Novel analogs of oxapazulfide therapeutic agents

Abstract

This invention provides a compound having the following structure:

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application 63 / 548,988, filed February 2, 2024, the contents of which are incorporated herein by reference.

[0002] Throughout this application, references have been made to various publications, including those in parentheses. The full disclosure of all publications mentioned herein is incorporated herein by reference to provide additional description of the art to which this invention pertains and the features that may be employed in this art.

[0003] Statement regarding federally sponsored research or development This invention was completed with government support under license number DA050613 granted by the National Institute on Drug Abuse / National Institutes of Health. The government owns certain rights to this invention. Background Technology

[0004] Ibogaine is in Ibogam ( Tabernanthe iboga The main psychoactive alkaloid found in the root bark of ibogaine (a plant native to western Central Africa) (Alper, KR 2001). The root bark is used as a religious and healing relic by indigenous Africans due to its unique hallucinogenic effects. Clinical claims regarding the anti-addictive properties of ibogaine, discovered in the United States in the 1960s, have been largely replicated in animal models of substance use disorder (SUD), where ibogaine and its main metabolite, noribogaine, have shown excessive effects associated with different aspects of SUD (Glick, SD et al. 2001; Belgers, M. et al. 2016; Mash, DC et al. 2016).

[0005] Sudden unmet needs (SUD) are a mental disorder affecting nearly 20 million adults in the United States. Unfortunately, these patients currently have limited treatment options available. Given the significant unmet need in SUD and general mental disorders, there is a strong incentive to develop novel analogues that improve the safety and therapeutic index of ibogain for treating these conditions. Additionally, there is a need for new compounds that can be used to investigate the biological mechanisms supporting the action of ibogain and enhance our understanding of its mechanisms of action.

[0006] This invention represents novel ibogaine analogues of previously disclosed compounds (US Patent No. 9,988,377; US Application Serial Nos. 14 / 240,681, 15 / 528,339; PCT International Application Nos. PCT / US2012 / 052327, PCT / US2015 / 062726). These analogues represent a further elucidation and deconstruction of the iboga skeleton to produce simpler and more unique structural systems with distinctive pharmacology and improved side effects. The compounds described herein may be used to treat opioid use disorder (OUD) and other SUDs, mood disorders, depression and anxiety disorders, migraines, and cluster headaches.

[0007] This invention identifies key structural features that enable novel benzofurano-azapyridine analogs to exhibit potent κ-opioid activity and a reduced profile of side effects (reduced hERG inhibition and absence of arrhythmogenic reactions). Furthermore, the efficacy of κ activity can be readily modulated through selective substitution.

[0008] These analogues can be used to treat opioid use disorder (OUD) and other SUDs, mood disorders, depression and anxiety disorders, migraines, and cluster headaches. They are safer ibogaine analogues for treating addiction disorders, neurological disorders, and psychiatric disorders. These analogues have enhanced pharmacological activity at relevant molecular targets (monoamine transporters, opioid receptors) and an improved side effect profile (reduced risk of cardiotoxicity). Summary of the Invention

[0009] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt. Attached Figure Description

[0010] Figure 1 A / Assays based on κ-opioid receptor G protein for selected examples of novel compounds. B / Nanobody (Nb33) recruitment assays allow for finer differentiation of novel compounds. Data are presented as mean (n=3) ± SEM.

[0011] Figure 2 A / Compounds 1 and 2 inhibited hERG ion channels to a lesser extent than isoborocaine. B / Primary adult cardiomyocytes showed no signs of arrhythmia up to 10 μM in the presence of compound 2.

[0012] Figure 3 Pharmacokinetic studies of compounds 1 and 2 (10 mg / kg, subcutaneously) in male C57BL / 6 mice showed favorable brain / plasma distribution. A / Total and free concentrations were determined for compound 1 and B / For compound 2. Free concentrations were calculated by correcting for nonspecific plasma protein and tissue binding using rodent (rat) data. Detailed Implementation

[0013] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R.10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

[0014] In some implementations, when X1 is C, X2 is NR1, E is NR1 and D is CR9R 10 If R1 and at least two of R2, R3, R4 and R8 are not hydrogen.

[0015] In some implementations, when X1 is C, X2 is NR1, E is NR1 and D is CR9R 10 When, then R9 and R 10 One of them is not H.

[0016] In some implementations, when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3 or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then at least two of R2, R3, R4 and R8 are not H.

[0017] In some implementations, when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4, and R8 is -OCH3 or -SCH3, then R9 and R 10 One of them is not H.

[0018] In some implementations, when X1 is C, X2 is O, and E is NH, then R2, R3, R4, R8, R9, and R... 10 At least one of them is not H.

[0019] In some implementations, when X1 is C, X2 is S, and R5, R9, and R 10 If each of them is H and R3 is Br, then D is not NH.

[0020] In some implementations, when X1 is N and X2 is CR 15 D is NR5, E is CR9R 10 R5, R9 and R 10 It is H, and R 15 If it is H, then one of R2, R3, R4 and R8 is not H, and R4 is not OMe, R3 is not Br, R2 is not Br and Cl, and R8 is not OMe.

[0021] In some implementations, when X1 is N and X2 is CR 15 D is NR5, E is CR9R 10 R5 is an alkyl group, R9 and R 10 It is H, and R 15 If it is CH3, then at least one of R2, R3, R4 and R8 is not H and CH3, and R3 is not a ketone or a carboxylic acid.

[0022] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; When X2 is O, D is NH, and R6 is propyl or methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; When X2 is O, D is -NCH3, and R6 is methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; and When X2 is -NH and R6 is propyl, then R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; Or its pharmaceutically acceptable salt.

[0023] In some implementations, D is NR5, and E and F are each independently CR9R. 10 .

[0024] In some implementations, X1 is C.

[0025] In some implementations, X2 is O or NR1.

[0026] In some embodiments, R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2.

[0027] In some embodiments, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc or -O(alkyl).

[0028] In some embodiments, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -OH or -O(alkyl).

[0029] In some embodiments, R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2.

[0030] In some embodiments, R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl).

[0031] In some implementations, R5 is H, -(alkyl), or -O(alkyl).

[0032] In some implementations, R5 is H or -(alkyl).

[0033] In some embodiments, R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl).

[0034] In some embodiments, R6 is -(C1-C6 alkyl), -(C1-C6 alkenyl), -(C1-C6 ynyl), -C1-C6 cycloalkyl, -(C1-C6 alkyl-alkenyl), -(C1-C6 alkyl-ynyl) or -(C1-C6 alkyl-cycloalkyl).

[0035] In some embodiments, R6 is a branched -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl).

[0036] In some implementations, R5 and R6 combine to form a 3-7 membered heterocyclic alkyl ring.

[0037] In some implementations, R5 and R6 combine to form a 5-membered heterocyclic alkyl ring.

[0038] In some embodiments, R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); preferably, R7 is -H or -(alkyl).

[0039] In some implementations, R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), or -(alkynyl); preferably, R9 and R 10 Each is independently H or -(alkyl).

[0040] In some implementation schemes, R 15 It is H or -(alkyl).

[0041] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; Or its pharmaceutically acceptable salt.

[0042] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, or CR 15 ; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2 alkyl), -(C 4-12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6 is -(C3 alkyl) and R3 is –(C=O)NH2; Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; Or its pharmaceutically acceptable salt.

[0043] This invention provides a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is NR1, and α does not exist while β does exist; R1, R2, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R3 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1 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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; or Or its pharmaceutically acceptable salt.

[0044] In some implementations, R6 is -(C3-C 12 Alkyl) and R7 is -(alkenyl).

[0045] In some embodiments, R6 is -(alkenyl) and R7 is -(C1-C3 alkyl).

[0046] This invention provides a compound having the following structure: in X2 is NR1 or O; R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; and R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (i) When R5 is H or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X2 is NH, R5 is NH, and R2, R3, R4 and R7 are H, then R6 is not propyl; (iii) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OH, then R6 is not propyl. (v) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not Hpropyl; (vi) When X2 is O, R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X2 is O, R5 is NH, R2, R4 and R6 are H, and R3 is -OH, then R7 is not propyl.

[0047] In some embodiments, the present invention provides a compound having the following structure: in R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (i) When R5 is H or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When R1 is H, R5 is H, and R2, R3, R4 and R7 are H, then R6 is not propyl; (iii) When R1 is H, R5 is H, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not propyl. (iv) When R1 is H, R5 is H, R2, R4, and R7 are H, and R3 is -OH, then R6 is not propyl; and (v) When R1 is H, R5 is H, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not Hpropyl.

[0048] In some embodiments, the present invention provides a compound having the following structure: in R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (i) If R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and (ii) If R5 is NH, R2, R4 and R6 are H, and R3 is -OH, then R7 is not propyl.

[0049] In some implementations, at least one of R2, R3, and R4 is not H.

[0050] In some implementations, R1 is -H or -Me.

[0051] In some implementations, R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or -C(O)NH2.

[0052] In some implementations, R5 is -H, methyl, or ethyl.

[0053] In some implementations, R6 is , , , , , , , , , , , or .

[0054] In some implementations, R7 is -H or -Me.

[0055] This invention provides a compound having the following structure: , , , , , , , or .

[0056] In some implementations, R5 is H or -Me.

[0057] This invention provides a compound having the following structure: , , , , , , , , , , , or .

[0058] This invention provides a compound having the following structure: or .

[0059] In some implementations, R1, R5, and R7 are independently H or -Me.

[0060] In some implementations, R1, R2, and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.

[0061] This invention provides a compound having the following structure: , , , , or .

[0062] In some implementations, R1 and R5 are independently H or -Me.

[0063] In some implementations, R1, R2, and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.

[0064] This invention provides a compound having the following structure: , or .

[0065] In some embodiments, the compounds of the present invention have monoamine transporter inhibitory activity.

[0066] In some embodiments, the compounds of the present invention have sufficient brain penetration.

[0067] In some embodiments, the compounds of the present invention reduce the off-target activity of hERG.

[0068] In some embodiments, the compounds of the present invention have little or no arrhythmic potential.

[0069] The present invention provides a pharmaceutical composition comprising the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0070] This invention provides a method for activating a 5HT2A receptor, a 5HT2C receptor, or both 5HT2A and 5HT2C receptors, the method comprising contacting the 5HT2A receptor and the 5HT2C receptor with a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR.15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

[0071] This invention provides a method for inhibiting SERT receptors, the method comprising contacting the SERT receptors with a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

[0072] This invention provides a method for activating a κ-opioid receptor, the method comprising contacting the κ-opioid receptor with a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

[0073] This invention provides a method for inhibiting nicotinic acetylcholine receptors, the method comprising contacting the nicotinic acetylcholine receptors with a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

[0074] This invention provides a method for treating a subject suffering from substance use disorder, the method comprising administering to the subject a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt. This is to treat subjects with substance use disorder.

[0075] This invention provides a method for treating a subject suffering from depression, mood disorder, anxiety disorder, Parkinson's disease, or traumatic brain injury, the method comprising administering to the subject a compound having the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt. This allows for the treatment of subjects suffering from depression, mood disorders, anxiety, Parkinson's disease, or traumatic brain injury.

[0076] In some implementations, when X1 is C, X2 is NR1, E is NR1 and D is CR9R 10 If R1 and at least two of R2, R3, R4 and R8 are not hydrogen.

[0077] In some implementations, when X1 is C, X2 is NR1, E is NR1 and D is CR9R 10 When, then R9 and R 10 One of them is not H.

[0078] In some implementations, when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3 or NCH(CH3)2, and one of R2, R3, R4 and R8 is -OCH3 or -SCH3, then at least two of R2, R3, R4 and R8 are not H.

[0079] In some implementations, when X1 is C, X2 is O, and D is NH, NCH3, NCH2CH3, or NCH(CH3)2, and one of R2, R3, R4, and R8 is -OCH3 or -SCH3, then R9 and R 10 One of them is not H.

[0080] In some implementations, when X1 is C, X2 is O, and E is NH, then R2, R3, R4, R8, R9, and R... 10 At least one of them is not H.

[0081] In some implementations, when X1 is C, X2 is S, and R5, R9, and R 10 If each of them is H and R3 is Br, then D is not NH.

[0082] In some implementations, when X1 is N and X2 is CR 15 D is NR5, E is CR9R 10 R5, R9 and R 10 It is H, and R 15 If it is H, then one of R2, R3, R4 and R8 is not H, and R4 is not OMe, R3 is not Br, R2 is not Br and Cl, and R8 is not OMe.

[0083] In some implementations, when X1 is N and X2 is CR 15 D is NR5, E is CR9R 10 R5 is an alkyl group, R9 and R 10 It is H, and R 15 If it is CH3, then at least one of R2, R3, R4 and R8 is not H and CH3, and R3 is not a ketone or a carboxylic acid.

[0084] In some embodiments, compounds having the following structures are used: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; When X2 is O, D is NH, and R6 is propyl or methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; When X2 is O, D is -NCH3, and R6 is methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; and When X2 is -NH and R6 is propyl, then R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; Or its pharmaceutically acceptable salt.

[0085] In some implementations, D is NR5, and E and F are each independently CR9R. 10 .

[0086] In some implementations, X1 is C.

[0087] In some implementations, X2 is O or NR1.

[0088] In some embodiments, R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2.

[0089] In some embodiments, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc or -O(alkyl).

[0090] In some embodiments, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -OH or -O(alkyl).

[0091] In some embodiments, R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2.

[0092] In some embodiments, R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl).

[0093] In some implementations, R5 is H, -(alkyl), or -O(alkyl).

[0094] In some implementations, R5 is H or -(alkyl).

[0095] In some embodiments, R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl).

[0096] In some embodiments, R6 is -(C1-C6 alkyl), -(C1-C6 alkenyl), -(C1-C6 ynyl), -C1-C6 cycloalkyl, -(C1-C6 alkyl-alkenyl), -(C1-C6 alkyl-ynyl) or -(C1-C6 alkyl-cycloalkyl).

[0097] In some embodiments, R6 is a branched -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl).

[0098] In some implementations, R5 and R6 combine to form a 3-7 membered heterocyclic alkyl ring.

[0099] In some implementations, R5 and R6 combine to form a 5-membered heterocyclic alkyl ring.

[0100] In some embodiments, R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); preferably, R7 is -H or -(alkyl).

[0101] In some implementations, R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), or -(alkynyl); preferably, R9 and R 10 Each is independently H or -(alkyl).

[0102] In some implementation schemes, R 15 It is H or -(alkyl).

[0103] In some embodiments, the compound has the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; Or its pharmaceutically acceptable salt.

[0104] In some embodiments, the compound has the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, or CR 15 ; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2 alkyl), -(C 4-12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6 is -(C3 alkyl) and R3 is –(C=O)NH2; Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; Or its pharmaceutically acceptable salt.

[0105] In some embodiments, the compound has the following structure: in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is NR1, and α does not exist while β does exist; R1, R2, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R3 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1 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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; or Or its pharmaceutically acceptable salt.

[0106] In some implementations, R6 is -(C3-C 12 Alkyl) and R7 is -(alkenyl).

[0107] In some embodiments, R6 is -(alkenyl) and R7 is -(C1-C3 alkyl).

[0108] In some embodiments, the compound has the following structure: in X2 is NR1 or O; R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; and R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (viii) When R5 is H or -N-(C1-C2 alkyl), then R6 is -(C3-C2 alkyl). 12 alkyl); (ix) When X2 is NH, R5 is NH, and R2, R3, R4 and R7 are H, then R6 is not propyl. (x) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not propyl. (xi) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OH, then R6 is not propyl. (xii) When X2 is NH, R5 is NH, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not Hpropyl; (xiii) When X2 is O, R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and (xiv) When X2 is O, R5 is NH, R2, R4 and R6 are H, and R3 is -OH, then R7 is not propyl.

[0109] In some embodiments, the compound has the following structure: in R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (vi) When R5 is H or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (vii) When R1 is H, R5 is H, and R2, R3, R4 and R7 are H, then R6 is not propyl. (viii) When R1 is H, R5 is H, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not propyl. (ix) When R1 is H, R5 is H, R2, R4, and R7 are H, and R3 is -OH, then R6 is not propyl; and (x) When R1 is H, R5 is H, R2, R4 and R7 are H, and R3 is -OMe, then R6 is not Hpropyl.

[0110] In some embodiments, the compound has the following structure: in R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); in (iii) If R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and (iv) If R5 is NH, R2, R4 and R6 are H, and R3 is -OH, then R7 is not propyl.

[0111] In some implementations, at least one of R2, R3, and R4 is not H.

[0112] In some implementations, R1 is -H or -Me.

[0113] In some implementations, R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or -C(O)NH2.

[0114] In some implementations, R5 is -H, methyl, or ethyl.

[0115] In some implementations, R6 is , , , , , , , , , , , or .

[0116] In some implementations, R7 is -H or -Me.

[0117] This invention provides a compound having the following structure: , , , , , , , or .

[0118] In some implementations, R5 is H or -Me.

[0119] This invention provides a compound having the following structure: , , , , , , , , , , , or .

[0120] This invention provides a compound having the following structure: or .

[0121] In some implementations, R1, R5, and R7 are independently H or -Me.

[0122] In some implementations, R1, R2, and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.

[0123] This invention provides a compound having the following structure: , , , , or .

[0124] In some implementations, R1 and R5 are independently H or -Me.

[0125] In some implementations, R1, R2, and R3 are each independently H, -OMe, -OH, -F, -Cl, -Br, or -CN.

[0126] In some embodiments, the compound has the following structure: , or .

[0127] In some embodiments, the compounds of the present invention have monoamine transporter inhibitory activity.

[0128] In some embodiments, the compounds of the present invention have sufficient brain penetration.

[0129] In some embodiments, the compounds of the present invention reduce the off-target activity of hERG.

[0130] In some embodiments, the compounds of the present invention have little or no arrhythmic potential.

