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WO2025240512A1 - Novel iboga alkaloid analogs and their uses thereof - Google Patents

Novel iboga alkaloid analogs and their uses thereof

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Publication number
WO2025240512A1
WO2025240512A1 PCT/US2025/029188 US2025029188W WO2025240512A1 WO 2025240512 A1 WO2025240512 A1 WO 2025240512A1 US 2025029188 W US2025029188 W US 2025029188W WO 2025240512 A1 WO2025240512 A1 WO 2025240512A1
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alkyl
aryl
alkenyl
alkynyl
heteroaryl
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French (fr)
Inventor
Dalibor Sames
David Lankri
Vaclav Havel
Bruno Rodrigo GONZALEZ NUNEZ
Christopher HWU
Inis SERRANO
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Columbia University in the City of New York
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Columbia University in the City of New York
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Publication of WO2025240512A1 publication Critical patent/WO2025240512A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • Ibogaine is the major psychoactive alkaloid found in the root bark of Tabernanthe iboga, a plant native to West Central Africa (Alper, K.R. 2001). The root bark has been used as a religious and healing sacrament by the native people in Africa owing to its distinct psychedelic and post-acute therapeutic effects. The clinical claims of ibogaine’s anti-addictive properties, discovered in the U.S.
  • QT prolongation is associated with an increased risk of life- threatening torsade de pointes (TdP) arrhythmias (Redfern, W. S. et al 2003).
  • TdP life- threatening torsade de pointes
  • Both ibogaine and noribogaine are reported to block human ether-a-go-go-related gene (hERG) potassium channels at clinically relevant low micromolar values (Alper, K. et al 2016), which can result in retardation of ventricular action potential (AP) repolarization and prolongation of the QT interval in the electrocardiogram (ECG) (Redfern, W. S. et al 2003).
  • the present invention relates to novel ibogaine analogs of compounds compared to previously disclosed ibogaine analogs in U.S. Application No. 14/240,681, patented as U.S. Patent No. 9,988,377; U.S. Application No 15/528,339; patented as U.S. Patent No. 11,840,541; and PCT International Application Nos. PCT/US2012/052327 and PCT/US2015/062726.
  • the present invention shows that novel analogs of the “neo-iboga” and “neo-oxa-iboga class”, defined as containing either an indole or benzofuran and a substituted azabicyclo[3.2.2]nonane cores represent a novel alternative for iboga alkaloids.
  • the targeted re-construction of the isoquinuclidine core of the iboga skeleton yielded a novel structural system that shows activity at SERT and VMAT2 transporters.
  • the parent compound of the novel class, neo- ibogamine shows nearly perfectly balanced potency at SERT and VMAT2, a rare property that is not feasible to design based on previously disclosed publications.
  • the compounds described herein may be useful in treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and PTSD and anxiety disorders, and neurological disorders such as traumatic brain injury (TBI) (Cherian, K.N. et al.2024).
  • OUD opioid use disorder
  • TBI traumatic brain injury
  • These analogs differ in the structure of the iboga skeletal core and thus represent a new extension of the iboga class while exhibiting pharmacological profile similar to ibogaine, but show improved safety in terms of the cardiac risk of iboga compounds.
  • These analogs may be useful in treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders (PTSD in particular), TBI and other neurological disorders. 2
  • the present invention provides a compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -
  • the present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF
  • X 1 when ⁇ is present, then X 1 is C and X 2 is N, S, or O, wherein when X 1 is C and X 2 is N, then Z 1 is present, and whenX 1 is C, and X 2 is O or S, then Z 1 is absent, or when ⁇ is present, then X 1 is N, X 2 is N and Z 1 is absent;
  • ⁇ and ⁇ each represents a bond that is present or absent, and either ⁇ is present or ⁇ is present, and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl
  • the present invention provides a process of producing a compound of formula I: (I), wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - 5
  • the present invention provides a process of producing a compound of formula I: (I), wherein 7
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloal
  • the present invention provides a process of producing a compound of formula V: V), wherein 9
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloal
  • Figure 1 Inhibition of hSERT and hVMAT2 transport by neo-iboga analogs in hSERT-HEK and hVMAT2-HEK cells.
  • Figure 2. Microsomal metabolism of neo-ibogamine in comparison to ibogamine in the presence of human and rat liver microsomes.
  • Figure 3. Neo-Ibogamine does not induce proarrhythmia signals up to 10 ⁇ M in ex vivo primary human cardiomyocyte assay.
  • Neo-Ibogamine and Neo-Ibogaine to a lower extent induce dose-dependent suppression of novelty-induced locomotion in mice as indicated by the Open Field Test (OFT) in a similar manner to Ibogamine. These results indicate significant bioavailability and brain penetration in vivo.
  • OFT Open Field Test
  • Figure 5. Neo-Ibogamine does not induce catalepsy in mice despite inhibiting the function of VMAT2.
  • Figure 6. Ibogamine and neo-Ibogamine pretreatment reduces catalepsy induced by a moderate dose of tetrabenazine (TBZ) in mice.
  • TZ tetrabenazine
  • FIG. 1 Scheme 1. General procedure for preparation of N-indoloethyl- azabicyclo[3.2.2]nonene intermediates. [0023] Figure 10. Scheme 2. Palladium-enabled assembly of neo-iboga scaffold. [0024] Figure 11. Scheme 3. Preparation of N-5-methoxybenzofuranoethyl-azabicyclo[3.2.2]nonene intermediates. [0025] Figure 12. Scheme 4. Preparation of neo-oxa-ibogaine by lithiation/iodination and reductive Heck sequence. [0026] Figure 13. Scheme 5.
  • the present invention provides a compound having the structure: , wherein A is a ring structure, with or without substitution; X 1 is C or N; X 2 is N, O, or S; Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z 1 is present or absent and when Z 1 is present, Z 1 is -H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl
  • the present invention provides a compound having the structure: Y 1 Y2 R 5 4 , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alky
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO 2 H, - CN, -CF 2 H, -OCF
  • the present invention provides a compound having the structure: Y 1 Y2 R 5 R 4 wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); 15
  • Z 1 is present or absent and when Z 1 is present, Z 1 is H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, - OCF 3 , -OH, -OAc, -O-(alkyl), alkyl, alkenyl, alkynyl, aryl, -SH, -S-(alkyl), -NH 2 , -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); ⁇ and ⁇ each represents a bond that is present or absent, wherein either ⁇ is present or ⁇ is present, and when ⁇ is present, then X 1 is C and X 2 is N, S, or O, or when ⁇ is present, then X 1 is N, X 2 is N and Z 1 is absent; wherein when
  • Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), -(alkynyl), or -(aryl).
  • R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl) 2.
  • R1 and R2 is methyl
  • R3 is not H and R4 is not ethyl; or R4 is not H and R 3 is not ethyl.
  • R1 and R2 when one of R1 and R2 is methyl, R5 is not H and R6 is not ethyl; or R6 is not H and R 5 is not ethyl.
  • R1, R2, R3, and R4 when one of R5 and R6 is ethyl, R1, R2, R3, and R4 are not all H.
  • each of R1, R2, R3, R4, R5 and R6 is H.
  • at least one of R1, R2, R3, R4, R5 and R6 is not H.
  • at least two of R1, R2, R3, R4, R5 and R6 are not H.
  • At least three of R1, R2, R3, R4, R5 and R6 are not H. [0043] In some embodiments, at least four of R1, R2, R3, R4, R5 and R6 are not H. [0044] In some embodiments, at least five of R1, R2, R3, R4, R5 and R6 are not H. [0045] In some embodiments, none of R1, R2, R3, R4, R5 and R6 are H.
  • the present invention provides a compound having the structure: , wherein A is an aryl or heteroaryl; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z 1 is present or absent and when Z 1 is present, Z 1 is H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, - OCF 3 , -OH, -OAc, -O-(alkyl), alkyl, alkenyl, alkynyl, aryl, -SH, -S-(al
  • ⁇ and ⁇ each represents a bond that is present or absent, wherein either ⁇ is present or ⁇ is present, and when ⁇ is present, then X 1 is C and X 2 is N, S, or O, or when ⁇ is present, then X 1 is N, X 2 is N and Z 1 is absent; wherein when ⁇ is present, X 1 is C and X 2 is N, then Z 1 is present and Z 1 is H, -CF 3 , -CF 2 H, alkyl, alkenyl, alkynyl or aryl; wherein when ⁇ is present, X 1 is C, and X 2 is O or S, then Z 1 is absent; and R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -
  • R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF 3 , -CF 2 H, -OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), - (heteroalkyl), -(hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O- (heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -SH, -S-(alkyl), -
  • R7, R8, R9 and R10 are each -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O- (alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(alkynyl), -
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). [0052] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, or -OH. 19
  • one of R7, R8, R9 and R10 is -F.
  • one of R7, R8, R9 and R10 is -OH.
  • one of R7, R8, R9 and R10 is -F and the rest of R7, R8, R9 and R10 is H.
  • one of R7, R8, R9 and R10 is -OH and the rest of R7, R8, R9 and R10 is H.
  • each of R7, R8, R9 and R10 is H.
  • the present invention provides a compound having the structure: Y 1 Y2 R 5 R 4 , or a salt thereof. [0059] The present invention provides a compound having the structure: Y 1 Y2 R 5 R 4 , wherein X1 is C or N; X2 is N, O, or S; ⁇ and ⁇ each represents a bond that is present or absent, 20
  • ⁇ is present and ⁇ is absent.
  • ⁇ is absent and ⁇ is present.
  • X1 is C and X2 is N, then Z1 is present and Z1 is H, - CF3, -CF2H, alkyl, alkenyl, alkynyl or aryl.
  • X1 is C or N; or X2 is N or O.
  • X1 is C and X2 is N or O.
  • X2 when X2 is N, Z1 is H, CF3, -CF2H, alkyl, alkenyl, or aryl.
  • Z1 when X2 is N, Z1 is H, alkyl, alkenyl, or aryl.
  • when X2 is N, Z1 when X2 is N, Z1 is H or alkyl.
  • when X2 is N, Z1 when X2 is N, Z1 is H.
  • ⁇ when X1 is N, X2 is N and Z1 is absent.
  • the present invention provides a compound having the structure: 21
  • the present invention provides a compound having the structure: , 3, -CF2H, - OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O- (alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl), or a salt thereof.
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). 22
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, Br, -CN, -CF3, - OCF 3 , -OH, -O-(alkyl), or -O-(alkenyl). [0074] In some embodiments, R7, R8, R9 and R10 are each H. [0075] In some embodiments, at least one of R7, R8, R9 and R10 is not H. [0076] In some embodiments, at least two of R7, R8, R9 and R10 are not H. [0077] In some embodiments, at least three of R7, R8, R9 and R10 are not H.
  • R7, R8, R9 and R10 are not H.
  • one of R7, R8, R9 and R10 is not H.
  • two of R7, R8, R9 and R10 are not H.
  • three of R7, R8, R9 and R10 are not H.
  • R7, R9 and R10 are each H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, F, or Cl.
  • R7, R9 and R10 are each H; and R8 is F, -CF3, or Cl.
  • R7 and R10 are each H; and R8 and R9 are each -O-Me.
  • the present invention provides a compound having the following structure: , wherein R8, R9, and R10 are each H; and R9 is OH, or a salt thereof.
  • the present invention provides a compound having the structure: 23 , wherein R7, R9, and R10 ar or a salt thereof.
  • Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl).
  • the present invention provides a compound having the following structure: wherein Y3, Y4 and Y5 are eac or -(alkyl)-O-(alkyl), or a salt thereof.
  • Y3, Y4 and Y5 are each independently H, or -(alkyl).
  • Y3, Y4 and Y5 are each H.
  • the present invention provides a compound having the following structure: , or
  • R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), or -(cycloalkyl); and R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), - (alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl), or a salt thereof.
  • the present invention provides a compound having the structure: . wherein R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), or -(cycloalkyl); and 25
  • R 7 , R 8 , R 9 and R 10 are each independently -H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, -OCF 3 , -(alkyl), - (alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl), or a salt thereof.
  • R7, R9 and R10 are each -H; and R8 is H, -CF3, -CN, -O-CF3, -O-Me, - OH, -F, or -Cl.
  • R7, R9 and R10 are each -H; and R8 is H, -F, -OH, -CF3, or -Cl.
  • R7, R9 and R10 are each -H; and R8 is H, -OH, or -F.
  • R1, R2, R3, R4, R5 and R6 are each H.
  • R1, R2, R3, R4, R5 and R6 is not -H.
  • at least two of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least three of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least four of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least five of R1, R2, R3, R4, R5 and R6 are not -H.
  • none of R1, R2, R3, R4, R5 and R6 are -H.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, - OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H.
  • one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H.
  • At least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least three of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least four of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least five of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least seven of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least eight of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least nine of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • none of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are -H. 26
  • R 3 and R 4 are each independently H, methyl, C 2 - 10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R 14 or -alkyl-C(O)R 15 , wherein R 14 is -OH, -O(alkyl), -NH 2 , -NH(alkyl) or halogen, and R 15 is -O(alkyl), -NH 2 , -NH(alkyl) or -N(alkyl) 2 ; and R 5 and R 6 are each independently H, methyl, C 2 - 10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O
  • R1 and R2 when one of R1 and R2 is methyl, R3 and R4 are not both H and ethyl. [0118] In some embodiments, when one of R1 and R2 is methyl, R5 and R6 is not both H and ethyl. [0119] In some embodiments, when one of R5 and R6 is ethyl, R1, R2, R3, and R4 are not all H. [0120] In some embodiments, when one of R5 and R6 is ethyl, at least one of R1, R2, R3, and R4 is not H.
  • R1, R2, R5 and R6 are each H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0122] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). [0123] In some embodiments, one of R3 and R4 is -methyl, ethyl, or -O-methyl. [0124] In some embodiments, the other R3 or R4 is H.
  • R1, R2, R3 and R4 are each H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0126] In some embodiments, one of R5 and R6 is -alkyl, or -O-(alkyl). [0127] In some embodiments, one of R5 and R6 is -methyl, ethyl, or -O-methyl. [0128] In some embodiments, the other R5 or R6 is H.
  • R3, R4, R5 and R6 are each H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0130] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). 27 [0131] In some embodiments, one of R3 and R4 is -methyl, ethyl, or -O-methyl. [0132] In some embodiments, the other R3 or R4 is H. [0133] The present invention provides a compound having the structure: salt [0134] The present invention provides a compound having the structure: , salt re:
  • the present invention provides a compound having the structure: 30 , , , , , , , , , , , , [01 e pese ve o pov es a co pou av g e s ucue: ,
  • A is a ring structure, with or without substitution;
  • X 1 is C or N;
  • X 2 is N, O, or S;
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • Z 1 is present or absent and when Z 1 is present, Z 1 is -H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, - OCF 3 , -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(
  • Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), -(alkynyl), or -(aryl).
  • the present invention provides a compound having the structure: 33
  • R 7 , R 8 , R 9 and R 10 are each independently, -H, -F, -Cl, -Br, -I, -NO 2 , -CN, -CF 3 , -CF 2 H, -OCF 3 , - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(S-(S-(alkynyl), -
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF 3 , -CF 2 H, -OCF 3 , -CONH 2 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF 3 , -CF 2 H, -OCF 3 , -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, - OCF3, -OH, -O-(alkyl), or -O-(alkenyl).
  • the compound has the structure: of. [0147] In some e [0148] In some embodiments, ⁇ is absent and ⁇ is present. [0149] In some embodiments, X1 is C or N; and/or X2 is N or O. [0150] In some embodiments, X1 is C and X2 is N or O.
  • R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl) 2 .
  • Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), or -(aryl).
  • Z1 is -H, -(alkyl), -(alkenyl), or -(aryl).
  • Z1 is -H or -(alkyl).
  • Z1 is -H.
  • the present invention provides a compound having the structure: ,
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O- (alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or - NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I
  • R7, R8, R9 and R10 are not -H.
  • at least two of R7, R8, R9 and R10 are not -H.
  • R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl.
  • R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl.
  • R7 and R10 are each -H; and R8 and R9 are each -O-Me.
  • the present invention provides a compound having the structure: r a salt thereof.
  • R7, R8, R9 and R10 are each -H.
  • at least one of R7, R8, R9 and R10 is not -H.
  • at least two of R7, R8, R9 and R10 are not -H.
  • R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl. [0170] In some embodiments, R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl. 37
  • R7 and R10 are each -H; and R8 and R9 are each -O-Me.
  • R7, R8, R9, and R10 are each -H; and R9 is -OH.
  • Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl).
  • the present invention provides a compound having the structure: , wherein Y3, Y4 and Y5 are eac ), or -(alkyl)-O-(alkyl) , or a salt thereof. [0175] In some embodiments, Y3, Y4 and Y5 are each independently -H, or -(alkyl). [0176] In some embodiments, Y3, Y4 and Y5 are each -H. [0177] The present invention provides a compound having the structure: , or [0178] T he present invention provides a compound having the structure: 38
  • R1, R2, R3, R4, R5 and R6 is not -H.
  • at least two of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least three of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least four of R1, R2, R3, R4, R5 and R6 are not -H.
  • at least five of R1, R2, R3, R4, R5 and R6 are not -H.
  • R1, R2, R3, R4, R5 and R6 are -H.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, - OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H.
  • one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H.
  • at least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least three of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least four of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • At least five of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least six of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least seven of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • at least eight of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H.
  • none of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are -H.
  • R3 and R4 are each independently -H, -CH 3 , C 2 - 10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R 14 or -alkyl-C(O)R 15 , wherein R 14 is -OH, -O(alkyl), -NH 2 , or -NH(alkyl), and R 15 is -O(alkyl), -NH 2 , -NH(alkyl) or - N(alkyl) 2 ; and R 5 and R 6 are each independently -H, -CH 3 , C 2 - 10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R 14 or -alkyl-C(O)R 15 , wherein R
  • R1, R2, R5 and R6 are each -H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, -alkylaryl, -aryl, or -heteroaryl.
  • one of R3 and R4 is -alkyl, or -O-(alkyl).
  • one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3.
  • one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H.
  • R1, R2, R3 and R4 are each -H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, -alkylaryl, -aryl, or -heteroaryl.
  • one of R5 and R6 is -alkyl, or -O-(alkyl).
  • one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3.
  • one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; and the other R5 or R6 is -H.
  • R3, R4, R5 and R6 are each -H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or -heteroaryl. [0209] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). [0210] In some embodiments, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3.
  • one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H.
  • the present invention provides a compound having the structure: 40 , , , , ,
  • H 1 O wherein at least one of H1, H2 or H3 is a iched -H site.
  • H 1 O one or two of R7, R8 R9 and R10 ar , wherein at least one of H 1 , H 2 or H 3 is a deuterium-enriched -H site.
  • H 1 O R7 and/or R8 ar , wherein at least one of H1, H2 or H3 is a deuterium-enriched -H site.
  • one, two, three or four of R7, R8 R9 and R10 are 45
  • H 4 H 5 H 1 wherein at least one of H 1 , H 2 or H 3 is a deuterium-enriched -H site.
  • H 4 H 5 H 1 [0218]
  • one or two of R7, R8 R9 and R10 ar wherein at least one of H1, H2, H3, H4 or H5 is a deuterium-enriched -H site.
  • H 4 H 5 H 1 [0219]
  • R7 and/or R8 ar wherein at least one of H1, H2, H3, H4 or H5 hed -H site.
  • the present invention provides a composition comprising a mixture of the compound disclosed H 4 H 5 herein or a pharmaceutically acceptable salt thereof, wherei , wherein in the mixture, the proportion of the com 0156% of molecules in the mixture.
  • the present invention provides a composition comprising a mixture of the compound disclosed herein or a pharmaceutically acceptable salt thereof, wherein R7 and/or R8 is H 1 O , wherein ( a) at least one of H1, H2 or H3 is a deuterium-enriched -H site; (b) each of H1-H3 are deuterium-enriched; (c) two of H1-H3 are deuterium-enriched; or (d) one of H1-H3 is deuterium-enriched. 46
  • each of H1-H3 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition.
  • two of H1-H3 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition.
  • one of H1-H3 is deuterium-enriched, and the proportion of the compound is substantially greater than 90% in the composition.
  • the present invention provides a composition comprising a mixture of the compound disclosed herein or a pharmaceutically acceptable salt thereof, wherein R 7 and/or R 8 is H 4 H 5 H 1 , wherein ( a) at least one of H1, H2, H3, H4 or H5 is a deuterium-enriched -H site; (b) each of H1-H5 are deuterium-enriched; or (c) each of H4-H5 are deuterium-enriched or one of H4-H5 is deuterium-enriched. [0226] In some embodiments, each of H1-H5 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition.
  • each of H4-H5 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition.
  • one of H4-H5 is deuterium-enriched, and the proportion of the compound is substantially greater than 90% in the composition.
  • R7 and/or R8 is H H D D , wherein D represents a deuterium-enriched -H site. 47
  • the present invention provides a composition comprising the compound disclosed herein and a pharmaceutically acceptable carrier or a pharmaceutically active agent.
  • the present invention provides a pharmaceutical composition comprising the compound disclosed herein and a pharmaceutically acceptable carrier.
  • the composition further comprises a mu-opioid receptor agonist.
  • the composition further comprises an opioid or opiate.
  • the opioid or opiate is morphine, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, oxycodone, nalbuphine, butorphanol, etorphine, dihydroetorphine, levorphanol, metazocine, pentazocine, meptazinol, meperidine (pethidine), fentanyl, sufentanil, alfentanil, buprenorphine, methadone, tramadol, tapentadol, mitragynine, 3-deutero-mitragynine, 7- hydroxymitragynine, 3-deutero-7-hydroxymitragynine, mitragynine pseudoindoxyl, tianeptine, 7-((3- bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-
  • the present invention provides a method of altering the psychological state of a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby alter the psychological state of the subject.
  • the present invention provides a method of enhancing the effect of psychotherapy in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby enhance the effect of the psychotherapy in the subject.
  • the present invention provides a method of inducing wakefulness or decreasing sleepiness in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby induce wakefulness or decrease sleepiness in the subject.
  • the present invention provides a method of inducing a stimulating effect in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby induce the stimulating effect in the subject.
  • the present invention provides a method of treating a subject afflicted with substance use disorder (SUD) comprising administering an effective amount of the compound disclosed herein, or the 48
  • the present invention provides a method of treating a subject afflicted with opioid withdrawal symptoms comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with the opioid withdrawal symptoms.
  • the present invention provides a method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with the depressive disorder, the mood disorder, the anxiety disorder, Parkinson’s disease or the traumatic brain injury.
  • the present invention provides a method of treating a subject afflicted with pain, the method comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with pain.
  • an effective amount of 10-1500 mg of the compound is administered to the subject.
  • an effective amount of 100-1500 mg of the compound is administered to the subject.
  • an effective amount of 500-1500 mg of the compound is administered to the subject.
  • an effective amount of 1000-1500 mg of the compound is administered to the subject.
  • an effective amount of 1000-1200 mg of the compound is administered to the subject.
  • an effective daily amount of 30 mg of the compound is administered to the subject.
  • the present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: 49
  • A is a ring structure, with or without substitution;
  • X1 is C or N;
  • X2 is N, O, or S;
  • Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(
  • the present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH,
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(
  • R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2.
  • R3 is not H and R4 is not ethyl; or R4 is not H and R3 is not ethyl.
  • R5 is not H and R6 is not ethyl; or R6 is not H and R5 is not ethyl.
  • the method is for a) altering the psychological state of the subject; b) enhancing the effect of psychotherapy in the subject; c) inducing wakefulness or decreasing sleepiness in the subject; d) inducing a stimulating effect in the subject; e) treating the subject afflicted with substance use disorder; f) treating the subject afflicted with opioid withdrawal symptoms; and/or g) treating the subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury.
  • the substance use disorder is opioid use disorder, alcohol use disorder or stimulant use disorder.
  • the method further comprises treating the subject afflicted with substance use disorder, Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease.
  • an effective amount of 10-1500 mg of the compound is administered to the subject.
  • an effective amount of 100-1500 mg of the compound is administered to the subject.
  • an effective amount of 500-1500 mg of the compound is administered to the subject.
  • an effective amount of 1000-1500 mg of the compound is administered to the subject.
  • an effective amount of 1000-1200 mg of the compound is administered to the subject.
  • an effective amount of 30 mg of the compound is administered to the subject daily and the subject does not induce catalepsy.
  • the compound has the structure: eof.
