Tetrahydro-5 h-pyrazino[2,3- d]azepines as novel 5-HT2a and / or 5-HT2c receptor agonists for therapeutic treatment

Abstract

Provided herein are novel tetrahydro-5H-pyrazino[2,3-d] azepine derivative compounds having the structure of Formula (I): (I) and pharmaceutically acceptable salts or solvates thereof. Also provided are synthetic processes for their preparation, compositions comprising said compounds, and their use in therapy.

Description

TETRAH YDRO-5 / 7-PYRAZINO [2, 3-Z>] AZEPINES AS NOVEL 5-HT2A AND / OR 5- HT2C RECEPTOR AGONISTS FOR THERAPEUTIC TREATMENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U. S. Provisional Patent Application No. 63 / 748,683 filed on January 23, 2025, U. S. Provisional Patent Application No. 63 / 749,194 filed on January 24, 2025, and U. S. Provisional Patent Application No. 63 / 926,636 filed on November 27, 2025, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Provided herein are novel tetrahydro-5H-pyrazino[2,3-d]azepine derivative compounds, processes for their preparation, compositions comprising said compounds, and their use in therapy. More particularly, the present disclosure relates to these compounds and their use in the treatment of diseases, disorders or conditions treatable by modulating the 5-HT2 receptor subtypes.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are novel tetrahydro-5H-pyrazino[2,3-d] azepine derivative compounds as 5-HT2a and / or 5 -HT2c receptor agonists, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.In some embodiments, compounds disclosed herein exhibit 5-HT2A, 5-HT2C, or both 5-HT2A and 5-HT2C selective receptor agonist activity while lacking at least some of the undesirable characteristics of 5-HT2B-agonist related activities of psilocybin / psilocin and other psychedelics. Compounds disclosed herein may be useful in the treatment of diseases and disorders, including but not limited to, anxiety, depression, mood disorders, alcoholism, tobacco and cocaine addiction, pain, inflammation, cluster headache, PTSD, epilepsy and other CNS disorders.

[0004] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, with the proviso that when Z is phenyl, at least one of R1, R2and R3is not H.

[0005] In some embodiments, the optionally substituents in the R1, R2and / or R3moieties are independently selected from halo, =0, OH, CN, Ci-ealkyl, Cs-ecycloalkyl, aryl, Cs-eheteroaryl, Cs-eheterocycloalkyl, Ci-ealkyleneCs-ecycloalkyl, Ci-ealkylenearyl, Ci-ealkyleneCs-eheteroaryl, Ci-ealkyleneCs-eheterocycloalkyl, C(O)Ci-ealkyl, OCi-ealkyl, OCi-ealkyleneOCi-ealkyl, C(0)NH2, C(O)NH(Ci-6alkyl), C(O)N(Ci-6alkyl)(Ci-6alkyl), NHC(O)Ci-6alkyl, N(Ci-6alkyl)C(O)Ci-6alkyl, NH2, NH(Ci-ealkyl), N(Ci-6alkyl)(Ci-6alkyl), SCi-6alkyl, S(O)Ci-6alkyl and S02Ci-ealkyl.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a use of a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, for treatment of a disease or disorder mediated by the 5-HT2 receptor in a subject in need thereof.

[0008] A related embodiment provides a method of treating a disease or disorder mediated by the 5-HT2 receptor in a subject in need thereof, said method comprising administering acompound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, to the subject.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference, in their entirety, for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of' the described features.

[0011] Definitions

[0012] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0013] " Amino" refers to the -NH2 radical.

[0014] " Cyano" refers to the -CN radical.

[0015] " Nitro" refers to the -NO2 radical.

[0016] " Oxa" refers to the -O- radical.

[0017] " Oxo" refers to the =0 radical.

[0018] " Thioxo" refers to the =S radical.

[0019] " Imino" refers to the =N-H radical.

[0020] " Oximo" refers to the =N-OH radical.

[0021] " Hydrazino" refers to the =N-NH2 radical.

[0022] " Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., Ci-Cis alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., Ci-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl ( / 7-propyl). 1-methylethyl (zso-propyl), 1 -butyl (zz-but l). 1 -methylpropyl (sec-butyl). 2-methylpropyl (zoobutyl), 1,1 -dimethylethyl ( / c / 7-butyl). 1 -pentyl (zr-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0024] " Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] " Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises twoto eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] " Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbonatoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] " Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0028] " Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-Cs alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0029] " Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0030] " Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0031] " Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0032] " Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0033] " Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0034] " Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Anunsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (z.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0035] " Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] " Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0037] " Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0038] As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0039] " Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0040] " Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0041] " Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0042] " V-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An ^-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limitedto, 1-morpholinyl, 1-piperidinyl, 1 -piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0043] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0044] " Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0045] " Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0046] " Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo|6|| l,4]dioxepinyl,benzo [b][ 1,4] oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- IT / -pyrrolyl. phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (z.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substitutedwith halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0047] " V-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0048] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0049] " Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0050] " Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted asdefined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0051] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as ( / )- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g, cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0052] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0053] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. In another particular embodiment, the compound is tritiated in at least one position. Such tritiated compounds can be useful, for example, as radioactive tracers for medical or scientific research purposes (e.g., receptor binding studies).

[0054] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0055] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0057] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem, 1981, 64(1-2), 9-32.

[0058] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0059] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-ds (CD3I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.CD3IbaseCD3Ibaseo

[0060] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.R.,LiAID4-RYNH2COoHLiA|D4 D D gLiA|D D R.D D R OH R R n^n.

[0061] Deuterium gas and palladium catalyst are employed to reduce unsaturated carboncarbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.Pd-C R"R" EtOAc D D

[0062] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0063] " Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heterocyclic 5-HT2a and / or 5-HT2c receptor agonists compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0064] " Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., " Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0065] " Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, poly amine resins and the like. See Berge et al., supra.

[0066] " Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0067] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0068] Heterocyclic 5-HTia and / or 5-HTic Receptor Agonists Compounds

[0069] Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one third of patients will not respond to current antidepressant drugs, and those who do will usually require at least two to four weeks of treatment before they experience any beneficial effects. Evidence from a combination of human imaging, postmortem studies, and animal models suggest that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. These structural changes, such as the retraction of neurites and loss of dendritic spines, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity. Recently the nonclassical psychedelics has shown remarkable clinical potential as a fast-acting antidepressant and anxiolytic, exhibiting efficacy in treatmentresistant populations. Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses.

[0070] Clinical studies have demonstrated the potential for using classical psychedelics to treat a variety of neuropsychiatric disorders including depression, anxiety, addiction, and post-traumatic disorders. However, their therapeutic mechanism of action remains poorly understood, and concerns about safety have severely limited their clinical usefulness.

[0071] Psychedelic compounds have the potential to meet the therapeutic needs for a number of indications without the addictiveness and overdose risk of other mind-altering drugs, such as cocaine, heroin, alcohol, methamphetamine, and so forth. The need for new therapies is urgent because addiction, overdose, and suicide deaths have risen throughout the North America and around the world. The problem is further exacerbated by the lack of significant advances in psychiatric drug development, as current treatments are plagued with limited efficacy, significant side effects, and dependency on long time use, which may lead some patients to develop treatment-resistance. Recent academic research effort along with anecdotal reports suggest that psychedelics have promising therapeutic potential (BMC Psychiatry 2018, 18, 245).

[0072] Psychedelic compound research has previously been stymied as a result of governmental regulation and societal taboo which has left many unanswered questions regarding the pharmacology and toxicology of psychedelics. There has been renewed interest in the therapeutic potential of psychedelics. For example, psilocy bin-assisted psychotherapy has been effective in the treatment of depression and anxiety in cancer patients and also in the treatment of resistant depression (J. Psychopharmacol. 2016, 30, 1181).

[0073] Psilocybin is a naturally occurring psychedelic prodrug compound produced by many species of mushrooms which are collectively known as psilocybin mushrooms. As a prodrug, psilocybin is quickly metabolized by the body to generate the bioactive compound psilocin, which has mind-altering effects not unlike those produced by LSD, mescaline, and DMT. These effects include, inter alia, euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and can also include possible adverse reactions such as nausea and panic attacks.

[0074] A major limitation to the therapeutic potential for psilocybin is a serious toxicological safety liability, namely cardiac valvulopathy, that can be anticipated from psilocin’s potent agonist activity at 5-HT2B receptors. Thus, previous drugs with 5-HT2B receptor agonist activity have been found to have life threatening side effects such as cardiac valvulopathy(Rothman, R., Baumann, M., Savage, J., Rauser, L., McBride, A., Hufeisen, S., Roth, B. L. " Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated with Fenfluramine and other Serotonergic Medications" Circulation 2000, 702, 2836; Fitzgerald, L., Bum, T., Brown, B., Patterson, J., Corjay, M., Valentine, P., Sun, J-H., Link, J., Abbaszade, I., Hollis, J., Largent, B., Hartig, P., Hollis, G., Meunier, P., Robichaud, A., Robertson, D. " Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine" Mol. Pharmacol. 2000, 57, 75) and pulmonary hypertension (Launay, J., Herve, P., Peoc'h, K., Toumois, C., Callebert, J., Nebigil, C., Etienne, N., Drouet, L., Humbert, M., Simonneau, G., Maroteaux, L. " Function of the Serotonin 5-Hydroxytryptamine 2B Receptor in Pulmonary Hypertension" Nature Med. 2002, 8, 1129).

[0075] Classical (serotonergic) psychedelics have undergone a recent resurgence of interest for their potential to produce rapid and sustained therapeutic effects. Recent findings suggest that psychedelic use may be further limited by their hallucinogenic effects, which can cause confusion and anxiety in some patients, necessitating close clinical supervision. However, further preclinical efforts suggest it may be possible to disentangle psychedelic properties from their therapeutic properties (Nature 2021: 589, 474-479; Nature 2022: 610, 582-591).

