claims 124-127, or the formulation of any one of claims 128-130.

[0018] These and other features, embodiments, and advantages of the present disclosure are mentioned not to limit or define the disclosure, but to provide examples that will aid in the understanding thereof when read in conjunction with the following description and in reference to the accompanying drawings. [Brief description of the drawings]

[0019] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments will now be described, by way of example only, with reference to the drawings in which:

[0020] [Figure 1] 1A and 1B show examples of 1H-NMR and 13C-NMR spectra of 2-bromolysergic acid (B) in DMSO-d6, respectively. [Diagram 2] 2A and 2B show an example of an electrospray ionization mass spectrum of 2-bromo-LSD. [Diagram 3] 3A and 3B show an example of the effect of pH on the purity and yield of E405. [Figure 4] FIG. 4 shows an example of an electrospray ionization mass spectrum of 2-bromo-LSD. [Diagram 5] FIG. 5 shows an example of the 1H-NMR spectrum of (5R,8R)-2-bromo-LSD hemi-D-tartrate in DMSO-d6. [Figure 6] 6A-6D show examples of high resolution PXRD of (5R,8R)-2-bromo-LSD hemi-D-tartrate: (6A) shows a small scale crystallization from ethanol; (6B) shows a crystallization from IPA; (6C) shows an overlay of crystallizations from ethanol (black) and IPA (red); (6D) shows a crystallization from ethanol performed on a ca. 350 g scale. [Figure 7] 7A to 7C show examples of a mass spectrum of (5R,8R)-2-bromo-LSD hemi-D-tartrate and an SEM image of (5R,8R)-2-bromo-LSD hemi-D-tartrate. [Figure 8]FIG. 8 shows an example of a high resolution PXRD of (5R,8R)-2-bromo-LSD hemi-L-tartrate recrystallized from ethanol. [Figure 9] FIG. 9 shows examples of FTIR spectra for (5R,8R)-2-bromo-LSD hemi-D-tartrate and (5R,8R)-2-bromo-LSD hemi-L-tartrate. [Figure 10] 10A / 10B are graphs showing that the LSD polymorph E559 has no hallucinogenic activity using the head-twitch response (HTR) in rodents. The E559 polymorph was administered at 0.1, 0.3, 1, 3, and 10 mg / kg or LSD (0.1 mg / kg). Data are presented as group mean ± standard deviation for the entire 60 min test session (A) and individual data points per 2 min block (B). [Figure 11] Figures 11A-11D are graphs showing that the LSD polymorph E559 crosses the blood-brain barrier. Plasma levels of the "E559 polymorph" increase in a time- and dose-dependent manner and appear rapidly (10 minutes) in plasma after administration in all dose groups of male and female mice (A) and (B). Brain tissue exposure to the compound increases proportionately in a time- and dose-dependent manner (C) and (D). [Figure 12] FIG. 12 is a graph showing that the LSD polymorph E559 exhibits good oral bioavailability that is not affected by feeding status, as indicated by the concentrations of the E559 polymorph measured in plasma samples between fasted and fed dogs. [Figure 13]Figures 13A-B show that the LSD polymorph E559 blocks the hallucinogenic effects of the hallucinogenic compound 2,5-dimethoxy-4-iodoamphetamine (DOI) in a mouse HTR model. Pretreatment of mice with the "E559 polymorph" significantly attenuated the ability of DOI to induce HTR in mice (Figure 13A). Figure 13B, pretreatment of mice with the "E559 polymorph" almost completely blocked DOI-induced HTR for the first 10 minutes, and this block gradually decreased until after 40-60 minutes, block was no longer detectable. [Figure 14] Figures 14A-D are graphs showing the binding and functional effects of LSD polymorph E559 at the 5HT2B receptor. In (A), (B), and (C), LSD shows strong 5-HT2B receptor agonism as seen by all three functional assessments, while the E559 polymorph does not show the agonism seen in the case of LSD. In (D), the E559 polymorph produces only weak hERG channel activity blockade at very high concentrations (EC50=31.6 μM), indicating a low risk of causing cardiac arrhythmia in humans. [Figure 15] FIG. 15 is a graph showing the activity of polymorph E559 at the CNS receptors / targets: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1e, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7A compared to the activity of serotonin (5-HT) and LSD. [Figure 16] FIG. 16A / B are graphs showing the activity of polymorph E559 on downstream second messenger activity of each target receptor: 5-HT1A, 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7. [Figure 17] Figure 17A is a graph showing polymorphism E559 antagonizing 5-HT mediated activation of the 5-HT2A receptor as assessed by a Gq dissociation assay. Figure 17B is a graph showing polymorphism E559 antagonizing 5-HT mediated activation of the 5-HT2A receptor as assessed by a β-arrestin 2 recruitment BRET assay. [Figure 18] Figure 18A shows images of MAP2 stained rat cortical neurons treated with vehicle (no drug control) or E559 polymorph on day in vitro 6 (DIV6), and Figure 18B shows a schematic of Sholl analysis, which generates a measure of neuronal branching complexity by assessing (A) the number of times neuronal processes cross over, (B) the total length of the neuron, and (C) the number of nodes and endpoints. [Figure 19] 19A-19F: E559 polymorphism improves neuroplasticity: (A) representative Sholl traces of neurons treated with vehicle (control) or increasing concentrations of E559 polymorphism; (B) shows the total number of Sholl radii crossings by MAP2 positive neurites after treatment with vehicle (control), E559 polymorphism, or ketamine; (C) shows the total number of dendritic branch lengths from the neurons in FIG. 19A and FIG. 19B; (D) shows representative fluorescent images of dendritic spines in cortical neurons treated with vehicle (control), E559 polymorphism, or ketamine; (E) shows the total number of spines per 10 μm cross section in the longest apical dendrite assessed from the first branch point (see FIG. 18B); and (F) shows the ratio of live to dead neuronal cells in randomly selected 40x objective fields in a cell viability assay. Horizontal lines in all figure panels represent the mean ± standard error of the mean (SEM). [Figure 20] 20A-C show that E559 polymorphism-mediated neuroplasticity acts through the 5-HT2A receptor: (A) shows traces of cortical neurons (DIV3) treated with 0.1, 0.5, or 1 mM Volinancerin (Vol) followed by either vehicle or E559 polymorphism (1 μM); (B) shows the total number of Sholl crosses of treated neurons in FIG. 20A; (C) represents the total dendritic arbour length of treated neurons in FIG. 20A. [Figure 21]Figure 21A / B shows that repeated administration of the E559 polymorph does not induce tolerance in vitro: (A) is a graph showing that the "E559 polymorph" is a weak recruiter of β-arrestin2 at the 5-HT2A receptor using a BRET-based β-arrestin2 recruitment assay (described in Example 8), compared to DOI and LSD activity; (B) is a graph showing that the E559 polymorph shows only weak internalization, in contrast to the strong 5-HT2A receptor internalization by LSD, DOI, and 5-HT. [Figure 22] FIG. 22 is a graph showing that repeated treatment with the E559 polymorph does not induce resistance in vivo (using the HTR model in mice), in comparison to the marked resistance induced by repeated administration of DOI. [Diagram 23] Figures 23A-D show that the E559 polymorphism exhibits antidepressant / anxiety activity in chronic stress animal models: (A) shows the test design of the self-grooming splash test; (B) shows the distance traveled in the open field by female mice treated with the E559 polymorphism; (C) shows the time spent in the center of the open field for mice in Figure 23B; (D) shows the time spent self-grooming in the splash test by female mice treated as described in Figure 23A. Horizontal lines represent the mean ± standard error of the mean (SEM) and asterisks indicate statistical significance. [Figure 24] Figures 24A-B: show the long-term antidepressant and anxiolytic effects of E559 polymorphism 28 days after the experiment described in Figure 23: (A) The effect of CVS to reduce time in the center in the OFT remained reversed 28 days after the last E559 polymorphism treatment (at a level similar to the acute effect of E559 polymorphism), CVS-saline vs. CVS-E559 polymorphism 4 x 1 mg / kg **p=0.0052; (B) represents the time spent self-grooming by female mice in the splash test 28 days after the last E559 polymorphism treatment shown in Figure 23A. [Diagram 25]Figures 25A-G show that E559 polymorphism exhibits antidepressant / anxiety activity in acute stress animal models: (A) represents the study design in which female / male mice (n=10 / group / sex) were treated by IP injection with E559 polymorphism or vehicle (saline), followed by open field and forced swimming tests 24 hours after treatment; (B) and (E) represent the total distance traveled in the open field test 24 hours after vehicle or E559 polymorphism in female and male mice, respectively; (C) and (F) represent the time in the center of the open field by female and male mice, respectively; (D) and (G) represent the immobility time during the last 4 minutes of the forced swimming test in female and male mice, respectively. Horizontal lines represent the mean ± standard error of the mean (SEM) and asterisks indicate statistical significance. [Figure 26] Figures 26A-D show that the E559 polymorphism exhibits antidepressant / anxiety effects with the involvement of 5-HT2A receptors in vivo, using the test of Example 14. (A) Pretreatment with borinancerin prevented the reduction in immobility induced by the E559 polymorphism in the FST in female mice; (B) Pretreatment with borinancerin prevented the reduction in immobility induced by the E559 polymorphism in the FST in female mice; (C) and (D) borinancerin or the combination of borinancerin and the E559 polymorphism did not affect locomotor activity in the OFT in female or male mice. [Figure 27] 27 is a graph showing the results of pain response evaluation after single dose treatment of E559 polymorph, vehicle, or gabapentin on day 7 after surgical procedure using von Frey filaments in a rat spared nerve injury (SNI) model. The E559 polymorph exhibits potent analgesic activity after a single dose in a neuropathic pain model. [Figure 28] 28 is a graph showing pain response assessment results after multiple dose treatment of E559 polymorph, vehicle, or gabapentin starting on post-surgery day 7. E559 polymorph exhibits potent analgesic activity with repeated dosing in a neuropathic pain model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] DETAILED DESCRIPTION OF EMBODIMENTS / EMBODIMENTS As used herein, the term "invention" or "present invention" is an open-ended term and is not intended to refer to any single embodiment of a particular invention, but rather encompasses all possible embodiments as described in the specification and claims.

[0022] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications mentioned herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0023] In case of discrepancies, the present specification, including definitions, shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the subject matter of this specification belongs. Furthermore, it will be understood that terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology and this disclosure, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0024] Reference to "one embodiment," "embodiment," "preferred embodiment," or any other phrase referring to the word "embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the disclosure, and also means that any particular feature, structure, or characteristic described in connection with an embodiment can be included in any embodiment, or can be omitted or excluded from any embodiment. The appearance of the phrase "in one embodiment" in various places in this specification does not necessarily refer to all of the same embodiment, nor to separate or alternative embodiments that are mutually exclusive with other embodiments. Furthermore, various features are described that may be shown in some embodiments and not shown in some other embodiments, and may be omitted from any embodiment. Furthermore, any particular feature, structure, or characteristic described herein may be optional. Similarly, various requirements are described that may be requirements in some embodiments and not requirements in other embodiments. Where appropriate, any of the features described herein in connection with one aspect or embodiment of the invention may also be applicable to other aspects or embodiments of the invention. Similarly, where appropriate, any feature described in this specification in the context of one aspect or embodiment of the invention may be optional and / or omitted with respect to that aspect or embodiment of the invention or any other aspect or embodiment of the invention discussed or disclosed herein.

[0025] (definition) Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the application described herein where they are suitable as would be understood by one of ordinary skill in the art.

[0026] It should be understood that all amounts are approximate and are given for illustration purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, suitable methods and materials are described below.

[0027] In understanding the scope of this application, the articles "a", "an" and "the" are intended to mean that there is one or more elements. Furthermore, as used herein, the term "comprising" and its derivatives are intended to be open-ended terms specifying the presence of, for example, recited features, elements, compounds / molecules, components, groups, integers, and / or steps, but not excluding, for example, the presence of other unrecited features, elements, compounds / molecules, components, groups, integers, and / or steps. The foregoing also applies to words of similar meaning, such as the terms "including", "having" and their derivatives.

[0028] It will be understood that any embodiment described as "comprising" a particular, e.g., feature, element, compound, molecule, component, group, integer, and / or step, can also "consist of" or "consist essentially of." Here, "consisting" has a closed-ended or limiting meaning, and "consisting essentially of" means, for example, including the specified and described feature, element, compound, molecule, component, group, integer, and / or step, but excluding materials present as impurities, e.g., unavoidable materials present as a result of the process used to provide the described feature, element, compound, molecule, component, group, integer, and / or step, as well as other components / components than the component / component that are added for any purpose other than achieving the technical effect of the invention. For example, a composition defined using the phrase "consisting essentially of" can include any known acceptable additives, excipients, diluents, carriers, and the like. Typically, a composition consisting essentially of a set of components will contain less than 5% by weight, typically less than 3% by weight, more typically less than 1%, and even more typically less than 0.1% by weight of unspecified components.

[0029] As used herein, terms of degree such as "substantially," "about," and "approximately" refer to a reasonable amount of deviation from the modified term such that the end result is not significantly altered. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term, provided that this deviation does not negate the meaning of the term it modifies.

[0030] The abbreviation "eg" is derived from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example."

[0031] The phrase "such as" should be interpreted as "for example, including."

[0032] As used herein, the term "and / or" means that the listed items may be present or utilized either individually or in any combination. In practice, this term means that "at least one of" or "one or more" of the listed items may be present or utilized.

[0033] The phrase "at least one of" is understood to mean one or more. The phrase "at least one of ... and ..." is understood to mean at least one of the recited elements or a combination thereof, unless expressly recited otherwise. For example, "at least one of A, B, and C" is understood to mean A alone or B alone or C alone or a combination of A and B or a combination of A and C or a combination of B and C or a combination of A, B, and C. "at least one of A, at least one of B, and at least one of C" is understood to mean at least one of A alone or at least one of B alone or at least one of C alone or a combination of at least one of A and at least one of B or a combination of at least one of A and at least one of C or a combination of at least one of B and at least one of C or a combination of at least one of A, at least one of B, and at least one of C.

[0034] Phrases such as "up to," "at least," "greater than," "less than," and the like all refer to ranges that include the recited numerical values ​​and can subsequently be broken down into ranges and subranges. Ranges include each individual member. Thus, for example, a group having 1 to 3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 6 members refers to groups having 1, 2, 3, 4, or 6 members, and so forth.

[0035] The modal verb "may" refers to the preferred use or selection of one or more options or choices among several described embodiments or features contained therein. When no options or choices are disclosed with respect to a particular embodiment or feature contained therein, the modal verb "may" refers to a positive action regarding the making or use and manner of the described embodiment or feature contained therein, or an explicit decision to use a particular technique with respect to the described embodiment or feature contained therein. In this latter context, the modal verb "may" has the same meaning and connotation as the auxiliary verb "can."

[0036] As used herein, the terms "reduce," "decrease," "lessen," and similar terms refer to a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, or more.

[0037] As used herein, the terms "improve," "increase," "enhance," and similar terms refer to an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.

[0038] Diseases and disorders are defined as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or in the International Classification of Diseases (ICD) published by the World Health Organization.

[0039] As used herein, the phrases "substantially non-hallucinogenic" or "without substantial hallucinations" or similar descriptions refer to derivatives that exhibit reduced hallucinogenicity to either an undetectable level of hallucinogenicity, or significantly reduced intensity of hallucinogenicity, or significantly reduced duration of hallucinogenicity, as compared to LSD, where significantly means a ≧50% reduction in the hallucinogenic activity of the derivative as compared to the hallucinogenic activity seen with LSD in animal models or a surrogate measure thereof. Hallucinations are the hallucinogenic / psychomimetic effects experienced by human subjects upon administration of psychelic drugs. In mouse models, the head-twitch response in mice is considered to be the most reliable animal surrogate for a compound's hallucinogenic activity in humans (Halbertstad AL et al., Neuropharmacology, Volume 167, 1 May 2020, 107933; Adam L. Halberstadt and Mark A. Geyer, Psychopharmacology (Berl). 2013 Jun; 227(4)).

[0040] As used herein, the phrases "effective amount" or "therapeutically effective amount" (used interchangeably herein) refer to an amount of a composition or formulation described herein that will elicit the diagnostic, biological, or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician.

[0041] As used herein, the term "modulate" means to decrease or inhibit and / or increase or enhance.

[0042] As used herein, "subject" may be interchangeable with "patient" or "individual" and means an animal, which may be a human or non-human animal, in need of treatment.

[0043] As used herein, the term "subject in need thereof" refers to a human or non-human subject that can be treated with any of the compounds or pharmaceutical compositions disclosed herein when such compounds or pharmaceutical compositions are utilized as therapeutic agents.

[0044] As used herein, "pharmaceutical acceptable" refers to materials and compositions that, when administered to humans, are physiologically tolerable and do not normally produce allergic or similar adverse reactions, such as stomach upset, dizziness, etc. Generally, as used herein, the term "pharmaceutical acceptable" means approved by a regulatory agency of the Federal or State government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly for use in humans.