  • p N HO o r In some embodiments, the compound has the structure: 53 , , , , , , , ,
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloal
  • the present invention provides a process of producing a compound of formula I: (I) wherein 57
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloal
  • the present invention provides a process of producing a compound of formula I: (I) wherein Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); 59
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO 2 H, - CN, -CF 2 H, -OCF 3 , -CO 2 -(C 2 -C 12 alkyl), C(O)-NH 2 , -C(O)-(alkyl), C(O)-(
  • the catalyst complex is a transition metal catalyst complex.
  • the transition metal catalyst complex is Pd(CH3CN)4(BF4)2.
  • the reducing agent is a hydride source.
  • the hydride source is LiBH4 or NaBH4.
  • step (a) includes a solvent.
  • the solvent is an organic solvent.
  • the solvent is a polar aprotic solvent.
  • the solvent is CH3CN.
  • step (b) includes a solvent.
  • the solvent is an alcohol.
  • the solvent is a primary alcohol.
  • the solvent is methanol, ethanol, propanol.
  • the solvent is MeOH.
  • step (a) and/or step (b) is conducted in an inert gas.
  • the inert gas is helium, neon, argon, krypton, and xenon.
  • the inert gas is argon.
  • step (a) is conducted at 20-35 °C.
  • step (a) is conducted at 25-30 °C. 61
  • step (a) is conducted at 25-27 °C.
  • step (b) the mixture from step(a) is heated for 13-23 hours.
  • step (b) the mixture from step(a) is heated for 16-19 hours.
  • the mixture from step(a) is heated at a temperature of 60-100 °C.
  • step (b) the mixture from step(a) is heated at a temperature of 79-90 °C.
  • step (b) the mixture from step(a) is heated at a temperature of 80 °C.
  • the mixture before step (b), the mixture is cooled at a temperature of 0-15 °C. [0295] In some embodiments, before step (b), the mixture is cooled at a temperature of 0-10 °C. [0296] In some embodiments, before step (b), the mixture is cooled at a temperature of 0-5 °C. [0297] In some embodiments, the process further comprises: (a) diluting the mixture from step (b) with AcOEt; (b) filtered the diluted mixture to obtain a residue; (c) washing the residue with AcOEt and Et3N to obtain a product; and (d) purifying the product. [0298] In some embodiments, the compound of formula II is produced by reacting a compound of formula III O O l II) with a compound of formula 62
  • the compound of formula II is produced by reacting a compound having formula III O O R Cl II) with a compound of formula V) in the presence of DCM and CH3C or a salt thereof.
  • the base is an organic base.
  • the organic base is a strong base.
  • the organic base is an amine base.
  • the organic base is triethylamine.
  • the organic base is N,N-diisopropylethylamine.
  • the above reaction is conducted at 0-30 °C. 63
  • the above reaction is conducted at a temperature of 0-25 °C.
  • the process further comprises adding LiAlH4 in Tetrahydrofuran (THF) at a temperature of 0-70 °C.
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF 3 , -CF 2 H, -OCF 3 , -CONH 2 , -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH 2 , -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl).
  • Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl).
  • Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(haloalkyl), or -(alkyl)-O-(alkyl). [0313] In some embodiments,Y1, Y2, Y3, Y4 and Y5 are each independently -H, or -(alkyl). [0314] In some embodiments,Y1, Y2, Y3, Y4 and Y5 are each -H.
  • Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl). [0316] In some embodiments, Y3, Y4 and Y5 are each independently H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl). [0317] In some embodiments, Y3, Y4 and Y5 are each independently H, or -(alkyl). [0318] In some embodiments, Y3, Y4 and Y5 are each H.
  • R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O- CH2CH3, -F, Br, Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2.
  • the present invention provides a process of producing a compound of formula V: 64
  • Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(
  • R 12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH 2 , -NH(alkyl) or -N(alkyl) 2
  • R 13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH 2 , -NH(alkyl) or -N(alkyl) 2, comprising: ( a) reacting a compound of formula (VI) VI) with a base and a halogena la (XI) nd ( b) reacting the compo un o ormu a w a ca a ys comp ex o produce the compound of formula V, or a salt thereof.
  • the present invention provides a process of producing the compound of formula V: 66
  • Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl);
  • R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl
  • R 12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH 2 , -NH(alkyl) or -N(alkyl) 2
  • R 13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH 2 , -NH(alkyl) or - N(alkyl) 2 .
  • the base is a strong base.
  • the base is an organic base.
  • the base is nBuLi.
  • the halogen solution is iodine solution.
  • the catalyst complex is a transition metal catalyst complex.
  • the transition metal catalyst complex is sodium formate, dichlorobis(tri- o-tolylphosphine)palladium(II).
  • step (a) includes a solvent; preferably, the solvent is an organic solvent; more preferably, the solvent is THF.
  • step (a) includes Na2S2O3.
  • step (b) includes a solvent; prefearbly, preferably, the solvent is an organic solvent; more preferably, the solvent is DMSO. 68
  • step (a) and/or step (b) are conducted in an inert gas; preferably, the inert gas is helium, neon, argon, krypton, and xenon.
  • the inert gas is argon;
  • step (a) is conducted at a temperature of -30 to -50 °C; preferably at a temperature of -40 °C;
  • step (c) before step (b), the mixture is diluted with water and extracted with diethyl ether for at least 3 times; and/or
  • step (b) is conducted at a temperature of 90 to 110 °C; preferably at a temperature of 100 °C.
  • the compound of formula VI is produced by reacting a compound of formula VII II) with a compound of form V) in the presence of a base, or a salt thereof.
  • formula VI is produced by reacting a compound having formula VII II) with a compound of form 69
  • the base is a strong base; preferably the base is an inorganic base; preferably the base is KOH, NaOH, Mg(OH)2, Fe(OH)3, Al(OH)3, Ca(OH)2, more preferably, the base is NaOH.
  • the reaction is conducted at 70-90 °C.
  • the reaction is conducted at a temperature of 80 °C.
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl).
  • R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl).
  • Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl).
  • Y3, Y4 and Y5 are each independently H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl). [0343] In some embodiments, Y3, Y4 and Y5 are each independently H, or -(alkyl). [0344] In some embodiments, Y3, Y4 and Y5 are each H.
  • R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O- CH 2 CH 3 , -F, Br, Cl, -CF 3 -CN, -OCF 3 , -CH 3 , -CH 2 CH 3 or - CONH 2 . 70
  • the compound of formula IV has the following structure: .
  • the present i vides compounds or compositions disclosed herein for use in ( a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); ( f) treating a subject afflicted with opioid withdrawal symptoms; (g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury; ( h) treating a subject afflicted with pain; and/or (i) treating a subject afflicted with Tardive dyskinesia (TD),
  • SUD substance use disorder
  • the SUD is opioid use disorder, alcohol
  • the present invention provides use of the compounds or the compositions disclosed herein in ( a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); ( f) treating a subject afflicted with opioid withdrawal symptoms; 71
  • compositions further comprising any of the compounds disclosed in U.S.
  • the present invention provides a method of decreasing the duration of REM sleep in a subject comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound so as to thereby decrease the duration of REM sleep in the subject.
  • the present invention provides a method of increasing energetic feelings in a subject comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound so as to thereby increase the energetic feelings in the subject.
  • the present invention provides a method of inducing a stimulating effect in a subject comprising administering to the subject the compound disclosed herein, or the composition disclosed herein comprising an effective amount of the compound, so as to thereby induce the stimulating effect in the subject.
  • the stimulating effect is a central stimulating effect.
  • the stimulating effect is induced substantially free of undesired side- effects in the subject.
  • the stimulating effect is induced without inducing an addictive effect in the subject to the compound.
  • the prevent invention provides a use of the composition disclosed herein comprising an effective amount of the compound as a stimulant. 72
  • the present invention provides a method of treating a subject afflicted with pain comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound and the opioid or opiate so as to thereby treat the subject afflicted with pain.
  • the compound disclosed herein inhibits serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2) or any combination thereof in a subject.
  • the compound disclosed herein inhibits serotonin transporter (SERT) in a subject.
  • the compound disclosed herein inhibits vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the compound disclosed herein inhibits serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2).
  • the present invention provides a method of altering the psychological state of a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of enhancing the effect of psychotherapy in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of inducing wakefulness or decreasing sleepiness in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of inducing a stimulating effect in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of treating a subject afflicted with substance use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of treating a subject afflicted with opioid use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • SERT serotonin transporter
  • VMAT2 vesicular monoamine transporter 2
  • the present invention provides a method of treating a subject afflicted with alcohol use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of treating a subject afflicted with stimulant use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • SERT serotonin transporter
  • VMAT2 vesicular monoamine transporter 2
  • the present invention provides a method of treating a subject afflicted with opioid withdrawal symptoms by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • the present invention provides a method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject.
  • SERT serotonin transporter
  • VMAT2 vesicular monoamine transporter 2
  • the present invention provides a method of inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject.
  • the present invention provides a method of treating a subject afflicted with substance use disorder by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject.
  • the present invention provides a method of treating a subject afflicted with Tardive dyskinesia (TD) by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject.
  • TD Tardive dyskinesia
  • the present invention provides a method of treating a subject afflicted with Tourette syndrome by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject.
  • the present invention provides a method of treating a subject afflicted with chorea associated with Huntington’s disease by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject.
  • the present invention provides a pharmaceutically acceptable salt of any of the compounds disclosed herein.
  • a salt of the compound of the present invention is used in any of the above methods, uses, packages or compositions.
  • a pharmaceutically acceptable salt of the compound of the present invention is used in any of the above methods, uses, packages or compositions.
  • Any of the above compounds may be used in any of the disclosed methods, uses, packages or pharmaceutical compositions. 74
  • any of the compounds used in the disclosed methods, uses, packages or pharmaceutical compositions may be replaced with any other compound disclosed in the present invention.
  • Any of the above generic compounds may be used in any of the disclosed methods, uses, packages or compositions.
  • the composition is orally administered to the subject.
  • 10 – 30 mg of the compound is administered to the subject.
  • 30 – 100 mg of the compound is administered to the subject.
  • 100 – 300 mg of the compound is administered to the subject.
  • 300 – 500 mg of the compound is administered to the subject.
  • 500 – 800 mg of the compound is administered to the subject.
  • 800 – 1100 mg of the compound is administered to the subject.
  • 1200 – 1500 mg of the compound is administered to the subject.
  • any of the above recited doses of the compound, and an opioid are administered to a subject afflicted with a substance use disorder, opioid withdrawal symptoms, pain, a mood disorder, an anxiety disorder or opioid cravings so as to thereby treat the subject afflicted with the substance use disorder, opioid withdrawal symptoms, pain or the mood disorder or reduce opioid cravings in the subject.
  • the opioid is morphine and 10-20 mg (oral) or 3-5 mg (parenteral) of the opioid is administered to the subject.
  • the opioid is codeine and 30-60 mg (oral) of the opioid is administered to the subject. 75
  • the opioid is oxycodone and 5-10 mg (oral) of the opioid is administered to the subject.
  • the opioid is fentanyl and 40-60 ⁇ g (parenteral) of the opioid is administered to the subject.
  • the opioid is butorphanol and 1-3 mg (parenteral) of the opioid is administered to the subject.
  • the opioid is nalbuphine and 5-15 mg (parenteral) of the opioid is administered to the subject.
  • mitragynine (15-100 mg – oral) or 3-deuteromitragynine (15-100 mg – oral) is administered to the subject.
  • tianeptine (12.5-100 mg – oral) is administered to the subject.
  • 7-((3-iodo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid (1.5-10 mg – oral) is administered to the subject.
  • 5-((3-iodo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)pentanoic acid (2-20 mg – oral) is administered to the subject.
  • administration of the composition disclosed herein comprising an effective amount of the compound lowers the effective amount of the opioid.
  • administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 75% or more.
  • administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 50% or more.
  • administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 25% or more.
  • 0.4 mg/kg – 30 mg/kg of the compound disclosed herein is administered to the subject.
  • the subject does not induce catalepsy.
  • 0.3-1.5 mg/kg of the opioid or opiate is administered to the subject.
  • the subject is a human.
  • the composition is clinically administered or physician administered to the subject.
  • the composition is clinically self-administered by the subject.
  • formation of noribogaine is attenuated within the subject.
  • formation of noribogaine is reduced within the subject.
  • metabolism of ibogaine is attenuated within the subject.
  • metabolism of ibogaine is enhanced within the subject.
  • metabolism of 10-ethoxy-ibogamine is attenuated within the subject.
  • metabolism of 10-ethoxy-ibogamine is enhanced within the subject.
  • the subject is afflicted with a depressive disorder, a mood disorder, or an anxiety disorder.
  • the anxiety disorder includes, but is not limited to, anxiety, generalized anxiety disorder (GAD), panic disorder, social phobia, social anxiety disorder, acute stress disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD).
  • the depressive disorder includes, but is not limited to, depression, major depression, dysthymia, cyclothymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, situational depression or adjustment disorder with depressed mood. Depressive disorders can also include other mood disorders and is not limited to the above list.
  • Preclinical evidence also shows that ibogaine/noribogaine enhances morphine’s analgesic effect (Sharma, S.S. et al. 1998) or reverses analgesic tolerance to morphine (Bhargava, H.N. et al.1997).
  • ibogaine decreased sleepiness and increased energetic feeling over the examined 24-hour period after one dose of 20 mg of ibogaine (Glue, P. et al.2015).
  • a stimulant effect was reported in cats (Schneider et. al 1957).
  • rats ibogaine induced wakefulness and suppressed the REM sleep as shown via EEG (González, J. et al 2018).
  • EEG Glial cell line-Derived Neurotrophic Factor
  • ibogaine provides structural and functional restorative effects in subjects afflicted with Parkinson’s disease.
  • GDNF itself has been shown to exert desired effects in Parkinson’s rodent and monkey models (Gash, D.M. et al.1996).
  • the subject is afflicted with Parkinson’s disease.
  • ibogaine is useful in treating opioid and stimulant use disorders (Alper, K.R. et al. 1999; Mash, D.C. et al. 2018; Schenberg, E.E. et al.2014) or in maintenance therapy (opioid use disorder) in combination with an opioid to lower effective opioid doses (Kroupa, P.K. & Wells, H.2005).
  • the substance use disorder is an opioid use disorder, alcohol use disorder or stimulant use disorder.
  • Opioid use disorder involves, but is not limited to, misuse of opioid medications or use of illicitly obtained opioids.
  • the Diagnostic and Statistical Manual of Mental Disorders 5 th Edition (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association, 2013), which is hereby incorporated by reference, describes opioid use disorder as a problematic pattern of opioid use leading to problems or distress, with at least two of the following occurring within a 12-month period: -Taking larger amounts or taking drugs over a longer period than intended. -Persistent desire or unsuccessful efforts to cut down or control opioid use. -Spending a great deal of time obtaining or using the opioid or recovering from its effects. 78
  • opioids or a strong desire or urge to use opioids.
  • -Tolerance i.e., need for increased amounts or diminished effect with continued use of the same amount).
  • -Experiencing withdrawal opioid withdrawal syndrome
  • taking opioids or a closely related substance
  • Alcohol use disorder involves, but is not limited to, a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using.
  • the Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition describes alcohol use disorder as a problematic pattern of alcohol use leading to problems or distress, with at least two of the following occurring within a 12-month period: -Being unable to limit the amount of alcohol you drink. -Wanting to cut down on how much you drink or making unsuccessful attempts to do so. -Spending a lot of time drinking, getting alcohol, or recovering from alcohol use. -Feeling a strong craving or urge to drink alcohol.
  • Stimulant use disorder involves, but is not limited to, a pattern of problematic use of amphetamine, methamphetamine, cocaine, or other stimulants except caffeine or nicotine, leading to at least two of the following problems within a 12-month period: -Taking more stimulants than intended. -Unsuccessful in trying to cut down or control use of stimulants, despite wanting to do so. -Spending excessive amounts of time to activities surrounding stimulant use. -Urges and cravings for stimulants. -Failing in the obligations of home, school, or work. -Carrying on taking stimulants, even though it has led to relationship or social problems. -Giving up or reducing important recreational, social, or work-related activities because of using stimulants.
  • MOR agonist is intended to mean any compound or substance that activates the mu-opioid receptor (MOR).
  • the agonist may be a partial, full, or super agonist.
  • a person skilled in the art may use the techniques disclosed herein to prepare deuterium analogs thereof.
  • a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, scalemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in “Enantiomers, Racemates and 80
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any notations of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C. Furthermore, any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
  • any notations of a hydrogen (H) in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H (D), or 3 H (T) except where otherwise specified.
  • any compounds containing 2 H (D) or 3 H (T) may specifically have the structure of any of the compounds disclosed herein except where otherwise specified.
  • Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the non-labeled reagents employed.
  • Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.0156%.
  • a composition comprising molecules of a naturally occurring compound
  • the level of deuterium at a particular hydrogen atom site in that compound is expected to be 0.0156%.
  • a composition comprising a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% is novel over its naturally occurring counterpart.
  • a hydrogen at a specific site in a compound is “deuterium-enriched” if the amount of deuterium at the specific site in the compound is more than the abundance of deuterium naturally occurring at that specific site in view of all of the molecules of the compound in a defined universe such as a composition or sample.
  • Naturally occurring as used above refers to the abundance of deuterium which would be present at a relevant site in a compound if the compound was prepared without any affirmative step to enrich the abundance of deuterium.
  • the abundance of deuterium at that site can range from more than 0.0156% to 100%. Examples of ways to 81
  • alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0447] In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
  • a package comprising: a) a first pharmaceutical composition comprising an amount of an opioid or opiate and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury, or Parkinson’s disease.
  • a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury or Parkinson’s disease which comprises: a) one or more unit doses, each such unit dose comprising: (i) a pharmaceutical composition comprising the compound of the present invention; and (ii) an amount of an opioid or opiate, 82
  • a pharmaceutical composition in unit dosage form useful in treating a subject afflicted with pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury or Parkinson’s disease, which comprises: ( i) a composition comprising the compound of the present invention; and (ii) an amount of an opioid or opiate, wherein the respective amounts of said composition and said opioid or opiate in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.
  • the pharmaceutical composition of the above embodiment, wherein the respective amounts of said compound and said opioid or opiate in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said composition in the absence of said opioid or opiate or the administration of said opioid or opiate in the absence of said composition.
  • the compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms.
  • This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2 H and/or wherein the isotopic atom 13 C. Accordingly, in the compounds 83
  • hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
  • the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove.
  • the present invention contemplates each integer between, and including, the upper and lower limits, unless otherwise stated.
  • the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention.
  • each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C-14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C.
  • any compounds containing 13 C or 14 C may specifically have the structure of any of the compounds disclosed herein.
  • any notation of a hydrogen in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H. Furthermore, any compounds containing 2 H or 3 H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed. 84
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0466] In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0468] In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5 th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5 th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.
  • Another aspect of the invention comprises a compound used in the method of the present invention as a pharmaceutical composition.
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically active agent means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30 th edition, 2010), which are hereby incorporated by reference.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.
  • the compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present 86
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).
  • the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
  • “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e.
  • the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
  • This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. [0479]
  • the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, 87
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids such as lecithin, sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds may be administered as components of tissue-targeted emulsions.
  • the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. 89
  • the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • suitable solvents for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. [0489] The compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen.
  • the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.
  • Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine.
  • Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate- methacrylic acid copolymers.
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • the compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.
  • Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention. 91
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-Cn as in “C1–Cn alkyl” is defined to include groups having 1, 2ising, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on.
  • Alkoxy represents an alkyl group as described above attached through an oxygen bridge.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present.
  • C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C 2 -C n alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon 92
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C 2 - C n alkynyl.
  • An embodiment can be C 2 -C 12 alkynyl, C 3 -C 12 alkynyl, C 4 -C 12 alkynyl and so on.
  • Alkylene alkenylene and alkynylene shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like.
  • heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • monocycle includes any stable polyatomic carbon ring of up to 10 atoms and may be unsubstituted or substituted.
  • non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aromatic monocycle elements include but are not limited to phenyl.
  • "bicycle” includes any stable polyatomic carbon ring of up to 10 atoms that is fused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted.
  • non-aromatic bicycle elements include but are not limited to: decahydronaphthalene.
  • aromatic bicycle elements include but are not limited to: naphthalene.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, 93
  • aryl substituent refers to bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • polycyclic refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above.
  • arylalkyl is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above.
  • alkylheteroaryl is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group.
  • alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.
  • heterocycle or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.
  • the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • esteer is intended to a mean an organic compound containing the R-O-CO-R’ group.
  • phenyl is intended to mean an aromatic six membered ring containing six carbons.
  • benzyl is intended to mean a –CH2R1 group wherein the R1 is a phenyl group.
  • halogen refers to F, Cl, Br, and I.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles. 95
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended.
  • about means within a standard deviation using measurements generally acceptable in the art.
  • about means a range extending to +/- 10% of the specified value.
  • each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
  • each of the verbs, “comprise,” “include” and “have” and conjugates thereof are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.
  • Other terms as used herein are meant to be defined by their well-known meanings in the art.
  • zeocin 100 ⁇ g/mL zeocin (InvivoGen; San Diego, CA) was supplemented to hVMAT2-HEK cell cultures (Black, C. A. et al 2021). All cultures were plated on 10 cm polystyrene culture plates (Corning Falcon; Corning, NY), grown in a humidified environment of 37 °C and five percent carbon dioxide atmosphere to full confluency, and subcultured every three to four days. [0534] Growth media is aspired and replaced by experimental media for conducting assays.
  • HEK cells stably transfected with hSERT cell cultures were seeded in white solid-bottom 96- well plates (Corning; Corning, NY) at a density of 1.00 ⁇ 10 6 cells/well and grown in a humidified environment of 37°C and five percent carbon dioxide to full confluency in approximately 48 hours.
  • the growth media was aspirated, and the cellular monolayer was rinsed twice with 120 ⁇ L of 1 ⁇ Phosphate Buffered Saline (PBS; Corning; Corning, NY).
  • Experimental media solutions consisting of tiered concentrations (ranging from 100 ⁇ M to 0.1 ⁇ M) of test compound, imipramine (hSERT standard inhibitor) or DMSO (vehicle, 0.02% v/v, Sigma-Aldrich; St. Louis, MO), were gently added to the cell cultures and subsequently, pre-incubated for approximately 60 minutes.
  • Liver microsomal incubation medium comprised of phosphate buffer (100 mM, pH 7.4), MgCl 2 (3.3 mM), NADP ⁇ (3 mM), glucose-6-phosphate (5.3 mM), glucose-6-phosphate dehydrogenase (0.67 units/ml) with 0.5 mg of liver microsomal protein per ml.
  • NADPH- cofactor system was substituted with phosphate buffer.
  • Test compounds (10 ⁇ M as well as for reference compounds, final solvent concentration 1.6 %) were incubated with microsomes at 37 °C, shaking at 100 rpm. Each reaction was performed in duplicates. Five time points over 90 or 60 minutes were analyzed. 99
  • Mass spectrometric analysis was performed using an API 5000 mass spectrometer from Applied Biosystems/ MDS Sciex (AB Sciex) with Turbo V ion source and TurboIonspray interface.
  • the TurboIonSpray ion source was used in both positive and negative ion modes.
  • the data acquisition and system control were performed using Analyst 1.6.3 software from AB Sciex.
  • Linear gradient 0 min 0% B, 1.0 min 100% B, 1.2 min 100% B, 1.21 min 0% B, 2.4 min stop.
  • Elution rate 400 ⁇ L/min.
  • a divert valve directed the flow to the detector from 0.9 to 1.4 min.
  • inverted Motic AE31E IonOptix
  • Olympus IX83P1ZF MyoBLAZER
  • recording buffer heated to 35 ⁇ 1 °C using an in-line heater from Warner Instruments (IonOptix & MyoBLAZER) and allowed to equilibrate for 5 minutes under constant perfusion.
  • the cells were field stimulated with supra-threshold voltage at a 1 Hz pacing frequency, with a bipolar pulse of 3 ms duration, using a pair of platinum wires placed on opposite sides of the chamber connected to a MyoPacer stimulator.
  • cardiomyocytes were then imaged at 240 Hz using an IonOptix MyoCam-S CCD camera (IonOptix) or at 148 Hz using an Optronis CP70-16-M/C-148 (MyoBLAZER) camera. Digitized images were displayed within the IonWizard acquisition software (IonOptix) or MyoBLAZER acquisition software.