[0131] In some embodiments, the present invention provides a compound having the following structure: .

[0132] The compounds disclosed in this invention may be used in combination with other compounds disclosed in U.S. Publication No. 2023 / 0382919 to treat opioid use disorder (OUD) and other SUDs, mood disorders, depression and anxiety disorders, migraines and cluster headaches, the contents of which are incorporated herein by reference.

[0133] In some implementations, anxiety disorders include, but are 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).

[0134] In some implementations, depression includes, but is not limited to, depression, major depressive disorder, dysphoric mood, cyclothymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual anxiety disorder, situational depression, or adjustment disorder with depressed mood. Depression may also include other mood disorders, and is not limited to the list above.

[0135] The present invention provides compounds or compositions for activating 5HT2A receptors, 5HT2C receptors, or both 5HT2A and 5HT2C receptors.

[0136] This invention provides compounds or compositions for inhibiting SERT receptors.

[0137] This invention provides compounds or compositions for activating κ-opioid receptors.

[0138] This invention provides compounds or compositions for inhibiting nicotinic acetylcholine receptors.

[0139] The present invention provides compounds or compositions for treating subjects suffering from substance use disorders.

[0140] The present invention provides compounds or compositions for treating subjects suffering from depression, mood disorders, anxiety disorders, Parkinson's disease, or traumatic brain injury.

[0141] This invention provides the use of compounds or compositions to activate 5HT2A receptors, 5HT2C receptors, or both 5HT2A and 5HT2C receptors.

[0142] This invention provides the use of compounds or compositions that inhibit SERT receptors.

[0143] This invention provides the use of compounds or compositions to activate κ-opioid receptors.

[0144] This invention provides the use of compounds or compositions that inhibit nicotinic acetylcholine receptors.

[0145] This invention provides the use of compounds or compositions to treat subjects suffering from substance use disorders.

[0146] This invention provides the use of compounds or compositions for treating subjects suffering from depression, mood disorders, anxiety disorders, Parkinson's disease, or traumatic brain injury.

[0147] This invention provides a method for synthesizing compounds having the following structures: , in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); and R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); and R9 and R 10 Each can be independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; This method involves making a compound of formula I: (Formula I) It reacts with organic bromides in the presence of a base; or It reacts with haloalkanes in the presence of a base, and then with organic bromides in the presence of a base; To produce compounds of formula II: (Formula II).

[0148] In some embodiments, the compound of formula II has the following structure: (Formula II).

[0149] In some embodiments, R6 is an alkyl, alkyl-alkenyl, or alkyl-ynyl group, and R7 is H or CH3.

[0150] In some implementations, the method further includes: (a) Converting the compound of Formula II into an oxime compound; (b) Converting the oxime compound into a lactam compound; and (c) The lactam compound is subjected to reduction, protection, and deprotection reactions to produce a compound of formula III: (Formula III)

[0151] In some embodiments, the method further includes reacting the compound of formula III with... The reaction is followed by a deprotection reaction to produce a compound of formula IV. (Form IV), Where X2 is O.

[0152] In some embodiments, the compound of formula IV has the following structure: (Formula IV).

[0153] In some embodiments, R2, R4, and R8 are each H, and R5 is H or an alkyl group.

[0154] In some embodiments, the compound of formula IV has the following structure: , , , , , , , , , , , or .

[0155] Preclinical evidence (rodents) has also shown that ibogain / noibogain enhances the analgesic effect of morphine (Sharma, SS et al. 1998) or reverses analgesic tolerance to morphine (Bhargava, HN et al. 1997).

[0156] In some implementations, the subject is subjected to methods that address pain. Reports of the stimulant effects of ibogaine date back to the late 1890s and early 20th century in descriptions of ritual and drug use by indigenous Africans. Ibogaine was recommended in France for the treatment of "asthenia" (dosage range 10-30 mg daily). During 1939–1970, ibogaine was marketed in France as "Lambarène," a "neuromuscular stimulant" (8 mg pills) recommended for fatigue, depression, and recovery from infectious diseases (Alper, KR 2001). In a clinical study, subjects underwent a visual analog scale (VAS, 0-100) test related to drowsiness, feelings of energy, and side effects such as nausea and anxiety relative to calmness. Subjects reported that after a single dose of 20 mg ibogaine, within a 24-hour period of examination, ibogaine reduced drowsiness and increased feelings of energy (Glue, P. et al. 2015). Stimulant effects have been reported in cats (Schneider et al. 1957). In rats, ibogain induces arousal and inhibits REM sleep, as shown via EEG (González, J. et al. 2018).

[0157] In rats, ibogaine has been shown to significantly upregulate BDNF (in addition to glial cell line-derived neurotrophic factor (GDNF)), which provided structural and functional recovery in subjects with TBI (Marton, S. et al. 2019). The efficacy of ibogaine has also been demonstrated in cases of soldiers with TBI and PTSD (Thoricatha, W. 2020).

[0158] In some implementations, the subject has a traumatic brain injury (TBI).

[0159] In rats, ibogaine has been shown to induce the expression of GDNF (He, DY. et al. 2005 and Marton, S. et al. 2019), a key neurotrophic factor that maintains and restores the dopaminergic system, which degenerates in Parkinson's disease. Therefore, ibogaine provides structural and functional restoration in subjects with Parkinson's disease. GDNF itself has been shown to play a desired role in rodent and monkey models of Parkinson's disease (Gash, DM et al. 1996).

[0160] In some implementations, the subject has Parkinson's disease.

[0161] In humans, ibogaine has been shown to be useful for the treatment of opioid and stimulant use disorders (Alper, KR et al. 1999; Mash, DC et al. 2018; Schenberg, EE et al. 2014), or in combination with opioids for maintenance therapy (opioid use disorder) to reduce the effective dose of opioids (Kroupa, PK and Wells, H. 2005).

[0162] In some implementations, the substance use disorder is an opioid substance use disorder, an alcohol use disorder, or a stimulant use disorder.

[0163] Opioid use disorder (OUD) involves, but is not limited to, the abuse of opioid substances or the use of illegally obtained opioid substances. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA: American Psychiatric Association, 2013) (which is incorporated herein by reference) describes Opioid use disorder as a problematic pattern of opioid use that causes problems or distress, characterized by at least two of the following over a 12-month period: - Taking a larger dose than expected or taking the medication for a longer period of time than expected.

[0164] - Unsuccessful persistent desire or efforts to reduce or control opioid use.

[0165] - Spending a significant amount of time acquiring or using opioids or recovering from their effects.

[0166] - Craving, or having a strong desire or urge to use opioid substances.

[0167] - Problems arise when fulfilling obligations at work, school, or family.

[0168] - Despite recurring social or interpersonal problems, continued use of opioid substances.

[0169] - Giving up or reducing activities due to the use of opioids.

[0170] - Use of opioid substances in situations that are harmful to the body.

[0171] - Continue to use opioids even though they may have caused or exacerbated persistent physical or psychological problems.

[0172] - Tolerance (i.e., the effect diminishes when the amount is increased or when the same amount is used continuously).

[0173] - Experiencing withdrawal (opioid withdrawal syndrome) or taking opioids (or closely related substances) to relieve or avoid withdrawal symptoms.

[0174] Alcohol use disorder (AUD) involves, but is not limited to, chronic relapsing brain disorders characterized by compulsive alcohol use, loss of control over alcohol intake, and negative emotional states when not using alcohol. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, describes alcohol use disorder as a problematic pattern of alcohol use that causes problems or distress, in which at least two of the following are present over a 12-month period: - There is no limit to the amount of alcohol you can drink.

[0175] - You want to reduce your alcohol consumption or have tried to do so but haven't been successful.

[0176] - Spending a lot of time drinking, obtaining alcohol, or recovering from alcohol use.

[0177] - Feeling a strong craving or urge to drink alcohol.

[0178] - Failure to fulfill primary obligations at work, school, or home due to repeated alcohol use.

[0179] - Continue drinking even if you know that alcohol is causing physical, social, or interpersonal problems.

[0180] - Give up or reduce social and work activities and hobbies.

[0181] - Using alcohol in unsafe situations, such as while driving or swimming.

[0182] - You develop a tolerance to alcohol, so you need more alcohol to feel its effects, or the effects you feel from the same amount of alcohol are weaker.

[0183] - Experience withdrawal symptoms—such as nausea, sweating, and trembling—when you don't drink alcohol, or drink alcohol to avoid these symptoms.

[0184] Doping disorders involve, but are not limited to, problematic patterns of use of amphetamine, methamphetamine, cocaine, or other stimulants other than caffeine or nicotine, resulting in at least two of the following problems over a 12-month period: - Taking more stimulants than expected.

[0185] - Despite attempts to reduce or control doping use, there has been no success.

[0186] - Spending too much time on activities related to doping.

[0187] - The urge and craving for stimulants.

[0188] - Failure to fulfill obligations at home, school, or work.

[0189] - Continue taking stimulants, even if it has led to interpersonal or social problems.

[0190] - Giving up or reducing important recreational, social, or work-related activities due to the use of stimulants.

[0191] - Using stimulants in a way that is harmful to the body.

[0192] - Continue to use stimulants, even knowing that it causes or worsens physical or psychological problems.

[0193] - Tolerance to stimulants.

[0194] - If you don't take stimulants, then quit them.

[0195] Multiple drug use disorder or multiple substance use disorder involves, but is not limited to, dependence on multiple drugs or substances.

[0196] The term "MOR agonist" is intended to refer to any compound or substance that activates the μ-opioid receptor (MOR). Agonists can be partial agonists, full agonists, or superagonists.

[0197] In some implementations, the compounds of the present invention may be safer and have fewer side effects compared to existing treatments.

[0198] In some embodiments, the compounds of the present invention may have better hERG profiles / cardiac profiles compared to ibogain and noibogain.

[0199] In some embodiments, the compounds of the present invention can be used as tool compounds for studying the mechanism of ibogain.

[0200] Those skilled in the art can use the techniques disclosed herein to prepare their deuterium analogs.

[0201] Unless otherwise stated, the compounds of this invention comprise asymmetric carbon atoms, and it should be understood that the compounds exist in racemic, racemic mixtures, scalemic mixtures, and isolated single enantiomers. All such isomers of these compounds are explicitly included in this invention. Unless otherwise stated, each stereocarbon may be in an R or S configuration. Therefore, it should be understood that, unless otherwise stated, isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and stereochemically controlled synthesis (such as those described in J. Jacques, A. Collet, and S. Wilen, “Enantiomers, Racemates and Resolutions”, Pub. John Wiley & Sons, NY, 1981). For example, resolution can be performed by preparative chromatography on a chiral column.

[0202] Unless otherwise stated, this invention is intended to include all atomic isotopes appearing in the compounds disclosed herein. Isotopes include atoms that have the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0203] It should be noted that throughout this application, any designation of carbon in the structure, when used without further designation, is intended to represent all isotopes of carbon, such as 12 C 13 C or 14 C. In addition, it contains 13 C or 14 Any compound of C may specifically have the structure of any of the compounds disclosed herein.

[0204] It should also be noted that, unless otherwise stated, throughout this application, any designation of hydrogen (H) in the structure, when used without further designation, is intended to represent all isotopes of hydrogen, such as 1 H, 2 H (D) or 3 H(T). Furthermore, unless otherwise stated, contains 2 H (D) or 3 Any compound of H(T) may specifically have the structure of any of the compounds disclosed herein.

[0205] Isotope-labeled compounds can typically be prepared using conventional techniques known to those skilled in the art, using appropriate isotope-labeled reagents instead of the unlabeled reagents employed.

[0206] deuterium( 2 H or D) is a stable, non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Hydrogen atoms in compounds are expressed as isotopes. 1 H (hydrogen or protium), D ( 2 H or deuterium) and T ( 3 It exists naturally in the form of a mixture of hydrogen (H or tritium). The natural abundance of deuterium is 0.0156%. Therefore, in a composition containing molecules of a naturally occurring compound, the level of deuterium at a specific hydrogen atom site in that compound is expected to be 0.0156%. Thus, a composition of a compound containing a deuterium level at any hydrogen atom site in the compound is novel relative to its naturally occurring counterpart, which has been enriched to a level greater than its natural abundance of 0.0156%.

[0207] As used herein, considering all molecules of a compound within a defined universe (such as a composition or sample), hydrogen at a specific site in the compound is “deuterium-enriched” if the amount of deuterium at that specific site is greater than the abundance of naturally occurring deuterium at that specific site. “Naturally occurring” as used above refers to the deuterium abundance present at the relevant site in the compound when the compound is prepared without using any definitive steps to enrich the deuterium abundance. Therefore, at a “deuterium-enriched” site in a compound, the deuterium abundance at that site can range from greater than 0.0156% to 100%. Examples of methods for obtaining deuterium-enriched sites in a compound include exchanging hydrogen with deuterium or synthesizing the compound using deuterium-enriched starting materials.

[0208] In the compounds used in the methods of this invention, substituents may be substituted or unsubstituted, unless otherwise specifically defined.

[0209] In the compounds used in the methods of this invention, alkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These groups include, but are not limited to, halogenated, hydroxyl, mercapto, amino, carboxyl, cyano, and carbamoyl groups.

[0210] It should be understood that the substituents and substitution patterns on the compounds used in the methods of this invention can be selected by those skilled in the art to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0211] When selecting compounds for use in the methods of this invention, those skilled in the art will recognize that various substituents (i.e., R1, R2, etc.) should be selected according to well-known principles of chemical structure linkage.

[0212] As used herein, "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups with a specific number of carbon atoms. Therefore, "C1–C n C1-C in "alkyl" n Defined as a group comprising a straight chain or a straight-chain arrangement having 1, 2, ..., n-1 or n carbons, and specifically including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl, etc. One embodiment may be C1-C 12 Alkyl, C2-C 12 Alkyl, C3-C 12 Alkyl, C4-C 12 Alkyl groups, etc. One embodiment may be C1-C8 alkyl, C2-C8 alkyl, C3-C8 alkyl, C4-C8 alkyl, etc. "Alkoxy" refers to an alkyl group as described above connected by an oxygen bridge bond.

[0213] The term "alkenyl" refers to a straight-chain or branched non-aromatic hydrocarbon group containing at least one carbon-carbon double bond, and can have the maximum possible number of non-aromatic carbon-carbon double bonds. Therefore, C2-C n Alkenyl groups are defined as having 1, 2, ..., n-1, or n carbon atoms. For example, "C2-C6 alkenyl" means having 2, 3, 4, 5, or 6 carbon atoms and at least one carbon-carbon double bond, and in the case of a C6 alkenyl group, up to, for example, 3 carbon-carbon double bonds. Alkenyl groups include vinyl, propenyl, butenyl, and cyclohexenyl. As described above regarding alkyl groups, the straight-chain, branched, or cyclic portion of the alkenyl group may contain double bonds and may be substituted if indicated by a substituted alkenyl group. One embodiment may be C2-C... 12Alkenyl or C2-C8 alkenyl.

[0214] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond and can have the maximum possible number of non-aromatic carbon-carbon triple bonds. Therefore, C2-C n An alkynyl group is defined as having 1, 2, ..., n-1, or n carbon atoms. For example, "C2-C6 alkynyl" means having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and at most 2 carbon-carbon triple bonds, or having 6 carbon atoms and at most 3 carbon-carbon triple bonds. Alynyl groups include ethynyl, propynyl, and butynyl. As described above regarding alkyl groups, the straight-chain or branched portion of the alkynyl group may contain a triple bond, and may be substituted if a substituted alkynyl group is indicated. One embodiment may be C2-C... n Alkyne group. One embodiment could be C2-C. 12 Alkyne group or C3-C8 alkynyl group.

[0215] The term "alkylaryl" refers to an alkyl group as described above, wherein one or more bonds to hydrogen atoms contained in the alkyl group are replaced by bonds to an aryl group as described above. It should be understood that an "alkylaryl" group is linked to the core molecule via bonds from the alkyl group, and the aryl group acts as a substituent on the alkyl group. Examples of aryl alkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, etc.

[0216] As used herein, “cycloalkyl” includes a cyclic ring of alkanes with a total of three to eight carbon atoms or any number of such cyclic atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0217] The term "alkylcycloalkyl" refers to an alkyl group as described above, wherein one or more bonds to hydrogen atoms contained in the alkyl group are replaced by bonds to a cycloalkyl group as described above. It should be understood that "alkylcycloalkyl" is linked to the core molecule via bonds derived from the alkyl group, and the cycloalkyl group acts as a substituent on the alkyl group.

[0218] As used herein, “aryl” is intended to mean any stable monocyclic, bicyclic, or polycyclic carbon ring having 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, but are not limited to: phenyl, p-tolyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indenyl, phenanthryl, anthraceneyl, or acenaphthene. Where the aryl substituent is bicyclic and one ring is non-aromatic, it should be understood that the linkage occurs via the aromatic ring.

[0219] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic ring having up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic aromatic heteroaryls include phenyl, pyridine, pyrimidine, or pyridazine rings that are fused with (a) a 6-membered aromatic (unsaturated) heterocycle having one nitrogen atom; (b) a 5- or 6-membered aromatic (unsaturated) heterocycle having two nitrogen atoms; (c) a 5-membered aromatic (unsaturated) heterocycle having one nitrogen atom and one oxygen atom or one sulfur atom; or (d) a 5-membered aromatic (unsaturated) heterocycle having one heteroatom selected from O, N, or S. The heteroaryl groups within this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzooxazolyl, carbazoleyl, carbolinyl, cinnolinyl, furanyl, indololinyl, indolyl, indolazinyl, indolazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthiazolyl Naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxacyclobutane, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, quinoxolinyl, tetrazolyl, tetrazodopyridyl, thiadiazolyl, thiazolyl, thiophene, triazolyl, aziridine, aziridinyl, 1,4-dioxacyclohexane, hexacyclohexane Hydrozazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzooxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dihydroquinolinyl, dihydrotetrazoleyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiaphenyl, dihydrotriazolyl, di... The heterocyclic substituents are butylene, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothiopheneyl, acridineyl, carbazoyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, benzothiazoyl, benzooxazolyl, isoxazolyl, isothiazolyl, furanyl, thiopheneyl, benzothiapheneyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrroleyl, and tetrahydroquinoline. Where the heteroaryl substituent is bicyclic and one ring is non-aromatic or does not contain a heteroatom, it should be understood that the connection occurs via either the aromatic ring or the ring containing the heteroatom. If the heteroaryl group contains a nitrogen atom, it should be understood that this definition also covers its corresponding N-oxide.