[0076] Serotonergic psychedelics are derived from multiple chemical scaffolds (e.g., tryptamines, phenethylamines, and lysergamides), all which activate the 5-HT2A receptor (5-HT2AR), a G protein-coupled receptor (GPCR). 5-HT2ARs appear to primarily mediate psychedelic experiences supported by evidence that the 5-HT2AR antagonist ketanserin attenuates subjective effects of psilocybin and LSD in humans (Proc. Natl Acad. Sci. USA 2019: 116, 2743-2748; Neuroreport 1998: 9, 3897-3902. Psychedelics have also been studied in preclinical behavioral models, including the head-twitch response (HTR), which is a 5-HT2AR-mediated involuntary head movement in mice that predicts human psychedelic activity.

[0077] The ability of 5-HT2AR agonists to induce the head twitch response (HTR) was found to be correlated with Gq-efficacy but not [3-arrestin2 recruitment. 5-HT2AR f>-arrestin2-biased agonists did not induce psychedelic-like behavioral effects, but blocked psychedelic-like behaviors in vivo. Overall, it appears that multiple structural and chemical features of psychedelics can be targeted to fine-tune 5- HT2AR activity, potentiallymodulating therapeutic efficacy and tolerability of 5-HT2AR ligands for various therapeutic indications including psychosis (Nature Communications 2023: 14:8221).

[0078] Emerging evidence also suggests that alterations in serotoninergic circuits may contribute to the pathogenesis of epilepsy (Epilepsia Open. 2022;7(2):231-246). Serotonin, a neurotransmitter known for its role in mood regulation and cognition, also modulates neuronal excitability and synaptic transmission in the brain. Dysregulation of serotonin signaling has been implicated in various neurological disorders, including epilepsy and pain.

[0079] Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in its genetic understanding, effective therapies targeting underlying pathophysiology are lacking. In DEEs, aberrant serotoninergic signaling may contribute to the disruption of neuronal networks, leading and contributing to hyperexcitability and seizure generation. To date, the only approved anti-siezure medication acting via 5-HT is fenfluramine (Front Pharmacol.2022; 13:832929). Understanding the interplay between serotoninergic dysfunctions and DEEs holds promise for the development of novel therapeutic strategies.

[0080] A selective and centrally acting 5-HT2C agonist is being developed for seizures associated with DEEs, such as Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD), and other epileptic disorders. Such 5-HT2C agonist agonists are designed to modulate GABAergic neurotransmission, thereby suppressing central hyperexcitability characteristic of seizures.

[0081] Also, of significant interest recently is the observation that a 5-HT2C / 2A mixed agonist, demonstrated similar efficacy to morphine in preclinical pain models without the associated risks of dependency and side effects. Preclinical pain models included plantar incision and L5 / L6 nerve ligation rat models and where the drug candidate was tested along with morphine and gabapentin as positive controls. The fact that the 5-HT2C / 2A mixed agonist outperforms morphine in preclinical models is a testament to the potential of serotonergic therapies in pain management (Poster at the Society for Neuroscience ’s conference 2024, October 5-9, Chicago). A selective 5-HT2A / 2C receptor agonist, was designed to harness the analgesic potential of serotonin modulation without the hallucinogenic effects commonly associated with 5-HT2A activation.

[0082] Therefore, the future of therapeutic psychedelics research in general holds enormous potential to save lives and meet unmet medical needs throughout the world.

[0083] The molecular features that could confer good metabolic and pharmacokinetic characteristic are unpredictable. The present inventors have identified key structural features in compounds of Formula I that offer improved metabolic properties for the treatment of diseases, disorders or conditions treatable by activating the 5HT2Aand / or 5HT2csignaling axis.

[0084] In one aspect, provided herein is a heterocyclic 5-HT2aand / or 5-HT2creceptor agonist compound.

[0085] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted C1-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0086] In some embodiments, there is provided a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I), as defined above, with the proviso that when Z is phenyl, at least one of R1, R2and R3is not H.

[0087] In some embodiments, the optionally substituents in the R1, R2and / or R3moieties are independently selected from halo, =0, OH, CN, Ci-ealkyl, Cs-ecycloalkyl, aryl, Cs-eheteroaryl, Cs-eheterocycloalkyl, Ci-ealkyleneCs-ecycloalkyl, Ci-ealkylenearyl, Ci-ealkyleneCs-eheteroaryl, Ci-ealkyleneCs-eheterocycloalkyl, C(O)Ci-ealkyl, OCi-ealkyl, OCi-ealkyleneOCi-ealkyl, C(0)NH2, C(O)NH(Ci-6alkyl), C(O)N(Ci-6alkyl)(Ci-6alkyl), NHC(O)Ci-6alkyl, N(Ci-6alkyl)C(O)Ci-6alkyl, NH2, NH(Ci-ealkyl), N(Ci-6alkyl)(Ci-6alkyl), SCi-6alkyl, S(O)Ci-6alkyl and SO2Ci-6alkyl.

[0088] In some embodiments, the heterocyclic 5-HT2aand / or 5 -HT2creceptor agonistX Xcompound as described herein has a structure provided in Table 1.Table 1MZ ZExample Number S otructure, NExample 1NHJ 0 N' X _ / Example 2Example 3Example 4 —1if J NHExample 5Example Number StructureV J J NHExample 6Example 7T10 Q z z w Example 8 z zOo Oz z z z^ z z z z zbExample 9 u.000 0 1 I 3 ®Example 10Example 11jf N-Et Example 12Example 13Example Number StructureExample 14Example 15 X I NHH q o N' \ / . HC1 T1QExample 16 q ■. z zO oX1111z zExample 17 u. u.0, HC1Example 18 Y'Y0 N. HC1 \1 JExample 19NHrj^T^O^N^ - / NC^^, HC1Jf J NH Example 20 N" \ —7. HC1Example 20Example Number Structure. HC1Example 21LL u.Example 22o06 / _ O o O o ^z zEx z z z z z z z zample 231 100 z z0 u 0 / oExample 24Example 25HO ■HCI;N1 JI 1Example 26Example 27<^NH2HO^ / Serotonin I H

[0089] In an aspect, the present disclosure provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted C1-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, with the proviso that when Z is phenyl, at least one of R1, R2and R3is not H.

[0090] In some embodiments, the optionally substituents in the R1, R2and / or R3moieties are independently selected from halo, =0, OH, CN, Ci-6alkyl, Cs-ecycloalkyl, aryl, Cs-eheteroaryl, Cs-eheterocycloalkyl, Ci-ealkyleneCs-ecycloalkyl, Ci-ealkylenearyl, Ci-ealkyleneCs-eheteroaryl, Ci-ealkyleneCs-eheterocycloalkyl, C(O)Ci-ealkyl, OCi-ealkyl, OCi-ealkyleneOCi-ealkyl, C(0)NH2, C(O)NH(Ci-6alkyl), C(O)N(Ci-6alkyl)(Ci-6alkyl), NHC(O)Ci-6alkyl, N(Ci-6alkyl)C(O)Ci-6alkyl, NH2, NH(Ci-ealkyl), N(Ci-6alkyl)(Ci-6alkyl), SCi-6alkyl, S(O)Ci-6alkyl and SO2Ci-ealkyl.

[0091] In some embodiments, the compound is provided in Table 1.

[0092] In an aspect, the present disclosure provides a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1 to 10 and a pharmaceutically acceptable excipient. In an aspect, thepresent disclosure provides a pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described as described herein and a pharmaceutically acceptable excipient.

[0093] In an aspect, the present disclosure provides a method comprising use of a composition comprising a 5-HT2Aand / or 5-HT2creceptor agonist in the treatment of a disease or disorder mediated by the 5-HT2 receptor, wherein the 5-HT2Aand / or 5-HT2creceptor agonist is a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted C1-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0094] In some embodiments, 5-HT2Aand / or 5-HT2creceptor agonist used in the method for treatment is a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I), as defined above, with the proviso that when Z is phenyl, at least one of R1, R2and R3is not H.

[0095] In some embodiments, the optionally substituents in the R1, R2and / or R3moieties are independently selected from halo, =0, OH, CN, Ci-ealkyl, Cs-ecycloalkyl, aryl, Cs-eheteroaryl, Cs-eheterocycloalkyl, Ci-ealkyleneCs-ecycloalkyl, Ci-ealkylenearyl, Ci-ealkyleneCs-eheteroaryl, Ci-ealkyleneCs-eheterocycloalkyl, C(O)Ci-ealkyl, OCi-ealkyl, OCi-ealkyleneOCi-ealkyl, C(O)NH2, C(O)NH(Ci-6alkyl), C(O)N(Ci-6alkyl)(Ci-6alkyl), NHC(O)Ci-6alkyl, N(Ci-6alkyl)C(O)Ci-6alkyl, NH2, NH(Ci-6alkyl), N(Ci-6alkyl)(Ci-6alkyl), SCi-6alkyl, S(O)Ci-6alkyl and SO₂C₁₋₆alkyl.

[0096] In an aspect, the present disclosure provides a method of use of the compound, salt, or solvate of any of the embodiments disclosed herein in the treatment of a disease or disorder mediated by the 5-HT2 receptor. In some embodiments, the disease or disorder is a 5-HT2A and / or 5-HT2c receptor-mediated disorder. In some embodiments, the disease or disorder is depressive disorder, an anxiety disorder, panic attack, agoraphobia, specific phobia, social phobia, bipolar disorder, post-traumatic stress, an eating disorder, a mood disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, sleep apnea, migraine, sexual dysfunction, inflammation, pain, neuropatic pain, epilepsy, a central nervous system disorder, trauma, stroke, spinal cord injury, a cardiovascular disorder, diabetes insipidus, or obsessive disorder.