  • the longitudinal axis of the selected cardiomyocyte was aligned parallel to the video raster line, by means of a cell framing adapter.
  • Optical intensity data was collected from a user-defined rectangular region placed over the cardiomyocyte image.
  • the optical intensity data represented the bright and dark bands corresponding to the Z-lines of the cardiomyocyte.
  • the IonWizard software or MyoBLAZER Analysis software analyzed the periodicity in the optical density of these bands by means of a fast Fourier transform algorithm.
  • Compound test solutions were formulated from stock solutions within 30 min prior to experimental application to the cells. Test solutions were applied after vehicle control (120 s interval, 1 Hz stimulation) in an increasing concentration order (in 300 s intervals, 1 Hz stimulation) and experiment was terminated after wash control (300 s interval, 1 Hz stimulation).
  • STV STV
  • Alternans were identified as repetitive alternating short and long contractility amplitude transients.
  • STV values were normalized to the vehicle control value of each cell.
  • AC, CF and Alternans were plotted and expressed as % of incidence of cells exhibiting each of the signals normalized by the total number of cardiomyocytes. It was shown that Neo-Ibogamine does not induce proarrhythmia signals up to 10 ⁇ M in ex vivo primary human cardiomyocyte assay (See Figure 3). 101
  • mice Behavioral Studies [0562] Drug preparation and administration for animal studies [0563] All compounds were dissolved in USP grade 0.85% saline with 5% Tween-80. Sonication and gentle heating are applied until complete dissolution. The compounds are subsequently filtered through 0.45 ⁇ m filters into a new glass vial. All compounds were administered at a selected subcutaneous dose at a volume of 10 mL/kg of body weight, unless specified otherwise. [0564] General mouse use [0565] All experimental procedures involving animals were approved by the Columbia University Institutional Animal Care and Use Committee (IACUC) and adhered to principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The studies were conducted at AAALAC accredited facilities.
  • IACUC Columbia University Institutional Animal Care and Use Committee
  • mice received regular veterinary care (weekly by institutional veterinarians) including daily health monitoring (by experimenters) of the animals (observing home cage behaviors, nesting, and body weight). All procedures were designed to minimize any stress/distress. Healthy adult male mice C57BL/6J (10 – 14 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed 5 mice per cage with food and water available ad libitum. Mice were maintained on a 12- h light/dark cycle (lights on 7:00-19:00) and all testing was done in the light cycle. Temperature was kept constant at 22 ⁇ 2 °C, and relative humidity was maintained at 50 ⁇ 5%.
  • TTZ Tetrabenazine
  • mice were allowed to habituate for 30 min. Immediately after receiving a subcutaneous injection of the compound solution, mice were then placed gently in a clear Plexiglass arena (27.31 ⁇ 27.31 ⁇ 20.32 cm, Med Associates ENV-510) lit with dim light ( ⁇ 5 lux) and allowed to ambulate freely for 60 102
  • neo-ibogamine and neo-ibogaine As shown in Figures 4 and 5, neo-ibogamine and neo-ibogaine, to a lower extent, induce dose- dependent suppression of novelty-induced locomotion in mice as indicated by the Open Field Test (OFT), in a similar manner to ibogamine. These results indicate significant bioavailability and brain penetration in vivo. Neo-ibogamine also does not induce catalepsy in mice despite inhibiting the function of VMAT2.
  • OFT Open Field Test
  • Neo-ibogamine and neo-ibogaine have the properties of inhibition of serotonin (SERT) and vesicular (VMAT2) monoamine transporters. They reduce cardiotoxicity in primary human cardiomyocyte assay and improve metabolic stability in comparison to closely related iboga alkaloids and have substantial effect on mice locomotion (demonstrates bioavailability and brain penetration).
  • SERT serotonin
  • VMAT2 vesicular
  • Benzofuran analogs of neo-ibogamine and neo-ibogaine are expected to have kappa opioid receptor activity
  • Pharmacokinetics Drug Distribution C57BL/6J Male mice, 10 mg/kg, SC
  • mice were injected IP with 2,2,2-tribromoethanol at the dose of 150 mg/kg prior to drawing the blood.
  • Blood collection was performed from the orbital sinus in microtainers containing K3EDTA. Animals were sacrificed by cervical dislocation after the blood samples collection. Blood samples were centrifuged for 10 minutes at 3000 rpm (+4oC). Brain samples (left hemisphere) were collected and weighed. The samples were immediately processed, flash-frozen at dry ice, and stored at -70 °C until subsequent analysis.
  • Sample Formulation Solid samples (hydrochloride salts) were suspended in Saline (0.9%), using ⁇ 98% of calculated volume in an 8 mL glass vials closed with a screw cap.
  • Brain samples (weight 108 mg – 160 mg) were homogenized with five volumes of IS(brain) solution (1 w + 5 v, e.g. 100 mg + 500 ⁇ L) using glass beads (115 mg ⁇ 5 mg) in The Bullet Blender® homogenizer for 30 seconds at speed 8. After this, the samples were centrifuged for four minutes at 14,000 rpm, and 1.0 or 2.0 ⁇ L of each supernatant was injected into LC-MS/MS system. Internal standards IS(brain) used (ibogamine: Sildenafil 400 ng/mL; neo-ibogamine: Raloxifene 100 ng/mL) in water- methanol mixture 1:4, v/v.
  • IS(brain) Internal standards IS(brain) used (ibogamine: Sildenafil 400 ng/mL; neo-ibogamine: Raloxifene 100 ng/mL) in water- methanol mixture 1:4, v/v.
  • Plasma calibration Blank mouse plasma samples (40 ⁇ L) were mixed with 200 ⁇ L of the corresponding calibration solution. After mixing by pipetting and centrifugation for four minutes at 6000 rpm, 2.0 ⁇ L of each supernatant was injected into LC-MS/MS system.
  • Brain calibration Blank brain samples (weight 100 mg ⁇ 1 mg) were homogenized in 500 ⁇ L of corresponding calibration solution using glass beads (115 mg ⁇ 5 mg) in The Bullet Blender® homogenizer for 30 seconds at speed 8. After this, the samples were centrifuged for four minutes at 14,000 rpm, and 1.0 or 2.0 ⁇ L of each supernatant was injected into LC-MS/MS system.
  • Pharmacokinetic Method Analysis Blank mouse plasma samples (40 ⁇ L) were mixed with 200 ⁇ L of the corresponding calibration solution. After mixing by pipetting and centrifugation for four minutes at 6000 rpm, 2.0 ⁇ L of each supernatant was injected into LC-MS/MS system.
  • Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (pentet); dd (doublet of doublets); td (triplet of doublets); dt (doublet of triplets); dq (doublet of quartets); ddd (doublet of doublet of doublets); ddt (doublet of doublet of triplets); m (multiplet); br (broad).
  • Low- resolution mass spectra were recorded on an Advion quadrupole instrument (ionization mode: APCI+ or ESI+).
  • RM was next warmed to RT and further stirred at 70 °C for 3h. After cooling to RT, mixture was diluted with THF (2 ⁇ initial volume used). RM was cooled in water/ice bath (0-5 °C) and carefully quenched with H2O, 15% aq. NaOH and H2O (1:1:3 mL per g of LiAlH4 used). Mixture was stirred untill solids were loose, (solid anhydrous MgSO4 was added after 30-60 min to absorb excess moisture). Solids were filtered and washed with THF, AcOEt and eventually 9:1 DCM:iPrOH, untill all product was eluted. Crude material was purified as specified for each example.

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Abstract

The present invention provides a compound having the structure: [STRUCTURE] wherein A, X1, X2, Y1-Y5, Z1, and R1-R6 are defined in the specification, or a salt thereof.

Description

Docket: 92407-A-PCT/GJG/YX NOVEL IBOGA ALKALOID ANALOGS AND THEIR USES THEREOF [0001] This application claims the benefit of U.S. Provisional Application No. 63/646,429, filed May 13, 2024, the content of which is hereby incorporated by reference. [0002] Throughout this application, various publications are referenced, including referenced in parenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0003] This invention was made with government support under DA050613 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION [0004] Ibogaine is the major psychoactive alkaloid found in the root bark of Tabernanthe iboga, a plant native to West Central Africa (Alper, K.R. 2001). The root bark has been used as a religious and healing sacrament by the native people in Africa owing to its distinct psychedelic and post-acute therapeutic effects. The clinical claims of ibogaine’s anti-addictive properties, discovered in the U.S. in the 1960’s, have largely been recapitulated in subsequent clinical case studies (Mash, D.C. et al. 2016), as well as animal models of substance use disorders (SUDs) where ibogaine and its main metabolite, noribogaine, show several effects relevant to different aspects of SUDs (Glick, S.D. et al.2001; Belgers, M. et al.2016). [0005] However, the use of ibogaine has unfortunately been associated with sudden death in humans (Koenig, X. & Hilber, K.2015), which has been attributed to adverse cardiac effects of ibogaine as well as its main active metabolite noribogaine (Glue et al 2016; Alper, K. et al 2016; Rubi, L. et al 2017), including QT interval prolongation and arrhythmias. QT prolongation is associated with an increased risk of life- threatening torsade de pointes (TdP) arrhythmias (Redfern, W. S. et al 2003). Both ibogaine and noribogaine are reported to block human ether-a-go-go-related gene (hERG) potassium channels at clinically relevant low micromolar values (Alper, K. et al 2016), which can result in retardation of ventricular action potential (AP) repolarization and prolongation of the QT interval in the electrocardiogram (ECG) (Redfern, W. S. et al 2003). Additionally, it was shown that ibogaine and its active metabolite noribogaine significantly delayed action potential repolarization in human cardiomyocytes, which may result in a prolongation of the QT interval in the electrocardiogram and cardiac arrhythmias (Rubi, L. et al 2017). All of this suggests that ibogaine administration entails a significant risk of cardiac arrhythmia for humans. 1
[0006] Considering the large unmet needs in SUDs and psychiatric disorders in general, there is a strong impetus to study biological mechanisms that underpin ibogaine’s effects, and to develop new analogs that increase ibogaine’s safety and therapeutic index. [0007] The present invention relates to novel ibogaine analogs of compounds compared to previously disclosed ibogaine analogs in U.S. Application No. 14/240,681, patented as U.S. Patent No. 9,988,377; U.S. Application No 15/528,339; patented as U.S. Patent No. 11,840,541; and PCT International Application Nos. PCT/US2012/052327 and PCT/US2015/062726. The present invention shows that novel analogs of the “neo-iboga” and “neo-oxa-iboga class”, defined as containing either an indole or benzofuran and a substituted azabicyclo[3.2.2]nonane cores represent a novel alternative for iboga alkaloids. The targeted re-construction of the isoquinuclidine core of the iboga skeleton yielded a novel structural system that shows activity at SERT and VMAT2 transporters. The parent compound of the novel class, neo- ibogamine, shows nearly perfectly balanced potency at SERT and VMAT2, a rare property that is not feasible to design based on previously disclosed publications. Other novel findings include an improved metabolic rate of degradation and a cardiac side effect profile compared to the parent iboga class. This will likely translate to greater drug exposure and oral bioavailability, and improved cardiac safety. Another unexpected finding was that at doses (e.g., 30 mg/kg) that completely suppress locomotion, neo-ibogamine does not induce catalepsy despite its inhibitory effect at VMAT2, which stands in contrast to the known VMAT2 inhibitors such as reserpine or tetrabenazine. In addition, pre-treatment of animal subjects with neo-ibogamine (10 mg/kg) suppresses the catalepsy induced by tetrabenazine (10 mg/kg). The compounds described herein may be useful in treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and PTSD and anxiety disorders, and neurological disorders such as traumatic brain injury (TBI) (Cherian, K.N. et al.2024). [0008] These analogs differ in the structure of the iboga skeletal core and thus represent a new extension of the iboga class while exhibiting pharmacological profile similar to ibogaine, but show improved safety in terms of the cardiac risk of iboga compounds. These analogs may be useful in treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders (PTSD in particular), TBI and other neurological disorders. 2
BRIEF SUMMARY OF THE INVENTION [0009] The present invention provides a compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present, and when X1 is C, and X2 is O or S, then Z1 is absent, or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- 3
alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0010] The present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and 4
when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present, and whenX1 is C, and X2 is O or S, then Z1 is absent, or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present, and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15; wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0011] The present invention provides a process of producing a compound of formula I: (I), wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - 5
(alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is -halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, - C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (II) 6
II) with a catalyst comple X), wherein M is a metal; a (b) reacting the compound of formula (IX) with a reducing agent to produce the compond of formula I, or a salt thereof. [0012] The present invention provides a process of producing a compound of formula I: (I), wherein 7
Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is -halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, - C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (II) 8
II) with a halogenating rea X), wherein A is a ha (b) adding a catalyst complex to produce the compond of formula I, or a salt thereof. [0013] The present invention provides a process of producing a compound of formula V: V), wherein 9
Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (VI) 10
VI) with a base and a halogen la (XI) nd a catalyst complex to produce a compound of formula V, or a salt thereof. 11
BRIEF DESCRIPTION OF THE DRAWINGS [0014] Figure 1. Inhibition of hSERT and hVMAT2 transport by neo-iboga analogs in hSERT-HEK and hVMAT2-HEK cells. [0015] Figure 2. Microsomal metabolism of neo-ibogamine in comparison to ibogamine in the presence of human and rat liver microsomes. [0016] Figure 3. Neo-Ibogamine does not induce proarrhythmia signals up to 10 µM in ex vivo primary human cardiomyocyte assay. [0017] Figure 4. Neo-Ibogamine and Neo-Ibogaine to a lower extent induce dose-dependent suppression of novelty-induced locomotion in mice as indicated by the Open Field Test (OFT) in a similar manner to Ibogamine. These results indicate significant bioavailability and brain penetration in vivo. [0018] Figure 5. Neo-Ibogamine does not induce catalepsy in mice despite inhibiting the function of VMAT2. [0019] Figure 6. Ibogamine and neo-Ibogamine pretreatment reduces catalepsy induced by a moderate dose of tetrabenazine (TBZ) in mice. [0020] Figure 7. Pharmacokinetic study of ibogamine in mouse plasma and brain. [0021] Figure 8. Pharmacokinetic study of neo-ibogamine in mouse plasma and brain. [0022] Figure 9. Scheme 1. General procedure for preparation of N-indoloethyl- azabicyclo[3.2.2]nonene intermediates. [0023] Figure 10. Scheme 2. Palladium-enabled assembly of neo-iboga scaffold. [0024] Figure 11. Scheme 3. Preparation of N-5-methoxybenzofuranoethyl-azabicyclo[3.2.2]nonene intermediates. [0025] Figure 12. Scheme 4. Preparation of neo-oxa-ibogaine by lithiation/iodination and reductive Heck sequence. [0026] Figure 13. Scheme 5. Transformation of neo-oxa-ibogaine to neo-oxa-noribogaine by demethylation. [0027] Figure 14. Scheme 6. Transformation of neo-ibogaine to neo-noribogaine by demethylation. [0028] Figure 15. synthesis of neo-iboga analogs. [0029] Figure 16. Synthesis of neo-oxa-iboga analogs – solid state conformation of the [2.2.3] bicyclic system (pseudo-boat of the 7-membered ring). [0030] Figure 17. Monoamine transporter inhibition profile. 12
DETAILED DESCRIPTION OF THE INVENTION [0031] The present invention provides a compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present and Z1 is -H, -CF3, -CF2H, - (alkyl), -(alkenyl), -(alkynyl), or -(aryl); and when X1 is C, and X2 is O or S, then Z1 is absent; or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - 13
CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O- alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15; wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0032] The present invention provides a compound having the structure: Y1 Y2 R5 4 , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present; and 14
when X1 is C, and X2 is O or S, then Z1 is absent; or when β is present, then X1 is N, X2 is N and Z1 is absent; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15; wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0033] The present invention provides a compound having the structure: Y1 Y2 R5 R4 wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); 15
Z1 is present or absent and when Z1 is present, Z1 is H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), alkyl, alkenyl, alkynyl, aryl, -SH, -S-(alkyl), -NH2, -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, or when β is present, then X1 is N, X2 is N and Z1 is absent; wherein when α is present, X1 is C and X2 is N, then Z1 is present and Z1 is H, -CF3, -CF2H, alkyl, alkenyl, alkynyl or aryl; wherein when α is present, X1 is C, and X2 is O or S, then Z1 is absent; and R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0034] In some embodiments, Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), -(alkynyl), or -(aryl). [0035] In some embodiments, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2. [0036] In some embodiments, when one of R1 and R2 is methyl, R3 is not H and R4 is not ethyl; or R4 is not H and R3 is not ethyl. 16
[0037] In some embodiments, when one of R1 and R2 is methyl, R5 is not H and R6 is not ethyl; or R6 is not H and R5 is not ethyl. [0038] In some embodiments, when one of R5 and R6 is ethyl, R1, R2, R3, and R4 are not all H. [0039] In some embodiments, each of R1, R2, R3, R4, R5 and R6 is H. [0040] In some embodiments, at least one of R1, R2, R3, R4, R5 and R6 is not H. [0041] In some embodiments, at least two of R1, R2, R3, R4, R5 and R6 are not H. [0042] In some embodiments, at least three of R1, R2, R3, R4, R5 and R6 are not H. [0043] In some embodiments, at least four of R1, R2, R3, R4, R5 and R6 are not H. [0044] In some embodiments, at least five of R1, R2, R3, R4, R5 and R6 are not H. [0045] In some embodiments, none of R1, R2, R3, R4, R5 and R6 are H. [0046] The present invention provides a compound having the structure: , wherein A is an aryl or heteroaryl; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), alkyl, alkenyl, alkynyl, aryl, -SH, -S-(alkyl), -NH2, -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); 17
α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, or when β is present, then X1 is N, X2 is N and Z1 is absent; wherein when α is present, X1 is C and X2 is N, then Z1 is present and Z1 is H, -CF3, -CF2H, alkyl, alkenyl, alkynyl or aryl; wherein when α is present, X1 is C, and X2 is O or S, then Z1 is absent; and R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and wherein R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or - N(alkyl)2, 18
or a salt thereof. [0047] In some embodiments, R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), - (heteroalkyl), -(hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O- (heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH- (alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, -SC(O)R12, - NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and wherein R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or - N(alkyl)2. [0048] In some embodiments, R7, R8, R9 and R10 are each -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O- (alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -C(O)R12, -S(O)R12, - SO2R12, -NHSO2R12, -OC(O)R12, -SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or - N(alkyl)2, and wherein R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2. [0049] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl). [0050] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). [0051] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). [0052] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, or -OH. 19
[0053] In some embodiments, one of R7, R8, R9 and R10 is -F. [0054] In some embodiments, one of R7, R8, R9 and R10 is -OH. [0055] In some embodiments, one of R7, R8, R9 and R10 is -F and the rest of R7, R8, R9 and R10 is H. [0056] In some embodiments, one of R7, R8, R9 and R10 is -OH and the rest of R7, R8, R9 and R10 is H. [0057] In some embodiments, each of R7, R8, R9 and R10 is H. [0058] The present invention provides a compound having the structure: Y1 Y2 R5 R4 , or a salt thereof. [0059] The present invention provides a compound having the structure: Y1 Y2 R5 R4 , wherein X1 is C or N; X2 is N, O, or S; α and β each represents a bond that is present or absent, 20
wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, or when β is present, then X1 is N, X2 is N and Z1 is absent; wherein when α is present, X1 is C and X2 is N, then Z1 is present and Z1 is H, -CF3, -CF2H, alkyl, alkenyl, or alkynyl; wherein when α is present, X1 is C, and X2 is O or S, then Z1 is absent; R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), or -(cycloalkyl); R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), - (alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl); and Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl), or a salt thereof. [0060] In some embodiments, α is present and β is absent. [0061] In some embodiments, α is absent and β is present. [0062] In some embodiments, when α is present, X1 is C and X2 is N, then Z1 is present and Z1 is H, - CF3, -CF2H, alkyl, alkenyl, alkynyl or aryl. [0063] In some embodiments, X1 is C or N; or X2 is N or O. [0064] In some embodiments, X1 is C and X2 is N or O. [0065] In some embodiments, when X2 is N, Z1 is H, CF3, -CF2H, alkyl, alkenyl, or aryl. [0066] In some embodiments, when X2 is N, Z1 is H, alkyl, alkenyl, or aryl. [0067] In some embodiments, when X2 is N, Z1 is H or alkyl. [0068] In some embodiments, when X2 is N, Z1 is H. [0069] In some embodiments, when β is present, then X1 is N, X2 is N and Z1 is absent. [0070] The present invention provides a compound having the structure: 21
, [0071] The present invention provides a compound having the structure: , 3, -CF2H, - OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O- (alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl), or a salt thereof. [0072] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). 22
[0073] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, Br, -CN, -CF3, - OCF3, -OH, -O-(alkyl), or -O-(alkenyl). [0074] In some embodiments, R7, R8, R9 and R10 are each H. [0075] In some embodiments, at least one of R7, R8, R9 and R10 is not H. [0076] In some embodiments, at least two of R7, R8, R9 and R10 are not H. [0077] In some embodiments, at least three of R7, R8, R9 and R10 are not H. [0078] In some embodiments, none of R7, R8, R9 and R10 are not H. [0079] In some embodiments, one of R7, R8, R9 and R10 is not H. [0080] In some embodiments, two of R7, R8, R9 and R10 are not H. [0081] In some embodiments, three of R7, R8, R9 and R10 are not H. [0082] In some embodiments, R7, R9 and R10 are each H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, F, or Cl. [0083] In some embodiments, R7, R9 and R10 are each H; and R8 is F, -CF3, or Cl. [0084] In some embodiments, R7 and R10 are each H; and R8 and R9 are each -O-Me. [0085] The present invention provides a compound having the following structure: , wherein R8, R9, and R10 are each H; and R9 is OH, or a salt thereof. [0086] The present invention provides a compound having the structure: 23 , wherein R7, R9, and R10 ar or a salt thereof. [0087] In some embodiments, Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl). [0088] The present invention provides a compound having the following structure: wherein Y3, Y4 and Y5 are eac or -(alkyl)-O-(alkyl), or a salt thereof. [0089] In some embodiments, Y3, Y4 and Y5 are each independently H, or -(alkyl). [0090] In some embodiments, Y3, Y4 and Y5 are each H. [0091] The present invention provides a compound having the following structure: , or
a salt thereof. [0092] nd having the structure: , wherein R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), or -(cycloalkyl); and R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), - (alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl), or a salt thereof. [0093] The present invention provides a compound having the structure: . wherein R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), or -(cycloalkyl); and 25
R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), - (alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl), or a salt thereof. [0094] In some embodiments, R7, R9 and R10 are each -H; and R8 is H, -CF3, -CN, -O-CF3, -O-Me, - OH, -F, or -Cl. [0095] In some embodiments, R7, R9 and R10 are each -H; and R8 is H, -F, -OH, -CF3, or -Cl. [0096] In some embodiments, R7, R9 and R10 are each -H; and R8 is H, -OH, or -F. [0097] In some embodiments, R1, R2, R3, R4, R5 and R6 are each H. [0098] In some embodiments, at least one of R1, R2, R3, R4, R5 and R6 is not -H. [0099] In some embodiments, at least two of R1, R2, R3, R4, R5 and R6 are not -H. [0100] In some embodiments, at least three of R1, R2, R3, R4, R5 and R6 are not -H. [0101] In some embodiments, at least four of R1, R2, R3, R4, R5 and R6 are not -H. [0102] In some embodiments, at least five of R1, R2, R3, R4, R5 and R6 are not -H. [0103] In some embodiments, none of R1, R2, R3, R4, R5 and R6 are -H. [0104] In some embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, - OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2. [0105] In some embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H. [0106] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H. [0107] In some embodiments, at least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0108] In some embodiments, at least three of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0109] In some embodiments, at least four of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0110] In some embodiments, at least five of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0111] In some embodiments, at least six of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0112] In some embodiments, at least seven of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0113] In some embodiments, at least eight of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0114] In some embodiments, at least nine of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0115] In some embodiments, none of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are -H. 26