[0045] The phrase "pharmaceutical acceptable salts" as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutical acceptable acid addition salts of such basic compounds include non-toxic acid addition salts, i.e., but are not limited to, sulfate, citrate, maleate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, and the like. The preferred acids include, but are not limited to, acids that form salts with pharmacologically acceptable anions, such as tert-butyl acetate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salts). Compounds included in the present compositions that contain an amino moiety may form pharma- ceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0046] As used herein, the term "pharmaceutical acceptable carrier" can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid in a mixture with the finely divided active ingredient. In tablets, the active ingredient(s) is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For parenteral injection, liquid preparations can be formulated into solutions in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0047] As used herein, a "therapeutic agent" may refer to any agent that is administered to a subject in order to treat the subject. A therapeutic agent may refer to, for example, an agent that modulates the biological activity of ornithine aminotransferase (OAT), which catalyzes the synthesis of glutamic acid or glutamine, by inhibiting the biological activity of OAT. A therapeutic agent may refer to, for example, an agent that modulates the biological activity of gamma-aminobutyric acid aminotransferase (GABA-AT), which degrades GABA to succinic semialdehyde (SSA), by inhibiting the biological activity of GABA-AT. Therapeutic agents include, but are not limited to, small molecules or compounds disclosed herein. Therapeutic agents include, but are not limited to, pharmaceutical compositions comprising small molecules or compounds disclosed herein.

[0048] As used herein, the term "binder" or "excipient" refers to an agent used to impart cohesive qualities to powdered materials. Binders, sometimes known as "granulators", impart cohesive qualities to tablet formulations, ensuring that the tablet remains intact after compression and improving free-flowing qualities by formulating granules of the desired hardness and size. Materials commonly used as binders include starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as gum arabic, sodium alginate, carrageenan extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, veegum, microcrystalline cellulose, microcrystalline dextrose, amylose, and larch arabogalactan. "Excipient" means an essentially inert substance used as a diluent or to give shape or consistency to a formulation. In general, an excipient can be defined as an ingredient of a pharmaceutical form that is ingested by or administered to a patient, other than the active substance; see, for example, Annex of Directive 2001 / 83 / EC. Some excipients may also act as disintegrants, i.e., they aid in the dispersion of a solid pharmaceutical composition when exposed to body fluids.

[0049] As used herein, a "diluent" is an inert substance added to increase the bulk of a formulation to make the tablet a practical size for compression. Commonly used diluents include calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and silica.

[0050] The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage, such as a pill, tablet, caplet, hard capsule, or soft capsule, each unit containing a predetermined amount of the LSA derivative (including its pharma- ceutically acceptable salts). By "hard capsule" is meant a capsule that includes a membrane forming a two-part capsule-shaped container capable of carrying a payload of solid or liquid drug and excipients. By "soft capsule" is meant a capsule molded as a single container carrying a payload of liquid or semi-solid drug and excipients.

[0051] As used herein, the terms "extended release," "controlled release," or "sustained release" refer interchangeably to the release of a derivative of lysergic acid diethylamide (LSD), including, for example, its polymorphs, that is absorbed by the body over a period of time, as compared to that observed with administration of an immediate release formulation administered at the same dosage level. 1 / 2 "Controlled release" refers to a manner in which the active agent is released from the formulation in such a way that the active ingredient slowly and periodically leeches out of the coating, for example, by embedding the active agent in a web of material that the body dissolves slowly, or by swelling the active agent to produce a gel with a nearly impermeable surface where the drug slowly escapes through a semipermeable layer.

[0052] As used herein, the term "dry weight" refers to a measurement of the mass of a sample after all or substantially all of the liquid has been removed from the sample. In one embodiment, removing the liquid includes dehydrating, heating, stirring, filtering, and / or any other method suitable for liquid water. In one embodiment, dry weight is measured in pounds. In one embodiment, dry weight is measured in ounces. In one embodiment, dry weight is measured in grams, e.g., milligrams, kilograms, etc.

[0053] As used herein, the term "dry powder" means a substance that is composed of fine particles and contains little or no liquid matter.

[0054] As used herein, the terms "weight percent," "weight percent," "% by weight," and the like refer to the amount of a compound as a percentage based on the total weight of a sample. In one embodiment, weight percent is calculated for the compound of interest by the following formula: (weight of the compound of interest in grams / (total weight of the composition in grams)×100%.

[0055] The term "purified" refers to a compound with a purity of 80% to 100%, which means that the compound accounts for 80% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound with a purity of 90% to 100%, which means that the compound accounts for 90% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound with a purity of 95% to 100%, which means that the compound accounts for 95% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound with a purity of 99% to 100%, which means that the compound accounts for 99% to 100% of the total mass of the composition.

[0056] In one embodiment, the term "purified" refers to a compound that is about 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% to 100% pure, where 99.9% to 100% purity means that the compound comprises 99.9% to 100% of the total mass of the composition.

[0057] As used herein, unless otherwise specified, the term "substantially pure," when used to describe a polymorph, crystalline form, or solid form of a compound or complex described herein, means a solid form of the compound or complex that comprises a particular polymorph and that is substantially free of other polymorphic forms and / or amorphous forms of the compound.

[0058] As used herein, unless otherwise specified, a composition that is "substantially free" of a compound means that the composition contains less than about 20% by weight, less than about 10% by weight, less than about 5% by weight, less than about 3% by weight, or less than about 1% by weight of the compound.

[0059] As used herein, unless otherwise specified, the term "stable" refers to a compound or composition that does not readily degrade or change in terms of chemical composition or physical state. Stable compositions or formulations provided herein do not significantly degrade under normal production or storage conditions. In some embodiments, the term "stable" when used in connection with a formulation or dosage form means that the active ingredients of the formulation or dosage form remain unchanged in terms of chemical composition or physical state for a specified length of time and do not significantly degrade, aggregate, or otherwise change (e.g., as determined by, for example, HPLC, FTIR, or XRPD). In some embodiments, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more of the compound remains unchanged after a specified period of time. In one embodiment, the polymorphs provided herein are stable upon extended storage (e.g., no significant change in polymorphic form after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, 48, 54, 60 months, or greater than about 60 months).

[0060] It will be understood that any element defined herein as being included may be expressly excluded from the claimed invention by provisos or negative limitations.

[0061] Additionally, all ranges given herein include the endpoints of the range, as well as any intermediate range points, whether or not expressly stated.

[0062] Definitions of certain functional groups and chemical terms are explained in more detail below: Chemical elements are identified in accordance with the Periodic Table of the Elements, inside cover of the CAS version, Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as set forth therein. Additionally, general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0063] With respect to compound nomenclature, generally, a reference to a particular element such as hydrogen or H is intended to include all isotopes of that element, where appropriate.

[0064] The term "alkyl group", whether used alone or within other terms such as "haloalkyl group" and "alkylamino group", includes straight or branched carbon radicals having, for example, 1 to about 20 carbon atoms, or, in specific embodiments, 1 to about 12 carbon atoms. In another embodiment, an alkyl group is a "lower alkyl group" having 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and the like. In more specific embodiments, a lower alkyl group has 1 to 4 carbon atoms.

[0065] The term "alkenyl group" includes linear or branched carbon radicals having at least one carbon-carbon double bond. The term "alkenyl group" can include conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. Alkenyl groups can include, for example, but are not limited to, from 2 to about 20 carbon atoms, or, in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, alkenyl groups are "lower alkenyl" groups having from 2 to about 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl group" and "lower alkenyl group" include groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

[0066] The term "alkynyl group" refers to a straight or branched carbon radical having at least one carbon-carbon triple bond. The term "alkynyl group" can include conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. Alkynyl groups can include, for example, but are not limited to, from 2 to about 20 carbon atoms, or, in certain embodiments, from 2 to about 12 carbon atoms. In embodiments, alkynyl groups are "lower alkynyl" groups having from 2 to about 10 carbon atoms. Some examples are lower alkynyl groups having from 2 to about 4 carbon atoms. Examples of such groups include propargyl, butynyl, and the like.

[0067] The term "halo" means halogens such as fluorine, chlorine, bromine, or iodine atoms.

[0068] The term "haloalkyl group" includes groups in which any one or more of the alkyl carbon atoms are substituted with halo as defined above. Specifically included are monohaloalkyl groups, dihaloalkyl groups, and polyhaloalkyl groups, including perhaloalkyl groups. Monohaloalkyl groups, by way of example, can have iodo, bromo, chloro, or fluoro atoms in the group. Dihalo and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. "Lower haloalkyl groups" include groups having 1 to 6 carbon atoms. In some embodiments, lower haloalkyl groups have 1 to 3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0069] The term "hydroxyalkyl group" includes, for example and without limitation, straight or branched alkyl groups having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more hydroxyl groups. In embodiments, the hydroxyalkyl group is a "lower hydroxyalkyl" group having from 1 to 6 carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl.

[0070] The term "alkoxy group" includes linear or branched oxy-containing groups each having an alkyl portion of, for example, but not limited to, 1 to about 10 carbon atoms. In an embodiment, the alkoxy group is a "lower alkoxy" group having 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. In an embodiment, the lower alkoxy group has 1 to 3 carbon atoms. The "alkoxy" group may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide a "haloalkoxy" group. In another embodiment, the lower haloalkoxy group has 1 to 3 carbon atoms. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0071] The term "aromatic group" or "aryl group" refers to an aromatic group having one or more rings, which may be attached together in a pendent manner or may be fused. In certain embodiments, the aromatic group has one, two, or three rings. Monocyclic aromatic groups may contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 4 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups have two or three rings. Polycyclic aromatic groups having two or three rings usually have 8 to 16 carbon atoms, preferably 8 to 14 carbon atoms in the ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl.

[0072] The term "heteroatom" means an atom other than carbon. Typically, heteroatoms are selected from the group consisting of sulfur, phosphorus, nitrogen, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0073] The term "heteroaromatic group" or "heteroaryl group" refers to an aromatic group having one or more rings, which may be linked together in a pendant fashion or may be fused, and which aromatic group has at least one heteroatom. Monocyclic heteroaromatic groups may contain 4 to 10 member atoms, typically 4 to 7 member atoms, and more typically 4 to 6 member atoms, in the ring. Typical polycyclic heteroaromatic groups have 2 or 3 rings. Polycyclic aromatic groups having 2 to 3 rings usually have 8 to 16 member atoms, more typically 8 to 14 member atoms, in the ring. Examples of heteroaromatic groups include, but are not limited to, pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, quinoline, isoquinoline, quinazoline, quinoxaline, and the like.

[0074] The term "carbocyclic group" means a saturated or unsaturated carbocyclic hydrocarbon ring. A carbocyclic group is not aromatic. A carbocyclic group is monocyclic or polycyclic. Polycyclic carbocyclic groups can be fused, spiro, or bridged ring systems. Monocyclic carbocyclic groups can contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 5 to 6 carbon atoms, in the ring. Bicyclic carbocyclic groups can contain 8 to 12 carbon atoms, typically 9 to 10 carbon atoms, in the ring.

[0075] The term "heterocyclic group" refers to a saturated or unsaturated ring structure containing carbon atoms and one or more heteroatoms in the ring. Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclic or polycyclic. Polycyclic heterocyclic groups can be fused, spiro, or bridged ring systems. Monocyclic heterocyclic groups may contain 4 to 10 member atoms (i.e., including both carbon atoms and at least one heteroatom), typically 4 to 7, more typically 5 to 6 member atoms in the ring. Bicyclic heterocyclic groups may contain 8 to 18 member atoms, typically 9 or 10 member atoms in the ring. Representative heterocyclic groups include, by way of example only, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline, and the like.

[0076] The term "heterogeneous group" refers to a saturated or unsaturated chain comprising carbon atoms and at least one heteroatom. A hybrid group typically has 1 to 25 member atoms. More typically, the chain contains 1 to 12 member atoms, 1 to 10, and most typically, 1 to 6 member atoms. The chain may be linear or branched. A typical branched hybrid group has 1 or 2 branches, more typically, 1 branch. Typically, the hybrid group is saturated. An unsaturated hybrid group may have one or more double bonds, one or more triple bonds, or both. A typical unsaturated hybrid group has 1 or 2 double bonds or 1 triple bond. More typically, an unsaturated hybrid group has 1 double bond.

[0077] The term "hydrocarbon group" or "hydrocarbyl group" refers to a chain of carbon atoms. In certain embodiments, the term contains 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms. The hydrocarbon group can have a straight or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Hydrocarbon groups include saturated, unsaturated, conjugated, non-conjugated, and combinations thereof. Unsaturated hydrocarbon groups can have one or more double bonds, one or more triple bonds, or combinations thereof.

[0078] When the term "unsaturated" is used in connection with any group, the group may be fully unsaturated or partially unsaturated. However, when the term "unsaturated" is used in connection with a specific group defined herein, the term maintains the limitations of that specific group. For example, an unsaturated "carbocyclic group" does not include aromatic groups under the limitations of "carbocyclic group" defined herein.

[0079] The terms "carboxy group" or "carboxyl group", whether used alone or with other terms, such as "carboxyalkyl group", mean -(C=O)-O-.

[0080] The term "carbonyl group", whether used alone or with other terms, such as "aminocarbonyl group", means --(C.dbd.O)--.

[0081] The term "alkylcarbonyl group" refers to a carbonyl group substituted with an alkyl group. In certain embodiments, a "lower alkylcarbonyl group" has a lower alkyl group as described above attached to a carbonyl group.

[0082] The term "aminoalkyl group" includes straight-chain or branched alkyl groups having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a "lower aminoalkyl" group having from 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0083] The term "alkylaminoalkyl group" embraces aminoalkyl groups having nitrogen atoms independently substituted with alkyl groups. In certain embodiments, alkylaminoalkyl groups are "lower alkylaminoalkyl" groups having alkyl groups of 1 to 6 carbon atoms. In other embodiments, lower alkylaminoalkyl groups have alkyl groups of 1 to 3 carbon atoms. Suitable alkylaminoalkyl groups can be mono- or di-alkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl, and the like.

[0084] The term "aralkyl group" includes aryl-substituted alkyl groups. In embodiments, aralkyl groups are "lower aralkyl" groups having an aryl group bonded to an alkyl group having 1 to 6 carbon atoms. In another embodiment, the lower aralkyl group phenyl is bonded to an alkyl moiety having 1 to 3 carbon atoms. Examples of such groups include benzyl, diphenylmethyl, and phenylethyl. The aryl in said aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0085] The term "arylalkenyl group" includes aryl-substituted alkenyl groups. In embodiments, arylalkenyl groups are "lower arylalkenyl" groups having an aryl group bonded to an alkenyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethenyl. The aryl in the arylalkenyl can be further substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy.

[0086] The term "arylalkynyl group" includes aryl-substituted alkynyl groups. In embodiments, arylalkynyl groups are "lower arylalkynyl" groups having an aryl group attached to an alkynyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethynyl. The aryl in the aralkyl can be further substituted with halo, alkyl, alkoxy, haloalkyl, and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.

[0087] The term "alkylthio group" embraces groups containing a linear or branched alkyl group, of one to ten carbon atoms, attached to a divalent sulfur atom. In certain embodiments, lower alkylthio groups have one to three carbon atoms. An example of an "alkylthio" is methylthio (CH3S-).

[0088] The term "alkylamino group" refers to amino groups substituted with one and two alkyl groups, including the terms "N-alkylamino" and "N,N-dialkylamino". In an embodiment, an alkylamino group is a "lower alkylamino" group having one or two alkyl groups of 1 to 6 carbon atoms attached to the nitrogen atom. In another embodiment, a lower alkylamino group has 1 to 3 carbon atoms. Suitable "alkylamino" groups can be mono- or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0089] The term "arylamino" means an amino group that is substituted with one or two aryl groups, such as N-phenylamino. The "arylamino" groups can be further substituted on the aryl ring portion of the group.

[0090] The term "heteroarylamino" means an amino group that is substituted with one or two heteroaryl groups, such as N-thienylamino. The "heteroarylamino" groups can be further substituted on the heteroaryl ring portion of the group.

[0091] The term "aralkylamino group" refers to an amino group substituted with one or two aralkyl groups. In another embodiment, there are phenyl-C1-C3-alkylamino groups, such as N-benzylamino. The "aralkylamino" groups may be further substituted on the aryl ring portion of the group.

[0092] The term "alkylaminoalkylamino group" means an alkylamino group substituted with one or two alkylamino groups. In an embodiment, a C1-C3-alkylamino-C1-C3-alkylamino group is present.

[0093] The term "arylthio group" includes aryl groups of 6 to 10 carbon atoms bonded to a divalent sulfur atom. An example of an "arylthio" is phenylthio. The term "aralkylthio group" includes aralkyl groups as described above bonded to a divalent sulfur atom. In one embodiment, a phenyl-C1-C3-alkylthio group is present. An example of an "aralkylthio" is benzylthio.

[0094] The term "aryloxy group" embraces optionally substituted aryl groups, as defined above, attached to an oxygen atom. Examples of such groups include phenoxy.

[0095] The term "aralkoxy group" embraces oxyaralkyl-containing groups attached to other groups through an oxygen atom. In certain embodiments, aralkoxy groups are "lower aralkoxy" groups having an optionally substituted phenyl group attached to a lower alkoxy group, as defined above.

[0096] The term "cycloalkyl group" includes saturated carbocyclic groups. In some embodiments, the cycloalkyl group includes a C3-C6 ring. In embodiments, there are compounds that include cyclopentyl, cyclopropyl, and cyclohexyl.

[0097] The term "cycloalkenyl group" includes carbocyclic groups having one or more carbon-carbon double bonds; conjugated or non-conjugated, or a combination thereof. "Cycloalkenyl" and "cycloalkyldienyl" compounds are included in the term "cycloalkenyl". In some embodiments, cycloalkenyl groups include a C3-C6 ring. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cycloheptadienyl. "Cycloalkenyl" groups can have one to three substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like.

