Thienyl compounds for treating depression or posttraumatic stress disorder

Abstract

Disclosed herein are thienyl compounds and salts, pharmaceutical compositions, and uses thereof.

Description

THIENYL COMPOUNDS FOR TREATING DEPRESSION OR POSTTRAUMA TIC STRESS DISORDERBACKGROUND

[0001] This application claims the benefit of priority of United States provisional application no. 63 / 707,933, filed October 16, 2024, and United States provisional application no. 63 / 712,730, filed October 28, 263 / 707,933024, the contents of which are incorporated by reference as if written herein in their entirety.

[0002] Depression (also known as major depression, major depressive disorder, or clinical depression) is characterized by a depressed mood or loss of interest that interferes with daily activities, such as sleeping, eating, or working. Depression is a major contributor to mortality, morbidity, disability, and economic costs (McLaughlin KA, “The public health impact of major depression: a call for interdisciplinary prevention efforts,” Prev Sei 2011, 72, 361-71).

[0003] An estimated 3.8% of the worldwide population experience depression, including 5% of adults (4% among men and 6% among women), and 5.7% of adults older than 60 years. Approximately 280 million people in the world have depression (Institute of Health Metrics and Evaluation. Global Health Data Exchange. http s : / / vizhub . healthdata. or g / gbd- results / ) . In the U.S., the age- standardized national prevalence of adults self-reporting a lifetime diagnosis of depression is 18.5%. (Lee B, Wang Y, Carlson SA, et al., “National, State-Level, and County-Level Prevalence Estimates of Adults Aged >18 Years Self-Reporting a Lifetime Diagnosis of Depression — United States, 2020,” MMWR Morb Mortal Wkly Rep 2023, 72, 644-650).

[0004] Posttraumatic Stress Disorder (PTSD) is an abnormal response to trauma that results in intrusive, distressing memories or dreams of a traumatic event, as well as severe impairments in mood and social function (Jellestad L, Vital NA, Malamud .1, et al., “Functional impairment in posttraumatic stress disorder: A systematic review and meta- analysis,” J Psychiatr Res. 2021, 136, 14-22). PTSD is common, with lifetime prevalence in the US estimated at 6.1% (Goldstein RB, Smith SM, Chou SP, et al., “The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and related Conditions - III,” Soc Psychiatry Psychiatr Epidemiol. 2016, 57, 1137-1148). Globally, the lifetime prevalence of PTSD varies heavily, with higher rates reported in poorer countries and those that have recently experienced conflict (Atwoli L, Stein DJ, Koenen KC, McLaughlin KA.“Epidemiology of posttraumatic stress disorder: prevalence correlates and consequences.” Curr Opin Psychiatry. 2015, 28(4). 307-311). Currently available treatments for PTSD have limited efficacy (de Moraes Costa G, Ziegelmann PK, Zanatta FB, et al., “Efficacy, acceptability, and tolerability of antidepressants for sleep quality disturbances in post-traumatic stress disorder: A systematic review and network metaanalysis,” Prog in Neuropyshopharmacol & Biol Psychi. 2022, 117. 110557.).

[0005] There remains a need for effective treatments for depression and PTSD. The present invention provides treatments to meet this critical need.SUMMARY

[0006] Provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1and R2are independently chosen from H and C1-C3alkyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring;R3is chosen from H and C1-C3alkyl;A is chosen from O and CH2;Z is chosen from O, -CH2O-, -OCH2-, and CX1X2; andX1and X2are independently chosen from H and halogen.

[0007] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in the (S) stereoisomer at the * carbon atom. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in the (R) stereoisomer at the * carbon atom.

[0008] Also provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided is a method for treating depression comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided is a method for treating PTSD comprising the step of administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided is a method for treating depression comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also provided is a method for treating PTSD comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula (T), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] These and other aspects of the invention will be apparent upon reference to the following description. References cited herein are hereby incorporated by reference in their entireties.BRIEF DESCRIPTION OF THE DRAWINGS[Oil] FIG. 1 shows the ORTEP structure of compound 8b.

[0012] FIG. 2 shows a photograph of single crystals of compound 8b.DETAILED DESCRIPTION

[0013] This description is intended to acquaint others skilled in the art with the present invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention is not limited to the embodiments or examples described herein.A. DEFINITIONS

[0014] The term “about” is intended to qualify a numerical value as including a margin of measurement accuracy, such as a standard error of a mean value. In some embodiments, “about” means the indicated numerical value ± 10%.

[0015] The term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon radical containing the indicated number of carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl. and isopropyl.

[0016] The term “halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.

[0017] The term “heterocycloalkyl” or “heterocycloalkyl group” or “heterocycle” or“heterocyclic” or “heterocyclic ring” or “heterocyclyl” refers to a monocyclic nonaromatic, saturated or partially unsaturated (if not defined as “saturated”) ring containing the indicated number of ring atoms, including at least one ring heteroatom, such asnitrogen, oxygen, or sulfur. Unless otherwise indicated, the ring is unsubstituted. Examples include, but are not limited to, azetidinyl, pyrrolidinyl and piperidinyl.

[0018] The term “patient” refers to a human being with depression or PTSD.

[0019] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound judgment, suitable for use in contact with the tissues of human beings with acceptable toxicity, irritation, allergic response, and other problems or complications commensurate with a reasonable benefit / risk ratio.

[0020] The term “pharmaceutical composition” refers to the combination of an active ingredient with a pharmaceutically acceptable excipient, in a form suitable for administration to a patient.

[0021] The term “safe and well tolerated” refers to a drug treatment method having an acceptable safety and tolerability profile in patients treated according to the method, as assessed by parameters such as AEs, ECGs, vital signs, safety laboratory parameters, and physical examinations, consistent with the safety and tolerability requirements of government agencies responsible for regulating drugs for human use, such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

[0022] The term “stable” or “chemically stable” refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture. The present invention is directed to stable compounds.

[0023] The term “therapeutically effective” refers to effective to treat depression or PTSD in a patient or patient population.

[0024] The term “treating” or “treatment” refers to any lessening, reducing, modulating, ameliorating, improving, stabilizing, inhibiting, slowing progression, or delaying onset of depression or PTSD or a symptom thereof. For example, treatment may include diminishment of a troublesome symptom of depression or PTSD.

[0025] Compounds described herein may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including R- and .S'-cnanliorners. the racemic mixtures thereof, and other mixtures thereof.

[0026] Chemical names and / or structural formulas described herein that do not specifically recite the isotope ratios of the constituent atoms are intended to include compounds in which the constituent atoms are present in any ratio of isotopes. For example, unless otherwise specified, a carbon atom may be present in any ratio of12C,13C, and14C, and a hydrogen atom may be present in any ratio of 'H,2H, and3H. In some embodiments, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotopes. In some embodiments, one or more of the constituent atoms in a compound of the present invention is enriched to contain a non-naturally occurring ratio of isotopes.B. COMPOUNDS

[0027] Provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1and R2are independently chosen from II and C1-C3alkyl, or R1and R2, taken together with the intervening nitrogen atom, fomr a 4-6 membered saturated heterocyclic ring;R3is chosen from H and C1-C3alkyl;A is chosen from O and CH2;Z is chosen from O, -CH2O-, -OCH2-, and CX1X2; andX1and X2are independently chosen from H and halogen.

[0028] In some embodiments, R1and R2are independently chosen from H and methyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

[0029] In some embodiments, R1and R2are independently chosen from H and methyl, or R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl, pyrrolidinyl, or piperidinyl ring.

[0030] In some embodiments, R1and R2arc independently chosen from H and C1-C3alkyl.

[0031] In some embodiments, R1and R2are independently chosen from H and methyl.

[0032] In some embodiments, R1is H and R2is chosen from H and C1-C3alkyl.

[0033] In some embodiments, R1is H and R2is chosen from H and methyl.

[0034] In some embodiments, R1is H and R2is chosen from C1-C3alkyl.

[0035] In some embodiments, R1is H and R2is methyl.

[0036] In some embodiments, R1and R2are H.

[0037] In some embodiments, R1and R2are C1-C3alkyl.

[0038] In some embodiments, R1and R2are methyl.

[0039] In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl, pyrrolidinyl, or piperidinyl ring. In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl ring. In some embodiments. R1and R2. taken together with the intervening nitrogen atom, form a pyrrolidinyl ring. In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form a piperidinyl ring.

[0040] In some embodiments, R3is chosen from H and methyl.

[0041] In some embodiments, R3is H.

[0042] In some embodiments, R3is methyl.

[0043] In some embodiments, A is O.

[0044] In some embodiments, A is CH2.

[0045] In some embodiments, Z is O.[046| In some embodiments, Z is -CH2O-.

[0047] In some embodiments, Z is -OCH2-.

[0048] In some embodiments, Z is C X1X2.

[0049] In some embodiments, X1and X2are independently chosen from H, F, and Cl.

[0050] In some embodiments, X1and X2are independently chosen from H and F.

[0051] In some embodiments, X1and X2are H.

[0052] In some embodiments, X1and X2are halogen.

[0053] In some embodiments, X1and X2are independently chosen from F and Cl.

[0054] In some embodiments, X1and X2are F.

[0055] In some embodiments, Z is chosen from O, -CH2O-, -OCH2-, CH2, and CF2.

[0056] In some embodiments, Z is CH2.

[0057] In some embodiments, Z is CF2.

[0058] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in which the * carbon atom is enriched in one stereoisomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is at least about 85% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), is at least about 99% enriched in the (R) stereoisomer at the * carbon atom.

[0059] Also provided is N-methyl-l,3.5.6.7.8-hexahydrobenzothiopheno|2,3-c|furan-6- amine ( ), N-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine ( ), 1, 3, 5, 6,7,8-hexahy drobenzothiopheno [2,3 -c] furan- 6- amine ( ), 2, 3, 5, 6,7,8- hexahydro- 1H-cyclopenta[b]benzothiophen-6-amine), N-methyl-4,12-dioxa-7-thiatricyclo[6.4.0.02,6]dodeca-l(8),2(6)-dien-10-amine (), N-methyl-3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine ( ), N-methyl-3,4,6,7,8,9-hexahydro-1H-benzothiopheno[3,2-c]pyran-7-amine ( ), 2, 2-difluoro-N- methyl-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-amine (c] furan- 6- amine ( ), or a pharmaceutically acceptable salt thereof, enriched in one enantiomer. In some embodiments, the N-methyl-1,3,5,6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan- 6-amine, 2,3,5,6,7,8-hexahydro- 1H-cyclopenta[b]benzothiophen-6-amine, N-methyl- 4,12-dioxa-7-thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3.4.5.6.7.8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9- hexahydro-1H-benzothiopheno[3,2-c]pyran-7-amine. 2,2-difluoro-N-methyl-l,3.5.6.7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro- 1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (S) enantiomer. In some embodiments, the N-methyl-1.3.5.6.7.8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro- 1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7.8.9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- bcnzothiophcno[2,3-c]furan-6-aminc, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (R) enantiomer. In some embodiments, the N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro- 1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-ainine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (S) enantiomer. In some embodiments, the N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodcca-l(8),2(6)-dicn-10-aminc, N-mcthyl-3,4,5,6,7,8-hcxahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno|3,2-c|pyran-7-amine. 2,2-difluoro-N-methyl-l,3,5.6.7.8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (R) enantiomer. In some embodiments, the N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (S) enantiomer. In some embodiments, the N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahy dro- 1 H-cy clopenta[b] benzothiophen- 6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-lII- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro- 1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (R) enantiomer. In some embodiments, the N-methyl-1.3.5.6.7.8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1,3 ,5 ,6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02'6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine. N-methyl-3.4.6.7.8.9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- bcnzothiophcno[2,3-c]furan-6-aminc, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (S) enantiomer. In some embodiments, the N-methyl-1.3.5.6.7.8-hexahydrobenzothiopheno|2,3-c|furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8).2(6)-dien-10-amine. N-methyl-3.4.5.6.7.8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-lII- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (R) enantiomer. In some embodiments, the N-methyl-1.3.5.6.7.8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro- 1H-cyclopenta[b]benzothiophen-6-amine, 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan- 6-amine, 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12- dioxa-7-thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8- hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-lII- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (S) enantiomer. In some embodiments, the N-methyl-1,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan-6- amine, 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12- dioxa-7-thiatricyclo[6.4.0.02 <5]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8- hexahydro-1H-benzothiopheno[2,3-c]pyran-7-aniine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (R) enantiomer.

[0060] Also provided is a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.C. PHARMACEUTICAL COMPOSITIONS

[0061] While it may be possible for the compounds and salts described herein to be administered to a patient as the raw chemical, they arc preferably administered as a pharmaceutical composition. Accordingly, provided herein is a pharmaceutical composition comprising a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in one stereoisomer at the * carbon atom. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%. 90%, 95% or 99% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8- hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- HI-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-lII- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro- 1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof.

[0062] Any of the well-known techniques and excipients may be used as suitable and as understood in the art (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkins, 2000). Pharmaceutically acceptable excipients include pharmaceutically acceptable binding agents, lubricants, wetting agents, disintegrants. and the like. Tablets, pills, capsules, troches and the like can contain any of the following excipients, or excipients of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a diluent such as starch or lactose, a dispersing agent such as alginic acid, sodium starch glycolate, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide. The amount of active ingredient that is combined with the pharmaceutically acceptable excipient (s) to produce a single dosage form will vary depending upon the particular mode of administration and the identity of the dosage form.

[0063] In certain embodiments, the pharmaceutical composition contains about 0.1 mg to about 2000 mg of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 0.5 mg to about 1500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 1 mg to about 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 2 mg, 25 mg, 75 mg, or 150 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein.

[0064] Compressed oral tablets may comprise the following ingredients:

[0065] To make the compressed oral tablets, first thoroughly mix ingredients 1-4 and granulate with purified water; then dry the granules, mill the dried granules to desired particle size, and finally add ingredient 5, mix thoroughly, and compress.

[0066] Powder filled oral capsules may comprise the following ingredients:

[0067] To make the powder filled oral capsules, first thoroughly mix ingredients 1-3 and mill to desired particle size; then add ingredients 4 and 5, mix thoroughly, and fill into capsules (e.g., hard gelatin capsules).

[0068] Sterile injection pharmaceutical composition may comprise the following ingredients:

[0069] To make the sterile injection pharmaceutical composition, mix thoroughly mix ingredients 1 and 2 and a portion of ingredient 4 to dissolve ingredient 1; then adjust to pH 5 with ingredient 3 and add ingredient 4 to about 1 mL total volume; and finally filter, fill into vials, and sterilize.D. TREATMENT METHODS

[0070] Also provided is a method of treating depression or PTSD in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in one stereoisomer at the * carbon atom. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (R) stereoisomer at the * carbon atom. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (S) stereoisomer at the * carbon atom. In some embodiments, the patient is administered a therapeutically effective amount of N-mcthyl- 1,3, 5,6,7, 8-hcxahydrobcnzothiophcno[2,3-c]furan-6- amine, N-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine,1.3.5.6.7.8-hexahydrobenzothiopheno|2,3-c|furan-6-amine, 2,3.5.6.7.8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8-hexahydro- 1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of N-methyl-1,3,5,6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan- 6-amine, 2,3,5,6,7,8-hexahydro- 1H-cyclopenta[b]benzothiophen-6-amine, N-methyl- 4,12-dioxa-7-thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3.4.5.6.7.8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9- hexahydro-1H-benzothiopheno[3,2-c]pyran-7-amine. 2,2-difluoro-N-methyl-l,3.5.6.7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro- 1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof, is enriched in one enantiomer. In some embodiments, the patient is an adult.

