Novel analogs of oxa-iboga class of therapeutics

Abstract

This invention provides a compound having the following structure: (I).

Description

Docket: 92367-A-PCT / GJG / YX / RJB NOVEL ANALOGS OF OXA-IBOGA CLASS OF THERAPEUTICS CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] Throughout this application, various publications are referenced, including referenced inparenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This invention was made with government support under DA050613 awarded by NationalInstitute on Drug Abuse / National Institute of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION

[0004] Ibogaine is the major psychoactive alkaloid found in the root bark of Tabernanthe iboga, a plantnative to West Central Africa (Alper, K.R. 2001). The root bark has been used as a religious and healing sacrament by the native people in Africa owing to its distinct psychedelic effects. The clinical claims of ibogaine’s anti-addictive properties, discovered in the U.S. in the 1960’s, have largely been recapitulated in animal models of substance use disorders (SUDs), where ibogaine and its main metabolite, noribogaine, show a plethora of effects relevant to different aspects of SUDs (Glick, S.D. et al.2001; Belgers, M. et al. 2016; Mash, D.C. et al.2016).

[0005] SUDs are psychiatric disorders that affect nearly 20 million adults in the US. Unfortunately,limited treatment options are currently available to these patients. Considering the large unmet needs in SUDs and psychiatric disorders in general, there is a strong impetus to develop new analogs that increase ibogaine’s safety and therapeutic index for the treatment of such diseases. Additionally, there is a need for new compounds that can be used to study biological mechanisms that underpin ibogaine’s effects and enhance our understanding of ibogaine’s mechanism of action.

[0006] The present invention represents novel ibogaine analogs of compounds previously disclosed(U.S. Patent No. 9,988,377; U.S. Application Serial No. 14 / 240,681, 15 / 528,339; PCT International Application No. PCT / US2012 / 052327, PCT / US2015 / 062726). These analogs represent a further elaboration and deconstruction of the iboga skeleton to yield simpler and distinct structural systems with distinct pharmacology as well as improved side effects. The compounds described herein may be useful in 4924-6694-6837v.1treating opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders, migraine and cluster headaches.

[0007] The present invention identified key structural features that enable the novel benzofurano-azepineanalogs to exhibit potent kappa opioid activity with reduced side effect profile (reduced hERG inhibition and no proarrhythmic response). Moreover, the efficacy of the kappa activity can be readily modulated by choice of substitution.

[0008] These analogs may be useful in treating opioid use disorder (OUD) and other SUDs, mooddisorders, depression, and anxiety disorders, migraine and cluster headaches. They are safer analogs of ibogaine for treatment of addiction, neurological and psychiatric disorders. These analogs have enhanced pharmacological activity at relevant molecular targets (monoamine transporters, opioid receptors) and improved side effect profile (reduced cardiotoxicity risk). 2 4924-6694-6837v.1BRIEF SUMMARY OF THE INVENTION

[0009] The present invention provides a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); 3 4924-6694-6837v.1R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof. 4 4924-6694-6837v.1BRIEF DESCRIPTION OF THE DRAWINGS

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

[0011] Figure 2. A / Compounds 1 and 2 inhibit hERG ion channel to a lower extent than noribogaine.B / Primary adult human cardiomyocytes in the presence of compound 2 did not exhibit any pro-arrhythmic signs up to 10 μM.

[0012] Figure 3. Pharmacokinetic study of compounds 1 and 2 (10 mg / kg, s.c.) in male C57BL / 6 mouseshow favorable brain / plasma distribution. A / Total concentration and free concentration determined for compound 1 and B / compound 2. Free concentration was calculated by correcting for non-specific plasma protein and tissue binding using rodent (rat) data. 5 4924-6694-6837v.1DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention provides a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); 6 4924-6694-6837v.1R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then R1 and at leasttwo of R2, R3, R4 and R8 are other than hydrogen.

[0015] In some embodiments, when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then one of R9 andR10 is other than H.

[0016] In some embodiments, 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 other than H.

[0017] In some embodiments, 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 one of R9 and R10 is other than H.

[0018] In some embodiments, when X1 is C, X2 is O, and E is NH, then at least one of R2, R3, R4, R8, R9and R10 is other than H.

[0019] In some embodiments, when X1 is C, X2 is S, and R5, R9 and R10 are each H, and R3 is Br, thenD is other than NH.7 4924-6694-6837v.1

[0020] In some embodiments, when X1 is N, X2 is CR15, D is NR5, E is CR9R10, R5, R9 and R10 are H,and R15is H, then one of R2, R3, R4and R8is other than H, and R4is other than OMe, R3is other than Br, R2is other than Br and Cl, and R8is other than OMe.

[0021] In some embodiments, when X1 is N, X2 is CR15, D is NR5, E is CR9R10, R5 is alkyl, R9 and R10are H, and R15is CH3, then at least one of R2, R3, R4and R8is other than H and CH3, and R3is other than a ketone and a carboxylic acid.

[0022] The present invention provides a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; α is absent and β is present;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-alkynl), -(alkyl-cycloalkyl), - (aryl) or -(heteroaryl); or R5and R6combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; 8 4924-6694-6837v.1R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), - (aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein when X2is O, D is NH, and R6is propyl or methyl, then R3is 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; wherein 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 wherein when X2 is -NH, and R6 is propyl, then R5 is 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 a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, D is NR5, and E and F are each independently CR9R10.

[0024] In some embodiments, X1 is C.

[0025] In some embodiments, 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, -OCF3or -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). 9 4924-6694-6837v.1

[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, -OCF3or -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 embodiments, R5 is H, -(alkyl), or -O(alkyl).

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

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

[0034] In some embodiments, R6 is -(C1-C6alkyl), -(C1-C6alkenyl), -(C1-C6alkynyl), -C1-C6cycloalkyl, -(C1-C6alkyl-alkenyl), -(C1-C6alkyl-alkynl), or -(C1-C6alkyl-cycloalkyl).

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

[0036] In some embodiments, R5 and R6 combine to form a 3-7 membered heterocycloalkyl, ring.

[0037] In some embodiments, R5 and R6 combine to form a 5 membered heterocycloalkyl ring.

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

[0039] In some embodiments, R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl);preferably, R9 and R10 are each independently H or -(alkyl).

[0040] In some embodiments, R15 is H, or -(alkyl).

[0041] The present invention provides a compound having the structure:wherein10 4924-6694-6837v.1α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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 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-C12 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0042] The present invention provides a compound having the structure:11 4924-6694-6837v.1wherein α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, or CR15; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6is -H, -(C2alkyl), -(C4-12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl- alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6is -(C3alkyl) and R3is –(C=O)NH2; or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and 12 4924-6694-6837v.1R15is H, -(alkyl) or -cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0043] The present invention provides a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is NR1and α is absent and β is present; 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, -OCF3or -NO2; R3is halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1alkyl), -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 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); 13 4924-6694-6837v.1or R5and R6combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; or or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, R6 is -(C3-C12 alkyl) and R7 is -(alkenyl).

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

[0046] The present invention provides a compound having the following structure:whereinX2 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, -OCF3or -NO2; 14 4924-6694-6837v.1R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5and R6combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and R7is -H, -(C1-C3alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein (i) when R5 is H, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 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 H propyl;(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:whereinR1 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; R5is H or –(alkyl); 15 4924-6694-6837v.1R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl) R7is -H, -(C1-C3alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein (i) when R5 is H, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 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 H propyl.

[0048] In some embodiments, the present invention provides a compound having the following structure:whereinR2, R3and R4are 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, -OCF3or -NO2; R5is H or –(alkyl); R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7is -H, -(C1-C3alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein 16 4924-6694-6837v.1(i) R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and(ii) R5 is NH, R2, R4, and R6 are H, and R3 is -OH, then R7 is not propyl.

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

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

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

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

[0055] The present invention provides a compound having the following structure:, ,

[0056]

[0057] The present invention provides a compound having the following structure:17 4924-6694-6837v.1O HO H2N HO , , orR4R R43R3.

[0059] -Me.

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

[0061] The present invention provides a compound having the following structure:18 4924-6694-6837v.1R R 34N R5,

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

[0064] The present invention provides a compound having the following structure:

[0065] In some embodiments, the compounds in the present invention have monoamine transporterinhibition.

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

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

[0068] In some embodiments, the compounds in the present invention have no or limited proarrhythmicpotential.

[0069] The present invention provides a pharmaceutical composition comprising a compound disclosedherein and a pharmaceutically acceptable carrier.

[0070] The present invention provides a method of activating 5HT2A, 5HT2C, or both 5HT2A and5HT2C receptors comprising contacting the 5HT2A and 5HT2C receptors with a compound having thestructure: 19 4924-6694-6837v.1wherein α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and 20 4924-6694-6837v.1R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof.

[0071] The present invention provides a method of inhibiting SERT receptor comprising contacting theSERT receptor with a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; α is absent and β is present; 21 4924-6694-6837v.1R1, 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; and 22 4924-6694-6837v.1(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 notpropyl; or a pharmaceutically acceptable salt thereof.

[0072] The present invention provides a method of activating kappa-opioid receptor comprisingcontacting the kappa-opioid receptor with a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; 23 4924-6694-6837v.1R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof.

[0073] The present invention provides a method of inhibiting nicotinic acetylcholine receptorcomprising contacting the nicotinic acetylcholine receptor with a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; 24 4924-6694-6837v.1X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; 25 4924-6694-6837v.1(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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof.

[0074] The present invention provides a method of treating a subject afflicted with substance usedisorder comprising administering to the subject a compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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; 26 4924-6694-6837v.1R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5and R6combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject afflicted with the substance use disorder.

[0075] The present invention provides a method of treating a subject afflicted with a depressive disorder,a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury comprisingadministering to the subject a compound having the structure:27 4924-6694-6837v.1wherein α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and 28 4924-6694-6837v.1R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof, so as to thereby treat the subject afflicted with the depressive disorder, the mood disorder, the anxiety disorder, Parkinson’s disease or the traumatic brain injury.

[0076] In some embodiments, when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then R1 and at leasttwo of R2, R3, R4 and R8 are other than hydrogen.

[0077] In some embodiments, when X1 is C, X2 is NR1, E is NR1 and D is CR9R10, then one of R9 andR10 is other than H.

[0078] In some embodiments, 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 other than H.

[0079] In some embodiments, 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 one of R9 and R10 is other than H.

[0080] In some embodiments, when X1 is C, X2 is O, and E is NH, then at least one of R2, R3, R4, R8, R9and R10 is other than H.

[0081] In some embodiments, when X1 is C, X2 is S, and R5, R9 and R10 are each H, and R3 is Br, thenD is other than NH.29 4924-6694-6837v.1

[0082] In some embodiments, when X1 is N, X2 is CR15, D is NR5, E is CR9R10, R5, R9 and R10 are H,and R15is H, then one of R2, R3, R4and R8is other than H, and R4is other than OMe, R3is other than Br, R2is other than Br and Cl, and R8is other than OMe.

[0083] In some embodiments, when X1 is N, X2 is CR15, D is NR5, E is CR9R10, R5 is alkyl, R9 and R10are H, and R15is CH3, then at least one of R2, R3, R4and R8is other than H and CH3, and R3is other than a ketone and a carboxylic acid.

[0084] In some embodiments, the compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; α is absent and β is present;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-alkynl), -(alkyl-cycloalkyl), - (aryl) or -(heteroaryl); 30 4924-6694-6837v.1or R5and R6combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), - (aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein when X2is O, D is NH, and R6is propyl or methyl, then R3is 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; wherein 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 wherein when X2 is -NH, and R6 is propyl, then R5 is 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 a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, D is NR5, and E and F are each independently CR9R10.

[0086] In some embodiments, X1 is C.

[0087] In some embodiments, 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, -OCF3or -NO2. 31 4924-6694-6837v.1

[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, -OCF3or -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 embodiments, R5 is H, -(alkyl), or -O(alkyl).

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

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

[0096] In some embodiments, R6 is -(C1-C6alkyl), -(C1-C6alkenyl), -(C1-C6alkynyl), -C1-C6cycloalkyl, -(C1-C6alkyl-alkenyl), -(C1-C6alkyl-alkynl), or -(C1-C6alkyl-cycloalkyl).

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

[0098] In some embodiments, R5 and R6 combine to form a 3-7 membered heterocycloalkyl, ring.

[0099] In some embodiments, R5 and R6 combine to form a 5 membered heterocycloalkyl ring.

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

[0101] In some embodiments, R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl);preferably, R9 and R10 are each independently H or -(alkyl).

[0102] In some embodiments, R15 is H, or -(alkyl).

[0103] In some embodiments, the compound has the structure:32 4924-6694-6837v.1wherein α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6is -H, -(C2-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and 33 4924-6694-6837v.1R15is H, -(alkyl) or -cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound has the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, or CR15; 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, -OCF3or -NO2; R5is 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), -(C4-12 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl- alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6 is -(C3 alkyl) and R3 is –(C=O)NH2; or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; 34 4924-6694-6837v.1R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the compound has the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is NR1and α is absent and β is present; 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, -OCF3or -NO2; R3is halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1alkyl), -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; 35 4924-6694-6837v.1R5is 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, -OCF3or -NO2; R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5and R6combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; or or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, R6 is -(C3-C12 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:whereinX2 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), 36 4924-6694-6837v.1-NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH-(heteroaryl), - CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6 is -(C3-C12 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and R7 is -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein (viii) when R5 is H, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 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 H propyl;(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:wherein R1is H or –(alkyl); 37 4924-6694-6837v.1R2, R3and R4are 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, -OCF3or -NO2; R5is H or –(alkyl); R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl) R7 is -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein (vi) when R5 is H, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 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 H propyl.