[0098] The term "suitable substituents", "substituents" or "substituted" used in connection with the groups described herein means a chemically acceptable group, i.e., a moiety that maintains the utility of the compounds of the invention. It is understood that the substituents and substitution patterns in the compounds of the invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and the methods described below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon / member atom or on different carbon / member atoms, so long as a stable structure results. Illustrative examples of some suitable substituents include cycloalkyl, heterocyclyl, hydroxyalkyl, benzyl, carbonyl, halo, haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, HO--(C=O)--, amido, amino, alkyl and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl, and arylsulfonyl. Exemplary substituents include aromatic groups, substituted aromatic groups, hydrocarbon groups including alkyl groups such as methyl, substituted hydrocarbon groups such as benzyl, and hybrid groups including alkoxy groups such as methoxy.

[0099] The term "fused" means that two or more carbon / member atoms are common to two adjacent rings, e.g., the rings are "fused rings."

[0100] The term "leaving group" is well understood in the art and is a molecular fragment that leaves with a set of electrons upon heterolytic bond cleavage. Leaving groups can be anions or neutral molecules that can stabilize the additional electron density that arises from bond heterolysis.

[0101] The term "isotopic form" refers to variants of a particular chemical element. All isotopes of a given element share the same number of protons, and each isotope differs from the others in its number of neutrons.

[0102] The term "solvate" refers to a solvate form of the compounds described herein that is usually associated with a solvent through a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include both stoichiometric and non-stoichiometric solvates. In some instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0103] The term "salt" includes salts of compounds prepared from appropriate acids or bases depending on the particular substituents present on the compounds described herein. When a compound described herein contains a relatively basic functional group, an acid salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid. Examples of inorganic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, combinations thereof, and the like. Examples of organic acid salts include acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene and those derived from organic acids such as sulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythratic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof.

[0104] The term "hemi" means that the ratio of compound to acid (whether organic or inorganic) within the crystal structure of a salt of a compound (e.g., Formula I) is 1:0.5 (or 2:1), respectively.

[0105] With respect to the formation of suitable salts, any suitable counterion may occur. A "counterion" or "anionic counterion" is a negatively charged group that is associated with, for example, a cationic quaternary amino group to maintain electrostatic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3- , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - Examples include PF6, sulfonate ions, and carboxylate ions.

[0106] Salts of the compounds described herein can be synthesized from the compounds described herein. Generally, salts of basic compounds are prepared by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid in an appropriate solvent or various combinations of solvents.

[0107] Also, the International Union of Pure and Applied Chemistry (IUPAC) nomenclature developed for 2-halo-LSD related compounds shows chiral centers at carbons 6 and 9. However, a more conventional numbering system is adopted herein that is consistent with the halo group being attached to the second carbon, and the two chiral carbons being at positions 5 and 8, as identified in the structures herein. Also, as used herein, the stereocenter nomenclature for "5aR,8R", "5aR,8S", "5aS,8R", and "5aS,8S" are interchangeable with "5R,8R", "5R,8S", "5S,8R", and "5S,8S", respectively.

[0108] The term "derivative" generally refers to a molecule that is modified and / or altered in some way compared to a reference or starting molecule.

[0109] The term "polymorph" refers to the crystal structures in which a compound (e.g., a salt or solvate thereof) can crystallize in a particular crystal packing arrangement. Different polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one polymorph to predominate. Polymorphs of a compound can be prepared by crystallization under various conditions.

[0110] It should be understood that the present specification encompasses any racemic, optically active, stereoisomeric, and / or polymorphic forms.

[0111] The recitation of a list of chemical groups in any definition of a variable herein includes a definition of that variable as any single group or combination of the groups listed. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0112] (Lysergic acid diethylamide (LSD) - its derivatives and polymorphs) Novel derivatives and polymorphs of LSD are provided. These are represented by formula I. These compounds have been shown to have desirable biological effects, are substantially non-hallucinogenic, and do not induce tolerance. The novel derivative(s) and polymorphs of LSD of formula I contain desirable properties (including, but not limited to, mechanical, thermal, physical, and chemical properties) that result in desirable effects on bioavailability, hygroscopicity, stability, and other performance characteristics. Thus, the compounds of the present invention are suitable for the development of therapeutic products.

[0113] i) One embodiment is a compound represented by formula I: [ka] (In the formula: R 1 ~R 14 are each independently selected from H or a substituted or unsubstituted hydrocarbon group, and X is selected from a halo group. The present invention includes compounds having the structure: embedded image or a pharma- ceutically acceptable salt thereof, a hydrate, a solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a polymorph, or a combination thereof. In an embodiment, the compound is crystalline. In a more particular embodiment, the compound is in an isolated crystalline form.

[0114] In another embodiment, the compound comprises a polymorph of formula I. In a further embodiment, the compound comprises a single polymorph thereof. In another embodiment, the compound is an isolated polymorph thereof. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally a polymorph thereof or a single polymorph thereof.

[0115] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. In one or more of these embodiments, the compound is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. In an embodiment, the compound is an acid salt. The salts may be of any of the following acids: hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, sulfuric acid, sulph ... The salt may be formed from any suitable organic or inorganic acid(s), such as valeric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. In any salt embodiment, the salt may be a hemisalt.

[0116] Regarding the options for Formula I, Formula I can be any suitable embodiment as listed above and as follows, in any combination:

[0117] In an embodiment of formula I, R 1 ~R 14 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 1 ~R 14 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 1 ~R 14 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. In a further embodiment, R 1 ~R 14 are each independently selected from H, a methyl group, or an ethyl group. 1 and R 2 are each independently selected from H, a methyl group, or an ethyl group; R 3 , R 4 , and R 6 ~R 14 are H and R 5 is a methyl group. 1 and R 2 are each independently selected from a methyl group or an ethyl group; R 3 , R 4 , and R 6 ~R 14 are each H; and R 5 is a methyl group. 1 and R 2 are each an ethyl group; R 3 , R 4 , and R 6 ~R 14 are each H; and R 5 is a methyl group.

[0118] In a further embodiment of formula I, X is selected from bromo, chloro, fluoro, or iodo. In another embodiment, X is selected from bromo, chloro, or fluoro. In another embodiment, X is selected from bromo or chloro. In yet another embodiment, X is bromo.

[0119] ii) Another embodiment has formula I': [ka] (In the formula: R 1 and R 2 are each independently selected from H or a substituted or unsubstituted hydrocarbon group. The present invention includes compounds having the structure: embedded image or a pharma- ceutically acceptable salt thereof, a hydrate, a solvate, a tautomer, an enantiomer, a diastereomer, a racemate, a polymorph, or a combination thereof. In an embodiment, the compound is crystalline. In a more particular embodiment, the compound is in an isolated crystalline form.

[0120] In another embodiment, the compound includes its polymorph(s). In a further embodiment, the compound includes its single polymorph. In another embodiment, the compound is its isolated polymorph. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally, its polymorph or its single polymorph.

[0121] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. In one or more of these embodiments, the compound is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. In a typical embodiment, the compound is an acid salt. The salts may be of any of the following acids: hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, sulfuric acid, sulph ... The salt may be formed from any suitable organic or inorganic acid(s), such as valeric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. In any salt embodiment, the salt may be a hemi-salt.

[0122] Regarding the options for Formula I', Formula I' can be any suitable embodiment as listed above and as follows, in any combination:

[0123] In the embodiment of Formula I', R 1 and R 2 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 1 and R 2 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 1 and R 2 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. In a further embodiment, R 1 and R 2 are each independently selected from H, a methyl group, or an ethyl group. 1 and R 2 are each independently selected from a methyl group or an ethyl group. 1 and R 2 are each an ethyl group.

[0124] iii) In another embodiment, the compound is: [ka] TIFF2024545931000029.tif71170(in formula:R 1 and R 2 are each independently selected from H or a substituted or unsubstituted hydrocarbon group. It is selected from its pharma- ceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, or combinations thereof. In an embodiment, the compound is crystalline. In a more particular embodiment, the compound is in an isolated crystalline form.

[0125] In another embodiment, the compound includes its polymorph(s). In a further embodiment, the compound includes its single polymorph. In another embodiment, the compound is its isolated polymorph. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally its polymorph or its single polymorph.

[0126] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. In one or more of these embodiments, the compound is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. In a typical embodiment, the compound is an acid salt. The salts may be of any of the following acids: hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, sulfuric acid, sulph ... The salt may be formed from any suitable organic or inorganic acid(s), such as valeric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. In any salt embodiment, the salt may be a hemi-salt.

[0127] With regard to the above options, the compound can be any suitable embodiment as listed above and as follows, in any combination:

[0128] In an embodiment, R 1 and R 2 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. 1 and R 2 are each independently selected from H, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, or a substituted or unsubstituted C2-C6 alkynyl group. 1 and R 2 are each independently selected from H or a substituted or unsubstituted C1-C6 alkyl group. In a further embodiment, R 1 and R 2 are each independently selected from H, a methyl group, or an ethyl group. 1 and R 2 are each independently selected from a methyl group or an ethyl group. 1 and R 2 are each an ethyl group.

[0129] iv) In another embodiment, the compound is: [ka] TIFF2024545931000031.tif70170 selected from its pharma- ceutical acceptable salts, hydrates, solvates, tautomers, polymorphs, or combinations thereof. In an embodiment, the compound is crystalline. In a more particular embodiment, the compound is in an isolated crystalline form.

[0130] In another embodiment, the compound includes its polymorph(s). In a further embodiment, the compound includes its single polymorph. In another embodiment, the compound is its isolated polymorph. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally, its polymorph or its single polymorph.

[0131] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds, each of which has two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. In one or more of these embodiments, the compound is a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof. In a typical embodiment, the compound is an acid salt. The salts may be of any of the following acids: hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, sulfuric acid, sulph ... The salt may be formed from any suitable organic or inorganic acid(s), such as valeric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. In any salt embodiment, the salt may be a hemi-salt.

[0132] v) In another embodiment, the compound is: [ka] TIFF2024545931000033.tif132170 or a combination thereof. In an embodiment, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

[0133] In another embodiment, the compound includes its polymorph(s). In a further embodiment, the compound includes its single polymorph. In another embodiment, the compound is its isolated polymorph. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally, its polymorph or its single polymorph.

[0134] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound includes one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound includes one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound includes one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. The acids include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, The acid may be any suitable organic or inorganic acid(s), such as suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. In any salt embodiment, the salt may be a hemi-salt.

[0135] vi) In a specific embodiment, the compound is 2-bromo-LSD acid salt: [ka] TIFF2024545931000035.tif148170TIFF2024545931000036.tif154170TIFF2024545931000037.tif142170 or combinations thereof. In another embodiment, the compound is a polymorph thereof. In an embodiment, the compound is crystalline. In a more specific embodiment, the compound is an isolated crystalline form.

[0136] In another embodiment, the compound includes its polymorph(s). In a further embodiment, the compound includes its single polymorph. In another embodiment, the compound is its isolated polymorph. In another embodiment, i) the compound is a diastereomer and / or an enantiomer; and / or ii) is crystalline, optionally, its polymorph or its single polymorph.

[0137] In further embodiments, i) the compound is one or more polymorphs thereof; and / or ii) the compound includes one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound includes one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound includes one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S. In further embodiments, the compound comprises 2-bromo LSD tartrate (about 1:about 0.5) and / or (about 1:about 1), i) the compound is one or more polymorphs thereof; and / or ii) the compound comprises one or more compounds each having two stereocenters independently selected from 5S,8R; 5R,8R; 5R,8S; or 5S,8S; iii) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S; 5R,8R; or 5S,8R; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5R,8S or 5R,8R; v) the compound has two stereocenters that are 5R,8R; or vi) the compound has two stereocenters that are 5R,8S.

[0138] In any of the above-mentioned acid derivatives of LSD, the ratio of the tetracyclic compound of formula I, formula I', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib', formula Ic', or formula Id' to the acid of formula I, formula I', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib', formula Ic', or formula Id' can be any suitable ratio, such as a hemi-salt (0.5:1 or 2:1), typically. In an embodiment, the ratio does not need to be perfectly matched in positive and negative charges. For example, the charge-balanced ratio of 2-bromo LSD to tartrate ion can be 2 to 1, with 2-bromo LSD being about +1 and tartrate being about -2. In the case of L-tartrate ion, the salt formed can be about 1 to about 1, meaning that there is an excess of negative charge. This can be balanced by hydrogen. The phosphates may be present in ratios of 1:3, 1:2, 1:1, or 2:1, and higher and lower ratios, where other spectator / counter ions may be used to balance the charge, such as, for example, hydrogen, hydroxide, sodium, chloride, calcium, and potassium, etc. In embodiments, the ratio depends on the total charge of the acid. In certain embodiments, the ratio is from about 0.5:1 to about 2:1 (hemisalt) (mol / mol basis) and any increment therebetween, e.g., from about 0.6:1 to about 2:1; from about 0.7:1 to about 2:1; from about 0.8:1 to about 2:1; from about 0.9:1 to about 2:1; from about 1:1 to about 2:1; from about 1.1:1 to about 2:1; from about 1.2:1 to about 2:1; from about 1.3:1 to about 2:1; from about 1.4:1 to about 2:1; from about 1.5:1 to about 2:1; from about 1.6:1 to about 2:1; from about 1.7:1 to about 2:1; from about 1.8:1 to about 2: 1; about 1.9:1 to about 2:1; about 0.5:1 to about 1.9:1; about 0.5:1 to about 1.8:1; about 0.5:1 to about 1.7:1; about 0.5:1 to about 1.6:1; about 0.5:1 to about 1.5:1; about 0.5:1 to about 1.4:1; about 0.5:1 to about 1.3:1; about 0.5:1 to about 1.2:1; about 0.5:1 to about 1.1:1; about 0.5:1 to about 1:1; about 0.5:1 to about 0.9:1; about 0.5:1 to about 0.8:1; about 0.5:1 to about 0.7:1; or about 0.5:1 to about 0.6:1, etc.

[0139] In an embodiment, the compound of formula I, formula I', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib', formula Ic', or formula Id' has a powder X-ray diffraction (PXRD) pattern comprising a peak at about 10.3° (2θ). In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7° (2θ), about 9.4° (2θ), and about 10.3° (2θ). In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7° (2θ), about 9.4° (2θ), about 10.3° (2θ), and about 20.1° (2θ).

[0140] In an embodiment, the compound of formula I, formula I', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib', formula Ic', or formula Id' 74 has a powder X-ray diffraction (PXRD) pattern comprising a peak at about 10.3 degrees 2θ with a d value of about 8.6 Å. In another embodiment, the compound has a powder X-ray diffraction (PXRD) pattern comprising peaks at about 4.7 degrees 2θ with a d value of about 18.8 Å, at about 9.4 degrees 2θ with a d value of about 9.4 Å, and at about 10.3 degrees 2θ with a d value of about 8.6 Å. In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7° (2θ) with a d value of about 18.8 Å, at about 9.4° (2θ) with a d value of about 9.4 Å, at about 10.3° (2θ) with a d value of about 8.6 Å, and at about 20.1° (2θ) with a d value of about 4.4 Å. In yet a further embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 10.3°±0.2° (2θ). In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7°±0.2° (2θ), 9.4°±0.2° (2θ), and 10.3°±0.2° (2θ). In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7°±0.2° 2θ, 9.4°±0.2° 2θ, 10.3°±0.2° 2θ, and 20.1°±0.2° 2θ.

[0141] In an embodiment, the compound of formula I, formula I', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib', formula Ic', or formula Id' has an optical rotation of about 0.30° to about 0.40°; optionally, about 0.30° to about 0.35°.

[0142] (Methods for making derivatives of LSD, including polymorphs thereof) Described herein are methods for making derivatives and polymorphs of LSD. In general, the methods described herein for making derivative(s) of LSD, including its polymorph(s), do not use lysergic acid diethylamide (LSD) as a substrate or intermediate. The absence of a scheduled substance as a starting material or in any step of the synthesis method is beneficial because it eliminates the need to seek a dedicated controlled substance handling license. The method produces derivatives and polymorphs of LSD intended for human use, and therefore Good Manufacturing Practice (GMP) applies. The method controls the level of impurities to ensure that the compounds of the invention are produced to consistently meet the prescribed specifications. The method can be used on a commercial scale, i.e., is, among other things, safe, scalable, efficient, economically viable, and / or has other desirable properties.

[0143] In an embodiment of the method for making the compounds described herein, the group (R 1 ~R 14and X) are defined as in the previous section, and R is -NR1R2 or -OR1, where R1 and R2 are each independently selected from any suitable group such that the CO(R) group can undergo hydrolysis. R1 and R2 are each independently selected from H, halo, hydroxyl, amino, substituted or unsubstituted hydrocarbon, substituted or unsubstituted hybrid, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aromatic, or substituted or unsubstituted heteroaromatic. In an embodiment, R1 and R2 are each independently selected from H, substituted or unsubstituted hydrocarbon, substituted or unsubstituted hybrid, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aromatic, or substituted or unsubstituted heteroaromatic. In another embodiment, R1 and R2 are each independently selected from H or substituted or unsubstituted heteroaromatic.