[0071] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein may be administered at a dose of from about 0.01 to about 300 mg / kgper day, such as about 0.03 to about 100 mg / kg per day. The dose range for adult humans is generally from about 0.05 mg to about 2 g / day. such as for example about 0.1 mg to about 1 g / day, about 0.1 to about 500 mg / day, or about 0.5 to about 400 mg / day. Dosage forms provided in discrete units (e.g., tablets or capsules) may conveniently contain an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is therapeutically effective at that amount or a multiple thereof, for instance, units containing about 0.1 mg to about 500 mg. such as about 0.25 mg to about 100 mg.E. EXAMPLES1. Synthesis

[0072] The examples below provide exemplary synthetic methods for the preparation of compounds of Formula (I), and pharmaceutically acceptable salts thereof, described herein. One of ordinary skill in the art will understand that similar methods may be employed.

[0073] Synthetic Route to N-Methyl-l,3,5,6,7,8-hexahydrobenzothiopheno[2,3- c]furan-6-amine hydrochloride enantiomer 1 (8a) and N-Methyl-1,3,5,6,7,8- hexahydrobenzothiophenol2,3-clfuran-6-amine hydrochloride enantiomer 2 (8b)

[0074] Procedure for preparation of ethyl 2-amino-6-[tert- butoxycarbonyU methyl)amino]-4,5, 6, 7-tetrahydrobenzothiophene-3-carboxylate ( 2 )To a solution of tert-butyl N-methyl-N-(4-oxocyclohexyl)carbamate (32 g, 140.78 mmol, 1 eq) and ethyl 2-cyanoacetate (20.70 g, 183.02 mmol, 19.51 mL, 1.3 eq) in EtOH (300 mL) was added S8 (5.42 g, 168.94 mmol, 1.2 eq) and TEA (21.37 g, 211.18 mmol, 29.39 mL, 1.5 eq) .The mixture was stirred at 25 °C for 16hr . The reaction mixture was concentrated under reduced pressure to remove EtOH. The product was triturated with EtOAc at 25 °C for 1 hr. The mixture was followed by filtration, the filter cake was dried to afford ethyl 2-amino-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate, (2), (43 g, 121.31 mmol, 86.2% yield) as a white solid.

[0075] Procedure for preparation of ethyl 6-[tertd)utoxycarbonyl(methyl)aminol- 4,5,6, 7-tetrahydrobenzothiophene-3-carboxylate (3)B loc B IocTo a solution of ethyl 2-amino-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (20 g, 56.42 mmol. 1 eq) in EtOH (300 mL) was added Cu(OAc)2 (12.30 g, 67.71 mmol, 1.2 eq), and then tert-butyl nitrite (7.56 g, 73.35 mmol, 8.72 mL, 1.3 eq) was added dropwise at 0 °C. The mixture was stirred at 60°C for 2 hr . The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford ethyl 6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate, (3), (12.5 g, 36.82 mmol, 65.26% yield) as a yellow solid. 41 NMR (400 MHz, CHLOROFORM-d) 5 = 7.93 (s, 1H), 4.58 - 4.37 (m, 1H), 4.34 - 4.25 (m, 2H), 3.31 - 3.21 (m, 1H), 2.94 - 2.77 (m, 6H), 2.01 - 1.78 (m, 2H), 1.48 - 1.46 (m, 1H). 1.48 (s, 8H), 1.36 (t, J = 7.1 Hz, 3H).

[0076] Procedure for preparation of ethyl 2-bromo-6-[tert- butoxycarbonyl(methyl)aminol-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (4)To a solution of ethyl 6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (9 g, 26.51 mmol, 1 eq) in DMF (100 mL) was added NBS (7.08 g, 39.77 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25 °C for 4hr . The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (100mL*2). The combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (LSCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate, (4), (9.7 g, 20.40 mmol. 76.96% yield, 88% purity) as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 6 = 4.57 - 4.21 (m, 3H), 3.08 (br dd, J = 3.6, 16.9 Hz, 1H), 2.88 - 2.66 (m, 6H), 1.97 - 1.76 (m, 2H), 1.48 (s, 9H), 1.39 (t, J = 7.2 IIz, 311).

[0077] Procedure for preparation of tert-butyl N-(2,3-diformyl-4,5,6,7- tetrahvdrobenzothiophen-6-yl}-N-methyl-carbamate (5)To a solution of ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (11.88 g, 24.99 mmol, 1 eq) in MeOH (150 mL) was TEA (5.06 g, 49.98 mmol, 6.96 mL, 2 eq) and Pd(dppf)C12 (1.83 g, 2.50 mmol, 0.1 eq) . The suspension was degassed and purged with CO for 3 times. The mixture was stirred under CO (50 Psi.) at 60 °C for 16hr . The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by flash silica gel chromatography (1SCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl N-(2,3- diformyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate, (5), (10.4 g, 24.86mmol, 99.47% yield, 95% purity) as yellow oil. ’H NMR (400 MHz, CHLOROFORM- d) 5 = 4.58 - 4.21 (m, 3H), 3.85 (s, 3H), 2.97 - 2.63 (m. 7H), 2.01 - 1.79 (m, 2H). 1.48 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H).

[0078] Procedure for preparation of tert-butyl N-f2,3-bis(hydroxymethyl)-4,5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate ( 6)To a solution of tert-butyl N-(2,3-diformyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)-N- methyl-carbamate (10.4 g, 24.86 mmol, 1 eq) in THF (100 mL) was added LiBH4 (4 M, 31.07 mL, 5 eq) and MeOH (2 mL) at 0°C . The mixture was slirrcd at 25 °C for 16hr . The reaction mixture was poured into NH4CI saturated solution (200 mL) and extracted with EtOAc (150mLx3).The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl N-[2,3-bis(hydroxymethyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate, (6), (8.1 g, 24.74 mmol, 99.52% yield) as yellow gum.1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.81 - 4.68 (m, 2H), 4.65 - 4.53 (m, 2H), 4.52 - 4.22 (m, 1H), 2.92 - 2.73 (m, 6H), 2.72 - 2.59 (m, 1H), 2.01 - 1.81 (m, 2H), 1.48 (s, 9H).

[0079] Procedure for preparation of tert-butyl N-(L3,5,6.7.8- hexahydrobenzothiophenof2,3-c]furan-6-yl)-N-methyl-carbamate (7)To the mixture of tert-butyl N-[2,3-bis(hydroxymethyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (1 g, 3.05 mmol, 1 eq) in DCM (20 mL) was added MnCh (1.33 g, 15.27 mmol, 5 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered. The filtrate was cooled to 0 °C and TFA (5.22 g,45.81 mmol, 3.40 mL, 15 eq) was added. Then EtsSiH (1.60 g, 13.74 mmol, 2.20 mL, 4.5 eq) was added dropwise. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by sat. Na?CCF (30 mL) and extracted with DCM (15 mLx3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~10 % Ethyl acetate / Petroleum ether @ 18 mL / min) to afford tert-butyl N-( 1,3.5.6.7,8- hexahydrobenzothiopheno[2,3-c]furan-6-yl)-N-methyl-carbamate, (7) (170 mg, 549.41 pmol, 17.99% yield) as a light yellow solid. 1H NMR (400 MHz, CDC13-d) 8 = 4.96 (br s, 2H), 4.79 (t, J = 3.6 Hz, 2H), 4.52 - 4.12 (m, 1H), 2.78 (br d, J = 6.6 Hz, 2H), 2.74 (s, 3H), 2.54 (br t, J = 5.8 Hz, 2H), 1.91 - 1.74 (m, 2H), 1.40 (s, 9H).

[0080] Procedure for preparation of tert-butxl N-(1,3,5.6.7.8- hexahydrobenzothiophenof2,3-c]furan-6-yl)-N-methyl-carbamate, enantiomer 1 (7a) and enantiomer 2 (7b)Boc Boc BocThe residue was separated by SFC (column: DAICEL CHIRALPAKIG(250mmx50mm,10pm);mobile phase: [CO2-EtOH(0.1%NH3H2O )];B%:31%, isocratic elution mode) to afford tert-butyl N-(l,3,5,6,7,8-hexahydrobenzothiopheno[2,3- c]furan-6-yl)-N-methyl-carbamate (70 mg, 226.23 pmol. 46.67% yield), (7a) as a yellow solid and tert-butyl N-( 1.3.5.6.7.8-hexahydrobenzothiopheno[2.3-cJfuran-6-yl)-N- methyl-carbamate (70 mg, 226.23 pmol, 46.67% yield), (7b) as a yellow solid.

[0081] Procedure for preparation of N-methyl-1,3,5,6,7,8- hexahydrobenzothiophenof2,3-c]furan-6-amine hydrochloride, enantiomer 1 (8a)To a solution of tert-butyl N-( 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan-6-yl)-N- methyl-carbamate, (7a) (70 mg, 226.23 pmol, 1 eq) in EtOAc (0.5 mL) was added HCl / EtOAc (2 M, 1.5 mL) .The mixture was stirred at 25 °C for 2hr . The mixture wasconcentrated. The product was triturated with EtOAc (1 mL) at 25°C for 10 min. The mixture was followed by filtration, the filter cake was dried to afford N-methyl- l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, (8a), (40.38 mg, 162.66 pmol, 72% yield, 99% purity, HC1) as a white solid. 1H NMR (400 MHz, METHANOL- d4) 8 = 4.99 (br s, 2H), 4.86 (br s, 2H), 3.63 - 3.52 (m, 1H), 3.28 (br d, J = 4.9 Hz, 1H), 2.91 (br dd, J = 8.8, 16.0 Hz, 1H), 2.79 (s, 3H), 2.76 - 2.60 (m, 2H), 2.33 - 2.21 (m, 1H). 2.05 - 1.89 (m, 1H); LC-MS: m / z [M+H]+= 210.1.

[0082] Procedure for preparation of N-methyl-1,3,5,6,7,8- hexahydrobenzothiophenof2,3-clfuran-6-amine hydrochloride, enantiomer 2, (8b)BocTo a solution of tert-butyl N-(l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-yl)-N- methyl-carbamate, (7b) (70 mg, 226.23 pmol, 1 eq) in EtOAc (0.5 mL) was added HCI / EtOAc (2 M, 1.5 mL) .The mixture was stirred at 25 °C for 2hr . The mixture was concentrated. The product was triturated with EtOAc at 25°C for 10 min. The mixture was followed by filtration, the filter cake was dried to afford N-methyl-1,3,5,6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine (37.62 mg, 151.54 pmol, 67% yield. 99% purity, HC1) as an off-white solid. I I NMR (400 MHz. METHANOL-d4) 6 = 4.99 (br s, 2H), 4.86 (br s, 2H), 3.63 - 3.52 (m, 1H), 3.30 - 3.25 (m, 1H), 2.96 - 2.86 (m, 1H), 2.79 (s, 3H), 2.74 - 2.60 (m, 2H), 2.32 - 2.21 (m, 1H), 2.02 - 1.88 (m, 1H); LC-MS: m / z [M+H]+= 210.1.

[0083] Synthetic Route for N-methyl-2,3,5,6, 7,8-hexahydro-lH- cyclopenta[b]benzothiophen-6-amine hydrochloride, enantiomer 1 (Ila) and N- methyl-2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]benzothiophen-6-amine hydrochloride, enantiomer 2 (11b)To a solution of ethyl 6-(tert-butoxycarbonylamino)-4,5.6.7-tetrahydrobenzothiophene-3- carboxylate (9.00 g, 27.6 mmol, 1.00 eq) in DMF (100 mL) was portion-wise added NBS (6.00 g, 33.7 mmol, 1.22 eq). The mixture was stirred at 25 °C for 4 h. The mixture was diluted with H2O (400 mL) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with saturated NaCl (100 mLx2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~9% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give ethyl 2-bromo-6-(tert-butoxycarbonylamino)-4,5.6.7-tetrahydrobenzothiophene-3- carboxylate (8.5 g, 21.0 mmol, 74.5% yield) as a light-yellow oil.!H NMR (400 MHz, MeOD-rk) 5 = 4.39 - 4.26 (m, 2H), 3.88 - 3.70 (m, 1H), 3.01 - 2.91 (m, 2H), 2.82 - 2.73 (m, 1H), 2.53 (dd, J = 9.2, 16.1 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.74 - 1.64 (m, 1H), 1.45 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H) LCMS: m / z [M-Boc+H]+= 304.1.

[0085] Procedure for preparation of ethyl 6-(tert-butoxycarbonylamino)-2-f(E}-3- ethoxy-3-oxo-prop-l-enyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (4)A mixture of ethyl 2-bromo-6-(tert-butoxycarbonylamino)-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (8.50 g, 21.0 mmol, 1.00 eq), ethyl (E)-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2-enoate (6.00 g, 26.5 mmol, 1.26 eq) , Pd(dppf)Ch (1.54 g, 2.10 mmol, 0.1 eq) , K2CO3(6.00 g, 43.4 mmol, 2.06 eq) in dioxane (100 mL) , H2O (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 4 h under N2 atmosphere. The mixture was poured into H2O (300 mL) and extracted with EtOAc (100 mLx2). The combined organic layers were washed with saturated NaCl (100 mLx2), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give ethyl 6-(tert- butoxycarbonylamino)-2-[(E)-3-ethoxy-3-oxo-prop- l-enyl]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (4) (7 g, 16.5 mmol, 78.5% yield) as a yellow solid. ’H NMR (400 MHz, McOD-A) 5 = 8.43 (d, J = 15.8 Hz, 1H), 6.24 (d, J = 15.8 Hz, 1H), 4.36 (dq, J = 1.7, 7.1 Hz, 2H), 4.23 (q, J= 7.1 Hz, 2H), 3.82 (br d, J = 1.7 Hz, 1H). 3.11 - 2.95 (m, 2H). 2.85 - 2.75 (m, 1H), 2.63 (br dd. J = 8.8, 16.5 Hz, 1H). 2.06 - 2.00 (m, 1H), 1.77 - 1.66 (m, 1H), 1.45 (s, 9H), 1.40 (t, J = 7.2 Hz, 3H), 1.31 (t, 7 = 7.1 Hz, 3H). LCMS: m / z [M+Na]+= 446.3.

[0086] Procedure for preparation of ethyl 6-(tert-butoxycarbonylamino)-2-(3-To a solution of ethyl 6-(tert-butoxycarbonylamino)-2-[(E)-3-ethoxy-3-oxo-prop-l- enyl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (6.5 g, 15.4 mmol, 1.00 eq) in THF (60 mL) was added Pd / C (1.63 g, 1.53 mmol, 10% purity, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 16 h. The reaction mixture was filtered and the cake was washed with EtOAc (50 mL). The combined organic phases were concentrated under vacuum to give ethyl 6-(tert-butoxycarbonylamino)-2-(3-ethoxy-3-oxo-propyl)- 4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (5) (5.8 g, 13.6 mmol, 88.3% yield) as a yellow solid which was used into next step without further purification, 1H NMR (400 MHz, CDCh-J) 8 = 4.65 (d, 7= 7.1 Hz, 1H), 4.31 (q, 7 = 7.1 Hz, 2H), 4.19 - 4.12 (m,2H), 4.04 (br s, 1H), 3.36 (t, J = 7.6 Hz, 2H), 3.05 (br dd, J = 4.3, 16.1 Hz, 1H), 2.96 - 2.80 (m, 2H), 2.68 (t, J = 7.6 Hz. 2H), 2.57 (br dd, J = 6.8, 16.1 Hz, 1H), 2.01 - 1.91 (m.1H), 1.78 (dt, J = 7.1, 13.8 Hz, 1H), 1.45 (s, 8H), 1.37 (t, J = 1.1 Hz, 3H), 1.30 - 1.25 (m,3H). LCMS: m / z [M+Na]+= 448.1.