[0110] In some embodiments, the compound has the following structure:whereinR2, R3and R4are 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); 38 4924-6694-6837v.1R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7is -H, -(C1-C3alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); wherein (iii) R5 is NH, R2, R4, and R6 are H, and R3 is -OMe, then R7 is not propyl; and(iv) R5 is NH, R2, R4, and R6 are H, and R3 is -OH, then R7 is not propyl.

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

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

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

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

[0117] The present invention provides a compound having the following structure:39 4924-6694-6837v.1, ,

[0118]

[0119] The present invention provides a compound having the following structure:HO , ,40 4924-6694-6837v.1or R4R R R43 3R5R5.

[0121] or -Me.

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

[0123] The present invention provides a compound having the following structure:R R4R4R R3 43R3,-

[0125] In some embodiments, 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:41 4924-6694-6837v.1.

[0127] sporterinhibition.

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

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

[0130] In some embodiments, the compounds in the present invention have no or limited proarrhythmicpotential.

[0131] In some embodiments, the present invention provides a compound having the following structure:.4924-6694-6837v.1

[0132] The compounds disclosed in the present invention can be used in combination with othercompounds disclosed in the U.S. Publication No. 2023 / 0382919 to treat opioid use disorder (OUD) and other SUDs, mood disorders, depression, and anxiety disorders, migraine and cluster headaches, the content of which is incorporated by reference.

[0133] In some embodiments, the anxiety disorder includes, but is not limited to, anxiety, generalizedanxiety 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 embodiments, the depressive disorder includes, but is not limited to, depression, majordepression, dysthymia, cyclothymia, postpartum depression, seasonal affective disorder, atypical depression, psychotic depression, bipolar disorder, premenstrual dysphoric disorder, situational depression or adjustment disorder with depressed mood. Depressive disorders can also include other mood disorders and is not limited to the above list.

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

[0136] The present invention provides compounds or composition for use in inhibiting SERT receptor.

[0137] The present invention provides compounds or composition for use in activating kappa-opioidreceptor.

[0138] The present invention provides compounds or composition for use in inhibiting nicotinicacetylcholine receptor.

[0139] The present invention provides compounds or composition for use in treating a subject afflictedwith substance use disorder.

[0140] The present invention provides compounds or composition for use in treating a subject afflictedwith a depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury.

[0141] The present invention provides use of compounds or composition to activate 5HT2A, 5HT2C, orboth 5HT2A and 5HT2C receptors.

[0142] The present invention provides use of compounds or composition to inhibit SERT receptor.

[0143] The present invention provides use of compounds or composition to activate kappa-opioidreceptor. 43 4924-6694-6837v.1

[0144] The present invention provides use of compounds or composition to inhibit nicotinicacetylcholine receptor.

[0145] The present invention provides use of compounds or composition is to treat a subject afflictedwith substance use disorder.

[0146] The present invention provides use of compounds or composition to treat a subject afflicted witha depressive disorder, a mood disorder, an anxiety disorder, Parkinson’s disease, or traumatic brain injury.

[0147] The present invention provides a process of synthesizing a compound having the followingstructure: , whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; 44 4924-6694-6837v.1R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); and R7is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); and R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; comprising reacting a compound of formula I: (formula I) with an organo-bromide in thea base; or with an alkyl halide in the presence of a base, then reacting with an organo bromide in the presence of a base to produce a compound of formula II: (formula II).

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

[0149] In someis alkyl, alkyl-alkenyl, or alkyl-alkynyl, and R7 is H or CH3.

[0150] In some embodiments, the process further comprises:(a) converting the compound of formula II to an oxime compound;45 4924-6694-6837v.1(b) converting the oxime compound to a lactam compound; and(c) performing reduction, protection and deprotection reactions to the lactam compoundto produce a compound of formula III: .

[0151] In some embodiments, thethe compound of formula III withfollowed by a deprotection reaction to produce a compound of formula IV, wherein X2is O.

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

[0153] In someare each H, and R5 is H or alkyl.

[0154] In some embodiments, the compound of formula IV has the following structure:,4924-6694-6837v.1O HO HO H2N N Me , , oranalgesic effect (Sharma, S.S. et al. 1998) or reverses analgesic tolerance to morphine (Bhargava, H.N. et al.1997).

[0156] In some embodiments, the method wherein the subject is afflicted with pain. Reports of stimulanteffects of Tabernanthe iboga date back to late 1890’s and early 1900’s in the descriptions of ritual and medicinal use by the native inhabitants in Africa. Ibogaine was recommended in France to treat “asthenia” (dose range of 10-30 mg per day). In the period of 1939-1970, ibogaine was commercially available in France as “Lambarène”, a “neuromuscular stimulant” (8 mg pills) recommended for fatigue, depression, and recovery from infectious diseases (Alper, K.R.2001). In one clinical study, subjects took visual analog scale tests (VAS, 0-100) related to sleepiness, energetic feelings, and the side effects such as nausea, anxiety versus calmness. Subjects reported that ibogaine decreased sleepiness and increased energetic feeling over the examined 24-hour period after one dose of 20 mg of ibogaine (Glue, P. et al.2015). A stimulant effect was reported in cats (Schneider et. al 1957). In rats, ibogaine induced wakefulness and suppressed the REM sleep as shown via EEG (González, J. et al 2018). 47 4924-6694-6837v.1

[0157] It has been shown in rats that ibogaine leads to a dramatic upregulation of BDNF (in addition toGlial cell line-Derived Neurotrophic Factor (GDNF)) which provides structural and functional restorative effects in subjects afflicted with TBI (Marton, S. et al.2019). The efficacy of ibogaine has also been shown in cases of soldiers afflicted with TBI and PTSD (Thoricatha, W.2020).

[0158] In some embodiments, the method wherein the subject is afflicted with traumatic brain injury(TBI).

[0159] It has been shown in rats that ibogaine induces expression of GDNF (He, D-Y. et al. 2005 andMarton, S. et al. 2019), a critical neurotrophic factor that maintains and restores the dopaminergic system (which degenerates in Parkinson’s disease). Thus, ibogaine provides structural and functional restorative effects in subjects afflicted with Parkinson’s disease. GDNF itself has been shown to exert desired effects in Parkinson’s rodent and monkey models (Gash, D.M. et al.1996).

[0160] In some embodiments, the method wherein the subject is afflicted with Parkinson’s disease.

[0161] It has been shown in humans that ibogaine is useful in treating opioid and stimulant use disorders(Alper, K.R. et al. 1999; Mash, D.C. et al. 2018; Schenberg, E.E. et al. 2014) or in maintenance therapy (opioid use disorder) in combination with an opioid to lower effective opioid doses (Kroupa, P.K. & Wells, H.2005).

[0162] In some embodiments, wherein the substance use disorder is an opioid use disorder, alcohol usedisorder or stimulant use disorder.

[0163] Opioid use disorder (OUD) involves, but is not limited to, misuse of opioid medications or useof illicitly obtained opioids. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association, 2013), which is hereby incorporated by reference, describes opioid use disorder as a problematic pattern of opioid use leading to problems or distress, with at least two of the following occurring within a 12-month period:

[0164] -Taking larger amounts or taking drugs over a longer period than intended.

[0165] -Persistent desire or unsuccessful efforts to cut down or control opioid use.

[0166] -Spending a great deal of time obtaining or using the opioid or recovering from its effects.

[0167] -Craving, or a strong desire or urge to use opioids.48 4924-6694-6837v.1

[0168] -Problems fulfilling obligations at work, school, or home.

[0169] -Continued opioid use despite having recurring social or interpersonal problems.

[0170] -Giving up or reducing activities because of opioid use.

[0171] -Using opioids in physically hazardous situations.

[0172] -Continued opioid use despite ongoing physical or psychological problem likely to have beencaused or worsened by opioids.

[0173] -Tolerance (i.e., need for increased amounts or diminished effect with continued use of the sameamount).

[0174] -Experiencing withdrawal (opioid withdrawal syndrome) or taking opioids (or a closely relatedsubstance) to relieve or avoid withdrawal symptoms.

[0175] Alcohol use disorder (AUD) involves, but is not limited to, a chronic relapsing brain diseasecharacterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition describes alcohol use disorder as a problematic pattern of alcohol use leading to problems or distress, with at least two of the following occurring within a 12-month period:

[0176] -Being unable to limit the amount of alcohol you drink.

[0177] -Wanting to cut down on how much you drink or making unsuccessful attempts to do so.

[0178] -Spending a lot of time drinking, getting alcohol, or recovering from alcohol use.

[0179] -Feeling a strong craving or urge to drink alcohol.

[0180] -Failing to fulfill major obligations at work, school or home due to repeated alcohol use.

[0181] -Continuing to drink alcohol even though you know it is causing physical, social, or interpersonalproblems.

[0182] -Giving up or reducing social and work activities and hobbies.

[0183] -Using alcohol in situations where it is not safe, such as when driving or swimming.

[0184] -Developing a tolerance to alcohol so you need more to feel its effect, or you have a reducedeffect from the same amount. 49 4924-6694-6837v.1

[0185] -Experiencing withdrawal symptoms — such as nausea, sweating and shaking — when you donot drink, or drinking to avoid these symptoms.

[0186] Stimulant use disorder involves, but is not limited to, a pattern of problematic use ofamphetamine, methamphetamine, cocaine, or other stimulants except caffeine or nicotine, leading to at least two of the following problems within a 12-month period:

[0187] -Taking more stimulants than intended.

[0188] -Unsuccessful in trying to cut down or control use of stimulants, despite wanting to do so.

[0189] -Spending excessive amounts of time to activities surrounding stimulant use.

[0190] -Urges and cravings for stimulants.

[0191] -Failing in the obligations of home, school, or work.

[0192] -Carrying on taking stimulants, even though it has led to relationship or social problems.

[0193] -Giving up or reducing important recreational, social, or work-related activities because of usingstimulants.

[0194] -Using stimulants in a physically hazardous way.

[0195] -Continuing to use stimulants even while knowing that it is causing or worsening a physical orpsychological problem.

[0196] -Tolerance to stimulants.

[0197] -Withdrawal from stimulants if you do not take them.

[0198] Polydrug use disorder or polysubstance use disorder involves, but is not limited to, dependenceon multiple drugs or substances.

[0199] The term “MOR agonist” is intended to mean any compound or substance that activates the mu-opioid receptor (MOR). The agonist may be a partial, full, or super agonist.

[0200] In some embodiments, the compounds of the present invention may be safer and have feweradverse effects compared to existing treatments.

[0201] In some embodiments, the compounds of the present invention may have better hERGprofile / cardiac profile compared to ibogaine and noriboagine. 50 4924-6694-6837v.1

[0202] In some embodiments, the compounds of the present invention may be useful as tool compoundsfor studying the mechanism of ibogaine.

[0203] A person skilled in the art may use the techniques disclosed herein to prepare deuterium analogsthereof.

[0204] Except where otherwise specified, the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, scalemic mixtures and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

[0205] Except where otherwise specified, the subject invention is intended to include all isotopes ofatoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0206] It will be noted that any notations of a carbon in structures throughout this application, when usedwithout further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.

[0207] It will also be noted that any notations of a hydrogen (H) in structures throughout this application,when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H (D), or3H (T) except where otherwise specified. Furthermore, any compounds containing2H (D) or3H (T) may specifically have the structure of any of the compounds disclosed herein except where otherwise specified.

[0208] Isotopically labeled compounds can generally be prepared by conventional techniques known tothose skilled in the art using appropriate isotopically labeled reagents in place of the non-labeled reagents employed. 51 4924-6694-6837v.1

[0209] Deuterium (2H or D) is a stable, non-radioactive isotope of hydrogen and has an atomic weightof 2.0144. Hydrogen atom in a compound naturally occurs as a mixture of the isotopes1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.0156%. Thus, in a composition comprising molecules of a naturally occurring compound, the level of deuterium at a particular hydrogen atom site in that compound is expected to be 0.0156%. Thus, a composition comprising a compound with a level of deuterium at any site of hydrogen atom in the compound that has been enriched to be greater than its natural abundance of 0.0156% is novel over its naturally occurring counterpart.

[0210] As used herein, a hydrogen at a specific site in a compound is “deuterium-enriched” if the amountof deuterium at the specific site in the compound is more than the abundance of deuterium naturally occurring at that specific site in view of all of the molecules of the compound in a defined universe such as a composition or sample. Naturally occurring as used above refers to the abundance of deuterium which would be present at a relevant site in a compound if the compound was prepared without any affirmative step to enrich the abundance of deuterium. Thus, at a "deuterium-enriched” site in a compound, the abundance of deuterium at that site can range from more than 0.0156% to 100%. Examples of ways to obtain a deuterium-enriched site in a compound are exchanging hydrogen with deuterium or synthesizing the compound with deuterium-enriched starting materials.

[0211] In the compounds used in the method of the present invention, the substituents may be substitutedor unsubstituted, unless specifically defined otherwise.