[0220] The terms "heterocycle," "heterocyclic group," or "heterocyclic" refer to a monocyclic or polycyclic ring system that may be saturated or contain one or more degrees of unsaturation and one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is tri- to ten-membered and is saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution permitted. Such a ring may optionally be fused with one or more of another "heterocycle," a heteroaryl ring, an aryl ring, or a cycloalkyl ring. 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-oxothiocyclopentane, etc.

[0221] The term "ester" is intended to refer to organic compounds containing RO-CO-R' groups.

[0222] The term "phenyl" is intended to refer to an aromatic six-membered ring containing six carbon atoms.

[0223] The term “benzyl” is intended to refer to the –CH2R1 group, where R1 is a phenyl group.

[0224] The terms “substitution,” “substituted,” and “substituent” refer to functional groups as described above, in which one or more bonds to hydrogen atoms contained in the functional group are replaced by bonds to non-hydrogen or non-carbon atoms, provided that the normal valence is maintained and the substitution produces a stable compound. Substituent groups also include groups in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds to heteroatoms (including double or triple bonds). 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, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl groups; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkoxy groups, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; thioalkyl groups, such as methylthioalkyl, ethylthioalkyl, and propylthioalkyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl groups. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted by one or more of the disclosed or claimed substituent moieties (mono-substituted or poly-substituted). Independent substitution means that (two or more) substituents can be the same or different.

[0225] The compounds used in the methods of this invention can be prepared using techniques well known in organic synthesis and familiar to those skilled in the art. However, these techniques may not be the only means of synthesizing or obtaining the desired compounds.

[0226] The compounds used in the methods of this invention can be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, AI Vogel, AR Tatchell, BS Furnis, AJ Hannaford, PWG 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 the references therein, which are incorporated herein by reference. However, these techniques may not be the only means of synthesizing or obtaining the desired compounds.

[0227] Another aspect of the present invention includes the compounds or compositions of the present invention as pharmaceutical compositions.

[0228] As used herein, the term "pharmaceutical active agent" means any substance or compound suitable for administration to a subject and which provides biological activity or other direct action in the treatment, cure, relief, diagnosis, or prevention of a disease, or affects the structure or any function of the subject. Pharmaceutical active agents include, but are not limited to, the substances and compounds described in the Physicians' Desk Reference (PDRNetwork, LLC; 64th edition; November 15, 2009) and "Approved Drug Products with Therapeutic Equivalence Evaluations" (US Department of Health and Human Services, 30th edition, 2010), which are incorporated herein by reference. Pharmaceutical active agents having a dangling carboxylic acid group can be modified according to the invention using standard esterification reactions and methods readily available and known to those skilled in the art of chemical synthesis. When a pharmaceutical active agent does not have a carboxylic acid group, those skilled in the art will be able to design and incorporate the carboxylic acid group into the pharmaceutical active agent, where esterification can then be performed, provided that the modification does not interfere with the biological activity or action of the pharmaceutical active agent.

[0229] The compounds used in the methods of this invention may be in salt form. As used herein, "salt" refers to a salt of the compound of this invention that has been modified by preparing an acid or base salt of the compound. The salt is pharmaceutically acceptable when the compound is used to treat a disease or medical condition. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines; acidic residues such as basic or organic salts of phenols; and acidic residues such as basic or organic salts of carboxylic acids. These salts can be prepared using organic or inorganic acids. Such acidic salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbic acid salts, etc. Phenolic salts are sodium, potassium, or lithium salts, etc. Carboxylic acid salts are sodium, potassium, or lithium salts, etc. In this respect, the term "pharmaceuticalally acceptable salt" refers to a relatively non-toxic inorganic or organic acid or base addition salt of the compound of this invention. These salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or by reacting the purified compounds of the present invention, in their free base or free acid form, with a suitable organic or inorganic acid or base alone and separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, glucono-p-ethyl, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts") J. Pharm. Sci. 66:1-19).

[0230] As used in this article, "treatment" means to prevent, slow, stop, or reverse the progression of a disease. Treatment can also mean to improve one or more symptoms of a disease.

[0231] The compounds used in the methods of this invention can be administered in various forms, including those detailed herein. Treatment with the compound can be part of a combination therapy or adjunctive therapy, i.e., treating a subject or patient requiring the drug in combination with one or more of the compounds of this invention, or administering another drug to the subject or patient for the disease. Such combination therapy can be sequential therapy, wherein the patient is first treated with one drug, followed by the simultaneous administration of another or two drugs. Depending on the dosage form used, these drugs can be administered independently via the same route of administration or via two or more different routes of administration.

[0232] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent, or excipient for delivering the compounds of the present invention to animals or humans. The carrier may be liquid or solid and is selected based on the planned method of administration. Liposomes are also pharmaceutically acceptable carriers, as are capsules, coatings, and various syringes.

[0233] The dosage of compounds administered during treatment will vary depending on factors such as: the pharmacodynamic characteristics of the specific chemotherapeutic agent and its administration mode and route; the recipient's age, sex, metabolic rate, absorption efficiency, health status, and weight; the nature and severity of symptoms; the type of concurrent treatment being administered; the frequency of treatment; and the desired therapeutic effect.

[0234] The dosage units of the compounds used in the methods of this invention may comprise a single compound or a mixture thereof with other pharmaceutical agents. The compounds may be administered in oral dosage forms such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, or introduced directly into or onto the site of disease, for example by injection, local application, or other methods, using dosage forms well known to those skilled in the art of pharmaceuticals.

[0235] The compounds used in the methods of this invention can be administered in combination with suitable pharmaceutical diluents, fillers, excipients, or carriers (collectively referred to herein as pharmaceutically acceptable carriers), which are appropriately selected according to the intended form of administration and in accordance with conventional pharmaceutical practice. The unit will be in a form suitable for oral, rectal, topical, intravenous, or direct injection or parenteral administration. The compound can be administered alone or in combination with a pharmaceutically acceptable carrier. This carrier can be solid or liquid, and the type of carrier is generally selected according to the type of administration used. The active agent can be administered in tablet or capsule form, liposome form, as a condensed powder form, or in liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsules or tablets are readily reconstituted and can be formulated for easy swallowing or chewing; other solid forms include granules and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, 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 particles, and effervescent preparations reconstituted from effervescent particles. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavoring agents and coloring agents. Parenteral and intravenous forms may also include inorganic and other materials to ensure compatibility with the type of injection or delivery system chosen.

[0236] The techniques and compositions used to prepare dosage forms applicable to this invention are described in the following references: 7 Modern Pharmaceuticals, Chapters 9 and 10 (edited by Banker and Rhodes, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd ed. (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (edited by David Ganderton and Trevor Jones, 1992); Advances in Pharmaceutical Sciences, Volume 7 (edited by David Ganderton, Trevor Jones, and James McGinity, 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Volume 36 (edited by James McGinity, 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol. 61 (edited by Alain Rolland, 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; edited by J.G. H. D., S. Davis, and Clive G. Wilson); Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, Vol. 40 (edited by Gilbert S. Banker and Christopher T. Rhodes). All of the above publications are incorporated herein by reference.

[0237] Tablets may contain suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and melting agents. For example, for oral administration in tablet or capsule dosage units, the active pharmaceutical ingredient may be combined with an orally accessible, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0238] The compounds used in the methods of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamine, or phosphatidylcholine. The compounds can be administered as components of tissue-targeted emulsions.

[0239] The compounds used in the methods of this invention can also be coupled to soluble polymers as targeted drug carriers or prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds can be coupled to a class of biodegradable polymers that can be used to achieve controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0240] Gelatin capsules can contain active ingredient compounds and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as immediate-release or sustained-release products to provide sustained drug release over a period of several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablet from atmospheric effects, or enteric-coated for selective disintegration in the gastrointestinal tract.

[0241] For oral administration of liquid dosage forms, the oral drug component is combined with any orally accessible, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. 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 particles, and effervescent preparations reconstituted from effervescent particles. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0242] Liquid dosage forms intended for oral administration may contain colorants and flavorings to increase patient acceptability. Generally, water, suitable oils, saline solutions, aqueous solutions of dextran (glucose) and related sugar solutions, as well as glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of the active ingredient, suitable stabilizers, and (if necessary) buffering agents. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite, or ascorbic acid, are suitable stabilizers. Citric acid and its salts, as well as sodium EDTA, are also used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol. Suitable drug carriers are described in Remington's Pharmaceutical Sciences, 17th edition, 1989, which is the standard reference text in the field.

[0243] The compounds used in the methods of the present invention can also be administered intranasally using a suitable intranasal medium, or via a transdermal route using transdermal skin patches in those forms known to those skilled in the art.

[0244] Parenteral and intravenous forms may also include inorganic and other materials to make them compatible with the type of injection or delivery system chosen.

[0245] Each embodiment disclosed herein is contemplated to be applicable to each of the other disclosed embodiments. Therefore, all combinations of the various elements described herein are within the scope of this invention. Any of the disclosed general or specific compounds may be applied to any of the disclosed compositions, processes, or methods.

[0246] The invention will be better understood by referring to the following experimental details, but those skilled in the art will readily understand that the specific experiments described are merely illustrative of the invention, as more fully described in the following claims.

[0247] Example Experimental details General considerations. Reagents and solvents are obtained from commercial sources and used without further purification unless otherwise specified. Reactions are monitored by TLC using a solvent mixture suitable for each reaction. Column chromatography is performed on silica gel (40–63 µm). For preparative TLC, glass plates coated with a 1 mm layer of silica are used. Nuclear magnetic resonance spectra are recorded on a Bruker 400 or 500 MHz instrument as instructed. Chemical shifts are reported as δ values ​​(in ppm), referring to CDCl3 (… 1 H NMR = 7.26 and 13 C NMR = 77.16) or methanol- d 4( 1 H NMR = 3.31 and 13 C NMR = 49.00. Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (quintet); dd (double doublet); td (triple doublet); dt (double triplet); dq (double quartet); ddd (double double doublet); ddt (double double triplet); m (multiplet); br (broad peak). All carbon peaks are rounded to one decimal place unless such rounding would result in two adjacent peaks being identical; in these cases, two decimal places are retained. Low-resolution mass spectra are recorded on an Advion quadrupole instrument (ionization mode: APCI+ or ESI+).

[0248] Compound 1 was prepared by modifying a published method (Hu et al., 2020). KOH (22.44 g, 0.4 mol) was added to a solution of 4-bromophenol (69.2 g, 0.4 mol) in 2-propanol (60 mL), toluene (100 mL), and water (10 mL), and the mixture was stirred at 85 °C for 1.5 h. Hydroxylamine- OA solution of sulfonic acid (11.31 g, 0.1 mol) in water (60 mL) was added dropwise to the reaction mixture over 15 minutes, and the reaction was continued at 85 °C for 20 min. The reaction mixture was cooled to room temperature, and an aqueous solution of NaOH (1 M, 300 mL) was added. The mixture was extracted with diethyl ether (2 × 200 mL). The combined extracts were washed with an aqueous solution of NaOH (1 M, 4 × 125 mL), dried over Na₂SO₄, filtered, and the diethyl ether was evaporated under reduced pressure. The resulting yellow solution was diluted with MeOH (60 mL), and a concentrated aqueous solution of HCl (12.1 M, 8.3 mL) was slowly added. After stirring at room temperature for 1 h, the resulting suspension was concentrated under reduced pressure, dissolved in MeOH, and concentrated again. Compound 1 was isolated as a light brown crystalline powder (9.26 g, 41% yield). Spectroscopic characterization was consistent with reported literature data.

[0249] 1 H NMR (400 MHz, DMSO)δ 9.08 (br, 3H), 7.61 – 7.45 (m, 2H), 7.21 –7.09 (m, 2H).

[0250] Scheme 1. Synthesis of allyl-lactam intermediate 2.

[0251] Compound 2 was prepared by a modified method as described in the publication (Sames et al., 2022). A solution of 1,4-cyclohexanedione monoethylene glycol acetal (17.18 g, 0.11 mol) in THF (200 mL) was cooled to -78 °C, and LHMDS (1 M in THF, 100 mL, 0.1 mol) was slowly added. The reaction mixture was further stirred for 50 min, and then allyl bromide (10.15 mL, 0.12 mol) was added in portions over 20 min. The reaction mixture was then slowly heated to room temperature. After 15 h, the reaction mixture was quenched with saturated NH4Cl solution (100 mL), the phases were separated, and the aqueous phase was further extracted with diethyl ether (2 × 100 mL). The combined extracts were washed with brine (2 × 100 mL), dried over MgSO4, filtered, and concentrated on diatomaceous earth. The crude material was filtered through silica using a gradient of AcOEt / hexane (2% to 10%, in 1% increments). The semi-crude material contained dialkylation byproducts and was used in the next step without further purification. The impure ketone intermediate (17.20 g) was dissolved in MeOH (140 mL), H₂O (35 mL), hydroxylamine hydrochloride (6.70 g, 96.4 mmol), and sodium acetate (7.91 g, 96.4 mmol) were added, and the reaction mixture was stirred at 80 °C. After 2 h, the MeOH was evaporated under reduced pressure, the mixture was diluted with brine (50 mL), and extracted with CH₂Cl₂:iPrOH 9:1 (4 × 50 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated into a slowly crystalline yellow oil. The crude oxime (19.7 g) was dissolved in acetone (352 mL), H₂O (528 mL), Na₂CO₃ (37.16 g, 350.6 mmol), and... p -TsCl (33.42 g, 175.30 mmol) was added, and the reaction mixture was stirred at 40 °C. After 17 h, acetone was evaporated under reduced pressure, and the resulting aqueous mixture was saturated with NaCl and extracted with CH2Cl2:iPrOH 9:1 (5 × 100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in refluxed acetone (60 mL), cooled to room temperature, and placed overnight in a refrigerator (+8 °C). The precipitate was collected by filtration as a white solid (10.54 g). The mother liquor was concentrated and purified by column chromatography using 25% to 50% acetone / hexane. Compound 2 was given as a white solid (12.13 g, 57% yield, in 3 steps). Spectroscopic characterization was consistent with reported literature data (Sames et al., 2022).

[0252] 1H NMR (400 MHz, CDCl3)δ 6.26 (s, 1H), 5.74 (ddt, J = 18.9, 9.6, 7.0 Hz,1H), 5.27 – 5.13 (m, 2H), 3.97 (dd, J = 4.1, 1.8 Hz, 4H), 3.74 – 3.60 (m, 1H), 2.70 (ddd, J = 14.9, 12.9, 2.3 Hz, 1H), 2.48 – 2.21 (m, 3H), 1.95 – 1.77 (m,3H), 1.70 (dd, J = 13.9, 10.5 Hz, 1H). LRMS (APCI + ): Regarding C 11 H 18 NO3 + [M+H] + Calculated value: 212.1, measured value: 212.3.

[0253] Scheme 2. Synthesis of intermediate 3.

[0254] Compound 3 was prepared by modifying the published procedure (Sames et al., 2022). 2Allyl lactam 2 (2.11 g, 10.0 mmol) was dissolved in EtOH (65 mL, non-dried) and moistened 10% Pd / C (200 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere (3 MPa) for 5–6 h. The suspension was then filtered through diatomaceous earth (thoroughly rinsed with CH2Cl2:MeOH 9:1) and the solution was concentrated to obtain a white solid. The dried crude product (2.13 g) was dissolved in THF (20 mL) and cooled in an ice bath (0 °C, where the lactam would partially precipitate). Initially, LiAlH4 (1.52 g, 40 mmol) was carefully added in small batches. After the exothermic reaction subsided, the remaining portion was added to the suspension. The reaction mixture was heated to room temperature and then to reflux for 3 h. After cooling to room temperature, the reaction mixture was diluted with THF (30 mL), cooled in an ice bath, and slowly quenched by adding H2O, 15% NaOH aqueous solution, and H2O (1:1:3 mL / g LiAlH4), and stirred until all salts were grayish-white and loose. The solids were filtered off and washed with THF until no further product elution was detected by TLC. The combined washes were acidified with aqueous HCl (12.1 M, 0.9 mL, 1.1 equivalents) and the volatile organic compounds were evaporated under reduced pressure. 10% HCl (40 mL) was added to the residue, and the mixture was stirred further at room temperature for 3 days. The solution was concentrated, the oily residue was dissolved in water (20 mL), carefully neutralized with solid NaHCO3, and the pH was adjusted to >10 with 15% NaOH. The mixture was further extracted with CH2Cl2:iPrOH 9:1 (6 × 20 mL), the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude intermediate (1.51 g) was immediately used in the next step. The orange residue was dissolved in CH₂Cl₂ (19.5 mL), Et₃N (3.39 mL, 24.3 mmol) was added, and the mixture was cooled in an ice bath. Trifluoroacetic anhydride (2.7 mL, 19.45 mmol) was added dropwise, and the mixture was further stirred at room temperature. After 18 h, the reaction mixture was slowly diluted with saturated NaHCO₃ solution (30 mL), vigorously mixed, and the phases were separated. The aqueous phase was further extracted with CH₂Cl₂ (2 × 20 mL), the combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The red oily residue was purified by column chromatography using ether / hexane at a ratio of 1:1 to 3:1. The compound was isolated as an orange oil (1.98 g, 79% yield, after 4 steps). NMR spectrum ( 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers. 1Partial integration in H NMR).