[0087] Procedure for preparation of ethyl 6-(tert-butoxycarbonylamino)-l-oxo-To the solution of ethyl 6-(tert-butoxycarbonylamino)-2-(3-ethoxy-3-oxo-propyl)- 4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (5.8 g, 13.6 mmol, 1.00 eq) in THF (120 mL) was added t-BuOK (3.82 g, 34.1 mmol, 2.50 eq) at 0 °C, after addition, the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by sat. NH4CI (60 mL), diluted with water (60 mL) and extracted with EtOAc (40 mLx3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give crude product. The crude product was dissolved with EtOAc (100 mL) and water ( 100 mL). The mixture was adjusted pH to 9-10 with Na2CO3 (solid) and separated. The organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give ethyl 6-(tert-butoxycarbonylamino)-l-oxo- 2,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophene-2-carboxylate (6) (2.9 g, 7.64 mmol, 56.1% yield) as a light-yellow solid. 1H NMR (400 MHz, CDC13-d ) δ = 4.57 (br s, 1H), 4.26 - 4.13 (m, 2H), 4.08 - 3.93 (m, 1H), 3.84 (td, J = 2.9, 7.2 Hz, 1H), 3.53 - 3.37 (m,1H), 3.33 - 3.16 (m, 1H), 3.06 (br d, J= 16.6 Hz, 1H), 2.79 (br d, J = 6.0 Hz, 2H), 2.56 (br dd, J= 6.9, 16.3 Hz, 1H), 1.91 (dt, J = 3.0, 6.5 Hz, 1H), 1.72 (br s, 1H), 1.38 (s, 9H).1.25 (t. J = 7.1 Hz, 3H) LCMS: m / z [M-tBu+H]+= 324.1.

[0088] Procedure for preparation of tert-butyl N-(l-oxo-2,3,5,6,7,8-To the solution of ethyl 6-(tert-butoxycarbonylamino)-l-oxo-2,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophene-2-carboxylate (2.9 g, 7.64 mmol, 1.00 eq) in DMSO (30 mL) was added LiCl (1.62 g, 38.2 mmol, 5 eq) and H2O (3 mL) . The mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (150 mL) and precipitate generated. The suspension was filtered and the cake was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25 % Ethyl acet ate / Petr oleum ether gradient @ 36 mL / min) to give tert-butyl N-(l -oxo- 2,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-yl)carbamate (1.5 g, 4.88 mmol, 63.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ = 4.64 (br s, 1H), 4.18 - 3.99 (m, 1H), 3.19 - 3.04 (m. 3H), 3.00 - 2.81 (m. 4H), 2.63 (br dd, J = 7.2. 16.3 Hz. 1H), 2.04 - 1.94 (m, 1H), 1.86 - 1.73 (m, 1H), 1.46 (s, 9H). LCMS: m / z [M-tBu+H]+= 252.1.

[0089] Procedure for yreyaration of tert-butyl N-f(lE}-l-(y- tolylsulfonylhydrazono)-2,3,5,6,7,8-hexahydrocycloyentafb]benzothioyhen-6- xUcarbainate (8)To the solution of tert-butyl N-(l-oxo-2,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl)carbamate (1.25 g, 4.07 mmol. 1.00 eq) in MeOH (5 mL) was added 4-methylbenzenesulfonohydrazide (1.06 g, 5.69 mmol, 1.40 eq). The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered. The cake was washed with MeOH (5 mL) and dried over vacuum to give tert-butyl N- [(lE)-l-(p-tolylsulfonylhydrazono)-2,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6- yl]carbamate (8) (1.9 g, 3.99 mmol, 98.2% yield) as a white solid which was used into next step without further purification. 1H NMR (400 MHz, CDCl3-d) δ = 7.83 (d, .7 = 8.4 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.85 - 3.73 (m, 1H), 3.05 - 2.93 (m, 5H), 2.92 - 2.81 (m, III), 2.68 - 2.53 (m, 211), 2.42 (s, 311), 2.08 - 1.94 (m, III), 1.76 - 1.60 (m, III), 1.46 (s, 9H). LCMS: m / z [M+H]+= 476.1.

[0090] Procedure for yreyaration of tert-butyl N-(2,3,5,6,7,8-hexahvdro-lH- cycloyenta [b] benzothioyhen-6-yl)carbamate (9)To the mixture of tert-butyl N-[(lE)-l-(p-tolylsulfonylhydrazono)-2,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl]carbamate (1.9 g, 3.99 mmol, 1 eq) in AcOH (20 mL) was added NaBHsCN (376 mg, 5.99 mmol, 1.50 eq). The mixture was stirred at 45 °C for 1 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (30 mLx3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~7 % Ethyl acetate / Petroleum ether gradient @ 36 mL / min) to give tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6- yl)carbamate (9) (810 mg, 2.76 mmol, 69.1% yield) as a white solid. 1H NMR (400 MHz, CDCh-J) 5 = 4.80 - 4.59 (m, 1H), 4.20 - 3.97 (m, 1H), 3.11 (br dd, 7 = 4.6, 15.9 Hz, 1H), 2.86 (br t, 7 = 7.1 Hz, 2H), 2.70 - 2.52 (m, 5H), 2.49 - 2.37 (m, 2H), 1.99 (dtd, 7 = 2.8, 6.3, 12.8 Hz, 1H), 1.90 - 1.75 (m, 1H), 1.47 (s, 9H) LCMS: m / z [M-tBu+H]+= 238.1.

[0091] Procedure for preparation of tert-butyl N-(2,3,5,6,7,8-hexahydro-lH- cyclopentafblbenzo thiophen-6-yl)carbamate enantiomer 1 (9a) and enantiomer 2 (9b)9 9a, 9bTert-butyl N-(2,3.5.6.7.8-hexahydro-1H-cyclopenta[b]benzothiophen-6-yl)carbamate (900 mg, 3.07 mmol, 1 eq) was separated by SFC (column: DATCEL CH1RALPAK IC(250mmx30mm,10um); mobile phase: [CCL-i-PrOH (0.1% NH3H2O)]; B%: 20%, isocratic elution mode) to give tert-butyl N-(2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-yl)carbamate (9a, 411 mg, 1.40 mmol. 45.7% yield) as a white solid and tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6- yl)carbamate (9b, 410 mg, 1.40 mmol, 45.6% yield) as a white solid.

[0092] Procedure for preparation of tert-butyl N-(2,3,5,6,7,8-hexahydro-lH- cyclopentafblbenzo thiophen-6-yl)-N-methylcarbamate enantiomer 1 (10a)To the solution of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)carbamate (110 mg, 375 pmol, 1.00 eq) in DMF (2 mL) was added NaH (23 mg, 562 pmol, 60% purity, 1.50 eq) at 0 °C. After stirring for 15 min, Mel (80 mg, 562 pmol, 1.50 eq) was added at 0 °C. Then the mixture was stirred at 20-25 °C for 1.5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mLx3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue to give tert-butyl N-(2,3,5,6,7,8-hexahydro- 1H-cyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (125 mg, crude) as a yellow oil which was used into next step without further purification.rH NMR (400 MHz, CDCh-rf) 8 = 4.68 - 4.19 (m, 1H), 2.89 - 2.74 (m, 7H), 2.71 - 2.52 (m, 4H), 2.49 - 2.38 (m. 2H), 1.96 - 1.81 (m, 2H). 1.48 (s, 9H). LCMS: m / z [M-tBu+H]+= 252.1.

[0093] Procedure for preparation of N-methyl-2,3,5,6,7,8-hexahydro-lH- cyclopentafblbenzo thiophen-6-amine hydrochloride enantiomer 1 (Ila)To the solution of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)-N-methyl-carbamate (125 mg, 406 pmol, 1.00 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 2 mL, 19.68 eq). The mixture was stirred at 20-25 °C for 1 h. The reaction mixture was filtered and the cake was dried over vacuum to give N-methyl- 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine (Ila) (66.6 mg, 272.74 pmol, 67.1% yield, 99.8% purity, HC1 salt) as a purple solid. ’H NMR (400 MHz, MeOD-ck) 8 = 3.59 - 3.48 (m, 1H), 3.28 - 3.19 (m, 1H), 2.92 - 2.80 (m, 3H), 2.78 (s. 3H), 2.74 - 2.55 (m, 4H), 2.48 - 2.36 (m, 2H), 2.31 - 2.20 (m, 1H), 1.93 (dddd, J = 6.4, 8.8, 10.2, 12.9 Hz, 1H). LCMS: m / z [M+H]+= 208.1.

[0094] Procedure for preparation of tert-butyl N-(2,3,5,6,7,8-hexahydro-lH- cyclopentafblbenzo thiophen-6-yl)-N-methyl-carbamate enantiomer 2 (10b)9b 10bTo the solution of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)carbamate (110 mg, 375 pmol, 1.00 eq) in DMT (2 mL) was added NaH (23 mg, 562 pmol, 60% purity, 1.50 eq) at 0 °C. After stirring for 15 min, Mel (79.82 mg, 562 pmol, 1.50 eq) was added at 0 °C. Then the mixture was stirred at 20-25 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mLx3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to tert-butyl N-(2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (10b) (122 mg, crude) as a yellow oil which was used into next step without further purification.JII NMR (400 MHz, CDCL-rf) 6 = 4.69 - 4.17 (m, 1H). 2.91 - 2.78 (m, 7H), 2.71 - 2.54 (m, 4H), 2.50 - 2.38 (m, 2H), 1.97 - 1.82 (m, 2H), 1.49 (s, 9H). LCMS: m / z [M-Boc +H]+= 208.1.

[0095] Procedure for preparation of N-methyl-2,3,5,6.7.8-hexahydro-lH- cyclopentafblbenzo thiophen-6-amine hydrochloride enantiomer 2 (lib)To the mixture of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)-N-methyl-carbamate (122 mg, 396.81 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 2 mL, 20.16 eq) . The mixture was stirred at 20-25 °C for 1 h. The reaction mixture was filtered, and the cake was dried over vacuum to give N-methyl- 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine (67.84 mg, 277.85 pmol, 70.0% yield, 99.85% purity, HC1 salt) as a purple solid.1H NMR (400 MHz, MeOD-d#) 8 = 3.61 - 3.48 (m, 1H), 3.25 (br dd, J = 5.1, 15.6 Hz, 1H), 2.93 - 2.81 (m, 3H), 2.80 (s. 3H), 2.76 - 2.57 (m, 4H). 2.50 - 2.39 (m, 2H). 2.32 - 2.22 (m, 1H), 1.95 (dddd, J = 6.4, 8.8, 10.2, 13.0 Hz, 1H). LCMS: m / z [M+H]+= 208.1

[0096] Procedure for preparation of 2,3,5,6,7,8-hexahydro-lH- cyclopentafb]benzothiophen-6-amine hydrochloride enantiomer 1 (12a)To the solution of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)carbamate (300 mg, 1.02 mmol, 1 eq) in EtOAc (5 mL) was added HCI / EtOAc (4 M, 5 mL, 19.56 eq) . The mixture was stirred at 20-25 °C for 1 h. The reaction mixture was filtered and the cake dried over vacuum to give 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine (12a) (190.8 mg, 830.40 pmol, 81.22% yield, 100% purity, HC1 salt) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ = 3.66 - 3.56 (m, 1H), 3.15 (br dd, J = 4.9, 15.5 Hz, 1H), 2.88 - 2.77 (m, 3H), 2.74 - 2.55 (m, 4H), 2.48 - 2.37 (m, 2H), 2.23 - 2.13 (m, 1H), 1.90 (dddd. J = 6.5, 8.9, 10.3, 12.9 Hz, 1H). LCMS: m / z |M+H|+= 194.1.

[0097] Procedure for preparation of 2,3,5,6,7,8-hexahydro-lH- cyclopentafblbenzothiophen-6-amine hydrochloride enantiomer 2 (12b)To the solution of tert-butyl N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen- 6-yl)carbamate (300 mg, 1.02 mmol, 1 eq) in EtOAc (5 mL) was added HCI / EtOAc (4 M, 5 mL, 19.56 eq). The mixture was stirred at 20-25 °C for 1 h. The reaction mixture was filtered and the cake was dried over vacuum to give 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine (205.34 mg, 893.68 pmol. 87.41% yield, 100% purity, HO salt) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ = 3.60 (dddd, J = 3.0, 5.3, 8.5, 10.4 Hz, 1H), 3.15 (br dd, J = 4.8, 15.8 Hz, 1H), 2.88 - 2.76 (m, 3H), 2.74 - 2.54 (m, 4H), 2.49 - 2.37 (m, 2H), 2.24 - 2.12 (m, 1H), 1.90 (dddd, J = 6.5, 8.8, 10.4, 12.9 Hz, 1H). LCMS: m / z [M+H]+= 194.1.

[0098] Synthetic Route for 1,3, 5, 6, 7,8-hexahydrobenzothiopheno[2,3-c]furan-6- amine hydrochloride enantiomer 1 (13a) and 1,3, 5, 6, 7, 8- hexahydrobenzothiopheno[2,3-c]furan-6-amine hydrochloride enantiomer 2 (13b)

[0099] Procedure for preparation of ethyl 2-aniino-6-(tert-butoxycarbanylaniino)-4,5,6.7-tetrahydrobenzothiophene-3-carboxylate (2)To a solution of tert-butyl N-(4-oxocyclohexyl)carbamate (10 g, 46.89 mmol, 10.00 mL, 1 eq) and ethyl 2-cyanoacetate (6.36 g, 56.27 mmol, 6.00 mL, 1.2 eq) in EtOH (150 mL) was added morpholine (4.90 g, 56.27 mmol, 4.95 mL, 1.2 eq) and S (2.1 g, 65.49 mmol, 1.40 eq). The mixture was stirred at 25 °C for 16hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford ethyl 2-amino-6- (tert-butoxycarbonylamino)-4,5,6,7-tetrahydro benzothiophene-3-carboxylate (2) (15 g, 44.06 mmol, 93.97% yield) as a yellow solid. LC-MS: m / z [M+H]+= 341.1.

[0100] Procedure for preparation of ethyl 2-bromo-6-(tert-butoxycarbonylamino}-To a solution of CuBr2(11.02 g, 49.35 mmol, 2.31 mL, 1.2 eq) in ACN (150 mL) was added t-BuONO (5.09 g, 49.35 mmol, 5.87 mL, 1.2 eq) stirred at 20 °C for 10 min. A solution of ethyl 2-amino-6-(tert-butoxycarbonylamino)-4,5.6.7-tetrahydrobenzothiophene-3-carboxylate (14 g, 41.12 mmol, 1 eq) in ACN (50 mL) was added to it over 30 min. The mixture was stirred at 20 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford ethyl 2-bromo-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3- carboxylate (3) (9.5 g, 19.03 mmol, 46.28% yield, 81% purity) as a yellow oil. LC-MS: m / z [M+H-Boc]+= 303.9

[0101] Procedure for preparation of diethyl 6-(tert-butoxycarbonylamino)-4,5.6.7- tetrahydrobenzothiophene-2,3-dicarboxylate ( 4)To a solution of ethyl 2-bromo-6-(tert-butoxycarbonylamino)-4, 5.6.7- tetrahydrobenzothiophene-3-carboxylate (9.5 g, 23.50 mmol, 1 eq) in EtOH (200 mL) was added TEA (4.76 g, 46.99 mmol, 6.54 mL, 2 eq) and Pd(dppf)CL (1.72 g, 2.35 mmol, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with CO 3 times. The mixture was stirred under CO (50 Psi ) at 60 °C for 16hr .The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-16% Ethyl acetate / Petroleum ether gradient @ 10OmL / min) to afford diethyl 6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-2,3- dicarboxylate (4) (7.8 g, 19.62 mmol, 83.52% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.62 (br d, J = 2.5 Hz, 1H), 4.39 (d, J = 7.1 Hz, 2H), 4.31 (d, J = 7.1 Hz, 2H), 4.09 - 4.02 (m, 1H), 3.15 (br dd, J = 4.7, 16.6 Hz, 1H), 2.81 - 2.60 (m, 3H), 2.05 - 1.96 (m, 1H), 1.91 - 1.76 (m, 1H), 1.46 (s, 9H), 1.41 - 1.36 (m, 2H), 1.37 - 1.31 (m, 4H); LC-MS: m / z [M+H -Boc]+= 296.0

[0102] Procedure for preparation of tert-butyl N-[2,3-bis(hydroxymethyl)-4,5,6,7- tetrahydro benzo thiophen-6-yllcarbamate (5)To a solution of diethyl 6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene- 2,3 -dicarboxylate (1.8 g, 4.53 mmol, 1 eq) in THF (20 mL) was added LiBH4 (4 M, 3.40 mF, 3 eq) and MeOH (0.5 mL) at 0 °C. The mixture was stirred at 0-25 °C for 16 hrs. The reaction mixture was poured into NH4CI saturated solution (50 mL) and extracted with EtOAc (30mLx2).The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl N-[2,3-bis(hydroxymcthyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]carbamate (1.2 g, 3.83 mmol, 84.55% yield) (5) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 = 5.17 (t, J = 5.6 Hz, 1H), 4.66 (t, J = 5.3 Hz. 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.32 - 4.21 (m, 2H), 3.71 - 3.56 (m, 1H), 3.36 - 3.33 (m, 1H), 3.30 (d, J = 1.6 Hz, 1H), 2.92 - 2.80 (m, 1H), 2.72 - 2.62 (m, 1H), 1.97 - 1.85 (m, 1H), 1.66 - 1.49 (m, 1H), 1.39 (s, 9H)

[0103] Procedure for preparation of 1,3,5.6.7.8--hexahxdrobenzothiophenol2,3- clfuran-6-amine (6)To the mixture of tert-butyl N-[2,3-bis(hydroxymethyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]carbamate (1 g, 3.19 mmol, 1 eq) in DCM (120 mL) was added MnO2(1.39 g, 15.95 mmol, 5 eq). The mixture was stirred at 25°C for 16 h. The reaction mixture was filtered. The filtrate was cooled to 0 °C and TFA (5.46 g, 47.86 mmol, 3.56 mL, 15 eq) was added. Then EtiSiH (1.67 g, 14.36 mmol, 2.29 mL, 4.5 eq) was added drop-wise. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-amine (6) (650 mg, crude) as a red gum.