[0212] In the compounds used in the method of the present invention, alkyl, alkenyl, alkynyl, alkylaryl,cycloalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

[0213] It is understood that substituents and substitution patterns on the compounds used in the methodof the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0214] In choosing the compounds used in the method of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well- known principles of chemical structure connectivity. 52 4924-6694-6837v.1

[0215] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cnas in “C1–Cnalkyl" is defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12alkyl, C2-C12alkyl, C3-C12alkyl, C4-C12alkyl and so on. An embodiment can be C1-C8alkyl, C2-C8alkyl, C3-C8alkyl, C4-C8alkyl and so on. ”Alkoxy" represents an alkyl group as described above attached through an oxygen bridge.

[0216] The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containingat least 1 carbon to carbon-to-carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present. Thus, C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched, or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl or C2-C8 alkenyl.

[0217] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1carbon-to-carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon- carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C2-Cn alkynyl. An embodiment can be C2-C12 alkynyl or C3-C8 alkynyl.

[0218] The term “alkylaryl” refers to alkyl groups as described above wherein one or more bonds tohydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “alkylaryl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. 53 4924-6694-6837v.1

[0219] As used herein, "cycloalkyl" includes cyclic rings of alkanes of three to eight total carbon atoms,or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

[0220] The term “alkylcycloalkyl” refers to alkyl groups as described above wherein one or more bondsto hydrogen contained therein are replaced by a bond to a cycloalkyl group as described above. It is understood that an “alkylcycloalkyl” group is connected to a core molecule through a bond from the alkyl group and that the cycloalkyl group acts as a substituent on the alkyl group.

[0221] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic, or polycyclic carbonring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include but are not limited to: phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0222] The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ringof up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridazine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, 54 4924-6694-6837v.1dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra- hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0223] The term "heterocycle", “heterocyclyl” or “heterocyclic” refers to a mono- or poly-cyclic ringsystem which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

[0224] The term “ester” is intended to a mean an organic compound containing the R-O-CO-R’ group.

[0225] The term “phenyl” is intended to mean an aromatic six membered ring containing six carbons.

[0226] The term “benzyl” is intended to mean a –CH2R1 group wherein the R1 is a phenyl group.

[0227] The term “substitution”, “substituted” and “substituent” refers to a functional group as describedabove in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such 55 4924-6694-6837v.1as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0228] The compounds used in the method of the present invention may be prepared by techniques wellknown in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0229] The compounds used in the method of the present invention may be prepared by techniquesdescribed in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5thEdition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5thEdition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.

[0230] Another aspect of the invention comprises a compound or composition of the present inventionas a pharmaceutical composition.

[0231] As used herein, the term “pharmaceutically active agent” means any substance or compoundsuitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S. Department of Health and Human Services, 30thedition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect. 56 4924-6694-6837v.1

[0232] The compounds used in the method of the present invention may be in a salt form. As used herein,a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat a disease or medical disorder, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols; alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the sodium, potassium, or lithium salts, and the like. Carboxylate salts are the sodium, potassium, or lithium salts, and the like. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic, and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).

[0233] As used herein, "treating" means preventing, slowing, halting, or reversing the progression of adisease. Treating may also mean improving one or more symptoms of a disease.

[0234] The compounds used in the method of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

[0235] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent,suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier, as are capsules, coatings, and various syringes. 57 4924-6694-6837v.1

[0236] The dosage of the compounds administered in treatment will vary depending upon factors suchas the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

[0237] A dosage unit of the compounds used in the method of the present invention may comprise asingle compound or mixtures thereof with additional agents. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or onto a site of disease, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

[0238] The compounds used in the method of the present invention can be administered in admixturewith suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous, or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavoring and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. 58 4924-6694-6837v.1

[0239] Techniques and compositions for making dosage forms useful in the present invention aredescribed in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al. 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

[0240] Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0241] The compounds used in the method of the present invention may also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue- targeted emulsions.

[0242] The compounds used in the method of the present invention may also be coupled to solublepolymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran 59 4924-6694-6837v.1copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0243] Gelatin capsules may contain the active ingredient compounds and powdered carriers, such aslactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0244] For oral administration in liquid dosage form, the oral drug components are combined with anyoral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0245] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patientacceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 17th ed., 1989, a standard reference text in this field. 60 4924-6694-6837v.1

[0246] The compounds used in the method of the present invention may also be administered inintranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

[0247] Parenteral and intravenous forms may also include minerals and other materials to make themcompatible with the type of injection or delivery system chosen.

[0248] Each embodiment disclosed herein is contemplated as being applicable to each of the otherdisclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. Any of the disclosed generic or specific compounds may be applicable to any of the disclosed compositions, processes, or methods.

[0249] This invention will be better understood by reference to the Experimental Details which follow,but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims, which follow thereafter. EXAMPLES

[0250] Experimental Details

[0251] General Considerations. Reagents and solvents were obtained from commercial sources andwere used without further purification unless otherwise stated. Reactions were monitored by TLC using solvent mixtures appropriate to each reaction. Column chromatography was performed on silica gel (40 – 63 µm). For preparative TLC, glass plates coated with a 1 mm silica layer were used. Nuclear magnetic resonance spectra were recorded on Bruker 400 or 500 MHz instruments, as indicated. Chemical shifts are reported as δ values in ppm referenced to CDCl3 (1H NMR = 7.26 and13C NMR = 77.16) or methanol-d4 (1H NMR = 3.31 and13C NMR = 49.00). Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (pentet); dd (doublet of doublets); td (triplet of doublets); dt (doublet of triplets); dq (doublet of quartets); ddd (doublet of doublet of doublets); ddt (doublet of doublet of triplets); m (multiplet); br (broad). All carbon peaks are rounded to one decimal place unless such rounding would cause two close peaks to become identical; in these cases, two decimal places are retained. Low-resolution mass spectra were recorded on an Advion quadrupole instrument (ionization mode: APCI+ or ESI+).4924-6694-6837v.1

[0252] Compound 1 was prepared by a modification of a published procedure (Hu et al, 2020). To asolution of 4-bromophenol (69.2 g, 0.4 mol) in 2-propanol (60 mL), toluene (100 mL) and water (10 mL) was added KOH (22.44 g, 0.4 mol) and the mixture was stirred at 85 °C for 1.5h. A solution of hydroxylamine-O-sulfonic acid (11.31 g, 0.1 mol) in water (60 mL) was added dropwise over 15 minutes to the reaction mixture and reaction was continued at 85 ° C for 20 min. The reaction mixture was cooled to room temperature, aqueous NaOH solution (1 M, 300 mL) was added, and the mixture was extracted with diethyl ether (2 × 200 mL). Combined extracts were washed with aqueous NaOH solution (1 M, 4 × 125 mL mL), dried over Na2SO4, filtered and diethyl ether was evaporated under reduced pressure. The resulting yellow solution was diluted with MeOH (60 mL) and concentrated aqueous HCl (12.1 M, 8.3 mL) was slowly added. After stirring for 1h at room temperature resulting suspension was concentrated under reduced pressure, dissolved in MeOH and concentrated one more time. Compound 1 was isolated as a light brown crystalline powder (9.26 g, 41 % yield). Spectral characterization was in agreement with reported literature data.

[0253] 1H NMR (400 MHz, DMSO) δ 9.08 (br, 3H), 7.61 – 7.45 (m, 2H), 7.21 – 7.09 (m, 2H).

[0255] Compound 2 was prepared by a modification of a published procedure (Sames et al, 2022).Solution of 1,4-Cyclohexanedione monoethylene acetal (17.18 g, 0.11 mol) in THF (200 mL) was cooled to -78°C and LHMDS (1M in THF, 100 mL, 0.1 mol) was slowly added. The reaction mixture was further stirred for 50 min, then allyl bromide (10.15 mL, 0.12 mol) was added in portions over 20 min. The reaction mixture was allowed to slowly warm to room temperature. After 15 h reaction was quenched with sat. NH4Cl solution (100 mL), phases were separated, and aq. phase was further extracted with diethyl ether (2 × 100 mL), combined extracts were washed with brine (2 × 100 mL), dried over MgSO4, filtered and concentrated onto celite. Crude material was filtered through silica using a gradient of AcOEt in hexanes (2 to 10% in 1% increments). Semi-crude material contained dialkylated side-products and was used for next step without further purification. 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 MeOH was evaporated under 62 4924-6694-6837v.1reduced pressure, mixture was diluted with brine (50 mL) and extracted with CH2Cl2:iPrOH 9:1 (4 × 50 mL). Combined extracts were dried over Na2SO4, filtered and concentrated to a yellow oil that slowly crystallized. 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) were added, and the reaction mixture was stirred at 40°C. After 17 h acetone was evaporated under reduce pressure and the resulting aqueous mixture was saturated with NaCl and extracted with CH2Cl2:iPrOH 9:1 (5 × 100 mL). Combined extracts were dried over Na2SO4, filtered and concentrated. The crude material was dissolved in refluxing acetone (60 mL), cooled to RT and placed in fridge (+8°C) overnight. Precipitate was collected by filtration, white solid (10.54 g). Mother liquor was concentrated and purified by column chromatography using 25 to 50% acetone in hexanes. Compound 2 was obtained as a white solid (12.13 g, 57% yield over 3 steps). Spectral characterization was in agreement with reported literature data (Sames et al, 2022).

[0256] 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+) calcd. for C11H18NO3+as [M+H]+ 212.1, found 212.3.

[0258] Compound 3 was prepared by a modification of a published procedure (Sames et al, 2022).2 Allyllactam 2 (2.11g, 10.0 mmol) was dissolved in EtOH (65 mL, not dry) and moist 10% Pd on C (200 mg) was added. Reaction mixture was stirred under hydrogen atmosphere (3 MPa), after 5-6 h suspension was filtered through celite (rinsed with thoroughly with CH2Cl2:MeOH 9:1), and solution was concentrated to obtain a white solid. Dried crude product (2.13 g) was dissolved in THF (20 mL), cooled in ice bath (0°C, lactam will partially precipitate) and LiAlH4 (1.52 g, 40 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added to the suspension. Reaction mixture was allowed to warm to room temperature and heated to reflux for 3 h. After cooling to room temperature reaction mixture was diluted with THF (30 mL), cooled in ice bath and slowly quenched by addition of H2O, 15% aq. NaOH and H2O, (1:1:3 mL per g of LiAlH4), and stirred until all salts were off- white and loose. Solid was filtered off and rinsed with THF, until no further product elution was detected 63 4924-6694-6837v.1by TLC. Combined washings were acidified with aq. HCl (12.1M, 0.9 mL, 1.1 equiv.) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (40 mL) and the mixture was further stirred at room temperature for 3 days. Solution was concentrated, oily residue was dissolved in water (20 mL), carefully neutralized with solid NaHCO3and pH adjusted to >10 with 15% NaOH. Mixture was further extracted with CH2Cl2:iPrOH 9:1 (6 × 20 mL), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude intermediate (1.51 g) was immediately used for next step. Orange reside was dissolved in CH2Cl2(19.5 mL), Et3N (3.39 mL, 24.3 mmol) was added and mixture was cooled in ice bath. Trifluoroacetic anhydride (2.7 mL, 19.45 mmol) was added dropwise and mixture was further stirred at room temperature. After 18 h reaction mixture was slowly diluted with sat. NaHCO3 solution (30 mL), vigorously mixed and phases were separated. Aq. phase was further extracted with CH2Cl2 (2 × 20 mL), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Red oily residue was purified by column chromatography using diethyl ether in hexanes 1:1 to 3:1. Compound was isolated as an orange oil (1.98 g, 79% yield over 4 steps). NMR spectra (1H,19F and13C) are complicated due to the presence of rotamers (partial integrals in1H NMR).

[0259] 1H 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).19F NMR (471 MHz, CDCl3)δ -67.86, -68.60. LRMS (APCI+) calcd. for C11H17F3NO2+ as [M+H]+ 252.1, found 252.5.

[0261] Allyl lactam 2 (2.95 g, 10.0 mmol) was dissolved in THF (28 mL), cooled in ice bath (0°C, lactamwill partially precipitate) and LiAlH4 (2.12 g, 55.9 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added to the suspension. Reaction mixture was allowed to warm to room temperature and was heated to 70°C for 3.5 h. After cooling to room temperature reaction mixture was diluted with THF (28 mL), cooled in ice bath and slowly quenched by addition of H2O, 15% aq. NaOH and H2O, (1:1:3 mL per g of LiAlH4), and stirred until all salts were off- white and loose. Solid was filtered off and rinsed with THF, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M, 1.1 equiv.) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (56 mL) and the mixture was further 64 4924-6694-6837v.1stirred at room temperature for 3 days. Solution was concentrated, oily residue was washed with diethyl ether (2 ×) and dried in vacuum. The crude intermediate (3.0 g) was suspended in CH2Cl2(31.7 mL), Et3N (7.7 mL, 55.4 mmol) was added and mixture was cooled in ice bath. Trifluoroacetic anhydride (4.4 mL, 31.6 mmol) was added dropwise and mixture was further stirred at room temperature. After 18 h reaction mixture was slowly diluted with sat. NaHCO3solution (50 mL), vigorously mixed and phases were separated. Aq. phase was further extracted with CH2Cl2(2 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Red oily residue was purified by column chromatography using diethyl ether in hexanes 1:1 to 2:1. Compound 4 was isolated as an impure complex mixture (3.0 g) and was used as is for next step. NMR spectra (1H,19F and13C) are complicated due to the presence ofrotamers (partial integrals in 1H NMR).LRMS (APCI+) calcd. for C11H15F3NO2+ as [M+H]+ 250.1, found250.0.1. 7-(cyclopropylmethyl)-1,4-dioxa-8-azaspiro[4.6]undecan-9-one 5.