[0116] In some embodiments, when one of R1 and R2 is methyl, R3 and R4 are each independently H, methyl, C2-10alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, -NH(alkyl) or halogen, and R15 is -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2; and R5 and R6 are each independently H, methyl, C2-10alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, -NH(alkyl) or halogen, and R15 is -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2; and wherein when one of R5 and R6 is ethyl, at least one of R1, R2, R3, and R4 is not H. [0117] In some embodiments, when one of R1 and R2 is methyl, R3 and R4 are not both H and ethyl. [0118] In some embodiments, when one of R1 and R2 is methyl, R5 and R6 is not both H and ethyl. [0119] In some embodiments, when one of R5 and R6 is ethyl, R1, R2, R3, and R4 are not all H. [0120] In some embodiments, when one of R5 and R6 is ethyl, at least one of R1, R2, R3, and R4 is not H. [0121] In some embodiments, R1, R2, R5 and R6 are each H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0122] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). [0123] In some embodiments, one of R3 and R4 is -methyl, ethyl, or -O-methyl. [0124] In some embodiments, the other R3 or R4 is H. [0125] In some embodiments, R1, R2, R3 and R4 are each H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0126] In some embodiments, one of R5 and R6 is -alkyl, or -O-(alkyl). [0127] In some embodiments, one of R5 and R6 is -methyl, ethyl, or -O-methyl. [0128] In some embodiments, the other R5 or R6 is H. [0129] In some embodiments, R3, R4, R5 and R6 are each H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or heteroaryl. [0130] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). 27 [0131] In some embodiments, one of R3 and R4 is -methyl, ethyl, or -O-methyl. [0132] In some embodiments, the other R3 or R4 is H. [0133] The present invention provides a compound having the structure: salt [0134] The present invention provides a compound having the structure: , salt re:
, , , , 29
H, - f. or [0139] The present invention provides a compound having the structure: 30 , , , , , , , , , , , , [01 e pese ve o pov es a co pou av g e s ucue: ,
wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present, and whenX1 is C, and X2 is O or S, then Z1 is absent, or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present, and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15; wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0141] In some embodiments, Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), -(alkynyl), or -(aryl). [0142] The present invention provides a compound having the structure: 33
, wherein A is an aryl or heteroaryl; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0143] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl). [0144] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). [0145] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, - OCF3, -OH, -O-(alkyl), or -O-(alkenyl). 34 [0146] In some embodiments, the compound has the structure: of. [0147] In some e [0148] In some embodiments, α is absent and β is present. [0149] In some embodiments, X1 is C or N; and/or X2 is N or O. [0150] In some embodiments, X1 is C and X2 is N or O. [0151] In some embodiments, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2. [0152] In some embodiments, when X2 is N, then Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), or -(aryl). [0153] In some embodiments, Z1 is -H, -(alkyl), -(alkenyl), or -(aryl). [0154] In some embodiments, Z1 is -H or -(alkyl). [0155] In some embodiments, Z1 is -H. [0156] The present invention provides a compound having the structure: ,
eof. , wherein F2H, -OCF3, - CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O- (alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or - NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -CN, - CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl), or a salt thereof. [0158] The present invention provides a compound having the structure: 36
r a salt thereof. [0159] In some e [0160] In some embodiments, at least one of R7, R8, R9 and R10 is not -H. [0161] In some embodiments, at least two of R7, R8, R9 and R10 are not -H. [0162] In some embodiments, R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl. [0163] In some embodiments, R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl. [0164] In some embodiments, R7 and R10 are each -H; and R8 and R9 are each -O-Me. [0165] The present invention provides a compound having the structure: r a salt thereof. [0166] In some embod iments, R7, R8, R9 and R10 are each -H. [0167] In some embodiments, at least one of R7, R8, R9 and R10 is not -H. [0168] In some embodiments, at least two of R7, R8, R9 and R10 are not -H. [0169] In some embodiments, R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl. [0170] In some embodiments, R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl. 37
[0171] In some embodiments, R7 and R10 are each -H; and R8 and R9 are each -O-Me. [0172] In some embodiments, R7, R8, R9, and R10 are each -H; and R9 is -OH. [0173] In some embodiments, Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl). [0174] The present invention provides a compound having the structure: , wherein Y3, Y4 and Y5 are eac ), or -(alkyl)-O-(alkyl) , or a salt thereof. [0175] In some embodiments, Y3, Y4 and Y5 are each independently -H, or -(alkyl). [0176] In some embodiments, Y3, Y4 and Y5 are each -H. [0177] The present invention provides a compound having the structure: , or [0178] The present invention provides a compound having the structure: 38
salt [0179] [0180] In some embodiments, at least one of R1, R2, R3, R4, R5 and R6 is not -H. [0181] In some embodiments, at least two of R1, R2, R3, R4, R5 and R6 are not -H. [0182] In some embodiments, at least three of R1, R2, R3, R4, R5 and R6 are not -H. [0183] In some embodiments, at least four of R1, R2, R3, R4, R5 and R6 are not -H. [0184] In some embodiments, at least five of R1, R2, R3, R4, R5 and R6 are not -H. [0185] In some embodiments, none of R1, R2, R3, R4, R5 and R6 are -H. [0186] In some embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, - OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2. [0187] In some embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H. [0188] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H. [0189] In some embodiments, at least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0190] In some embodiments, at least three of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0191] In some embodiments, at least four of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0192] In some embodiments, at least five of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0193] In some embodiments, at least six of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0194] In some embodiments, at least seven of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0195] In some embodiments, at least eight of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0196] In some embodiments, at least nine of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H. [0197] In some embodiments, none of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are -H. 39
[0198] In some embodiments, when one of R1 and R2 is -CH3, then R3 and R4 are each independently -H, -CH3, C2-10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, -NH(alkyl) or - N(alkyl)2; and R5 and R6 are each independently -H, -CH3, C2-10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2. [0199] In some embodiments, when one of R5 and R6 is -CH2CH3, then at least one of R1, R2, R3, and R4 is not -H. [0200] In some embodiments, R1, R2, R5 and R6 are each -H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, -alkylaryl, -aryl, or -heteroaryl. [0201] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). [0202] In some embodiments, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3. [0203] In some embodiments, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H. [0204] In some embodiments, R1, R2, R3 and R4 are each -H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, -alkylaryl, -aryl, or -heteroaryl. [0205] In some embodiments, one of R5 and R6 is -alkyl, or -O-(alkyl). [0206] In some embodiments, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3. [0207] In some embodiments, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; and the other R5 or R6 is -H. [0208] In some embodiments, R3, R4, R5 and R6 are each -H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or -heteroaryl. [0209] In some embodiments, one of R3 and R4 is -alkyl, or -O-(alkyl). [0210] In some embodiments, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3. [0211] In some embodiments, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H. [0212] The present invention provides a compound having the structure: 40 , , , ,
42 or , , , , , , , , , , , ,
, , or [0214] H1 O , wherein at least one of H1, H2 or H3 is a iched -H site. H1 O [0215] In some embodiments, one or two of R7, R8 R9 and R10 ar , wherein at least one of H1, H2 or H3 is a deuterium-enriched -H site. H1 O [0216] In some embodiments, R7 and/or R8 ar , wherein at least one of H1, H2 or H3 is a deuterium-enriched -H site. [0217] In some embodiments, one, two, three or four of R7, R8 R9 and R10 are 45
H4 H5 H1 , wherein at least one of H1, H2 or H3 is a deuterium-enriched -H site. H4 H 5 H1 [0218] In some embodiments, one or two of R7, R8 R9 and R10 ar , wherein at least one of H1, H2, H3, H4 or H5 is a deuterium-enriched -H site. H4 H5 H1 [0219] In some embodiments, R7 and/or R8 ar , wherein at least one of H1, H2, H3, H4 or H5 hed -H site. [0220] The present invention provides a composition comprising a mixture of the compound disclosed H4 H5 herein or a pharmaceutically acceptable salt thereof, wherei , wherein in the mixture, the proportion of the com 0156% of molecules in the mixture. [0221] The present invention provides a composition comprising a mixture of the compound disclosed herein or a pharmaceutically acceptable salt thereof, wherein R7 and/or R8 is H1 O , wherein (a) at least one of H1, H2 or H3 is a deuterium-enriched -H site; (b) each of H1-H3 are deuterium-enriched; (c) two of H1-H3 are deuterium-enriched; or (d) one of H1-H3 is deuterium-enriched. 46
[0222] In some embodiments, each of H1-H3 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition. [0223] In some embodiments, two of H1-H3 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition. [0224] In some embodiments, one of H1-H3 is deuterium-enriched, and the proportion of the compound is substantially greater than 90% in the composition. [0225] The present invention provides a composition comprising a mixture of the compound disclosed herein or a pharmaceutically acceptable salt thereof, wherein R7 and/or R8 is H4 H5 H1 , wherein (a) at least one of H1, H2, H3, H4 or H5 is a deuterium-enriched -H site; (b) each of H1-H5 are deuterium-enriched; or (c) each of H4-H5 are deuterium-enriched or one of H4-H5 is deuterium-enriched. [0226] In some embodiments, each of H1-H5 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition. [0227] In some embodiments, each of H4-H5 are deuterium-enriched and the proportion of the compound is substantially greater than 90% in the composition. [0228] In some embodiments, one of H4-H5 is deuterium-enriched, and the proportion of the compound is substantially greater than 90% in the composition. [0229] In some embodiments, R7 and/or R8 is H H D D , wherein D represents a deuterium-enriched -H site. 47
[0230] In some embodiments, the present invention provides a composition comprising the compound disclosed herein and a pharmaceutically acceptable carrier or a pharmaceutically active agent. [0231] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound disclosed herein and a pharmaceutically acceptable carrier. [0232] In some embodiments, the composition further comprises a mu-opioid receptor agonist. [0233] In some embodiments, the composition further comprises an opioid or opiate. [0234] In some embodiments, the opioid or opiate is morphine, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, oxycodone, nalbuphine, butorphanol, etorphine, dihydroetorphine, levorphanol, metazocine, pentazocine, meptazinol, meperidine (pethidine), fentanyl, sufentanil, alfentanil, buprenorphine, methadone, tramadol, tapentadol, mitragynine, 3-deutero-mitragynine, 7- hydroxymitragynine, 3-deutero-7-hydroxymitragynine, mitragynine pseudoindoxyl, tianeptine, 7-((3- bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid, 7-((3- iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid, 5-((3- bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)pentanoic acid or 5- ((3-iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f] [1,2]thiazepine-11-yl)amino)pentanoic acid. [0235] The present invention provides a method of altering the psychological state of a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby alter the psychological state of the subject. [0236] The present invention provides a method of enhancing the effect of psychotherapy in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby enhance the effect of the psychotherapy in the subject. [0237] The present invention provides a method of inducing wakefulness or decreasing sleepiness in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby induce wakefulness or decrease sleepiness in the subject. [0238] The present invention provides a method of inducing a stimulating effect in a subject comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby induce the stimulating effect in the subject. [0239] The present invention provides a method of treating a subject afflicted with substance use disorder (SUD) comprising administering an effective amount of the compound disclosed herein, or the 48
composition disclosed herein to the subject, so as to thereby treat the subject afflicted with the substance use disorder. [0240] In some embodiments, the substance use disorder is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking). [0241] The present invention provides a method of treating a subject afflicted with opioid withdrawal symptoms comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with the opioid withdrawal symptoms. [0242] The present invention provides a method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with the depressive disorder, the mood disorder, the anxiety disorder, Parkinson’s disease or the traumatic brain injury. [0243] The present invention provides a method of treating a subject afflicted with pain, the method comprising administering an effective amount of the compound disclosed herein, or the composition disclosed herein to the subject, so as to thereby treat the subject afflicted with pain. [0244] In some embodiments, an effective amount of 10-1500 mg of the compound is administered to the subject. [0245] In some embodiments, an effective amount of 100-1500 mg of the compound is administered to the subject. [0246] In some embodiments, an effective amount of 500-1500 mg of the compound is administered to the subject. [0247] In some embodiments, an effective amount of 1000-1500 mg of the compound is administered to the subject. [0248] In some embodiments, an effective amount of 1000-1200 mg of the compound is administered to the subject. [0249] In some embodiments, an effective daily amount of 30 mg of the compound is administered to the subject. [0250] The present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: 49
, wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present and Z1 is -H, -CF3, -CF2H, - (alkyl), -(alkenyl), -(alkynyl), or -(aryl); and whenX1 is C, and X2 is O or S, then Z1 is absent; or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - 50
O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. [0251] The present invention provides a method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), alkyl, alkenyl, alkynyl, aryl, -SH, -S-(alkyl), -NH2, -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, or when β is present, then X1 is N, X2 is N and Z1 is absent; 51
wherein when α is present, X1 is C and X2 is N, then Z1 is present and Z1 is H, -CF3, -CF2H, alkyl, alkenyl, alkynyl or aryl; wherein when α is present, X1 is C, and X2 is O or S, then Z1 is absent; R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2 or a salt thereof. [0252] In some embodiments, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2. [0253] In some embodiments, when one of R1 and R2 is methyl, R3 is not H and R4 is not ethyl; or R4 is not H and R3 is not ethyl. [0254] In some embodiments, when one of R1 and R2 is methyl, R5 is not H and R6 is not ethyl; or R6 is not H and R5 is not ethyl. [0255] In some embodiments, the method is for a) altering the psychological state of the subject; b) enhancing the effect of psychotherapy in the subject; c) inducing wakefulness or decreasing sleepiness in the subject; d) inducing a stimulating effect in the subject; e) treating the subject afflicted with substance use disorder; f) treating the subject afflicted with opioid withdrawal symptoms; and/or g) treating the subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury. 52
[0256] In some embodiments, the substance use disorder is opioid use disorder, alcohol use disorder or stimulant use disorder. [0257] In some embodiments, the method further comprises treating the subject afflicted with substance use disorder, Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease. [0258] In some embodiments, an effective amount of 10-1500 mg of the compound is administered to the subject. [0259] In some embodiments, an effective amount of 100-1500 mg of the compound is administered to the subject. [0260] In some embodiments, an effective amount of 500-1500 mg of the compound is administered to the subject. [0261] In some embodiments, an effective amount of 1000-1500 mg of the compound is administered to the subject. [0262] In some embodiments, an effective amount of 1000-1200 mg of the compound is administered to the subject. [0263] In some embodiments, an effective amount of 30 mg of the compound is administered to the subject daily and the subject does not induce catalepsy. [0264] In some embodiments, the compound has the structure: eof. [0265] , p N HO or [0266] In some embodiments, the compound has the structure: 53 , , , , , , ,
, , , , , [02 ] e present nventon prov es a process o pro ucng a compoun o ormua : (I) wherein 55
Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is -halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, - C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (II) 56
II) with a catalyst complex t X), (b) reacting the compound of formula (IX) with a reducing agent to produce the compond of formula I, or a salt thereof. [0268] The present invention provides a process of producing a compound of formula I: (I) wherein 57
Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is -halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, - C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (II) 58
II) with a halogenating reag X), wherein A is a halog (b) adding a catalyst complex to produce the compond of formula I, or a salt thereof. [0269] The present invention provides a process of producing a compound of formula I: (I) wherein Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); 59
R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, wherein R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and wherein R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or - N(alkyl)2. comprising: (a) reacting a compound of formula (II) with Pd(CH3CN)4(BF4)2 and CH3CN, under an inner gas at room temperature to obtain a mixture, 60
II) (b) adding MeOH and N or a salt thereof. [0270] In some embodiments, the catalyst complex is a transition metal catalyst complex. [0271] In some embodiments, the transition metal catalyst complex is Pd(CH3CN)4(BF4)2. [0272] In some embodiments, the reducing agent is a hydride source. [0273] In some embodiments, the hydride source is LiBH4 or NaBH4. [0274] In some embodiments, step (a) includes a solvent. [0275] In some embodiments, the solvent is an organic solvent. [0276] In some embodiments, the solvent is a polar aprotic solvent. [0277] In some embodiments, the solvent is CH3CN. [0278] In some embodiments, step (b) includes a solvent. [0279] In some embodiments, the solvent is an alcohol. [0280] In some embodiments, the solvent is a primary alcohol. [0281] In some embodiments, the solvent is methanol, ethanol, propanol. [0282] In some embodiments, the solvent is MeOH. [0283] In some embodiments, step (a) and/or step (b) is conducted in an inert gas. [0284] In some embodiments, the inert gas is helium, neon, argon, krypton, and xenon. [0285] In some embodiments, the inert gas is argon. [0286] In some embodiments, step (a) is conducted at 20-35 °C. [0287] In some embodiments, step (a) is conducted at 25-30 °C. 61
[0288] In some embodiments, step (a) is conducted at 25-27 °C. [0289] In some embodiments, before step (b), the mixture from step(a) is heated for 13-23 hours. [0290] In some embodiments, before step (b), the mixture from step(a) is heated for 16-19 hours. [0291] In some embodiments, before step (b), the mixture from step(a) is heated at a temperature of 60-100 °C. [0292] In some embodiments, before step (b), the mixture from step(a) is heated at a temperature of 79-90 °C. [0293] In some embodiments, before step (b), the mixture from step(a) is heated at a temperature of 80 °C. [0294] In some embodiments, before step (b), the mixture is cooled at a temperature of 0-15 °C. [0295] In some embodiments, before step (b), the mixture is cooled at a temperature of 0-10 °C. [0296] In some embodiments, before step (b), the mixture is cooled at a temperature of 0-5 °C. [0297] In some embodiments, the process further comprises: (a) diluting the mixture from step (b) with AcOEt; (b) filtered the diluted mixture to obtain a residue; (c) washing the residue with AcOEt and Et3N to obtain a product; and (d) purifying the product. [0298] In some embodiments, the compound of formula II is produced by reacting a compound of formula III O O l II) with a compound of formula 62
V) in the presence of a base, or a salt thereof. [0299] In some embodiments, the compound of formula II is produced by reacting a compound having formula III O O R Cl II) with a compound of formula V) in the presence of DCM and CH3C or a salt thereof. [0300] In some embodiments, the base is an organic base. [0301] In some embodiments, the organic base is a strong base. [0302] In some embodiments, the organic base is an amine base. [0303] In some embodiments, the organic base is triethylamine. [0304] In some embodiments, the organic base is N,N-diisopropylethylamine. [0305] In some embodiments, the above reaction is conducted at 0-30 °C. 63
[0306] In some embodiments, the above reaction is conducted at a temperature of 0-25 °C. [0307] In some embodiments, the process further comprises adding LiAlH4 in Tetrahydrofuran (THF) at a temperature of 0-70 °C. [0308] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl). [0309] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). [0310] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). [0311] In some embodiments, Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl). [0312] In some embodiments, Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(haloalkyl), or -(alkyl)-O-(alkyl). [0313] In some embodiments,Y1, Y2, Y3, Y4 and Y5 are each independently -H, or -(alkyl). [0314] In some embodiments,Y1, Y2, Y3, Y4 and Y5 are each -H. [0315] In some embodiments, Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl). [0316] In some embodiments, Y3, Y4 and Y5 are each independently H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl). [0317] In some embodiments, Y3, Y4 and Y5 are each independently H, or -(alkyl). [0318] In some embodiments, Y3, Y4 and Y5 are each H. [0319] In some embodiments, R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O- CH2CH3, -F, Br, Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2. [0320] The present invention provides a process of producing a compound of formula V: 64
V) wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, 65
wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (VI) VI) with a base and a halogena la (XI) nd (b) reacting the compo un o ormu a w a ca a ys comp ex o produce the compound of formula V, or a salt thereof. [0321] The present invention provides a process of producing the compound of formula V: 66
V) wherein Y1, Y2, Y3, Y4 and Y5 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -OH, -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, 67
wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and wherein R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or - N(alkyl)2. comprising: (a) reacting a compound of formula (VI) with sequentially: nBuLi in the presence of an idoine solution, THF, and Na2S2O3, under an inner gas at room temperature to obtain a mixture, VI) (b) adding sodium form m(II) and dimethyl sulfoxide (DMSO) under an inner gas to the mixture, or a salt thereof. [0322] In some embodiments, the base is a strong base. [0323] In some embodiments, the base is an organic base. [0324] In some embodiments, the base is nBuLi. [0325] In some embodiments, the halogen solution is iodine solution. [0326] In some embodiments, the catalyst complex is a transition metal catalyst complex. [0327] In some embodiments, the transition metal catalyst complex is sodium formate, dichlorobis(tri- o-tolylphosphine)palladium(II). [0328] In some embodiments, step (a) includes a solvent; preferably, the solvent is an organic solvent; more preferably, the solvent is THF. [0329] In some embodiments, step (a) includes Na2S2O3. [0330] In some embodiments, step (b) includes a solvent; prefearbly, preferably, the solvent is an organic solvent; more preferably, the solvent is DMSO. 68
[0331] In some embodiments, step (a) and/or step (b) are conducted in an inert gas; preferably, the inert gas is helium, neon, argon, krypton, and xenon. [0332] In some embodiments, (a) the inert gas is argon; (b) step (a) is conducted at a temperature of -30 to -50 °C; preferably at a temperature of -40 °C; (c) before step (b), the mixture is diluted with water and extracted with diethyl ether for at least 3 times; and/or (d) step (b) is conducted at a temperature of 90 to 110 °C; preferably at a temperature of 100 °C. [0333] In some embodiments, the compound of formula VI is produced by reacting a compound of formula VII II) with a compound of form V) in the presence of a base, or a salt thereof. [0334] In some embodiments, formula VI is produced by reacting a compound having formula VII II) with a compound of form 69