[0104] Procedure for preparation of tert-butxl N-( 1,3,5.6.7.8 hexahydrobenzothiophenof2,3-c ]furan-6-yl)carbamate (7)To a solution of l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-ainine (650 mg, 3.33 mmol, 1 eq) in EtOAc (10 mL) and H2O (10 mL) was added NaHCCh (1.40 g, 16.64 mmol, 647.57 pL, 5 eq) and (Boc)2O (1 .45 g, 6.66 mmol, 1 .53 mL, 2 eq) .The mixture was stirred at 25 °C for 16hr . The reaction mixture was poured into H2O (5 mL) and extracted with EtOAc (30mLx2).The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acctatc / Pctrolcum ether gradient @ 30 mL / min) to afford tert-butyl N-( 1,3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-yl)carbamate (250 mg, 846.32 pmol, 25.43% yield) as a white solid. I I NMR (400 MHz. CHLOROFORM-d) 5 = 5.04 (t, J = 3.4 Hz. 2H), 4.95 - 4.83 (m, 2H), 4.66 (br d, J = 3.8 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.14 (br dd, J = 4.6, 15.9 Hz, 1H), 2.65 (br dd, J = 7.1, 16.4 Hz, 1H), 2.61 - 2.51 (m, 2H), 1.99 (tdd, J = 3.1, 6.3, 9.5 Hz, 1H), 1.90 - 1.75 (m, 1H), 1.46 (s, 9H); LC-MS: m / z [M+H-tBu]+= 240.0.

[0105] Procedure for preparation of tert-butyl N-( 1,3,5.6.7.8- hexahydrobenzothiophenof2,3-c]furan-6-yl)carbamate enantiomer 1 (7a) and enantiomer 2 (7b)The residue was separated by SEC (column: DAICEL CHIRALPAK IG (250mmx30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O )];B%:20%, isocratic elution mode) to afford tert-butyl N-( 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan- 6-yl)carbamate (7a) (120 mg, 406.23 pmol, 42.86% yield) as a white solid and tert-butyl N-(l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6-yl)carbamate (7b) (130 mg, 440.09 pmol, 46.43% yield) as a white solid.

[0106] Procedure for preparation of 1,3,5.6.7.8-hexahydrobenzothiophenof2,3- clfuran-6-amine Hydrochloride Enantiomer 1 (13a)To a solution of tert-butyl N-(l,3,5,6,7,8-hexahydrobenzothiopheno[2,3-c]furan-6- yljcarbamate (7a) (120 mg, 406.23 pmol, 1 eq) in EtOAc (1 mL) was added HCI / EtOAc (2 M, 2 mL, 9.85 eq) .The mixture was stirred at 25 °C for 2hr. The reaction mixture was concentrated under reduced pressure to remove EtOAc. Compound 1, 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine (13a) (91.91 mg, 392.64 pmol, 96.65% yield, 99% purity. HCI) was obtained as a white solid. 1H NMR (400 MHz.METHANOL-d4) 5 = 4.99 (br d, J = 3.4 Hz, 2H), 4.84 (br s, 2H), 3.70 - 3.59 (m, 1H), 3.21 (br dd, .1 = 4.8, 15.8 Hz, 1H), 2.93 - 2.81 (m, 1H), 2.73 - 2.60 (m, 2H), 2.25 - 2.13 (m, 1H), 1.98 - 1.85 (m, 1H); LC-MS: m / z [M+H]+= 196.1.

[0107] Procedure for preparation of l,3,5,6,7,8-hexahydrobenzothiopheno[2,3- c]furan-6-amine Hydrochloride Enantiomer 2 (13b)7b 13bTo a solution of tert-butyl N-( 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan-6- yl)carbamate (7b) (130 mg, 440.09 pmol, 1 eq) in EtOAc (1 mL) was added HCI / EtOAc (2 M, 2 mL, 9.09 eq) .The mixture was stirred at 25 °C for 2hr . The reaction mixture was concentrated under reduced pressure to remove EtOAc. Compound 1, 3, 5, 6,7,8- hexahydrobenzothiopheno|2,3-c|furan-6-amine (13b) (99.77 mg, 426.22 pmol, 96.85% yield, 99% purity, HCI) was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) 5 = 4.99 (br d, J = 3.4 Hz, 2H), 4.84 (br s, 2H), 3.69 - 3.59 (m, 1H), 3.20 (br dd, J = 5.1, 16.4 Hz, 1H), 2.86 (br dd, J = 9.1, 16.1 Hz, 1H), 2.75 - 2.60 (m, 2H), 2.24 - 2.13 (m, 1H). 1.99 - 1.86 (m, 1H); LC-MS: m / z [M+H]+= 196.1.

[0108] Synthetic route to N-methyl-4,12-dioxa-7-thiatricyclo[6.4.0.02’6]dodeca- 1(8), 2(6)-dien-10-amine hydrochloride, enantiomer 1 (14a) and N-methyl-4,12-dioxa- 7-thiatricyclo[6.4.0.02’6]dodeca-l(8),2(6)-dien-10-amine hydrochloride, enantiomer 2 (14b)To a solution of 4-bromothiophene-3-carboxylic acid (25 g, 120.75 mmol, 1 eq) and HMPA (5.41 g, 30.19 mmol, 5.28 mL, 0.25 eq) in THF (500 mL) was added dropwise LDA (2 M, 241.49 mL, 4 eq) at -78°C under atmosphere. After addition, the mixture was stirred at -78 for Ihr, and then CO2 (5.31 g, 120.75 mmol, 1 eq) was added. The resulting mixture was stirred at -78 °C for 2hr. The reaction mixture was quenched with sat.NlLCl 100 mL and adjusted pH with HC1(1N) to 1. The reaction mixture extracted with EtOAc (100mLx2). The combined organic layers were washed with sat. NaCl (10OmL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 4-bromothiophene-2,3-dicarboxylic acid (30 g, crude) was obtained as a yellow oil. LCMS: m / z [M+H]+ =250.8 / 252.9.

[0110] Procedure for preparation of f4-bromo-2-(hydroxymefhyl)-3- thienyllmethanol (3)To a solution of 4-bromothiophene-2,3-dicarboxylic acid (30 g, 119.50 mmol, 1 eq) and 4-bromothiophene-2,3,5-tricarboxylic acid (35.26 g, 119.50 mmol, 1 eq) in THF (300mL) was added BH3-Me2S (10 M, 35.85 mL, 3 eq). The mixture was stirred at 60 °C for 16hr. The reaction was quenched by addition of 50 mL of methanol at 0°C and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 0-55% Ethyl acetate / Petroleum ethergradient @ 40 mL / min). Compound [4-bromo-2- (hydroxymelhyl)-3-thienyl]melhanol (7.2 g, 32.27 mmol, 27.01% yield) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.02 (s, 1H), 6.09 (t, J = 5.6 Hz, 1H), 5.44 (t, J = 5.4 Hz, 1H), 5.24 (d, J = 5.6 Hz, 2H), 4.89 (d, J = 5.4 Hz, 2H).

[0111] ration of 3-bromo-4,6-dihydrothieno[2,3-c]furan (4) 1 ). MnO2, DCM, rt, 16 h 4 jT ° 2). TFA, Et3SiH, O~rt, 2 hBr3 4To a solution of [4-bromo-2-(hydroxymethyl)-3-thienyl]methanol (7.2 g, 32.27 mmol. 1 eq) in DCM (140 mL) was added MnO2 (14.03 g, 161.37 mmol, 5 eq). The mixture was stirred at 25 °C for 16hr. The reaction mixture was filtered. The filtrate was cooled to 0 °C and TFA (55.20 g, 484.12 mmol, 35.96 mL, 15 eq) was added. Then Et3SiH (18.76 g, 161.37 mmol, 25.77 mL, 5 eq) was added drop-wise. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with sat.NaHCO3 100 mL and extracted with DCM (50mLx2). The combined organic layers were washed with satNaCl (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound 3-bromo-4,6-dihydrothieno[2,3-c]furan (2.8 g, 13.65 mmol, 42.31% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 8 = 7.19 (s, 1H), 5.17 - 5.11 (m, 2H), 4.96 - 4.91 (m, 2H).

[0112] Procedure for preparation of 3-bromo-4,6-dihvdrothienof2,3-c]furan-2- carboxylic acid (5)To a solution of 3-bromo-4,6-dihydrothieno[2,3-c]furan (2.3 g, 11.22 mmol, 1 eq) inTHF (20 mL) was added dropwise LDA (2 M, 7.29 mL, 1.3 eq) at -78°C and purgedwith N2 for 3 times. After addition, the mixture was stirred at -78°C for Ihr, and then CO2 (493.59 mg, 11.22 mmol, 1 eq) was added at -78°C. The resulting mixture was stirred at -78°C for 2hr. The reaction mixture was quenched with sat.NITiCl 50 mL, The pH of the aqueous phase was adjusted to 1 with HC1( IN) and extracted with EtOAc (30mLx2). The combined organic layers were washed with sat.NaCl (10mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Compound 3-bromo-4,6-dihydrothieno[2,3-c]furan-2-carboxylic acid (2.6 g, crude) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 13.90 - 13.00 (m, 1H), 5.27 - 4.99 (m, 2H), 4.95 - 4.80 (m, 2H); LCMS: m / z [M+H]+ =249.0 / 250.9.

[0113] Procedure for preparation of (3-bromo-4,6-dihydrothienof2,3-c]furan-2-To a solution of 3-bromo-4,6-dihydrothieno[2,3-c]furan-2-carboxylic acid (2.6 g, 10.44 mmol, 1 eq) in THF (30 mL) was added BH3-Me2S (10 M, 5.22 mL, 5 eq) at 0°C and purged with N23 times .The mixture was stirred at 60 °C for Ihr. The reaction was quenched by addition of 20 mL of methanol at 0°C and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound (3-bromo-4,6-dihydrothieno[2,3-c]furan-2- yljmethanol (1.3 g, 5.53 mmol, 52.97% yield) was obtained as a white solid. 1H NMR (400 MHz. CHLOROFORM-d) 5 = 5.18 - 5.08 (m, 2H), 4.98 - 4.88 (m, 2H), 4.76 (s, 2H)

[0114] Procedure for preparation of 3-bromo-2-(bromomethyl)-4,6- dihydrothienof2,3-c]furan (7)To a solution of (3-bromo-4,6-dihydrothieno[2.3-c]furan-2-yl)methanol (1.5 g, 6.38 mmol, 1 eq) in DCM (15 mL)was added PBr3 (2.59 g, 9.57 mmol, 1.5 eq) .The mixture was stirred at 0 °C for Ihr. The reaction mixture was quenched with sat.NaHCCh 10 mL and extracted with DCM (10mLx2). The combined organic layers were washed withsat.NaCl (10mL), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure to give a residue. Compound 3-bromo-2-(bromomethyl)-4,6-dihydrothieno[2,3- c]furan (1.6 g, crude) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 5.15 - 5.09 (m, 2H), 4.96 - 4.90 (m, 2H), 4.66 (s, 2H).

[0115] Procedure for preparation of methyl 3-(3-bromo-4,6-dihydrothienof2,3- c lfuran-2-yl)-2-ftert-butoxycarbonyl( methyl)amino]propanoate (8)To a solution of LDA (2 M, 4.03 mL, 1.5 eq) in THF (20 mL) was added dropwise methyl 2-[tert-butoxycarbonyl(methyl)amino]acetate ( 1.64 g, 8.05 mmol. 1.5 eq)at - 78°C, after addition, the mixture was stirred at -78°C for 1 hr, and then 3-bromo-2- (bromomethyl)-4,6-dihydrothieno[2,3-c]furan (1.6 g, 5.37 mmol, 1 eq) in THF (10 mL) was added at -78°C. The resulting mixture was stirred at 25°C for 15 hr under N2. The reaction mixture was quenched with sat.NH4Cl 50 mL and extracted with EtOAc (30mLx2). The combined organic layers were washed with sat.NaCl solution (20mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (IS CO®; 20g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound methyl 3-(3-bromo-4,6-dihydrothieno|2,3-c|furan- 2-yl)-2-[tert-butoxycarbonyl(methyl)amino]propanoate (1.8 g, 4.28 mmol, 79.76% yield) was obtained as a colorless oil. LCMS: m / z [M+H-Boc]+ =321.9.

[0116] Procedure for preparation of tert-butyl N-fl-f(3-bromo-4,6- dihydrothienol2,3-c ]furan-2-yl}methyl]-2-hydroxy-ethyl]-N-methyl-carbamate ( 9)To a solution of methyl 3-(3-bromo-4,6-dihydrothieno[2,3-c]furan-2-yl)-2-[tert- butoxycarbonyl(methyl)amino]propanoate (1.8 g. 4.28 mmol, 1 eq) in THE (20 mL) was added dropwise LiBH4 (4 M, 4.28 mL, 4 eq) at 0 °C. After addition, the mixture wasstirred at 0°C for 10 min, and then MeOH (2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0°C for 2hr. The reaction mixture was quenched with sat.NH4Cl 20 mL and extracted with EtOAc (30mLx2). The combined organic layers were washed with sat.NaCl (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound tert-butyl N-[l-[(3- bromo-4,6-dihydrothieno[2,3-c]furan-2-yl)methyl]-2-hydroxy-ethyl]-N-methyl- carbamate (1.2 g, 3.06 mmol, 71.43% yield) was obtained as a colorless oil. LCMS: m / z [M+Na]+ =414.1 / 416.0.