[0264] Diethyl zinc (1M in toluene, 15 mL, 15 mmol) was diluted with CH2Cl2 (15 mL) and cooled to0°C in water / ice bath. Solution of CF3COOH (1.15 mL, 15 mmol) in CH2Cl2 (5 mL) was added dropwise over 5 min and mixture was further at 0°C. After 20 min CH2I2 (1.21 mL, 15 mmol) in CH2Cl2 (5 mL) was added in one portion, followed by solution of allyl lactam 3 (1.06 g, 5 mmol) in CH2Cl2 (5 mL). Cooling was removed and mixture was stirred at room temperature. After 66 h mixture was poured to sat. NH4Cl 65 4924-6694-6837v.1solution (50 ml), phases were separated, and aq. phase was further extracted with CH2Cl2(2 x 20 mL), combined extracts were dried over Na2SO4, filtered and concentrated. Only 70% conversion was achieved, crude material was purified by column chromatography using acetone in hexanes 1:2 to 1:1 to obtain inseparable mixture of starting allyl and methylcyclopropyl lactam. Reaction was repeated one more time using the mixture of allyl and methylcyclopropyl lactam. After 24.5 h reaction was stopped and work-up repeated as previously. Crude material was purified by column chromatography using acetone in hexanes 1:1 to obtain product as white solid (1.03 g, 91% yield).

[0265] 1H 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+) calcd. for C12H20NO3+ as [M+H]+ 226.1, found 226.3.2. 2-(cyclopropylmethyl)-1-(2,2,2-trifluoroacetyl)azepan-4-one 6.Methylcyclopropyl lactam 5 (1.03 g, 4.6 mmol) was dissolved in THF (9.2 mL), cooled in ice bath (0°C, lactam will partially precipitate) and LiAlH4 (0.69 g, 18.3 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added to the suspension. Reaction mixture was allowed to warm to room temperature and heated to reflux for 3 h. After cooling to room temperature reaction mixture was diluted with THF (15 mL), cooled in ice bath and slowly quenched by addition of H2O, 15% aq. NaOH and H2O, (1:1:3 mL per g of LiAlH4), and stirred until all salts were off- white and loose. Solid was filtered off and rinsed with THF, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M, 1.1 equiv.) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (20 mL) and the mixture was further stirred at room temperature for 3 days. Solution was concentrated, oily residue was dissolved in water (20 mL), carefully neutralized with solid NaHCO3and pH adjusted to >10 with 15% NaOH. Mixture was further extracted with CH2Cl2:iPrOH 9:1 (5 × 20 mL), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude intermediate (0.76 g) was immediately used for next step. Orange reside was dissolved in CH2Cl2(9.2 mL), Et3N (1.58 mL, 11.4 mmol) was added, and mixture was cooled in ice bath. Trifluoroacetic anhydride (1.3 mL, 9.09 mmol) was added dropwise and mixture was further stirred at room temperature. After 18 h reaction mixture was slowly diluted with sat. NaHCO366 4924-6694-6837v.1solution (15 mL), vigorously mixed and phases were separated. Aq. phase was further extracted with CH2Cl2(2 × 10 mL), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Red oily residue was purified by column chromatography using diethyl ether in hexanes 1:1. Impure compound 6 was as obtained as an orange oil (0.93 g) and was used for next step without further purification.

[0267] LRMS (APCI+) calcd. for C12H17F3NO2+ as [M+H]+ 264.1, found 264.1.

[0270] Solution of 1,4-Cyclohexanedione monoethylene acetal (5.14g, 32.9 mmol) in THF (0.5 M, 65.8mL) was cooled to -78°C and LHMDS (1M in THF, 32.9 mL) was slowly added. The reaction mixture was further stirred for 50 min, then crotonyl bromide (3.7 g, 27.4 mmol) was added in portions over 20 min and reaction was allowed to slowly warm to room temperature. After 15 h reaction was quenched with sat. NH4Cl solution (50 mL), phases were separated, and aq. Phase further extracted with Et2O (50 mL), combined extracts were washed with brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated onto celite. Crude material was purified by column chromatography using gradient of AcOEt in hexanes (5 to 10%). Material still contained dialkylated side-products and was used for next step without additional 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 67 4924-6694-6837v.1the reaction mixture was stirred at 80°C. After 2 h MeOH was evaporated under reduced pressure, mixture was diluted with brine (30 mL) and extracted with DCM:iPrOH 9:1 (4 × 30 mL). 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) were added, and the reaction mixture was stirred at 40°C for 2.5 days. Acetone was evaporated under reduce pressure and the aqueous mixture was diluted with brine (15 mL), extracted with DCM:iPrOH 9:1 (4 × 50 mL). 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 RT and placed in fridge (+8°C) overnight. Precipitate was collected by filtration and recrystallized one more time from acetone. Solid material (0.56 g) was dissolved in MeOH (12.5 mL), 10% Pd / C (53 mg) was added, and mixture was stirred overnight under hydrogen atmosphere (1.5 MPa). Next day reaction mixture was filtered through celite pad (rinsed several times with MeOH) and MeOH solution was concentrated to obtain product 7 (0.56 g, 11% yield over 4 steps) as a white solid.

[0271] 1H 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).13C NMR (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+) calcd. for C12H22NO3+ as [M+H]+ 228.2, found 228.2.4. 2-butyl-1-(2,2,2-trifluoroacetyl)azepan-4-one 8.

[0274] Lactam intermediate (0.56 g) was dissolved in THF (9.8 mL, 0.25M), cooled in ice bath (0°C)and LiAlH4(0.28 g, 7.4 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added to the suspension (starting material precipitates from cold solution). Reaction mixture was allowed to warm to room temperature and further heated to reflux for 2.5 h. Reaction mixture was further cooled in ice bath and quenched slowly by addition of H2O, 15% NaOH 68 4924-6694-6837v.1and H2O (1:1:3 mL per g of LiAlH4), thick suspension was diluted with AcOEt (10 mL) and stirred until all salts were off-white and loose. Solid was filtered off and rinsed with AcOEt, until no further product elution was detected by TLC. Combined washings were acidified with aq. HCl (12.1M) and org. volatiles were evaporated under reduced pressure. To the residue was added 10% HCl (25 mL) and the mixture was further stirred at room temperature for 2.5 days. Solution was washed with CH2Cl2(2 × 20 mL), carefully neutralized with solid NaHCO3and basified with 15% NaOH. Mixture was further extracted with CH2Cl2(6 × 20 mL), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude intermediate (0.42 g) was immediately used for next step. Orange reside was dissolved in CH2Cl2(4.9 mL), Et3N (0.86 mL, 6.2 mmol) was added, mixture was cooled in ice bath and trifluoroacetic anhydride (0.68 mL, 4.9 mmol) was added dropwise. Mixture was further stirred at room temperature. After 3h it was poured to sat. NaHCO3 solution (15 mL), mixture was extracted with CH2Cl2 (3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Oily residue was purified by column chromatography using a gradient of diethyl ether in hexanes 1:1, 3:1. Compound 8 was isolated as an orange oil (0.69 g), NMR spectra (1H,19F and13C) are complicated due to the presence of rotamers.

[0275] LRMS (APCI+) calcd. for C12H19F3NO2+ as [M+H]+ 266.1, found 266.2.1H-benzofuro[3,2-c]azepine derivatives.

[0277] Procedure was published previously (Sames et al, 2022). General procedure A: corresponding N-(trifluoroacetyl)azepan-4-one (1 equivalent) and O-(4-bromophenyl)hydroxylamine hydrochloride were combined in 1,4-dioxane (anhydrous, 0.5 M based on azepan-4-one) and warmed to 80 °C. After 5 min at 80 °C methanesulfonic acid (2 equivalents) was added and reaction mixture was stirred at 80 °C for 5 hours. After cooling to room temperature reaction was quenched using saturated aqueous NaHCO3 solution. The resulting mixture was extracted with diethyl ether (3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified as specified for each example. 69 4924-6694-6837v.1n of 2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol and derivatives thereof.

[0279] General procedure B: To a reaction vessel containing corresponding N-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine derivative (1 equivalent) were added 1,4-dioxane (1 M based onazepine) and degassed H2O (1 M based on azepine), solid KOH (6 equivalents), catalyst Pd2Dba3 (3 mol%) and ligand tBuBrettPhos (6 mol%). Reaction mixture was stirred at 80 °C until full conversion of starting material was observed 5 - 22 h. After cooling to room temperature reaction mixture was acidified using aq. 2M HCl solution (to pH 5-6) and further adjusted to Ph ~ 7 using sat. aq. NaHCO3solution. The resulting mixture was repeatedly extracted with CH2Cl2:iPrOH 9:1 mixture (3-6 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified as specified for each example.1,2,4,5-tetrahydro-3H-benzofuro[2,3-d]azepin-3-yl)-2,2,2-trifluoroethan-1-one 9 and 2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 10.

[0281] Compound 9 was synthetized according to general procedure A. Mixture of both isomers wasseparated by column chromatography using gradient of 10, 15 and 20% AcOEt in hexanes to obtain compound 9 (1.17 g, 32% yield) compound 10 (1.31 g, 36% yield) and a mixed fractions (0.18 g) as viscous yellow oils that slowly solidified. Spectral characterization was in agreement with reported literature data (Sames et al, 2022).

[0282] Compound 9:

[0283] 1H 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+) calcd. forC14H12BrF3NO2+ as [M+H]+ 362.0, found 362.2.

[0284] Compound 10:70 4924-6694-6837v.1

[0285] 1H 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+) calcd. for C14H12BrF3NO2+ as [M+H]+ 362.0, found 362.2.HO NH6. 2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 11.

[0287] Compound 11 was synthetized according to general procedure B. Crude material was purified bycolumn chromatography using 95:5:0.5 to 90:10:1 (CH2Cl2:MeOH:NH4OH). Compound 11 was obtained as a brown solid (0.5 g, 76% yield). Spectral characterization was in agreement with reported literature data (Sames et al, 2022).

[0288] 1H NMR (400 MHz, MeOD) δ 7.19 (dd, J = 8.7, 0.8 Hz, 1H), 6.82 (d, J = 2.5 Hz, 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+) calcd. forC12H14NO2+ as [M+H]+ 204.1, found 204.1.1H-benzofuro[2,3-d]azepin-9-ol 13.

[0290] Compound 12 was synthetized according to general procedure A. Crude material was purified bycolumn chromatography using 5 to 10% AcOEt in hexanes. Compound 12 was further transformed according to general procedure B. Crude material was purified repeated column chromatography, 1stcolumn 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and 2ndcolumn 0 to 5% MeOH in AcOEt + 0.5% NH4OH to. Slightly impure product was dissolved in 9:1 CH2Cl2 / MeOH, treated with 2M HCl in diethyl ether, formed suspension was chilled in freezer, solid was collected by filtration and washed with cold 9:1 CH2Cl2 / MeOH mixture. Compound 13 was obtained as a beige solid (198 mg, 35 % yield over two steps). Spectral characterization was in agreement with reported literature data.

[0291] 1H 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+) calcd. for C15H20NO2+as [M+H]+246.2, found 246.2. 71 4924-6694-6837v.1-1H-benzofuro[2,3-d]azepin-9-ol 15.

[0293] Compound 14 was synthetized according to general procedure A. Crude material was purified bycolumn chromatography using 5 to 10% AcOEt in hexanes. Compound 14 was further transformed according to general procedure B. Crude material was purified column chromatography 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). Analytical sample for characterization was obtained by transforming the product into hydrochloride in CH2Cl2 / MeOH mixture and adding aq. HCl (12.1 M), until pH ~ 1 on pH paper. Solution was concentrated under reduced pressure and twice recrystallized from MeOH.

[0294] Characterized as hydrochloride salt: 1H 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).13C 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+) calcd. for C15H18NO2+as [M+H]+244.1, found 244.2.-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 16.

[0296] Compound was prepared using general procedure A. Trifluoroacetamide intermediate waspurified by column chromatography using a gradient of 5 to 10 % AcOEt in hexanes. Major isomer was isolated as an orange oil (0.51 g, 34 %) NMR spectra (1H,19F and13C) are complicated due to the presenceof rotamers. LRMS (APCI+) calcd. for C18H18BrF3NO2+ as [M+H]+ 416.1, found 416.2.

[0297] Next step was carried out according to general procedure B. Crude material was purified bycolumn chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Orange brown solid (0.23 g, 73 %). 72 4924-6694-6837v.1

[0298] To obtain analytical sample ½ of product was suspended in EtOH (1.8 mL), solid was sedimentedby centrifugation and liquid was decanted. Washing was repeated one more time using diethyl ether. Solid was further dissolved in CH2Cl2 / MeOH mixture, treated with aq. HCl (12.1 M), until pH ~ 1 on pH paper. Solution was concentrated under reduced pressure and residue evaporated from MeOH (2 ×). Pure product hydrochloride was obtained as a beige solid (21 mg).

[0299] Characterized as hydrochloride salt: 1H 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).13C 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+) calcd. for C16H20NO2+ as [M+H]+ 258.2, found258.2.2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 17.