[0255] 1 H NMR (400 MHz, CDCl3)δ 4.67 (q, J = 6.5 Hz, 0.6H), 4.43 (dt, J = 14.3,4.1 Hz, 0.4H), 4.11 (p, J = 7.0 Hz, 0.4H), 3.94 (dd, J = 15.9, 5.4 Hz, 0.6H), 3.62 – 3.20 (m, 1H), 3.11 – 2.46 (m, 4H), 2.08 – 1.83 (m, 2H), 1.77 – 1.48(m, 2H), 1.42 – 1.19 (m, 2H), 0.99 – 0.89 (m, 3H). 19 F NMR (471 MHz, CDCl3)δ -67.86, -68.60. LRMS (APCI + ): Regarding C 11 H 17 F3NO2 + [M+H] + Calculated value: 252.1, measured value: 252.5.

[0256] Scheme 3. Synthesis of intermediate 4.

[0257] Allyl lactam 2 (2.95 g, 10.0 mmol) was dissolved in THF (28 mL) and cooled in an ice bath (0 °C, where the lactam would partially precipitate). LiAlH4 (2.12 g, 55.9 mmol) was initially added carefully in small batches, and after the exothermic reaction subsided, the remaining portion was added to the suspension. The reaction mixture was heated to room temperature and then to 70 °C for 3.5 h. After cooling to room temperature, the reaction mixture was diluted with THF (28 mL), cooled in an ice bath, and slowly quenched by adding H2O, 15% NaOH aqueous solution, and H2O (1:1:3 mL / g LiAlH4), stirring until all salts were off-white and loose. The solids were filtered off and washed with THF until no further product was detected by TLC. The combined washes were acidified with aqueous HCl (12.1 M, 1.1 equivalents), and the volatile organic compounds were evaporated under reduced pressure. Add 10% HCl (56 mL) to the residue and stir the mixture further at room temperature for 3 days. Concentrate the solution, wash the oily residue with diethyl ether (2 ×) and dry under vacuum. Suspend the crude intermediate (3.0 g) in CH2Cl2 (31.7 mL), add Et3N (7.7 mL, 55.4 mmol), and cool the mixture in an ice bath. Add trifluoroacetic anhydride (4.4 mL, 31.6 mmol) dropwise and stir the mixture further at room temperature. After 18 h, slowly dilute the reaction mixture with saturated NaHCO3 solution (50 mL), mix vigorously and separate the phases. Further extract the aqueous phase with CH2Cl2 (2 ×), dry the combined extracts with Na2SO4, filter and concentrate under reduced pressure. Purify the red oily residue by column chromatography using diethyl ether / hexane at a ratio of 1:1 to 2:1. Separate compound 4 as an impure complex mixture (3.0 g) and use it as is for the next step. NMR spectrum ( 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers. 1 Partial integration in H NMR). LRMS (APCI) + ): Regarding C 11 H 15 F3NO2 + [M+H] + Calculated value: 250.1, measured value: 250.0.

[0258] Scheme 3. Synthesis of intermediates 5 and 6.

[0259] Example 1.7-(cyclopropylmethyl)-1,4-dioxa-8-azaspiro[4.6]undecane-9-one 5.

[0260] Diethylzinc (1 M in toluene, 15 mL, 15 mmol) was diluted with CH2Cl2 (15 mL) and cooled to 0 °C in a water / ice bath. A solution of CF3COOH (1.15 mL, 15 mmol) in CH2Cl2 (5 mL) was added dropwise over 5 min, and the mixture was further cooled to 0 °C. After 20 min, a solution of CH2I2 (1.21 mL, 15 mmol) in CH2Cl2 (5 mL) was added in one go, followed by a solution of allyl lactam 3 (1.06 g, 5 mmol) in CH2Cl2 (5 mL). The cooling was removed, and the mixture was stirred at room temperature. After 66 h, the mixture was poured into a saturated NH4Cl solution (50 mL), the phases were separated, and the aqueous phase was further extracted with CH2Cl2 (2 x 20 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. Only 70% conversion was achieved. The crude material was purified by column chromatography using acetone / hexane at a ratio of 1:2 to 1:1 to obtain an inseparable mixture of starting allyl and methylcyclopropyl lactam. The reaction was repeated once more using the mixture of allyl and methylcyclopropyl lactam. After 24.5 h, the reaction was stopped, and the post-treatment was repeated as before. The crude material was purified by column chromatography using acetone / hexane at a ratio of 1:1 to obtain the product as a white solid (1.03 g, 91% yield).

[0261] 1 H NMR (500 MHz, CDCl3)δ 5.94 (s, 1H), 4.08 – 3.89 (m, 4H), 3.76 –3.63 (m, 1H), 2.73 (ddd, J = 14.9, 13.0, 2.0 Hz, 1H), 2.40 (ddt, J = 14.5, 7.1,2.0 Hz, 1H), 1.99 – 1.80 (m, 3H), 1.74 (dd, J = 13.8, 10.5 Hz, 1H), 1.53 – 1.38 (m, 2H), 0.78 – 0.63 (m, 1H), 0.63 – 0.50 (m, 2H), 0.21 – 0.07 (m, 2H). LRMS(APCI + ): Regarding C 12 H 20 NO3 + [M+H]+ Calculated value: 226.1; measured value: 226.3.

[0262] Example 2.2-(cyclopropylmethyl)-1-(2,2,2-trifluoroacetyl)azacycloheptane-4-one 6.

[0263] Methylcyclopropyllactam 5 (1.03 g, 4.6 mmol) was dissolved in THF (9.2 mL) and cooled in an ice bath (0 °C, where the lactam would partially precipitate). LiAlH4 (0.69 g, 18.3 mmol) was initially added carefully in small batches. After the exothermic reaction subsided, the remaining portion was added to the suspension. The reaction mixture was heated to room temperature and then to reflux for 3 h. After cooling to room temperature, the reaction mixture was diluted with THF (15 mL), cooled in an ice bath, and slowly quenched by adding H2O, 15% NaOH aqueous solution, and H2O (1:1:3 mL / g LiAlH4), stirring until all salts were off-white and loose. The solids were filtered off and washed with THF until no further product was detected by TLC. The combined washes were acidified with aqueous HCl (12.1 M, 1.1 equivalence) and the volatile organic compounds were evaporated under reduced pressure. Add 10% HCl (20 mL) to the residue and stir the mixture further at room temperature for 3 days. Concentrate the solution, dissolve the oily residue in water (20 mL), carefully neutralize with solid NaHCO3, and adjust the pH to >10 with 15% NaOH. Extract the mixture further with CH2Cl2:iPrOH 9:1 (5 × 20 mL), dry the combined extracts with Na2SO4, filter, and concentrate under reduced pressure. The crude intermediate (0.76 g) is immediately used for the next step. Dissolve the orange residue in CH2Cl2 (9.2 mL), add Et3N (1.58 mL, 11.4 mmol), and cool the mixture in an ice bath. Add trifluoroacetic anhydride (1.3 mL, 9.09 mmol) dropwise and stir the mixture further at room temperature. After 18 h, slowly dilute the reaction mixture with saturated NaHCO3 solution (15 mL), mix vigorously, and separate the phases. The aqueous phase was further extracted with CH2Cl2 (2 × 10 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The red oily residue was purified by column chromatography using 1:1 diethyl ether / hexane. Impure compound 6, an orange oil (0.93 g), was obtained and used in the next step without further purification.

[0264] LRMS (APCI + ): Regarding C12 H 17 F3NO2 + [M+H] + Calculated value: 264.1, measured value: 264.1.

[0265] Scheme 4. Synthesis of butyl-lactam intermediate 7.

[0266] Example 3.7-Butyl-1,4-dioxa-8-azaspiro[4.6]undecane-9-one 7.

[0267] A solution of 1,4-cyclohexanedione monoethylene glycol acetal (5.14 g, 32.9 mmol) in THF (0.5 M, 65.8 mL) was cooled to -78 °C, and LHMDS (1 M in THF, 32.9 mL) was slowly added. The reaction mixture was stirred further for 50 min, followed by the addition of crotonyl bromide (3.7 g, 27.4 mmol) in portions over 20 min, and the mixture was slowly heated to room temperature. After 15 h, the mixture was quenched with saturated NH4Cl solution (50 mL), the phases were separated, and the aqueous phase was further extracted with Et2O (50 mL). The combined extracts were washed with brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated on diatomaceous earth. The crude material was purified by column chromatography using a gradient of AcOEt / hexane (5% to 10%). The material still contained dialkylation byproducts and was used in the next step without further purification. Impure ketone intermediate (4.25 g) was dissolved in MeOH (32 mL), H₂O (8 mL), hydroxylamine hydrochloride (1.54 g, 22.2 mmol), and sodium acetate (1.82 g, 22.2 mmol) were added, and the reaction mixture was stirred at 80 °C. After 2 h, the MeOH was evaporated under reduced pressure, the mixture was diluted with brine (30 mL), and extracted with DCM:iPrOH 9:1 (4 × 30 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated. Crude oxime (4.55 g) was dissolved in acetone (40 mL), H₂O (61 mL), Na₂CO₃ (6.43 g, 60.6 mmol), and... p-TsCl (5.78 g, 30.3 mmol) was added, and the reaction mixture was stirred at 40 °C for 2.5 days. Acetone was evaporated under reduced pressure, and the aqueous mixture was diluted with brine (15 mL) and extracted with DCM:iPrOH 9:1 (4 × 50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude material (brown oil, 4.72 g) was dissolved in hot acetone (20 mL), cooled to room temperature, and placed in a refrigerator (+8 °C) overnight. The precipitate was collected by filtration and recrystallized once from acetone. The solid material (0.56 g) was dissolved in MeOH (12.5 mL), 10% Pd / C (53 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere (1.5 MPa). The next day, the reaction mixture was filtered through a diatomaceous earth pad (washed several times with MeOH) and the MeOH solution was concentrated to obtain product 7 (0.56 g, 11% yield, after 4 steps), which was a white solid.

[0268] 1 H NMR (500 MHz, CDCl3)δ 5.63 (s, 1H), 3.95 (dd, J = 3.9, 2.0 Hz, 4H), 3.56 – 3.44 (m, 1H), 2.66 (ddd, J = 14.8, 13.1, 2.1 Hz, 1H), 2.33 (ddt, J = 14.3,7.0, 1.9 Hz, 1H), 1.92 – 1.75 (m, 3H), 1.64 (dd, J = 13.8, 10.4 Hz, 1H), 1.47(ddt, J = 8.6, 6.3, 2.5 Hz, 2H), 1.41 – 1.26 (m, 4H), 0.95 – 0.84 (m, 3H). 13 CNMR (126 MHz, CDCl3)δ 176.9, 109.1, 64.8, 64.6, 48.8, 45.6, 35.6, 33.1, 31.1, 28.1, 22.4, 14.0. LRMS (APCI + ): Regarding C 12 H 22 NO3 + [M+H] + Calculated value: 228.2, measured value: 228.2.

[0269] Scheme 5. Synthesis of compound 8.

[0270] Example 4.2-Butyl-1-(2,2,2-trifluoroacetyl)azacycloheptane-4-one 8.

[0271] The lactam intermediate (0.56 g) was dissolved in THF (9.8 mL, 0.25 M), cooled in an ice bath (0 °C), and LiAlH4 (0.28 g, 7.4 mmol) was initially added carefully in small batches. After the exothermic reaction subsided, the remaining fraction was added to the suspension (the starting material precipitated from the cold solution). The reaction mixture was heated to room temperature and then further heated to reflux for 2.5 h. The reaction mixture was further cooled in an ice bath and slowly quenched by adding H2O, 15% NaOH, and H2O (1:1:3 mL / g LiAlH4). The thick suspension was diluted with AcOEt (10 mL) and stirred until all salts were off-white and loose. The solids were filtered off and washed with AcOEt until no further product was detected by TLC. The combined washes were acidified with an aqueous HCl solution (12.1 M), and the volatile organic compounds were evaporated under reduced pressure. Add 10% HCl (25 mL) to the residue and stir the mixture further at room temperature for 2.5 days. Wash the solution with CH2Cl2 (2 × 20 mL), carefully neutralize with solid NaHCO3, and alkalize with 15% NaOH. Extract the mixture further with CH2Cl2 (6 × 20 mL), dry the combined extracts with Na2SO4, filter, and concentrate under reduced pressure. The crude intermediate (0.42 g) was immediately used for the next step. Dissolve the orange residue in CH2Cl2 (4.9 mL), add Et3N (0.86 mL, 6.2 mmol), cool the mixture in an ice bath, and add trifluoroacetic anhydride (0.68 mL, 4.9 mmol) dropwise. Stir the mixture further at room temperature. After 3 h, pour it into a saturated NaHCO3 solution (15 mL), extract the mixture with CH2Cl2 (3 ×), dry the combined extracts with Na2SO4, filter, and concentrate under reduced pressure. The oily residue was purified by column chromatography using a 1:1, 3:1 gradient of diethyl ether / hexane. Compound 8 was isolated as an orange oil (0.69 g), and its NMR spectrum was as follows: 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers.

[0272] LRMS (APCI + ): Regarding C 12 H19 F3NO2 + [M+H] + The calculated value is 266.1, and the measured value is 266.2.

[0273] Scheme 6. Used for preparation N -(trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -Benzofurano[3,2-] c General procedure A for azazolide derivatives.

[0274] The procedure was previously published (Sames et al., 2022). General Procedure A: [The following text appears to be a separate, unrelated section:] ...the corresponding... N -(trifluoroacetyl)azacycloheptan-4-one (1 equivalent) and O-(4-bromophenyl)hydroxylamine hydrochloride were combined in 1,4-dioxane (anhydrous, 0.5 M, based on azacycloheptan-4-one) and heated to 80 °C. After 5 min at 80 °C, methanesulfonic acid (2 equivalents) was added, and the reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reactants were quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with diethyl ether (3 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified as specified for each example.

[0275] Scheme 7. Used for the preparation of 2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d General procedure B for azircon-9-ol and its derivatives.

[0276] General Procedure B: To the corresponding... N -(trifluoroacetyl)-2,3,4,5-tetrahydro-1 H -Benzofurano[3,2-] c1,4-Dioxane (1 M, based on azirconium) and degassed H₂O (1 M, based on azirconium), solid KOH (6 equivalents), catalyst Pd₂Dba₃ (3 mol%), and ligand tBuBrettPhos (6 mol%) were added to the reaction vessel for the azirconium derivative (1 equivalent). The reaction mixture was stirred at 80 °C until complete conversion of the starting material was observed after 5–22 h. After cooling to room temperature, the reaction mixture was acidified with 2 M HCl aqueous solution (to pH 5–6) and further adjusted to pH ~ 7 using saturated NaHCO₃ aqueous solution. The resulting mixture was repeatedly extracted with a CH₂Cl₂:iPrOH 9:1 mixture (3–6 x), and the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The crude material was purified as specified for each example.

[0277] Example 5.1 - (9-bromo-1,2,4,5-tetrahydro-3- H -Benzofurano[2,3- d [Zaziro-3-yl)-2,2,2-trifluoroethyl-1-one 9 and 2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 10.]

[0278] Compound 9 was synthesized according to general procedure A. A mixture of the two isomers was separated by column chromatography using gradients of 10%, 15%, and 20% AcOEt / hexane to obtain slowly solidifying compounds 9 (1.17 g, 32% yield), 10 (1.31 g, 36% yield), and a mixed fraction (0.18 g), all of which were viscous yellow oils. Spectroscopic characterization was consistent with reported literature data (Sames et al., 2022).

[0279] Compound 9: 1 H NMR (400 MHz, CDCl3)δ 7.52 (dd, J = 10.7, 2.0 Hz, 1H), 7.37 – 7.27(m, 1H), 7.27 – 7.21 (m, 1H), 3.95 – 3.85 (m, 4H), 3.17 (t, J = 5.8 Hz, 2H),2.95 – 2.86 (m, 2H). LRMS (APCI + ): Regarding C 14 H 12 BrF3NO2 + [M+H]+ Calculated value: 362.0, measured value: 362.2.

[0280] Compound 10: 1 H NMR (400 MHz, CDCl3)δ 7.58 (dd, J = 54.9, 1.9 Hz, 1H), 7.33 (m, 1H),7.29 – 7.21 (m, 1H), 4.82 – 4.53 (m, 2H), 3.90 (q, J = 5.5 Hz, 2H), 3.06 (t, J =6.8 Hz, 2H), 2.19 – 1.94 (m, 2H). LRMS (APCI + ): Regarding C 14 H 12 BrF3NO2 + [M+H] + Calculated value: 362.0, measured value: 362.2.

[0281] Example 6.2,3,4,5-Tetrahydro-1 H -Benzofurano[2,3- d ]Zaza-9-ol 11.

[0282] Compound 11 was synthesized according to general procedure B. The crude material was purified by column chromatography using a ratio of 95:5:0.5 to 90:10:1 (CH₂Cl₂:MeOH:NH₄OH). Compound 11 was obtained as a brown solid (0.5 g, 76% yield). Spectroscopic characterization was consistent with reported literature data (Sames et al., 2022).

[0283] 1 H NMR (400 MHz, MeOD)δ 7.19 (dd, J = 8.7, 0.8 Hz, 1H), 6.82 (d, J = 2.5Hz, 1H), 6.72 (m, 1H), 3.49 (q, J = 5.3 Hz, 4H), 3.36 – 3.22 (m, 2H), 3.06 –2.99 (m, 2H). LRMS (APCI + ): Regarding C 12 H 14 NO2 + [M+H] +Calculated value: 204.1, measured value: 204.1.