[0117] Procedure for preparation of tert-butyl N-(4,12-dioxa-7- thiatricyclo[6.4.0.O2’6ldodeca-l(8),2(6)-dien-10-yl)-N-methyl-carbamate (10)BrettPhos Pd G4, Cs2CO3dioxane, 90 °C, 16 hA mixture of tert-butyl N-[l-[(3-bromo-4,6-dihydrothieno[2,3-c]furan-2-yl)methyl]-2- hydroxy-ethyl]-N-methyl-carbamate (1.2 g, 3.06 mmol, 1 eq), BrettPhos Pd G4 (281.57 mg, 305.88 pmol, 0.1 eq) and Cs2CO3 (2.99 g, 9.18 mmol, 3 eq) in dioxane (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16hr under N2 atmosphere. The reaction mixture was diluted with H2O 100 mL and extracted with EtOAc (50mLx2). The combined organic layers were washed with sat.NaCl (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl N-(4,12-dioxa-7- thiatricyclo|6.4.0.02,6Jdodeca-l(8),2(6)-dien-10-yl)-N-methyl-carbamate (760 mg, 2.44 mmol, 79.8% yield) was obtained as a yellow oil.NMR (400 MHz, CHLOROFORM- d) 8 = 5.01 (br d, J = 1.7 Hz, 2H), 4.91 - 4.86 (m, 2H), 4.62 - 4.35 (m, 1H), 4.20 - 4.03 (m, 3H), 2.94 (br s, 2H), 2.83 (s, 3H), 1.49 (s, 9H); LCMS: m / z [M+H-tBu]+ =256.0.

[0118] Procedure for preparation of tert -butyl N-(4,12-dioxa-7- thiatricvclof6.4.0.02’6ldodeca-l(8},2( 6)-dien-10-yl)-N-methyl-carbamate enantiomer 1 (10a) and enantiomer 2 ( 10b}The residue (250 mg) was separated by SFC (column: DAICEL CHIRALPAK IC(250mmx30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:20%, isocratic elution mode ). Compound tcrt-butyl N-(4,12-dioxa-7-thiatricyclo[6.4.0.02,6]dodcca- l(8),2(6)-dien-10-yl)-N-methyl-carbamate (10a) (91 mg, 292.23 pmol, 35.0% yield) was obtained as a colorless oil. Compound tert-butyl N-(4,12-dioxa-7- thiatricyclo[6.4.0.02, 6]dodeca-l(8),2(6)-dien-10-yl)-N-methyl-carbamate (10b) (93 mg, 298.66 pmol, 35.77% yield) was obtained as a colorless oil.

[0119] Procedure for preparation of N-methyl-4,12-dioxa-7- thiatricyclof6.4.0.02’6]dodeca-l(8},2(6}-dien-10-amine hydrochloride enantiomer 1 (14aiTo a solution of tert-butyl N-(4,12-dioxa-7-thiatricyclo[6.4.0.02,6]dodeca-l(8),2(6)-dien- 10-yl)-N-methyl-carbamate (91 mg, 292.23 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2 mL, 13.69 eq).The mixture was stirred at 25 °C for Ihr. The mixture was concentrated. The product was triturated with EtOAc (2ml) at 25 °C for 10 min. The mixture was followed by filtration, the filter cake was dried. Compound N-methyl-4,12- dioxa-7-thiatricyclo[6.4.0.02,6]dodeca-l(8),2(6)-dien-10-amine (47.71 mg, 191.35 pmol, 65.48% yield. 99.36% purity, HC1) was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) 5 = 4.97 (br s, 2H), 4.86 (br s, 2H), 4.54 - 4.47 (m, 1H), 4.24 (d, J = 12.5 Hz, 1H), 3.82 (br d, J = 1.8 Hz, 1H), 3.38 - 3.32 (m, 1H), 3.00 (br d, J = 17.6 Hz, 1H), 2.82 (s, 3H); LCMS: m / z [M+H]+ =212.2.

[0120] Procedure for preparation of N-methyl-4,12-dioxa-7- thiatricyclo[6.4.0.()2’6]dodeca-l(8),2( 6}-dien-10-amine hydrochloride enantiomer 2 O4blTo a solution of tert-butyl N-(4,12-dioxa-7-thiatricyclo[6.4.0.02,6]dodeca-l(8),2(6)-dien- 10-yl)-N-methyl-carbamate (91 mg, 292.23 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2 mL, 13.69 eq).The mixture was stirred at 25 °C for Ihr. The product was triturated with EtOAc(2ml) at 25 °C for 10 min, followed by filtration, the filter cake was dried. Compound N-methyl-4,12-dioxa-7-thiatricyclo[6.4.0.02.6]dodeca-l(8).2(6)- dien- 10-amine (42.33 mg, 167.02 pmol, 57.2% yield, 97.75% purity, HO) was obtained as a yellow solid. 1H NMR (400 MHz, METHANOL-d4) 8 = 4.97 (br s, 2H), 4.86 (br s, 2H), 4.54 - 4.46 (m, 1H), 4.24 (d, J = 12.5 Hz, 1H), 3.82 (br d, J = 1.5 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.00 (br d, J = 17.3 Hz, 1H), 2.82 (s, 3H). LCMS: m / z [M+H]+ =212.2.

[0121] Synthetic route to N-methyl-3,4,5,6,7,8-hexahydro-lH-benzothiopheno[2,3- c]pyran-7 -amine hydrochloride enantiomer 1 (15a) and N-methyl-3,4,5,6,7,8- hexahydro-lH-benzothiopheno[2,3-c]pyran-7-amine hydrochloride enantiomer 2 (15b)

[0122] Procedure for preparation of ethyl 2-amino-6-(benzyloxycarbonylamino)-4,5,6, 7-tetrahydrobenzothiophene-3-carboxylate (2)To a solution of benzyl N-(4-oxocyclohexyl)carbamate (36 g, 145.58 mmol, 1 eq) and ethyl 2-cyanoacetate (19.76 g, 174.69 mmol, 18.62 mL, 1.2 eq) in EtOH (450 mL) was added morpholine (15.22 g, 174.69 mmol, 15.37 mL, 1.2 eq) and S (5.74 g, 178.98 mmol, 1.23 eq).The mixture was stirred at 25 °C for 16hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The crude product was triturated with PE: EA=3:1 at 25 °C for 30 min. The mixture was followed by filtration, the filter cake was dried to afford ethyl 2-amino-6-(benzyloxycarbonylamino)-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (45 g, 120.18 mmol, 82.55% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.40 - 7.29 (m, 5H), 5.11 (s, 2H), 4.95 - 4.85 (m, 1H), 4.27 (q, .1 = 7.3 Hz, 2H), 4.18 - 4.06 (m, 1H), 2.95 - 2.86 (m, 1H), 2.85 - 2.79 (m, 2H), 2.51 - 2.39 (m, 1H), 2.01 - 1.88 (m, 2H), 1.86 - 1.74 (m, 2H). LC- MS: m / z [M +H]+= 375.1.

[0123] Procedure for preparation of ethyl 6-(benzyloxycarbonylamino)-4,5,6,7-To a solution of ethyl 2-amino-6-(benzyloxycarbonylamino)-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (25 g, 66.76 mmol, 1 eq) in EtOH (300 mL) was added t-BuONO (8.26 g. 80.12 mmol, 9.53 mL, 1.2 eq) and Cu(OAc)2(18.19 g. 100.15 mmol, 1.5 eq) at 0°C.The mixture was stirred at 60°C for 2hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to afford ethyl 6-(benzyloxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3- carboxylate (13.6 g, 37.84 mmol, 56.67% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 8 = 7.95 (s, 1H), 7.43 - 7.30 (m, 5H), 5.22 - 5.04 (m, 2H), 4.87 (br d, J = 7.1 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.22 - 4.07 (m, 1H), 3.23 - 3.10 (m, 1H).3.01 (br s, 2H), 2.70 (br dd. J = 6.2, 16.4 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.93 - 1.81 (m, 1H), 1.36 (t, J = 7.2 Hz. 3H). LC-MS: m / z [M-tBu+H]+= 314.0.

[0124] Procedure torn reparation of ethyl 6-fbenzyloxycarbonyl(methyPaminol-4,5,6.7-tetrahydrobenzothiophene-3-carboxylate (4)To a solution of ethyl 6-(benzyloxycarbonylamino)-4,5,6,7-tetrahydrobenzothiophene-3- carboxylate (13.6 g, 37.84 mmol, 1 eq) in DMF (200 mL) was added dropwise NaH (2.27 g, 56.76 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 hr, and then CH3I (8.06 g, 56.76 mmol, 3.53 mL, 1.5 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 0-25 °C for 1.5hr. The reaction mixture was poured into NH4CI saturated solution (100 mL) and extracted with EtOAc (100mLx2). Combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 100 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to afford ethyl 6-[benzyloxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (13 g, 34.81 mmol, 92.00% yield) as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) 8 = 7.94 (s. 1H), 7.42 - 7.30 (m, 5H). 5.17 (s, 2H), 4.61 - 4.38 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.27 (br dd, J = 4.3, 17.3 Hz, 1H), 2.93 - 2.77 (m, 6H), 2.05 - 1.79 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0125] Procedure for preparation of 6-[benzyloxycarbonyl(methyl)amino]-4,5,6,7- tetrahydrobenzothiophene-3-carboxylic acid (5)Cbz CbzTo a solution of ethyl 6-[benzyloxycarbonyl(methyl)amino]-4,5,6,7- tetrahydrobenzothiophene-3-carboxylate (13 g, 34.81 mmol, 1 eq) in MeOH (130 mL) was added NaOH (4.18 g, 104.43 mmol, 3 eq) and H2O (40 mL) .The mixture was stirred at 60 °C for Ihr. The reaction mixture was concentrated under reduced pressure toremove MeOH. 1 M HC1 aqueous solution was added into the mixture to adjust pH to 5, followed by filtration, the filter cake was concentrated to afford 6- [benzyloxycarbonyl(methyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (12 g, 34.74 mmol, 99.80% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 8 = 8.07 (s, 1H), 7.45 - 7.28 (m, 5H), 5.18 (s, 2H), 4.61 - 4.32 (m, 1H), 3.28 (br dd, J = 3.6, 16.9 Hz, 1H), 3.01 - 2.77 (m, 6H), 2.07 - 1.82 (m, 2H).

[0126] Procedure for preparation of benzyl 3-chlorocarbt)nyl-4, 5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate ( 6)To a solution of 6-[benzyloxycarbonyl(methyl)amino]-4.5,6,7- tetrahydrobenzothiophene-3-carboxylic acid (12 g, 34.74 mmol. 1 eq) in DCM (150 mL) was added DMF (190.00 mg, 2.60 mmol, 0.2 mL) and SOCh (4.55 g, 38.22 mmol, 2.78 mL, 1.1 eq) at 0°C.The mixture was stirred at 0~30°C for 3 hr. The reaction mixture was concentrated under vacuum. The crude product benzyl N-(3-chlorocarbonyl-4, 5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate (15 g. crude) was used in the next step without further purification.

[0127] Procedure for preparation of benzyl N-[3-(2-diazoacetyl)-4,5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (7)To a solution of benzyl N-(3-chlorocarbonyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)-N- methyl-carbamate (15 g, 41.22 mmol, 1 eq) in ACN (100 mL) ang THF (100 mL) was added TEA (8.34 g, 82.45 mmol, 11.48 mL, 2 eq) and TMSCHN2 (2 M, 24.73 mL, 1.2 eq) at 0°C.The mixture was stirred at 25 °C for 32 hr. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford benzyl N-[3-(2-diazoacetyl)-4,5,6,7-tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (9.5 g, 25.71 mmol, 62.38% yield, N / A purity) as a yellow oil. LC-MS: m / z [M+Na]+= 392.2

[0128] Procedure for preparation of methyl 2-!6- fbenzyloxycarbonyU methyl)aminol-4,5, 6, 7-tetrahydrobenzothiophen-3-yl lacetate ( 8)To a solution of benzyl N-[3-(2-diazoacetyl)-4,5,6,7-tetrahydrobenzothiophen-6-yl]-N- methyl-carbamate (8.5 g, 23.01 mmol, 1 eq) in MeOH (100 mL) was added Ag2O (1.07 g, 4.60 mmol, 0.2 eq). The mixture was stirred at 60 °C for 16hr . The reaction mixture was filtered and the cake was washed with EtOAc (10 mL). The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford methyl 2- [6- [benzyloxycarbonyl(methyl)amino]-4,5.6.7-tetrahydrobenzothiophen-3-yl]acetate (4.7 g, 12.58 mmol, 54.70% yield, N / A purity) as a yellow oil.!H NMR (400 MHz, CHLOROFORM-d) 8 = 7.42 - 7.30 (m, 5H), 6.96 (s, 1H), 5.17 (s, 2H), 4.61 - 4.37 (m,1H), 3.71 (s, 3H), 3.51 (d, J = 1.4 Hz, 2H), 2.89 (br s, 5H), 2.76 - 2.51 (m, 2H). 2.02 -1.84 (m, 2H).

[0129] Procedure for preparation of benzyl N-l3-(2-hydroxyethyl)-4,5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate ( 9)CbzTo a solution of methyl 2-[6-[benzyloxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophen-3-yl]acetate (4.7 g, 12.58 mmol, 1 eq) in THF (50 ml.) was added LiBH4 (4 M, 15.73 mL, 5 eq) and MeOH (1 mL) at 0°C.The mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into NH4CI saturated solution (50 mL) and extracted with EtOAc (50mLx2).The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford benzyl N-[3-(2-hydroxyethyl)- 4,5,6,7-tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (4.3 g, 12.45 mmol, 98.91% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.43 - 7.29 (m, 5H), 6.85 (s, 1H), 5.17 (s, 2H), 4.65 - 4.32 (m, 1H), 3.92 - 3.73 (m, 2H), 2.90 (br s, 5H). 2.81 - 2.68 (m, 3H), 2.68 - 2.52 (m. 1H), 2.03 - 1.86 (m. 2H).

[0130] Procedure for preparation of benzyl N-(3,4,5,6,7,8-hexahydro-lH- benzothiophenof2,3-cIpyran-7-yl)-N-methyl-carbamate (10)A mixture of benzyl N-[3-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzothiophen-6-yl]-N- methyl-carbamate (1.8 g, 5.21 mmol, 1 eq), Paraformaldehyde (390.79 mg, 13.03 mmol, 2.5 eq), Bi(OTf)3 (341.91 mg, 521.05 pmol, 0.1 eq) in Tol. (60 mL) was degassed and purged with N23 times, and then the mixture was stirred at 80 °C for 16hr under N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50mLx2). Combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) and purified by prep-HPLC (column: Waters Xbridge 150x25mmx5pm;mobile phase: [water( NH4HCO3)-ACN];gradient:54%-84% B over 9 min) to afford benzyl N- (3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-yl)-N-methyl-carbamate (70 mg, 195.82 pmol, 3.76% yield) as a white solid. LC-MS: m / z [M +H]+= 358.1.

[0131] Procedure for preparation of benzyl \'-(3,4,5,6,7,8-hexah\dro-l II- benzothiopheno[2,3-c]pyran-7-yl)-N-methyl-carbamate enantiomer 1 (10a) and enantiomer 2 (10b)The residue was separated by SFC (column: DAICEL CHIRALCEL OX (250mmx30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O )];B%:40%, isocratic elution mode) to afford benzyl N-(3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3- c]pyran-7-yl)-N-methyl-carbamate (10a) (33 mg, 92.32 pmol, 47.14% yield) and benzyl N-(3.4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-yl)-N-methyl-carbamate (10b) (30 mg, 83.92 μmol, 42.86% yield).