[0097] In an aspect, the present disclosure provides a method of use of the composition of any of the preceding claims to ameliorate at least one symptom of a brain disorder, stress, anxiety, addiction, depression, compulsive behavior, or by promoting weight loss, or by improving mood, or by treating or preventing a psychological disorder, or by enhancing performance.

[0098] In an aspect, the present disclosure provides a method of treating at least one symptom of a brain disorder, stress, anxiety, addiction, depression, or compulsive behavior comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein. In an aspect, the present disclosure provides a method of promoting weight loss comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein. In an aspect, the present disclosure provides a method of improving mood comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein. In an aspect, the present disclosure provides a method of preventing a psychological disorder comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein. In an aspect, the present disclosure provides a method of enhancing performance comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein. In an aspect, the present disclosure provides a method of treating depressive disorder, an anxiety disorder, panic attack, agoraphobia, specific phobia, social phobia, bipolar disorder, post-traumatic stress, aneating disorder, a mood disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, sleep apnea, migraine, sexual dysfunction, inflammation, pain, neuropatic pain, epilepsy, a central nervous system disorder, trauma, stroke, spinal cord injury, a cardio-vascular disorder, diabetes insipidus, or obsessive disorder comprising administering to a patient in need thereof the compound, salt, or solvate of any of the embodiments disclosed herein.

[0099] Preparation of Compounds

[0100] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature." Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U. K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U. K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U. K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U. K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0101] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, " Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., " Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, " Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, " Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, " Advanced Organic Chemistry:Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992.Additional suitable reference books and treatise that detail the synthesis of reactants useful inthe preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. " Organic Synthesis:Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. " Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. " Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. " Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) " Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. " Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. " Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., " Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; " Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; " Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and " Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0102] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D. C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g, those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth " Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.The compounds of Formula I generally can be prepared according to the processes illustrated in the Scheme 1 below. In the structural formulae shown below the variables are as defined in Formula I unless otherwise stated.1) Br2, dioxane Methyl acrylate TMSCI, Na, MeOH, 70 °C Toluene, 110 °C 2HBr Step 1 Step 2 Step3 73% 83% (crude) 64%Step 4 64% tBuONO, TICI41) 1 -chloroethyl chloroformate, toluene, 100°C ZR'kTRJaH 2) MeOH, 80°C KOH, DMSO Step 6 Step 5 Formula I (R3=H) 16 -49% 42 - 86%Common Intermediate Scheme 1The required tetrahydro-4, 5-bis(trimethylsilyloxy)-azepines C may be obtained by acyloin condensation from dicarboxylic acid diester B (commercial from Ambeed, Frontier, JW Labs and Comiblock) with sodium in the presence of chloro-trimethylsilane [see J. Org. Chem.1977, 42, (24), 3393 or Synthesis 263 (1971)] which in turn can be prepared from the addition of benzylamine A to methyl acrylate. Cyclocondensation of amino-acetamidine hydrochloride with C affords amino-pyrazine D. Diazotization with TiCh provides intermediate E. Subsequent coupling of the intermediate E with various arylalkyl alcohol or heteroarylarylalkyl alcohols provides the intermediates F-F13. Followed up selective deprotection of the benzyl group afforded compounds of Formula I wherein R3=H.Reductive Aminationsor alkylationszFormula I (R3=H)Formula IScheme 2An alternative to compounds of Formula 1 for wherein R3 is selected from C1-C6 alkyl can also be prepared according to Scheme 2.Generally, the reactions described above are performed in a suitable inert organic solvent and at temperatures and for times that will optimize the yield of the desired compounds.Examples of suitable inert organic solvents include, but are not limited to, dimethylformamide (DMF), dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0103] Pharmaceutical Compositions

[0104] In certain embodiments, the heterocyclic 5-HT2a and / or 5-HT2c receptor agonist compound, salt, or solvate of any of the embodiments disclosed herein is administered as a pure chemical. In other embodiments, the heterocyclic 5-HT2a and / or 5-HT2C receptor agonists compound, salt, or solvate described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005).

[0105] Provided herein is a pharmaceutical composition comprising at least one heterocyclic 5-HT2a and / or 5-HT2c receptor agonists compound, as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0106] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0107] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0108] In certain embodiments, the heterocyclic 5-HT2a and / or 5-HT2c receptor agonists compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0109] In some embodiments, the pharmaceutical composition is an oral formulation, a buccal formulation, a nasal formulation, parenteral formulation (e.g. intravenous,subcutaneous, intramuscular), intranasal formulation, topical formulation, rectal formulation, transdermal formulation or an inhalation formulation. In some embodiments, the pharmaceutical composition is in a form selected from a spray, aerosol, mist, nebulae, ointment, cream, gel, paste, salve, solution, suspension, tincture, patch, injectable and atomized vapor.

[0110] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005).

[0111] In some embodiments, the heterocyclic 5-HT2a and / or 5-HT2c receptor agonists compound as described by Formula (I), or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a nonaqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0112] The dose of the composition comprising at least one heterocyclic 5-HT2a and / or 5-HT2c receptor agonists compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0113] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptomseverity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0114] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

[0115] Methods of Treatment

[0116] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

[0117] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of a disease or disorder mediated by the 5-HT2A and / or 5-HT2c receptor. In some embodiments, the disease or disorder is is mediated by activating the 5-HT2A and / or 5 -HT2c receptor signaling axis. In some embodiments, the disease, disorder or condition that is treatable by activating the 5-HT2Aand / or 5HT2C receptor, is a CNS disorder. In some embodiments, the treatment comprises administration of an amount of at least one compounds described herein that is effective to ameliorate at least one symptom of a brain disorder, for example, improvement in mental or physical well-being in the subject (e.g., by treating stress, anxiety, addiction, depression, compulsive behavior, by promoting weight loss, by improving mood, by treating or preventing a condition (e.g. psychological disorder), or by enhancing performance.

[0118] A “5-HT2A and / or 5 -HT2c receptor-mediated disorder or condition”, as used herein, is a disorder or condition in which there is believed or shown to be involvement of the pathway controlled by the 5-HT2A and / or 5 -HT2c receptor and which is ameliorated by treatment with an agonist of the 5-HT2A and / or 5 -HT2c receptor.

[0119] In some embodiments, the disorders or conditions are Central Nervous System (CNS) or neurological disorders or conditions. In some embodiments, the disorders or conditions are neurocognitive disorders or conditions. In some embodiments, the disorders or conditions are neurodegenerative disorders or conditions. In some embodiments, the symptoms of the neurological condition are physical, behavioral, emotional, mental, or a combination thereof.

[0120] Examples of the disorders, conditions and symptoms which may be managed or treated include, by way of non-limiting examples: addiction disorders, such as but not limited to alcohol abuse, substance abuse, smoking, obesity, eating disorders and auditory disorders, pain, such as but not limited to chronic pain, depression, bipolar disorder, post- traumatic stress disorder (PTSD), panic disorder, phobia, schizophrenia, psychopathy, or antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome or autism, compulsive disorder, such as but not limited to obsessive compulsive disorder (OCD), gambling, or aberrant sexual behavior, personality disorders, such as but not limited to conduct disorder, antisocial personality, or aggressive behavior.

[0121] Further examples of the disorders, conditions and symptoms which may be managed or treated include, by way of non-limiting examples:- Neurodevelopmental disorders such as, but not limited to, attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder, learning disorders and the like.- Schizophrenia spectrum and other psychotic disorders including but not limited to detachment from reality, delusions, hallucinations, and disorganized thinking and speech. - Bipolar and related disorders which may involve episodes of mania (periods of excessive excitement, activity, and energy) alternating with periods of depression.- Depressive disorders which may involve feelings of extreme sadness, reduced interest in previously enjoyable activities, including but not limited to depression, severe depression, major depressive disorder (MDD), premenstrual dysphoric disorder (PMDD) and the like. - Anxiety disorders which may involve worrying excessively about potential bad things or situations. Examples include generalized anxiety disorder (GAD), panic disorder and phobias (irrational fears of specific things) and the like.- Obsessive-compulsive and related disorders which may involve repeated, unwanted urges, thoughts, or images (obsessions) and feeling driven to taking repeated actions in response to them (compulsions). Non-limiting examples include obsessive-compulsive disorder (OCD), hoarding disorder, extreme nail biting, and hair-pulling disorder (trichotillomania). - Trauma and stressor-related disorders which may develop during or after stressful or traumatic life events. Non-limiting examples include post-traumatic stress disorder (PTSD) and acute stress disorder.- Dissociative disorders wherein the sense of self may be disrupted, such as but not limited to dissociative identity disorder, dissociative amnesia and the like.- Somatic syndrome and related disorders which may involve distressing and incapacitating physical symptoms with no clear medical cause. Non-limiting examples include illness anxiety disorder, somatic symptom disorder (hypochondriasis), factitious disorder and the like.- Feeding and eating disorders which may involve disturbances related to eating, such as but not limited to anorexia nervosa, bulimia nervosa, and binge eating disorder.- Elimination disorders which may involve inappropriate elimination (release) of urine or stool by accident or deliberately, such as but not limited to bedwetting (enuresis).- Sleep-wake disorders which may involve severe sleep disorders, including but not limited to insomnia disorder, nightmare disorder, sleep apnea, and restless legs syndrome.- Disruptive, impulse-control, and conduct disorders which may involve difficulty with emotional and / or behavioral self-control, such as but not limited to kleptomania (repeated stealing), pyromania, and intermittent explosive disorder.- Substance-related disorders which may involve problems associated with excessive use of substances such as alcohol (alcohol dependence, alcoholism), tobacco products, drugs, opioids (for example, cocaine, oxycodone, morphine and the like), recreational drugs, hallucinogens and the like.- Addictive disorders which may involve problems associated with excessive use of particular behaviors or fixations, such as but not limited to gambling disorder.- Neurocognitive disorders which may affect the ability to think and reason, such as but not limited to traumatic brain injury (TBI), Alzheimer's disease and the like.- Personality disorders which may involve enduring patterns of emotional instability and unhealthy behaviors that disrupt daily living and relationships. Examples include but are not limited to borderline, antisocial, and narcissistic personality disorders.- Gender dysphoria which may involve distress caused by a person's desire to be a different gender.- Sexual dysfunctions such as but not limited to premature ejaculation, erectile disorder, and female orgasmic disorder.- Paraphilic disorders (sexual perversion, sexual deviation) which may involve sexual interest in atypical objects, situations, fantasies, behaviors, or individuals. Examples include but are not limited to sexual sadism disorder, voyeuristic disorder, and pedophilic disorder.