[0301] Compound was prepared using general procedure A. Trifluoroacetamide intermediate waspurified by column chromatography using a gradient of 5 to 10 % AcOEt in hexanes. Major isomer was isolated as an orange oil (0.62 g, 57 %) NMR spectra (1H,19F and13C) are complicated due to the presenceof rotamers. LRMS (APCI+) calcd. for C18H20BrF3NO2+ as [M+H]+ 418.1, found 418.3.

[0302] Next step was carried out according to general procedure B. Crude material was purified bycolumn chromatography using (5% MeOH in AcOEt) + 0.5% NH4OH. Foamy brown solid was dissolved in CH2Cl2 / MeOH mixture, treated with 2M HCl in diethyl ether, solution was concentrated under reduced pressure and residue evaporated one more time from MeOH. Product 17 was obtained as a beige solid (0.22 g, 52% over two steps).

[0303] Characterized as hydrochloride salt. 1H 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, 3.6 Hz, 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).13C 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+) calcd. forC15H20NO2+ as [M+H]+ 260.2, found 260.4.73 4924-6694-6837v.1epin-8-ol 20.11. 2,3,5,6,12,12a-hexahydro-1H-benzofuro[2,3-d]pyrrolo[1,2-a]azepin-8-ol 20.

[0306] Intermediate 14 (201 mg, 0.5 mmol) was vigorously stirred in a mixture of 3:1 THF / H2O (2 mL)and LiOH·H2O (126 mg, 3 mmol). After 3 h reaction was diluted with brine (5 mL), extracted with CH2Cl2(6 x), combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. 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 one portion and suspension was stirred at room temperature for 1h. Dipea (109 µL, 0.63 mmol) and iodine (159 mg, 0.63 mmol) were added and the resulting clear solution was stirred overnight. Reaction was quenched using saturated aqueous NaHCO3solution, the resulting mixture was extracted with CH2Cl2, combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and used as is for next step. Intermediate 19 was further transformed according to general procedure B. Crude material was purified by column chromatography 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH), plate was developed twice. Solid material was dissolved in CH2Cl2 / MeOH mixture and treated with aq. HCl (12.1 M), until pH ~ 1 on pH paper, resulting solution was concentrated and evaporated from MeOH. Solid residue was twice recrystallized from MeOH to obtain compound 20 as brown solid (30 mg, 23% yield).

[0307] Characterized as hydrochloride salt. 1H 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, 74 4924-6694-6837v.14H), 3.18 – 3.00 (m, 2H), 2.60 – 2.48 (m, 1H), 2.22 – 2.06 (m, 2H), 2.06 – 1.91 (m, 1H).13C NMR (126MHz, MeOD) 13C 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+) calcd. for C15H18NO2+ as [M+H]+ 244.1, found 244.2.1H-benzofuro[2,3-d]azepine-9-carboxamide 21.propyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-carboxamide 21.

[0310] 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) followed by Co2(CO)8 and dipea (0.26 mL, 1.5 mmol) were added and vial was sealed using a Teflon-lined screw cap. Reaction mixture was vigorously stirred at 80°C for 22 h. After cooling to room temperature reaction mixture was filtered through a plug of silica using 5% MeOH in CH2Cl2 and concentrated. Residue was further purified by a column chromatography using 5% MeOH in CH2Cl2. Intermediate was obtained as a brown foamy solid (164 mg, 0.45 mmol) that was further vigorously stirred in a mixture of 3:1 THF / H2O (1.8 mL) and LiOH·H2O (112 mg, 2.7 mmol). After 17.5 h reaction was diluted with brine (5mL), extracted with CH2Cl2:iPrOH (3 x), combined organic extracts were dried over Na2SO4, filtered andconcentrated under reduced pressure. Crude material was purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH), plate was developed twice. Solid material was dissolved in MeOH and treated with aq. HCl (12.1 M), until pH ~ 1 on pH paper. Solution was concentrated to obtain compound 21 as a beige solid (59 mg, 77% yield over two steps).

[0311] Characterized as hydrochloride salt: 1H 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 = 7.3 Hz, 3H).13C NMR (126 MHz, MeOD) δ 172.4, 157.1, 154.1, 130.2, 130.0, 125.3, 75 4924-6694-6837v.1120.0, 115.8, 111.8, 58.4, 47.2, 36.6, 31.1, 20.8, 19.7, 14.1. LRMS (APCI+) calcd. for C16H21N2O2+as [M+H]+273.2, found 273.1.N-methylation.

[0313] General procedure C: Corresponding 2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin derivative(1 equivalent in free base form, hydrochloride salt reacts poorly) was suspended in EtOH (0.5 M based on azepine). Aq. HCHO solution (36.5% wt. %, 5 equivalents) and HCHO (10 equivalents) were added and the resulting solution was stirred at 80 °C until full conversion of starting material was observed 3 - 4 h. After cooling to room temperature reaction mixture was poured into sat. aq. NaHCO3 solution. The resulting mixture was repeatedly extracted with CH2Cl2 or CH2Cl2:iPrOH 9:1 mixture (3-6 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified as specified for each example.methyl-4-propyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 22.

[0315] Compound was prepared using general procedure C. Crude material was purified by columnchromatography using AcOEt + 0.5% NH4OH to 95:5:0.5 (CH2Cl2:MeOH:NH4OH) and preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Product was dissolved in CH2Cl2 / MeOH, treated with 2M HCl in diethyl ether, resulting solution was concentrated under reduced pressure and residue evaporated from MeOH. Compound 22 was obtained as a beige solid (261 mg, 71% yield).

[0316] Characterized as hydrochloride salt: 1H 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).13C NMR (126 MHz, MeOD) δ 154.5, 152.3, 149.7, 76 4924-6694-6837v.1130.9, 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+) calcd. forC16H22NO2+ as [M+H]+ 260.2, found 260.1.

[0317] Under certain circumstances compound in salt form (HCl or CH3SO3H) can exist in two distinctforms in solution, partial1H NMR integrals: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 = 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 1H).tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol23.methyl-4-allyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 23.

[0320] Compound 15 (122 mg, 0.5 mmol) was suspended in MeOH (1 mL). Clear solution was formedafter addition of 36.5 wt. % HCHO solution (75 µL, 1 mmol). After 30 min stirring at room temperature sodium borohydride (28 mg, 0.75 mmol) was added in one portion, exothermic reaction was controlled using ice / water bath. After exothermic reaction subsided mixture was further stirred at room temperature for 1 h. Reaction mixture was, poured into sat. NaHCO3solution, extracted with CH2Cl2(3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by repeated preparative TLC using 95:5:0.5 and 93:7:0.7 (CH2Cl2:MeOH:NH4OH). Product 23 was obtained as a viscous brown oil (104 mg, 81 %).

[0321] Free base: 1H 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).13C 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+) calcd. for C16H20NO2+ as [M+H]+ 258.2, found 258.4.77 4924-6694-6837v.1hydro-1H-benzofuro[2,3-d]azepin-9-carboxamide

[0323] Compound was prepared using general procedure C. Crude material was purified by preparativeTLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH), plate developed twice. Product 25 and undesired side- product 24 were isolated. Product was transformed to hydrochloride in MeOH using a drop of aq. HCl (12.1M). Side-product 24 was dissolved in 2M aq. HCl and after 2 h at room temperature formed additional product. Both solutions were combined, concentrated and evaporated from MeOH. Compound 25 was obtained as a beige solid (56 mg, 87% yield).

[0324] Hydrochloride salt: present in two forms in solution, partial 1H NMR integrals, majority of 13Csignals are duplicated.1H 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).13C 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.

[0325] LRMS (APCI+) calcd. for C17H23N2O2+ as [M+H]+ 287.2, found 287.3.methyl-4-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 26.

[0327] Compound was prepared using general procedure C. Crude material was purified by columnchromatography using 50 to 100% AcOEt in hexanes + 0.5% NH4OH. Product was transformed to hydrochloride in MeOH using 2M HCl in diethyl ether and purified by preparative TLC using 90:10:0.1 (CH2Cl2:MeOH:aq. HCl). Isolated material as oily residue was suspended in diethyl ether and sonicated. Formed solid precipitate was collected by filtration. Compound 25 was obtained as a beige solid (59 mg, 43% yield). 78 4924-6694-6837v.1

[0328] Characterized as hydrochloride salt: 1H 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, 7.5 Hz, 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).13C 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+) calcd. for C17H2NO2+ as [M+H]+ 272.2, found272.1.ethyl-4-propyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 27.

[0330] Starting material (59 mg, 0.24 mmol) dissolved in MeOH (1 mL) after addition of AcOH (28 µL,0.48 mmol) and acetaldehyde (27 µL, 0.48 mmol). After 10 min stirring at room temperature sodium triacetoxyhydroborate (77 mg, 0.36 mmol) was added and mixture was stirred at room temperature over weekend. Only partial conversion was detected. Additional acetaldehyde (134 µL, 2.4 mmol) and sodium triacetoxyhydroborate (77 mg, 0.36 mmol) were added and reaction continued additional 24h. Reaction mixture was, poured to sat. NaHCO3solution, extracted with CH2Cl2:iPrOH (3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Product was dissolved in CH2Cl2 / MeOH, treated with aq. HCl (12.1 M) and solution was concentrated under reduced pressure. Hydrochloride salt was further purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:aq. HCl). Product was obtained as a beige solid (18 mg, 27% yield).

[0331] Characterized as hydrochloride salt: 1H 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, 6.7 Hz, 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+) calcd.for C17H24NO2+ as [M+H]+ 274.2, found 274.3.4924-6694-6837v.1

[0332] Example 18. 3-methyl-4-butyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 28.

[0333] Compound was synthesized using general procedure C. Crude material was purified bypreparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Isolated solid was dissolved in MeOH, treated with aq. HCl (12.1 M), until pH ~ 1 on pH paper. Solution was concentrated under reduced pressure and residue evaporated from MeOH (2 ×). Hydrochloride salt was obtained as a brown solid (21 mg).

[0334] Free base: 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 2.5 Hz, 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).

[0335] Hydrochloride salt: present in two forms in solution, partial 1H NMR integrals, majority of 13Csignals are duplicated.1H 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).13C 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+) calcd. forC17H24NO2+ as [M+H]+ 274.2, found 274.5[2,3-d]azepin-9-ol 29.

[0337] Product was prepared using two alternative conditions:

[0338] Starting material 11 (41 mg, 0.2 mmol) was dissolved in mixture of H2O:EtOH (1:1, 0.8 mL) andHCOOH (75 µL, 2 mmol). 1,1-diethoxypropane (162 µL, 1 mmol) was added and mixture was stirred at 80°C for 3 h.

[0339] Starting material 11 (41 mg, 0.2 mmol) and 1-iodopropane (23 µL, 0.3 mmol) were combined inCH3CN (4 mL) and the mixture was heated to 80°C in a vial closed with Teflon-lined solid screw cap for 3h. 80 4924-6694-6837v.1

[0340] After cooling to room temperature, crude mixtures were combined, poured to sat. NaHCO3solution, extracted with CH2Cl2(3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Residue was further suspended in diethyl ether and filtered through cotton plug, solution was concentrated to obtain foamy solid. Isolated solid was further purified by preparative TLC using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). Product was dissolved in CH2Cl2, treated with 2M HCl in diethyl ether and suspension was concentrated under reduced pressure. Hydrochloride salt was further purified by preparative TLC using 95:5:0.1 (CH2Cl2:MeOH:aq. HCl). Product was obtained as a beige solid (55 mg, 56%).

[0341] Characterized as hydrochloride salt: 1H 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 = 7.4 Hz, 3H).13C 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+)calcd. for C15H20NO2+ as [M+H]+ 246.2, found 246.3.9-ol 30.

[0343] Starting material (101 mg, 0.5 mmol) dissolved in MeOH (1 mL) after addition of AcOH (57 µL,1 mmol) and butyraldehyde (88 µL, 1 mmol). After 30 min stirring at room temperature sodium triacetoxyhydroborate (159 mg, 0.75 mmol) was added and mixture was stirred at room temperature for 15h. Reaction mixture was combined, poured into sat. NaHCO3 solution, extracted with CH2Cl2 (4 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by short column chromatography using AcOEt + 2% Et3N. Residue was further suspended in diethyl ether and filtered through cotton plug, solution was concentrated to obtain beige solid. Isolated solid was dissolved in CH2Cl2 / iPrOH (few drops), treated with aq. HCl (12.1 M, 1.1 equiv.), loaded onto preparative TLC and purified using 95:5:0.1 (CH2Cl2:MeOH:aq. HCl). Product was obtained as a beige solid (106 mg, 84%).

[0344] Characterized as hydrochloride salt: 1H 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 = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H).13C NMR (126 81 4924-6694-6837v.1MHz, 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+) calcd. for C16H22NO2+ as [M+H]+ 260.2, found 260.3.O(but-2-yn-1-yl)-1,4-dioxa-8-azaspiro[4.6]undecan-9-one 31.