[0144] In an embodiment of the method, the compound can be made as follows: a) hydrolyzing a compound of formula IA to form a compound of formula IB: [ka] wherein the hydrolysis is acid or base hydrolysis. The substrates employed in the first step of the synthesis of these compounds can be obtained commercially or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid can be used in the acid hydrolysis; however, any suitable acid can be used. Potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used in the base hydrolysis; however, any suitable base can be used. The reaction may be carried out in a water-miscible solvent (e.g., an alcohol (methanol, ethanol, isopropyl alcohol (IPA), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and / or may be heated to a suitable reaction temperature. In an embodiment, the temperature ranges from about 50°C to about 95°C. In certain embodiments, the temperature ranges from about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0145] b) reacting an intermediate of formula IB with R 1 -NH-R 2 to produce a compound of formula IC (eg, the free base). [ka]

[0146] The hydroxyl group of the carboxylic acid may be converted to a better leaving group (LG). Any suitable leaving group may be used, for example, selected from halides (e.g., Cl, Br, I), tosylates, mesylates, and weak bases such as perfluoroalkylsulfonates. The hydroxyl group may be converted to a better leaving group to provide the amine (R 1 -NH-R 2Any suitable reactant may be used to aid in the reaction with the amine (R 1 -NH-R 2 ) and base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI) (e.g., coupling agent) may be used. The reaction may be carried out in any solvent suitable for making a solution of the reactants (e.g., THF, 2-methyl-THF, etc.). The reaction may be carried out at any suitable reaction temperature. In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0147] In an embodiment, the reaction comprises reacting said amine of formula IB (R 1 -NH-R 2The reaction proceeds by base catalyzed amide bond formation upon reaction with 1,3,5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof.In specific embodiments, the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethylammonium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof.

[0148] In steps (a) and (b), the pH of the intermediates of formula IB and formula IC was adjusted to cause precipitation. The pH can be adjusted, for example, from about 4 to about 8 or from about 6 to about 8 (e.g., with hydrochloric acid).

[0149] Formula IC may also be reacted, in situ or in a separate reaction with (b), as appropriate, with hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acids, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, The amide may be converted to any suitable salt or hydrate (Formula ID) using any suitable organic or inorganic acid(s), such as succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. With regard to the formation of suitable salts, as outlined in the definition, the counterion may be, for example, any negatively charged group associated with the amide (e.g., Formula IC). Exemplary counterions include halide ions (e.g., F -, Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - PF6, sulfonate ions, and carboxylate ions (e.g., acetate, ascorbate, ethanoate, isoascorbate, propanoate, benzoate, glycerate, lactate, tartrate, glutamate, glycolate, etc.). The reaction can take place in any suitable solvent, such as, but not limited to, water-miscible solvents (e.g., alcohols (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

[0150] [ka] In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 60°C to about 65°C. In an embodiment, the compound of formula IC is heated with the organic or inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It can then be cooled, for example, to about room temperature. In another embodiment, it is cooled to about 0°C to about 10°C, optionally about 3°C ​​to about 7°C, optionally about 5°C, and optionally about 30 minutes to about 2 hours.

[0151] In another embodiment of the method for making the compounds described herein, the compounds can be made as follows, 1 ~R 14 , and X) are defined as in the previous sections.

[0152] a) hydrolysis of a compound of formula IAA (5R,8R) to produce an intermediate of formula IBB: [ka] (wherein the hydrolysis is acid or base hydrolysis). The substrates employed in the first step of the synthesis of these compounds can be commercially obtained or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid can be used in the acid hydrolysis; however, any suitable acid can be used. Potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used in the base hydrolysis; however, any suitable base can be used. The reaction can be carried out in a water-miscible solvent (e.g., alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and / or heated to a suitable reaction temperature. In an embodiment, the temperature ranges from about 50°C to about 95°C. In certain embodiments, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0153] b) reacting an intermediate of formula IBB with R 1 -NH-R 2 to produce a compound of formula ICC (e.g., the free base). [ka] .

[0154] The hydroxyl group of the carboxylic acid may be converted to a better leaving group (LG). Any suitable leaving group may be used, and may be selected from, for example, halides (e.g., Cl, Br, I), tosylates, mesylates, and weak bases such as perfluoroalkylsulfonates. The hydroxyl group may be converted to a better leaving group to provide the amine (R 1 -NH-R 2 Any suitable reactant may be used to aid in the reaction with the amine (R 1 -NH-R 2 ) and base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI) (e.g., coupling agent) may be used. The reaction may be carried out in any solvent suitable for making a solution of the reactants (e.g., THF, 2-methyl-THF, etc.). The reaction may be carried out at any suitable reaction temperature. In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0155] In an embodiment, the reaction is carried out by reacting said amine of formula IBB (R 1 -NH-R 2The reaction proceeds by base catalyzed amide bond formation upon reaction with 1,3,5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof.In specific embodiments, the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate azabenzotriazole tetramethylnium (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof.

[0156] In steps (a) and (b), the acidity of the intermediates of formula IBB and formula ICC was adjusted to cause precipitation. The pH can be adjusted, for example, to about 6 to about 8 using an acid (e.g., hydrochloric acid).

[0157] Formula ICC may also be used, where appropriate, in situ with (b) or in a separate reaction with hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acids, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, The amide may be converted to any suitable salt or hydrate (formula IDD) using any suitable organic or inorganic acid(s), such as succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. With regard to the formation of suitable salts, as outlined in the definition, the counterion may be, for example, any negatively charged group associated with the amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., F -, Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - PF6, sulfonate ions, and carboxylate ions (e.g., acetate, ascorbate, ethanoate, isoascorbate, propanoate, benzoate, glycerate, lactate, tartrate, glutamate, glycolate, etc.). The reaction can take place in any suitable solvent, such as, but not limited to, water-miscible solvents (e.g., alcohols (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

[0158] [ka]

[0159] In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 60°C to about 65°C. In an embodiment, the compound of formula ICC is heated with the organic or inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It can then be cooled, for example, to about room temperature. In another embodiment, it is cooled to about 0°C to about 10°C, optionally about 3 to about 7°C, optionally about 5°C, and optionally about 30 minutes to about 2 hours.

[0160] In another embodiment of the method for making the compounds described herein, the compounds can be made as follows, 1 ~R 14, and X) are defined as in the previous sections.

[0161] a) hydrolysis of compound of formula IAA' (5S,8R) to give intermediate of formula IBB': [ka] (wherein the hydrolysis is acid or base hydrolysis). The substrates employed in the first step of the synthesis of these compounds can be commercially obtained or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid can be used in the acid hydrolysis; however, any suitable acid can be used. Potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used in the base hydrolysis; however, any suitable base can be used. The reaction can be carried out in a water-miscible solvent (e.g., alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and / or heated to a suitable reaction temperature. In an embodiment, the temperature ranges from about 50°C to about 95°C. In certain embodiments, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0162] b) reacting an intermediate of formula IBB′ with R 1 -NH-R 2 to produce a compound of formula ICC' (e.g., the free base). [ka] .

[0163] The hydroxyl group of the carboxylic acid may be converted to a better leaving group (LG). Any suitable leaving group may be used, and may be selected from, for example, halides (e.g., Cl, Br, I), tosylates, mesylates, and weak bases such as perfluoroalkylsulfonates. The hydroxyl group may be converted to a better leaving group to provide the amine (R 1 -NH-R 2 Any suitable reactant may be used to aid in the reaction with the amine (R 1 -NH-R 2 ) and base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI) (e.g., coupling agent) may be used. The reaction may be carried out in any solvent suitable for making a solution of the reactants (e.g., THF, 2-methyl-THF, etc.). The reaction may be carried out at any suitable reaction temperature. In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0164] In an embodiment, the reaction comprises reacting said amine of formula IBB (R 1 -NH-R 2The reaction proceeds by base catalyzed amide bond formation upon reaction with 1,3,5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof.In specific embodiments, the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethylnium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof.

[0165] In steps (a) and (b), the acidity of the intermediates of formula IBB' and formula ICC' is adjusted to cause precipitation. The pH can be adjusted, for example, to about 6 to about 8 using an acid (e.g., hydrochloric acid).

[0166] Formula ICC' may also be used, where appropriate, in situ with (b) or in a separate reaction with hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acids, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, The amide may be converted to any suitable salt or hydrate (formula IDD') with any suitable organic or inorganic acid(s), such as succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. With regard to the formation of suitable salts, as outlined in the definition, the counterion may be, for example, any negatively charged group associated with the amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., F -, Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - PF6, sulfonate ions, and carboxylate ions (e.g., acetate, ascorbate, ethanoate, isoascorbate, propanoate, benzoate, glycerate, lactate, tartrate, glutamate, glycolate, etc.). The reaction can take place in any suitable solvent, such as, but not limited to, water-miscible solvents (e.g., alcohols (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

[0167] [ka] In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 60°C to about 65°C. In an embodiment, the compound of formula ICC' is heated with the organic or inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It can then be cooled, for example, to about room temperature. In another embodiment, it is cooled to about 0°C to about 10°C, optionally about 3°C ​​to about 7°C, optionally about 5°C, and optionally about 30 minutes to about 2 hours.

[0168] In another embodiment of the method for making the compounds described herein, the compounds can be made as follows, 1 ~R 15 , and X) are defined as in the previous sections.

[0169] a) hydrolysis of compound (5S,8S) of formula IAA″ to give intermediate of formula IBB″: [ka] (wherein the hydrolysis is acid or base hydrolysis). The substrates employed in the first step of the synthesis of these compounds can be commercially obtained or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid can be used in the acid hydrolysis; however, any suitable acid can be used. Potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used in the base hydrolysis; however, any suitable base can be used. The reaction can be carried out in a water-miscible solvent (e.g., alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and / or heated to a suitable reaction temperature. In an embodiment, the temperature ranges from about 50°C to about 95°C. In certain embodiments, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0170] b) reacting an intermediate of formula IBB″ with R 1 -NH-R 2 to produce a compound of formula ICC″ (eg, the free base). [ka]

[0171] The hydroxyl group of the carboxylic acid may be converted to a better leaving group (LG). Any suitable leaving group may be used, and may be selected from, for example, halides (e.g., Cl, Br, I), tosylates, mesylates, and weak bases such as perfluoroalkylsulfonates. The hydroxyl group may be converted to a better leaving group to provide the amine (R 1 -NH-R 2 Any suitable reactant may be used to aid in the reaction with the amine (R 1 -NH-R 2 ) and base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI) (e.g., coupling agent) may be used. The reaction may be carried out in any solvent suitable for making a solution of the reactants (e.g., THF, 2-methyl-THF, etc.). The reaction may be carried out at any suitable reaction temperature. In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0172] In an embodiment, the reaction comprises reacting said amine of formula IBB″ (R 1 -NH-R 2The reaction proceeds by base catalyzed amide bond formation upon reaction with 1,3,5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof.In specific embodiments, the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate azabenzotriazole tetramethylruthenium (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof.

[0173] In steps (a) and (b), the acidity of the intermediates of formula IBB″ and formula ICC″ was adjusted to cause precipitation. The pH can be adjusted, for example, to about 6 to about 8 using an acid (e.g., hydrochloric acid).

[0174] Formula ICC″ may also be used, where appropriate, in situ with (b) or in a separate reaction with hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acids, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (−)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, The amide may be converted to any suitable salt or hydrate (formula IDD'') with any suitable organic or inorganic acid(s), such as succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. With regard to the formation of suitable salts, as outlined in the definition, the counterion may be, for example, any negatively charged group associated with the amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., F- , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - PF6, sulfonate ions, and carboxylate ions (e.g., acetate, ascorbate, ethanoate, isoascorbate, propanoate, benzoate, glycerate, lactate, tartrate, glutamate, glycolate, etc.). The reaction can take place in any suitable solvent, such as, but not limited to, water-miscible solvents (e.g., alcohols (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

[0175] [ka]

[0176] In an embodiment, the temperature is in the range of about 50°C to about 95°C. In some embodiments, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 60°C to about 65°C. In an embodiment, heating the compound of formula ICC'' with the organic or inorganic acid is heated for any suitable time (e.g., about 30 minutes to about 1 hour). It can then be cooled, for example, to about room temperature. In another embodiment, it is cooled to about 0 to about 10°C, optionally about 3 to about 7°C, optionally about 5°C, and optionally about 30 minutes to about 2 hours.

[0177] In another embodiment of the method for making the compounds described herein, the compounds can be made as follows, 1 ~R14 , and X) are defined as in the previous sections.

[0178] a) hydrolysis of compound of formula IAA''' (5S,8R) to produce intermediate of formula IBB''': [ka] (wherein the hydrolysis is acid or base hydrolysis). The substrates employed in the first step of the synthesis of these compounds can be commercially obtained or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid, and / or nitric acid can be used in the acid hydrolysis; however, any suitable acid can be used. Potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used in the base hydrolysis; however, any suitable base can be used. The reaction can be carried out in a water-miscible solvent (e.g., alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and / or heated to a suitable reaction temperature. In an embodiment, the temperature ranges from about 50°C to about 95°C. In certain embodiments, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0179] b) reacting an intermediate of formula IBB''' with R 1 -NH-R 2 to produce a compound of formula ICC''' (eg, the free base). [ka]

[0180] The hydroxyl group of the carboxylic acid may be converted to a better leaving group (LG). Any suitable leaving group may be used, and may be selected from, for example, halides (e.g., Cl, Br, I), tosylates, mesylates, and weak bases such as perfluoroalkylsulfonates. The hydroxyl group may be converted to a better leaving group to provide the amine (R 1 -NH-R 2 Any suitable reactant may be used to aid in the reaction with the amine (R 1 -NH-R 2 ) and base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1'-carbonyldiimidazole (CDI) (e.g., coupling agent) may be used. The reaction may be carried out in any solvent suitable for making a solution of the reactants (e.g., THF, 2-methyl-THF, etc.). The reaction may be carried out at any suitable reaction temperature. In an embodiment, the temperature is in the range of about 50°C to about 95°C. In an embodiment, the temperature is in the range of about 50°C to about 95°C, about 60°C to about 95°C, about 70°C to about 95°C, about 80°C to about 95°C, about 90°C to about 95°C, about 50°C to about 90°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, or about 50°C to about 60°C.

[0181] In an embodiment, the reaction comprises reacting said amine of formula IBB''' (R 1 -NH-R 2The reaction proceeds by base catalyzed amide bond formation upon reaction with 1,3,5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), ethyl 2-cyano-2-(hydroxyamino)acetate (OxymaPure), benzotriazome-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylindenaminooxy)dimethylaminomorpholino)]uranium hexafluorophosphate (uranium hexafluorphosphate)(COMU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (E)-(ethyl cyano({[tris(pyrrolidin-1-yl)phosphaniumyl]oxy}imino)formate) (PyOxim), and (5E)-6-cyano-N,N,2-trimethyl-7-oxo-4,8-dioxa-2,5-diazadec-5-ene-3-iminium tetrafluoroborate (TOTU), or a combination thereof.In specific embodiments, the coupling agent is selected from carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate azabenzotriazole tetramethylnium (HATU), propylphosphonic anhydride (T3P), phosphorus oxychloride (POCl3), or a combination thereof.

[0182] In steps (a) and (b), the acidity of the intermediates of formula IBB″ and formula ICC″ was adjusted to cause precipitation. The pH can be adjusted, for example, to about 6 to about 8 using an acid (e.g., hydrochloric acid).

[0183] Formula ICC''' may also be used in situ or in a separate reaction with (b), where appropriate, to produce an acid such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1,2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-)-10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, The amide may be converted to any suitable salt or hydrate (formula IDD''') with any suitable organic or inorganic acid(s), such as succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), mesotartaric acid (or erythronic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), or combinations thereof. With regard to the formation of suitable salts, as outlined in the definition, the counterion may be, for example, any negatively charged group associated with the amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., F- , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , - BF4, - PF6, sulfonate ions, and carboxylate ions (e.g., acetate, ascorbate, ethanoate, isoascorbate, propanoate, benzoate, glycerate, lactate, tartrate, glutamate, glycolate, etc.). The reaction can take place in any suitable solvent, such as, but not limited to, water-miscible solvents (e.g., alcohols (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

[0184] [ka] In an embodiment, the temperature ranges from about 50° C. to about 95° C. In certain embodiments, the temperature ranges from about 50° C. to about 95° C., about 60° C. to about 95° C., about 70° C. to about 95° C., about 80° C. to about 95° C., about 90° C. to about 95° C., about 50° C. to about 90° C., about 50° C. to about 80° C., about 50° C. to about 75° C., about 50° C. to about 70° C., about 50° C. to about 65° C., or about 60° C. to about 65° C. In an embodiment, heating the compound of formula ICC''' with the organic or inorganic acid is heated for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In another embodiment, it is cooled to about 0° C. to about 10° C., optionally about 3 to about 7° C., optionally about 5° C., and optionally about 30 minutes to about 2 hours.