[0122] Further examples of the disorders, conditions and symptoms which may be managed or treated using the compounds described herein include, by way of non-limiting example, Fragile X syndrome, Down syndrome, migraine headache, cluster headache, psychiatric disorders, neurodevelopmental disorders, attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder, learning disorders, schizophrenia spectrum, psychotic disorders, bipolar disorders, depression, severe depression, major depressive disorder (MDD), premenstrual dysphoric disorder (PMDD), suicidality, mood related disorders, panic disorder, panic attack, phobias, agoraphobia, selective mutism, obsessive-compulsive disorder (OCD), hoarding disorder, hair-pulling disorder (trichotillomania), excoriation (skin-picking) disorder, substance-Zmedication-induced obsessive-compulsive disorder, trauma-related disorders, traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), acute stress disorder, dissociative disorders, dissociative identity disorder, dissociative amnesia, anxiety, anxiety disorders, generalized anxiety disorder (GAD), social anxiety disorder, separation anxiety disorder, illness anxiety disorders, somatic disorders and diseases, somatic symptom disorder (hypochondriasis), factitious disorder, feeding disorders, eating disorders, anorexia, anorexia nervosa, bulimia nervosa, binge eating disorder, elimination disorders, enuresis, sleep disorders, insomnia, nightmare disorder, sleep apnea, central sleep apnea, narcolepsy, obstructive sleep apnea, hypopnea, and sleep-related hypoventilation, restless legs syndrome, jet lag, sexual dysfunction, premature ejaculation, erectile disorder, female orgasmic disorder, gender identity disorder, gender dysphoria, disruptive disorders, impulse-control disorders, conduct disorders, disruptive conduct disorders, impulse-control disorders, oppositional defiant disorder (ODD), aggression, kleptomania, pyromania, addictive disorders, substance dependence, substance abuse, alcoholism, drug addiction, opioid addiction, cocaine addiction, gambling addiction, tobacco dependence, food addiction, other forms of addiction to substances and behaviors, obesity, cognitive disorders, memory related disorders, learning related disorders, neurocognitive disorders, Alzheimer's disease, personality disorders, narcissistic personality disorders, Asperger syndrome, Tourette syndrome, Huntington’s disease, Parkinson’s disease, Lewy body disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, muscular atrophy, prion disease, dementia, vascular dementia, dementia / neurocognitive issues due to infection, dementia due to substance abuse or exposure to toxins, frontotemporal degeneration, mood disorders, delirium, aphasia, apraxia, agnosia, concussion, amnesia, anterograde amnesia, retrograde amnesia, body dysmorphic disorder, reactive attachment disorder, Fragile X syndrome, Down syndrome, migraines, migraineheadache, cluster headache, cardiovascular disease, inflammatory conditions, fibromyalgia and pain.

[0123] Further examples of the disorders, conditions and symptoms which may be managed or treated include by way of non-limiting examples, include epilepsy, pain, tubular sclerosis, attention disorders, diseases with monogenic alterations, psychological, cognitive, behavioral, and / or mood disorders. In certain instances, the methods included by way of nonlimiting example, include improved motivation, attention, accuracy, speed of response, perseveration, and / or cognitive engagement. In some embodiments, the management or treatment of disorders, such as where motivation, attention, accuracy, speed of response, perseverance, and / or cognitive engagement play a role, are contemplated. In certain embodiments, compositions provided herein are useful in or used in the treatment of depression, anxiety, apathy and / or low motivation, attention disorders, disorders of executive function and / or cognitive engagement, obsessive compulsive disorder, and / or neurocognitive disorders.

[0124] Further examples of the disorders, conditions and symptoms which may be managed or treated include by way of non-limiting example, schizophrenia, depression / suicide, anxiety, obsessive compulsive disorders (OCD), bipolar disorders, attention deficit hyperactivity disorder (ADHD), eating disorders such as anorexia nervosa, weight gain or loss, autism and autism spectrum disorders, Asperger’s, neuropsychiatric diseases and disorders, sexual disorders such as erectile dysfunction, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, metabolic diseases such as obesity and diabetes, central nervous system disorders, peripheral nervous system disorders, Alzheimer’s disease, snoring, sleep apnea (obstructive sleep apnea, central sleep apnea), insomnia, sleep deprivation, restless legs syndrome, parasomnia, nightmares, night terrors, sleepwalking, hypersomnia (daytime sleepiness), narcolepsy, pain (e.g. post-surgical, cancer-related and otherwise), cognitive function and social interaction.

[0125] Lack of side effects

[0126] In some embodiments, a disorder or condition described herein is treated by administration of a therapeutically effective amount of a compound as described herein without resulting in an adverse effect (e.g., hallucinogenic or other adverse effect, such aspanic attacks, psychosis, nausea, vomiting, muscle weakness, lack of coordination, and / or a cardiac condition (e.g. cardiac valvulopathy).Route of Administration

[0127] Provided hereing is a method wherein the pharmaceutical composition is administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g. intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal administration routes.

[0128] In one embodiment, the pharmaceutical composition is administered orally.

[0129] In one embodiment, the pharmaceutical composition is administered by injection.

[0130] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.EXAMPLES

[0131] I. Chemical Synthesis

[0132] The compounds of Formula I were generally prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below for representative Example 1, the variables are as defined in Formula I unless otherwise stated.Scheme 3: Synthesis of compounds of Examples 1 to Example 11

[0133] Step 1: Synthesis of dimethyl 3,3'-(benzylazanediyl)dipropionate (B).

[0134] A solution of benzylamine A (50.00 g, 466.6 mmol, 1 eq.) and methyl acrylate (80.34 g, 933.2 mmol, 2 eq.) in MeOH (250 mL) was stirred for 4 h at 70°C. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (Biotage Isolera, 0 - 5% MeOH in DCM) to give dimethyl 3,3'-(benzylazanediyl)dipropionate B (94.70 g, 73% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34 – 7.19 (m, 5H), 3.64 (s, 6H), 3.58 (s, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.46 (t, J = 7.2 Hz, 4H). LCMS (ESI), [M+H]⁺ = 280.1 m / z.

[0135] Step 2: Synthesis of l-benzyl-4,5-bis((trimethylsilyl)oxy)-2, 3,6,7-tetrahydro-lH-azepine (C).

[0136] Sodium metal (8.64 g, 375.9 mmol, 4.2 eq.) was powdered in toluene (150 mL) at reflux with vigorous stirring. Once cooled, the mixture was sparged with argon for 5 minutes before TMSC1 (52.25 mL, 411.7 mmol, 4.6 eq.) was added. While the solution was heating up to reflux, a solution of dimethyl 3,3'-(benzylazanediyl)dipropionate B (25.00 g,89.5 mmol, 1 eq.) in argon-sparged Toluene (50mL) was added by addition funnel over 25 min. After the addition was complete, the reaction mixture was refluxed with stirring for 90 minutes. The reaction was cooled to room temperature and solids were removed from the mixture by filtration. The filtrate was washed with sat. NaHCO₃ (2 x 100 mL), dried over Na2SO4, and evaporated to dryness to give crude l-benzyl-4,5-bis((trimethylsilyl)oxy)-2,3,6,7-tetrahydro-17 / -azepine C (27.10 g, 83% crude yield) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34 – 7.31 (m, 4H), 7.25 (d, J = 3.8 Hz, 1H), 3.57 (s, 2H), 2.66 – 2.57 (m, 4H), 2.35 – 2.25 (m, 4H), 0.16 (s, 18H).

[0137] Step 3: Synthesis of 7-benzyl-6.7.8.9-tetraliydro-5 / / -pyrazino|2.3-rfJazepin-2-amine (D).

[0138] To a stirred solution of crude l-benzyl-4,5-bis((trimethylsilyl)oxy)-2, 3,6,7-tetrahydro- Irt-azepine C (27.00 g, 74.3 mmol, 1 eq.) in 1,4-dioxane (200 mL) at 0°C was added solution of Br₂ (3.81 mL, 74.3 mmol, 1 eq.) in 1,4-dioxane (100 mL). After stirring for about 5 minutes, pyridine (24.0 mL, 297.0 mmol, 4 eq.) was added and the resulting slurry was added slowly to a solution of 2-aminoacetamidine dihydrobromide (27.91 g, 118.8 mmol, 1.6 eq.) in water (400 mL) at 0°C. After stirring for 4 hours at room temperature, the product mixture was concentrated under reduced pressure, diluted with water, made strongly alkaline with NaOH (5 M), and extracted with DCM. The combined organic fractions were dried over Na2SO4and evaporated to dryness. The crude product was purified by flash chromatography (Biotage Isolera, 0 - 20% MeOH in DCM) to give 7-benzyl-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepin-2-amine D (7.87 g, 42% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.40 – 7.30 (m, 4H), 7.29 – 7.23 (m, 1H), 4.35 (s, 2H), 3.65 (s, 2H), 3.06 – 2.99 (m, 2H), 2.99 – 2.92 (m, 2H), 2.70 – 2.62 (m, 4H). LCMS (ESI), [M+H]⁺ = 255.1 m / z.