[0347] Solution of 1,4-Cyclohexanedione monoethylene acetal (5.87g, 37.6 mmol) in diethyl ether (0.5M, 75.0 mL) was cooled to -78°C and LHMDS (1M in THF, 37.6 mL) was slowly added to the cold thin suspension. The reaction mixture was further stirred for 30 min, then 1-bromobut-2-yne (5.0 g, 37.6 mmol) was added dropwise over 30 min using syringe pump and reaction was allowed to slowly warm to room temperature. After 15 h reaction was quenched with sat. NH4Cl solution (50 mL), phases were separated, and aq. Phase further extracted with Et2O (50 mL), combined extracts were washed with brine (2 × 50 mL), dried over MgSO4, filtered, and concentrated onto celite. Crude material was purified by column chromatography using 10% AcOEt in hexanes. Slightly impure ketone intermediate (4.6 g) was dissolved in MeOH (35 mL), H2O (9 mL), hydroxylamine hydrochloride (1.69 g, 24.3 mmol) and sodium acetate (1.99 g, 24.3 mmol) were added, and the reaction mixture was stirred at 80°C. After 2 h MeOH was evaporated under reduced pressure, mixture was diluted with brine (30 mL) and extracted with DCM:iPrOH 9:1 (50 and 4 × 25 mL). Combined extracts were dried over Na2SO4, filtered and concentrated. Crude oxime (4.93 g) was dissolved in acetone (44 mL), H2O (66 mL), Na2CO3 (7.02 g, 66.2 mmol) and p-TsCl (6.31 g, 82 4924-6694-6837v.133.1 mmol) were 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), extracted with DCM:iPrOH 9:1 (3 × 40 mL). Combined extracts were dried over Na2SO4, filtered and concentrated. The crude material (yellow solid) was dissolved in hot acetone (~ 12 - 15 mL), cooled to RT and placed in fridge (+8°C) overnight. Precipitate was collected by filtration and washed with small amount of cold acetone. Product 31 (2.26 g, 27% yield over 3 steps) was obtained as a white solid.

[0348] 1H 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).13C 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+) calcd. for C12H18NO3+ as [M+H]+ 224.1, found 224.2.22. 1-(7-(but-2-yn-1-yl)-1,4-dioxa-8-azaspiro[4.6]undecan-8-yl)-2,2,2-trifluoroethan-1-one 32.

[0351] Lactam intermediate (1.2 g) was suspended in THF (10.8 mL, 0.5M), cooled in ice bath (0°C)and LiAlH4 (0.31 g, 8.1 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added. Reaction mixture was allowed to warm to room temperature and further heated to reflux for 2 h. Reaction mixture was further cooled in ice bath, diluted with diethyl ether (20 mL) and quenched slowly by addition of H2O, 15% NaOH and H2O (1:1:3 mL per g of LiAlH4) and stirred until all salts were off-white and loose. Solid was filtered off and rinsed with diethyl ether, until no further product elution was detected by TLC. Combined washings were concentrated under reduced pressure. The crude intermediate (1.12 g) was immediately used for next step. Yellow oil was dissolved in CH2Cl2 (10.8 mL), Et3N (1.12 mL, 8.1 mmol) was added, mixture was cooled in ice bath and 83 4924-6694-6837v.1trifluoroacetic anhydride (0.93 mL, 6.7 mmol) was added dropwise. Mixture was further stirred at room temperature. After 4h it was poured to sat. NaHCO3solution (15 mL), mixture was extracted with CH2Cl2(3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Oily residue was purified by column chromatography using 20% AcOEt in hexanes. Compound 32 was isolated as a yellow oil (1.32 g, 81% over two steps), NMR spectra (1H,19F and13C) are complicated due to the presence of rotamers.

[0352] LRMS (APCI+) calcd. for C14H19F3NO3+ as [M+H]+ 306.1, found 306.2.2-yn-1-yl)-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepine-9-carboxamide33.

[0355] Compound 32 (1.26 g, 4.13 mmol) and O-(4-bromophenyl)hydroxylamine hydrochloride (0.93g, 4.13 mmol were combined in 1,4-dioxane (8.3 mL, 0.5 M) and warmed to 80 °C. After 5 min at 80 °C methanesulfonic acid (0.54 mL, 8.25 mmol) was added, and reaction mixture was stirred at 80 °C for 5 hours. After cooling to room temperature reaction was quenched using saturated aqueous NaHCO3solution (15 mL). The resulting mixture was extracted with CH2Cl2(3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified using gradient of 5 to 10% AcOEt in 84 4924-6694-6837v.1hexanes. Complex mixture of rotamers was used for next step. Bromobenzofuran-intermediate (207 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) followed by Co2(CO)8(103 mg, 0.3 mmol) and dipea (0.26 mL, 1.5 mmol) were added and vial was sealed using a Teflon-lined solid screw cap. Reaction mixture was vigorously stirred at 80°C for 22 h. After cooling to room temperature reaction mixture was filtered through a plug of silica using 5% MeOH in CH2Cl2and concentrated. Residue was further purified by a column chromatography using 2.5% MeOH in CH2Cl2. Intermediate was obtained as a red-brown foamy solid (92 mg, 0.45 mmol) that was further vigorously stirred in a mixture of 3:1 THF / H2O (2.4 mL) and LiOH·H2O (51 mg, 1.2 mmol). After 17.5 h reaction was extracted with AcOEt (3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Crude material was purified by column chromatography using 95:5:0.5 (CH2Cl2:MeOH:NH4OH). For final purification solid material was dissolved in MeOH and treated with aq. HCl (12.1 M), until pH ~ 1 on pH paper. Solution was concentrated and the residue was suspended and sonicated in MeCN (2 mL),sedimented by centrifugation and solvent decanted. Compound 33 was obtained as a beige solid (29 mg,12% yield over three steps).

[0356] Characterized as hydrochloride salt: 1H 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).13C 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+) calcd. for C17H19N2O2+ as [M+H]+ 283.1, found 282.7.85 4924-6694-6837v.124. 7-allyl-7-methyl-1,4-dioxa-8-azaspiro[4.6]undecane 34.

[0359] To a solution of LHMDS (1.0 M in THF, 42.9 mL, 1.0 equiv.) in THF (120 mL) at -78°C wasadded a solution of 1,4-Cyclohexanedione monoethylene acetal (6.70 g, 42.90 mmol) in THF (40 mL) slowly over 15 min and the resulting mixture was stirred at -78°C for 30 min. Iodomethane (3.2 mL, 51.5 mmol, 1.2 equiv.) was added to the reaction mixture and the resulting solution was stirred at -78°C for 20 min and at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated NH4Cl (120 mL) and extracted with ether (3 x 120 mL). Combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (20% EtOAc in hexanes) afforded 2-methyl-1,4- cyclohexanedione monoethylene acetal (4.85 g, 66% yield).1H 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+) calcd. for C9H15O3+ as [M+H]+ 171.2, found 171.1.

[0360] This intermediate and NaI (0.85 g, 5.64 mmol) were dissolved in THF (56.4 mL), and NaH (60%oil dispersion, 1.13g, 28.2 mmol) was added under argon portionwise. After stirring at room temperature 86 4924-6694-6837v.1for 30 min allyl bromide was added dropwise and the mixture was stirred for an additional 2 h. The reaction mixture was quenched by the allow addition of water (50 mL) and extracted with EtOAc (3 x 100 mL). Combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (20% EtOAc in hexanes) afforded 2-allyl-2-methyl-1,4-cyclohexanedione monoethylene acetal (3.1 g, 52% yield).1H NMR (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).13C 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+) calcd. for C12H19O3+ as [M+H]+ 211.3, found 211.1.

[0361] Ketone intermediate (3.1 g, 14.7 mmol) was dissolved in MeOH (25 mL), H2O (5 mL),hydroxylamine hydrochloride (1.13 g, 16.2 mmol) and sodium acetate (1.33 g, 16.2 mmol) were added, and the reaction mixture was stirred at 80°C. After 2 h MeOH was evaporated under reduced pressure, mixture was diluted with brine (30 mL) and extracted with DCM:iPrOH 9:1 (4 × 50 mL). Combined extracts were dried over Na2SO4, filtered and concentrated. Crude oxime (3.32 g) was dissolved in acetone (60 mL), H2O (90 mL), Na2CO3 (6.25 g, 59.0 mmol) and p-TsCl (5.62 g, 29.5 mmol) were added, and the reaction mixture was stirred at 40°C for 17 h. Acetone was evaporated under reduce pressure and the aqueous mixture was diluted with brine (50 mL), extracted with DCM:iPrOH 9:1 (3 × 30 mL). Combined extracts were dried over Na2SO4, filtered, and concentrated. Flash chromatography (30% EtOAc in hexanes) afforded the lactam intermediate (1.6 g, 49% yield over 2 steps).1H 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).13C 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+) calcd. for C12H20NO3+ as [M+H]+ 226.3, found226.0.

[0362] Lactam intermediate (1.63 g) was suspended in THF (14 mL, 0.5M), cooled in ice bath (0°C) andLiAlH4 (0.548 g, 14.4 mmol) was carefully added in small portions at first, after exothermic reaction subsided, the entire remaining portion was added. The reaction mixture was allowed to warm to room temperature and further heated to reflux for 2 h. The reaction mixture was further cooled in ice bath, diluted with diethyl ether (20 mL) and quenched slowly by addition of H2O, 15% NaOH and H2O (1:1:3 mL per g of LiAlH4) and stirred until all salts were off-white and loose. Solid was filtered off and rinsed with diethyl ether, until no further product elution was detected by TLC. Combined washings were concentrated under reduced pressure. Flash chromatography (98% EtOAc and 2% TEA) afforded the compound 34 (1.05 g, 69% yield) as a clear oil.1H 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, 87 4924-6694-6837v.13H).13C 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+) calcd. for C12H22NO2+ as [M+H]+ 212.3, found 212.01H-benzofuro[2,3-d]azepin-9-ol 35 and 4-allyl-3,4-dimethyl-2,3,4,5-tetrahydro-1H-benzofuro[2,3-d]azepin-9-ol 36. 88 4924-6694-6837v.1

[0365] Compound 34 (0.20 g, 0.96 mmol) was dissolved in CH2Cl2 (3.8 mL), dipea (0.41 mL, 2.4 mmol)was added, mixture was cooled in ice bath and trifluoroacetic anhydride (0.27 mL, 1.9 mmol) was added dropwise. Mixture was further stirred at room temperature. After 20 h it was poured to sat. NaHCO3solution (15 mL), mixture was extracted with CH2Cl2(3 ×), combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Oily residue was passed through a short silica column using 20% AcOEt in hexanes. Complex mixture of rotamers was combined with O-(4-bromophenyl)hydroxylamine hydrochloride (0.22 g, 0.96 mmol) in 1,4-dioxane (1.9 mL, 0.5 M) and warmed to 80 °C. After 5 min at 80 °C methanesulfonic acid (0.13 mL, 1.9 mmol) was added, and reaction mixture was stirred at 80 °C for 5 hours. After cooling to room temperature reaction was quenched using saturated aqueous NaHCO3 solution. The resulting mixture was extracted with diethyl ether (3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified using 5% AcOEt in hexanes and obtained complex mixture of rotamers was used for next step. To a vial containing bromobenzofuran-intermediate (192 mg, 0.46 mmol) were added 1,4-dioxane (0.9 mL) and 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). Reaction mixture was stirred at 80°C for 15.5 h. After cooling to room temperature reaction mixture was acidified using aq. 2M HCl solution (to pH 5-6) and further adjusted to Ph ~ 7 using sat. aq. NaHCO3 solution. The resulting mixture was repeatedly extracted with AcOEt (4 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material consisted of a mixture of product 35 and its TFA amide precursor. As such the crude material was dissolved in a mixture of 3:1 THF:H2O (2 mL), LiOH·H2O (116 mg, 2.77 mmol) was added and mixture vigorously stirred overnight. Mixture was acidified using aq.2M HCl solution (to pH 5-6) and further adjusted to Ph ~ 7 using sat. aq. NaHCO3 solution. The resulting mixture was repeatedly extracted with AcOEt (4 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Column chromatography using DCM:MeOH:NH4OH (95:5:0.5) was used to separate the unreacted 35-TFA amide from product 35, which was further purified by PTLC (DCM:MeOH:NH4OH 95:5:0.5) and transformed to hydrochloride by in MeOH, by addition of methanolic HCl (until pH ~ 1) and concentrated to obtain compound 35 (23 mg, 17% over three steps) as a beige solid.

[0366] Crude intermediate 35-TFA amide (120 mg) was further suspended in MeOH (2 mL), H2O (1mL), LiOH·H2O (144 mg, 3.4 mmol) was added, and mixture was stirred at 50°C for one day (only partial conversion). Mixture was concentrated under reduced pressure, residue was dissolved in a mixture of THF + H2O (1 + 1 mL), LiOH·H2O (144 mg, 3.4 mmol) was added and mixture vigorously stirred one day longer at 60°C (major conversion). After cooling to room temperature reaction mixture was acidified using aq.2M HCl solution (to pH 5-6) and further adjusted to Ph ~ 7 using sat. aq. NaHCO3solution. The resulting 89 4924-6694-6837v.1mixture was repeatedly extracted with AcOEt (4 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Crude material was purified by column chromatography DCM:MeOH:NH4OH (95:5:0.5) and the obtained slightly impure compound 35 (26 mg, 22%, complete yield over three steps 39%) was used for next step. Compound 35 (free base, 26 mg, 0.1 mmol) was suspended in MeOH (1 mL) and formaldehyde (aq.36.5% solution, 0.015 mL, 0.2 mmol) was added. Resulting solution was stirred for 10 min, after which solid NaBH4(8 mg, 0.2 mmol) was added. After 1 h stirring at room temperature incomplete conversion was observed, additional formaldehyde (aq. 36.5% solution, 0.03 mL, 0.4 mmol) was added, and after 30 min solid NaBH4(16 mg, 0.4 mmol). After stirring for 30 min reaction was diluted with saturated NaHCO3 solution (2 mL), extracted with AcOEt (3 x), combined organic extracts were dried over Na2SO4, filtered and concentrated. Due to incomplete conversion reaction was repeated using the crude material, MeOH (1 mL), formaldehyde (aq.36.5% solution, 0.03 mL, 0.4 mmol), stirring for 60 min, solid NaBH4 (16 mg, 0.4 mmol) and stirring for 30 min. Reaction was worked up as previously. Residue was purified using PTLC (DCM:MeOH:NH4OH 97.5:2.5:0.2, developed 2x), transformed to hydrochloride in MeOH with methanolic HCl and concentrated to obtain compound 36 (14.5 mg, 17%).