[0185] In the methods described herein, the products and intermediates can be purified by washing and recrystallization without the need for any chromatography; however, chromatography may be used. Recrystallization of a compound of Formula ID, Formula IDD, Formula IDD', Formula IDD'', or Formula IDD''', produces a crystalline compound, such as an isolated crystalline form, a polymorph thereof, a single polymorph thereof, or an isolated polymorph thereof. A compound of Formula IC is recrystallized using a water-miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc., or a combination thereof. The water-miscible solvent can be selected from methanol, ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, where the water-miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA). Recrystallization can include heating a salt or hydrate of a compound of formula ID, IDD, IDD', IDD'', or IDD''', in the solvent to a suitable temperature for a suitable period of time and cooling to yield the compound. In embodiments, recrystallization includes heating a compound of formula ID, IDD, IDD', IDD'', or IDD''', (e.g., a salt or hydrate of a compound of formula IC, ICC, ICC', ICC'', or ICC''', in the solvent at about 60° C. to about 80° C., optionally about 60° C. to about 70° C. In another embodiment, recrystallization includes heating a compound of formula ID, IDD, IDD', IDD'', or IDD''', in the solvent at about 60° C. to about 80° C., optionally about 60° C. to about 70° C., for about 1 hour to about 2 hours. In further embodiments, recrystallization comprises heating a salt or hydrate of a compound of Formula ID, Formula IDD, Formula IDD', Formula IDD'', or Formula IDD''', in said solvent at about 60° C. to about 80° C., optionally about 60° C. to about 70° C., for about 1 hour to about 2 hours, and cooling the compound in solution to about 0 to about 10° C., optionally about 3 to about 7° C., optionally about 5° C., optionally for about 1 hour to about 2 hours.In embodiments, the recrystallized compound is about 99% to about 99.9% pure, optionally about 99.5% to about 99.9% pure.

[0186] In another example, formula IA, formula IAA, formula IAA', formula IAA", or formula IAA'" is a bromine-containing ergoline derivative, such as bromocriptine mesylate. These substrates can be prepared by known methods and / or are commercially available.

[0187] With respect to the methods outlined above and in the embodiments, the methods provide polymorphs of Formula ID, Formula IDD, Formula IDD', Formula IDD'', or Formula IDD'''. In embodiments of the methods, R is -NR1R2 or -OR1, where R1 and R2 are each independently selected from any suitable group such that the CO(R) group is capable of undergoing hydrolysis; R 3 ~R 14 are each independently selected from H or methyl; X is bromo; and R 1 and R 2 are each independently selected from H, methyl, or ethyl.

[0188] In any of the methods of making the derivative(s) of acid LSD described above, it is understood that the ratio of the compound (e.g., Formula I, Formula I', Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ia', Formula Ib', Formula Ic', or Formula Id') to the acid can be any suitable ratio, such as a hemi-salt (0.5:1 or 2:1), typically. In embodiments, the ratio does not need to be perfectly matched in positive and negative charges. For example, the charge-balanced ratio of 2-bromo LSD to tartrate ion can be 2 to 1, with 2-bromo LSD being about +1 and tartrate being about -2. In the case of L-tartrate ion, the salt formed can be about 1 to about 1, meaning that there is an excess of negative charge. This can be balanced by hydrogen. The phosphates may be present in ratios of 1:3, 1:2, 1:1, or 2:1 and higher and lower ratios, where other spectator / counter ions may be used to balance the charge, such as hydrogen, hydroxide, sodium, chloride, calcium, potassium, etc. In embodiments, the ratio depends on the total charge of the acid. In certain embodiments, the ratio is from about 0.5:1 to about 2:1 (hemisalt) (mol / mol basis) and any increment therebetween, e.g., from about 0.6:1 to about 2:1; from about 0.7:1 to about 2:1; from about 0.8:1 to about 2:1; from about 0.9:1 to about 2:1; from about 1:1 to about 2:1; from about 1.1:1 to about 2:1; from about 1.2:1 to about 2:1; from about 1.3:1 to about 2:1; from about 1.4:1 to about 2:1; from about 1.5:1 to about 2:1; from about 1.6:1 to about 2:1; from about 1.7:1 to about 2:1; from about 1.8:1 to about 2: 1; about 1.9:1 to about 2:1; about 0.5:1 to about 1.9:1; about 0.5:1 to about 1.8:1; about 0.5:1 to about 1.7:1; about 0.5:1 to about 1.6:1; about 0.5:1 to about 1.5:1; about 0.5:1 to about 1.4:1; about 0.5:1 to about 1.3:1; about 0.5:1 to about 1.2:1; about 0.5:1 to about 1.1:1; about 0.5:1 to about 1:1; about 0.5:1 to about 0.9:1; about 0.5:1 to about 0.8:1; about 0.5:1 to about 0.7:1; or about 0.5:1 to about 0.6:1, etc.

[0189] (Formulations - LSD derivatives and their polymorphs) The LSD derivative(s) and polymorph(s) thereof disclosed herein may be provided in a formulation suitable for administration to a mammal, in certain embodiments for human and / or veterinary use.

[0190] In some embodiments, the disclosed compounds may be formulated as a pharmaceutical composition comprising: (a) an amount of one or more compounds disclosed herein or (b) a therapeutically effective amount of one or more compounds disclosed herein, and (c) one or more pharma- ceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may comprise the compound in any desired range as understood by one of skill in the art. For example, a non-limiting range may be in the range of about 0.001 to 2000 mg (preferably about 0.05 to 500 mg, more preferably about 0.25 to 100 mg). The pharmaceutical composition may be administered to provide a daily dose of the compound of about 0.005 to about 1000 mg / kg body weight (preferably about 0.01 to about 500 mg / kg body weight, more preferably about 0.01 to about 100 mg / kg body weight). In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., about 1, 2, 3, 4, 5, or 6 hours after administration), the concentration of the compound at the site of action can be within a concentration range bounded by endpoints selected from 0.001 μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM, and 100 μM (e.g., 0.1 μM to 10.0 μM).

[0191] The disclosed compounds and pharmaceutical compositions comprising the disclosed compounds can be administered in methods / uses to treat a subject in need thereof. In some embodiments of the disclosed therapeutic methods / uses, to treat a disease or disorder in a subject, the subject may be administered, for example, but not limited to, 0.25 mg, 0.75 mg, 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 100 mg, 125 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 100 mg, 125 mg, 145 mg, 160 mg, 180 mg, 190 mg, 200 mg, 215 mg, 225 mg, 235 mg, 245 mg, 250 mg, 265 mg, 275 mg, 285 mg, 290 mg, 300 mg, 315 mg, 325 mg, 335 mg, 345 mg, 350 mg, 365 mg, 375 mg, 385 mg, 390 mg, 400 mg, 425 mg, 45 mg, 465 mg Doses as low as 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg of the compound may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times weekly. In some embodiments, to treat a disease or disorder in a subject, the subject is administered 0.25 mg, 0.75 mg, 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52 mg, 54 mg, 56 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 108 mg, 109 mg, 108 mg, 109 mg, 102 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 109 mg, 108 Doses as high as 0.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg of the compounds may be administered once a day, twice a day, three times a day, four times a day, once a week, twice a week, or three times a week. Minimum and / or maximum doses of the compounds may include doses that fall within a dose range (e.g., 2.5 mg to 200 mg) having any of these disclosed doses as an endpoint.

[0192] In some embodiments, the minimum dosage level of the compound to achieve therapy in the disclosed methods / uses for treatment may be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng / kg of subject body weight. In some embodiments, the maximum dosage level of the compound to achieve therapy in the disclosed methods / uses for treatment should not exceed about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 μg / kg of subject body weight. The minimum and / or maximum dosage levels of the compounds for achieving therapy in the disclosed methods / uses for treatment may include dosage levels that fall within a range having any of these disclosed dosage levels as an endpoint (e.g., 5-2000 μg / kg of subject body weight).

[0193] The compounds utilized in the methods / uses disclosed herein may be formulated as pharmaceutical compositions in solid dosage forms, although any pharma- ceutically acceptable dosage form may be utilized. Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form may be, for example, a fast melt dosage form, a controlled release dosage form, a lyophilized dosage form, a delayed release dosage form, a sustained release dosage form, a pulsed release dosage form, a mixed immediate release and controlled release dosage form, or a combination thereof.

[0194] The compounds utilized in the methods / uses disclosed herein may be formulated as pharmaceutical compositions comprising a carrier. For example, the carrier may be selected from the group consisting of proteins, carbohydrates, sugars, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste.

[0195] The compounds utilized in the methods / uses disclosed herein may be formulated as pharmaceutical compositions comprising one or more binders, filling agents, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, and effervescent agents. Fillers can include lactose monohydrate, lactose anhydrous, and various starches; examples of binders include various celluloses as well as cross-linked polyvinylpyrrolidone, microcrystalline cellulose (such as Avicel® PH101 and Avicel® PH102), microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv). SMCC™. Suitable lubricants, including agents that affect the flowability of the powder to be compressed, include colloidal silicon dioxide (such as Aerosil® 200), talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents include Magnasweet® (a trademark of MAFCO), bubble gum flavor, and fruit flavors. Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid (such as butylparaben), alcohol (such as ethyl or benzyl alcohol), phenolic compounds (such as phenol), or quaternary compounds (such as benzalkonium chloride).

[0196] Suitable diluents include pharma- ceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, calcium phosphate dibasic, saccharides, and mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose (such as Avicel® PH101 and Avicel® PH102); lactose (such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21); calcium phosphate dibasic (such as Emcompress®); mannitol; starch; sorbitol; sucrose; and glucose.

[0197] Suitable disintegrants include lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof.

[0198] Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, as well as anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate salts, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present.

[0199] The crystalline LSD polymorphs described herein can be formulated as pharmaceutical compositions using one or more pharma- ceutically acceptable carriers or excipients.

[0200] In some embodiments, the disclosure provides pharmaceutical formulations comprising high purity LSD derivatives and polymorphs, and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising crystalline LSD and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising crystalline LSD polymorphs and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising high purity crystalline LSD polymorphs and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising high purity crystalline LSD polymorphs and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising high purity crystalline LSD polymorphs and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical formulations comprising high purity crystalline LSD polymorphs and one or more pharma- ceutically acceptable carriers or excipients.

[0201] Suitable pharmaceutical excipients for oral formulations include: diluents such as microcrystalline cellulose, starch, mannitol, calcium hydrogen phosphate, anhydrous or a co-mixture of silicon dioxide, calcium carbonate, microcrystalline cellulose, and talc; disintegrants such as sodium starch glycolate or croscarmellose sodium; binders such as povidone, copovidone, or hydroxylpropylcellulose; lubricants such as magnesium stearate or sodium stearyl fumurate; flow agents such as colloidal silicon dioxide; and film coats such as Opadry II White or PVA-based brown Opadry II. Oral dosage forms also include disintegrants such as, but not limited to: starch glycolate, croscarmellose sodium, and / or mixtures thereof. In an embodiment, the oral dosage form comprises 3% or less of disintegrant, less than 3% and more than 0.001% by weight of disintegrant, about 2.5% or less of disintegrant; 2% or less of disintegrant; 1.5% or less of disintegrant; 1% or less of disintegrant; 0.7% or less of disintegrant; 0.5% or less of disintegrant, or 0.3% or less of disintegrant. The disintegrant is sodium starch glycolate present at less than 3% by weight, about 2% or less by weight, about 2% or less by weight, about 1% or less by weight, about 1% or less by weight, about 0.7% or less by weight, about 0.7% or less by weight, about 0.5% or less by weight, or about 0.5% or less by weight. In yet another embodiment, the sodium starch glycolate is present at about 0.5% to 1% by weight.

[0202] The compound utilized in the method / use disclosed herein can be formulated as a pharmaceutical composition for delivery by any suitable route.For example, the pharmaceutical composition can be administered by oral, intravenous, intramuscular, subcutaneous, topical, and pulmonary routes.Examples of pharmaceutical compositions for oral administration include capsules, syrups, concentrates, powders, and granules.In some embodiments, the compound is formulated as a composition for oral administration (e.g., in a solvent such as 5% DMSO in oil such as vegetable oil).

[0203] The compounds utilized in the methods / uses disclosed herein may be administered in conventional dosage forms prepared by combining the active ingredients with standard pharmaceutical carriers or diluents by conventional procedures well known in the art, which may involve mixing, granulating, compressing or dissolving the ingredients as appropriate to provide the desired preparation.

[0204] Pharmaceutical compositions containing the compounds may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example, by combining the active ingredient with the carrier(s) or excipient(s).

[0205] Pharmaceutical compositions adapted for oral administration may be provided as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water or water-in-oil emulsions. Suitable excipients for tablets or hard gelatin capsules include lactose, corn starch or derivatives thereof, stearic acid or its salts. Suitable excipients for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, etc.

[0206] In one embodiment of the present invention, oral tablets can be produced by direct compression of the compounds disclosed herein. In general, the advantages of direct compression are known to include fewer production steps required, physical stability, and heat and moisture removal. In addition, the direct compression tablets according to the present invention can contain binders, disintegrants, and colorants, such as those well known to those skilled in the art. In another embodiment, pre-produced oral capsules contain the compounds disclosed herein with excipients. To further modify the release characteristics of the active agent in the gastrointestinal tract, pharma-ceutical acceptable coatings can be applied to these presentations of the present invention after the tablets are compressed or the capsules are closed. The selection of the optimal release site depends on the type of disease, the intended plasma peak concentration, the intended plasma time / concentration profile, and the intended time / concentration profile at the target site.

[0207] In a further embodiment, the present invention relates to a process for preparing a pharmaceutical product based on a formulation of a compound disclosed herein suitable for oral administration, which is directly compressed into a tablet, optionally mixed with one or more excipients (pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, and stearic acid), and the mixture is filled into size 4 white opaque hard gelatin two-piece capsules to provide 5 mg or 10 mg of a compound disclosed herein per capsule, which can be used as an oral formulation for immediate release in the gastrointestinal tract.

[0208] Pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time, for example, the active ingredient may be delivered from the patch by iontophoresis.

[0209] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols, or oils and may contain suitable conventional additives such as preservatives, solvents to assist drug penetration, and, in ointments and creams, emollients.

[0210] For application to the eye or other external tissues, e.g., mouth and skin, the pharmaceutical compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the compounds may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compounds may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0211] Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0212] Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include coarse powders having a particle size (for example in the range 20 to 500 microns) administered in the manner in which a snuff is taken (i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose). Formulations suitable for administration as a nasal spray or as nasal drops wherein the carrier is a liquid include aqueous or oily solutions of the active ingredient.

[0213] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions 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 contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0214] Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients (binding agents such as syrups, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone); fillers such as lactose, sugar, corn-starch, calcium phosphate, sorbitol, or glycine; tabletting lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated by methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate, or gum arabic; non-aqueous vehicles (such as edible oils), for example, almond oil, oily esters (such as glycerin, propylene glycol, or ethyl alcohol); preservatives, for example, p-hydroxybenzoate or methyl or propyl sorbate, and, if desired, conventional flavorings or colorings.

[0215] In some embodiments, the pharmaceutical compositions disclosed herein are modified release dosage forms that provide a modified release profile. The modified release profile may be an immediate release, delayed release, or sustained release profile. Conventional (or non-modified) release oral dosage forms, such as tablets, capsules, suppositories, syrups, solutions, and suspensions, usually release drugs into the mouth, stomach, or intestines when the tablets, capsule shells, or suppositories dissolve, or in the case of syrups, solutions, and suspensions, when they are swallowed. In order to achieve desired therapeutic objectives and / or better patient compliance, the pattern of drug release from modified release (MR) dosage forms is intentionally changed from that of conventional dosage forms. Types of MR drug products include oral disintegrating dosage forms (ODDF) that provide immediate release, sustained release dosage forms, delayed release dosage forms (e.g., enteric coating), and pulsatile release dosage forms.

[0216] ODDFs are solid dosage forms containing medicinal substances or active ingredients that disintegrate rapidly, usually within a few seconds, when placed on the tongue. The disintegration time of ODDFs generally ranges from 1 or 2 seconds to about 1 minute. ODDFs are designed to disintegrate or dissolve rapidly when in contact with saliva. This mode of administration may be beneficial for those who may have difficulty swallowing tablets, whether due to physical infirmity or of a psychiatric nature. Some subjects with eye disorders may exhibit such behavior. ODDFs can provide rapid delivery of drugs to the bloodstream via mucous membranes, resulting in rapid onset of action. Examples of ODDFs include orally disintegrating tablets, capsules, and fast-dissolving films and wafers.

[0217] An extended release dosage form (ERDF) has a sustained release profile, allowing for reduced dosing frequency compared to that provided by conventional dosage forms, such as solutions or non-modified release dosage forms. ERDF provides a long period of drug action. Suitable formulations that provide extended release profiles are well known in the art. For example, any of the compounds described herein can be coated onto beads, such as confectioners nonpareil beads, and then coated with a conventional release retarding material (wax, enteric coating, etc.) to form a coated extended release bead or granule ("beads" and "granules" are used interchangeably herein). In an embodiment, any of the compounds described herein can be formed into beads that are mixed with a material to provide a mass from which the compound can leach out. In an embodiment, beads can be designed and made to provide different release rates by varying the coating or mass characteristics, such as thickness, porosity, using various materials, etc. Beads with different release rates can be combined into a single dosage form to provide variable or continuous release. The beads may be contained in a capsule or compressed into a tablet.