V) in the presence of DCM and CH3C or a salt thereof. [0335] In some embodiments the base is a strong base; preferably the base is an inorganic base; preferably the base is KOH, NaOH, Mg(OH)2, Fe(OH)3, Al(OH)3, Ca(OH)2, more preferably, the base is NaOH. [0336] In some embodiments, the reaction is conducted at 70-90 °C. [0337] In some embodiments, the reaction is conducted at a temperature of 80 °C. [0338] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O- (alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl). [0339] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, - CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl). [0340] In some embodiments, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). [0341] In some embodiments, Y3, Y4 and Y5 are each independently H, -(alkyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl). [0342] In some embodiments, Y3, Y4 and Y5 are each independently H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl). [0343] In some embodiments, Y3, Y4 and Y5 are each independently H, or -(alkyl). [0344] In some embodiments, Y3, Y4 and Y5 are each H. [0345] In some embodiments, R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O- CH2CH3, -F, Br, Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2. 70
[0346] In some embodiments of the process, the compound of formula IV has the following structure: . [0347] In some embodiments, the present i vides compounds or compositions disclosed herein for use in (a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); (f) treating a subject afflicted with opioid withdrawal symptoms; (g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury; (h) treating a subject afflicted with pain; and/or (i) treating a subject afflicted with Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease. [0348] In some embodiments, 10-1500 mg of the compound is administered to the subject; more preferably, 100-1500 mg of the compound is administered to the subject; more preferably, 500-1500 mg of the compound is administered to the subject. [0349] In some embodiments, the present invention provides use of the compounds or the compositions disclosed herein in (a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); (f) treating a subject afflicted with opioid withdrawal symptoms; 71
(g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury; (h) treating a subject afflicted with pain; and/or (i) treating a subject afflicted with Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease. [0350] In some embodiments, 10-1500 mg of the compound is administered to the subject; more preferably, 100-1500 mg of the compound is administered to the subject; more preferably, 500-1500 mg of the compound is administered to the subject. [0351] In some embodiments of any of the above compositions, the composition further comprising any of the compounds disclosed in U.S. Application No.14/240,681, patented as U.S. Patent No.9,988,377; U.S. Application No 15/528,339; patented as U.S. Patent No. 11,840,541; PCT International Application Nos. PCT/US2012/052327, PCT/US2015/062726, PCT International Publication Nos. WO 2015/138791, WO 2017/049158, WO 2018/170275 or WO 2020/037136, the contents of each of which are hereby incorporated by reference. [0352] The present invention provides a method of decreasing the duration of REM sleep in a subject comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound so as to thereby decrease the duration of REM sleep in the subject. [0353] The present invention provides a method of increasing energetic feelings in a subject comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound so as to thereby increase the energetic feelings in the subject. [0354] The present invention provides a method of inducing a stimulating effect in a subject comprising administering to the subject the compound disclosed herein, or the composition disclosed herein comprising an effective amount of the compound, so as to thereby induce the stimulating effect in the subject. [0355] In some embodiments, the stimulating effect is a central stimulating effect. [0356] In some embodiments, the stimulating effect is induced substantially free of undesired side- effects in the subject. [0357] In some embodiments, the stimulating effect is induced without inducing an addictive effect in the subject to the compound. [0358] In some embodiments, the prevent invention provides a use of the composition disclosed herein comprising an effective amount of the compound as a stimulant. 72
[0359] The present invention provides a method of treating a subject afflicted with pain comprising administering to the subject the composition disclosed herein comprising an effective amount of the compound and the opioid or opiate so as to thereby treat the subject afflicted with pain. [0360] In some embodiments, the compound disclosed herein inhibits serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2) or any combination thereof in a subject. [0361] In some embodiments, the compound disclosed herein inhibits serotonin transporter (SERT) in a subject. [0362] In some embodiments, the compound disclosed herein inhibits vesicular monoamine transporter 2 (VMAT2) in a subject. [0363] In some embodiments, the compound disclosed herein inhibits serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2). [0364] The present invention provides a method of altering the psychological state of a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0365] The present invention provides a method of enhancing the effect of psychotherapy in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0366] The present invention provides a method of inducing wakefulness or decreasing sleepiness in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0367] The present invention provides a method of inducing a stimulating effect in a subject by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0368] The present invention provides a method of treating a subject afflicted with substance use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0369] The present invention provides a method of treating a subject afflicted with opioid use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0370] The present invention provides a method of treating a subject afflicted with alcohol use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. 73
[0371] The present invention provides a method of treating a subject afflicted with stimulant use disorder by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0372] The present invention provides a method of treating a subject afflicted with opioid withdrawal symptoms by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0373] The present invention provides a method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury by inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject. [0374] The present invention provides a method of inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject. [0375] The present invention provides a method of treating a subject afflicted with substance use disorder by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject. [0376] The present invention provides a method of treating a subject afflicted with Tardive dyskinesia (TD) by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject. [0377] The present invention provides a method of treating a subject afflicted with Tourette syndrome by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject. [0378] The present invention provides a method of treating a subject afflicted with chorea associated with Huntington’s disease by inhibiting vesicular monoamine transporter 2 (VMAT2), or inhibiting both VMAT2 and SERT in a subject. [0379] The present invention provides a pharmaceutically acceptable salt of any of the compounds disclosed herein. [0380] In some embodiments, a salt of the compound of the present invention is used in any of the above methods, uses, packages or compositions. [0381] In some embodiments, a pharmaceutically acceptable salt of the compound of the present invention is used in any of the above methods, uses, packages or compositions. [0382] Any of the above compounds may be used in any of the disclosed methods, uses, packages or pharmaceutical compositions. 74
[0383] Any of the compounds used in the disclosed methods, uses, packages or pharmaceutical compositions may be replaced with any other compound disclosed in the present invention. [0384] Any of the above generic compounds may be used in any of the disclosed methods, uses, packages or compositions. [0385] In some embodiments of any of the above methods, the composition is orally administered to the subject. [0386] In some embodiments of any of the above methods, 10 – 30 mg of the compound is administered to the subject. [0387] In some embodiments of any of the above methods, 30 – 100 mg of the compound is administered to the subject. [0388] In some embodiments of any of the above methods, 100 – 300 mg of the compound is administered to the subject. [0389] In some embodiments of any of the above methods, 300 – 500 mg of the compound is administered to the subject. [0390] In some embodiments of any of the above methods, 500 – 800 mg of the compound is administered to the subject. [0391] In some embodiments of any of the above methods, 800 – 1100 mg of the compound is administered to the subject. [0392] In some embodiments of any of the above methods, 1200 – 1500 mg of the compound is administered to the subject. [0393] In some embodiments, wherein any of the above recited doses of the compound, and an opioid are administered to a subject afflicted with a substance use disorder, opioid withdrawal symptoms, pain, a mood disorder, an anxiety disorder or opioid cravings so as to thereby treat the subject afflicted with the substance use disorder, opioid withdrawal symptoms, pain or the mood disorder or reduce opioid cravings in the subject. [0394] In some embodiments, the opioid is morphine and 10-20 mg (oral) or 3-5 mg (parenteral) of the opioid is administered to the subject. [0395] In some embodiments, the opioid is codeine and 30-60 mg (oral) of the opioid is administered to the subject. 75
[0396] In some embodiments, the opioid is oxycodone and 5-10 mg (oral) of the opioid is administered to the subject. [0397] In some embodiments, the opioid is fentanyl and 40-60 µg (parenteral) of the opioid is administered to the subject. [0398] In some embodiments, the opioid is butorphanol and 1-3 mg (parenteral) of the opioid is administered to the subject. [0399] In some embodiments, the opioid is nalbuphine and 5-15 mg (parenteral) of the opioid is administered to the subject. [0400] In some embodiments, mitragynine (15-100 mg – oral) or 3-deuteromitragynine (15-100 mg – oral) is administered to the subject. [0401] In some embodiments, tianeptine (12.5-100 mg – oral) is administered to the subject. [0402] In some embodiments, 7-((3-iodo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid (1.5-10 mg – oral) is administered to the subject. [0403] In some embodiments, 5-((3-iodo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)pentanoic acid (2-20 mg – oral) is administered to the subject. [0404] In some embodiments, administration of the composition disclosed herein comprising an effective amount of the compound lowers the effective amount of the opioid. [0405] In some embodiments, administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 75% or more. [0406] In some embodiments, administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 50% or more. [0407] In some embodiments, administration of the composition disclosed herein lowers the effective dosage amount of the opioid by 25% or more. [0408] In some embodiments, 0.4 mg/kg – 30 mg/kg of the compound disclosed herein is administered to the subject. [0409] In some embodiments, the subject does not induce catalepsy. [0410] In some embodiments, 0.3-1.5 mg/kg of the opioid or opiate is administered to the subject. 76
[0411] In some embodiments, the subject is a human. [0412] In some embodiments, the composition is clinically administered or physician administered to the subject. [0413] In some embodiments, the composition is clinically self-administered by the subject. [0414] In some embodiments, formation of noribogaine is attenuated within the subject. [0415] In some embodiments, formation of noribogaine is reduced within the subject. [0416] In some embodiments, metabolism of ibogaine is attenuated within the subject. [0417] In some embodiments, metabolism of ibogaine is enhanced within the subject. [0418] In some embodiments, metabolism of 10-ethoxy-ibogamine is attenuated within the subject. [0419] In some embodiments, metabolism of 10-ethoxy-ibogamine is enhanced within the subject. [0420] In some embodiments, wherein the subject is afflicted with a depressive disorder, a mood disorder, or an anxiety disorder. [0421] In some embodiments, the anxiety disorder includes, but is not limited to, anxiety, generalized anxiety disorder (GAD), panic disorder, social phobia, social anxiety disorder, acute stress disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD). [0422] In some embodiments, the depressive disorder includes, but is not limited to, depression, major depression, dysthymia, cyclothymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, situational depression or adjustment disorder with depressed mood. Depressive disorders can also include other mood disorders and is not limited to the above list. [0423] Preclinical evidence (rodents) also shows that ibogaine/noribogaine enhances morphine’s analgesic effect (Sharma, S.S. et al. 1998) or reverses analgesic tolerance to morphine (Bhargava, H.N. et al.1997). [0424] In some embodiments, wherein the subject is afflicted with pain. Reports of stimulant effects of Tabernanthe iboga date back to late 1890’s and early 1900’s in the descriptions of ritual and medicinal use by the native inhabitants in Africa. Ibogaine was recommended in France to treat “asthenia” (dose range of 10-30 mg per day). In the period of 1939-1970, ibogaine was commercially available in France as “Lambarène”, a “neuromuscular stimulant” (8 mg pills) recommended for fatigue, depression, and recovery from infectious diseases (Alper, K.R. 2001). In one clinical study, subjects took visual analog scale tests (VAS, 0-100) related to sleepiness, energetic feelings, and the side effects such as nausea, anxiety versus 77
calmness. Subjects reported that ibogaine decreased sleepiness and increased energetic feeling over the examined 24-hour period after one dose of 20 mg of ibogaine (Glue, P. et al.2015). A stimulant effect was reported in cats (Schneider et. al 1957). In rats, ibogaine induced wakefulness and suppressed the REM sleep as shown via EEG (González, J. et al 2018). [0425] It has been shown in rats that ibogaine leads to a dramatic upregulation of BDNF (in addition to Glial cell line-Derived Neurotrophic Factor (GDNF)) which provides structural and functional restorative effects in subjects afflicted with TBI (Marton, S. et al.2019). The efficacy of ibogaine has also been shown in cases of soldiers afflicted with TBI and PTSD (Thoricatha, W.2020). [0426] In some embodiments, the subject is afflicted with traumatic brain injury (TBI). [0427] It has been shown in rats that ibogaine induces expression of GDNF (He, D-Y. et al. 2005 and Marton, S. et al. 2019), a critical neurotrophic factor that maintains and restores the dopaminergic system (which degenerates in Parkinson’s disease). Thus, ibogaine provides structural and functional restorative effects in subjects afflicted with Parkinson’s disease. GDNF itself has been shown to exert desired effects in Parkinson’s rodent and monkey models (Gash, D.M. et al.1996). [0428] In some embodiments, the subject is afflicted with Parkinson’s disease. [0429] It has been shown in humans that ibogaine is useful in treating opioid and stimulant use disorders (Alper, K.R. et al. 1999; Mash, D.C. et al. 2018; Schenberg, E.E. et al.2014) or in maintenance therapy (opioid use disorder) in combination with an opioid to lower effective opioid doses (Kroupa, P.K. & Wells, H.2005). [0430] In some embodiments, the substance use disorder is an opioid use disorder, alcohol use disorder or stimulant use disorder. [0431] Opioid use disorder (OUD) involves, but is not limited to, misuse of opioid medications or use of illicitly obtained opioids. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association, 2013), which is hereby incorporated by reference, describes opioid use disorder as a problematic pattern of opioid use leading to problems or distress, with at least two of the following occurring within a 12-month period: -Taking larger amounts or taking drugs over a longer period than intended. -Persistent desire or unsuccessful efforts to cut down or control opioid use. -Spending a great deal of time obtaining or using the opioid or recovering from its effects. 78
-Craving, or a strong desire or urge to use opioids. -Problems fulfilling obligations at work, school, or home. -Continued opioid use despite having recurring social or interpersonal problems. -Giving up or reducing activities because of opioid use. -Using opioids in physically hazardous situations. -Continued opioid use despite ongoing physical or psychological problem likely to have been caused or worsened by opioids. -Tolerance (i.e., need for increased amounts or diminished effect with continued use of the same amount). -Experiencing withdrawal (opioid withdrawal syndrome) or taking opioids (or a closely related substance) to relieve or avoid withdrawal symptoms. [0432] Alcohol use disorder (AUD) involves, but is not limited to, a chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition describes alcohol use disorder as a problematic pattern of alcohol use leading to problems or distress, with at least two of the following occurring within a 12-month period: -Being unable to limit the amount of alcohol you drink. -Wanting to cut down on how much you drink or making unsuccessful attempts to do so. -Spending a lot of time drinking, getting alcohol, or recovering from alcohol use. -Feeling a strong craving or urge to drink alcohol. -Failing to fulfill major obligations at work, school or home due to repeated alcohol use. -Continuing to drink alcohol even though you know it is causing physical, social, or interpersonal problems. -Giving up or reducing social and work activities and hobbies. -Using alcohol in situations where it is not safe, such as when driving or swimming. -Developing a tolerance to alcohol so you need more to feel its effect, or you have a reduced effect from the same amount. -Experiencing withdrawal symptoms — such as nausea, sweating and shaking — when you do not drink, or drinking to avoid these symptoms. 79
[0433] Stimulant use disorder involves, but is not limited to, a pattern of problematic use of amphetamine, methamphetamine, cocaine, or other stimulants except caffeine or nicotine, leading to at least two of the following problems within a 12-month period: -Taking more stimulants than intended. -Unsuccessful in trying to cut down or control use of stimulants, despite wanting to do so. -Spending excessive amounts of time to activities surrounding stimulant use. -Urges and cravings for stimulants. -Failing in the obligations of home, school, or work. -Carrying on taking stimulants, even though it has led to relationship or social problems. -Giving up or reducing important recreational, social, or work-related activities because of using stimulants. -Using stimulants in a physically hazardous way. -Continuing to use stimulants even while knowing that it is causing or worsening a physical or psychological problem. -Tolerance to stimulants. -Withdrawal from stimulants if you do not take them. [0434] Polydrug use disorder or polysubstance use disorder involves, but is not limited to, dependence on multiple drugs or substances. [0435] The term “MOR agonist” is intended to mean any compound or substance that activates the mu-opioid receptor (MOR). The agonist may be a partial, full, or super agonist. [0436] A person skilled in the art may use the techniques disclosed herein to prepare deuterium analogs thereof. [0437] Except where otherwise specified, the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, scalemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in “Enantiomers, Racemates and 80
Resolutions” by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. [0438] Except where otherwise specified, the subject invention is intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. [0439] It will be noted that any notations of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein. [0440] It will also be noted that any notations of a hydrogen (H) in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H (D), or 3H (T) except where otherwise specified. Furthermore, any compounds containing 2H (D) or 3H (T) may specifically have the structure of any of the compounds disclosed herein except where otherwise specified. [0441] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the non-labeled reagents employed. [0442] Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes 1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.0156%. Thus, in a composition comprising molecules of a naturally occurring compound, the level of deuterium at a particular hydrogen atom site in that compound is expected to be 0.0156%. Thus, a composition comprising a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% is novel over its naturally occurring counterpart. [0443] As used herein, a hydrogen at a specific site in a compound is “deuterium-enriched” if the amount of deuterium at the specific site in the compound is more than the abundance of deuterium naturally occurring at that specific site in view of all of the molecules of the compound in a defined universe such as a composition or sample. Naturally occurring as used above refers to the abundance of deuterium which would be present at a relevant site in a compound if the compound was prepared without any affirmative step to enrich the abundance of deuterium. Thus, at a “deuterium-enriched” site in a compound, the abundance of deuterium at that site can range from more than 0.0156% to 100%. Examples of ways to 81
obtain a deuterium-enriched site in a compound are exchanging hydrogen with deuterium or synthesizing the compound with deuterium-enriched starting materials. [0444] In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise. [0445] In the compounds used in the method of the present invention, alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl. [0446] It is understood that substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0447] In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. [0448] In some embodiments, a package comprising: a) a first pharmaceutical composition comprising an amount of an opioid or opiate and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury, or Parkinson’s disease. [0449] In some embodiments, a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury or Parkinson’s disease, which comprises: a) one or more unit doses, each such unit dose comprising: (i) a pharmaceutical composition comprising the compound of the present invention; and (ii) an amount of an opioid or opiate, 82
wherein the respective amounts of said composition and said opioid or opiate in said unit dose are effective, upon concomitant administration to said subject, to treat the subject, and (b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject. [0450] The therapeutic package of the above embodiment, wherein the respective amounts of said composition and opioid or opiate in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said composition in the absence of said opioid or opiate or the administration of said opioid or opiate in the absence of said composition. [0451] A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with pain, a depressive disorder, a mood disorder, an anxiety disorder, a substance use disorder, opioid withdrawal symptoms, traumatic brain injury or Parkinson’s disease, which comprises: (i) a composition comprising the compound of the present invention; and (ii) an amount of an opioid or opiate, wherein the respective amounts of said composition and said opioid or opiate in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject. [0452] The pharmaceutical composition of the above embodiment, wherein the respective amounts of said compound and said opioid or opiate in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said composition in the absence of said opioid or opiate or the administration of said opioid or opiate in the absence of said composition. [0453] The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. [0454] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule. [0455] This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2H and/or wherein the isotopic atom 13C. Accordingly, in the compounds 83
provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. [0456] It is understood that the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove. [0457] It is understood that where a numerical range is recited herein, the present invention contemplates each integer between, and including, the upper and lower limits, unless otherwise stated. [0458] Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column. [0459] The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. [0460] It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein. [0461] It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein. [0462] Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed. 84
[0463] In the compounds used in the method of the present invention, the substituents may be substituted or unsubstituted, unless specifically defined otherwise. [0464] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl. [0465] It is understood that substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0466] In choosing the compounds used in the method of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. [0467] It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. [0468] In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. [0469] The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference. [0470] The compounds used in the method of the present invention may be prepared by techniques well known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds. 85
[0471] The compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds. [0472] Another aspect of the invention comprises a compound used in the method of the present invention as a pharmaceutical composition. [0473] In some embodiments, a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier. [0474] As used herein, the term “pharmaceutically active agent” means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department Of Health And Human Services, 30th edition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect. [0475] The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present 86
invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19). [0476] The compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance. [0477] As used herein, “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art. The administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally. [0478] The compounds used in the method of the present invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. [0479] The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect. [0480] A dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, 87
subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. [0481] The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. [0482] Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in 88
Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein. [0483] Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. [0484] The compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as lecithin, sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. [0485] The compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. [0486] Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. 89
[0487] For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. [0488] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. [0489] The compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. [0490] Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen. [0491] The compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. 90
[0492] Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept.2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein. [0493] The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms. [0494] Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine. Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate- methacrylic acid copolymers. [0495] The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. [0496] Variations on those general synthetic methods will be readily apparent to those of ordinary skill in the art and are deemed to be within the scope of the present invention. 91
[0497] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. [0498] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Definitions [0499] Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. [0500] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cn as in “C1–Cn alkyl" is defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on. ”Alkoxy" represents an alkyl group as described above attached through an oxygen bridge. [0501] The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non- aromatic carbon-carbon double bonds may be present. Thus, C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on. [0502] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon 92
triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2- Cn alkynyl. An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on. [0503] “Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted. [0504] As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. [0505] As used herein, "heterocycle" or "heterocyclyl" as used herein is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. [0506] As herein, "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). [0507] As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 10 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to phenyl. [0508] As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 10 atoms that is fused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene. [0509] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, 93
tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. [0510] As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted. [0511] The term “arylalkyl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. [0512] The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra- 94
hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. [0513] The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like. [0514] The term "heterocycle" or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like. [0515] The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl. [0516] The term “ester” is intended to a mean an organic compound containing the R-O-CO-R’ group. [0517] The term “phenyl” is intended to mean an aromatic six membered ring containing six carbons. [0518] The term “benzyl” is intended to mean a –CH2R1 group wherein the R1 is a phenyl group. [0519] As used herein, the term “halogen” refers to F, Cl, Br, and I. [0520] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles. 95
[0521] The terms “substitution”, “substituted” and “substituent” refer to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly. By independently substituted, it is meant that the (two or more) substituents can be the same or different. [0522] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins. [0523] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application. [0524] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters 96
set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. [0525] In the description and claims of the present application, each of the verbs, “comprise,” “include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art. General [0526] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. [0527] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention. [0528] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. [0529] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements. [0530] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only. 97
EXAMPLES Example 1 [0531] In Vitro Assays [0532] Cell Culture Maintenance and Experimental Preparations. [0533] Human Embryonic Kidney 293 cells (HEK) stably transfected with either human serotonin (hSERT), or vesicular monoamine transporter 2 (Black, C. A. et al; 2021) (hVMAT2; generously provided by Dr. Gary W. Miller and Mr. Joshua M. Bradner (Columbia University Mailman School of Public Health, Department of Environmental Health Sciences, New York, NY 10032) were maintained in Dulbecco’s Minimal Essential Medium (DMEM) with GlutaMAX (Gibco-Thermo Fisher Scientific; Waltham, MA) supplemented with 10% (v/v) fetal bovine serum (FBS; Atlanta Biologicals; Flowery Branch, GA), 100 U/mL penicillin (Invitrogen; Waltham, MA), and 10 μg/mL streptomycin (Invitrogen; Waltham, MA).500 μg/mL G418 (Gibco-Thermo Fisher Scientific; Waltham, MA) was added to the media to maintain the hSERT transgene. 100 μg/mL zeocin (InvivoGen; San Diego, CA) was supplemented to hVMAT2-HEK cell cultures (Black, C. A. et al 2021). All cultures were plated on 10 cm polystyrene culture plates (Corning Falcon; Corning, NY), grown in a humidified environment of 37 °C and five percent carbon dioxide atmosphere to full confluency, and subcultured every three to four days. [0534] Growth media is aspired and replaced by experimental media for conducting assays. For hSERT-HEK cell cultures, the experimental media consisted of DMEM minus phenol red (Gibco-Thermo Fisher Scientific; Waltham, MA), 1% (v/v) FBS, 100 U/mL penicillin, and 10 μg/mL streptomycin. Alternatively, for hVMAT2 cells, 1% (v/v) L-glutamine (Gibco-Thermo Fisher Scientific; Waltham, MA) was additionally included in the above medium recipe. [0535] Determination of IC50 Metrics of at hSERT Through APP+ Uptake Blockage. [0536] HEK cells stably transfected with hSERT cell cultures were seeded in white solid-bottom 96- well plates (Corning; Corning, NY) at a density of 1.00 × 106 cells/well and grown in a humidified environment of 37°C and five percent carbon dioxide to full confluency in approximately 48 hours. At the start of this functional fluorescent inhibition assay, the growth media was aspirated, and the cellular monolayer was rinsed twice with 120 μL of 1× Phosphate Buffered Saline (PBS; Corning; Corning, NY). Experimental media solutions, consisting of tiered concentrations (ranging from 100 ^M to 0.1 ^M) of test compound, imipramine (hSERT standard inhibitor) or DMSO (vehicle, 0.02% v/v, Sigma-Aldrich; St. Louis, MO), were gently added to the cell cultures and subsequently, pre-incubated for approximately 60 minutes. An equivalent volume of experimental media solutions containing both tiered concentrations (ranging from 100 ^M to 0.1 ^M) of test compound, imipramine, or DMSO (vehicle, 0.02% v/v, Sigma- 98
Aldrich; St. Louis, MO) and 4-(4-dimethylamino)phenyl-1-methylpyridinium (APP+; hSERT substrate; final concentration: 1.1 ^M; Sigma-Aldrich; St. Louis, MO) was added to each well and then incubated for an additional 30 minutes to encourage fluorescent probe uptake. At the conclusion of the incubation period, the solution contained within each well was aspirated and cells were washed with two successive washes of 120 ^L 1× PBS. A final addition of 120 ^L of 1× PBS in each well was necessary for fluorescent uptake readout by BioTek Synergy Neo2 Hybrid Multi-Mode Reader (Agilent; Santa Clara, CA), using 3 × 3 area scan and bottom-read mode, at the excitation and emission wavelengths of 436 and 500 nm, respectively. To determine IC50 values for each of test compounds and imipramine, the average fluorescence from vehicular wells was subtracted by the average fluorescence from wells containing test compound or imipramine to quantify respective fluorescence uptake (in mean fluorescence units). These latter values were then fit to the nonlinear curve model, (log[inhibitor] versus response (three parameters)), as provided by Graphpad Prism 10 software (Graphpad Prism Inc.; San Diego, CA) (See Figure 1). [0537] Determination of IC50 Metrics of test compounds at hVMAT2 Through FFN206 Uptake Blockage. [0538] A similar experimental procedure was conducted as in the section titled “Determination of IC50 Metrics of test compounds at hSERT Through APP+ Blockage”. However, the fluorescent substrate used was FFN206 (Hu, G. et al; 2013) (final concentration: 0.75 µM) and the standard inhibitor utilized was reserpine (Sigma-Aldrich; St. Louis, MO) in hVMAT-transfected HEK cells. The tested compound, reserpine or DMSO vehicle were added (pre-incubation of 30 minutes), followed by incubation with VMAT2 substrate (incubation of 60 minutes) (See Figure 1). [0539] Microsomal Stability Assays in Human and Rat Liver Microsomes [0540] Rat Liver Microsomes: pooled, male Sprague Dawley rats (XenoTech, R1000/lot #1910100) (See Figure 2) [0541] Human Liver Microsomes: pooled, mixed gender (XenoTech, H0630/lot N#1210097) (See Figure 2) [0542] Microsomal incubations were carried out in 96-well plates in 5 aliquots of 30 μL each (one for each time point). Liver microsomal incubation medium comprised of phosphate buffer (100 mM, pH 7.4), MgCl2 (3.3 mM), NADPН (3 mM), glucose-6-phosphate (5.3 mM), glucose-6-phosphate dehydrogenase (0.67 units/ml) with 0.5 mg of liver microsomal protein per ml. In the control reactions the NADPH- cofactor system was substituted with phosphate buffer. Test compounds (10 μM as well as for reference compounds, final solvent concentration 1.6 %) were incubated with microsomes at 37 °C, shaking at 100 rpm. Each reaction was performed in duplicates. Five time points over 90 or 60 minutes were analyzed. 99
The reactions were stopped by adding 5 volumes of acetonitrile containing internal standard to incubation aliquots, followed by protein sedimentation by centrifuging at 5500 rpm for 4 minutes. Supernatants were analyzed using the HPLC system coupled with tandem mass spectrometer. [0543] The elimination constant (kel), half-life (t1/2), and intrinsic clearance (Clint) were determined in a plot of ln(AUC) versus time, using linear regression analysis: [0544] All measu cluding vacuum degasser, gradient pumps, reverse phase HPLC column, column oven, and autosampler. Mass spectrometric analysis was performed using an API 5000 mass spectrometer from Applied Biosystems/ MDS Sciex (AB Sciex) with Turbo V ion source and TurboIonspray interface. The TurboIonSpray ion source was used in both positive and negative ion modes. The data acquisition and system control were performed using Analyst 1.6.3 software from AB Sciex. [0545] Chromatographic Conditions: [0546] Column: Phenomenex Luna® C18 HPLC column, 2.1x50 mm, 5 μm (Cat #5291-126). [0547] Mobile phase А: Acetonitrile : Water : Formic acid = 50 : 950 : 1. [0548] Mobile phase B: Acetonitrile : Formic acid = 100 : 0.1. [0549] Linear gradient: 0 min 0% B, 1.0 min 100% B, 1.2 min 100% B, 1.21 min 0% B, 2.4 min stop. [0550] Elution rate: 400 μL/min. A divert valve directed the flow to the detector from 0.9 to 1.4 min. [0551] Column temperature: 30 °C [0552] MS/MS Detection: [0553] Scan type: Positive MRM, Ion source: Turbo spray, Ionization mode: ESI [0554] Collision gas: 5, Curtain gas: 35 L/min, Ion Source gas 1: 44 L/min, Ion Source gas 2: 44 L/min [0555] Ionspray voltage: 5200 V, Temperature: 500 °C [0556] Cardiotoxicity Assay in Adult Human Primary Cardiomyocytes [0557] Cardiotoxicity of novel analogs was assessed according to published procedure (Abi-Gerges et al., 2020; Nguyen et al. 2017) using a commercially available assay service. Briefly, adult human primary ventricular myocytes were isolated from ethically consented donor hearts that were enzymatically digested using a proprietary protocol. Cardiomyocytes were placed in a perfusion chamber mounted on the stage of 100
inverted Motic AE31E (IonOptix) or Olympus IX83P1ZF (MyoBLAZER) microscope and continuously perfused at approximately 2 mL/min with recording buffer heated to 35 ± 1 °C using an in-line heater from Warner Instruments (IonOptix & MyoBLAZER) and allowed to equilibrate for 5 minutes under constant perfusion. The cells were field stimulated with supra-threshold voltage at a 1 Hz pacing frequency, with a bipolar pulse of 3 ms duration, using a pair of platinum wires placed on opposite sides of the chamber connected to a MyoPacer stimulator. Starting at 1 V, the amplitude of the stimulating pulse was increased until the cardiomyocytes started generating contractility transients, and a value 1.5× threshold was used throughout the experiment. Cardiomyocytes were then imaged at 240 Hz using an IonOptix MyoCam-S CCD camera (IonOptix) or at 148 Hz using an Optronis CP70-16-M/C-148 (MyoBLAZER) camera. Digitized images were displayed within the IonWizard acquisition software (IonOptix) or MyoBLAZER acquisition software. The longitudinal axis of the selected cardiomyocyte was aligned parallel to the video raster line, by means of a cell framing adapter. Optical intensity data was collected from a user-defined rectangular region placed over the cardiomyocyte image. The optical intensity data represented the bright and dark bands corresponding to the Z-lines of the cardiomyocyte. The IonWizard software or MyoBLAZER Analysis software analyzed the periodicity in the optical density of these bands by means of a fast Fourier transform algorithm. [0558] Compound test solutions were formulated from stock solutions within 30 min prior to experimental application to the cells. Test solutions were applied after vehicle control (120 s interval, 1 Hz stimulation) in an increasing concentration order (in 300 s intervals, 1 Hz stimulation) and experiment was terminated after wash control (300 s interval, 1 Hz stimulation). [0559] Positive control 30 nM ATX-II (toxin from anemonia sulcate) was applied after vehicle control (120 s interval, 1 Hz stimulation) and the data were recorded (300 s interval, 1 Hz stimulation). [0560] An aftercontraction (AC) was visually identified as spontaneous secondary change in the slope of the contractility transient that occurred before the next stimulus-induced contraction and that produced an abnormal and unsynchronized contraction. Contraction Failure (CF) was also visually identified when an electrical stimulus was unable to induce a contraction. Alternans and Short-Term Variability (STV) are visualized in Poincaré plots of Contraction Amplitude variability. STV (STV = Σ|CAn+1−CAn| (20×√2)−1) was calculated with the last 20 transients of each control and test article concentration period. Alternans were identified as repetitive alternating short and long contractility amplitude transients. STV values were normalized to the vehicle control value of each cell. AC, CF and Alternans were plotted and expressed as % of incidence of cells exhibiting each of the signals normalized by the total number of cardiomyocytes. It was shown that Neo-Ibogamine does not induce proarrhythmia signals up to 10 µM in ex vivo primary human cardiomyocyte assay (See Figure 3). 101
[0561] Mice Behavioral Studies [0562] Drug preparation and administration for animal studies [0563] All compounds were dissolved in USP grade 0.85% saline with 5% Tween-80. Sonication and gentle heating are applied until complete dissolution. The compounds are subsequently filtered through 0.45 µm filters into a new glass vial. All compounds were administered at a selected subcutaneous dose at a volume of 10 mL/kg of body weight, unless specified otherwise. [0564] General mouse use [0565] All experimental procedures involving animals were approved by the Columbia University Institutional Animal Care and Use Committee (IACUC) and adhered to principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The studies were conducted at AAALAC accredited facilities. Animals received regular veterinary care (weekly by institutional veterinarians) including daily health monitoring (by experimenters) of the animals (observing home cage behaviors, nesting, and body weight). All procedures were designed to minimize any stress/distress. Healthy adult male mice C57BL/6J (10 – 14 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed 5 mice per cage with food and water available ad libitum. Mice were maintained on a 12- h light/dark cycle (lights on 7:00-19:00) and all testing was done in the light cycle. Temperature was kept constant at 22 ± 2 °C, and relative humidity was maintained at 50 ± 5%. [0566] Catalepsy Bar Test protocol [0567] To assess for catalepsy, C57BL6J mice were randomly administered a drug/dose combination at t = 0 min via subcutaneous injection. Mice were tested individually at t = 30, 60, and 90 min. Catalepsy is defined by the absence of movement and maintenance of the same body posture for 30–60 seconds with a cutoff time set to 60 seconds. The automated Maze Engineers Catalepsy Bar test, featuring sensors to detect forelimb removal from the bar, facilitates automatic recording of forelimb movement duration from the bar to the ground. [0568] A moderate dose (10 mg/kg, SC) of Tetrabenazine (TBZ) induces catalepsy in the Bar Test. Pretreatment of animal subjects with iboga analogs 30 min before TBZ administration diminishes cataleptic response in this test (See Figure 6) [0569] Open field (OF) locomotion protocol [0570] Mice were allowed to habituate for 30 min. Immediately after receiving a subcutaneous injection of the compound solution, mice were then placed gently in a clear Plexiglass arena (27.31 × 27.31 × 20.32 cm, Med Associates ENV-510) lit with dim light (~5 lux) and allowed to ambulate freely for 60 102
min. The locomotion of the animals was tracked by infrared beams embedded along the X, Y, Z axes of the area and automatically recorded. Data was collected on Activity Monitor by Med Associates. [0571] As shown in Figures 4 and 5, neo-ibogamine and neo-ibogaine, to a lower extent, induce dose- dependent suppression of novelty-induced locomotion in mice as indicated by the Open Field Test (OFT), in a similar manner to ibogamine. These results indicate significant bioavailability and brain penetration in vivo. Neo-ibogamine also does not induce catalepsy in mice despite inhibiting the function of VMAT2. [0572] Neo-ibogamine and neo-ibogaine have the properties of inhibition of serotonin (SERT) and vesicular (VMAT2) monoamine transporters. They reduce cardiotoxicity in primary human cardiomyocyte assay and improve metabolic stability in comparison to closely related iboga alkaloids and have substantial effect on mice locomotion (demonstrates bioavailability and brain penetration). [0573] Benzofuran analogs of neo-ibogamine and neo-ibogaine are expected to have kappa opioid receptor activity [0574] Pharmacokinetics Drug Distribution (C57BL/6J Male mice, 10 mg/kg, SC) [0575] Study design male C57BL/6J mice 11-12 weeks old, body weight ranged from 21.7 g to 25.3 g were used in this study. The animals were randomly assigned to the treatment groups before the pharmacokinetic study; all animals were fasted for four hours before dosing. Subcutaneous (SC) route of administration; six sampling time points (5, 15, 30, 60, 180, and 360 minutes) were set for this pharmacokinetic study. Each of the time point treatment groups included three animals. There was also a control group of one animal. Mice were injected IP with 2,2,2-tribromoethanol at the dose of 150 mg/kg prior to drawing the blood. Blood collection was performed from the orbital sinus in microtainers containing K3EDTA. Animals were sacrificed by cervical dislocation after the blood samples collection. Blood samples were centrifuged for 10 minutes at 3000 rpm (+4ºC). Brain samples (left hemisphere) were collected and weighed. The samples were immediately processed, flash-frozen at dry ice, and stored at -70 °C until subsequent analysis. [0576] Sample Formulation. Solid samples (hydrochloride salts) were suspended in Saline (0.9%), using ~98% of calculated volume in an 8 mL glass vials closed with a screw cap. The mixture was vortexed (~10 seconds) and sonicated at 85 ºC (~five minutes). Process was repeated multiple times as needed, until the initially coarse suspension gradually turned into a fine dispersion, and eventually into a clear solution. Mildly acidic formulation pH (4.0 – 6.0) was neutralized with 1M NaOH to pH 7.0 and volume was adjusted to the final desired concentration using Saline. [0577] Study compounds were administered in 5 mL/kg dose volume (dose 10 mg/kg), using concentration of 2 mg/mL. Doses and formulations were calculated based on the free base form of 103
compound and corrected for drug purity. Working formulations were prepared five minutes prior to initiation of PK study. [0578] Bio-samples Processing. [0579] Plasma samples (40 μL) were mixed with 200 μL of IS(plasma) solution. After mixing by pipetting and centrifuging for four minutes at 6,000 rpm, 0.5-1.0 μL of each supernatant was injected into LC-MS/MS system. Internal standards IS(plasma) used (ibogamine: Sildenafil 400 ng/mL; neo-ibogamine: Raloxifene 100 ng/mL) in water-methanol mixture 1:9, v/v. [0580] Brain samples (weight 108 mg – 160 mg) were homogenized with five volumes of IS(brain) solution (1 w + 5 v, e.g. 100 mg + 500 μL) using glass beads (115 mg ± 5 mg) in The Bullet Blender® homogenizer for 30 seconds at speed 8. After this, the samples were centrifuged for four minutes at 14,000 rpm, and 1.0 or 2.0 μL of each supernatant was injected into LC-MS/MS system. Internal standards IS(brain) used (ibogamine: Sildenafil 400 ng/mL; neo-ibogamine: Raloxifene 100 ng/mL) in water- methanol mixture 1:4, v/v. [0581] Bio-samples Analysis. [0582] The analyte concentration in samples was determined using high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). Shimadzu HPLC system comprised 2 isocratic pumps LC-20AD, an autosampler SIL-20ACXR, a sub-controller FCV-14H and a degasser DGU- 20As. Mass spectrometric analysis was performed using an API 3000 (triple-quadrupole) instrument from AB Sciex (Canada) with an electro-spray (ESI) interface. The data acquisition and system control were performed using Analyst 1.6.3 software from AB Sciex. [0583] Chromatographic Conditions: [0584] Column A: InfinityLab Poroshell 120 EC-C18, 2.1 × 50 mm, 4 μm or Column B: Phenomenex Luna C18(2) 100A 2 x 30 mm, 5 μm [0585] Mobile phase А: Acetonitrile : Water : Formic acid = 50 : 950 : 1 [0586] Mobile phase B: Acetonitrile : Formic acid = 100 : 0.1 [0587] Linear gradient: Column A: 4 min 0% B, 1 min 100% B, 1.2 min 100% B, 1.21 min 4% B, 2.7 min stop; Column B: 0 min 0% B, 1.3 min 100% B, 1.55 min 100% B, 156 min 0% B, 3.0 min stop [0588] Elution rate: 400 μL/min. A divert valve directed the flow to the detector from Column A: 1.1 to 1.5 min Column B: 1.0 to 2.0 min [0589] Column temperature: 30 °C 104
[0590] MS/MS Detection: [0591] Scan type: Positive MRM, Ion source: Turbo spray, Ionization mode: ESI [0592] Nebulize gas: 15 L/min, Curtain gas: 8 L/min, Collision gas: 4 L/min [0593] Ionspray voltage: 5000 V, Temperature: 400 °C [0594] Table 1 Compound ID Parent, Daughter, Time, DP, FP, EP, CE, CXP, V m/z m/z ms V V V V 51 33 [0596] Calibration solutions: Stock solution (2 mg/kg) of test compound in DMSO was consecutively diluted with either IS(plasma) or IS(brain) to obtain a series of calibration solutions with final concentrations of 10,000, 4,000, 2,000, 1,000, 400, 200, 100, 40, 20, 10, 4, and 2 ng/mL. [0597] Plasma calibration: Blank mouse plasma samples (40 μL) were mixed with 200 μL of the corresponding calibration solution. After mixing by pipetting and centrifugation for four minutes at 6000 rpm, 2.0 μL of each supernatant was injected into LC-MS/MS system. [0598] Brain calibration: Blank brain samples (weight 100 mg ± 1 mg) were homogenized in 500 μL of corresponding calibration solution using glass beads (115 mg ± 5 mg) in The Bullet Blender® homogenizer for 30 seconds at speed 8. After this, the samples were centrifuged for four minutes at 14,000 rpm, and 1.0 or 2.0 μL of each supernatant was injected into LC-MS/MS system. [0599] Pharmacokinetic Method Analysis. The concentrations of the test compound below the lower limits of quantitation (LLOQ = 20 ng/mL for plasma, 50 ng/g for brain samples) were designated as zero. The pharmacokinetic data analysis was performed using noncompartmental, bolus injection or extravascular input analysis models in WinNonlin 5.2 (PharSight). Data below LLOQ were presented as missing to improve the validity of T½ calculations. [0600] For each treatment condition, the final concentration values obtained at each time point were analyzed for outliers using Grubbs' test with the level of significance set at p < 0.05. [0601] Plasma and Brain Tissue Protein Binding (Equilibrium Dialysis). 105