[0284] Example 7.4 -Propyl-2,3,4,5-Tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 13.]

[0285] Compound 12 was synthesized according to general procedure A. The crude material was purified by column chromatography using 5% to 10% AcOEt / hexane. Compound 12 was further transformed according to general procedure B. The crude material was purified by repeated column chromatography, with the first column being 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and the second column being 0 to 5% MeOH / AcOEt + 0.5% NH4OH. The slightly impure product was dissolved in 9:1 CH2Cl2 / MeOH, treated with 2M HCl in diethyl ether, and the resulting suspension was cooled in a refrigerator. The solid was collected by filtration and washed with a cold 9:1 CH2Cl2 / MeOH mixture. Compound 13 was obtained as a beige solid (198 mg, 35% yield, in two steps). Spectroscopic characterization was consistent with reported literature data.

[0286] 1 H NMR (400 MHz, MeOD)δ 7.21 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 3.73 – 3.64 (m, 1H), 3.59 (m, J = 10.3, 7.9,5.6, 2.9 Hz, 1H), 3.44 – 3.36 (m, 1H), 3.34 – 3.27 (m, 1H), 3.20 – 2.94 (m,3H), 1.85 – 1.69 (m, 2H), 1.54 (ddt, J = 15.7, 13.6, 6.9 Hz, 2H), 1.03 (t, J =7.3 Hz, 3H). LRMS (APCI) + ): Regarding C 15 H 20 NO2 + [M+H] + Calculated value: 246.2, measured value: 246.2.

[0287] Example 8.4-Allyl-2,3,4,5-Tetrahydro-1H-benzofurano[2,3-d]azapyro-9-ol 15.

[0288] Compound 14 was synthesized according to general procedure A. The crude material was purified by column chromatography using 5% to 10% AcOEt / hexane. Compound 14 was further converted according to general procedure B. The crude material was purified by column chromatography using 95:5:0.5 to 90:10:1 (CH2Cl2:MeOH:NH4OH) and preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Compound 15 was obtained as a beige foamy solid (81 mg, 26% yield, based on O-(4-bromophenyl)hydroxylamine hydrochloride). The analytical sample used for characterization was obtained by converting the product to hydrochloride in a CH2Cl2 / MeOH mixture and adding aqueous HCl (12.1 M) until the pH on pH paper was about 1. The solution was concentrated under reduced pressure and recrystallized twice from MeOH.

[0289] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.21 (d, J = 8.8 Hz, 1H), 6.84(d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 5.94 – 5.84 (m, 1H), 5.37 –5.29 (m, 2H), 3.73 – 3.63 (m, 2H), 3.43 – 3.35 (m, 1H), 3.30 – 3.25 (m, 1H),3.21 – 3.14 (m, 1H), 3.11 – 3.05 (m, 1H), 3.04 – 2.97 (m, 1H), 2.71 – 2.59 (m, 1H), 2.59 – 2.47 (m, 1H). 13 C NMR (126 MHz, MeOD) δ 154.6, 152.8, 149.6, 132.6, 130.9, 121.3, 115.1, 113.9, 112.1, 104.4, 57.8, 47.6, 38.8, 31.1, 20.9. LRMS (APCI + ): Regarding C 15 H 18 NO2 + [M+H]+ Calculated value: 244.1, measured value: 244.2.

[0290] Example 9.4 -(cyclopropylmethyl)-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 16.]

[0291] The compound was prepared using standard procedure A. The trifluoroacetamide intermediate was purified by column chromatography using a gradient of 5% to 10% AcOEt / hexane. The major isomer was separated as an orange oil (0.51 g, 34%). NMR spectrum ( 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers. LRMS (APCI) + ): Regarding C 18 H 18 BrF3NO2 + [M+H] + Calculated value: 416.1, measured value: 416.2.

[0292] Proceed to the next step according to standard procedure B. The crude material was purified by column chromatography using a 95:5:0.5 (CH₂Cl₂:MeOH:NH₄OH) solution. The product was an orange-brown solid (0.23 g, 73%).

[0293] To obtain the analytical sample, half of the product was suspended in EtOH (1.8 mL), the solid was precipitated by centrifugation, and the liquid was decanted. Washing was repeated once more with diethyl ether. The solid was further dissolved in a CH2Cl2 / MeOH mixture and treated with an aqueous HCl solution (12.1 M) until the pH on pH paper was approximately 1. The solution was concentrated under reduced pressure, and the residue was evaporated from MeOH (2 ×). The purified product hydrochloride was obtained as a beige solid (21 mg).

[0294] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.21 (d, J = 8.7 Hz, 1H), 6.84(d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 3.75 – 3.62 (m, 2H), 3.47 –3.36 (m, 2H), 3.27 (dd, J= 17.4, 10.3 Hz, 1H), 3.12 – 2.98 (m, 2H), 1.82 –1.63 (m, 2H), 0.93 – 0.81 (m, 1H), 0.71 – 0.55 (m, 2H), 0.31 – 0.18 (m, 2H). 13 C NMR (126 MHz, MeOD)δ 154.6, 153.1, 149.6, 130.9, 115.1, 113.8, 112.0,104.4, 59.2, 47.4, 39.0, 31.3, 20.9, 7.8, 5.7, 4.7. LRMS (APCI + ): Regarding C 16 H 20 NO2 + [M+H] + Calculated value: 258.2, measured value: 258.2.

[0295] Example 10.4-Butyl-2,3,4,5-Tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 17.]

[0296] The compound was prepared using standard procedure A. The trifluoroacetamide intermediate was purified by column chromatography using a gradient of 5% to 10% AcOEt / hexane. The major isomer was separated as an orange oil (0.62 g, 57%). NMR spectrum ( 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers. LRMS (APCI) + ): Regarding C 18 H 20 BrF3NO2 + [M+H] + Calculated value: 418.1, measured value: 418.3.

[0297] Proceed to the next step according to general procedure B. The crude material was purified by column chromatography using (5% MeOH in AcOEt solution) + 0.5% NH4OH. The foamy brown solid was dissolved in a CH2Cl2 / MeOH mixture, treated with 2M HCl in diethyl ether, the solution was concentrated under reduced pressure, and the residue was evaporated once more from MeOH. Product 17 was obtained as a beige solid (0.22 g, 52% yield, after two steps).

[0298] Characterized as a hydrochloride:1 H NMR (500 MHz, MeOD)δ 7.21 (d, J = 8.8 Hz, 1H), 6.84(d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 3.68 (ddd, J = 13.5, 6.3, 3.6Hz, 1H), 3.62 – 3.52 (m, 1H), 3.42 – 3.36 (m, 1H), 3.34 – 3.28 (m, 1H), 3.20 – 3.12 (m, 1H), 3.12 – 2.96 (m, 2H), 1.89 – 1.70 (m, 2H), 1.56 – 1.36 (m,4H), 0.99 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, MeOD)δ 154.6, 152.9, 149.6,130.9, 115.0, 113.9, 112.1, 104.4, 58.7, 47.2, 34.2, 31.2, 28.5, 23.5, 20.9,14.1. LRMS (APCI + ): Regarding C 15 H 20 NO2 + [M+H] + The calculated value is 260.2, and the measured value is 260.4.

[0299] Preparation of Scheme 8.2,3,5,6,12,12a-hexahydro-1H-benzofurano[2,3-d]pyrrolo[1,2-a]azapyro-8-ol 20.

[0300] Example 11.2,3,5,6,12,12a-hexahydro-1 H -Benzofurano[2,3- d ]Pyrrolo[1,2-a]azapyro-8-ol 20.

[0301] Intermediate 14 (201 mg, 0.5 mmol) was vigorously stirred in a 3:1 mixture of THF / H2O (2 mL) and LiOH·H2O (126 mg, 3 mmol). After 3 h, the reactants were diluted with brine (5 mL), extracted with CH2Cl2 (6 x), dried over Na2SO4, filtered, and concentrated under reduced pressure. The dried crude material 18 (153 mg, 0.5 mmol) was dissolved in CH2Cl2 (2 mL), and Schwartz's reagent Cp2Zr(H)Cl (387 mg, 15 mmol) was added in a single addition. The suspension was stirred at room temperature for 1 h. N,N-diisopropylethylamine (Dipea) (109 µL, 0.63 mmol) and iodine (159 mg, 0.63 mmol) were added, and the resulting clear solution was stirred overnight. The reactants were quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with CH2Cl2, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and used as is for the next step. Intermediate 19 was further converted according to general procedure B. The crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH), with the plates developed twice. The solid material was dissolved in a CH2Cl2 / MeOH mixture and treated with an aqueous solution of HCl (12.1 M) until the pH on the pH paper was approximately 1. The resulting solution was concentrated and evaporated from MeOH. The solid residue was recrystallized twice from MeOH to give compound 20 as a brown solid (30 mg, 23% yield).

[0302] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.21 (d, J = 8.8 Hz, 1H), 6.84(d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 4.02 – 3.74 (m, 2H), 3.62(br, 1H), 3.48 – 3.20 (m, 4H), 3.18 – 3.00 (m, 2H), 2.60 – 2.48 (m, 1H), 2.22– 2.06 (m, 2H), 2.06 – 1.91 (m, 1H).13 C NMR (126 MHz, MeOD) 13 C NMR (126 MHz, MeOD) δ 154.6, 152.7, 149.4, 130.9, 114.6, 114.0, 112.1, 104.4, 66.9, 59.0, 55.4, 32.1, 31.2, 21.6, 21.2. LRMS (APCI + ): Regarding C 15 H 18 NO2 + [M+H] + Calculated value: 244.1, measured value: 244.2.

[0303] Preparation of Scheme 9,4-propyl-2,3,4,5-tetrahydro-1H-benzofurano[2,3-d]azapyro-9-carboxamide 21.

[0304] Example 12.4-Propyl-2,3,4,5-Tetrahydro-1 H -Benzofurano[2,3- d [Zyzo-9-carboxamide 21]

[0305] Intermediate 12 (202 mg, 0.5 mmol), NH4Cl (80 mg, 1.5 mmol), imidazole (14 mg, 0.2 mmol), and Pd(dppf)Cl2·CH2Cl2 (41 mg, 0.05 mmol) were combined in a reaction vial. 1,4-Dioxane (2 mL) was added, followed by Co2(CO)8 and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), and the vial was sealed with a Teflon-lined screw cap. The reaction mixture was stirred vigorously at 80 °C for 22 h. After cooling to room temperature, the reaction mixture was filtered through a silica-stopper using a 5% MeOH / CH2Cl2 solution and concentrated. The residue was further purified by column chromatography using 5% MeOH / CH2Cl2. An intermediate was obtained as a brown, foamy solid (164 mg, 0.45 mmol), which was further stirred vigorously in a mixture of 3:1 THF / H2O (1.8 mL) and LiOH·H2O (112 mg, 2.7 mmol). After 17.5 h, the reaction mixture was diluted with brine (5 mL), extracted with CH2Cl2:iPrOH (3 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH), with the plate developed twice. The solid material was dissolved in MeOH and treated with aqueous HCl (12.1 M) until the pH on the pH paper was approximately 1. The solution was concentrated to give compound 21 as a beige solid (59 mg, 77% yield, in two steps).

[0306] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 8.19 – 8.06 (m, 1H), 7.84 (dd, J = 8.7, 1.8 Hz, 1H), 7.49 (dd, J = 8.7, 0.6 Hz, 1H), 3.73 (ddd, J = 13.6, 6.2,3.5 Hz, 1H), 3.68 – 3.59 (m, 1H), 3.47 – 3.35 (m, 2H), 3.28 – 3.18 (m, 2H), 3.16 – 3.07 (m, 1H), 1.88 – 1.73 (m, 2H), 1.63 – 1.48 (m, 2H), 1.04 (t, J = 7.3Hz, 3H). 13C NMR (126 MHz, MeOD)δ 172.4, 157.1, 154.1, 130.2, 130.0, 125.3,120.0, 115.8, 111.8, 58.4, 47.2, 36.6, 31.1, 20.8, 19.7, 14.1. LRMS (APCI + ): Regarding C 16 H 21 N2O2 + [M+H] + Calculated value: 273.2; measured value: 273.1.

[0307] Option 10. Used for reducing properties N The general procedure for methylation is C.

[0308] General procedure C: Add the corresponding 2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d Azazolide derivative (1 equivalent, in free base form, poorly reacting with hydrochloride) was suspended in EtOH (0.5 M, based on azazolide). An aqueous solution of HCHO (36.5% by weight, 5 equivalents) and HCHO (10 equivalents) were added, and the resulting solution was stirred at 80°C until complete conversion of the starting material was observed after 3–4 h. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of NaHCO3. The resulting mixture was repeatedly extracted with CH2Cl2 or a CH2Cl2:iPrOH 9:1 mixture (3–6 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified as specified for each example.

[0309] Example 13. 3-Methyl-4-propyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d ]Zaza-9-ol 22.

[0310] The compound was prepared using standard procedure C. The crude material was purified by column chromatography using AcOEt + 0.5% NH4OH to a concentration of 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and preparative TLC using a concentration of 95:5:0.5 (CH2Cl2:MeOH:NH4OH). The product was dissolved in CH2Cl2 / MeOH, treated with 2M HCl in diethyl ether, concentrated under reduced pressure, and the residue was evaporated from MeOH. Compound 22 was given as a beige solid (261 mg, 71% yield).

[0311] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.20 (d, J = 8.7 Hz, 1H), 6.83(d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 3.73 – 3.62 (m, 2H), 3.59 –3.51 (m, 1iiH), 3.41 – 3.34 (m, 1H), 3.19 (dd, J = 17.9, 8.0 Hz, 1H), 3.03 (td, J = 5.4, 2.8 Hz, 2H), 2.95 (s, 3H), 1.82 – 1.64 (m, 2H), 1.59 – 1.41 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). 13 C NMR (126 MHz, MeOD) δ 154.5, 152.3, 149.7, 130.9, 114.6, 113.8, 112.0, 104.4, 64.7, 54.2, 37.3, 33.7, 28.2, 20.6, 18.8, 14.0. LRMS (APCI + ): Regarding C 16 H 22 NO2 + [M+H] + Calculated value: 260.2; measured value: 260.1.

[0312] In some cases, compounds in salt form (HCl or CH3SO3H) can exist in solution in two different forms, partially 1 H NMR integral: 1H NMR (500 MHz, MeOD)δ 7.22 (dd, J = 8.8, 3.5 Hz, 1H), 6.84(t, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 3.84 – 3.51 (m, 3.5H), 3.37– 2.91 (m, 6.5H), 1.84 – 1.65 (m, 2H), 1.65 – 1.38 (m, 2H), 1.02 (t, J = 7.3Hz, 2H), 0.97 (t, J = 7.3 Hz, 1H).

[0313] Scheme 11.3-Methyl-4-allyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d Synthesis of azircon-9-ol 23.

[0314] Example 14. 3-Methyl-4-allyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 23.]

[0315] Compound 15 (122 mg, 0.5 mmol) was suspended in MeOH (1 mL). A clear solution was formed after the addition of 36.5 wt% HCHO solution (75 µL, 1 mmol). After stirring at room temperature for 30 min, sodium borohydride (28 mg, 0.75 mmol) was added in a single dose, and the exothermic reaction was controlled using an ice bath / water bath. After the exothermic reaction subsided, the mixture was stirred further at room temperature for 1 h. The reaction mixture was poured into a saturated NaHCO3 solution and extracted with CH2Cl2 (3 ×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by repeated preparative TLC using 95:5:0.5 and 93:7:0.7 (CH2Cl2:MeOH:NH4OH). Product 23 was given as a viscous brown oil (104 mg, 81%).

[0316] Free base: 1 H NMR (500 MHz, CDCl3)δ 7.19 (dd, J= 8.7, 0.5 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 8.6, 2.6 Hz, 1H), 5.89 – 5.77 (m, 1H), 5.30 (br,1H), 5.13 – 5.04 (m, 2H), 3.40 (ddd, J = 14.2, 6.0, 3.8 Hz, 1H), 3.22 – 3.12(m, 2H), 3.08 – 2.97 (m, 2H), 2.85 – 2.77 (m, 1H), 2.64 (ddd, J = 16.6, 6.0,3.5 Hz, 1H), 2.50 (s, 3H), 2.45 (dt, J = 13.0, 6.2 Hz, 1H), 2.30 – 2.22 (m,1H). 13 C NMR (126 MHz, CDCl3)δ 154.4, 151.6, 148.8, 136.1, 131.1, 117.1, 114.8,111.8, 111.1, 103.9, 60.8, 53.6, 38.3, 34.2, 30.0, 19.5. LRMS (APCI + ): Regarding C 16 H 20 NO2 + [M+H] + The calculated value is 258.2, and the measured value is 258.4.

[0317] Example 15. 3-Methyl-4-propyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d ]Zazepine-9-carboxamide The compound was prepared using standard procedure C. The crude material was purified by preparative TLC using a 95:5:0.5 (CH₂Cl₂:MeOH:NH₄OH) mixture, with the plate developed twice. Product 25 and the undesirable byproduct 24 were separated. The product was converted to hydrochloride in MeOH using one drop of aqueous HCl (12.1 M). Byproduct 24 was dissolved in 2 M aqueous HCl and allowed to form a separate product after 2 h at room temperature. The two solutions were combined, concentrated, and evaporated from MeOH. Compound 25 was obtained as a beige solid (56 mg, 87% yield).