[0218] Therapeutic modalities include: monotherapy; adjunctive therapy (i.e., add-on to standard drug therapy); use in combination with other medications approved for use in the treatment of neurological and neurodegenerative disorders; use in combination with other medications approved for use in the treatment of psychiatric and related disorders; use in combination with other medications approved for use in the treatment of various pain disorders; antidepressants and related medications for the treatment of neuropsychiatric disorders, including serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors, noradrenaline and specific serotonergic antidepressants (NASSAs), ketamine, N,N-dimethyltryptamine and other tryptamine derivatives, 3,4- combinations with other agents for the treatment of neuropsychiatric disorders; combinations with standard therapies for the treatment of neurodegenerative diseases; combinations with standard therapies for the treatment of various pain disorders; combinations with neuroprotectants (such as dihydrohonokiol-B) for the treatment of neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, normal aging and progeria syndromes); combinations with anxiolytics and similar agents (including benzodiazepines, cannabinoids, and dihydrohoniol-B) for the treatment of neuropsychiatric disorders; combinations with hallucinogens to reduce the side effects of hallucinogens in the treatment of neuropsychiatric disorders.

[0219] The schedule for treatment may include induction treatment and / or maintenance treatment, including short-term maintenance, intermediate-term maintenance, long-term maintenance, and variations thereof.

[0220] The LSD derivatives and polymorphs described herein may be provided in discreet dosage forms including: capsules or tablets for sublingual or buccal administration; as nasal sprays, metered dose inhalers, or the like for inhalation; as patches for controlled release over one or many days; and as depot formulations for controlled release.

[0221] In the context of the present disclosure, it is understood that samples may contain small amounts of liquid that are negligible in the final sample measurement. In some instances, it may be acceptable for the compositions of the present disclosure to contain, for example, up to about 7% water as measured by weight percent.

[0222] As described herein, an effective amount of the pharmaceutical composition or compound(s) disclosed herein provides therapeutic benefit without causing substantial toxicity. Those skilled in the art will recognize that the toxicity of the pharmaceutical composition or compound(s) disclosed herein can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population). In some embodiments, the dose ratio between toxic and therapeutic effects is the therapeutic index. In some embodiments, the data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that is not toxic for use in humans. In some embodiments, the dosage of the compounds described herein is within a range of circulating concentrations that include the effective dose with little or no toxicity. In some embodiments, the dosage can vary within this range depending on the dosage form employed and the route of administration utilized. In some embodiments, the exact formulation, route of administration, and dosage can be selected by the individual physician in view of the patient's condition. (See, e.g., Fingl et al., 1996 (Chapter 2, p. 29, The Pharmacological Basis of Therapeutics, 9th ed., Elliot M. Ross)).

[0223] Examples of therapeutically effective doses of the pharmaceutical compositions or compound(s) disclosed herein for various mental and / or mood disorders are described below. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±1%. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±2%. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±2.5%. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±5%. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±10%. In some embodiments, the term "about" when used in reference to the amount of the pharmaceutical compositions or compound(s) disclosed herein means about ±15%. In some embodiments, the term "about" when used in reference to amounts of pharmaceutical compositions or compound(s) disclosed herein means about ±20%.

[0224] With respect to the pharmaceutical compositions disclosed herein, pharma- ceutically acceptable carriers include diluents and excipients commonly used in pharmaceutical preparations, such as fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants, etc. Non-limiting examples of suitable carriers are described herein.

[0225] (Diluent) The diluent may be selected from, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, glucose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, maltodextrin, maltitol. In some embodiments, the diluent is selected from starch, lactose, cellulose derivatives, powdered sugar, and the like. Various grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, and others. Various starches include, but are not limited to, corn starch, potato starch, rice starch, wheat starch, pregelatinized starch, and others. Various celluloses that can be used include crystalline celluloses, such as microcrystalline cellulose, and powdered cellulose.Other useful diluents include, but are not limited to, carmellose, sugar alcohols (such as mannitol, sorbitol, and xylitol), calcium carbonate, magnesium carbonate, calcium phosphate dibasic, and calcium phosphate tribasic.

[0226] (Binding Agent) The binder may be selected from, for example, gum arabic, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low substituted hydroxypropylcellulose, glucose, sorbitol.

[0227] (Filler) Suitable fillers may be selected from, for example, starch derivatives such as corn starch, potato starch, or rice starch; polysaccharides such as dextrin, maltodextrin, dextrates, microcrystalline cellulose, powdered cellulose, mixtures of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols such as xylitol and sorbitol.

[0228] (Disintegrant) Disintegrants may be selected from, for example, alginic acid, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropylcellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch, low substituted hydroxypropylcellulose.

[0229] (Superplasticizer) The flow agent may be selected, for example, from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

[0230] (lubricant) Lubricants may be selected from, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulfate, talc, polyethylene glycol, and glyceryl behenate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium sodium stearate, sodium or magnesium lauryl sulfate, calcium soap, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combination thereof.

[0231] The pharmaceutical compositions of the present disclosure may be formulated as conventional pharmaceutical preparations, for example, in the form of tablets, flash melt tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injections (liquids, suspensions, etc.), troches, intranasal sprays, transdermal patches, and the like.

[0232] (Absorption enhancer) Absorption enhancers for use with certain embodiments of the present disclosure include, for example, Gelucire 44 / 14; Gelucire 50 / 13; Tagat TO; Tween 80; isopropyl myristate, polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic / capric glycerides, sodium lauryl sulfate, dioctyl sulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, ethoxylated glyceryl fatty acids (C8-C18), oleic acid, linoleic acid, glycol These include ceryl caprylate / caprate, glyceryl monooleate, glyceryl monolaurate, caprylic / capric triglyceride, ethoxylated nonylphenol, PEG-(8-50) stearate, olive oil PEG-6 ester, triolein PEG-6 ester, lecithin, d-alpha tocopherol polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrin, citric acid, sodium citrate, triacetin, combinations thereof, etc. In one preferred embodiment, the absorption enhancer is triacetin.

[0233] (Sweeteners / Flavors) Suitable sweeteners may be selected from sugars such as sucrose, lactose, and glucose; cyclamate and its salts; saccharin and its salts; and aspartame.

[0234] Flavoring agents that may be incorporated into the composition may be selected from synthetic flavor oils and flavoring aromatics, natural oils, and plant extracts. Examples include cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, or almond oil. Examples of flavoring agents include, but are not limited to, almond, apple, banana, berry, bubble gum, caramel, citrus, cherry, chocolate, coconut, grape, green tea, honey, lemon, licorice, lime, mango, maple, mint, orange, peach, pineapple, raisin, strawberry, vanilla, watermelon, and combinations thereof. Flavoring agents may be present in an amount ranging from about 0.001% to about 5% based on the total weight of the formulation. In some embodiments, the flavoring agent may be selected from natural or synthetic flavors such as, for example, strawberry flavor, wild cherry flavor, green apple flavor, spearmint flavor, and peppermint flavor, hi some embodiments, the flavoring agent is selected from menthol, peppermint, wintergreen, orange, cherry and other fruits, vanilla, almond and other nuts, and the like.

[0235] In some embodiments, the pharmaceutical composition of the present disclosure is in the form of a tablet, which may contain any of the following: lactose, saccharose, sodium chloride, glucose, urea, starch, xylitol, mannitol, erythritol, sorbitol, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and other disintegrants; sucrose, stearin, cocoa butter, hydrogenated oils, and other disintegration inhibitors; quaternary ammonium salts, sodium lauryl sulfate, and other absorption enhancers; glycerin, starch, and other moisture retaining agents. retainer); starch, lactose, kaolin, bentonite, colloidal silicic acid, and other adsorbents; and one or more pharma- ceutically acceptable carriers or excipients selected from purified talc, stearic acid salts, powdered boric acid, polyethylene glycol, and other lubricants, etc. Tablets can also be formulated with conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, and film-coated tablets, as well as double- and multi-layered tablets.

[0236] In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of a pill, which may contain one or more pharma- ceutically acceptable carriers or excipients selected from glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc, and other excipients; powdered acacia, powdered traganth, gelatin, ethanol, and other binders; and laminaran, agar, and other disintegrants, and the like.

[0237] In some embodiments, the pharmaceutical composition of the present disclosure is in the form of capsule.Capsule is prepared by mixing the carbostyril derivative such as anhydrous aripiprazole crystal as the first component and the serotonin reuptake inhibitor as the second component and various carriers as mentioned above, and filling them into hard gelatin capsule, soft capsule, hydroxypropyl methylcellulose capsule (HPMC capsule) etc. in a conventional manner.

[0238] In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of suppositories, which may contain one or more pharma- ceutically acceptable carriers or excipients selected from polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin semisynthetic glycerides, and the like.

[0239] (Route of administration and dosage form) The administration of the formulation to a subject according to the present disclosure can be by any commonly used route, as long as the target tissue can be reached by said route.Conveniently, the formulation can be provided in a unit dosage form and can be prepared by any of the methods well known in the pharmaceutical field.In some embodiments, the formulation is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into desired dosage form.Of course, those skilled in the art will recognize that the active ingredient (e.g., the compound(s) disclosed herein) is included in an amount sufficient to produce the desired pharmacological effect.

[0240] In some embodiments, the composition is administered according to the type of preparation form and the age, sex, and other conditions of the patient (such as the degree and condition of the disease).For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally.For injection preparations, they are administered intravenously either alone or mixed with commonly used auxiliary liquids such as glucose or amino acid solutions.Furthermore, if necessary, injection preparations are administered intradermally, subcutaneously, intramuscularly, or intraperitoneally alone.For suppositories, they are administered rectally.

[0241] In some embodiments, the pharmaceutical composition or compound(s) disclosed herein is administered at least once a day at a dosage such as the dosages described herein. In some embodiments, the pharmaceutical composition or compound(s) disclosed herein is administered at least twice a day at a dosage such as the dosages described herein. In some embodiments, the pharmaceutical composition or compound(s) disclosed herein is administered at least three times a day at a dosage such as the dosages described herein.

[0242] In another embodiment, the pharmaceutical composition or compound(s) disclosed herein is administered at least once every other day at a dosage such as the dosages described herein. In yet another embodiment, the pharmaceutical composition or compound(s) disclosed herein is administered at least once every third day at a dosage such as the dosages described herein. In a further embodiment, the pharmaceutical composition or compound(s) disclosed herein is administered at least once every fourth day at a dosage such as the dosages described herein. In a further embodiment, the pharmaceutical composition or compound(s) disclosed herein is administered at least once every fifth day at a dosage such as the dosages described herein.

[0243] In some embodiments, the method and formulation can be carried out as a single dose or chronically. By chronically, it is meant that the disclosed method and composition is carried out more than once for a given subject or individual. For example, as will be clear to those skilled in the art, chronic administration can be multiple doses of pharmaceutical composition administered to a subject daily, weekly, biweekly, monthly, or more or less frequently. Chronic administration can last for weeks, months, or years, as appropriate according to the judgment of a skilled professional in the art. Furthermore, if a dose shows an unacceptable tolerability profile in the judgment of a skilled professional in the art, the professional can reduce the dose to reduce such profile.

[0244] (Therapeutic use of LSD derivatives and their polymorphs) The novel LSD derivatives and polymorphs thereof disclosed herein are suitable for formulation as therapeutic agents for treating subjects in need thereof. They have been shown to promote synapse growth (improve neuroplasticity) and may result in "rewiring" the central and / or peripheral nervous system to produce long-lasting results without hallucinations. They have also been shown to be non-hallucinogenic and, surprisingly, do not induce tolerance, so they can be used in multiple daily, weekly, monthly, etc. doses. Advantageously, this avoids the need for spaced dosing schedules where subjects may wait several days (e.g., 3 or more days) before receiving the next dose.

[0245] Applicants have synthesized novel LSD derivative polymorphs that have been characterized as moderate to strong agonists across all 5-HT1 receptor subtypes with a slightly lower Emax (maximum drug effect) compared to LSD. Examples disclosed herein disclose the E559 polymorph [(5R,8R)-2-Br-LSD hemi-D-tartrate] that has been characterized with potency / activity at the 5-HT1F and 5-HT1D receptors, known targets of anti-migraine and pain perception drugs (Ramirez Rosas et al., "5-Hydroxytryptamine as a Mechanism of Action of Antimigraine Drugs"). 1B / 1D / 1F Receptor activation (Activation of 5-hydroxytryptamine 1B / 1D / 1F receptors as a mechanism of action of antimigraine drugs), Expert Opinion on Pharmacotherapy, 2013, 14:12, 1599-1610) and (Clemow, DB et al., "Mechanism of Action of Lasmiditan - Selective 5-HT 1FLasmiditan mechanism of action - review of a selective 5-HT 1F agonist”, J Headache Pain, 2020, 21, 71). The E559 polymorphism was shown to be a potent agonist at the 5-HT1F and 1D receptor subtypes, indicating its therapeutic potential to alleviate symptoms of, for example, headache, migraine, and pain disorders.

[0246] The E559 polymorph is characterized herein as a 5-HT6 partial agonist similar to LSD. 5-HT6 is a new target receptor for treating cognitive deficits and disorders (Drop et al., "2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity," ACS Chemical Neuroscience 2021 12 (7), 1228-1240) and (Khoury et al., "The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update," Expert Opinion on Investigational Drugs, 2018, 27:6, 523-533). Thus, the E559 polymorph, demonstrated as a potent partial agonist at the 5-HT6 receptor, has therapeutic applications in the treatment of cognition, learning, and memory, and thus for the treatment of cognitive disorders, including cognitive decline associated with neurological and psychiatric disorders, such as, but not limited to, Alzheimer's disease, Parkinson's disease, schizophrenia, Down's syndrome, and autism spectrum disorder.

[0247] The E559 polymorphism is characterized herein as being a partial agonist at the 5-HT2A and 5-HT1A receptor subtypes, which are known drug targets in the treatment of mood disorders such as depression and anxiety (Celada et al., "5-HT in Depression"). 1A and 5-HT 2A The therapeutic role of 5-HT 1A and 5-HT 2A receptors in depression), J Psychiatry Neurosci. 2004 Jul; 29(4): 252-265), and thus has utility for the treatment of antidepressant or anti-anxiety therapy.

[0248] The E559 polymorphism is shown herein to have high potency at D2-like receptors, including D2 and D4. As a potent agonist at D2 / D4 dopamine receptors, it has therapeutic potential in D2 / D4-related neuropsychiatric disorders, including but not limited to Parkinson's disease, schizophrenia, restless legs syndrome, psychosis, attention deficit hyperactivity disorder (ADHD), substance use disorder, hyperprolactinemia, and neuroleptic malignant syndrome (Bonifazi et al., "Novel and Potent Dopamine D2 Receptor Go-Protein Biased Agonists," ACS Pharmacology & Translational Science 2019 2 (1), 52-65) and (Paul E Keck Jr and Susan L McElroy, "Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic," Expert Opinion on Investigational Drugs, 2003, 12:4, 655-662) and (Woolley et al., "Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rats." Behavioural Pharmacology: December 2008-Volume 19-Issue 8-p765-776).

[0249] (Depressive Disorder) In some embodiments, the pharmaceutical composition or compound(s) disclosed herein can be used to treat a disease and / or disorder selected from the group consisting of: depressive state, major depressive disorder (including major depressive episode), major mood dysregulation disorder, atypical depression, major psychotic depression, catatonic depression, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, substance / medication-induced depressive disorder, dual depression, depressive personality disorder, persistent depressive disorder (dysthymia), recurrent brief depression, minor depressive disorder, depressive disorder due to a medical condition, and depressive disorder not otherwise specified. In some embodiments, the subject suffers from a treatment-resistant depressive disorder.

[0250] In some embodiments, suitable doses for use with this group of depressive disorders are as follows: [Table 1]

[0251] The term "major depressive disorder" refers to a condition characterized by periods of depressed mood that are present in most situations. Major depressive disorder is often accompanied by low self-esteem, disinterest in activities that one would normally enjoy, low energy, and pain without clear cause. In some instances, major depressive disorder is characterized by signs and symptoms that are present for two weeks, years, or almost all the time. Major depressive disorder may negatively affect a person's personal, work, or school life, as well as sleep, eating habits, and general health. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, but has less severe but longer-lasting symptoms. Exemplary symptoms of major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness, or hopelessness, anger, irritability or frustration (even over small things), loss of interest or pleasure in most or all usual activities, sleep disturbances (such as insomnia or hypersomnia), fatigue and lack of energy, loss of appetite, weight loss or gain, anxiety, agitation, or restlessness, slowing of thought, speech, or physical movements, feelings of worthlessness or guilt, preoccupation with past failures or self-blame, difficulty thinking, concentrating, making decisions, and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems for an unknown reason (such as back pain or headaches).

[0252] "Atypical depression" refers to a condition in which an individual exhibits a long-lasting pattern of signs of mood reactivity (i.e., mood brightening in response to actual or potential positive events), significant weight gain, increased appetite, hypersomnia, heavy, leaden feelings in arms or legs, and / or interpersonal sensitivity that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily sad or depressed mood, inability to find pleasure in things that were once pleasant, significant weight change (gain or loss) or appetite change, near-daily insomnia or hypersomnia, physical restlessness or weakness that is noticeable to others, daily fatigue or loss of energy, near-daily feelings of hopelessness, worthlessness, or excessive guilt, near-daily problems with concentration or decision-making, recurrent thoughts of death or suicide, suicide plans, or suicide attempts.

[0253] "Catatonic depression" refers to a condition that causes an individual to remain silent and immobile for extended periods of time. Exemplary symptoms of catatonic depression include, but are not limited to, a feeling of sadness that may occur on a daily basis, decreased interest in most activities, rapid or sudden weight gain or loss, changes in appetite, difficulty falling asleep or getting out of bed, restlessness, irritability, feelings of worthlessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or attempted suicide.