[0367] Compound 35 hydrochloride salt: 1H 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, 7.4 Hz, 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).13C NMR (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+) calcd. forC16H20NO2+ as [M+H]+ 258.2, found 258.1.

[0368] Compound 36 hydrochloride salt (some signals are multiplied due to presence of rotamers): 1HNMR (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).13C 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+)calcd. for C17H22NO2+ as [M+H]+ 272.2, found 272.1.

[0369] Biological Characterization

[0370] BRET Functional Opioid Assays (G-protein and Nb33 recruitment)90 4924-6694-6837v.1

[0371] HEK-293T cells were obtained from the American Type Culture Collection (Rockville, MD) andwere cultured in a 5% CO2atmosphere at 37 °C in Dulbecco’s Modified Eagle Medium (high glucose #11965; Life Technologies Corp.; Grand Island, NY) supplemented with 10% Fetal Bovine Serum (FBS, #35-010-CV, Corning, Corning, NY, USA), 100 U·mL-1penicillin (#30-002-CI, Corning, Corning, NY, USA), and 100 µg·mL-1streptomycin (#30-002-CI; Corning, Corning, NY, USA). The following chemicals were used without further modification: coelenterazine H (#DC-001437, Dalton Pharma Services, Toronto, ON, Canada), PEI (#NC1014320, Polysciences, Warrington, PA, USA) and (±)-U-50488 HCl (Tocris Biosciences, Minneapolis, MN, USA).

[0372] DNA Constructs (G-protein and Nb33): The rat KOR (rKOR) was provided by Dr. Lakshmi Deviat Mount Sinai School of Medicine. GαoB with Renilla luciferase 8 (RLuc8) inserted at position 91 (GαoB- RLuc8), and Gβ1 (β1) were provided by C. Galés (Rives et al. 2012; Negri et al. 2013). Gγ2, which was fused to the full-length mVenus at its N-terminus via the amino acid linker GSAGT (mVenus-γ2), were constructed in house. The expression vectors coding for rat KOR tagged at the C-terminus with Nanoluc (KOR-nluc) were constructed using standard techniques in molecular biology and confirmed by DNA sequencing (Genewiz, South Plainfield, NJ, USA). Briefly, three DNA inserts were PCR amplified, one coding for the N-terminal signal peptide and flag tag, one coding for KOR, and one coding for nanoluc. The inserts were ligated and cloned into a pcDNA3.1 (+) vector (#V79020, ThermoFisher Scientific, Waltham, MA, USA). The plasmid coding for the nanobody33Venus (Nb33) construct (Gilis et al., 2020) was a gift from Dr. Meritxell Canals at the University of Nottingham.

[0373] The following cDNA amounts were transfected into HEK-293T cells (4 x 106 cells / plate) in 10-cm dishes using polyethylenimine (PEI) in a 1.5:1 ratio (diluted in DMEM, Life Technologies). G-protein β-γ release: 2.5 μg KOR, 0.1 μg GαoBRLuc8, 6.2 μg β1, 6.2 μg mVenus-γ2. Cells were maintained in the HEK-293T media described above. After 24 hours the media was changed, and the experiment wasperformed 48 hours after transfection. Nb33 recruitment: A total of 5 μg of cDNA was transientlytransfected into HEK-293T cells (2 × 106cells per plate) in 10 cm dishes (1 μg receptor-nluc, and 4 μg Nb- 33-Venus), using PEI in a 6:1 ratio (diluted in DMEM). Cells were maintained in the HEK-293T media described above. Experiments were performed 48 hours after transfection.

[0374] Transfected cells were dissociated and re-suspended in phosphate-buffered saline (PBS).Approximately 200,000 cells / well were added to a black-framed, white-well, 96-well plate (#60050; Perkin Elmer; Waltham, MA). At time zero, the luciferase substrate coelenterazine H (5 μM) was added to each well. Ligands were added after 5 min, then BRET signal was measured 5 min later for G-protein, and 10 min 91 4924-6694-6837v.1later for Nb33 recruitment. BRET measurements were performed using a PHERAstar FS plate reader (BMG Labtech, Cary, NC, USA). The BRET signal was calculated as the ratio of the light emitted by the mVenus acceptor (510–540 nm) over the light emitted by the NanoLuc donor (475 nm). This drug-induced BRET signal was normalized using the Emaxof U-50,488 as the maximal response at KOR. Data were analyzed using the dose-response-stimulation nonlinear curve fitting model (log[agonist] vs. response (four parameters)). All experiments were repeated in three independent trials each with triplicate determinations.

[0375] hSERT and VMAT2 Inhibition Assays

[0376] Stably transfected cell cultures were seeded in white solid-bottom 96-well plates (Corning;Corning, NY) at a density of 1.00 × 106cells / well and allowed to proliferate in a humidified environment of 37°C and 5% carbon dioxide to full confluency in approximately 48 hours. Upon commencement of the experiment, growth media was aspirated, and the cell culture monolayer was rinsed twice with 120 μL of 1× Phosphate Buffered Saline (PBS; Corning; Corning, NY). Experimental media solutions consisting of 2× tiered concentrations (ranging from 100 ^M to 0.1 ^M) of a test compound or DMSO (vehicle, 0.02% v / v, Sigma-Aldrich; St. Louis, MO) were added gently to the cell cultures and consequently, pre-incubated for approximately (SERT: 60 min, VMAT2: 30 min). A standard was utilized for each experiment depending on the specific transporter being evaluated (Imipramine for hSERT and Reserpine for VMAT2; Sigma-Aldrich; St. Louis, MO). Subsequently, an equivalent amount of experimental media solutions containing both 2× tiered concentrations (ranging from 100 ^M to 0.1 ^M) of a test compound or DMSO (vehicle, 0.02% v / v, Sigma-Aldrich; St. Louis, MO) and APP+ (for hSERT; final concentration: 1.1 ^M; Sigma-Aldrich; St. Louis, MO) or FFN206 (Hu et al., 2013, for VMAT2 final concentration: 0.75 µM) was added to each well and then incubated for an additional period (SERT: 30 min, VMAT2: 60 min) to encourage fluorescent probe uptake. Afterwards, the solution contained with each well was aspirated and cells were washed with two successive washes with 120 μL 1× PBS washes. A final addition of 120 μL of 1× PBS in each well was necessary for fluorescent uptake bottom mode readout by BioTek Synergy Neo2 Hybrid Multi-Mode Reader (Agilent; Santa Clara, CA) at the following excitation and emission wavelengths of 436 and 500 nm, respectively. For IC50 data analysis, the average fluorescence of vehicular wells was subtracted by that of wells containing each ibogaine derivative to quantify the respective fluorescence uptake (in mean fluorescence units). These numerics were then fit to a nonlinear curve model ([inhibitor] versus response (three parameters)) as provided by Graphpad Prism 8 software (Graphpad Prism Inc.; San Diego, CA). Outputted IC50 (± SEM) quantities for each ibogaine derivative can be converted into Ki(± SEM) values using the Cheng-Prusoff equation (Yung-Chi and Prusoff, 1973). 92 4924-6694-6837v.1

[0377] Cardiotoxicity Assay in Adult Human Primary Cardiomyocytes

[0378] Cardiotoxicity of novel analogs was assessed according to published procedure (Abi-Gerges etal., 2020; Nguyen et al.2017) using a commercially available assay services. Briefly, adult human primary ventricular myocytes were isolated from ethically consented donor hearts that were enzymatically digested using a proprietary protocol. Cardiomyocytes were placed in a perfusion chamber mounted on the stage of inverted Motic AE31E (IonOptix) or Olympus IX83P1ZF (MyoBLAZER) microscope and continuously perfused at approximately 2 mL / min with recording buffer heated to 35 ± 1 °C using an in-line heater from Warner Instruments (IonOptix & MyoBLAZER) and allowed to equilibrate for 5 minutes under constant perfusion. The cells were field stimulated with supra-threshold voltage at a 1 Hz pacing frequency, with a bipolar pulse of 3 ms duration, using a pair of platinum wires placed on opposite sides of the chamber connected to a MyoPacer stimulator. Starting at 1 V, the amplitude of the stimulating pulse was increased until the cardiomyocytes started generating contractility transients, and a value 1.5× threshold was used throughout the experiment. Cardiomyocytes were then imaged at 240 Hz using an IonOptix MyoCam-S CCD camera (IonOptix) or at 148 Hz using an Optronis CP70-16-M / C-148 (MyoBLAZER) camera. Digitized images were displayed within the IonWizard acquisition software (IonOptix) or MyoBLAZER acquisition software. The longitudinal axis of the selected cardiomyocyte was aligned parallel to the video raster line, by means of a cell framing adapter. Optical intensity data was collected from a user-defined rectangular region placed over the cardiomyocyte image. The optical intensity data represented the bright and dark bands corresponding to the Z-lines of the cardiomyocyte. The IonWizard software or MyoBLAZER Analysis software analyzed the periodicity in the optical density of these bands by means of a fast Fourier transform algorithm.

[0379] Compound test solutions were formulated from stock solutions within 30 min prior toexperimental application to the cells. Test solutions were applied after vehicle control (120 s interval, 1 Hz stimulation) in an increasing concentration order (in 300 s intervals, 1 Hz stimulation) and experiment was terminated after wash control (300 s interval, 1 Hz stimulation).

[0380] Positive control 30 nM ATX-II (toxin from anemonia sulcate) was applied after vehicle control(120 s interval, 1 Hz stimulation) and the data were recorded (300 s interval, 1 Hz stimulation).

[0381] An aftercontraction (AC) was visually identified as spontaneous secondary change in the slopeof the contractility transient that occurred before the next stimulus-induced contraction and that produced an abnormal and unsynchronized contraction. Contraction Failure (CF) was also visually identified when an electrical stimulus was unable to induce a contraction. Alternans and Short-Term Variability (STV) are 93 4924-6694-6837v.1visualized in Poincaré plots of Contraction Amplitude variability. STV (STV = Σ|CAn+1−CAn| (20×√2)−1) was calculated with the last 20 transients of each control and test article concentration period. Alternans were identified as repetitive alternating short and long contractility amplitude transients. STV values were normalized to the vehicle control value of each cell. AC, CF and Alternans were plotted and expressed as % of incidence of cells exhibiting each of the signals normalized by the total number of cardiomyocytes.

[0382] Pharmacokinetic Studies

[0383] Total of twenty-one male mice were used per study (3 animals per each time point). Mice wereadministered subcutaneously (s.c.).10 mg / kg dose. Compounds 13 and 22 were used as hydrochlorides and were solubilized using 0.85% saline (with addition of 1% tween80 for compound 22). Formulations heated and sonicated until a clear solution was obtained (formulation strength 2 mg / mL). The dosing volume for subcutaneous administration was 5 mL / kg.

[0384] Blood samples (~60 µL from mice) were collected under light isoflurane anesthesia (Surgivet®)from retro orbital plexus from a set of three animals at specified time points into labeled micro-tubes, containing K2EDTA solution (20% K2EDTA solution) as an anticoagulant. Immediately after blood collection, plasma was harvested by centrifugation at 4000 rpm, 10 min at 40 °C and samples were stored at -70 ± 10 °C until bioanalysis. Following blood collection, animals were immediately sacrificed, the abdominal vena-cava was cut open and whole body was perfused from heart using (10 mL) of normal saline. Brain samples were collected from a set of three animals at specified time points. After isolation, brain samples were rinsed three times in ice cold normal saline (for 5-10 seconds / rinse using (~5-10 mL) of normal saline in disposable petri dish for each rinse) and dried on blotting paper. Brain samples were homogenized using ice-cold phosphate buffer saline (pH - 7.4). Total homogenate volume was three times the tissue weight. All homogenates were stored below -70 ± 10 °C until bioanalysis. The extraction procedure for plasma and brain samples and the spiked plasma and brain calibration standards were identical. A 25 µL of study sample or spiked plasma calibration standard was added to individual pre- labeled micro-centrifuge tubes followed by 100 µL of internal standard prepared in acetonitrile (Glipizide, 500 ng / mL) was added except for blank, where 100 µL of acetonitrile was added. Samples were vortexed for 5 minutes and then centrifuged for 10 minutes at a speed of 4000 rpm at 4 °C. Following centrifugation, 100 µL of clear supernatant was transferred in 96 well plates and the concentrations of analyte were determined by fit for purpose LC-MS / MS method.