[0602] Determined plasma / brain concentrations and pharmacokinetic parameters were corrected for non-specific plasma and brain tissue protein binding using data determined according to published procedure (Di et al., 2011; Kochansky et al.2008). [0603] Pooled rat brains (Sprague Dawley, male, n = 3) and non-sterile rat (Sprague Dawley) plasma with Li-heparin were used. [0604] Synthesis [0605] General Considerations [0606] Reagents and solvents were obtained from commercial sources and were used without further purification unless otherwise stated. Reactions were monitored by TLC using solvent mixtures appropriate to each reaction. Column chromatography was performed on silica gel (40 – 63 µm). For preparative TLC, glass plates coated with a 1 mm silica layer were used. Nuclear magnetic resonance spectra were recorded on Bruker 400 or 500 MHz instruments, as indicated. Chemical shifts are reported as δ values in ppm referenced to CDCl3 (1H NMR = 7.26 and 13C NMR = 77.16) or methanol-d4 (1H NMR = 3.31 and 13C NMR = 49.00). Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (pentet); dd (doublet of doublets); td (triplet of doublets); dt (doublet of triplets); dq (doublet of quartets); ddd (doublet of doublet of doublets); ddt (doublet of doublet of triplets); m (multiplet); br (broad). Low- resolution mass spectra were recorded on an Advion quadrupole instrument (ionization mode: APCI+ or ESI+). [0607] General Procedure A [0608] Methylene diurethane (1 equiv.) was suspended in dry toluene and boron trifluoride diethyl etherate BF3·OEt2 (0.25 equiv.) was added at room temperature (RT). Mixture was further heated to 85 °C for one hour, a clear solution formed when reaction temp. was reached. Cyclohepta-1,3-diene (1 equiv.) was added dropwise and the reaction mixture (RM) was further heated and stirred for 2 h. After cooling to RT mixture was washed with aq. sat. NaHCO3, water and partially concentrated. Product in toluene was directly loaded onto silica gel column and eluted using 100% DCM (14% yield). The bicyclic product was dissolved in DCM, cooled in water/ice bath (0-5 °C) and trimethylsilyl iodide (2.0 equiv, calculated on basis of asuming semi-crude intermediate = pure product) was added dropwise. RM was allowed to warm to RT and was stirred (overnight). RM was slowly quenched with excess MeOH and concentrated under reduced pressure. Oily material containing the corresponding hydroiodide salt was used in the next reaction with no further purification. [0609] General Procedure B 106
[0610] Corresponding indole (1.2 equiv., based on crude 6-azabicyclo[3.2.2]non-8-ene hydroiodide) was dissolved in diethyl ether (0.25M based on indole) cooled in water/ice bath (0-5 °C) and oxyallyl chloride (1.15 equiv., based on indole) was added dropwise. After 1h precipitated corresponding indol-3- yl-2-oxoacetyl chloride was collected by filtration, washed with diethyl ether (in instance where no/limited precipitation occurred RM was concentrated under reduced pressure) and dried under reduced pressure before use. Thus prepared slight excess of corresponding indol-3yl-2-oxoacetyl chloride was combined with crude azabicyclo[3.2.2]nonene hydroiodide (prepared according to general procedure A). Solids were further suspended in DCM (0.5 M, based on indole used), cooled in water/ice bath (0-5 °C) and an appropriate base (triethylamine or N,N-diisopropylethylamine, 2.5 equiv. based on indole used) was added dropwise. Cooling bath was removed and RM was further stirred at RT untill azabicyclo[3.2.2]nonene was consumed. RM was diluted with DCM, washed with aq. HCl (1M), and sat. aq. NaHCO3 solution. Combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by silicagel column chromatography (gradient of 50 to 70% AcOEt in Hexanes), giving the corresponding glyoxyamide intermediates. Specific example: Glyoxyamide intermediate to compound 1 was isolated as an orange color amorphous solid (57% yield). [0611] Corresponding glyoxamide (1 equiv.,) was suspended in THF (0.25 M), suspension was cooled in water/ice bath (0-5 °C) and solid LiAlH4 (3 equiv.) was added in portions (small initially, after exothermic reaction subsided the remainder was added). RM was next warmed to RT and further stirred at 70 °C for 3h. After cooling to RT, mixture was diluted with THF (2× initial volume used). RM was cooled in water/ice bath (0-5 °C) and carefully quenched with H2O, 15% aq. NaOH and H2O (1:1:3 mL per g of LiAlH4 used). Mixture was stirred untill solids were loose, (solid anhydrous MgSO4 was added after 30-60 min to absorb excess moisture). Solids were filtered and washed with THF, AcOEt and eventually 9:1 DCM:iPrOH, untill all product was eluted. Crude material was purified as specified for each example. (See Figure 9) [0612] General Procedure C [0613] Appropriate starting material (SM) was combined with Pd(CH3CN)4(BF4)2 (1.05 equiv.) in a reaction vessel, CH3CN (0.1 M based on SM) was added under argon and the resulting dark red solution was stirred at room temperature (RT). After 2h mixture was heated to 80 °C overnight (typically 16 to 19h). After cooling to RT, mixture was cooled in water/ice bath (0-5 °C), MeOH (0.25 M based on SM) and solid NaBH4 granules (3 equiv.) were added in one portion. Mixture was further stirred 20 min at the same temperature, then diluted with AcOEt and filtered through plug of celite, washing with AcOEt and AcOEt + 2% Et3N untill all product eluted. Crude material was purified as specified for each example. (See Figure 10). 107
[0614] [0615] s prepared according to a modification of general procedure B, using 6- azabicyclo[3.2.2]non-8-ene free base instead of hydroiodide salt. Crude material was purified by silicagel column chromatography (gradient of 50 % AcOEt in Hexanes + 2%Et3N to AcOEt + 2%Et3N). Product was obtained as a beige solid (549 mg, 46% over 2 steps calculated on the basis of free amine used). [0616] 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.69 – 7.59 (m, 1H), 7.35 (dt, J = 8.1, 1.0 Hz, 1H), 7.18 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.11 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.22 – 6.12 (m, 2H), 3.44 (p, J = 4.0 Hz, 1H), 3.09 (d, J = 10.3 Hz, 1H), 3.05 – 2.85 (m, 4H), 2.77 (ddt, J = 10.3, 4.7, 1.2 Hz, 1H), 2.54 – 2.44 (m, 1H), 1.79 – 1.60 (m, 3H), 1.60 – 1.38 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 136.35, 131.29, 131.18, 127.80, 122.02, 121.54, 119.29, 119.11, 115.11, 111.17, 59.18, 56.95, 56.62, 32.89, 29.88, 29.17, 24.68, 21.39. LRMS (APCI+) calcd. for C18H23N2+ [M+H]+ 267.2, found 267.6. ared according to general procedure B. Crude material was purified by silicagel column chromatography (gradient of 50 % AcOEt in Hexanes + 2%Et3N to AcOEt + 2% Et3N). Product was obtained as a beige solid (873 mg, 45% over 3 steps calculated on the basis of 5-methoxyindole used). [0619] 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.24 (dd, J = 8.7, 0.6 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.20 – 6.12 (m, 2H), 3.87 (s, 3H), 3.44 (s, 1H), 3.08 (d, J = 10.3 Hz, 1H), 3.00 – 2.83 (m, 4H), 2.77 (dd, J = 10.4, 4.7 Hz, 1H), 2.52 – 2.45 (m, 1H), 1.76 – 1.59 (m, 3H), 1.60 – 1.38 (m, 3H).13C NMR (126 MHz, CDCl3) δ 154.03, 131.52, 131.26, 128.20, 122.41, 114.84, 112.13, 111.85, 101.13, 59.04, 56.91, 56.65, 56.16, 32.88, 29.90, 29.09, 24.72, 21.37. LRMS (APCI+) calcd. for C19H25N2O+ [M+H]+ 297.2, found 297.3. [0620] 108
[0621] Compound was prepared according to general procedure C. Crude material was purified by silicagel column chromatography (eluted AcOEt + 2% Et3N) and preparative TLC (50 % AcOEt in Hexanes + 2%Et3N). Product contaminated with small quantity of reduced uncyclized side-product was dissolved in hot CH3CN, cooled to RT and in freezer (-20 °C). Solvent was siphoned off and precipitated solid was dried, transformed to hydrochloride in MeOH using aq. HCl (12.1 M). Product (neo-ibogamine) was obtained as a beige solid (18 mg, 35%). [0622] For larger scale the following procedure was used: [0623] To a solution of substrate (1) (1.84 g, 6.89 mmol, 1 eq.) in anhydrous DCM (70 mL, 0.1 M), a solution of trimethyl-phenylammonium tribromide (2.85 g, 7.58 mmol, 1.1 eq.) in anhydrous DCM (38 mL, 0.2 M) was added dropwise at 0 °C over 20 minutes. The resulting dark-red solution was stirred at room temperature until TLC showed no starting material (∼10-20 minutes). The solution was then quenched with H2O (15.0 mL) and basified with aqueous saturated NH4OH (3 mL). The aqueous layer was removed. The remaining organic layer was then washed with H2O (60.0 mL) and concentrated in vacuo to provide the crude bromide as a foamy brown solid. To the crude bromide, tetrakis(triphenylphosphine)palladium(0) (796 mg, 0.69 mmol, 10 mol%) and sodium formate (1.87 g, 27.57 mmol, 4 eq., powdered and dried with gentle heating under vacuum before use) was added along with anhydrous DMSO (27 mL, 0.25 M). The resulting mixture was heated to 130 °C for 1 h (gas evolution occurs). The reaction was then diluted with H2O (60 mL) and extracted with DCM (3 × 100 mL). The crude product was purified by flash column chromatography (using 20% of EtOAc in hexanes + 2% Et3N). The product was isolated as a light-yellow solid (404mg, 22% over 2 steps).453 mg of starting material (1) was recovered (24%). [0624] 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.50 – 7.44 (m, 1H), 7.28 – 7.23 (m, 1H), 7.15 – 7.07 (m, 2H), 3.47 – 3.17 (m, 6H), 3.11 – 3.05 (m, 1H), 2.76 – 2.70 (m, 1H), 2.24 – 2.12 (m, 2H), 1.97 – 1.79 (m, 4H), 1.79 – 1.70 (m, 2H), 1.67 – 1.57 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 143.99, 134.48, 129.95, 121.02, 119.30, 117.95, 110.33, 108.51, 60.45, 56.36, 50.50, 38.31, 37.02, 34.63, 32.22, 29.09, 21.20, 20.79. LRMS (APCI+) calcd. for C18H23N2 + [M+H]+ 267.2, found 267.1. p p pared according to general procedure C. Crude material was purified by silicagel column chromatography (gradient of DCM:MeOH:NH4OH 95:5:0.5 to 90:10:1) and repeated preparative TLC: AcOEt + 2% Et3N (first PTLC) and DCM:MeOH:NH4OH 95:5:0.5 (second PTLC). Product was obtained as a beige solid (22 mg, 15%). 109
[0627] 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.7, 2.4 Hz, 1H), 3.86 (s, 3H), 3.44 (td, J = 3.6, 1.7 Hz, 1H), 3.42 – 3.26 (m, 3H), 3.22 (dd, J = 3.2, 1.5 Hz, 2H), 3.06 (ddd, J = 11.5, 4.2, 1.2 Hz, 1H), 2.71 – 2.63 (m, 1H), 2.19 (ddt, J = 14.4, 11.5, 1.5 Hz, 1H), 2.16 – 2.11 (m, 1H), 1.95 – 1.84 (m, 3H), 1.84 – 1.69 (m, 3H), 1.67 – 1.55 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 154.15, 144.86, 130.26, 129.57, 111.08, 110.82, 108.26, 100.44, 60.55, 56.45, 56.16, 50.56, 38.01, 36.67, 34.50, 32.07, 28.94, 21.11, 20.71. LRMS (APCI+) calcd. for C19H25N2O+ [M+H]+ 297.2, found 297.4. [0628] [0629] nzofuran-3-yl)ethan-1-ol (2.18g, 11.3 mmol) and 4-dimethylaminopyridine (0.14 g, 1.13 mmol) were dissolved in DCM (11.3 mL), N,N-diisopropylethylamine (3.95 mL, 22.7 mmol) was added and reaction mixture was cooled in ice/water bath (0-5 °C). Methanesulfonyl chloride (1.32 mL, 17.0 mmol) was added dropwise, mixture was allowed to warm to RT and was stirred for 3h. Reaction mixture was washed with aq. HCl (0.5M, 40 mL), phases separated, and aq. phase was further extracted with DCM (2 × 30 mL). Combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by a short silicagel column chromatography using 50% DCM in hexanes to 100% DCM. Product was initally obtained as a viscous yellow oil that slowly solidified to off-white amorphous solid (2.73 g, yield 89%). [0630] 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 1.1 Hz, 1H), 7.37 (dd, J = 8.9, 0.5 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H), 4.48 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.12 (td, J = 6.8, 1.0 Hz, 2H), 2.92 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 156.16, 150.37, 143.37, 128.15, 115.39, 113.50, 112.30, 101.91, 68.71, 56.12, 37.63, 24.22. LRMS (APCI+) calcd. for C12H15O5S+ [M+H]+ 271.1, found 270.9. p . g, 2.59 mmol) was combined with crude 6-azabicyclo[3.2.2]non-8-ene hydroiodide, (0.65 g, 2.59 mmol, prepared according to general procedure A and calculated as if pure) and NaHCO3 (0.87 g, 10.4 mmol) in reaction vessel. CH3CN (10.4 mL) was added, and mixture was heated to 80 °C for 15h. After cooling to RT mixture was poured to H2O, (pH made basic with few drops of 15% aq. 110
NaOH) and further extracted with DCM (3 ×). Combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by repeated silicagel column chromatography using 20% AcOEt in hexanes to gradient of 20-40% AcOEt in hexanes + 2% Et3N (first column) and gradient of DCM:MeOH:NH4OH 97:3:0.3 to 95:5:0.5 (second column). Product was obtained as a viscous dark brown oil (2.73 g, yield 26%). (See Figure 11). [0633] 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 1.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.24 – 6.09 (m, 2H), 3.86 (s, 3H), 3.44 (s, 1H), 3.13 (s, 1H), 3.03 – 2.77 (m, 4H), 2.71 (dd, J = 10.4, 4.7 Hz, 1H), 2.50 (s, 1H), 1.82 – 1.38 (m, 6H).13C NMR (126 MHz, CDCl3) δ 155.73, 150.17, 142.35, 131.53, 112.67, 111.80, 102.35, 57.76, 57.05, 56.34, 56.06, 32.57, 29.52, 28.95, 22.84, 21.14. LRMS (APCI+) calcd. for C19H24NO2+ [M+H]+ 298.2, found 298.5. erial (201 mg, 0.676 mmol) in THF (1.4 mL) was cooled to -40 °C in acetone/dry ice bath. nBuLi (0.54 mL, 1.35 mmol, 2.5M solution in hexane) was added dropwise and resulting orange solution was further stirred at -40 °C. After 1h solution of iodine (292 mg, 1.15 mmol) in THF (1.4 mL) was added dropwise, after addition concluded mixture was allowed to slowly warm to RT and was further stirred. After 1h reaction was quenched with sat. solution of Na2S2O3 and vigorously stirred untill excess iodine was consumend. Mixture was further diluted with water and repeatedly (3×) extracted with diethyl ether. Combined extracts were dried over Na2SO4, filtered and concentrated. Crude iodo- intermediate containing ~ 5-10% of unreacted starting material was used for next step without further purification. [0636] Powdered and pre-dried sodium formate (159 mg, 2.33 mmol) and dichlorobis(tri-o- tolylphosphine)palladium(II) (9.2 mg, 0.012 mmol) were added into a vial containing crude iodo- intermediate. Anhydrous DMSO (2.3 mL) was added under argon and mixture was heated to 100 °C and vigorously stirred (after content reached reaction temperature vial was briefly shaken to fully dislodge all material adhering to walls). After 15 min when mixture turned dark brown-black, it was cooled to room temperature, diluted with water (20 mL) and repeatedly (3×) extracted with diethyl ether. Combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by silicagel column chromatography using gradient of 10 to 20% AcOEt in hexanes containing 2% Et3N. Product was obtained as a pale orange amorphous solid (107 mg, yield 53% over two steps). (See Figure 12), 111
[0637] 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 3.84 (s, 3H), 3.47 (s, 2H), 3.42 – 3.35 (m, 1H), 3.32 (d, J = 11.2 Hz, 1H), 3.28 – 3.15 (m, 2H), 3.11 (dd, J = 11.0, 4.0 Hz, 1H), 2.73 – 2.57 (m, 1H), 2.25 (t, J = 12.9 Hz, 1H), 2.19 (s, 1H), 2.11 – 1.85 (m, 4H), 1.81 – 1.69 (m, 2H), 1.69 – 1.58 (m, 1H).13C NMR (126 MHz, CDCl3) δ 162.59, 155.85, 148.36, 131.41, 111.47, 111.02, 110.86, 101.85, 59.64, 56.16, 55.14, 49.84, 38.36, 36.69, 34.15, 30.93, 29.14, 20.90, 19.55. LRMS (APCI+) calcd. for C19H24NO2 + [M+H]+ 298.2, found 298.5. [0638] [0639] Solution of neo-oxa-ibogaine (107 mg, 0.36 mmol) in DCM (1.4 mL) was cooled in water/ice bath (0-5 °C). Aluminum chloride (144 mg, 1.08 mmol) and ethane thiol (234 µL, 3.24 mmol) were added, mixture was allowed to warm to room temperature and vigorously stirred. After 1h reaction mixture was poured to a solution of Rochelle salt (2 equiv. per AlCl3) in sat. aq. sodium bicarbonate solution. Mixture was repeatedly extracted with DCM (5×), combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by silicagel column chromatography using a gradient of DCM:MeOH:NH4OH 95:5:0.5 to 90:10:1. Slightly impure product was dissolved in MeOH/DCM acidified with aq. HCl (12.1M), concentrated and dried. Residue was repeatedly suspended in MeCN (2 x 2 mL), solid sedimented by centrifugation and solvent decanted. Solid was further suspended in MeOH (2 mL), briefly heated to reflux, cooled to room temperature and in freezer (-20 °C). Solvent was siphoned off and remaining solid was dried. Product was obtained as a brown amorphous solid (66 mg, yield 58%). [0640] Hydrochloride: 1H NMR (500 MHz, MeOD) δ 7.20 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.7, 2.5 Hz, 1H), 4.02 (dt, J = 6.0, 1.8 Hz, 1H), 3.78 – 3.67 (m, 2H), 3.65 – 3.59 (m, 1H), 3.50 (t, J = 2.4 Hz, 2H), 3.25 (ddd, J = 17.6, 10.6, 6.8 Hz, 1H), 3.10 (dt, J = 18.0, 3.9 Hz, 1H), 2.51 – 2.39 (m, 2H), 2.32 – 2.24 (m, 1H), 2.20 – 2.05 (m, 2H), 1.94 – 1.74 (m, 4H). 13C NMR (126 MHz, MeOD) δ 160.32, 154.60, 149.33, 131.34, 113.96, 112.03, 110.63, 104.64, 63.41, 57.11, 51.93, 33.80, 33.70, 32.65, 28.93, 28.46, 20.39, 18.06. LRMS (APCI+) calcd. for C18H22NO2+ [M+H]+ 284.2, found 284.5. [0641] [0642] To a solution of neo-ibogaine (67 mg, 0.23 mmol) in 1,2-DCE (0.9 mL) were added boron tribromide (1M in DCM, 0.45 mL, 0.45 mmol, 2 equiv.) and ethane thiol (98 µL, 1.36 mmol, 6 equiv.), 112
mixture was vigorously stirred at 50 °C. After 1.5h reaction mixture was cooled to RT and quenched with MeOH (until a clear solution is formed). Mixture was diluted with sat. aq. NaHCO3 and repeatedly extracted with AcOEt (3×), combined extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by preparative TLC using DCM:MeOH:NH4OH 95:5:0.5. Product was transformed to a hydrochloride salt in MeOH acidified with methanolic HCl, concentrated and dried. Product 9 was obtained as a brown amorphous solid (36 mg, yield 50%). [0643] Hydrochloride: 1H NMR (500 MHz, MeOD) δ 7.10 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 8.6, 2.3 Hz, 1H), 3.97 (dt, J = 6.4, 1.7 Hz, 1H), 3.71 – 3.54 (m, 3H), 3.54 – 3.43 (m, 2H), 3.34 – 3.25 (m, 1H), 3.14 (dt, J = 17.7, 3.8 Hz, 1H), 2.51 – 2.37 (m, 2H), 2.34 – 2.22 (m, 1H), 2.08 (ddt, J = 13.4, 11.5, 3.9 Hz, 2H), 1.94 – 1.73 (m, 4H). 13C NMR (126 MHz, MeOD) δ 151.73, 143.02, 131.13, 130.61, 112.34, 112.31, 105.75, 102.95, 64.05, 58.52, 52.37, 33.80, 33.54, 33.30, 30.29, 28.59, 20.71, 19.22.LRMS (APCI+) calcd. for C18H23N2O+ [M+H]+ 283.2, found 283.1. [0644] [0645] pared according to general procedure B. Crude material was purified by repeated silicagel column chromatography, collumn 1 (gradient of 50 % AcOEt in Hexanes + 2%Et3N to AcOEt + 2% Et3N) and collumn 2 (DCM:MeOH 95:5 to DCM:MeOH:NH4OH 95:5:0.5 to 90:10:1). Product was obtained as a beige solid (349 mg, 34% over 3 steps calculated on the basis of 6-methoxyindole used). [0646] 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.79 (dd, J = 8.6, 2.3 Hz, 1H), 6.23 – 6.09 (m, 2H), 3.84 (s, 3H), 3.48 (d, J = 12.3 Hz, 1H), 3.11 (s, 1H), 3.05 – 2.83 (m, 4H), 2.83 – 2.68 (m, 1H), 2.55 – 2.43 (m, 1H), 1.84 – 1.60 (m, 3H), 1.60 – 1.38 (m, 3H).13C NMR (126 MHz, CDCl3) δ 156.63, 137.08, 131.46, 130.88, 122.20, 120.34, 119.65, 114.81, 109.31, 94.82, 59.16, 57.06, 56.53, 55.86, 32.77, 29.76, 28.93, 24.55, 21.28. LRMS (APCI+) calcd. for C19H25N2O+ [M+H]+ 297.2, found 297.1. [0647] 113
[0648] Compound was prepared according to general procedure C. Crude material was purified by silicagel column chromatography (gradient of 50 % AcOEt in Hexanes + 2%Et3N to 70% AcOEt + 2% Et3N). Analytical sample of product was obtained obtained with further purification via preparative TLC (70% AcOEt in hexane + 2% Et3N) and subsequent convertion to the HCl salt upon treatment with anhydrous HCl saturated diethylether. [0649] 1H NMR (500 MHz, MeOD) δ 7.31 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 8.7, 2.2 Hz, 1H), 3.99 (d, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.66 (tt, J = 11.0, 6.0 Hz, 2H), 3.58 (dd, J = 13.1, 4.3 Hz, 1H), 3.53 – 3.46 (m, 2H), 3.38 – 3.33 (m, 1H), 3.21 (dt, J = 17.5, 3.6 Hz, 1H), 2.51 – 2.43 (m, 1H), 2.41 (d, J = 5.4 Hz, 1H), 2.33 – 2.24 (m, 1H), 2.09 (qd, J = 12.6, 4.8 Hz, 2H), 1.83 (dddd, J = 29.9, 14.8, 9.9, 3.7 Hz, 4H).13C NMR (126 MHz, MeOD) δ 156.34, 139.54, 135.67, 122.86, 117.71, 108.75, 104.82, 93.92, 62.83, 57.02, 54.62, 50.97, 32.49, 32.03, 31.88, 28.98, 27.21, 19.28, 17.90. LRMS (APCI+) calcd. for C19H25N2O+ [M+H]+ 297.2, found 297.1. epared according to general procedure B. Crude material was purified by repeated silicagel column chromatography, collumn 1 (gradient of 50 % AcOEt in Hexanes + 2%Et3N to AcOEt + 2% Et3N) and collumn 2 (DCM:MeOH 95:5 to DCM:MeOH:NH4OH 95:5:0.5 to 90:10:1). Product was obtained as a beige solid (166 mg, 37% over 3 steps calculated on the basis of 5-fluoroindole used). [0652] 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.26 – 7.22 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.92 (td, J = 9.1, 2.5 Hz, 1H), 6.20 – 6.11 (m, 2H), 3.49 – 3.42 (m, 1H), 3.11 (d, J = 9.8 Hz, 1H), 3.00 – 2.83 (m, 4H), 2.76 (ddd, J = 10.2, 4.8, 1.0 Hz, 1H), 2.53 – 2.47 (m, 1H), 1.79 – 1.68 (m, 2H), 1.68 – 1.60 (m, 1H), 1.60 – 1.38 (m, 3H).13C NMR (126 MHz, CDCl3) δ 158.73, 156.87, 132.83, 131.46, 130.82, 128.16, 128.08, 123.54, 114.96, 111.81, 111.73, 110.43, 110.22, 104.01, 103.83, 58.98, 57.07, 56.54, 32.77, 29.76, 28.96, 24.45, 21.29.19F NMR (470 MHz, CDCl3) δ -125.05. LRMS (APCI+) calcd. for C18H22FN2+ [M+H]+ 285.2, found 285.1. 114
[0653] [0654] Compound was prepared according to general procedure C. Crude material was purified by silicagel column chromatography (gradient of 50 to 100% of AcOET in Hexanes + 2% Et3N) and preparative TLC: DCM:MeOH:NH4OH 95:5:0.5. After vacuum drying product was transformed into a hydrochloride salt in DCM/MeOH with methanolic HCl and evaporated to dryness. Residue was further suspended in MeCN with sonication, solid was sedimented by centrifugation and liquid decanted. After evaporation from MeOH and drying product 13 was obtained as a beige solid (33 mg, 21%). [0655] Hydrochloride: 1H NMR (500 MHz, MeOD) δ 7.23 (dd, J = 8.7, 4.4 Hz, 1H), 7.13 (dd, J = 9.9, 2.4 Hz, 1H), 6.85 (td, J = 9.1, 2.5 Hz, 1H), 4.00 (dt, J = 6.5, 1.6 Hz, 1H), 3.71 – 3.57 (m, 3H), 3.57 – 3.48 (m, 2H), 3.39 – 3.32 (m, 1H), 3.20 (dt, J = 17.8, 3.9 Hz, 1H), 2.49 (ddt, J = 14.5, 12.0, 2.4 Hz, 1H), 2.45 – 2.40 (m, 1H), 2.33 – 2.25 (m, 1H), 2.15 – 2.03 (m, 2H), 1.93 – 1.76 (m, 4H).13C NMR (126 MHz, MeOD) δ 160.19, 158.34, 144.32, 132.85, 130.26, 130.18, 112.70, 112.63, 110.57, 110.36, 106.83, 103.46, 103.27, 63.89, 58.43, 52.50, 33.84, 33.61, 33.32, 30.17, 28.61, 20.72, 19.16.19F NMR (470 MHz, MeOD) δ -127.03 (td, J = 9.7, 4.6 Hz).LRMS (APCI+) calcd. for C18H22FN2 + [M+H]+ 285.2, found 285.1. 115
REFERENCES 1. Abi-Gerges N, Indersmitten T, Truong K et al. Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes. Sci Rep.2020; 10, 7692. DOI: 10.1038/s41598-020- 64657-2 2. Alper KR. Ibogaine: a review. Alkaloids Chem Biol. 2001; 56:1-38. DOI: 10.1016/s0099- 9598(01)56005-8. PMID: 11705103. 3. Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y. hERG Blockade by Iboga Alkaloids. Cardiovasc Toxicol. 2016; 16, 1, 14-22. DOI:10.1007/s12012-015-9311-5. PMID: 25636206. 4. Belgers M, Leenaars M, Homberg JR, Ritskes-Hoitinga M, Schellekens AF, Hooijmans CR. Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Transl Psychiatry.2016; 6, 5, e826. DOI: 10.1038/tp.2016.71. PMID: 27244235; PMCID: PMC5545647. 5. Bhargava HN, Cao Y-J. Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice. 1997; 771, 2, 343-346. DOI:10.1016/S0006-8993(97)00914-1 6. Black CA, Bucher ML, Bradner JM, Jonas L, Igarza K, Miller GW. Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters. Chem Res Toxicol. 2021; 34, 5, 1256-1264. DOI: 10.1021/acs.chemrestox.0c00380 7. Cherian KN, Keynan JN, Anker L et al. Magnesium–ibogaine therapy in veterans with traumatic brain injuries. Nat Med. 2024; 30, 373–381. DOI: 10.1038/s41591-023-02705-w 8. Di L, Umland, JP, Chang, G.; Huang, Y.; Lin, Z.; Scott, D. O.; Troutman, M. D.; Liston, T. E. Species Independence in Brain Tissue Binding Using Brain Homogenates. Drug Metab. Dispos. Biol. Fate Chem.2011; 39, 7, 1270–1277. DOI: 10.1124/dmd.111.038778. 9. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA. Functional recovery in parkinsonian monkeys treated with GDNF. Nature.1996; 380, 6571, 252-255. DOI: 10.1038/380252a0 10. Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener. Alkaloids Chem Biol. 2001; 56, 39-53. DOI: 10.1016/s0099-9598(01)56006-x. PMID: 11705115. 11. Glue P, Cape G, Tunnicliff D, Lockhart M, Lam F, Hung N, Hung CT, Harland S, Devane J, Crockett RS, Howes J, Darpo B, Zhou M, Weis H, Friedhoff L. Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients. Clin Pharmacol Drug Dev.2016; 5, 6, 460-468. DOI: 10.1002/cpdd.254 12. González J, Prieto JP, Rodríguez P, Cavelli M, Benedetto L, Mondino A, Pazos M, Seoane G, Carrera I, Scorza C, Torterolo P. Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting 116
REM Sleep Suppression, and a Distinctive Motor Profile. Front Pharmacol. 2018; 9, 374. DOI: 10.3389/fphar.2018.00374. 13. Marton S, González B, Rodríguez-Bottero S, Miquel E, Martínez-Palma L, Pazos M et al. Ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits. Front. Pharmacol. 2019; 10, 193–213. DOI: 10.3389/fphar.2019.00193 14. Hu, G.; Henke, A.; Karpowicz, R. J.; Sonders, M. S.; Farrimond, F.; Edwards, R.; Sulzer, D.; Sames, D. New Fluorescent Substrate Enables Quantitative and High-Throughput Examination of Vesicular Monoamine Transporter 2 (VMAT2). ACS Chem. Biol. 2013, 8 (9), 1947–1954. DOI: 10.1021/cb400259n. 15. Kochansky, C. J.; McMasters, D. R.; Lu, P.; Koeplinger, K. A.; Kerr, H. H.; Shou, M.; Korzekwa, K. R. Impact of pH on Plasma Protein Binding in Equilibrium Dialysis. Mol. Pharm. 2008; 5, 3, 438– 448. DOI: 10.1021/mp800004s. 16. Koenig, X.; Hilber, K. The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation. Molecules 2015, 20, 2208-2228. DOI: 10.3390/molecules20022208 17. Kroupa PK, Wells H. Ibogaine in the 21st Century: Boosters, Tune-ups and. Maintenance. MAPS 2005; 15, 21–24. 18. Mash DC, Ameer B, Prou D, Howes JF, Maillet EL. Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. J Psychopharmacol.2016; 30, 7, 688-97. DOI: 10.1177/0269881116641331. PMID: 27044509. 19. Mash DC, Duque L, Page B, Allen-Ferdinand K. Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes. Front. Pharmacol.2018; 9, 529. DOI: 10.3389/fphar.2018.00529 20. Nguyen N, Nguyen W, Nguyenton B, Ratchada P, Page G, Miller PE, Ghetti A, Abi-Gerges N. Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk. Front Physiol.2017; 19, 8, 1073. DOI: 10.3389/fphys.2017.01073. PMID: 29311989; PMCID: PMC5742250. 21. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003; 58, 1, 32-45. DOI: 10.1016/s0008-6363(02)00846-5. PMID: 12667944. 22. Rubi L, Eckert D, Boehm S, Hilber K, Koenig X. Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cardiovasc Toxicol. 117
2017 Apr;17(2):215-218. DOI: 10.1007/s12012-016-9366-y. PMID: 27020671; PMCID: PMC5334404. 23. Schenberg EE, Comis MAdC, Chaves BR, Silveira DX. Treating drug dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol. 2014; 28, 11, 993-1000. Doi: 10.1177/0269881114552713 24. Schneider JA, Sigg EB. Neuropharmacological Studies on Ibogaine, an Indole Alkaloid with Central- Stimulant Properties. Ann NY Acad Sci.1957; 66, 765. DOI: 10.1111/j.1749-6632.1957.tb40765.x 25. Thoricatha W. Special Forces: How Ibogaine is Helping Former Special Operations Soldiers with Traumatic Brain Injury and PTSD. Psychedelic Times.2020; 118

Claims

CLAIMS 1. A compound having the structure: , wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present and Z1 is -H, -CF3, -CF2H, - (alkyl), -(alkenyl), -(alkynyl), or -(aryl); and when X1 is C, and X2 is O or S, then Z1 is absent; or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - 119 CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O- alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- (heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. 2. The compound of claim 1 having the structure: Y1 Y2 R5 4 . 3. The compound ,