[0254] "Depressive disorder caused by a medical condition" means a condition in which an individual experiences depressive symptoms caused by another illness. Examples of medical conditions known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders (such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease), metabolic conditions (e.g., vitamin B12 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes).

[0255] "Postpartum depression" means a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Postpartum depression is often associated with women, but men can suffer from postpartum depression as well. Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopelessness, emptiness, or overwhelm; crying more often than usual or for no apparent reason; excessive worry or anxiety; feeling cranky, irritable, or restless; oversleeping or not being able to sleep even when the baby is sleeping; having trouble concentrating, remembering details, and making decisions; experiencing anger or rages; losing interest in normally enjoyable activities; suffering from physical aches and pains (including frequent headaches, stomach upset, and muscle aches); eating too little or too much; withdrawing or avoiding friends and family; having difficulty establishing close bonds or forming emotional attachments with the baby; continuing to doubt oneself or one's parenting abilities; and thoughts of harming oneself or the baby.

[0256] "Premenstrual dysphoric disorder" refers to a condition in which an individual exhibits mood lability, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the premenstrual phase of the menstrual cycle and that subside around the onset of menstruation or shortly thereafter. Exemplary symptoms of premenstrual dysphoric disorder include, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, decreased interest in usual activities, difficulty concentrating, lethargy and lack of energy, changes in appetite (e.g., overeating or craving certain foods), hypersomnia or insomnia, feeling overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, "bloating" and weight gain), self-deprecating thoughts, feelings of tension or irritability, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective difficulty concentrating, and fatigue.

[0257] "Seasonal affective disorder" refers to a condition in which an individual experiences mood swings depending on the time of year. In some instances, an individual experiences depressed mood, low energy, or other depressive symptoms during the fall and / or winter seasons. In some instances, an individual experiences depressed mood, low energy, or other depressive symptoms during the spring and / or summer seasons.

[0258] In some embodiments, the disclosed methods reduce at least one sign or symptom of a depressive state. In some embodiments, the sign or symptom of a depressive state is a depressed mood, a decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retarded psychomotor development, fatigue or reduced energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to concentrate or indecisiveness, suicidal thoughts or suicidal-related behaviors.

[0259] In some embodiments, the method described herein is provided to a newly diagnosed subject with depression.In some embodiments, the subject has been treated with one or more other antidepressant treatments but has not achieved adequate depression symptom management, or has achieved adequate depression symptom management but is adversely affected by the side effects of the treatment.In some embodiments, the method described herein is provided to a subject with treatment-resistant depression.In some embodiments, the subject has been diagnosed with "treatment-resistant depression", which means that the subject does not respond to or is resistant to at least one or more treatment attempts at appropriate doses and durations, which refers to a type of depression.

[0260] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by about 5% to about 100% compared to before treatment.

[0261] In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder by about 5% to about 100% compared to before treatment.

[0262] In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression by about 5% to about 100% compared to before treatment.

[0263] In some embodiments, the methods provided herein reduce at least one sign or symptom of catatonic depression by about 5% to about 100% compared to before treatment.

[0264] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder caused by a medical condition by about 5% to about 100% compared to before treatment.

[0265] In some embodiments, the methods provided herein reduce at least one sign or symptom of postpartum depression or premenstrual dysphoric disorder by about 5% to about 100% compared to before treatment.

[0266] In some embodiments, the subject is not receiving any other treatment to reduce signs or symptoms of depression following administration of the LSD derivatives or polymorphs disclosed herein.

[0267] In some embodiments, the method of the present disclosure further comprises administering at least one additional therapeutic agent to the subject to reduce signs or symptoms of depression.In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist.In some embodiments, the at least one additional therapeutic agent is administered before the administration of the LSD derivative or polymorph disclosed herein, on the same day as the administration of the LSD derivative or polymorph disclosed herein, or after the administration of the LSD derivative or polymorph disclosed herein.In some embodiments, the at least one additional therapeutic agent is administered on the same schedule as the LSD derivative or polymorph disclosed herein (e.g., once every other day or twice or once a week). In some embodiments, at least one additional therapeutic agent is administered on a schedule different from that of the LSD derivative or polymorph disclosed herein. In some embodiments, the duration of treatment with the LSD derivative or polymorph may be the same as, or shorter than, or longer than, the duration of treatment with the additional therapeutic agent.

[0268] (Bipolar and Related Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of bipolar disorder and related disorders, including bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder not otherwise specified.

[0269] In some embodiments, the doses to be used for this group of disorders are as follows: [Table 2]

[0270] "Bipolar disorder" refers to a condition that causes an individual to experience unusual changes in mood levels, energy levels, activity levels, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of abnormally intense emotions, periods of changes in sleep patterns and activity levels, and periods of abnormal behavior. These distinct periods are called "mood episodes." Mood episodes differ significantly from the person's typical mood and behavior. Exemplary symptoms of mania or hyperbehavior include, but are not limited to, abnormally cheerful, nervous, or excited behavior; increased activity, energy, or agitation, exaggerated feelings of happiness and self-confidence, decreased need for sleep, abnormal talkativeness, racing thoughts, distractibility, and poor decision-making.

[0271] Bipolar disorder includes bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Bipolar I disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms requiring hospitalization. Subjects with bipolar I disorder may also experience depressive episodes, usually lasting at least 2 weeks. Depressive episodes with mixed characteristics, i.e., simultaneous depressive and manic symptoms, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (elevation and euphoria) and periods of depressive symptoms that last for at least 2 years.

[0272] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder by about 5% to about 100% compared to before treatment.

[0273] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar I disorder by about 5% to about 100% compared to pre-treatment.

[0274] In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar II disorder by about 5% to about 100% compared to pre-treatment.

[0275] (Schizophrenia Spectrum Disorders and Other Psychotic Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of schizophrenia spectrum disorders and other psychotic disorders, including delusional disorder, brief psychotic disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, substance / drug-induced psychotic disorder, schizotypal (personality) disorder, psychotic disorder caused by another medical condition, catatonia associated with another psychiatric disorder, and other specified or unspecified schizophrenia spectrum, as well as other psychotric disorders.

[0276] In some embodiments, the doses to be used for this group of disorders are as follows: [Table 3]

[0277] (Personality Disorder) In further embodiments, the pharmaceutical compositions or compound(s) disclosed herein can be used to treat personality disorders as classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); American Psychiatric Association, 2013, the disclosure of which is incorporated herein by reference in its entirety. Briefly, personality disorders are classified by the DSM-5 into 10 specific disorders: paranoid personality disorder (a pattern of distrust and suspiciousness such that the motives of others are interpreted as malicious); schizoid personality disorder (a pattern of withdrawal from social relationships and a limited range of emotional expression); schizotypal personality disorder (a pattern of intense discomfort with intimate relationships, cognitive or perceptual distortions, and odd behavior); antisocial personality disorder (a pattern of disregard for and violation of the rights of others); borderline personality disorder (a pattern of instability in interpersonal relationships, self-image, and emotions, and marked impulsivity); histrionic personality disorder (a pattern of excessive emotionality and attention deficit disorder). personality disorder (patterns of grandiosity, need for praise, and lack of empathy); avoidant personality disorder (patterns of social inhibitions, feelings of inadequacy, and hypersensitivity to negative evaluation); dependent personality disorder (patterns of submissive and obsessive behavior associated with an excessive need for care); obsessive-compulsive personality disorder (patterns of preoccupation with orderliness, perfectionism, and control); personality change due to another medical condition (a persistent personality disorder judged to be due to the direct physiological effects of a medical condition); and other specified and unspecified personality disorders.

[0278] (Anxiety Disorder) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of anxiety disorders classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); American Psychiatric Association, 2013, the disclosure of which is incorporated herein by reference in its entirety. Briefly, anxiety disorders are classified by DSM-5 as: generalized anxiety disorder, separation anxiety disorder, panic disorder, selective mutism, specific phobias (fear of animals, natural environment, blood / injections / trauma, situational, other), social anxiety disorder, panic disorder, panic attack specific term, agoraphobia, substance / drug-induced anxiety, anxiety disorders due to other medical conditions, and other specified or unspecified anxiety disorders.

[0279] In some embodiments, the doses to be used for the above group of disorders are as follows: [Table 4]

[0280] (Trauma and Stress Related Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of trauma- and stressor-related disorders, including attachment disorder, disinhibited interpersonal disorder, post-traumatic stress disorder (PTSD), acute stress disorder, adjustment disorder, other specified or unspecified trauma- and stressor-related disorders.

[0281] In some embodiments, the doses to be used for the above group of disorders are as follows: [Table 5]

[0282] (Obsessive-Compulsive and Related Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders caused by another medical condition, and other specified and unspecified obsessive-compulsive disorder and related disorders (e.g., body-focused repetitive behavior disorder, obsessive jealousy).

[0283] In some embodiments, the doses to be used for the above group of disorders are as follows: [Table 6]

[0284] (Disruptive, Impulse Control, Conduct Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of disruptive-impulse-control-conduct disorders, including oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, trichotillomania, and other specified and unspecified disruptive-impulse-control-conduct disorders.

[0285] (Eating behavior disorders and eating disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of eating disorders and eating disorders including pica, rumination disorder, avoidant and restrictive food intake disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, binge eating or bulimia, diabetic binge eating disorder, Prader-Willi syndrome, and hypothalamic obesity, body dysmorphic disorder, and other specified and unspecified eating disorders or eating disorders.

[0286] (Dissociative Disorder) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of dissociative disorders, including dissociative identity disorder, dissociative amnesia, depersonalization-derealization disorder, and other specified and unspecified dissociative disorders.

[0287] (Somatic Symptom Disorders and Related Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of somatic symptom disorder and related disorders, including somatic symptom disorder, illness anxiety disorder, conversion disorder (functional neurological symptom disorder), factitious disorder (imposed on self and other), and other specified and unspecified somatic symptom disorder and related disorders.

[0288] (Neurodevelopmental Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of a disease and / or disorder selected from the group consisting of: intellectual disability (intellectual developmental disorder), global developmental delay, communication (language, speech, childhood-onset fluency or stuttering, social, non-specific) disorders, autism spectrum disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), specific learning disorder, movement disorders (developmental coordination, stereotypy, Tourette's disorder, persistent / chronic motor or vocal tic disorder, provisional tic disorder), and other specified or unspecified neurodevelopmental disorders including.

[0289] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of seizures (including generalized seizures, focal seizures, seizures of unknown onset, and bilateral seizures of focal onset) and epilepsy (including generalized epilepsy, focal epilepsy, generalized and focal epilepsy, Dravet syndrome, and epilepsy of unknown onset).

[0290] (Sleep-wake disorder) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of a disease and / or disorder selected from the group consisting of: insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorder (e.g., obstructive sleep apnea-hypopnea, central sleep apnea, idiopathic central sleep apnea, sleep-related hypoventilation), circadian rhythm sleep-wake disorder, non-rapid eye movement (NREM) sleep-wake disorder, nightmare disorder, rapid eye movement (REM) sleep behavior disorder, restless legs syndrome, substance / drug-induced sleep disorder, and other specified and unspecified sleep-wake disorders.

[0291] (Substance-Related and Addictive Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of substance-related disorders (SRDs) and addictive disorders, including, but not limited to, the following classes of drugs: alcohol, nicotine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (amphetamine-type substances, cocaine, and other stimulants), and solvent abuse, pharmaceuticals, and other specified or unspecified substance-induced disorders.

[0292] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of non-substance related disorders, including, but not limited to, gambling disorder.

[0293] Substance Dependence Disorder, also known as Substance Use Disorder, or Substance Abuse Disorder, is a condition in which the use of one or more substances leads to significant impairment, impairment in functioning, or distress. Addiction and dependence are components of SRD, where addiction represents the more severe form of the disorder.

[0294] (Headache Disorders) In further embodiments, the pharmaceutical compositions or compound(s) disclosed herein can be used to treat headaches classified in the International Classification of Headache Disorders, 3rd Edition, Cephalalgia, 2018, 38 (1), 1-211, a publication of the Headache Classification Committee of the International Headache Society (IHS), the disclosure of which is incorporated herein by reference in its entirety. Briefly, headaches are classified by the IHS into three broad categories as primary headaches, secondary headaches, or other headache disorders.

[0295] In some embodiments, the pharmaceutical composition or compound(s) disclosed herein can be used to treat and / or prevent and / or reduce the occurrence / duration of headaches classified by the HIS as "primary headaches", including migraine (including migraine without aura, migraine with aura, and chronic migraine), tension-type headache (including infrequent episodic, frequent episodic, and chronic tension-type headache), trigeminal-autonomic headaches (including cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua), and other primary headache disorders.

[0296] Trigeminal autonomic cephalopathy (TAC) includes cluster headache, including all its subgroups, such as episodic cluster headache and recurrent or chronic cluster headache (sometimes called familial cluster headache, histaminergic headache, or vasculogenic facial pain); as well as short-lasting unilateral neuralgiform headache (SUNHA) and its subgroups, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA). The major subcategories of TAC are defined by the IHS as follows:

[0297] Trigeminal autonomic headache (TAC) 1. Cluster headaches 1.1. Episodic cluster headache 1.2. Chronic cluster headache 2. Paroxysmal hemicrania 2.1. Episodic paroxysmal hemicrania 2.2. Chronic paroxysmal unilateral headache 3. Short-lasting unilateral neuralgiform headache attacks 3.1. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) 3.1.1. Iterative SUNCT 3.1.2. Chronic SUNCT 3.2. Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA) 3.2.1. Recurrent SUNA 3.2.2. Chronic SUNA 4. Persistent unilateral headache 4.1. Hemicrania continua, remitting type 4.2. Hemicrania continua, non-remitting 5. Suspected trigeminal / autonomic headache 5.1. Suspected cluster headache 5.2. Suspected paroxysmal hemicrania 5.3. Suspected short-lasting unilateral neuralgiform headache 5.4. Suspected hemicrania continua

[0298] In some embodiments, the pharmaceutical composition or compound(s) disclosed herein can be used to treat and / or prevent and / or reduce the onset / duration of headaches classified by the IHS as "secondary headaches", which include headache due to trauma or injury to the head and / or neck, headache due to vascular disorders of the head and / or neck, headache due to non-vascular intracranial disorders, headache due to a substance or its withdrawal, headache due to an infection, headache due to a disorder of homeostasis, headache or facial pain due to a disorder of the skull, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structures, headache due to a psychiatric disorder, and headache categories of painful lesions of the cranial nerves and other facial pain, including pain due to lesions or diseases of the trigeminal nerve.

[0299] Trigeminal neuralgia (TN) is defined by the IHS as "a disorder characterized by recurrent unilateral, brief, electric shock-like pain triggered by non-noxious stimuli, with abrupt onset and termination, confined to the distribution of one or more parts of the trigeminal nerve, and characterized by non-noxious stimuli" [**] and includes both classical TN (formerly called idiopathic trigeminal neuralgia), which refers to TN caused solely by neurovascular compression (which is further classified into two forms: 1) typical TN, pure paroxysmal, and 2) typical TN with concurrent persistent facial pain); and secondary TN, which refers to trigeminal neuralgia-like pain associated with underlying diseases, including tumors, trauma, viral infections, and multiple sclerosis (where such secondary TN has a similar clinical picture to typical TN, but may also present with some additional and / or different features (e.g., TN due to multiple sclerosis, which may have bilateral symptoms, and TN associated with tumors, which often show abnormalities in electrophysiological tests such as the trigeminal brainstem reflex).

[0300] In some embodiments, the pharmaceutical compositions or compound(s) disclosed herein can be used to treat and / or prevent and / or reduce the occurrence / duration of headaches classified by the IHS as "other headache disorders," including unclassifiable and unspecified.

[0301] (pain) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are useful in treating neuropathic factors including conditions that cause nerve damage leading to pain such as inflammation (e.g., rheumatoid arthritis, lupus, Behcet's disease), genetic factors (e.g., erythromelalgia), diabetes, cancer, and cancer treatments such as chemotherapy, neurological conditions such as multiple sclerosis (MS), neurodegenerative conditions such as Parkinson's disease, stroke, shingles, HIV, leprosy, Guillain-Barre syndrome, vascular diseases, angiodysplasia, and autoimmune conditions, peripheral neuropathies, autonomic neuropathies, regional neuropathies, proximal neuropathies, diabetic neuropathies, and compressive neuropathies. For use in the treatment of pain caused by conditions such as all neuropathies including mononeuropathies, phantom limb pain, residual limb pain, and all radiculopathies including complex regional pain syndrome (CRPS), trigeminal neuralgia, postherpetic neuralgia, radicular pain, radiculitis and thoracic or lumbar radiculopathy, nociceptive pain (e.g. trauma-induced pain, cancer pain), high prevalence of somatization or nociceptive pain (e.g. chronic widespread pain, fibromyalgia, chronic temporomandibular joint disorder, chronic low back pain of unknown etiology, irritable bowel syndrome, chronic primary bladder pain syndrome, chronic primary pelvic pain syndrome), and various other forms of chronic pain whatever the aetiology (e.g. chronic low back pain).