[0385] Non-Compartmental-Analysis tool of Phoenix WinNonlin® (Version 8.0 for oxa-noribogaine,Version 7.0 for noribogaine) was used to assess the pharmacokinetic parameters. Peak plasma concentration 94 4924-6694-6837v.1(Cmax) and time for the peak plasma concentration (Tmax) were the observed values. The areas under the concentration time curve (AUClastand AUCinf) were calculated by linear trapezoidal rule. The terminal elimination rate constant, ke was determined by regression analysis of the linear terminal portion of the log plasma concentration-time curve. The terminal half-life (T1 / 2z) was estimated by 0.693 / ke. Clearance was estimated as Dose / AUCinfand Vssas CL × MRT. Tissue-Kps were calculated using Microsoft Excel.

[0386] Table 1. Opioid agonist activity of compounds, potency expressed as [EC50] = nM and efficacyas % of control agonist activity (KOR: U50,488, MOR: DAMGO, DOR: DPDPE). Nanobody (Nb33) based assay was used to compare relative efficacy of compounds showing full agonist activity in amplified G- protein based assay. N / D = not determined G-protein BRET Assay Nb33 Assay Compound EC50 rKOR EC50 mMOR EC50 mDOR EC50 rKOR4924-6694-6837v.11 (103 %) 88 (61 %) 50 (88 %) 29 (61 %)

[0387] Table 2. Inhibition of monoamine and vesicular transporters, potency expressed as [IC50] = μM.Compounds IC50 hSERT IC50 hVMAT296 4924-6694-6837v.1REFERENCES (1) Hu, Y. E.; Kaur, J.; Mcfadden, R.; Murry, J. P.; Schultz, B. E.; Truong, H. H.; Yu, H. Protein Kinase C Agonists. WO2020176505A1, September 3, 2020. (2) Sames, D.; Havel, V.; BECHAND, B.; Lankri, D. Oxa-Ibogaine Inspired Analogues for Treatment of Neurological and Psychiatric Disorders. WO2022170268A1, August 11, 2022. https: / / patents.google.com / patent / WO2022170268A1 / en?oq=WO2022170268A1 (accessed 2024-01- 27). (3) Rives, M.-L.; Rossillo, M.; Liu-Chen, L.-Y.; Javitch, J. A. 6′-Guanidinonaltrindole (6′-GNTI) Is a G Protein-Biased κ-Opioid Receptor Agonist That Inhibits Arrestin Recruitment. Journal of Biological Chemistry 2012, 287 (32), 27050–27054. https: / / doi.org / 10.1074 / jbc.C112.387332.(4) Negri, A.; Rives, M.-L.; Caspers, M. J.; Prisinzano, T. E.; Javitch, J. A.; Filizola, M. Discovery of a Novel Selective Kappa-Opioid Receptor Agonist Using Crystal Structure-Based Virtual Screening. J. Chem. Inf. Model. 2013, 53 (3), 521–526. https: / / doi.org / 10.1021 / ci400019t.(5) Gillis, A.; Gondin, A. B.; Kliewer, A.; Sanchez, J.; Lim, H. D.; Alamein, C.; Manandhar, P.; Santiago, M.; Fritzwanker, S.; Schmiedel, F.; Katte, T. A.; Reekie, T.; Grimsey, N. L.; Kassiou, M.; Kellam, B.; Krasel, C.; Halls, M. L.; Connor, M.; Lane, J. R.; Schulz, S.; Christie, M. J.; Canals, M. Low IntrinsicEfficacy for G Protein Activation Can Explain the Improved Side Effect Profiles of New Opioid Agonists. Science Signaling 2020, 13 (625), eaaz3140. https: / / doi.org / 10.1126 / scisignal.aaz3140.(6) Hu, G.; Henke, A.; Karpowicz, R. J.; Sonders, M. S.; Farrimond, F.; Edwards, R.; Sulzer, D.; Sames, D. New Fluorescent Substrate Enables Quantitative and High-Throughput Examination of Vesicular Monoamine Transporter 2 (VMAT2). ACS Chemical Biology 2013, 8 (9), 1947–1954.https: / / doi.org / 10.1021 / cb400259n. (7) Yung-Chi, C.; Prusoff, W. H. Relationship between the Inhibition Constant (KI) and the Concentration of Inhibitor Which Causes 50 per Cent Inhibition (I50) of an Enzymatic Reaction. Biochemical Pharmacology 1973, 22 (23), 3099–3108. https: / / doi.org / 10.1016 / 0006-2952(73)90196-2.(8) Abi-Gerges, N.; Indersmitten, T.; Truong, K.; Nguyen, W.; Ratchada, P.; Nguyen, N.; Page, G.; Miller, P. E.; Ghetti, A. Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes. Sci Rep 2020, 10 (1), 7692. https: / / doi.org / 10.1038 / s41598-020-64657-2.(9) Nguyen, N.; Nguyen, W.; Nguyenton, B.; Ratchada, P.; Page, G.; Miller, P. E.; Ghetti, A.; Abi-Gerges, N. Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug- Induced Inotropic and Pro-Arrhythmia Risk. Front. Physiol. 2017, 8, 1073.https: / / doi.org / 10.3389 / fphys.2017.01073. 97 4924-6694-6837v.1

Claims

Claims 1. A compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); 98 4924-6694-6837v.1R9and R10are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15is H, -(alkyl) or -cycloalkyl; wherein (i) when D is NH, or -N-(C1-C2 alkyl), then R6 is -(C3-C12 alkyl);(ii) when X1 is C, X2 is NH, D is NH, and R2, R3, R4, R7, 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 notpropyl; (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 notpropyl; (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 notH propyl; (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 notpropyl; 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 notpropyl; or a pharmaceutically acceptable salt thereof.

2. A compound having the structure:whereinα and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5 and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, NR1 or CR15 and when X2 is NR1; α is absent and β is present; 99 4924-6694-6837v.1R1, 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, -OCF3or -NO2; R5is 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-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, - alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; wherein 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; wherein 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 100 4924-6694-6837v.1wherein when X2is -NH, and R6is propyl, then R5is 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, -OCF3or -NO2; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein D is NR5, and E and F are each independently CR9R10.

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), -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 independentlyH, halogen, -(alkyl), -OH, or -O(alkyl).

7. The compound of claim 1, 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); more preferably, R5 is H or -(alkyl).

8. The compound of claim 1, wherein R6 is -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), or -(alkyl-cycloalkyl); preferably R6 is -(C1-C6alkyl), -(C1-C6alkenyl), -(C1-C6alkynyl), -C1-C6cycloalkyl, -(C1-C6alkyl-alkenyl), -(C1-C6alkyl-alkynl), or -(C1-C6alkyl-cycloalkyl).

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

10. The compound of claim 1, wherein R5 and R6 combine to form a 3-7 membered heterocycloalkyl, ring;preferably; R5and R6combine to form a 5 membered heterocycloalkyl ring. 101 4924-6694-6837v.

111. The compound of claim 1, wherein R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); preferably; R7is -H or -(alkyl).

12. The compound of claim 1, wherein R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl);preferably, R9and R10are each independently H or -(alkyl).

13. The compound of claim 1, wherein R15 is H, or -(alkyl).

14. The compound of claim 1 having the structure:whereinX2 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; R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5and R6combine to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and 102 4924-6694-6837v.1R7is -H, -(C1-C3alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 having the structure:whereinR1 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-C12 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl) R7 is -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl).

16. The compound of claim 1 having the structure:wherein 103 4924-6694-6837v.1R2, R3and R4are 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, -OCF3or -NO2; R5is H or –(alkyl); R6is -(C3-C12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); R7 is -H, -(C1-C3 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl).

17. The compound of any one of claim 1-16, whereinR1 is -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 of any one of claims 1-17. wherein R6,19.

20. The compound of claim 1 having the structure:104 4924-6694-6837v.1, ,21. The compound of claim 20, wherein R5 is -H or methyl.

22. The compound of claim 1 having the structure:HO , ,105 4924-6694-6837v.1or2R4R R R43 3R5R5. 24.R1is -H or -Me; R2,R3,and R4are each independently -H, -OH, -F, -Cl, -Br,-CN, or -OMe; R5is -H, methyl; and / or R7is -H or -Me.

25. The compound of claim 1 having the structure:R R R4R4R3 43R3,106 4924-6694-6837v.1R1is -H or -Me; R2,R3,and R4are each independently -H, -OH, -F, -Cl, -Br,-CN, or -OMe; R5is -H, methyl; and / or R7is -H or -Me.

27. The compound of claim 1 having the structure:

28. The compound of claim 1 having the structure:.

29. Awherein[A] α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NR5, or CR9R10, and wherein one of D, E and F is NR5and the remaining two of D, E and F are CR9R10; X1is C or N, and when X1is N; α is absent and β is present; X2is O, S, N, NR1or CR15and when X2is NR1; α is absent and β is present; 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- 107 4924-6694-6837v.1(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, -OCF3or -NO2; R5is 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-C12 alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), - (alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; [B] α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is O, S, N, or CR15; 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; 108 4924-6694-6837v.1R5is 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, -OCF3or -NO2; R6is -H, -(C2alkyl), -(C4-12alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl- alkynl), -(alkyl-cycloalkyl), -(aryl) or -(heteroaryl); or R6is -(C3alkyl) and R3is –(C=O)NH2; or R5and R6combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; or [C] α and β represent a bond that is present or absent, and wherein either α or β is present, D, E and F are each independently NH, or CR9R10, and wherein one of D, E and F is NH and the remaining two of D, E and F are CR9R10; X1 is C or N, and when X1 is N; α is absent and β is present; X2 is NR1 and α is absent and β is present; 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 halogen, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(aryl), -(heteroaryl), -OAc, -O(C1alkyl), -O-(alkenyl), -O-(alkynyl), -O-(aryl), -O-(heteroaryl), -SH, -S(alkyl), -S-(alkenyl), -S-(alkynyl), - 109 4924-6694-6837v.1S-(aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH-(alkynyl), -NH-(aryl), -NH- (heteroaryl), -CO2(alkyl), -CONH2, -CN, -CF3, -CF2H, -OCF3or -NO2; R5is 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, -OCF3or -NO2; R6is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); or R5 and R6 combined to form a 3-7 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; R7 is -H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -(alkyl-alkenyl), -(alkyl-alkynl), -(alkyl- cycloalkyl), -(aryl) or -(heteroaryl); R9 and R10 are each independently H, -(alkyl), -(alkenyl), -(alkynyl), -cycloalkyl, -alkylcycloalkyl, -aryl, heteroaryl or -alkylaryl; and R15 is H, -(alkyl) or -cycloalkyl; or or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound of any of claims 1-29 and a pharmaceuticallyacceptable carrier.

31. A method of activating 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors comprising contactingthe 5HT2A and 5HT2C receptors with the compound of any one of claims 1-29.

32. A method of inhibiting SERT receptor comprising contacting the SERT receptor with the compoundof any one of claims 1-29.

33. A method of activating kappa-opioid receptor comprising contacting the kappa-opioid receptor withthe compound of any one of claims 1-29. 110 4924-6694-6837v.

134. A method of inhibiting nicotinic acetylcholine receptor comprising contacting the nicotinicacetylcholine receptor with the compound of any one of claims 1-29.

35. A method of treating a subject afflicted with substance use disorder comprising administering to thesubject the compound of any one of claims 1-29, or the composition of claim 30, comprising an effective amount of the compound, so as to thereby treat the subject afflicted with the substance use disorder.

36. A method of treating a subject afflicted with a depressive disorder, a mood disorder, an anxietydisorder, Parkinson’s disease, or traumatic brain injury comprising administering to the subject the compound of any one of claims 1-29, or the composition of claim 30 comprising an effective amount of the compound, so as to thereby treat the subject afflicted with the depressive disorder, the mood disorder, the anxiety disorder, Parkinson’s disease or the traumatic brain injury.

37. The compounds of any one of claims 1-29 or the composition of claim 30 for use ina) activating 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors,b) inhibiting SERT receptor,c) activating kappa-opioid receptor,d) inhibiting nicotinic acetylcholine receptor,e) treating a subject afflicted with substance use disorder, orf) treating a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder,Parkinson’s disease, or traumatic brain injury.

38. The use of compounds of any one of claims 1-29 or the composition of claim 30 toa) activate 5HT2A, 5HT2C, or both 5HT2A and 5HT2C receptors,b) inhibit SERT receptor,c) activate kappa-opioid receptor,d) inhibit nicotinic acetylcholine receptor,e) treat a subject afflicted with substance use disorder, or111 4924-6694-6837v.1f) treat a subject afflicted with a depressive disorder, a mood disorder, an anxiety disorder,Parkinson’s disease, or traumatic brain injury.

39. A process of synthesizing the compound of claim 1 comprising reacting a compound of formula I(formula I) (a) with an organo-bromide in thea base; or(b) with an alkyl halide in the presence of a base, then reacting with an organo bromide in the presenceof a base; to produce a compound of formula II (formula II) preferably, R6 is alkyl, alkyl-alkenyl,and R7 is H or alkyl.

40. The process of claim 39, further comprising(a) converting the compound of formula II to an oxime compound;(b) converting the oxime compound to a lactam compound; and(c) performing reduction, protection and deprotection reactions to the lactam compoundto produce a compound of formula III .4924-6694-6837v.

141. The process of claim 40, further comprising reacting the compound of formula III with followed by a deprotection reaction to produce a compound of formula IV (formula IV),R4and R8are each H, and R5is H or alkyl.

42. The process of claim 41, wherein formula IV has the following structure: HO , ,113 4924-6694-6837v.1or114 4924-6694-6837v.1