wherein A is an aryl or heteroaryl; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13; wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2. 4. The compound of claim 3, wherein R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, - NO2, -CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), - OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), - (alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). 5. The compound of any one of claims 1-4 having the structure: , wherein 121 (a) α is present and β is absent; (b) X1 is C or N; and/or X2 is N or O; preferably, X1 is C and X2 is N or O; (c) R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and/or (d) when X2 is N, then Z1 is -H, CF3, -CF2H, alkyl, alkenyl, or aryl, preferably, Z1 is -H, -(alkyl), -(alkenyl), or -(aryl); more preferably, Z1 is -H or -(alkyl); more preferably, Z1 is H. 6. The compound of any one of claims 1-5 having the structure: , ; H, - -O-
(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, Br, -CN, - CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). 7. The compound of any one of claims 1-6 having the structure: , wherein (a) R7, R8, R9 and R10 are each -H; (b) at least one of R7, R8, R9 and R10 is not -H; (c) at least two of R7, R8, R9 and R10 are not -H; (d) R7, R9 and R10 are each -H; and R8 is H, -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl; preferably, R7, R9 and R10 are each -H; and R8 is H, -F, -OH, -CF3, or -Cl; more preferably, R7, R9 and R10 are each -H; and R8 is H, -OH, or -F; or (e) R7 and R10 are each -H; and R8 and R9 are each -O-Me. 8. The compound of any one of claims 1-6 having the structure: , wherein 123 (a) R7, R8, R9 and R10 are each -H; (b) at least one of R7, R8, R9 and R10 is not -H; (c) at least two of R7, R8, R9 and R10 are not -H; (d) R7, R9 and R10 are each -H; and R8 is H, -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl; preferably, R7, R9 and R10 are each -H; and R8 is H, -F, -OH, -CF3, or -Cl; more preferably, R7, R9 and R10 are each -H; and R8 is H, -OH, or -F; (e) R7 and R10 are each -H; and R8 and R9 are each -O-Me; or (f) R7, R8, R9, and R10 are each -H; and R9 is -OH. 9. The compound of any one of claims 1-8, wherein Y1, Y2, Y3, Y4 and Y5 are each independently - H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl). 10. The compound of any one of claims 1-6 having the structure: , wherein Y3, Y4 and Y5 are eac , or -(alkyl)-O-(alkyl); preferably, Y3, Y4 and Y5 are each independently -H, or -(alkyl); more preferably, Y3, Y4 and Y5 are each -H. 11. The compound of any one of claims 1-10 having the structure: , or
. 12. The compound of any one of claims 1-11, wherein (a) R1, R2, R3, R4, R5 and R6 are each H; (b) at least one of R1, R2, R3, R4, R5 and R6 is not -H; (c) at least two of R1, R2, R3, R4, R5 and R6 are not -H; (d) R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, -OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2; (e) R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H; (f) one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H; (g) at least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H; (h) when one of R1 and R2 is -CH3, then R3 and R4 are each independently -H, -CH3, -C2-10 alkyl, -alkenyl, -alkynyl, -alkylaryl, -aryl, -heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2, and R5 and R6 are each independently -H, -CH3, -C2-10 alkyl, -alkenyl, -alkynyl, -alkylaryl, - aryl, -heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2; (i) when one of R5 and R6 is -CH2CH3, then at least one of R1, R2, R3, and R4 is not -H; 125 (j) R1, R2, R5 and R6 are each -H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, - alkylaryl, -aryl, or -heteroaryl; preferably, one of R3 and R4 is -alkyl, or -O-(alkyl); more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H; (k) R1, R2, R3 and R4 are each -H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or -heteroaryl; preferably, one of R5 and R6 is -alkyl, or -O-(alkyl); more preferably, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; and the other R5 or R6 is -H; or (l) R3, R4, R5 and R6 are each -H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or -heteroaryl; preferably, one of R3 and R4 is -alkyl, or -O-(alkyl); more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H. 13. The compound of claim 1 having the structure: , , , , ,
, peea y, e co pou as e s ucue: , N HO , , , , , , , , , , , , , ,
14. The compound of claim 1 having the structure: . 15. The compound of claim 14 ha , wherein A is an aryl or heteroaryl; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2. 16. The compound of claim 15, wherein R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), - 131 OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), - NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), - (alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O-(alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). 17. The compound of any one of claims 14-16 having the structure: , wherein (a) α is present and β is absent; (b) X1 is C or N; and/or X2 is N or O; preferably, X1 is C and X2 is N or O; (c) R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and/or (d) when X2 is N, then Z1 is -H, -CF3, -CF2H, -(alkyl), -(alkenyl), or -(aryl); preferably, Z1 is -H, -(alkyl), -(alkenyl), or -(aryl); more preferably, Z1 is -H or -(alkyl); more preferably, Z1 is -H. 18. The compound of any one of claims 14-17 having the structure: ,
bly, H, - OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O- (alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -CN, - CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl). 19. The compound of any one of claims 14-18 having the structure: 133
, wherein (a) R7, R8, R9 and R10 are each -H; (b) at least one of R7, R8, R9 and R10 is not -H; (c) at least two of R7, R8, R9 and R10 are not -H; (d) R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl; preferably, R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl; or (e) R7 and R10 are each -H; and R8 and R9 are each -O-Me. 20. The compound of any one of claims 14-18 having the structure: , wherein (a) R7, R8, R9 and R10 are each -H; (b) at least one of R7, R8, R9 and R10 is not -H; (c) at least two of R7, R8, R9 and R10 are not -H; (d) R7, R9 and R10 are each -H; and R8 is -CF3, -CN, -O-CF3, -O-Me, -OH, -F, or -Cl; preferably, R7, R9 and R10 are each -H; and R8 is -F, -CF3, or -Cl; (e) R7 and R10 are each -H; and R8 and R9 are each -O-Me; or (f) R7, R8, R9, and R10 are each -H; and R9 is -OH. 134
21. The compound of any one of claims 14-20, wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)-O-(alkyl) or -(alkyl)-(cycloalkyl). 22. The compound of any one of claims 14-18 having the structure: , wherein Y3, Y4 and Y5 are eac ), or -(alkyl)-O-(alkyl); preferably, Y3, Y4 and Y5 are each independently -H, or -(alkyl); more preferably, Y3, Y4 and Y5 are each -H. 23. The compound of any one of claims 14-22 having the structure: , or 135
. 24. The compound of any one of claims 14-23, wherein (a) R1, R2, R3, R4, R5 and R6 are each H; (b) at least one of R1, R2, R3, R4, R5 and R6 is not -H; (c) at least two of R1, R2, R3, R4, R5 and R6 are not -H; (d) R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently, -H, -OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, -CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2; (e) R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each H; (f) one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is not each H; (g) at least two of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are not -H; (h) when one of R1 and R2 is -CH3, then R3 and R4 are each independently -H, -CH3, C2-10 alkyl, - alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2; and R5 and R6 are each independently -H, -CH3, C2-10 alkyl, -alkenyl, -alkynyl, alkylaryl, -aryl, heteroaryl, -alkyl-R14 or -alkyl-C(O)R15, wherein R14 is -OH, -O(alkyl), -NH2, or -NH(alkyl), and R15 is -O(alkyl), -NH2, - NH(alkyl) or -N(alkyl)2; (i) when one of R5 and R6 is -CH2CH3, then at least one of R1, R2, R3, and R4 is not -H; (j) R1, R2, R5 and R6 are each -H; and one of R3 and R4 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, - alkylaryl, -aryl, or -heteroaryl; preferably, one of R3 and R4 is -alkyl, or -O-(alkyl); more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H; 136 (k) R1, R2, R3 and R4 are each -H; and one of R5 and R6 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, - alkylaryl, -aryl, or -heteroaryl; preferably, one of R5 and R6 is -alkyl, or -O-(alkyl); more preferably, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R5 and R6 is -CH3, -CH2CH3, or -O-CH3; and the other R5 or R6 is -H; or (l) R3, R4, R5 and R6 are each -H; and one of R1 and R2 is -alkyl, -O-(alkyl), -alkenyl, -alkynyl, alkylaryl, -aryl, or -heteroaryl; preferably, one of R3 and R4 is -alkyl, or -O-(alkyl); more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; more preferably, one of R3 and R4 is -CH3, -CH2CH3, or -O-CH3; and the other R3 or R4 is -H. 25. The compound of claim 14 having the structure: , , , R7 N ,
or , , , , , , , , , ,
, , , , or 26. (a) one, two, three or four of R7, R8, R9, and R10 are H1 O preferably, one or two of R7, ; 141
H1 O more preferably, R7 and/or R8 are , wherein at least one of H1, H2 and H3 is a deuterium-enriched -H site; or (b) one, two, three or four of R7, R8, R9, and R10 are H4 H5 H1 , H4 H5 H1 preferably, one or two of R7, R8, R9, and R10 ar ; H more preferably, R7 and/or R8 ar , wherein at least one of H1, H2, H3, H4 and H5 is a -H site. 27. A composition comprising the compound of any one of claims 1-26 and a pharmaceutically acceptable carrier or a pharmaceutically active agent. 28. The composition of claim 27, wherein H4 H5 (a) R7 and/or R8 are nd the weight proportion of the compound in the composition is su 0156%; (b) R7 and/or R8 is H1 O nd wherein 142
(i) at least one of H1, H2 and H3 is deuterium-enriched; (ii) each of H1-H3 are deuterium-enriched; (iii) two of H1-H3 are deuterium-enriched; (iv) each of H1-H3 is deuterium-enriched and the weight proportion of the compound in the composition is substantially greater than 90%; (v) two of H1-H3 are deuterium-enriched and the weight proportion of the compound in the composition is substantially greater than 90%; or (vi) one of H1-H3 is deuterium-enriched, and the weight proportion of the compound in the composition is substantially greater than 90%; (c) R7 and/or R8 is H4 H5 H1 , wherein (i) at least one of H1, H2, H3, H4 and H5 is deuterium-enriched; (ii) each of H1-H5 are deuterium-enriched; (iii) each of H4-H5 are deuterium-enriched or one of H4-H5 is deuterium- enriched; (iv) each of H1-H5 are deuterium-enriched and the weight proportion of the compound in the composition is substantially greater than 90%; (v) each of H4-H5 are deuterium-enriched and the weight proportion of the compound in the composition is substantially greater than 90%; or (vi) one of H4-H5 is deuterium-enriched, and the weight proportion of the compound in the composition is substantially greater than 90%; or (d) R7 and/or R8 is 143
H H D D D O D O D O D H , ite. 29. The composition of any one of claims 27-28 further comprises a mu-opioid receptor agonist, an opioid, opiate, or a combination thereof; preferably, the opioid or opiate is morphine, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, oxycodone, nalbuphine, butorphanol, etorphine, dihydroetorphine, levorphanol, metazocine, pentazocine, meptazinol, meperidine (pethidine), fentanyl, sufentanil, alfentanil, buprenorphine, methadone, tramadol, tapentadol, mitragynine, 3-deutero- mitragynine, 7-hydroxymitragynine, 3-deutero-7-hydroxymitragynine, mitragynine pseudoindoxyl, tianeptine, 7-((3-bromo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11- yl)amino)heptanoic acid, 7-((3-iodo-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepine- 11-yl)amino)heptanoic acid, 5-((3-bromo-6-methyl-5,5-dioxido-6,11- dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)pentanoic acid or 5-((3-iodo-6-methyl-5,5-dioxido- 6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)pentanoic acid. 30. A method of (a) altering the psychological state of a subject comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby alter the psychological state of the subject; (b) enhancing the effect of psychotherapy in a subject comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby enhance the effect of the psychotherapy in the subject; (c) inducing wakefulness or decreasing sleepiness in a subject comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby induce wakefulness or decrease sleepiness in the subject; (d) inducing a stimulating effect in a subject comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby induce the stimulating effect in the subject; 144
(e) treating a subject afflicted with substance use disorder (SUD) comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby treat the subject afflicted with the SUD; preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); (f) treating a subject afflicted with opioid withdrawal symptoms comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby treat the subject afflicted with the opioid withdrawal symptoms; (g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby treat the subject afflicted with the depressive disorder, the mood disorder, the anxiety disorder, Parkinson’s disease or the traumatic brain injury; and/or (h) treating a subject afflicted with pain comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby treat the subject afflicted with pain; (i) treating a subject afflicted with Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease comprising administering an effective amount of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 to the subject, so as to thereby treat the subject afflicted with TD, Tourette syndrome, and chorea associated with Huntington’s disease; preferably, 10-1500 mg of the compound is administered to the subject in (a)-(i); more preferably, 30 mg of the compound is administered to the subject in (a)-(i). 31. A method of inhibiting serotonin transporter (SERT) and/or vesicular monoamine transporter 2 (VMAT2) in a subject comprising administering to the subject an effective amount of a compound having the structure: 145
, wherein A is a ring structure, with or without substitution; X1 is C or N; X2 is N, O, or S; Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); Z1 is present or absent and when Z1 is present, Z1 is -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, - OCF3, -OH, -OAc, -O-(alkyl), -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -SH, -S-(alkyl), -NH2, -NH- (alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), or -NH-(heteroaryl); α and β each represents a bond that is present or absent, wherein either α is present or β is present, and when α is present, then X1 is C and X2 is N, S, or O, wherein when X1 is C and X2 is N, then Z1 is present; and when X1 is C, and X2 is O or S, then Z1 is absent; or when β is present, then X1 is N, X2 is N and Z1 is absent; γ and δ each represents a bond that is present or absent, and either γ is present or δ is present; and R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-(cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(C2-C12 alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), C(O)-NH-(aryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH- 146
(heteroaryl), -O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, - OC(O)R14, -SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, or a salt thereof. 32. A process of producing a compound of formula I: (I) wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is -halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and 147 R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - (hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), -C(O)-NH2, - C(O)-NH-(alkyl), -C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (II) II) with a catalyst complex t X),
(b) reacting the compound of formula (IX) with a reducing agent to produce the compond of formula I; or (a) reacting a compound of formula (II) II) with a halogenating reag X), wherein A is a halog en; an (b) adding a catalyst complex to produce the compond of formula I, or a salt thereof. 33. The process of claim 32, wherein the catalyst complex is a transition metal catalyst complex; preferably, the transition metal catalyst complex is Pd(CH3CN)4(BF4)2; the reducing agent is a hydride source, preferably, the hydride source is LiBH4 or NaBH4; step (a) includes a solvent; preferably, the solvent is an organic solvent; more preferably, the solvent is a polar aprotic solvent; more preferably, the solvent is CH3CN; 149
step (b) includes a solvent; preferably, the solvent is an alcohol; more preferably, the solvent is a primary alcohol; more preferably, the solvent is methanol, ethanol, propanol; more prefearbly, the solvent is MeOH; step (a) and/or step (b) is conducted in an inert gas; preferably, the inert gas is helium, neon, argon, krypton, and xenon; more preferably, the inert gas is argon; step (a) is conducted at 20-35 °C; preferably, at 25-30 °C; more preferably, at 25-27 °C; before step (b), the mixture from step (a) is heated for a period of time; preferably for 13-23 hours, more preferably for 16 -19 hours; step (a) is conducted at a temperature of 60-100 °C; preferably at a temperature of 70-90 °C; more preferably, at a temperature of 80 °C; and/or before step (b), the mixture is cooled at a temperature of 0-15 °C; preferably, at 0-10°C; more preferably at 0-5 °C; or wherein the process of claim 32 further comprises: adding BBr3 and EtSH in step (b); a dilution step in step (b) with AcOEt; a filtration step in step (b) to obtain a residue; washing the residue with AcOEt and Et3N; and a purification step. 34. The process of any one of claims 32-33, wherein the compound of formula II is produced by reacting a compound of formula III O O Cl (III) with a compound of formula IV 150
V) in the presence of a base. 35. The process of claim 34, wherein (a) the base is an organic base; preferably, the organic base is a strong base; more preferably, the organic base is an amine base; more preferably, the organic base is triethylamine or N,N- diisopropylethylamine; (b) the reaction is conducted at 0-30 °C; preferably, at a temperature of 0-25°C; (c) the reaction is conducted in a solvent, preferably, the solvent is an organic solvent; more preferably, the solvent is a polar aprotic solvent; more preferably, the solvent is DCM and CH3CN; and/or (d) the process further comprises adding LiAlH4 in Tetrahydrofuran (THF) at a temperature of 0- 70°C. 36. The process of any one of claims 32-35, wherein (a) R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O- (alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl); more preferably, R7, R8, R9 and R10 are each -H; (b) Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)- O-(alkyl) or -(alkyl)-(cycloalkyl); preferably, Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl); more preferably, Y1, Y2, Y3, Y4 and Y5 are each independently -H, or -(alkyl); 151
more preferably, Y1, Y2, Y3, Y4 and Y5 are each -H; and/or (c) R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, - CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2; preferably, R1, R2, R3, R4, R5, and R6 are each H. 37. A process of producing a compound of formula V: V) wherein Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(alkenyl), -(alkynyl), -(cycloalkyl), - (haloalkyl), -(alkyl)-O-(alkyl) or –(alkyl)-(cycloalkyl); R1, R2, R3, R4, R5, and R6 are each independently -H, -halogen, -(alkyl), -(alkenyl), -(alkynyl), - (haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), -(hydroxyalkyl), -(alkyl)-(aryl), - (alkyl)-(heteroaryl), -(alkyl)-( cycloalkyl), -(alkyl)-OH, -(alkyl)-O-(alkyl), -OH, -OAc, -CO2H, - CN, -CF2H, -OCF3, -CO2-(alkyl), -C(O)-NH2, -C(O)-NH-(alkyl), -C(O)-NH-(aryl), -O-alkyl, -O- alkenyl, -O-alkynyl, -O-aryl, -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NO2, -NH2, -NH-alkyl, -NH-alkenyl, -NH-alkynyl, -NH-aryl, -NH-(heteroaryl), - O-C(O)(alkyl), -C(O)-N(alkyl)2, -C(O)R14, -S(O)R14, -SO2R14, -NHSO2R14, -OC(O)R14, - SC(O)R14, -NHC(O)R15, -NHC(S)R15, -alkyl-R14, or -alkyl-C(O)R15, wherein R14 is halogen, -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, preferably, R14 is -(alkyl), -(aryl), -(heteroaryl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R15 is -(alkyl), -(aryl), -O(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2; and R7, R8, R9 and R10 are each independently, -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, - (alkyl), -(alkenyl), -(alkynyl), -(haloalkyl), -(cycloalkyl), -(aryl), -(heteroaryl), -(heteroalkyl), - 152
(hydroxyalkyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2H, -CO2-(alkyl), -O-C(O)(alkyl), C(O)-NH2, C(O)-NH-(alkyl), or C(O)-NH-(aryl), -C(O)R12, -S(O)R12, -SO2R12, -NHSO2R12, -OC(O)R12, - SC(O)R12, -NHC(O)R13 or -NHC(S)R13, wherein R12 is -(alkyl), -(aryl), -(heteroaryl), -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and R13 is -(alkyl), -(aryl), -O-(alkyl), -S-(alkyl), -S-(aryl), -NH2, -NH(alkyl) or -N(alkyl)2, comprising: (a) reacting a compound of formula (VI) VI) with a base and a halogena la (XI) nd (b) reacting the compo und of formula XI with a catalyst complex to produce the compound of formula V, or a salt thereof. 153
38. The process of claim 37, wherein the base is a strong base; preferably, the base is an organic base; more preferably, the base is nBuLi; the halogen solution is iodine solution; the catalyst complex is a transition metal catalyst complex; preferably, the transition metal catalyst complex is sodium formate, dichlorobis(tri-o-tolylphosphine)palladium(II); step (a) includes a solvent; preferably, the solvent is an organic solvent; more preferably, the solvent is THF; step (a) includes Na2S2O3; step (b) includes a solvent; prefearbly, preferably, the solvent is an organic solvent; more preferably, the solvent is DMSO; step (a) and/or step (b) are conducted in an inert gas; preferably, the inert gas is helium, neon, argon, krypton, and xenon; more preferably, the inert gas is argon; step (a) is conducted at a temperature of -30 to -50 °C; preferably at a temperature of -40 °C; before step (b), the product from step (a) is diluted with water and extracted with diethyl ether for at least 3 times; and/or step (b) is conducted at a temperature of 90 to 110 °C; preferably at a temperature of 100 °C. 39. The process of any one of claims 37-38, wherein the compound of formula VI is produced by reacting a compound of formula VII II) with a compound of form V) in the presence of a base. 154
40. The process of claim 39, wherein (a) the base is a strong base; preferably the base is an inorganic base; preferably the base is KOH, NaOH, Mg(OH)2, Fe(OH)3, Al(OH)3, Ca(OH)2, more preferably, the base is NaOH; and (b) the reaction is conducted at 70-90 °C; preferably, at a temperature of 80 °C. 41. The process of any one of claims 37-40, wherein (a) R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -CONH2, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -OH, -OAc, -O-(alkyl), -O- (alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), or -NH-(heteroaryl); preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(alkenyl), -(alkynyl), -OH, -OAc, -O-(alkyl), -O-(alkenyl), or -O- (alkynyl); more preferably, R7, R8, R9 and R10 are each independently -H, -F, -Cl, -CN, -CF3, -OCF3, -OH, -O-(alkyl), or -O-(alkenyl); more preferably, R7, R9 and R10 are each -H and R8 is OH; (b) Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(cycloalkyl), -(haloalkyl), -(alkyl)- O-(alkyl) or –(alkyl)-(cycloalkyl); preferably, Y1, Y2, Y3, Y4 and Y5 are each independently -H, -(alkyl), -(haloalkyl), or - (alkyl)-O-(alkyl); more preferably, Y1, Y2, Y3, Y4 and Y5 are each independently -H, or -(alkyl); more preferably, Y1, Y2, Y3, Y4 and Y5 are each -H; and/or (c) R1, R2, R3, R4, R5, and R6 are each independently, -H, -OH, -OMe, -O-CH2CH3, -F, -Br, -Cl, - CF3 -CN, -OCF3, -CH3, -CH2CH3 or - CONH2; preferably, R1, R2, R3, R4, R5, and R6 are each H. 42. The process of claim 34 or 39, wherein the compound of formula IV has the following structure: .
43. The compound of any one of claims 1-26, or the composition of any one of claims 27-29 for use in (a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); (f) treating a subject afflicted with opioid withdrawal symptoms; (g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury; (h) treating a subject afflicted with pain; and/or (i) treating a subject afflicted with Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease; preferably, 10-1500 mg of the compound is administered to the subject in (a)-(i); more preferably, 100- 1500 mg of the compound is administered to the subject in (a)-(i); more preferably, 500-1500 mg of the compound is administered to the subject in (a)-(i). 44. Use of the compound of any one of claims 1-26, or the composition of any one of claims 27-29 in (a) altering the psychological state of a subject; (b) enhancing the effect of psychotherapy in a subject; (c) inducing wakefulness or decreasing sleepiness in a subject; (d) inducing a stimulating effect in a subject; (e) treating a subject afflicted with substance use disorder (SUD); preferably, the SUD is opioid use disorder, alcohol use disorder, stimulant use disorder, or nicotine use disorder (smoking); (f) treating a subject afflicted with opioid withdrawal symptoms; (g) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury; (h) treating a subject afflicted with pain; and/or (i) treating a subject afflicted with Tardive dyskinesia (TD), Tourette syndrome, and chorea associated with Huntington’s disease; 156
preferably, 10-1500 mg of the compound is administered to the subject in (a)-(i); more preferably, 100- 1500 mg of the compound is administered to the subject in (a)-(i); more preferably, 500-1500 mg of the compound is administered to the subject in (a)-(i). 157
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150361080A1 (en) * 2012-12-20 2015-12-17 Demerx, Inc. Substituted noribogaine
US20170334923A1 (en) * 2014-11-26 2017-11-23 The Trustees Of Columbia University In The City Of New York Opioid receptor modulators
WO2022178099A1 (en) * 2021-02-17 2022-08-25 The Trustees Of Columbia University In The City Of New York Oxa-ibogaine analogues for treatment of substance use disorders
US20240376116A1 (en) * 2023-04-28 2024-11-14 Atai Therapeutics, Inc. Ibogaine and noribogaine analogs and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150361080A1 (en) * 2012-12-20 2015-12-17 Demerx, Inc. Substituted noribogaine
US20170334923A1 (en) * 2014-11-26 2017-11-23 The Trustees Of Columbia University In The City Of New York Opioid receptor modulators
WO2022178099A1 (en) * 2021-02-17 2022-08-25 The Trustees Of Columbia University In The City Of New York Oxa-ibogaine analogues for treatment of substance use disorders
US20240376116A1 (en) * 2023-04-28 2024-11-14 Atai Therapeutics, Inc. Ibogaine and noribogaine analogs and methods of use

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