[0132] Procedure for preparation of -niethxl-3.4.5.6.7.8-hexah\dro-l like uz.ot hit >phe no! 2,3- c lpyran-7 -amine hydrochloride enantiomer 1 (15a)10a 15aTo a solution of benzyl N-(3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-yl)- N-methyl-carbamate (33 mg, 92.32 jamol, 1 eq) in MeOH (10 mL) was added Pd / C (19.65 mg, 18.46 pmol. 10% purity, 0.2 eq) and NH3.H2O (8.74 mg, 92.32 pmol, 9.61 pL, 37% purity, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (30 Psi ) at 25 °C for 5hr . The mixture was followed by filtration, the filtrate was concentrated was concentrated. The residue was purified by prep-HPLC (column: Agela DuraShell C18 150x25mmx5um;mobile phase: [water(HCl)-ACN];gradient:0%-30% B over 20 min) to afford N-methyl-3,4,5,6,7,8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine (15a) (2.59 mg, 9.87 pmol, 10.69% yield, 99% purity, HC1) as a white solid.NMR (400 MHz, METHANOL-d4) 5 = 4.70 (s, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.61 - 3.51 (m, 1H), 3.25 (br dd, J = 4.7, 16.1 Hz, 1H), 2.86 (br dd, J = 8.8, 15.3 Hz, 1H), 2.79 (s, 3H), 2.73 - 2.58 (m, 2H), 2.58 - 2.47 (m, 2H), 2.34 - 2.22 (m, 1H), 1.94 (dtd, .1 = 6.2, 9.6, 12.8 Hz, 1H). LC-MS: m / z [M+H]+= 224.1.

[0133] Procedure for preparation of N-methyl-3,4,5,6,7,8-hexahydro-lH- benzothiopheno[2,3-c]pyran-7-amine Hydrochloride Enantiomer 2 (15b)To a solution of benzyl N-(3.4,5.6.7.8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-yl)-N-methyl-carbamate (30 mg, 83.92 jjmol, 1 eq) in MeOH (10 mL) was added Pd / C (17.86 mg, 16.78 pmol, 10% purity, 0.2 eq) and NH3.H2O (7.95 mg, 83.92 pmol, 8.74 pL, 37% purity, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (30 Psi) at 25 °C for 5hr . The mixture was followed by filtration, the filtrate was concentrated was concentrated. The residue was purified by prep-HPLC (column: Agela DuraShell C18 150x25mmx5um;mobile phase: [water(HCl)-ACN];gradient:0%-30% B over 20 min) to afford N-methyl-3.4.5.6.7.8-hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine (2.45 mg, 9.34 pmol,11.12% yield, 99% purity, HC1) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 = 4.70 (s, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.62 - 3.51 (m, 1H), 3.25 (br dd, J = 5.0, 16.3 Hz, 1H), 2.85 (br dd, J = 8.1, 15.8 Hz, 1H), 2.79 (s, 3H), 2.73 - 2.59 (m, 2H), 2.54 (br d, J = 2.3 Hz. 2H), 2.32 - 2.23 (m, 1H). 2.00 - 1.88 (m, 1H); LC-MS: m / z [M+H]+= 224.1.

[0134] Synthetic Route for N-methyl-3,4,6, 7,8,9-hexahydro-lH- benzothiopheno[3,2-c]pyran-7-amine hydrochloride enantiomer l(16a) and N-methyl-3.4.6.7.8.9-hexahydro-lH-benzothiopheno[3,2-c]pyran-7-amine hydrochloride

[0135] Procedure for preparation of ethyl 2-amino-6-ftert- butoxycarbonyl(methyl)aminol-4,5, 6, 7-tetrahvdrobenzothiophene-3-carboxylate ( 2 )A mixture of tert-butyl N-methyl-N-(4-oxocyclohexyl)carbamate (50 g. 219.97 mmol. 1 eq), ethyl 2-cyanoacetate (29.86 g, 263.97 mmol, 28.14 mL, 1.2 eq), morpholine (23.00 g, 263.97 mmol, 23.23 mL, 1.2 eq) and S8 (8.46 g, 263.97 mmol, 1.2 eq) in EtOH (500 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16hr under N2 atmosphere. The reaction mixture was concentrated. The product was triturated with EtOAc (100ml) at 25°C for 30 min. The mixture was followed by filtration, the filter cake was dried. Compound ethyl 2-amino-6-[tert- butoxycarbonyl(methyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (69 g, crude) was obtained as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 = 5.97 (br s, 2H), 4.27 (q. J = 7.1 Hz. 3H). 3.04 (br dd, J = 4.5, 17.2 Hz, 1H), 2.79 (s, 3H), 2.74 - 2.51 (m, 3H), 1.95 - 1.72 (m, 2H), 1.48 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H); LC-MS: m / z [M +H]+= 355.1.

[0136] Procedure for preparation of ethyl 2-bromo-6-[tert- butoxxcarbonxl(inethxl)ainino 1-4,5, 6, 7-tetrahxdrobenzothiophene-3-carboxxlate ( 3 )To a solution of CuBn (15.12 g, 67.71 mmol, 3.17 mL, 1.2 eq) in ACN (200 mL) was added t-BuONO (6.98 g, 67.71 mmol, 8.05 mL, 1.2 eq)stirred at 0 °C for 10 min. A solution of ethyl 2-amino-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (20 g, 56.42 mmol. 1 eq) in ACN (200 mL) was added. The mixture was stirred at 25 °C for 2 hr. The reaction filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound ethyl 2-bromo-6-[tert- butoxycarbonyl(methyl)amino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (10.8 g, 25.82 mmol, 45.75% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) 8 = 4.35 (br dd, J = 3.3, 7.1 Hz, 2H), 3.08 (br dd, J = 4.2, 16.7 Hz,1H), 2.94 - 2.66 (m, 7H), 1.95 - 1.80 (m, 2H), 1.48 (s, 9H). 1.39 (t, J = 7.2 Hz, 3H); LC- MS: m / z [M +H]+= 440.1 / 442.

[0137] Procedure for preparation of dimethyl 2-f6-ftert- butoxycarbonyl(methyl)amino]-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophen-2-A mixture of ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (10.8 g, 25.82 mmol, 1 eq), dimethyl propanedioate (6.82 g, 51.63 mmol, 5.92 mL, 2 eq), Cui (491.67 mg, 2.58 mmol, 0.1 eq), CS2CO3 (25.23 g, 77.45 mmol, 3 eq) and pyridine- 2-carboxylic acid;hydrochloride (411.95 mg, 2.58 mmol, 0.1 eq) in dioxane (100 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash®Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound dimethyl 2-[6-[tert-butoxycarbonyl(methyl)amino]-3- ethoxycarbonyl-4,5,6,7-tetrahydrobenzothiophen-2-yl]propanedioate (3 g, 6.38mmol, 24.74% yield) was obtained as a yellow oil. LC-MS: m / z [M+Na]+= 492.3.

[0138] Procedure for preparation of 6-ftert-butoxycarbonyl(methyl)aminol-2- (carboxymethyl)-4,5,6, 7-tetrahydrobenzothiophene-3-carboxylic acid (5)To a solution of dimethyl 2-[6-[tert-butoxycarbonyl(methyl)amino]-3-ethoxycarbonyl- 4,5,6,7-tetrahydrobenzothiophen-2-yl]propanedioate (3 g, 6.39 mmol, 1 eq) in MeOH (20 mL) and H2O (20 mL) was added NaOH (1.28 g, 31.95 mmol. 5 eq). The mixture was stirred at 40 °C for 16hr. The reaction mixture was diluted with H2O 10 mL and concentrated under vacuum to remove MeOH. The separated aqueous phase wasadjusted pH with HC1 (IN) to 3-4. There were solids separated out, filtered and the cake was washed with H2O (10mL). The crude product was used into next step without further purification. Compound 6-[tert-butoxycarbonyl(methyl)amino]-2-(carboxymethyl)- 4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid (1.7 g, 4.60 mmol, 72.02% yield) was obtained as a yellow solid. LC-MS: m / z [M+Na]+= 392.0.

[0139] Procedure for preparation of tert-butyl N-f2-(2-hydroxyethyl)-3-(hydroxymethyl)-4,5,6, 7-tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate ( 6)To a solution of 6-[tert-butoxycarbonyl(methyl)amino]-2-(carboxymethyl)-4, 5.6.7- tetrahydrobenzothiophene-3-carboxylic acid (1.7 g, 4.60 mmol, 1 eq) in THF (20 mL) was added dropwise BH3-Me2S (10 M, 1.38 mL, 3 eq) at 0°C under N2 atmosphere. After addition, the mixture was stirred at 0°C for 10min, and then the resulting mixture was stirred at 60°C for Ihr. The reaction was quenched by addition of 10 mL of methanol at 0°C and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl N-[2-(2-hydroxyethyl)-3-(hydroxymethyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (900 mg, 2.64 mmol, 57.28% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.45 (s, 3H), 3.91 - 3.75 (m, 2H), 3.04 (br t, J = 5.3 Hz, 2H), 2.90 - 2.61 (m, 7H), 1.92 - 1.83 (m, 2H), 1.48 (s, 9H). LC-MS: m / z [M +Na]+= 364.1.

[0140] Procedure for preparation of tert-butyl N-(3,4,6,7,8,9-hexahydro-lH- benzothiophenof3,2-c]pyran-7-yl}-N-methyl-carbamate (7)To a solution of tert-butyl N-[2-(2-hydroxyethyl)-3-(hydroxymethyl)-4, 5.6.7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (900 mg, 2.64 mmol, 1 eq) in DCM (18 mL) was added MnCL (1.15 g, 13.18 mmol, 5 eq). The mixture was stirred at 25°Cfor 16h. The reaction mixture was filtered. The filtrate was cooled to 0 °C and Et3SiH (1.53 g, 13.18 mmol, 2.10 mL, 5 eq) was added. Then TFA (4.51 g, 39.54 mmol. 2.94 mL, 15 eq) was added drop- wise. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with sat. NaHCO310 mL. To a reaction mixture was added NaHCO3(664.25 mg, 7.91 mmol, 307.67 pL, 3 eq) and (BochO (1.15 g, 5.27 mmol, 1.21 mL, 2 eq) in EtOAc (10 mL) and H2O (10 mL). The mixture was stirred at 25°C for 2h. The reaction mixture was extracted with EtOAc (30mLx2). The combined organic layers were washed with sat.NaCl (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaElash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx()um;mobile phase: [water(FA)-ACN];gradient:58%-88% B over 11 min). Compound tert-butyl N- (3,4,6,7,8,9-hcxahydro-1H-bcnzothiophcno[3,2-c]pyran-7-yl)-N-mcthyl-carbamatc (400 mg, 1.24 mmol, 46.92% yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.56 (d, J = 1.3 Hz, 2H), 4.49 - 4.21 (m, 1H), 4.00 - 3.89 (m, 2H), 2.81 (br s, 7H), 2.56 - 2.46 (m, 2H), 1.96 - 1.81 (m, 2H), 1.48 (s, 9H)LC-MS: m / z [M +Na]+= 346.0.

[0141] Procedure for preparation of tert-butyl N-(3,4,6J,8,9-hexahydro-lH- benzothiophenof3f2-c]pwan-7-yl)-N-methyl-carbamates enantiomer 1 (7a) and enantiomer 2 (7b)BocThe residue, compound 7, was separated by SFC (column: DAICEL CHIRALPAK AD(250mmx50mm, 10um) ;mobile phase: [CCL-MeOI 1(0.1 %NI 13112O)] ;B %:25 %, isocratic elution mode ). Compound tert-butyl N-(3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-yl)-N-methyl-carbamate (7a) (190 mg, 587.42 pmol, 47.50% yield) was obtained as a yellow oil. Compound tert-butyl N-(3,4,6,7,8,9- hexahydro-1H-benzothiopheno[3,2-c]pyran-7-yl)-N-methyl-carbamate (7b) (170 mg, 525.58 pmol, 42.50% yield) was obtained as a yellow oil.

[0142] Procedure for preparation of N-methyl-3,4,6,7,8,9-hexahydro-lH- benzothiopheno! 3.2-c lp\ran-7-amine Hydrochloride Enantiomer 1 (16a}To a solution of tert-butyl N-(3,4,6,7,8,9-hexahydro-1H-benzothiopheno|3.2-c|pyran-7- yl)-N-methyl-carbamate (190 mg, 587.42 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2 mL, 6.81 eq) .The mixture was stirred at 25 °C for Ihr. The reaction mixture was concentrated. The product was triturated with EtOAc (2mL) at 25°C for 10 min. The mixture was followed by filtration, the filter cake was dried. Compound N- methyl-3,4,6,7,8,9-hexahydro-1H-benzothiopheno[3,2-c]pyran-7-amine (118.90 mg, 448.97 pmol, 76.43% yield, 98.10% purity, HC1) was obtained as a white solid.1H NMR (400 MHz, METHANOL-d4) 8 = 4.61 - 4.49 (m, 2H), 3.92 (t, J = 5.4 Hz, 2H), 3.55(dddd, J = 2.9. 5.3, 8.1, 10.6 Hz, 1H), 3.25 (br dd, J = 4.9, 15.9 Hz, 1H), 2.85 (br dd, J = 8.8, 15.9 Hz, 1H). 2.78 (s, 5H), 2.64 - 2.48 (m, 2H), 2.31 - 2.22 (m, 1H), 1.99 - 1.87 (m. 1H); LC-MS: m / z [M +H]+= 224.1.

[0143] Procedure for preparation of N-methyl-3,4,6,7,8,9-hexahydro-lH- benzothiophenof 3,2-c]pyran-7 -amine hydrochloride enantiomer 2 (16b)To a solution of tert-butyl N-(3,4,6,7,8,9-hexahydro-1H-benzothiopheno[3,2-c]pyran-7- yl)-N-methyl-carbamate (170 mg, 525.58 pmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2 mL, 7.61 eq) .The mixture was stirred at 25 °C for Ihr. The reaction mixture was concentrated. The product was triturated with EtOAc (2mL) at 25 °C for 10 min. The mixture was followed by filtration, the filter cake was dried. Compound N- methyl-3,4,6,7,8,9-hexahydro-1H-benzothiopheno[3,2-c]pyran-7-amine (118.93 mg, 456.64 pmol, 86.88% yield, 99.75% purity, HCl)was obtained as a white solid. 1H NMR (400 MHz. METHANOL-d4) 8 = 4.55 (br d, J = 1.0 Hz, 2H), 3.92 (t, J = 5.4 Hz, 2H), 3.55 (dddd, J = 2.8, 5.3, 8.1, 10.6 Hz, 1H), 3.25 (br dd. J = 4.9, 15.9 Hz, 1H). 2.85 (br dd,J = 8.6, 16.0 Hz, 1H), 2.81 - 2.73 (m, 5H), 2.64 - 2.48 (m, 2H), 2.31 - 2.21 (m, 1H), 2.00- 1.87 (m, 1H); LC-MS: m / z [M +H]+= 224.1.

[0144] Synthetic Route to 2,2-difluoro-N-methyl-l,3,5,6, 7,8- hexahydrocyclopenta[b]benzothiophen-6-amine hydrochloride enantiomer 1 (17a) and2,2-difluoro-N-methyl-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-amine

[0145] Procedure for preparation of ethyl 2-amino-6-[tert- butoxycarbonyl(methyl)aminol-4,5, 6, 7-tetrahydrobenzothiophene-3-carboxylate ( 2 )To a solution of tert-butyl N-methyl-N-(4-oxocyclohexyl)carbamate (32 g, 140.78 mmol, 1 eq) and ethyl 2-cyanoacetate (20.70 g, 183.02 mmol, 19.51 mL, 1.3 eq) in EtOH (300 mL) was added S (5.42 g, 168.94 mmol, 1.2 eq) and TEA (21.37 g, 211.18 mmol, 29.39 mL, 1.5 eq) .The mixture was stirred at 25 °C for 16hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The product was triturated with EtOAc at 25°C for 1 hr. The mixture was followed by filtration, the filter cake was driedto afford ethyl 2-amino-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (43 g, 121.31 mmol, 86.17% yield) as a white solid.