[0139] Step 4: Synthesis of7-benzyl-2-chloro-6.7.8.9-tetrahydro-5 / / -pyrazino [2, 3-ti| azepine (E).

[0140] To a stirred solution of 7-benzyl-6.7.8.9-tetrahydro-57 / -pyrazino|2.3- / |azepin-2-amine D (3.56 g, 14.0 mmol, 1 eq.) in DCM (150 mL) at 0°C was added TiCl₄ (1 M in DCM, 33.6 mL, 33.6 mmol, 2.4 eq.) and tert-butyl nitrite (3.33 mL, 28.0 mmol, 2 eq.) was added dropwise. The reaction mixture was allowed to warm to room temperature with stirring for 1 hour. Once complete, the product mixture was basified to a pH of 8 with 2M NaOH.The suspension was filtered and the filtrate was partitioned between water and DCM (50 mL). The aqueous fraction was extracted with DCM (2x 30 mL), washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by flash chromatography (Biotage Isolera, 0 - 10% MeOH in DCM) to give 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine E (2.45 g, 64% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 7.38 – 7.30 (m, 4H), 7.30 – 7.21 (m, 1H), 3.66 (s, 2H), 3.13 – 3.03 (m, 4H), 2.69 – 2.62 (m, 4H). LCMS (ESI), [M+H]⁺ = 274.1 m / z.

[0141] Step 5: General Procedure A - synthesis of intermediates Fl and F6 through F13.

[0142] To a mixture of 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (1 eq.) and potassium hydroxide (1.5 - 3 eq.) in DMSO (0.35 M) was added the appropriate aromatic alcohol (Ri-OH) (1.1 - 2 eq.) at room temperature with stirring. Once complete by LCMS, the resulting product mixture was poured into ice water and extracted with EtOAc. The combined organic fractions were washed with ice water and brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of EtOAc in hexanes to give intermediates Fl & F6 - F13 (45 - 86% yield).

[0143] Synthesis of 7-benzyl-2-(benzyl()xy)-6.7.8.9-tetrahydro-5 / / -pyrazino|2.3-rfjazepine (Fl).

[0144] Benzyl alcohol (0.47 mL, 4.57 mmol, 1.25 eq.), 7-benzyl-2-chl oro-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (1.00 g, 3.65 mmol, 1 eq.), and potassium hydroxide (358.68 mg, 6.39 mmol, 1.75 eq.) were reacted in DMSO (10 mL) according to General Procedure A to give 7-benzyl-2-(benzyloxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine Fl (1.03 g, 82% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.49 – 7.43 (m, 2H), 7.41 – 7.36 (m, 2H), 7.36 – 7.29 (m, 5H), 7.29 – 7.21 (m, 1H), 5.33 (s, 2H), 3.64 (s, 2H), 3.05 – 2.96 (m, 4H), 2.67 – 2.57 (m, 4H). LCMS (ESI), [M+H]⁺ = 346.2 m / z.

[0145] Synthesis of (5')-7-benzyl-2-( l-phenylethoxy)-6.7.8.9-tetrahydro-5 / / -pyrazino [2, 3-i / | azepine (F6).

[0146] (5')-l -Phenylethanol (0.1378mL, 1.14mmol), 7-benzyl-2-chl oro-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250.0 mg, 0.91 mmol, 1 eq.), and potassiumhydroxide (89.67 mg, 1.60 mmol, 1.75 eq.) were reacted in DMSO (3mL) according to General Procedure A to give (S)-7-benzyl-2-(1-phenylethoxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine F6 (196.4 mg, 60% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.47 – 7.39 (m, 2H), 7.38 – 7.29 (m, 6H), 7.29 – 7.20 (m, 2H), 6.11 (q, J = 6.5 Hz, 1H), 3.61 (s, 2H), 3.00 – 2.89 (m, 4H), 2.57 (ddd, J = 13.6, 6.7, 3.3 Hz, 4H), 1.57 (d, J = 6.6 Hz, 3H). LCMS (ESI), [M+H]⁺ = 360.2 m / z.

[0147] Synthesis of ( / )-7-benzyl-2-(l-plienyletlioxy)-6.7.8.9-tetrahydro-5 / / -pyrazino [2, 3-rf] azepine (F7).

[0148] (R)- 1 -Phenylethanol (0.1397mL, 1.14mmol, 1.25 eq.), 7-benzyl-2-chloro- 6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250.0 mg, 0.91 mmol, 1 eq.) and potassium hydroxide (89.6702mg, 1.6mmol) were reacted in DMSO (3mL) according to General Procedure A to give (7?)-7-benzyl-2-(l-phenylethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F7 (259.2 mg, 79% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.47 – 7.39 (m, 2H), 7.38 – 7.29 (m, 6H), 7.29 – 7.20 (m, 2H), 6.11 (q, J = 6.5 Hz, 1H), 3.61 (s, 2H), 3.00 – 2.89 (m, 4H), 2.57 (ddd, J = 13.7, 6.4, 3.3 Hz, 4H), 1.57 (d, J = 6.6 Hz, 3H). LCMS (ESI), [M+H]⁺ = 360.2 m / z.

[0149] Synthesis of 7-benzyl-2-((2-chlorobenzyl)oxy)-6.7.8.9-tetrahydro-5 / / -pyrazino [2, 3-rf] azepine (F8).

[0150] 2-chlorobenzyl alcohol (208.3 mg, 1.46 mmol, 2 eq.), 7-benzyl-2-chloro- 6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (200 mg, 0.73 mmol, 1 eq.), and potassium hydroxide (122.9 mg, 2.19 mmol, 3 eq.) were reacted in DMSO (3 mL) according to General Procedure A to give 7-benzyl-2-((2-chlorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F8 (158.0 mg, 42% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.64 – 7.56 (m, 1H), 7.55 – 7.45 (m, 1H), 7.44 – 7.31 (m, 6H), 7.26 (ddt, J = 8.6, 5.3, 2.7 Hz, 1H), 5.41 (s, 2H), 3.64 (s, 2H), 3.06 – 2.97 (m, 4H), 2.62 (t, J = 11.3 Hz, 4H). LCMS (ESI), [M+H]⁺ = 380.2 m / z.

[0151] Synthesis of 7-benzyI-2-((4-fluorobenzyI)oxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, 3-rf] azepine (F9).

[0152] 4-Fluorobenzyl alcohol (0.11 mL, 1.00 mmol, 1.1 eq.), 7-benzyl-2-chloro- 6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassiumhydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-((4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F9 (266.7 mg, 80% yield) as a yellow oil. 'H NMR (400 MHz, DMSO- L) δ 8.00 (s, 1H), 7.56 – 7.48 (m, 2H), 7.39 – 7.31 (m, 4H), 7.28 – 7.24 (m, 1H), 7.24 – 7.16 (m, 2H), 5.31 (s, 2H), 3.64 (s, 2H), 3.05 – 2.97 (m, 4H), 2.67 – 2.57 (m, 4H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ -114.24 (tt, J = 9.2, 5.5 Hz). LCMS (ESI), [M+H]⁺ = 334.2 m / z.

[0153] Synthesis of 7-benzy l-2-((2.4-d inuorobenzyl )oxy)-6.7.8.9-tet rally dro-5 / / -pyrazino [2, 3-i / | azepine (F10).

[0154] 2,4-Difluorobenzyl alcohol (89.8 pL, 0.80 mmol, 1.1 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (200 mg, 0.73 mmol, 1 eq.), and potassium hydroxide (61.5 mg, 1.10 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-((2,4-difluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F10 (125.2 mg, 45% yield) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (s, 1H), 7.64 (td, J = 8.6, 6.6 Hz, 1H), 7.39 – 7.33 (m, 4H), 7.30 (ddd, J = 10.4, 2.3, 1.2 Hz, 1H), 7.26 (ddt, J = 6.6, 5.3, 2.6 Hz, 1H), 7.11 (tdd, J = 8.5, 2.6, 1.1 Hz, 1H), 5.34 (d, J = 1.1 Hz, 2H), 3.64 (s, 2H), 3.01 (dt, J = 7.2, 3.9 Hz, 4H), 2.67 – 2.57 (m, 4H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ -109.48 – -109.78 (p, J = 8.5 Hz), -113.44 – -113.79 (m). LCMS (ESI), [M+H]⁺ = 382.1 m / z.

[0155] Synthesis of 7-benzyl-2-((5-fluoropyridin-2-yl)methoxy)-6, 7,8,9-tet rall d ro-5 / / -py razino [2,3-rf] azepine (F 11).

[0156] (5-Fluoropyridin-2-yl)methanol (139.3 mg, 1.10 mmol, 1.2 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-((5-fluoropyridin-2-yl)methoxy)-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine Fll (286.6 mg, 86% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (dt, J = 2.9, 0.7 Hz, 1H), 8.06 (s, 1H), 7.75 (td, J = 8.8, 3.0 Hz, 1H), 7.59 (ddd, J = 8.6, 4.5, 0.6 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.29 – 7.21 (m, 1H), 5.40 (s, 2H), 3.64 (s, 2H), 3.06 – 2.94 (m, 4H), 2.65 – 2.56 (m, 4H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ 19F NMR (377 MHz, DMSO) δ -128.58 – -128.77 (m). LCMS (ESI), [M+H]⁺ = 365.1 m / z.

[0157] Synthesis of 7-benzy l-2-(py ridin-2-y linethoxy)-6.7.8.9-tet rally dro-5 / / -pyrazino [2, 3-i / | azepine (F12).