[0318] Hydrochloride: exists in solution in two different forms, some 1 H NMR integration, most 13 The C signal is repetitive. 1 H NMR (500 MHz, MeOD)δ 8.11 (d, J = 1.7 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.53 – 7.46 (m, 1H), 3.91 – 3.59 (m, 3.56H), 3.46 – 3.32 (m, 1.02H), 3.29 – 3.15(m, 2.42H), 3.14 (s, 1.10H), 2.97 (s, 1.90H), 1.89 – 1.69 (m, 2H), 1.64 –1.41 (m, 2H), 1.03 (t, J = 7.3 Hz, 1.88H), 0.97 (t, J = 7.3 Hz, 1.12H). 13 C NMR(126 MHz, MeOD)δ 172.5, 157.5, 157.2, 153.4, 153.1, 130.2, 130.0, 129.6,125.4, 125.3, 120.2, 120.2, 115.4, 115.2, 111.9, 111.8, 65.4, 64.5, 55.6,51.5, 40.7, 35.5, 34.1, 33.2, 28.5, 26.7, 20.6, 20.5, 18.7, 18.2, 14.1, 13.9.

[0319] LRMS (APCI + ): Regarding C 17 H 23 N2O2 + [M+H] + Calculated value: 287.2; measured value: 287.3.

[0320] Example 16. 3-Methyl-4-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 26.]

[0321] The compound was prepared using standard procedure C. The crude material was purified by column chromatography using 50% to 100% AcOEt / hexane + 0.5% NH4OH. The product was converted to hydrochloride in MeOH using a 2M HCl solution in diethyl ether and purified by preparative TLC using a 90:10:0.1 (CH2Cl2:MeOH:HCl aqueous solution) ratio. The separated material, in the form of an oily residue, was suspended in diethyl ether and sonicated. The solid precipitate formed was collected by filtration. Compound 25 was given as a beige solid (59 mg, 43% yield).

[0322] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.19 (d, J = 8.8 Hz, 1H), 6.81(d, J = 2.4 Hz, 1H), 6.75 – 6.70 (m, 1H), 3.66 – 3.57 (m, 1H), 3.57 – 3.50 (m,1H), 3.46 – 3.38 (m, 2H), 3.29 – 3.20 (m, 1H), 2.94 (t, J = 5.7 Hz, 2H), 2.82(s, 3H), 1.72 (ddd, J = 13.6, 6.3, 4.0 Hz, 1H), 1.52 (ddd, J = 13.7, 10.0, 7.5Hz, 1H), 0.84 – 0.75 (m, 1H), 0.66 – 0.58 (m, 1H), 0.57 – 0.50 (m, 1H), 0.20 – 0.12 (m, 2H). 13 C NMR (126 MHz, MeOD)δ 154.4, 153.1, 149.7, 131.2, 114.9,113.5, 111.9, 104.4, 64.7, 54.1, 37.0, 36.9, 28.9, 19.2, 9.0, 6.2, 4.3. LRMS(APCI + ): Regarding C 17 H2NO2 + [M+H] + Calculated value: 272.2, measured value: 272.1.

[0323] Example 17. 3-Ethyl-4-propyl-2,3,4,5-Tetrahydro-1H -Benzofurano[2,3- d [Zaza-9-ol 27.]

[0324] After adding AcOH (28 µL, 0.48 mmol) and acetaldehyde (27 µL, 0.48 mmol), the starting material (59 mg, 0.24 mmol) was dissolved in MeOH (1 mL). After stirring at room temperature for 10 min, sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for the entire weekend. Only partial conversion was detected. Additional acetaldehyde (134 µL, 2.4 mmol) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added, and the reaction was continued for another 24 h. The reaction mixture was poured into a saturated NaHCO3 solution and extracted with CH2Cl2:iPrOH (3 ×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). The product was dissolved in CH₂Cl₂ / MeOH, treated with aqueous HCl (12.1 M), and the solution was concentrated under reduced pressure. The hydrochloride was further purified by preparative TLC using a 95:5:0.5 ratio (CH₂Cl₂:MeOH: HCl aqueous solution). The product was obtained as a beige solid (18 mg, 27% yield).

[0325] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.20 (d, J = 8.7 Hz, 1H), 6.84(d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.7, 2.5 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.74 –3.66 (m, 1H), 3.66 – 3.58 (m, 1H), 3.48 – 3.33 (m, 3H), 3.18 (dd, J = 17.9, 6.7Hz, 1H), 3.10 – 2.97 (m, 2H), 1.80 – 1.67 (m, 2H), 1.58 – 1.39 (m, 5H), 0.98(t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, MeOD)δ 154.5, 151.9, 149.8, 130.8, 114.4,113.8, 112.0, 104.5, 63.9, 50.2, 47.4, 33.6, 27.9, 20.7, 18.8, 14.0, 10.5. LRMS (APCI + ): Regarding C 17 H 24 NO2 + [M+H] + Calculated value: 274.2; measured value: 274.3.

[0326] Example 18. 3-Methyl-4-butyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 28.]

[0327] The compound was synthesized using standard procedure C. The crude material was purified by preparative TLC using a 95:5:0.5 (CH₂Cl₂:MeOH:NH₄OH) solution. The separated solid was dissolved in MeOH and treated with an aqueous HCl solution (12.1 M) until the pH on pH paper was approximately 1. The solution was concentrated under reduced pressure, and the residue was evaporated from MeOH (2 ×). The hydrochloride was obtained as a brown solid (21 mg).

[0328] Free base: 1 H NMR (500 MHz, CDCl3)δ 7.18 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 2.5Hz, 1H), 6.71 (dd, J = 8.7, 2.5 Hz, 1H), 5.49 (br, 1H), 3.43 – 3.32 (m, 1H), 3.19 – 3.10 (m, 1H), 3.10 – 2.95 (m, 3H), 2.84 – 2.73 (m, 1H), 2.65 – 2.57(m, 1H), 2.47 (s, 3H), 1.68 – 1.58 (m, 1H), 1.54 – 1.43 (m, 1H), 1.39 – 1.25(m, 4H), 0.89 (t, J = 7.0 Hz, 3H).

[0329] Hydrochloride: exists in solution in two different forms, some 1 H NMR integration, most 13 The C signal is repetitive. 1 H NMR (500 MHz, MeOD)δ 7.25 – 7.14 (m, 1H), 6.87 – 6.77 (m, 1H), 6.77 –6.69 (m, 1H), 3.80 – 3.47 (m, 3.48H), 3.28 – 2.80 (m, 6.52H), 1.91 – 1.78 (m,1H), 1.78 – 1.64 (m, 1H), 1.53 – 1.26 (m, 4H), 0.99 – 0.86 (m, 3H). 13 C NMR(126 MHz, MeOD)δ 153.2, 153.2, 150.8, 150.5, 148.6, 148.2, 129.4, 129.2,113.2, 113.0, 112.6, 112.5, 110.7, 110.7, 103.1, 64.5, 63.5, 54.4, 50.4,39.6, 34.8, 30.3, 29.3, 28.1, 28.0, 27.3, 25.4, 22.1, 21.9, 17.6, 17.0, 12.8,12.7. LRMS (APCI + ): Regarding C 17 H 24 NO2 + [M+H] + Calculated value: 274.2; Measured value: 274.5 Example 19. 3-Propyl-2,3,4,5-Tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 29.]

[0330] The product was prepared using two alternative conditions: Starting material 11 (41 mg, 0.2 mmol) was dissolved in a mixture of H2O:EtOH (1:1, 0.8 mL) and HCOOH (75 µL, 2 mmol). 1,1-Diethoxypropane (162 µL, 1 mmol) was added and the mixture was stirred at 80 °C for 3 h.

[0331] Starting material 11 (41 mg, 0.2 mmol) and 1-iodopropane (23 µL, 0.3 mmol) were combined in CH3CN (4 mL), and the mixture was heated to 80 °C for 3 h in a vial sealed with a Teflon-lined solid screw cap.

[0332] After cooling to room temperature, the crude mixture was combined and poured into a saturated NaHCO3 solution, extracted with CH2Cl2 (3 ×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). The residue was further suspended in diethyl ether and filtered through a cotton plug. The solution was concentrated to obtain a foamy solid. The separated solid was further purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). The product was dissolved in CH2Cl2, treated with a 2M HCl solution in diethyl ether, and the suspension was concentrated under reduced pressure. The hydrochloride was further purified by preparative TLC using 95:5:0.1 (CH2Cl2:MeOH: HCl aqueous solution). The product was obtained as a beige solid (55 mg, 56%).

[0333] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.21 (d, J = 8.7 Hz, 1H), 6.85(d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 3.66 (t, J = 5.7 Hz, 4H), 3.34– 3.27 (m, 4H), 3.08 (t, J = 5.5 Hz, 2H), 1.96 – 1.77 (m, 2H), 1.07 (t, J = 7.4Hz, 3H). 13 C NMR (126 MHz, MeOD) δ 154.5, 153.8, 149.6, 130.8, 114.8, 113.7, 112.0, 104.4, 58.5, 55.9, 53.5, 24.8, 19.6, 18.8, 11.2. LRMS (APCI + ): Regarding C 15 H 20 NO2 + [M+H] +Calculated value: 246.2; measured value: 246.3.

[0334] Example 20.3-propyl-2,3,4,5-tetrahydro-1 H -Benzofurano[2,3- d [Zaza-9-ol 30]

[0335] After adding AcOH (57 µL, 1 mmol) and butyraldehyde (88 µL, 1 mmol), the starting material (101 mg, 0.5 mmol) was dissolved in MeOH (1 mL). After stirring at room temperature for 30 min, sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 15 h. The reaction mixtures were combined, poured into a saturated NaHCO3 solution, and extracted with CH2Cl2 (4 ×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by short-column chromatography using AcOEt + 2% Et3N. The residue was further suspended in diethyl ether, filtered through a cotton plug, and the solution was concentrated to obtain a beige solid. The separated solid was dissolved in CH₂Cl₂ / iPrOH (a few drops), treated with aqueous HCl (12.1 M, 1.1 equivalents), loaded onto preparative TLC, and purified using a 95:5:0.1 (CH₂Cl₂:MeOH: HCl aqueous solution) ratio. The product was obtained as a beige solid (10⁶ mg, 84%).

[0336] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.20 (d, J = 8.8 Hz, 1H), 6.83(d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.8, 2.5 Hz, 1H), 3.65 (d, J = 7.1 Hz, 4H), 3.36– 3.28 (m, 4H), 3.07 (t, J = 5.7 Hz, 2H), 1.86 – 1.78 (m, 2H), 1.47 (h, J = 7.4Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, MeOD)δ 154.5, 153.7, 149.7,130.8, 114.8, 113.8, 112.0, 104.4, 56.9, 56.0, 53.6, 27.3, 24.9, 20.9, 19.6,13.9. LRMS (APCI + ): Regarding C 16 H 22 NO2 + [M+H] + Calculated value: 260.2; measured value: 260.3.

[0337] Scheme 12. Synthesis of alkynyl-lactam intermediate 31.

[0338] Example 21.7-(but-2-yn-1-yl)-1,4-dioxa-8-azaspiro[4.6]undecane-9-one 31.

[0339] A solution of 1,4-cyclohexanedione monoethylene glycol acetal (5.87 g, 37.6 mmol) in diethyl ether (0.5 M, 75.0 mL) was cooled to -78 °C, and LHMDS (1 M in THF, 37.6 mL) was slowly added to the cold, dilute suspension. The reaction mixture was stirred further for 30 min, and then 1-bromobut-2-yne (5.0 g, 37.6 mmol) was added dropwise over 30 min using a syringe pump, while the reaction mixture was slowly heated to room temperature. After 15 h, the reaction mixture was quenched with saturated NH4Cl solution (50 mL), the phases were separated, and the aqueous phase was further extracted with Et2O (50 mL). The combined extracts were washed with brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated on diatomaceous earth. The crude material was purified by column chromatography using 10% AcOEt / hexane. A slightly impure ketone intermediate (4.6 g) was dissolved in MeOH (35 mL), and H₂O (9 mL), hydroxylamine hydrochloride (1.69 g, 24.3 mmol), and sodium acetate (1.99 g, 24.3 mmol) were added. The reaction mixture was stirred at 80 °C. After 2 h, the MeOH was evaporated under reduced pressure, the mixture was diluted with brine (30 mL), and extracted with DCM:iPrOH 9:1 (50 and 4 × 25 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated. The crude oxime (4.93 g) was dissolved in acetone (44 mL), and H₂O (66 mL), Na₂CO₃ (7.02 g, 66.2 mmol), and...p -TsCl (6.31 g, 33.1 mmol) was added, and the reaction mixture was stirred at 40 °C for 3 days. Acetone was evaporated under reduced pressure, and the aqueous mixture was diluted with brine (10 mL) and extracted with DCM:iPrOH 9:1 (3 × 40 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude material (yellow solid) was dissolved in hot acetone (~12-15 mL), cooled to room temperature, and placed in a refrigerator (+8 °C) overnight. The precipitate was collected by filtration and washed with a small amount of cold acetone. Product 31 (2.26 g, 27% yield, after 3 steps) was given as a white solid.

[0340] 1 H NMR (500 MHz, CDCl3)δ 5.91 (s, 1H), 4.01 – 3.91 (m, 4H), 3.74 –3.66 (m, 1H), 2.69 (ddd, J = 15.0, 12.9, 2.3 Hz, 1H), 2.48 – 2.27 (m, 3H), 1.94– 1.80 (m, 4H), 1.79 (t, J = 2.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3)δ 176.59,108.97, 79.82, 73.29, 64.86, 64.60, 47.66, 44.96, 32.95, 31.27, 26.01, 3.56. LRMS (APCI + ): Regarding C 12 H 18 NO3 + [M+H] + Calculated value: 224.1, measured value: 224.2.

[0341] Scheme 13. Synthesis of compound 32.

[0342] Example 22.1-(7-(but-2-yn-1-yl)-1,4-dioxa-8-azaspiro[4.6]undecane-8-yl)-2,2,2-trifluoroethyl-1-one 32.

[0343] The lactam intermediate (1.2 g) was suspended in THF (10.8 mL, 0.5 M) and cooled in an ice bath (0 °C). LiAlH4 (0.31 g, 8.1 mmol) was initially added carefully in small portions, with the remainder added after the exothermic reaction subsided. The reaction mixture was heated to room temperature and then further heated to reflux for 2 h. The reaction mixture was further cooled in an ice bath, diluted with diethyl ether (20 mL), and slowly quenched by adding H2O, 15% NaOH, and H2O (1:1:3 mL / g LiAlH4) while stirring until all salts were off-white and loose. The solids were filtered off and washed with diethyl ether until no further product was detected by TLC. The combined washes were concentrated under reduced pressure. The crude intermediate (1.12 g) was immediately used for the next step. The yellow oily substance was dissolved in CH2Cl2 (10.8 mL), and Et3N (1.12 mL, 8.1 mmol) was added. The mixture was cooled in an ice bath, and trifluoroacetic anhydride (0.93 mL, 6.7 mmol) was added dropwise. The mixture was stirred further at room temperature. After 4 h, it was poured into a saturated NaHCO3 solution (15 mL), and the mixture was extracted with CH2Cl2 (3 ×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The oily residue was purified by column chromatography using 20% ​​AcOEt / hexane. Compound 32 was isolated as a yellow oily substance (1.32 g, 81%, in two steps), and its NMR spectrum was ( 1 H, 19 F and 13 C) It becomes complicated due to the presence of rotational isomers.

[0344] LRMS (APCI + ): Regarding C 14 H 19 F3NO3 + [M+H] + Calculated value: 306.1, measured value: 306.2.

[0345] Scheme 14. Synthesis of compound 33.

[0346] Example 23.4-(but-2-yne-1-yl)-2,3,4,5-tetrahydro-1H-benzofurano[2,3-d]azapyro-9-carboxamide 33.

[0347] Compound 32 (1.26 g, 4.13 mmol) and O-(4-bromophenyl)hydroxylamine hydrochloride (0.93 g, 4.13 mmol) were combined in 1,4-dioxane (8.3 mL, 0.5 mol) and heated to 80 °C. After 5 min at 80 °C, methanesulfonic acid (0.54 mL, 8.25 mmol) was added, and the reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (15 mL). The resulting mixture was extracted with CH2Cl2 (3 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified using a gradient of 5% to 10% AcOEt / hexane. A complex mixture of rotational isomers was used for the next step. Bromobenzofuran-intermediate (207 mg, 0.5 mmol), NH4Cl (80 mg, 1.5 mmol), and imidazole (14 mg, 0.2 mmol) were added. 1,4-Dioxane (2 mL) and Pd(dppf)Cl2·CH2Cl2 (41 mg, 0.05 mmol) were combined in a reaction vial. 1,4-Dioxane (2 mL) was added, followed by Co2(CO)8 (103 mg, 0.3 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), and the vial was sealed with a Teflon-lined solid screw cap. The reaction mixture was stirred vigorously at 80 °C for 22 h. After cooling to room temperature, the reaction mixture was filtered through a silica gel stopper using a 5% MeOH CH2Cl2 solution and concentrated. The residue was further purified by column chromatography using 2.5% MeOH / CH2Cl2. An intermediate was obtained as a reddish-brown foamy solid (92 mg, 0.45 mmol), which was further purified by reaction in a 3:1 THF / H2O (2.4 mL) and LiOH·H2O (51 mg, 1.2 mmol) solution. The mixture was stirred vigorously in a solution of 1 mmol. After 17.5 h, the reactants were extracted with AcOEt (3 x), the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). For final purification, the solid material was dissolved in MeOH and treated with an aqueous HCl solution (12.1 M) until the pH on pH paper was about 1. The solution was concentrated, and the residue was resuspended and sonicated in MeCN (2 mL), precipitated by centrifugation, and the solvent was decanted. Compound 33 was given as a beige solid (29 mg, 12% yield, in three steps).