[0146] Procedure for preparation of ethyl 6-ltert-butoxycarbonyl(methyl)aminol-4,5,6, 7-tetrahydrobenzothiophene-3-carboxylate (3)To a solution of ethyl 2-amino-6-[tert-butoxycarbonyl(methyl)amino]-4,5,6,7-tetrahydro benzothiophene-3 -carboxylate (20 g, 56.42 mmol, 1 eq) in EtOH (300 mL) was added CU(OAC)2 (12.30 g, 67.71 mmol, 1.2 cq), and then tert-butyl nitrite (7.56 g, 73.35 mmol, 8.72 mL, 1.3 eq) was added dropwise at 0 °C. The mixture was stirred at 60°C for 2 hr . The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford ethyl 6-[tert-butoxycarbonyl(methyl)amino]-4,5,6,7- tetrahydrobenzothiophene-3-carboxylate (12.5 g, 36.82 mmol, 65.26% yield) as a yellow solid. ’H NMR (400 MHz, CHLOROFORM-d) 6 = 7.93 (s, 1H), 4.58 - 4.37 (m, 1H), 4.34 - 4.25 (m, 2H), 3.31 - 3.21 (m, 1H), 2.94 - 2.77 (m, 6H), 2.01 - 1.78 (m, 2H), 1.48 - 1.46 (m, 1H), 1.48 (s, 8H), 1.36 (t, J = 7.1 Hz, 3H).

[0147] Procedure for preparation of ethyl 2-bromo-6-[tert- butoxycarbonyl(methyl}amino]-4,5,6,74etrahvdrobenzothiophene-3-carboxylate (4)To a solution of ethyl 6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (9 g, 26.51 mmol, 1 eq) in DMF (100 mL) was added NBS (7.08 g, 39.77 mmol, 1.5 eq) at 0°C .The mixture was stirred at 25 °C for 4hr . The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (100mLx2).The combined organic phases were washed with brine ( 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. Theresidue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-4, 5,6,7- tetrahydrobenzothiophene-3-carboxylate (9.7 g, 20.40 mmol, 76.96% yield, 88% purity) as yellow oil.NMR (400 MHz, CHLOROFORM-d) 8 = 4.57 - 4.21 (m, 3H), 3.08 (br dd, J = 3.6, 16.9 Hz, 1H), 2.88 - 2.66 (m, 6H), 1.97 - 1.76 (m, 2H), 1.48 (s, 9H), 1.39 (t, J = 7.2 Hz, 3H).

[0148] Procedure for preparation of tert-butyl N-(2,3-diformyl-4,5,6,7- tetrahydrobenzothiovhen-6-yl)-N-methyl-carbamate (5)To a solution of ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-4,5,6,7-tetrahydro benzo thiophenc-3-carboxylatc (11.88 g, 24.99 mmol, 1 eq) in MeOH (150 mL) was TEA (5.06 g, 49.98 mmol, 6.96 mL, 2 eq) and Pd(dppf)Ch (1.83 g, 2.50 mmol, 0.1 eq) . The suspension was degassed and purged with CO 3 times. The mixture was stirred under CO (50 Psi.) at 60 °C for 16hr . The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford tert-butyl N-(2,3- diformyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate (10.4 g, 24.86 mmol, 99.47% yield, 95% purity) as yellow oil. 1H NMR (400 MHz, CHLOROFORM- d) 8 = 4.58 - 4.21 (m, 3H), 3.85 (s, 3H), 2.97 - 2.63 (m, 7H), 2.01 - 1.79 (m, 2H), 1.48 (s,9H), 1.38 (t, J = 7.2 Hz. 3H).

[0149] Procedure for preparation of tert-butyl N-l2,3-bis(hydroxymethyl)-4,5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate ( 6)To a solution of tert-butyl N-(2,3-difomiyl-4,5,6,7-tetrahydrobenzothiophen-6-yl)-N- methyl-carbamate (10.4 g, 24.86 mmol, 1 eq) in THF (100 mL) was added LiBH4 (4 M, 31.07 mL, 5 eq) and MeOH (2 mL) at 0°C .The mixture was stirred at 25 °C for 16hr . The reaction mixture was poured into NH4CI saturated solution (200 mL) and extracted with EtOAc (150mLx3).The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Fluent of 0-100% Ethyl acet ate / Petr oleum ether gradient @ 100 mL / min) to afford tert-butyl N-[2,3-bis(hydroxymethyl)-4, 5,6,7- tetrahydrobenzothiophen-6-yl]-N-methyl-carbamate (8.1 g, 24.74 mmol, 99.52% yield) as yellow gum. H NMR (400 MHz. CHLOROFORM-d) 5 = 4.81 - 4.68 (m, 2H), 4.65 - 4.53 (m, 2H), 4.52 - 4.22 (m, 1H), 2.92 - 2.73 (m, 6H), 2.72 - 2.59 (m, 1H), 2.01 - 1.81 (m, 2H), 1.48 (s, 9H).

[0150] Procedure for preparation of tert-butyl N-(2,3-difonnyl-4,5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate ( 7)To a solution of tert-butyl N-[2,3-bis(hydroxymethyl)-4,5,6,7-tetrahydrobenzothiophen- 6-yl]-N-methyl-carbamate (5 g, 15.27 mmol, 1 eq) in DCM (500 mL) was added DMP (19.43 g, 45.81 mmol, 14.19 mL, 3 eq) at 0°C. The mixture was stirred at 25 °C for 2 hr . The reaction mixture was quenched by addition NaHCCF saturated solution 300 mL at 0 °C, and then diluted with Na2S2Os saturated solution 100 mL and extracted with EtOAc mL (10 mLx3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-26% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford tert-butyl N-(2,3-diformyl-4, 5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate (2.8 g, 8.66 mmol, 56.70% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 6 = 10.48 (s. 1H). 10.38 (s. 1H), 4.67 - 4.28 (m, 1H), 3.33 - 3.19 (m, 1H), 3.07 - 2.80 (m, 6H), 2.05 - 1.87 (m, 2H), 1.49 (s, 9H). LC-MS: m / z [M+H]+= 324.0.

[0151] Procedure for preparation of [(Z)-f6-[tert-butoxycarbonyl(methyl)aminol-A solution of KOH (1.21 g, 21.64 mmol, 2.5 eq) tert-butyl N-(2,3-diformyl-4,5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate (2.8 g, 8.66 mmol, 1 eq) in MeOH (6 mL) was added to a solution of tert-butyl N-(2,3-diformyl-4, 5,6,7- tetrahydrobenzothiophen-6-yl)-N-methyl-carbamate (2.8 g, 8.66 mmol, 1 eq) in MeOH (21 mL) at 0 °C, then a solution of nitromethane (739.86 mg, 12.12 mmol, 656.49 pL, 1.4 eq) in MeOH (3 mL) was added dropwise over 0.1 h. Some solid was separated out. The mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered. The filtered cake was washed with cold MeOH (20 mL), dried under reduced pressure to give [(Z)- [6-[tert-butoxycarbonyl(methyl)amino]-L3-dihydroxy-L3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-2-ylidene]-oxido-ammonio]oxypotassium (4.2 g, crude) as a yellow solid.

[0152] Procedure for preparation of 6-(methylamino)-l,3,5,6,7,8- hexahydrocyclopentafblbenzo thiophen-2-one (9)8 9To the mixture of SnC12.2H2O (6.41 g, 28.40 mmol, 3 eq) and HC1 (12 M, 25 mL, 31.69 eq) in H2O (25 mL) was added [(Z)-[6-[tert-butoxycarbonyl(methyl)amino]-l,3- dihydroxy- 1,3, 5,6,7, 8-hexahydrocyclopenta[b]benzothiophen-2-ylidene]-oxido- ammonio]oxypotassium (4 g, 9.47 mmol, 1 eq) by potions at 0 °C. After addition, the mixture was allowed to warm to 25 °C and stirred for 16 hr. The reaction mixture was quenched by addition N al ICO saturated solution 50 mL, filtered and concentrated under reduced pressure to give 6-(methylamino)-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-2-one (2g, crude) as yellow solid. LC-MS: m / z [M+H]+= 222.1.

[0153] Procedure for preparation of tert-butyl N-methyl-N-(2-oxo-l,3,5,6f7di- hexahydroTo a solution of 6-(methylamino)-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-2- one (2 g, 9.04 mmol, 1 eq) in EtOAc (50 mL) and H2O (50 mL) was added NaHCOs (3.80 g, 45.18 mmol, 1.76 mL, 5 eq) and (BochO (3.94 g, 18.07 mmol, 4.15 mL, 2 eq) .The mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50mLx2).The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaElash® Silica Elash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford tert-butyl N-methyl-N-(2-oxo- l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-yl)carbamate (740 mg, 2.30 mmol, 25.48% yield) as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.63 - 4.23 (m, 1H), 3.50 (s, 2H), 3.26 (s, 2H), 2.96 - 2.77 (m, 5H), 2.76 - 2.58 (m, 2H), 2.01 - 1.82(m. 2H), 1.49 (s, 9H).

[0154] Procedure for preparation of tert-butyl N-(2,2-difluoro-l,3,5,6,7,8- hexahydrocyclopenta [b]benzothiophen-6-yl)-N-methyl-carbaniate (11)To a solution of tert-butyl N-methyl-N-(2-oxo-l,3,5,6,7,8-hexahydrocyclopenta [b]benzo thiophen-6-yl)carbamate (300 mg, 933.32 pmol, 1 eq) in DCM (4 mL) was added BAST (619.47 mg, 2.80 mmol, 613.33 pL, 3 eq) at 0°C .The mixture was stirred at 25°C for 2 days . The reaction mixture was poured into NallCCL saturated solution (10 mL) and extracted with EtOAc (20mLx2). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaElash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to afford tert-butyl N-(2,2-difluoro-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (150 mg, 436.77 pmol, 46.80% yield) as a white solid. 1H NMR (400 MHz. CHLOROFORM-d) 5 = 4.58 - 4.20 (m, 1H), 3.38 (br t, J = 14.1 Hz, 2H), 3.14 (t, J = 14.3 Hz, 2H), 2.89 - 2.75 (m, 5H), 2.67 - 2.56 (m, 2H), 1.97 - 1.81 (m, 2H), 1.48 (s, 9H).

[0155] Procedure for preparation of tert-butyl N-(2,2-difluoro-l,3,5,6,7,8-11a 11 bThe residue was separated by SFC (column: DAICEL CHIRALPAK IG (250mmx50mm,10pm);mobile phase: [CO2-EtOH(0.1%NH3H2O )];B%:10%, isocratic elution mode) to afford tert-butyl N-(2,2-difluoro-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (Ila) (60 mg, 174.71 pmol, 40.00% yield) as a yellow solid and tert-butyl N-(2,2-difluoro-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (11b) (70 mg, 203.83 pmol, 46.67% yield) as a yellow solid.

[0156] Procedure for preparation of 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta [b]benzothiophen-6-amine Hydrochloride Enantiomer 1 (17a)To a solution of tert-butyl N-(2,2-difluoro-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (60 mg, 174.71 pmol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (2 M, 2 mL, 22.90 eq) . The mixture was stirred at 25 °C for 2hr . The mixture was concentrated. The product was triturated with EtOAc (1 mL) at 25°C for 10 min. The mixture was filtered, the filter cake was dried to afford 2,2-difluoro-N-methyl-l,3,5,6,7,8-hexahydrocyclopenta[b]benzothiophen-6-amine (44.30 mg, 156.76 pmol, 89.73% yield, 99% purity, HC1) as a white solid. 1H NMR (400 MHz, METHANOL-d4) 5 = 3.61 - 3.52 (m, 1H), 3.38 (t, J = 14.3 Hz, 2H), 3.26 (br d, J = 4.9 Hz. 1H), 3.16 (t. J = 14.3 Hz. 2H), 2.94 - 2.83 (m, 1H). 2.79 (s, 3H), 2.74 - 2.60 (m, 2H), 2.31 - 2.23 (m, 1H), 2.01 - 1.88 (m, 1H); LC-MS: m / z [M+H]+= 244.3.

[0157] Procedure for preparation of 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopentalbl benzothiophen-6-amine Hydrochloride Enantiomer 2 (17b}To a solution of tert-butyl N-(2,2-difluoro-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-yl)-N-methyl-carbamate (70 mg, 203.83 pmol, 1 cq) in EtOAc (1 mL) was added HCI / EtOAc (2 M, 2.33 mL, 22.90 eq). The mixture was stirred at 25 °C for 2hr. The mixture was concentrated. The product was triturated with EtOAc (1 mL) at 25°C for 10 min. The mixture was filtered, the filter cake was dried to afford 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine (43.56 mg, 154.14 pmol, 75.62% yield, 99% purity, HC1) as a yellow solid.’H NMR (400 MHz, METHANOL-d4) 5 = 3.62 - 3.51 (m, 1H), 3.43 - 3.34 (m. 2H), 3.26 (br d, J = 4.8 Hz. 1H), 3.16 (t. J = 14.4 Hz, 2H), 2.89 (br dd, J = 8.8, 16.2 Hz, 1H), 2.79 (s, 3H), 2.76 - 2.59 (m, 2H), 2.32 - 2.22 (m, 1H), 1.95 (dtd, J = 6.6, 9.5, 12.7 Hz, 1H). LC-MS: m / z [M+H]+= 244.3.

[0158] Synthetic route to N,6-dimethyl-3,5,7,8-tetrahydro-lH-benzothiopheno[2,3- c]furan-6-amine hydrochloride enantiomer 1 (18a) and N,6-dimethyl-3,5,7,8-To a solution of ethyl 6-[tert-butoxycarbonyl(methyl)amino]-6-methyl-5,7-dihydro-4H- benzothiophene-3 -carboxylate (14.66 g, 41.47 mmol, 1 eq) in DMF (150 mL) was added NBS (11.07 g, 62.21 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16hr. The reaction mixture was quenched with sat.NH4Cl 500 mL and extracted with EtOAc (50mLx2). The combined organic layers were washed with sat.NaCl (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-6-methyl- 5,7-dihydro-4H-benzothiophene-3-carboxylate (7.2 g, 16.65 mmol, 40.15% yield) was obtained as a yellow oil. LC-MS: m / z [M+H-Boc]+= 332.1.

[0160] Procedure for diethyl 6-ltert-butoxxcarbonxl(niethxhaininol-6-inethxl-5.7- dihydro-4H-benzothiophene-2,3-dicarboxylate ( 9)Boc CO, Pd(dppf)CI2BocTEA, EtOH, 60 °C, 16 hTo a solution of ethyl 2-bromo-6-[tert-butoxycarbonyl(methyl)amino]-6-methyl-5.7- dihydro-4H-benzothiophene-3-carboxylate (7.2 g, 16.65 mmol, 1 eq) in EtOH (70 mL) were added TEA (3.37 g, 33.30 mmol, 4.64 mL, 2 eq) and Pd(dppf)Cl2(1.22 g, 1.67 mmol, 0.1 eq). The suspension was degassed and purged with CO 3 times. The mixture was stirred under CO (50Psi) at 60 °C for 16hr. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0-11% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound diethyl 6-[tert-butoxycarbonyl(methyl)amino]-6-methyl-5,7- dihydro-4H-benzothiophene-2,3-dicarboxylate (5.8 g, 13.63 mmol, 81.85% yield) was obtained as a yellow oil. II NMR (400 MHz. CHLOROFORM-d) 5 = 4.39 (q, J = 7.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.31 (d, J = 17.1 Hz, 1H), 2.90 (d, J = 17.3 Hz, 1H), 2.85 - 2.75 (m, 4H), 2.60 (t, J = 6.1 Hz, 2H), 1.82 - 1.69 (m, 1H), 1.46 (s, 9H), 1.42 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H). LC-MS: m / z [M+Na]+= 448.1.To a stirred solution of diethyl 6-[tert-butoxycarbonyl(methyl)amino]-6-methyl-5,7- dihydro-4H-benzothiophene-2,3-dicarboxylate (1.8 g, 4.23 mmol, 1 eq) in THF (20 mL) at 0 °C was added LiBH4(4 M, 4.23 mL, 4 cq). After 10 min at 0 °C, McOH (1 mL) was added. The reaction was stirred for 2 h at 0 °C. The reaction mixture was quenched with satNEUCl 30 mL and extracted with EtOAc (30mLx2). The combined organic layers were washed with sat.NaCl (20mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0-72% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl N- [2,3-bis(hydroxymethyl)-6-methyl-5,7-dihydro-4H-benzothiophen-6-yl]-N-methyl-To the mixture of tert-butyl N-[2,3-bis(hydroxymethyl)-6-methyl-5,7-dihydro-4H- benzothiophen-6-yl]-N-methylcarbamate (1.6 g, 4.69 mmol, 1 eq) in DCM (32 mL) was added MnCh (2.04 g, 23.43 mmol, 5 eq). The mixture was stirred at 25-30 °C for 16 h. The reaction mixture was filtered. The filtrate was cooled to 0 °C and TEA (8.01 g, 70.29 mmol, 5.22 mL, 15 eq) was added. Then Et?SiH (2.72 g, 23.43 mmol, 3.74 mL, 5 eq) was added dropwise. The mixture was stirred at 25-30 °C for 0.5 h. The reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in EtOAc (10 mL) and H2O (10 mL). NaHCO3(1.18 g, 14.06 mmol, 3 eq) and (BocLO (2.05 g, 9.37 mmol. 2.15 mL, 2 eq) were added. The resulting mixture was stirred at 25 °C for 2h. The reaction mixture was diluted with H2O 10 mL and extracted with EtOAc (10mLx2). The combined organic layers were washed with sat.NaCl (10mL), dried over anhydrousNazSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0-11% Ethyl acetate / Petroleum ether gradient @ 40 mL / min).Compound tert-butyl N-methyl-N-(6-methyl-3,5,7,8-tetrahydro-1H-benzothiopheno[2,3- c]furan-6-yl)carbamate (700 mg, 2.16 mmol, 46.19% yield) was obtained as a yellow solid. ’H NMR (400 MHz, CHLOROFORM-d) 5 = 5.08 - 4.99 (m, 2H), 4.94 - 4.81 (m, 2H), 3.20 (d, J = 17.1 Hz. 1H). 2.95 - 2.76 (m, 5H). 2.47 (t, J = 6.1 Hz, 2H), 1.82 - 1.70 (m, 1H), 1.47 (s, 9H), 1.43 (s, 3H). EC-MS: m / z [M+Na]+= 346.2.