[0158] 2-Pyridinemethanol (0.11 mL, 1.14 mmol, 1.25 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine F12 (232.3 mg, 73% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.07 (s, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.49 (dt, J = 7.8, 1.1 Hz, 1H), 7.38 – 7.30 (m, 5H), 7.25 (ddt, J = 8.6, 5.5, 2.9 Hz, 1H), 5.41 (s, 2H), 3.63 (s, 2H), 3.06 – 2.93 (m, 4H), 2.61 (td, J = 6.6, 2.5 Hz, 4H). LCMS (ESI), [M+H]⁺ = 347.2 m / z.

[0159] Synthesis of 7-benzy l-2-(py ridin-3-y lmethoxy)-6.7.8.9-tet rally dro-5 / / -pyrazino [2, 3-i / | azepine (F13).

[0160] Nicotinyl alcohol (97.5 pL, 1.00 mmol, 1.1 eq.), 7-benzyl-2-chl oro-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-(pyridin-3-ylmethoxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-rf]azepine F13 (247.7mg,0.7150mmol, 78.296% yield) as alight yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (dd, J = 2.3, 0.8 Hz, 1H), 8.54 (dd, J = 4.8, 1.7 Hz, 1H), 8.02 (s, 1H), 7.89 (ddd, J = 7.8, 2.3, 1.7 Hz, 1H), 7.41 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 7.38 – 7.30 (m, 4H), 7.26 (ddt, J = 8.5, 5.3, 2.7 Hz, 1H), 5.37 (s, 2H), 3.64 (s, 2H), 3.05 – 2.97 (m, 4H), 2.67 – 2.56 (m, 4H). LCMS (ESI), [M+H]⁺ = 347.2 m / z.

[0161] Step 6: General procedure B - synthesis of Examples 1-9.

[0162] 1-chloroethyl chloroformate (5 eq.) was added to a solution of intermediates Fl & F6 - F13 (1 eq.) in toluene (0.2 M). The reaction mixture was heated to reflux under argon with stirring. After 2 hours, the volatiles were removed under reduced pressure and the residue was dissolved in MeOH (0.2 M). After refluxing for 1 hour and cooling, MP Carbonate (5 eq.) was added, and the product mixture was stirred for 1 hour. The MP-carbonate was removed by filtration and washed with MeOH. The combined filtrates were concentrated under reduced pressure and the crude product was purified by flashchromatography eluting with a gradient of MeOH in DCM) to give 2-(benzyloxy)-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine Examples 1- 9 (16 - 49% yield).

[0163] Synthesis of 2-(benzyloxy)-6.7.8.9-tet rally dro-5 / / -pyrazino [2, 3-ti| azepine (Example 1).

[0164] 1-chloroethyl chloroformate (1.61 mL, 14.97 mmol, 5 eq.) and 7-benzyl-2-(benzyloxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine F-l (1.03 g, 2.99 mmol, 1 eq.) were reacted in toluene (15 mL) and methanol (15 mL) according to General Procedure B to give 2-(benzyloxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine Example 1 (263.7 mg, 34% yield) as a tan solid. 'H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.12 (s, 1H), 7.51 -7.44 (m, 2H), 7.42 - 7.31 (m, 3H), 5.36 (s, 2H), 3.27 (d, J= 7.4 Hz, 8H). HRMS (ESI) m / z calcd. for C15H17N3O [M + H]+: 256.1450; found, 256.1452. HPLC purity > 99%.

[0165] Synthesis of (5')-2-(l-phenylethoxy)-6.7.8.9-tetrahydro-5 / / -pyrazino|2.3-d\ azepine (Example 2).

[0166] 1-chloroethyl chloroformate (0.29 mL, 2.73 mmol, 5 eq.) and (< S)-7-benzyl-2-(l-phenylethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F6 (196.4 mg, 0.55 mmol, 1 eq.) were reacted in toluene (4 mL) and methanol (4 mL) according to General Procedure B to give (5 -2-(l-phenylethoxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine (Example 2) (23.2 mg, 16% yield) as a brown oil. 'H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.47 -7.40 (m, 2H), 7.39 - 7.31 (m, 2H), 7.30 - 7.22 (m, 1H), 6.10 (q, J= 6.5 Hz, 1H), 3.78 (s, 1H), 2.95 (dd, J= 6.1, 3.8 Hz, 2H), 2.92 - 2.87 (m, 2H), 2.87 - 2.75 (m, 4H), 1.57 (d, J= 6.5 Hz, 3H). HRMS (ESI) m / z calcd. for C16H19N3O [M + H]+: 270.1606; found, 270.1610. HPLC purity > 99%.

[0167] Synthesis of (7?)-2-(l-phenylethoxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino[2,3-d\ azepine (Example 3).

[0168] 1-chloroethyl chloroformate (0.38 mL, 3.55 mmol, 5 eq.) and (7?)-7-benzyl-2-(l-phenylethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F7 (255.0 mg, 0.71 mmol, 1 eq.) were reacted in toluene (5 mL) and methanol (5 mL) according to General Procedure B to give (7?)-2-(l-phenylethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine (Example 3) (67.4 mg, 35% yield) as a yellow solid. ' H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.48 -7.40 (m, 2H), 7.39 - 7.32 (m, 2H), 7.31 - 7.24 (m, 1H), 7.09 (s, 1H), 6.12 (q, J= 6.5 Hz, 1H),3.11 - 2.93 (m, 8H), 1.58 (d, J= 6.5 Hz, 3H). HRMS (ESI) m / z calcd. for C16H19N3O [M + H]+: 270.1606; found, 270.1611. HPLC purity > 99%.

[0169] Synthesis of 2-((2-chlorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d] azepine (Example 4).

[0170] 1-chloroethyl chloroformate (0.34 mL, 3.16 mmol, 8 eq.) and 7-benzyl-2-((2-chlorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F8 (150.mg, 0.39mmol, 1 eq.) were reacted in toluene (2 mL) and methanol (2 mL) according to General Procedure B to give 2-((2-chlorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine (Example 4) (29.0 mg, 25% yield) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.64 -7.57 (m, 1H), 7.56 - 7.47 (m, 1H), 7.44 - 7.33 (m, 2H), 5.41 (s, 2H), 3.04 - 2.92 (m, 4H), 2.88 - 2.78 (m, 4H). HRMS (ESI) m / z calcd. for C15H16ClN3O [M + H]+: 290.1060; found, 290.1066. HPLC purity > 99%.

[0171] Synthesis of 2-((4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino[2,3-d\ azepine (Example 5).

[0172] 1-chloroethyl chloroformate (0.39 mL, 3.58 mmol, 5 eq.) and 7-benzyl-2-((4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F9 (260.0 mg, 0.72 mmol, 1 eq.) were reacted in toluene (5 mL) and methanol (5 mL) according to General Procedure B to give 2-((4-fluorobenzyl)oxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine (Example 5) (78.6 mg, 40% yield) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.56 - 7.47 (m, 2H), 7.26 - 7.17 (m, 2H), 5.31 (s, 2H), 5.16 (s, 1H), 3.07 - 2.98 (m, 4H), 2.98 - 2.88 (m, 4H).19F NMR (377 MHz, DMSO- L) 8 -114.22 (tt, J= 9.1, 5.5 Hz). HRMS (ESI) m / z calcd. for C15H16FN3O [M + H]+: 274.1356; found, 274.1352. HPLC purity > 99%.

[0173] Synthesis of 2-((2,4-difhiorobenzyl)oxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, 3-r / | azepine (Example 6).

[0174] 1-chloroethyl chloroformate (0.25 mL, 2.29 mmol, 5 eq.) and 7-benzyl-2-((2,4-difluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F10 (175.0 mg, 0.46 mmol, 1 eq.) were reacted in toluene (3 mL) and methanol (3 mL) according to General Procedure B to give 2-((2,4-difluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-d\ azepine (Example 6) (67.0 mg, 49% yield) as a tan solid. 'H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.64 (td, J= 8.6, 6.6 Hz, 1H), 7.30 (ddd, J= 10.5, 9.3, 2.5 Hz, 1H), 7.12 (tdd,.7= 8.5, 2.6, 1.1 Hz, 1H), 5.35 (s, 2H), 5.28 (s, 1H), 3.03 (ddd, J= 9.3, 4.6, 2.2 Hz, 4H), 2.99 - 2.88 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -109.57 (dt, J= 16.1, 8.3 Hz), -113.58 (q, J= 8.8 Hz). HRMS (ESI) m / z calcd. for C15H15F2N3O [M + H]+: 292.1261; found, 292.1269. HPLC purity = 97.4%.

[0175] Synthesis of 2-((5-fluoropyridin-2-yl)methoxy)-6,7,8,9-tetrahydro-527-pyrazino [2, 3-rf] azepine (Example 7).

[0176] 1-chloroethyl chloroformate (0.42 mL, 3.93 mmol, 5 eq.) and 7-benzyl-2-((5-fluoropyridin-2-yl)methoxy)-6,7,8,9-tetrahydro-577-pyrazino[2,3-< / ]azepine Fll (286.6 mg, 0.79 mmol, 1 eq.) were reacted in toluene (5 mL) and methanol (5 mL) according to General Procedure B to give 2-((5-fluoropyridin-2-yl)methoxy)-6,7,8,9-tetrahydro-577-pyrazino[2,3-<7]azepine (Example 7) (85.0 mg, 38% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 88.57 (d, J= 2.9 Hz, 1H), 8.10 (s, 1H), 7.77 (td, J= 8.7, 2.9 Hz, 1H), 7.60 (dd, J= 8.7, 4.5 Hz, 1H), 6.98 (s, 1H), 5.41 (s, 2H), 3.15 - 3.09 (m, 2H), 3.09 - 3.03 (m, 4H), 3.03 - 2.98 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -128.51 – -128.76 (m). HRMS (ESI) m / z calcd. for C14H15FN4O [M + H]+: 275.1308; found, 275.1316. HPLC purity = 97.1%.