[0348] Characterized as a hydrochloride: 1 H NMR (500 MHz, MeOD)δ 8.11 (d,J = 1.9 Hz, 1H), 7.87 –7.82 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 3.81 – 3.71 (m, 2H), 3.50 – 3.41 (m,3H), 3.28 – 3.11 (m, 2H), 2.85 – 2.70 (m, 2H), 1.86 (t, J = 2.5 Hz, 3H). 13 C NMR(126 MHz, MeOD)δ 172.33, 157.15, 153.60, 130.27, 130.10, 125.33, 120.07,115.59, 111.76, 82.29, 72.40, 57.48, 47.73, 31.37, 24.60, 20.71, 3.23. LRMS(APCI + ): Regarding C 17 H 19 N2O2 + [M+H] + Calculated value: 283.1; Measured value: 282.7.

[0349] Scheme 15. Synthesis of compound 34.

[0350] Example 24.7-Allyl-7-methyl-1,4-dioxa-8-azaspiro[4.6]undecane 34.

[0351] Over 15 min, a solution of 1,4-cyclohexanedione monoethylene glycol acetal (6.70 g, 42.90 mmol) in THF (40 mL) was slowly added to a solution of LHMDS (1.0 M in THF, 42.9 mL, 1.0 equivalent) in THF (120 mL) at -78 °C, and the resulting mixture was stirred at -78 °C for 30 min. Iodomethane (3.2 mL, 51.5 mmol, 1.2 equivalent) was added to the reaction mixture, and the resulting solution was stirred at -78 °C for 20 min and then at room temperature for 2 h. The reaction mixture was quenched by adding saturated NH4Cl (120 mL) and extracted with diethyl ether (3 x 120 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated under vacuum. Rapid chromatography (20% EtOAc / hexane) yielded 2-methyl-1,4-cyclohexanedione monoethylene glycol acetal (4.85 g, 66% yield).1 H NMR (500 MHz, CDCl3)δ 4.13 – 3.96 (m,4H), 2.80 – 2.55 (m, 2H), 2.42 – 2.33 (m, 1H), 2.12 – 1.91 (m, 4H), 1.74 (td, J = 13.3, 2.2 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H). LRMS (APCI) + ): Targeting C9H 15 O3 + [M+H] + Calculated value: 171.2, measured value: 171.1.

[0352] The intermediate and NaI (0.85 g, 5.64 mmol) were dissolved in THF (56.4 mL), and NaH (60% oil dispersion, 1.13 g, 28.2 mmol) was added in portions under argon atmosphere. After stirring at room temperature for 30 min, allyl bromide was added dropwise, and the mixture was stirred for another 2 h. The reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined extracts were dried (Na₂SO₄), filtered, and concentrated under vacuum. Rapid chromatography (20% EtOAc / hexane) yielded 2-allyl-2-methyl-1,4-cyclohexanedione monoethylene glycol acetal (3.1 g, 52% yield). 1HNMR (500 MHz, CDCl3)δ 5.73 – 5.60 (m, 1H), 5.07 – 4.99 (m, 2H), 4.07 – 3.92(m, 4H), 2.61 – 2.50 (m, 2H), 2.41 – 2.27 (m, 2H), 2.06 – 1.92 (m, 3H), 1.78– 1.71 (m, 1H), 1.12 (s, 3H). 13 C NMR (126 MHz, CDCl3)δ 213.88, 133.77, 118.40,107.59, 64.43, 64.35, 47.51, 44.35, 42.77, 35.75, 34.49, 23.90. LRMS (APCI + ): Regarding C 12 H 19 O3 + [M+H] + Calculated value: 211.3, measured value: 211.1.

[0353] The ketone intermediate (3.1 g, 14.7 mmol) was dissolved in MeOH (25 mL), and H₂O (5 mL), hydroxylamine hydrochloride (1.13 g, 16.2 mmol), and sodium acetate (1.33 g, 16.2 mmol) were added. The reaction mixture was stirred at 80 °C. After 2 h, the MeOH was evaporated under reduced pressure, the mixture was diluted with brine (30 mL), and extracted with DCM:iPrOH 9:1 (4 × 50 mL). The combined extracts were dried over Na₂SO₄, filtered, and concentrated. The crude oxime (3.32 g) was dissolved in acetone (60 mL), and H₂O (90 mL), Na₂CO₃ (6.25 g, 59.0 mmol), and... p -TsCl (5.62 g, 29.5 mmol) was added, and the reaction mixture was stirred at 40 °C for 17 h. Acetone was evaporated under reduced pressure, and the aqueous mixture was diluted with brine (50 mL) and extracted with DCM:iPrOH 9:1 (3 × 30 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. Rapid chromatography (30% EtOAc / hexane) gave the lactam intermediate (1.6 g, 49% yield, in 2 steps). 1 H NMR (500 MHz, CDCl3)δ 5.87 (s, 1H), 5.86 – 5.77 (m, 1H), 5.24 – 5.12 (m, 2H), 4.02 – 3.91 (m, 4H), 2.69 – 2.55 (m, 2H), 2.38 – 2.31 (m, 2H), 1.98 – 1.82 (m, 4H), 1.34 (s, 3H). 13 C NMR (126 MHz, CDCl3)δ 176.26, 132.48, 120.23, 109.60, 64.51, 64.35, 53.18, 48.11, 47.41, 32.46, 31.59, 27.76. LRMS (APCI + ): Regarding C 12 H 20 NO3 + [M+H] + Calculated value: 226.3, measured value: 226.0.

[0354] The lactam intermediate (1.63 g) was suspended in THF (14 mL, 0.5 M), cooled in an ice bath (0 °C), and LiAlH4 (0.548 g, 14.4 mmol) was initially added carefully in small portions. After the exothermic reaction subsided, the remaining portion was added. The reaction mixture was heated to room temperature and then further heated to reflux for 2 h. The reaction mixture was further cooled in an ice bath, diluted with diethyl ether (20 mL), and slowly quenched by adding H2O, 15% NaOH, and H2O (1:1:3 mL / g LiAlH4) while stirring until all salts were grayish-white and loose. The solids were filtered off and washed with diethyl ether until no further product elution was detected by TLC. The combined washes were concentrated under reduced pressure. Rapid chromatography (98% EtOAc and 2% TEA) gave compound 34 (1.05 g, 69% yield) as a clear oil. 1 H NMR (500 MHz, CDCl3)δ 5.87 – 5.73 (m,1H), 5.11 – 4.99 (m, 2H), 3.94 – 3.82 (m, 4H), 2.88 – 2.79 (m, 2H), 2.23 –2.16 (m, 2H), 1.93 – 1.74 (m, 4H), 1.65 – 1.55 (m, 2H), 1.10 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 134.75, 117.98, 111.27, 64.32, 64.01, 53.25, 48.37, 47.31, 42.40, 38.46, 27.34, 26.62. LRMS (APCI + ): Regarding C 12 H 22 NO2 + [M+H] + Calculated value: 212.3; Measured value: 212.0 Scheme 16. Synthesis of compound 35.

[0355] Example 25: 4-Allyl-4-methyl-2,3,4,5-tetrahydro-1H-benzofurano[2,3-d]azapyrrol-9-ol 35 and 4-Allyl-3,4-dimethyl-2,3,4,5-tetrahydro-1H-benzofurano[2,3-d]azapyrrol-9-ol 36.

[0356] Compound 34 (0.20 g, 0.96 mmol) was dissolved in CH₂Cl₂ (3.8 mL), and N,N-diisopropylethylamine (0.41 mL, 2.4 mmol) was added. The mixture was cooled in an ice bath, and trifluoroacetic anhydride (0.27 mL, 1.9 mmol) was added dropwise. The mixture was stirred further at room temperature. After 20 h, it was poured into a saturated NaHCO₃ solution (15 mL), and the mixture was extracted with CH₂Cl₂ (3 ×). The combined extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The oily residue was passed through a short silica gel column using 20% ​​AcOEt / hexane. The complex mixture of the rotational isomers was then compared with... O1,4-(bromophenyl)hydroxylamine hydrochloride (0.22 g, 0.96 mmol) was combined in 1,4-dioxane (1.9 mL, 0.5 M) and heated to 80 °C. After 5 min at 80 °C, methanesulfonic acid (0.13 mL, 1.9 mmol) was added, and the reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with diethyl ether (3 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified using 5% AcOEt / hexane, and the resulting complex mixture of rotational isomers was used in the next step. 1,4-Dioxane (0.9 mL), degassed H₂O (0.9 mL), solid KOH (0.16 g, 2.8 mmol), Pd₂Dba₃ (3 mol%, 13 mg, 0.014 mmol), and tBuBrettPhos (6 mol%, 14 mg, 0.028 mmol) were added to a vial containing a bromobenzofuran intermediate (192 mg, 0.46 mmol). The reaction mixture was stirred at 80 °C for 15.5 h. After cooling to room temperature, the reaction mixture was acidified with 2 M HCl aqueous solution (to pH 5–6) and further adjusted to pH ~ 7 with saturated NaHCO₃ aqueous solution. The resulting mixture was repeatedly extracted with AcOEt (4 x), and the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The crude material consisted of a mixture of product 35 and its TFA amide precursor. Therefore, the crude material was dissolved in a 3:1 THF:H2O mixture (2 mL), LiOH·H2O (116 mg, 2.77 mmol) was added, and the mixture was stirred vigorously overnight. The mixture was acidified with 2M HCl aqueous solution (to pH 5–6) and further adjusted to pH ~ 7 with saturated NaHCO3 aqueous solution. The resulting mixture was repeatedly extracted with AcOEt (4 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. Unreacted 35-TFA amide was separated from product 35 by column chromatography of DCM:MeOH:NH4OH (95:5:0.5), which was further purified by PTLC (DCM:MeOH:NH4OH 95:5:0.5) and converted to hydrochloride in MeOH by adding methanol HCl (until pH is about 1), and concentrated to give compound 35 (23 mg, 17%, in three steps) as a beige solid.

[0357] The crude intermediate 35-TFA amide (120 mg) was further suspended in MeOH (2 mL), H₂O (1 mL), LiOH·H₂O (144 mg, 3.4 mmol) was added, and the mixture was stirred at 50 °C for one day (partial conversion only). The mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of THF + H₂O (1 + 1 mL), LiOH·H₂O (144 mg, 3.4 mmol) was added, and the mixture was stirred vigorously at 60 °C for another day (major conversion). After cooling to room temperature, the reaction mixture was acidified with 2M HCl aqueous solution (to pH 5–6) and further adjusted to pH ~ 7 with saturated NaHCO₃ aqueous solution. The resulting mixture was repeatedly extracted with AcOEt (4 x), and the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by column chromatography using DCM:MeOH:NH4OH (95:5:0.5), and the slightly impure compound 35 (26 mg, 22%, total yield of 39% over three steps) was used for the next step. Compound 35 (free base, 26 mg, 0.1 mmol) was suspended in MeOH (1 mL), and formaldehyde (36.5% solution, 0.015 mL, 0.2 mmol) was added. The resulting solution was stirred for 10 min, followed by the addition of solid NaBH4 (8 mg, 0.2 mmol). After stirring at room temperature for 1 h, incomplete conversion was observed, and additional formaldehyde (36.5% aqueous solution, 0.03 mL, 0.4 mmol) was added, followed by the addition of solid NaBH4 (16 mg, 0.4 mmol) after 30 min. After stirring for 30 min, the reactants were diluted with saturated NaHCO3 solution (2 mL), extracted with AcOEt (3 x), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. Due to incomplete conversion, the reaction was repeated using crude material, MeOH (1 mL), formaldehyde (36.5% aqueous solution, 0.03 mL, 0.4 mmol), stirred for 60 min; and solid NaBH4 (16 mg, 0.4 mmol), stirred for 30 min. The reactants were post-processed as before. The residues were purified by PTLC (DCM:MeOH:NH4OH 97.5:2.5:0.2, developed 2x), converted to hydrochloride in MeOH with methanol-HCl, and concentrated to give compound 36 (14.5 mg, 17%).

[0358] Compound 35 hydrochloride: 1 H NMR (500 MHz, MeOD)δ 7.22 (d, J = 8.8 Hz, 1H), 6.86(d,J = 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 5.90 (ddt, J = 17.6, 10.2, 7.4Hz, 1H), 5.39 – 5.21 (m, 2H), 3.50 (ddd, J = 7.1, 5.0, 2.7 Hz, 2H), 3.29 – 3.19(m, 2H), 3.07 (td, J = 5.3, 2.3 Hz, 2H), 2.60 – 2.47 (m, 2H), 1.43 (s, 3H). 13 CNMR (126 MHz, MeOD)δ 154.63, 151.93, 149.84, 131.25, 130.69, 122.49, 114.64,113.90, 112.18, 104.42, 60.88, 42.91, 42.45, 36.70, 22.82, 20.93. LRMS (APCI + ): Regarding C 16 H 20 NO2 + [M+H] + The calculated value is 258.2, and the measured value is 258.1.

[0359] Compound 36 hydrochloride (some signals are amplified due to the presence of a rotational isomer): 1 H NMR (500 MHz,MeOD)δ 7.22 (dd, J = 8.8, 4.6 Hz, 1H), 6.86 (t, J = 2.2 Hz, 1H), 6.76 (dt, J = 8.8, 2.6 Hz, 1H), 5.91 (tdt, J = 17.4, 10.2, 7.4 Hz, 1H), 5.38 – 5.23 (m, 2H), 3.78(tdd, J = 17.9, 8.4, 5.1 Hz, 1H), 3.73 – 3.64 (m, 1H), 3.50 (t, J= 16.3 Hz, 1H), 3.35 (s, 1H), 3.17 – 3.07 (m, 2H), 3.05 (s, 3H), 2.73 – 2.55 (m, 2H), 1.52(d, J = 9.4 Hz, 3H). 13 C NMR (126 MHz, MeOD)δ 154.68, 151.06, 150.81, 149.95,131.58, 131.53, 130.77, 130.73, 122.61, 122.57, 114.09, 114.06, 114.01,113.94, 112.18, 112.16, 104.53, 104.50, 68.23, 67.67, 52.22, 51.36, 41.71,41.37, 36.58, 36.23, 34.96, 34.43, 22.13, 21.87, 18.75. LRMS (APCI + ): Regarding C 17 H 22 NO2 + [M+H] + Calculated value: 272.2, measured value: 272.1.

[0360] Biological characterization BRET functional opioid assay (G protein and Nb33 recruitment) HEK-293T cells were obtained from the American Type Culture Collection (Rockville, MD) and cultured at 37°C in a 5% CO2 atmosphere in Durbecco's Modified Eagle Medium (high glucose #11965; Life Technologies Corp.; Grand Island, NY). This medium was supplemented with 10% fetal bovine serum (FBS, #35-010-CV, Corning, Corning, NY, USA) and 100 U / mL of glucose. -1 Penicillin (#30-002-CI, Corning, Corning, NY, USA) and 100 µg / mL -1Streptomycin (#30-002-CI; Corning, Corning, NY, USA). The following chemicals are used without further modification: Coelenterin H (#DC-001437, Dalton Pharma Services, Toronto, ON, Canada), PEI (#NC1014320, Polysciences, Warrington, PA, USA), and (±)-U-50488 HCl (Tocris Biosciences, Minneapolis, MN, USA).

[0361] DNA constructs (G protein and Nb33): Rat KOR (rKOR) was provided by Dr. Lakshmi Devi of the Mount Sinai School of Medicine. It possesses Gα cells with a Renalis luciferase 8 (RLuc8) inserted at position 91. oB (Gα oB Gγ2 (mVenus-γ2) and Gβ1 (β1) were provided by C. Galés (Rives et al. 2012; Negri et al. 2013). Gγ2 (mVenus-γ2) was constructed internally by fusing it to full-length mVenus via the amino acid linker GSAGT at its N-terminus. An expression vector encoding rat KOR (KOR-nluc) labeled with Nanoluc at the C-terminus was constructed using standard techniques in molecular biology and confirmed by DNA sequencing (Genewiz, South Plainfield, NJ, USA). Briefly, three DNA inserts were amplified by PCR: one encoding an N-terminal signal peptide and a flag tag, one encoding KOR, and one encoding nanoluc. The inserts were ligated and cloned into the pcDNA3.1 (+) vector (#V79020, ThermoFisher Scientific, Waltham, MA, USA). The plasmid encoding the nanobody 33Venus (Nb33) construct (Gilis et al., 2020) was provided by Dr. Meritxell Canals of the University of Nottingham.

[0362] The following amounts of cDNA were transfected into HEK-293T cells (4 x 10⁻⁶ cells) in 10 cm culture dishes using polyethyleneimine (PEI) at a 1.5:1 ratio (diluted in DMEM (Life Technologies)). 6 In cells / plate). G protein β-γ release: 2.5 μg KOR, 0.1 μg Gα oBRLuc8, 6.2 μg β1, 6.2 μg mVenus-γ2. Cells were maintained in the above-mentioned HEK-293T medium. After 24 hours, the medium was changed, and experiments were performed 48 hours post-transfection. Nb33 recruitment: A total of 5 μg cDNA was transiently transfected into 2 × 10⁻⁶ HEK-293T cells (2 × 10⁻⁶ cells) in 10 cm culture dishes (1 μg receptor-nluc and 4 μg Nb-33-Venus) using PEI at a 6:1 ratio (diluted in DMEM). 6 Cells were cultured in HEK-293T medium (number of cells per plate). Experiments were performed 48 hours post-transfection.

[0363] Transfected cells were dissociated and resuspended in phosphate-buffered saline (PBS). Approximately 200,000 cells / well were added to black-framed, white-well, 96-well plates (#60050; Perkin Elmer; Waltham, MA). At time zero, the luciferase substrate coelentin H (5 μM) was added to each well. Ligands were added after 5 min, followed by BRET signaling against the G protein after 5 min, and then against Nb33 recruitment after 10 min. BRET measurements were performed using a PHERAstar FS plate reader (BMGLabtech, Cary, NC, USA). The BRET signal was calculated as the ratio of light emitted by the mVenus receptor (510–540 nm) to light emitted by the NanoLuc donor (475 nm). The E-50,488 was used. max The drug-induced BRET signal was normalized to represent the maximum response at KOR. Data were analyzed using a dose-response-stimulus nonlinear curve fitting model (log[agonist] versus response (four parameters)). All experiments were replicated in three independent trials, with three measurements per trial.