[0163] Procedure for tert-butyl N-methyl-N-(6-methyl-3,5.7.8-tetrahydro-lH- benzothiovhenof2,3-c]furan-6-yl)carbamate Enantiomer 1 (12a)and Enantiomer 2 (12blThe racemic compound 12 was separated by prep-Chiral-SFC (column: Phenomenex- Cellulose-2 (250mmx30mm,10pm); mobile phase: [CO2-MeOH(0.1%NH?H2O)];B%:25%, isocratic elution mode) to afford the 1st enantiomer 12a (RT = 1.025 min) and the 2nd enantiomer 12b (RT = 1.365 min).

[0164] Procedure for N,6-dimethyl-3,5, 7.8-tetrahydro-lH-benzothiot)henof2.3- c] furan- 6-amine hydrochloride enantiomer 1 (18a}To a solution of tert-butyl N-methyl-N-(6-methyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-yl)carbamate (12a) (90 mg, 278.25 pmol, 1 eq) in EtOAc (2 mL) was added HCFEtOAc (2 M, 2 mL). The mixture was stirred at 25 °C for Ihr. Remove the solvent on a rotary evaporator. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmxl0pm;mobile phase: [water(HCl)- ACN];gradient: l%-25% B over 1 min ). Compound N,6-dimethyl-3, 5,7, 8-tetrahydro- 1H-benzothiopheno[2,3-c]furan-6-amine (18a) (35.81 mg, 132.31 pmol, 47.55% yield,95.99% purity, HC1) was obtained as an off-white solid.rH NMR (400 MHz, METHANOL-d4) 8 = 4.99 (s, 2H), 4.87 (s, 2H), 3.12 - 2.99 (m, 2H), 2.75 - 2.63 (m. 5H), 2.12 - 1.99 (m, 2H), 1.44 (s, 3H). LC-MS: m / z [M+H]+= 224.0.

[0165] Procedure for N,6-dimethyl-3,5, 7,8-tetrahydro-lH-benzothioyhenof2,3- clfuran-6-amine hydrochloride enantiomer 2 (18b)12b Enantiomer 2 18bTo a solution of tert-butyl N-methyl-N-(6-methyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-yl)carbamate (12b) (100 mg, 309.17 pmol, 1 eq) in EtOAc (2 mL) was added HCI / EtOAc (2 M, 2 mL). The mixture was stirred at 25 °C for Ihr. Remove the solvent on a rotary evaporator. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 150x25mmxl0pm;mobile phase: [water(HCl)-ACN] ;gradient: l%-25% B over 1 min). Compound N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine (18b) (19.94 mg, 76.50 pmol, 24.74% yield, 99.67% purity, HC1) was obtained as a yellow solid. 1H NMR (400 MHz, METHANOL- d4) 8 = 5.00 (s, 2H), 4.87 (s, 2H), 3.10 - 2.98 (m, 2H), 2.77 - 2.64 (m. 5H), 2.12 - 1.97 (m, 2H), 1.43 (s, 3H). LC-MS: m / z [M+H]+= 224.0.2. X-Ray Crystallography

[0166] An X-ray crystallographic analysis was performed on the enantiomer 8b and the absolute stereochemistry was shown to be (5). The symmetry of the crystal structure was assigned the orthorhombic space group P21212 with the following parameters: a = 20.1188(3) A, b = 8.46580(10) A, c = 6.97870(10) A, a = 90°,y5 = 90°, y = 90°, V = 1188.62(3) A3, Z = 4, De = 1.373 g / cm3, / / (CuKa) = 4.269 mm’1, and F(000) = 520.0. The absolute configuration structure is judged by the value of Flack parameter, and the structure of the tested crystal is as follows:. The ORTEP structure is shown in FIG. 1. A picture of the crystals is shown in FIG. 2.

[0167] Description of equipment:• Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector• Cryogenic system: Oxford Cryostream 800• Cu: A=l.54184 A, 50W• Distance from the crystal to the CCD detector: d = 35 mm• Tube Voltage: 50 kV; Tube Current: 1 mA[0168J A suitable crystal 0.20 x 0.20 x 0.15 mm3was selected for testing. Data collection temperature: T = 149.99(10) K. Total of 17134 reflections were collected in the 20 range from 8.79 to 133.18°. The limiting indices were: -23 < h < 23, -10 < k < 10, -8 < 1 < 8; which yielded 2087 unique reflections (Rint = 0.0508). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 137, compared with 2087 data. All reflections were included in the refinement. The goodness of fit on F2was 1.057 with a final R value for [I >= 2o (I)] Ri = 0.0221 and WR2 = 0.0564. The largest differential peak and hole were 0.24 and -0.19 eA-3.Summary of X-ray Crystallographic Data.Atomic coordinates (x104) and equivalent isotropic displacement parameters (A2xl03).Atom x y z U(eq)Cll 7082.3(3) 3375.6(6) 3107.3(7) 25.66(15)S I 4894.8(2) 7645.0(6) 4843.0(8) 24.55(15)01 3637.8(8) 9176(2) 8879(3) 36.8(4)N1 7177.1 (8) 5146.9(19) 6919(3) 18.8(4)C2 6472.2(9) 5453(2) 7515(3) 17.9(4)C3 6450.5(9) 6466(2) 9318(3) 19.1(4)C4 5728.5(9) 6705(3) 9973(3) 21.8(4)C8 4661.3(10) 7975(2) 8414(3) 20.2(4)C5 5296.0(9) 7204(2) 8324(3) 19.0(4)C7 6127.4(10) 6253(2) 5818(3) 21.1(4)Cll 4400.2(10) 8290(2) 6685(3) 22.1(4)CIO 3751.2(10) 9137(3) 6838(4) 26.9(5)C9 4203.6(10) 8573(3) 9936(3) 25.4(5)C6 5480.3(10) 6962(2) 6476(3) 20.0(4)Cl 7562.1(10) 4082(3) 8203(4) 25.0(5)Bond lengths [A].Atom Atom Length / A Atom Atom Length / ASI Cl l 1.715(2) C3 C4 1.536(3)SI C6 1.738(2) C4 C5 1.504(3)01 CIO 1.443(3) C8 C5 1.436(3)01 C9 1.450(3) C8 Cl l 1.343(3)N1 C2 1.500(3) C8 C9 1.494(3)N1 Cl 1.488(3) C5 C6 1.358(3)C2 C3 1.523(3) C7 C6 1.505(3)C2 C7 1.530(3) Cl l CIO 1.494(3)Bond angles [deg].Atom Atom Atom Angle / " Atom Atom Atom Angle / "Cl l SI C6 90.45(10) C6 C5 C4 121.77(18)CIO 01 C9 111.73(16) C6 C5 C8 110.71(19)Cl N1 C2 115.46(16) C6 C7 C2 109.44(17)N1 C2 C3 110.67(16) C8 Cl l S I 112.56(16)N1 C2 C7 106.90(16) C8 Cl l CIO 111.89(19)C3 C2 C7 112.16(16) CIO Cl l S I 135.54(18)C2 C3 C4 110.31(16) 01 CIO Cl l 102.70(18)C5 C4 C3 110.89(18) 01 C9 C8 103.96(18)C5 C8 C9 137.2(2) C5 C6 S I 1 12.78(15)Cl l C8 C5 113.5(2) C5 C6 C7 125.89(19)Cl l C8 C9 109.33(18) C7 C6 SI 121.28(16)C8 C5 C4 127.5(2)Hydrogen Bonds.N1 H1A Cll 0.91 2.16 3.0598(18) 170.4N1 H1B Cll10.91 2.20 3.1131(17) 176.0‘S^-X.l^+Y.l-ZTorsion angles [deg].A B C D Angle / " A B C D Angle / "SI Cl l CIO 01 176.74(18) C7 C2 C3 C4 63.5(2)N1 C2 C3 C4 -177.23(16) Cl l SI C6 C5 0.76(17)N1 C2 C7 C6 -165.64(16) Cl l SI C6 C7 -176.72(17)C2 C3 C4 C5 -48.4(2) Cl l C8 C5 C4 179.16(19)C2 C7 C6 SI -168.25(14) Cl l C8 C5 C6 -0.5(3)C2 C7 C6 C5 14.6(3) Cl l C8 C9 01 3.2(2)C3 C2 C7 C6 -44.2(2) CIO 01 C9 C8 -6.0(2)C3 C4 C5 C8 -160.16(19) C9 01 CIO Cl l 6.3(2)C3 C4 C5 C6 19.5(3) C9 C8 C5 C4 0.8(4)C4 C5 C6 SI -179.99(15) C9 C8 C5 C6 -178.9(2)C4 C5 C6 C7 -2.7(3) C9 C8 Cl l SI 179.92(15)C8 C5 C6 SI -0.3(2) C9 C8 Cl l CIO 0.6(2)C8 C5 C6 C7 177.06(19) C6 SI Cl l C8 -1.07(16)C8 Cl l CIO 01 -4.2(2) C6 SI Cl l CIO 178.0(2)C5 C8 Cl l SI 1.1(2) Cl N1 C2 C3 69.7(2)C5 C8 Cl l CIO -178.16(17) Cl N1 C2 C7 -167.91(17)C5 C8 C9 01 -178.4(2)3. Biology

[0169] To demonstrate the utility of the provided compounds to treat neurological and psychiatric diseases and disorders, compounds are evaluated using theneuropharmacological screen described in S.L. Roberds et al. Front. Neurosci. 2011 Sep 9;5: 103 (doi: 10.3389 / fnins.2011.00103) (“Roberds”). As reported in Roberds, because psychiatric diseases generally result from disorders of cell-cell communication or circuitry, intact systems are useful in detecting improvement in disease-relevant endpoints. These endpoints are typically behavioral in nature, often requiring human observation and interpretation. To facilitate testing of multiple compounds for behavioral effects relevant to psychiatric disease, PsychoGenics, Inc. (Tarrytown, NY, "PGI") developed SmartCube™, an automated system in which behaviors of compound-treated mice are captured by digital video and analyzed with computer algorithms. (D. Brunner et al. Drug Discov. Today 2002, 7:S 107-S 112). PGI Analytical Systems uses data from SmartCube™ to compare the behavioral signature of a test compound to a database of behavioral signatures obtained using a large set of diverse reference compounds. (The composition of the database and validation of the method are further described in Roberds). In this way, the neuropharmacological effects of a test compound can be predicted by similarity to major classes of compounds, such as antipsychotics, anxiolytics and antidepressants.

[0170] The SmartCube™ system produces an activity signature indicating the probability that the activity of the test compound at the administered dose matches a given class of neuropharmacological agents (“Activity”). (See, e.g., Roberds, Figures 2 and 3). The test compound is simultaneously compared against multiple classes of agents; thus, a separate probability is generated for each behavioral effect measured (e.g., anxiolytic activity, analgesic activity, etc.). In Table 2 below, these probabilities are reported for each behavioral effect measured as described in Table 1 below:Table 1

[0171] Provided compounds were dissolved in a mixture of Pharmasolve™ (N- methyl-2-pyrrolidone), polyethylene glycol and propylene glycol, and were injected i.p.15 min. before the behavioral test. Test compounds are routinely examined at dose levels of 0.3, 1. 3 and 10 mg / kg, although the dose range is increased or decreased, if necessary, to obtain a full dose response curve. For each behavioral effect measured, results for the 3.0 mg / kg dose are presented below. A compound’s minimal effective dose (MED) is a measure of the compound’s potency. The MED is defined as the dose (in mg / kg) having 45% or more total Activity across all tested classes. The potencies of the compounds are shown in Table 2.Table 2INCORPORATION BY REFERENCE

[0172] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0173] The foregoing embodiments are illustrative rather than limiting the invention described herein. The scope of the invention is thus indicated by the appended claims, and all embodiments that come within the meaning and range of equivalency of the claims arc intended to be encompassed therein.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, whereinR1and R2are independently chosen from H and C1-C3alkyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring;R3is chosen from H and C1-C3alkyl;A is chosen from O and CH2;Z is chosen from O, -CH2O-, -OCH2-, and CX3X2; andX1and X2are independently chosen from H and halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently chosen from H and C1-C3alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently chosen from H and methyl.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1is H and R2is chosen from C1-C3alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1and R2are H.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R3is chosen from H and methyl.

8. The compound of claim 7, wherein R3is H.

9. The compound of claim 7, wherein R3is methyl.

10. The compound of any one of claims 1 -9, or a pharmaceutically acceptable salt thereof, wherein A is O.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein A is CH2.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Z is O.

13. The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein Z is -CH2O-.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Z is -OCH2-.

15. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Z is CX1X2.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Z is CH2.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Z is CF2.

18. The compound of claim 1, wherein the compound is N-methyl-1,3,5,6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, N-methyl-2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]benzothiophen-6-amine, 1,3, 5,6,7, 8-hexahydrobenzothiopheno[2,3-c]furan-6-amine, 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]benzothiophen-6-amine, N-methyl-4,12- dioxa-7-thiatricyclo[6.4.0.02,6]dodeca-l(8),2(6)-dien-10-amine, N-methyl-3,4,5,6,7,8- hexahydro-1H-benzothiopheno[2,3-c]pyran-7-amine, N-methyl-3,4,6,7,8,9-hexahydro-1H- benzothiopheno[3,2-c]pyran-7-amine, 2,2-difluoro-N-methyl-l,3,5,6,7,8- hexahydrocyclopenta[b]benzothiophen-6-amine, or N,6-dimethyl-3,5,7,8-tetrahydro-1H- benzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein the compound is N-methyl-1 , 3, 5, 6,7,8- hexahydrobenzothiopheno[2,3-c]furan-6-amine, or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, at least about 80% enriched in the (R) stereoisomer at the * carbon atom.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, at least about 80% enriched in the (S) stereoisomer at the * carbon atom.

22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22.

24. A method of treating PTSD in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22.

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