[0177] Synthesis of 2-(pyridin-2-ylmethoxy)-6,7,8,9-tetrahydro-527-pyrazino[2,3-d\ azepine (Example 8).

[0178] 1-chloroethyl chloroformate (0.35 mL, 3.25 mmol, 5 eq.) and 7-benzyl-2-(pyridin-2-ylmethoxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine F12 (225. mg, 0.65mmol, 1 eq.) were reacted in toluene (5 mL) and methanol (5 mL) according to General Procedure B to give 2-(pyridin-2-ylmethoxy)-6,7.8.9-tetrahydro-5H-pyrazino[2,3-d]azepine (Example 8) (66.5 mg, 40% yield) as a pink solid. 'H NMR (400 MHz, DMSO-d6) δ 8.57 (ddd, J= 4.8, 1.8, 0.9 Hz, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.83 (td, J= 7.7, 1.8 Hz, 1H), 7.50 (dt, J=7.9, 1.1 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 5.43 (s, 2H), 3.19 - 3.07 (m, 8H). HRMS (ESI) m / z calcd. for C14H16N4O [M + H]+: 257.1402; found, 257.1398. HPLC purity > 99%.

[0179] Synthesis of 2-(pyridin-3-ylmethoxy)-6,7,8,9-tetrahydro-527-pyrazino[2,3-d\ azepine (Example 9).

[0180] 1-chloroethyl chloroformate (0.37 mL, 3.46 mmol, 5 eq.) and 7-benzyl-2-(pyridin-3-ylmethoxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine F13 (240.0 mg, 0.69mmol, 1 eq.) were reacted in toluene (5 mL) and methanol (5 mL) according to General Procedure B to give 2-(pyridin-3-ylmethoxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine (Example 9) (57.8 mg, 31% yield) as an orange solid. 'H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.55 (dd, J= 4.8, 1.7 Hz, 1H), 8.13 (s, 1H), 7.90 (dt, J= 7.8, 2.0 Hz, 1H), 7.43 (ddd, J= 7.9, 4.8, 0.9 Hz, 1H), 5.40 (s, 2H), 3.25 (dq, J= 5.8, 2.7, 2.2 Hz, 8H). HRMS (ESI) m / z calcd. for C14H16N4O [M + H]+: 257.1402; found, 257.1407. HPLC purity = 95.5%.

[0181] Step 7: General Procedure C - synthesis of (Examples 10 and 11).

[0182] To a solution of 2-(benzyloxy)-6,7,8,9-tetrahydro-577-pyrazino[2,3-< / ]azepine Example 1 (1 eq.) in DCM (0.1 M) was added either formaldehyde ( 37% in water, 1.3 eq.) or acetone (2 eq.) and acetic acid (1.3 -2 eq.). After stirring for 30 minutes, sodium triacetoxyborohydride (1.5 - 2 eq.) was added and the reaction mixture was stirred at room temperature. Once complete, the reaction was quenched with sat NH4CI. The product was extracted with EtOAc and the combined organic fractions were washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by flash chromatography (Biotage Isolera, 0 - 25% MeOH in DCM) to give Targets 4 & 5 (23 - 52% yield).

[0183] Synthesis of 2-(benzyloxy)-7-methyl-6,7,8,9-tetrahydro-5 / 7-pyrazino[2,3-d\ azepine (Example 10).

[0184] 2-(Benzyloxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine Example 1 (75.0 mg, 0.29 mmol, 1 eq.) was reacted with formaldehyde (28.4 pL, 0.38 mmol, 1.3 eq.), acetic acid (21.8 pL, 0.38 mmol, 1.3 eq.), and sodium triacetoxyborohydride (93.4 mg, 0.44 mmol, 1.5 eq.) in DCM (2.5 mL) according to General Procedure C to give 2-(benzyloxy)-7-methyl-6,7,8,9-tetrahydro-577-pyrazino[2,3-< / ]azepine (Example 10) (41.1 mg, 52% yield) as an off white solid. 'H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.50 - 7.42 (m, 2H), 7.42 -7.28 (m, 3H), 5.34 (s, 2H), 2.99 (td, J= 7.0, 3.7 Hz, 4H), 2.56 - 2.50 (m, 4H), 2.29 (s, 3H). HRMS (ESI) m / z calcd. for C16H19N3O [M + H]+: 270.1606; found, 270.1609. HPLC purity > 99%.

[0185] Synthesis of 2-(benzyloxy)-7-isopropyl-6,7,8,9-tetrahydro-5 / 7- pyrazino [2, 3-rf] azepine (Example 11).

[0186] 2-(Benzyloxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine Example 1 (75.0 mg, 0.29 mmol, 1 eq.) was reacted with acetone (43.1 pL, 0.59 mmol, 2 eq.), acetic acid (33.6 pL, 0.59 mmol, 2 eq.), and sodium triacetoxyborohydride (124.4 mg, 0.59 mmol, 2 eq.) in DCM (2.5 mL) according to General Procedure C to give 2-(benzyloxy)-7-isopropyl- 6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine (Example 11) (20.3 mg, 23% yield) as an yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.50 - 7.43 (m, 2H), 7.42 - 7.29 (m, 3H), 5.33 (s, 2H), 3.01 - 2.93 (m, 4H), 2.90 (hept, J = 6.7 Hz, 1H), 2.66 - 2.57 (m, 4H), 0.96 (d, J= 6.6 Hz, 6H). HRMS (ESI) m / z calcd. for C18H23N3O [M + H]+: 298.1919; found, 198.1924. HPLC purity > 99%.

[0187] Synthesis of 2-(benzyloxy)-7-ethyl-6,7,8,9-tetrahydro-5 / f-pyrazino[2,3- d\ azepine (Example 12)

[0188] 2-(Benzyloxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine Example 1 (100.0 mg, 0.34 mmol, 1 eq.) was reacted with acetaldehyde (18.3 pL, 0.36 mmol, 1.05 eq.), acetic acid (49.0 pL, 0.86 mmol, 2.5 eq.), and sodium triacetoxyborohydride (110.0 mg, 0.51mmol, 1.5 eq.) in THF (3.5 mL) according to General Procedure C to give 2-(benzyloxy)-7-ethyl-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine (Example 1) (62.7mg, 64% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.50 - 7.44 (m, 2H), 7.44 - 7.29 (m, 3H), 5.34 (s, 2H), 2.99 (td, J= 6.9, 3.4 Hz, 4H), 2.65 - 2.55 (m, 4H), 2.52 (t, J= 7.2 Hz, 2H), 1.02 (t, J= 7.1 Hz, 3H). HRMS (ESI) m / z calcd. for C17H21N3O [M + H]+: 284.1763; found, 284.1765. HPLC purity = 98.7%.

[0189] Synthesis of 2-((4-fhiorobenzyl)oxy)-7-isopropyl-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, -r / | azepine (Example 13)

[0190] A mixture of 2-((4-fluorobenzyl)oxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3- <7]azepine Example 9 (68.4mg, 0.22 mmol, 1 eq.) and potassium carbonate (91.5 mg, 0.6 6mmol, 3 eq.) in anhydrous acetonitrile (0.9 mL) was allowed to stir at room temperature before 2-iodopropane (44.2 pL, 0.44 mmol, 2 eq.) was added. The reaction was allowed to stir at 90°C overnight before the solids were removed by filtration. The filtrate was evaporated to dryness and purified by flash chromatography (Biotage Isolera, 0 - 25% MeOH in EtOAc) to give Synthesis of 2-((4-fluorobenzyl)oxy)-7-isopropyl-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine (Example 13) (43.3 mg, 61% yield) as a tan solid. 'H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.52 (dd, J= 8.7, 5.4 Hz, 2H), 7.21 (t, J= 8.7 Hz, 2H), 5.32 (s, 2H), 2.97 (s, 4H), 2.62 (s, 4H), 2.61 (s, 1H), 1.00 - 0.94 (m, 6H). HRMS (ESI) m / z calcd. for C18H22FN3O [M + H]+: 316.1825; found, 316.1829. HPLC purity = 98.2%.

[0191] Synthesis of 2-((5-fhioropyridin-2-yl)methoxy)-7-isopropyl-6, 7,8,9-tet rally dro-5 / / -pyrazino [2, 3-i / | azepine (Example 14).

[0192] A mixture of 2-((5-fluoropyridin-2-yl)methoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine (Example 11) (41.0 mg, 0.15 mmol, 1 eq.) and potassium carbonate (60.2 mg, 0.44 mmol, 3 eq.) were stirred in acetonitrile (0.75 mL) for before 2-iodopropane (29.0 pL, 0.29 mmol, 2 eq.) was added and the mixture was heated to 90°C. After 2 hours, product mixture was cooled to room temperature and diluted with EtOAc. The residual solids were removed by filtration and washed with EtOAc. The combined filtrates were evaporated and the crude product was purified by flash chromatography (Biotage Isolera, 0 - 25% MeOH in DCM) and dried under high vacuum to give 2-((5-fluoropyridin-2-yl)methoxy)-7-isopropyl-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine (Example 14) (27.5 mg, 58% yield) as a light orange solid. 'H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J= 2.9 Hz, 1H), 8.06 (s, 1H), 7.76 (td,J= 8.7, 3.0 Hz, 1H), 7.59 (dd, J= 8.7, 4.5 Hz, 1H), 5.41 (s, 2H), 3.05 - 2.96 (m, 2H), 2.93 (t, J = 4.9 Hz, 3H), 2.61 (s, 4H), 0.97 (d, J = 6.5 Hz, 6H).19F NMR (377 MHz, DMSO-d6) δ -128.71 (dd, J= 8.9, 4.5 Hz). HPLC purity = 97.3%.