[0364] hSERT and VMAT2 inhibition assays Stable transfected cell cultures were inoculated at 1.00 10 6 Cells were seeded at a density of 10 cells / well in white solid-bottom 96-well plates (Corning; Corning, NY) and allowed to proliferate in a humid environment of 37°C and 5% CO2, reaching complete confluence in approximately 48 hours. At the start of the experiment, the growth medium was aspirated, and the cell culture monolayer was prepared using 120 μL of 1 Rinse twice with phosphate-buffered saline (PBS; Corning; Corning, NY). The solution will be 2... A stratified concentration (ranging from 100 μM to 0.1 μM) of the test compound or an experimental medium solution consisting of DMSO (mediator, 0.02% v / v, Sigma-Aldrich; St. Louis, MO) was gently added to the cell culture and followed by pre-incubation for approximately (SERT: 60 min, VMAT2: 30 min). One standard was used for each experiment, depending on the specific transporter being evaluated (imipramine for hSERT and reserpine for VMAT2; Sigma-Aldrich; St. Louis, MO). Subsequently, equal volumes containing 2... A fractionated concentration (ranging from 100 μM to 0.1 μM) of the test compound or experimental medium solution of DMSO (medium, 0.02% v / v, Sigma-Aldrich; St. Louis, MO) and APP+ (for hSERT; final concentration: 1.1 μM; Sigma-Aldrich; St. Louis, MO) or FFN206 (Hu et al., 2013, for VMAT2, final concentration: 0.75 µM) was added to each well, followed by incubation (SERT: 30 min, VMAT2: 60 min) to promote fluorescent probe uptake. The solution contained in each well was then aspirated and diluted with 120 μL of 1... Wash cells twice with PBS. Add 120 μL of PBS to each well as a final wash. PBS is necessary for bottom-mode readout of fluorescence uptake via a BioTek Synergy Neo2 hybrid multimode reader (Agilent; Santa Clara, CA) at excitation and emission wavelengths of 436 and 500 nm, respectively. For IC 50 Data analysis was performed to quantify the corresponding fluorescence uptake (in units of average fluorescence) by subtracting the average fluorescence of the medium pores from the average fluorescence of the pores containing each ibogaine derivative. These values ​​were then fitted to a nonlinear curve model ([inhibitor] vs. reaction (three parameters)) provided by Graphpad Prism 8 software (Graphpad Prism Inc.; San Diego, CA). Using the Cheng-Prusoff equation (Yung-Chi and Prusoff, 1973), the IC50 of the output for each ibogaine derivative was calculated. 50 (± SEM) quantity converted to K i (± SEM) values.

[0365] Cardiotoxicity assay of primary cardiomyocytes in adults The cardiotoxicity of the novel analogues was assessed using commercially available assay services according to published procedures (Abi-Gerges et al., 2020; Nguyen et al., 2017). Briefly, primary adult ventricular myocytes were isolated from ethically consented donor hearts, which were enzymatically digested using a proprietary protocol. The myocytes were placed in perfusion chambers on the stage of an inverted Motic AE31E (IonOptix) or Olympus IX83P1ZF (MyoBLAZER) microscope and continuously perfused at approximately 2 mL / min with recording buffer heated to 35 °C ± 1 °C using an in-line heater from Warner Instruments (IonOptix and MyoBLAZER), and equilibrated at constant perfusion for 5 min. The cells were field-stimulated using a pair of platinum wires positioned on opposite sides of the chamber connected to a MyoPacer stimulator, with bipolar pulses at a pacing frequency of 1 Hz and a duration of 3 ms. Starting at 1 V, the amplitude of the stimulation pulse was increased until the cardiomyocytes began to generate a contractility transient, and a value of 1.5 × the threshold was used throughout the experiment. The cardiomyocytes were then imaged using an IonOptix MyoCam-S CCD camera (IonOptix) at 240 Hz or an Optronis CP70-16-M / C-148 (MyoBLAZER) camera at 148 Hz. The digitized images were displayed within the IonWizard acquisition software (IonOptix) or MyoBLAZER acquisition software. Using a cellframing adapter, the longitudinal axis of the selected cardiomyocytes was aligned parallel to the video raster lines. Light intensity data was collected from a user-defined rectangular area set above the cardiomyocyte image. The light intensity data represented bright and dark bands corresponding to the Z-line of the cardiomyocytes. The periodicity of the light density of these bands was analyzed using the Fast Fourier Transform algorithm in the IonWizard or MyoBLAZER analysis software.

[0366] Compound test solutions were prepared from stock solutions within 30 min prior to application to cells. Test solutions were applied in ascending order of concentration (at 300 s intervals, 1 Hz stimulation) after the media control (120 s interval, 1 Hz stimulation), and the experiment was terminated after the wash control (300 s interval, 1 Hz stimulation).

[0367] The positive control 30 nM ATX-II (toxin from anemones sulcata) was applied after the mediator control (120 s interval, 1 Hz stimulation) and data were recorded (300 s interval, 1 Hz stimulation).

[0368] Aftercontraction (AC) was visually identified as a spontaneous secondary change in the slope of the contraction transient, which occurred before the contraction induced by the next stimulus and produced an anomalous and asynchronous contraction. Contraction failure (CF) was also visually identified when electrical stimulation failed to induce contraction. Alternation and short-term variability (STV) were visualized in a Poincaré plot of contraction amplitude variability. Calculations were performed using the last 20 transients at each control and test concentration period. Alternation was identified as short, long transients of repetitive alternation of contraction amplitude. STV values ​​were normalized to mediator control values ​​per cell. AC, CF, and alternation were plotted and expressed as a percentage of the incidence of each of the signals, which were normalized to the total number of cardiomyocytes.

[0369] Pharmacokinetic studies Twenty-one male mice were used in each study (3 animals at each time point). Subcutaneous (sc) administration was administered to mice at a dose of 10 mg / kg. Compounds 13 and 22 were administered as hydrochloride salts and dissolved in 0.85% saline (1% Tween 80 was added for compound 22). The formulations were heated and sonicated until a clear solution was obtained (formulation concentration of 2 mg / mL). The administration volume for subcutaneous administration was 5 mL / kg.

[0370] Under mild isoflurane anesthesia (Surgivet®), blood samples (approximately 60 µL from mice) were collected from the retroorbital plexus of three animals at specific time points into labeled microtubes containing K2EDTA solution (20% K2EDTA solution) as an anticoagulant. Immediately following blood collection, plasma was harvested by centrifugation at 4000 rpm for 10 min at 40 °C, and the samples were stored at -70 °C ± 10 °C until bioanalysis. Animals were immediately euthanized after blood collection, the abdominal vena cava was incised, and the whole body was perfused with (10 mL) physiological saline from the heart. Brain samples were collected from three animals at specific time points. After separation, the brain samples were rinsed three times in ice-cold physiological saline (for 5–10 seconds / rinse, each rinse using (approximately 5–10 mL) of physiological saline in a disposable culture dish) and dried on absorbent paper. Brain samples were homogenized using ice-cold phosphate-buffered saline (pH - 7.4). The total homogenate volume was three times the tissue weight. All homogenates were stored below -70°C ± 10°C until bioanalysis. The extraction procedures for plasma and brain samples, as well as the spiked plasma and brain calibration standards, were identical. 25 µL of the study sample or spiked plasma calibration standard was added to each pre-labeled microcentrifuge tube, followed by 100 µL of an internal standard prepared in acetonitrile (glipizide, 500 ng / mL), except for a blank (containing 100 µL of acetonitrile). The sample was vortexed for 5 min and then centrifuged at 4000 rpm for 10 min at 4°C. After centrifugation, 100 µL of the clear supernatant was transferred to a 96-well plate, and the analyte concentrations were determined by LC-MS / MS methods suitable for the purpose.

[0371] Pharmacokinetic parameters were assessed using Phoenix WinNonlin®'s non-compartmental analysis tools (version 8.0 for oxa-boregarin and version 7.0 for boregarin). Peak plasma concentration (C0.0) max ) and time to peak plasma concentration (T) max The observed value is 0. The area under the concentration-time curve (AUC) is calculated using the linear trapezoidal rule. 最后 and AUC inf The terminal elimination rate constant ke was determined by regression analysis of the linear terminal portion of the logarithmic plasma concentration-time curve. The terminal half-life (T0) was estimated using 0.693 / ke. 1 / 2z Clearance was estimated as dose / AUC. inf And V ss The estimate is CL × MRT. Organization Kp is calculated using Microsoft Excel.

[0372] Table 1. Opioid agonist activity of the compounds, potency expressed as [EC]. 50 = nM, and efficacy is expressed as a percentage of control agonist activity (KOR: U50,488, MOR: DAMGO, DOR: DPDPE). Assays based on nanobody (Nb33) were used to compare the relative efficacy of compounds that showed full agonist activity in amplified G protein-based assays. N / D = Undetermined

[0373] Table 2. Inhibition of monoamines and vesicle transporters, efficacy expressed as [IC50] 50 = μM.

[0374] References

Claims

1. A compound having the following structure: ， in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; in (i) When D is NH or -N-(C1-C2 alkyl), then R6 is -(C3-C4 alkyl). 12 alkyl); (ii) When X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, and R8 are H, then R6 is not propyl. (iii) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not propyl. (iv) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OH, then R6 is not propyl. (v) When X1 is C, X2 is NH, D is NH, R2, R4, R7 and R8 are H, and R3 is -OMe, then R6 is not Hpropyl. (vi) When X1 is C, X2 is O, D is NH, R2, R4, R6, and R8 are H, and R3 is -OMe, then R7 is not propyl; and (vii) When X1 is C, X2 is O, D is NH, R2, R4, R6 and R8 are H, and R3 is -OH, then R7 is not propyl. Or its pharmaceutically acceptable salt.

2. A compound having the following structure: ， in α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; When X2 is O, D is NH, and R6 is propyl or methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; When X2 is O, D is -NCH3, and R6 is methyl, then R3 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; and When X2 is -NH and R6 is propyl, then R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; Or its pharmaceutically acceptable salt.

3. The compound of claim 1, wherein D is NR5, and E and F are each independently CR9R. 10 .

4. The compound of claim 1, wherein X1 is C.

5. The compound of claim 1, wherein X2 is O or NR1.

6. The compound of claim 1, wherein R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), Aryl), -CO2 (alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; preferably, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc or -O (alkyl); more preferably, R1, R2, R3, R4 and R8 are each independently H, halogen, -(alkyl), -OH or -O (alkyl).

7. The compound of claim 1, wherein R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; preferably, R5 is H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OH, -OAc, -O(alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl-NH-(alkynyl); more preferably, R5 is H, -(alkyl), or -O(alkyl); even more preferably, R5 is H or -(alkyl).

8. The compound of claim 1, wherein R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl); preferably, R6 is -(C1-C6 alkyl), -(C1-C6 alkenyl), -(C1-C6 alkynyl), -C1-C6 cycloalkyl, -(C1-C6 alkyl-alkenyl), -(C1-C6 alkyl-alkynyl) or -(C1-C6 alkyl-cycloalkyl).

9. The compound of claim 8, wherein R6 is a branched -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl) or -(alkyl-cycloalkyl).

10. The compound of claim 1, wherein R5 and R6 combine to form a 3-7 membered heterocyclic alkyl ring; preferably, R5 and R6 combine to form a 5-membered heterocyclic alkyl ring.

11. The compound of claim 1, wherein R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); preferably, R7 is -H or -(alkyl).

12. The compound of claim 1, wherein R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), or -(alkynyl); preferably, R9 and R 10 Each is independently H or -(alkyl).

13. The compound of claim 1, wherein R 15 It is H or -(alkyl).

14. The compound of claim 1, having the following structure: ， in X2 is NR1 or O; R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; and R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Or its pharmaceutically acceptable salt.

15. The compound of claim 1, having the following structure: ， in R1 is H or -(alkyl); R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl).

16. The compound of claim 1, having the following structure: ， in R2, R3, and R4 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is H or -(alkyl); R6 is -(C3-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 can be -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl).

17. The compound according to any one of claims 1 to 16, wherein R1 is either -H or -Me; R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or -C(O)NH2; and R5 is -H, methyl, or ethyl.

18. The compound according to any one of claims 1 to 17, wherein R6 is , , , , , , , , , , , or .

19. The compound according to any one of claims 1 to 18, wherein R7 is -H or -Me.

20. The compound of claim 1, having the following structure: , , , , , , , or .

21. The compound of claim 20, wherein R5 is -H or methyl.

22. The compound of claim 1, having the following structure: , , , , , , , , , , , or .

23. The compound of claim 1, having the following structure: or .

24. The compound of claim 23, wherein R1 is either -H or -Me; R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or -OMe; R5 is -H, methyl; and / or R7 is either -H or -Me.

25. The compound of claim 1, having the following structure: , , , , or .

26. The compound of claim 25, wherein... R1 is either -H or -Me; R2, R3, and R4 are each independently -H, -OH, -F, -Cl, -Br, -CN, or -OMe; R5 is -H, methyl; and / or R7 is either -H or -Me.

27. The compound of claim 1, having the following structure: , or .

28. The compound of claim 1, having the following structure: , or .

29. A compound having the following structure: ， in [A] α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NR5 or CR9R. 10 ,and One of D, E, and F is NR5, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, NR1, or CR. 15 Furthermore, when X2 is NR1, α does not exist and β does exist; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2-C 12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; [B] α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is O, S, N, or CR 15 ; R1, R2, R3, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(C2 alkyl), -(C6) 4-12 Alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6 is -(C3 alkyl) and R3 is –(C=O)NH2; Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; or [C] α and β represent bonds that are present or not present, and where α or β is present. D, E, and F are each independently NH or CR9R. 10 ,and One of D, E, and F is NH, and the other two of D, E, and F are CR9R. 10 ; X1 is C or N, and when X1 is N, α does not exist and β exists; X2 is NR1, and α does not exist while β does exist; R1, R2, R4, and R8 are each independently H, halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3, or -NO2; R3 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1 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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R5 is a halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(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), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3 or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); Alternatively, R5 and R6 can combine to form 3-7 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings; R7 can be -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynyl), -(alkyl-cycloalkyl), -(aryl), or -(heteroaryl); R9 and R 10 Each is independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl, or -alkylaryl; and R 15 It is H, -(alkyl) or -cycloalkyl; or Or its pharmaceutically acceptable salt.

30. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 29 and a pharmaceutically acceptable carrier.

31. A method for activating a 5HT2A receptor, a 5HT2C receptor, or both a 5HT2A receptor and a 5HT2C receptor, comprising contacting the 5HT2A receptor and the 5HT2C receptor with a compound as described in any one of claims 1 to 29.

32. A method of inhibiting a SERT receptor, comprising contacting the SERT receptor with a compound as claimed in any one of claims 1 to 29.

33. A method of activating a κ-opioid receptor, comprising contacting the κ-opioid receptor with a compound as described in any one of claims 1 to 29.

34. A method for inhibiting nicotinic acetylcholine receptors, comprising contacting the nicotinic acetylcholine receptors with a compound as described in any one of claims 1 to 29.

35. A method of treating a subject suffering from a substance use disorder, comprising administering to the subject a compound as described in any one of claims 1 to 29 or a composition as described in claim 30 containing an effective amount of the compound, thereby treating the subject suffering from the substance use disorder.

36. A method of treating a subject suffering from depression, mood disorder, anxiety disorder, Parkinson's disease, or traumatic brain injury, comprising administering to the subject a compound as described in any one of claims 1 to 29 or a composition as described in claim 30 comprising an effective amount of the compound, thereby treating the subject suffering from the depression, mood disorder, anxiety disorder, Parkinson's disease, or traumatic brain injury.

37. The compound of any one of claims 1 to 29 or the composition of claim 30, used for a) Activation of 5HT2A receptor, 5HT2C receptor, or both 5HT2A and 5HT2C receptors. b) Inhibit SERT receptors, c) Activation of κ-opioid receptors, d) Inhibition of nicotinic acetylcholine receptors, e) Treating subjects with substance use disorders, or f) Treatment of subjects with depression, mood disorders, anxiety, Parkinson's disease, or traumatic brain injury.

38. The compound according to any one of claims 1 to 29 or the composition according to claim 30 a) Activation of 5HT2A receptor, 5HT2C receptor, or both 5HT2A and 5HT2C receptors. b) Inhibit SERT receptors, c) Activation of κ-opioid receptors, d) Inhibition of nicotinic acetylcholine receptors, e) Treating subjects with substance use disorders, or f) Use for the treatment of subjects with depression, mood disorders, anxiety, Parkinson's disease, or traumatic brain injury.

39. A method for synthesizing the compound of claim 1, comprising making the compound of formula I (Equation I), (a) Reaction with organic bromides in the presence of a base; or (b) Reaction with a haloalkane in the presence of a base, followed by reaction with an organic bromide in the presence of a base; To produce compounds of formula II (Formula II), Preferably, R6 is an alkyl, alkyl-alkenyl, or alkyl-ynyl group, and R7 is H or an alkyl group.

40. The method of claim 39, further comprising: (a) Converting the compound of Formula II into an oxime compound; (b) Converting the oxime compound into a lactam compound; as well as (c) The lactam compound is subjected to reduction, protection, and deprotection reactions to produce a compound of formula III. (Formula III) 41. The method of claim 40, further comprising reacting the compound of formula III with... The reaction is followed by a deprotection reaction to produce a compound of formula IV. (Form IV), Preferably, X is O, and R2, R4 and R8 are each H, and R5 is H or an alkyl group.

42. The method of claim 41, wherein formula IV has the following structure: , , , , , , , , , , , or .

Images