[0302] In further embodiments, the pharmaceutical compositions or compound(s) disclosed herein can be used to treat chronic pain as classified by the International Association for the Study of Pain (IASP) taskforce (PAIN: June 2015 - Volume 156 - Issue 6 - p 1003-1007), the disclosure of which is incorporated herein by reference in its entirety. Briefly, chronic pain is defined as persistent or recurrent pain lasting more than three months and includes the following seven categories: chronic primary pain (such as fibromyalgia, chronic pelvic pain, nonspecific back pain, and chronic primary pain not otherwise specified); chronic cancer pain (such as pain due to cancer and metastases, chemotherapy-induced pain, pain due to radiation therapy, pain due to cancer surgery, and other chronic pain related to cancer); chronic post-operative and post-traumatic pain (including all post-operative and post-traumatic pain, and post-operative / post-traumatic pain not otherwise specified); chronic neuropathic pain (including peripheral neuropathic pain, central neuropathic pain, and other neuropathic pain, and neuropathic pain not otherwise specified). chronic headache and orofacial pain (including chronic primary headache, chronic secondary headache, chronic orofacial pain, and headache and orofacial pain not otherwise specified); chronic visceral pain (including chronic visceral pain as a result of persistent inflammation, and / or vascular mechanisms, and / or obstruction / distention, and / or traction / compression, and / or combined mechanisms, or from other sites, referred chronic visceral pain from cancer, or chronic pain of functional or unknown etiology); and chronic musculoskeletal pain (including chronic musculoskeletal pain as a result of persistent inflammation and / or structural bone-joint changes, and / or chronic musculoskeletal pain originating from diseases of the nervous system, such as spasmodic pain, and chronic nonspecific musculoskeletal pain and referred pain syndromes).

[0303] In further embodiments, the pharmaceutical compositions or compound(s) disclosed herein can be used to treat and / or prevent or reduce the onset / duration of acute pain, which is defined as pain of any type including inflammatory, nociceptive, neuropathic, nociceptive, and other types of pain, lasting for a short period of time, from a few hours or days up to three months, and including acute pain as a result of tissue injury, such as that resulting from any type of surgical procedure, dental procedure, labor and delivery, cuts, burns, fractures, and other accidents or trauma, acute pain resulting from any disease state, acute pain resulting from any type of trauma, and acute pain of unknown cause.

[0304] (spasticity) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of conditions associated with spasticity with or without neuropathic pain, including, but not limited to, cerebral palsy, stroke, multiple sclerosis (MS), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia, adrenoleukodystrophy (ALD), phenylketonuria, Krabbe's disease, and spinal cord injury.

[0305] (Nerve Damage) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of disorders and diseases associated with nerve injury or trauma, including peripheral nerve injury or trauma, regardless of cause, and / or central nervous system (brain and spinal cord) nerve injury or trauma, regardless of cause, including disorders and diseases resulting from external physical factors, such as accidents, sports injuries, falls, gunshots, or explosive blaststrokes; or disorders and diseases resulting from internal factors, such as stroke, ruptured cerebral aneurysm, lack of oxygen, infections (viral, bacterial, prion, or other), and autoimmune diseases; and including all other nerve injuries or trauma caused directly or indirectly by external factors, and / or nerve injuries or trauma resulting directly or indirectly from disease states.

[0306] (fatigue) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of chronic fatigue (e.g., physical fatigue, psychological fatigue, or mental fatigue) due to traumatic brain injury (TBI), chronic fatigue syndrome (CFS), and related conditions, and other diseases and / or disorders that cause chronic fatigue.

[0307] (Neurodegeneration) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of a disease and / or disorder selected from the group consisting of neurodegenerative disorders such as: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Batten disease, Friedreich's ataxia, Huntington's disease, Lewy body disease, motor neuron disease, multiple sclerosis, Parkinson's disease, prion diseases, spinal muscular atrophy, neurodegenerative conditions caused by viral (e.g., HIV) or bacterial infections, substance / drug caused neurodegenerative conditions, and other aging-related and non-aging-related neurodegenerative conditions.

[0308] (Sexual Dysfunction and Gender Dysphoria) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of a disease and / or disorder selected from the group consisting of sexual dysfunction including delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, substance / drug induced sexual dysfunction, other specified and unspecified sexual dysfunction.

[0309] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of gender dysphoria in children, adolescents, adults, and other specified and unspecified gender dysphoria.

[0310] (Neurocognitive Disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of a disease and / or disorder selected from the group consisting of neurocognitive disorders (NCDs), including delirium, neurocognitive disorder (NCD) due to Alzheimer's disease, vascular NCD, Lewy body NCD, Parkinson's disease, frontotemporal NCD, traumatic brain injury, HIV infection, substance / drug induced NCD; NCD due to Huntington's disease, NCD due to prion disease; NCD due to another medical condition, NCD due to multiple etiologies, and unspecified NCD.

[0311] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of neurocognitive / learning dysfunction including memory problems, lack of mental clarity, poor concentration, and / or inability to concentrate due to infection (viral / bacterial / prion / other), or other identified or unidentified disorder, disease, or other unknown causes.

[0312] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of memory, cognition, and / or learning decline with or without overt signs of a neurodegenerative or neurodevelopmental disorder and / or in the prevention of memory, cognition, and / or learning decline at any age with or without overt signs of a neurodegenerative or neurodevelopmental disorder.

[0313] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of decline in memory, cognition, and / or learning with or without overt signs of a neurodegenerative disorder associated with normal aging.

[0314] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of: neurological and / or neuropsychiatric disorders and / or conditions associated with normal aging and / or progeria syndromes.

[0315] According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of: neurological and / or neuropsychiatric disorders and / or conditions associated with normal aging and / or progeria syndromes.

[0316] (Neurologic-Viral Infections) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of: neurological diseases caused by viral infections that utilize neuronal cell surface receptors for entry, such as serotonergic (5-HT) receptors (particularly the 5-HT2A receptor), such as progressive multifocal leukoencephalopathy (PML) caused by the JC virus.

[0317] (countering the side effects of other drugs) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders selected from the group consisting of: reduction and / or prevention of side effects (hallucinations, bad trips, etc.) of hallucinogens (e.g., psilocybin and LSD).

[0318] (In good condition) In another embodiment, the pharmaceutical composition or compound(s) disclosed herein can be used for self-administration to produce a general feeling of wellness.

[0319] (5-HT1 receptor-mediated therapeutic effects in headache and pain disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders in which the therapeutic mechanism is associated with 5-HT1 receptor activation (receptor agonism at one or more 5-HT1 receptor subtypes, such as 5-HT1A, 1B, 1D, 1E, and 1F), e.g., headache disorders and pain disorders.

[0320] (5-HT6 receptor-mediated therapeutic effects on cognition, learning, and memory) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders associated with deficits or decline in cognition / learning / memory, such as Alzheimer's disease, Parkinson's disease, schizophrenia, Down's syndrome, and autism spectrum disorder, in which the therapeutic mechanism is associated with 5-HT6 receptor activation (agonism).

[0321] (5-HT2A receptor-mediated therapeutic effects in depressive and anxiety-related disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders, such as depressive disorders and anxiety-related disorders, in which the therapeutic mechanism is associated with 5-HT2A receptor activation (agonism).

[0322] (D2-like receptor-mediated therapeutic effects in various neuropsychiatric disorders) According to another embodiment, the pharmaceutical composition or compound(s) disclosed herein are for use in the treatment of diseases and / or disorders in which the therapeutic mechanism is associated with D2-like receptor (such as D2 and D4 receptor subtypes) activation (agonism), such as depressive disorders, Parkinson's disease, schizophrenia, restless legs syndrome, psychiatric disorders, attention deficit hyperactivity disorder (ADHD), substance use disorders, hyperprolactinemia, and neuroleptic malignant syndrome.

[0323] (Non-hallucinogenic and neuroplasticity inducers and receptors) Hallucinations caused by LSD or other serotonergic hallucinogenic compounds are believed to be driven by receptor agonism at the 5HT2A receptor (Halberstadt AL, Behavioural Brain Research. 2015, 15; 277:99-120). Thus, LSD derivatives that are 5HT2A agonists are expected to be hallucinogenic, i.e., induce hallucinations. Thus, it is unexpected and novel that LSD derivatives with 5HT2A receptor agonism are also substantially non-hallucinogenic.

[0324] Several 5-HT receptor subtypes have been identified in mammals to date, including 5HT-1A, 1B, 1D, 1E, 1F, 2A, 2B, 2C, 3, 4, 5A, 5B, 6, and 7. It is also known that LSD exhibits 5HT-2B receptor agonism. This receptor agonism at the 5HT-2B receptor is undesirable because it is believed to lead to fibrosis and subsequent cardiovascular side effects, such as valvular heart disease caused by LSD (Cavero and Guillon, Journal of Pharmacological and Toxicological Methods, 2014, 69:150-161). An LSD derivative that has 5HT2A receptor agonism and is not a 5HT-2B agonist would be novel and unexpected.

[0325] Neuroplasticity inducer (neuroplastogen) is any compound that induces / improves neuroplasticity. Neuroplasticity can be defined as structural and functional changes in the nervous system, including neurogenesis, regulation of neuronal or astrocyte cell body or neurite size, shape, and length, or synaptic plasticity (including synapse formation, synaptic strengthening, spinogenesis, loss of synaptic spines, "pruning", changes in synaptic spine volume, changes in synaptic density), or changes in specific synaptic proteins and pathways. It is believed that improving neuroplasticity is an important therapeutic mechanism for the treatment of most neuropsychiatric and neurological diseases and / or disorders.

[0326] Thus, in some embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic and exhibit some degree of agonism at the 5HT2A receptor.

[0327] In further embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic and exhibit neuroplasticity-inducing properties with or without any degree of receptor agonism at the 5HT2A receptor.

[0328] In further embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic, exhibit weak to no agonism, antagonism or inverse agonism at the 5HT2B receptor, and induce neuroplasticity with or without some agonism at the 5HT2A receptor.

[0329] In further embodiments, the LSD derivatives and polymorphs thereof disclosed herein do not produce substantial hallucinogenic effects and therefore have the potential to modulate neuroplasticity and are suitable as "neuroplasticity inducers" or "neuroplasticity inducers" formulated and provided as "neuroplasticity inducing doses."

[0330] In further embodiments, the administration of the LSD derivatives and polymorphs thereof disclosed herein is at a safe and tolerable dose that can exert a neuroplasticity inducing effect: to induce / improve neuroplasticity to aid in the treatment of psychiatric diseases / disorders; to treat and / or prevent / reduce decline in cognition, learning and memory in all age groups, particularly in normal aging; to treat and / or prevent / reduce decline in cognition, learning and memory in neurological diseases / disorders at any age; and / or to treat and / or prevent / reduce decline in cognition, learning and memory in psychiatric diseases / disorders at any age.

[0331] In further therapeutic embodiments, the LSD derivatives and polymorphs disclosed herein are useful for modulating neurological receptors, said modulation being receptor agonism, antagonism, or any partial version, where said neurological receptor modulation aids in the treatment of disease or disorder.As a non-limiting example, the LSD derivatives and polymorphs disclosed herein can modulate 5-HT receptors, such as 5-HT2A subtype, and thus affect neurological and psychiatric disorders that are influenced by 5-HT type, which may include various forms of depression, anxiety, PTSD, and pain.

[0332] In further embodiments, transporters called solute carriers (SLC) can be modulated by the novel LSD derivatives and polymorphs disclosed herein, said modulation being receptor agonism, antagonism, or partial of either, where modulation of the transporters aids in the treatment of a disease or disorder.

[0333] Thus, in some embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic and exhibit some degree of agonism at the 5HT2A receptor.

[0334] In further embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic and exhibit neuroplasticity-inducing properties with or without any degree of receptor agonism at the 5HT2A receptor.

[0335] In further embodiments, the LSD derivative(s) or polymorph(s) thereof disclosed herein are substantially non-hallucinogenic, exhibit weak to no agonism, antagonism or inverse agonism at the 5HT2B receptor, and induce neuroplasticity with or without some agonism at the 5HT2A receptor.

[0336] In further embodiments, the LSD derivatives and polymorphs thereof disclosed herein do not produce substantial hallucinogenic effects and are therefore suitable as "neuroplasticity inducers" or "neuroplasticity inducers" that have the potential to modulate neuroplasticity and are formulated and provided as "neuroplasticity inducing doses."

[0337] In further embodiments, the administration of the LSD derivatives and polymorphs thereof disclosed herein is at a dose shown to be safe and tolerable to exert a neuroplasticity inducing effect: to induce / improve neuroplasticity to aid in the treatment of psychiatric diseases / disorders; to support cognition, learning, and memory in all age groups, particularly in normal aging; to support cognition, learning, and memory in neurological diseases / disorders at any age; and / or to support cognition, learning, and memory in psychiatric diseases / disorders at any age.

[0338] The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific examples. These examples are set forth for illustrative purposes only and are not intended to limit the scope of the present invention. Changes in the form and substitution of equivalents are envisaged as circumstances may suggest and may be expedient. Although specific terms are employed herein...

Claims

1. below: 【Chemical 1】 【change】 【change】 【change】 A substantially pure crystalline form of a compound selected from The crystalline form, wherein the compound has a powder X-ray diffraction (PXRD) pattern comprising a peak at 10.3°±0.2° 2θ.

2. 10. A substantially pure crystalline form of the compound of claim 1 which is 2-bromo-LSD tartrate.

3. 2. A substantially pure crystalline form of the compound of claim 1, wherein the stereocenters of said compound are 5R and 8R, or 5R and 8S.

4. 4. A substantially pure crystalline form of the compound of claim 3, which is (5R,8R) 2-bromo-LSD hemi-D-tartrate.

5. 5. A substantially pure crystalline form of the compound of claim 4, which is a substantially pure polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate.

6. 6. The substantially pure crystalline form of the compound of claim 5, wherein a PXRD pattern of the compound further comprises peaks at 4.7°±0.2° 2θ, 9.4°±0.2° 2θ, and 20.1°±0.2° 2θ.

7. 7. A substantially pure crystalline form of the compound of claim 6, having an optical rotation of about 0.30° to about 0.40°.

8. 8. A substantially pure crystalline form of the compound of claim 7, wherein the compound is substantially non-hallucinogenic.

9. 10. A substantially pure crystalline form of the compound of claim 8, which enhances neuroplasticity in neurons.

10. 10. A substantially pure crystalline form of the compound of claim 9, wherein the compound is: i) does not induce tolerance to the compound in a subject; ii) is a moderate to potent pan-agonist across all 5-HT1 receptor subtypes; iii) is a potent 5-HT6 receptor partial agonist; iv) are partial agonists at the 5-HT2A and 5-HT1A receptor subtypes; v) is not an agonist or is an antagonist at the 5-HT2B receptor; and vi) D2-like receptor activating activity The crystalline form exhibiting one or more of the following:

11. 10. A substantially pure crystalline form of the compound of claim 1, which is at least 98% pure.

12. 10. A substantially pure crystalline form of the compound of claim 1, which is at least 99% pure.

13. 100% pure crystalline form of the compound of claim 1.

14. below: 【Chemistry 2】 【change】 【change】 【change】 A substantially pure crystalline form of a compound selected from The crystalline form of the compound having a powder X-ray diffraction (PXRD) pattern comprising one or more peaks at 10.3°±0.2° 2θ, 4.7°±0.2° 2θ, 9.4°±0.2° 2θ, and 20.1°±0.2° 2θ.

15. A composition comprising a substantially pure crystalline form of the compound of any one of claims 1 to 14, and a pharmaceutically acceptable carrier, diluent, or excipient.

16. 16. A formulation comprising the composition of claim 15, wherein the formulation is a liquid or a solid, optionally wherein the solid is a powder, tablet, or pill.

17. 17. The formulation of claim 16, wherein the formulation contains an established amount of the compound and is for oral or parenteral administration.

18. 15. Use of a compound according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment of one or more of the following: depressive disorders; bipolar disorders and related disorders; schizophrenia spectrum disorders and other psychotic disorders; personality disorders; anxiety disorders; trauma and stressor-related disorders; obsessive-compulsive disorders and related disorders; disruptive, impulse control and conduct disorders; eating and eating disorders; dissociative disorders; somatic symptom disorders and related disorders; neurodevelopmental disorders; sleep-wake disorders; substance-related and addictive disorders; headache disorders; pain disorders; spasticity; nerve injury disorders; fatigue; neurodegenerative disorders; sexual dysfunction and gender dysphoria disorders; neurocognitive disorders; and neurological viral infections.

19. a) hydrolyzing a compound of formula IA to produce an intermediate of formula IB; 【Chemistry 3】 b) converting the intermediate of formula IB into R 1 -NH-R 2 to form a compound of formula IC; 【Chemistry 4】 ,and c) converting the compound of formula IC to a salt or hydrate using an organic or inorganic acid; R is -OR 1 or -NR 1 R 2 Selected from R 1 and R 2 are each independently selected from H, halo, hydroxyl, amino, substituted or unsubstituted hydrocarbon, substituted or unsubstituted hybrid, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aromatic, or substituted or unsubstituted heteroaromatic, and optionally, R 1 and R 2 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted hybrid group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group; A method of making a compound according to any one of claims 1 to 14.

20. 1. A substantially pure crystalline polymorph of (5R,8R) 2-bromo-LSD hemi-D-tartrate, wherein the PXRD pattern of the polymorph comprises peaks at one or more of 4.7°±0.2° 2θ, 9.4°±0.2° 2θ, and 20.1°±0.2° 2θ.

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