[0193] Step 5: Synthesis of (A)-7-benzyl-2-(l-(2-chlorophenyl)ethoxy)-6, 7,8,9-tet rally d ro-5 / / -py razino 12.3-i / | azepine (F 17).

[0194] GS')-l-(2-Chlorophenyl)ethanol (171.6 mg, 1.10 mmol, 1.2 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give (S)-7-benzyl-2-(l-(2-chlorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F17 (231.5 mg, 64% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.53 (dd, J=7.5, 2.0 Hz, 1H), 7.43 (dd, J=7.7, 1.5 Hz, 1H), 7.37 -7.21 (m, 7H), 6.35 (q, J= 6.5 Hz, 1H), 3.60 (s, 2H), 3.04 - 2.92 (m, 2H), 2.88 (td, J= 5.6, 3.1 Hz, 2H), 2.64 - 2.51 (m, 4H), 1.57 (d, J= 6.5 Hz, 3H). LCMS (ESI), [M+H]+= 394.1 m / z.

[0195] Synthesis of (A)-7-benzyl-2-(l-(4-fluorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -py razino [2, 3-«7| azepine (F18).

[0196] (< S)-l-(4-Fluorophenyl)ethanol (153.6 mg, 1.10 mmol, 1.2 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give (S)-7-benzyl-2-(l-(4-fluorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F18 (260.0 mg, 75% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.53 - 7.43 (m, 2H), 7.37 - 7.28 (m, 4H), 7.28 - 7.21 (m, 1H), 7.21 - 7.10 (m, 2H), 6.10 (q, J= 6.5 Hz, 1H), 3.61 (s, 2H), 3.00 - 2.89 (m, 4H), 2.64 - 2.52 (m, 4H), 1.56 (d, J= 6.5 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -114.87 (tt, J= 9.0, 5.5 Hz). LCMS (ESI), [M+H]+= 378.2 m / z.

[0197] Synthesis of 7-benzyl-2-((2-chloro-4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -py razino [2, 3-«7| azepine (F20).

[0198] 2-Chloro-4-fluorobenzyl alcohol (161.3 mg, 1.00 mmol, 1.1 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-((2-chloro-4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine F20 (135.9 mg, 37% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.67 (dd, J= 8.6, 6.3 Hz, 1H), 7.51 (dd, J= 8.8, 2.6 Hz, 1H), 7.38 -7.31 (m, 4H), 7.31 - 7.19 (m, 2H), 5.37 (s, 2H), 3.64 (s, 2H), 3.01 (td, J= 6.5, 3.1 Hz, 4H), 2.67 - 2.56 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -111.47 (td, J= 8.6, 6.1 Hz). LCMS (ESI), [M+H]+= 398.1 m / z.

[0199] Step 5B: General Procedure D - Synthesis of intermediates F21 and F22.

[0200] A mixture of 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7] azepine E (1 eq.), appropriate aromatic alcohol (Ri-OH) (1.1 eq), cesium carbonate (2 eq.), palladium(II) acetate (0.06 eq.), and BINAP (0.12 eq.) was dispersed in anhydrous 1,4-dioxane (0.2 M) and sparged with argon. The reaction mixture was stirred at 90 °C until complete. The product mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography to give intermediates F21and F22 (28 - 64% yield).

[0201] Synthesis of 5-(((7-benzyl-6.7.8.9-tetrahydr()-5 / / -pyrazino|2.3-i / |azepin-2-yl)oxy)methyl)-2-fluorobenzonitrile (F21).

[0202] 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (200.0 mg, 0.73 mmol, 1 eq.), 2-fluoro-5-(hydroxymethyl)benzonitrile (121.3 mg, 0.8 mmol, 1.1 eq), cesium carbonate (475.6 mg, 1.46 mmol, 2 eq.), palladium(II) acetate (9.8 mg, 0.04 mmol, 0.06 eq.), and BINAP (54.5 mg, 0.09 mmol, 0.12 eq.) were reacted 1,4-dioxane (4 mL) according to General Procedure D to give 5-(((7-benzyl-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepin-2-yl)oxy)methyl)-2-fluorobenzonitrile F21 (79.0 mg, 28% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.04 (m, 1H), 8.04 (s, 1H), 7.90 (ddd, J= 8.7, 5.3, 2.3 Hz, 1H), 7.55 (t, J= 9.0 Hz, 1H), 7.38 - 7.31 (m, 4H), 7.25 (ddt, J= 8.6, 5.5, 2.8 Hz, 1H), 5.34 (s, 2H), 3.64 (s, 2H), 3.01 (td, J= 8.4, 3.7 Hz, 4H), 2.66 - 2.56 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -109.66 (dt, J = 9.5, 5.9 Hz). LCMS (ESI), [M+H]+= 389.2 m / z.

[0203] Synthesis of 4-(((7-benzyl-6.7.8.9-tetrahydr()-5 / / -pyrazino|2.3-i / |azepin-2-yl)oxy)methyl)benzonitrile (F22).

[0204] 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (75.0 mg, 0.27 mmol, 1 eq.), 4-(hydroxymethyl)benzonitrile (40.1 mg, 0.30 mmol, 1.1 eq), cesium carbonate (178.5 mg, 0.55 mmol, 2 eq.), palladium(II) acetate (3.7 mg, 0.02 mmol, 0.06 eq.),and BINAP (20.5 mg, 0.03 mmol, 0.12 eq.) were reacted 1,4-dioxane (1 mL) according to General Procedure D to give 4-(((7-benzyl-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepin-2-yl)oxy)methyl)benzonitrile F22 (65.0 mg, 64% yield) as a yellow oil. 'H NMR (400 MHz, CDCh) 88.00 (s, 1H), 7.66 (d, J= 8.2 Hz, 2H), 7.54 (d, J= 7.9 Hz, 2H), 7.40 - 7.23 (m, 5H), 5.41 (s, 2H), 3.66 (s, 2H), 3.14 - 3.07 (m, 2H), 3.07 - 3.00 (m, 2H), 2.71 - 2.64 (m, 4H). LCMS (ESI), [M+H]+= 371.2 m / z.

[0205] Synthesis of 7-benzyl-2-((3-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, 3-rf] azepine (F23).

[0206] 3-Fluorobenzyl alcohol (0.12 mL, 1.10 mmol, 1.2 eq.), 7-benzyl-2-chloro-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine E (250 mg, 0.91 mmol, 1 eq.), and potassium hydroxide (76.9 mg, 1.37 mmol, 1.5 eq.) were reacted in DMSO (4 mL) according to General Procedure A to give 7-benzyl-2-((3-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F23 (268.2 mg, 81% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.42 (td, J= 8.1, 6.1 Hz, 1H), 7.36 - 7.29 (m, 5H), 7.29 - 7.20 (m, 2H), 7.20 - 7.10 (m, 1H), 5.34 (s, 2H), 3.63 (s, 2H), 3.05 - 2.95 (m, 4H), 2.65 - 2.56 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -113.06 – -113.39 (m). LCMS (ESI), [M+H]+= 364.2 m / z.

[0207] Step 6: General procedure E - synthesis of (Example 15-20)

[0208] 1 -chloroethyl chloroformate (5 eq.) was added to a solution of intermediates F27 - F23 (1 eq.) in toluene (0.2 M). The reaction mixture was heated to reflux under argon with stirring. After 2 hours, the volatiles were removed under reduced pressure and the residue was dissolved in MeOH (0.2 M). After refluxing for 1 hour and cooling the product mixture was evaporated to dryness under reduced pressure and the crude product was triturated with diethyl ether to give the hydrochloride salts of Example 15 and Example 17-20 (19 - 82% yield).

[0209] Synthesis of (A)-2-(l-(2-chlorophenyl)ethoxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, 3-r / | azepine hydrochloride (Example 15)

[0210] 1-chloroethyl chloroformate (0.30 mL, 2.87 mmol, 5 eq.) and (< S)-7-benzyl-2-(l-(2-chlorophenyl)ethoxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine F17 (225.0 mg, 0.67 mmol, 1 eq.) were reacted in toluene (3.5 mL) and methanol (3.5 mL) according to General Procedure E to give 2(S)-2-(l-(2-chlorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine hydrochloride (Example 15) (188.8 mg, 82% yield) as a pink solid. 'H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J= 18.0 Hz, 2H), 8.12 (s, 1H), 7.56 (dd, J= 7.5, 2.0 Hz, 1H), 7.46 (dd, J= 7.6, 1.6 Hz, 1H), 7.40 - 7.26 (m, 2H), 6.39 (q, J= 6.5 Hz, 1H), 3.31 - 3.18 (m, 6H), 3.17 - 3.08 (m, 2H), 1.59 (d, J= 6.5 Hz, 3H). HRMS (ESI) m / z calcd. for C16H18N3O [M + H]+: 304.1216; found, 304.1223. HPLC purity > 99%. Elemental Anal. calcd for C16H18ClN3O·HCl: C, 56.48; H, 5.63; N, 12.35; Cl, 20.84. Found: C, 52.44; H, 5.61; N, 11.46; Cl, 22.27 - Best Result: C16H18ClN3O · 1.3 HCl · 0.8 H2O.

[0211] Synthesis of (A)-2-(l-(4-fluorophenyl)ethoxy)-6,7,8,9-tetrahydro-5 / 7-pyrazino [2, 3-r / | azepine (Example 16).

[0212] 1-chloroethyl chloroformate (0.24 mL, 2.35 mmol, 5 eq.) and (< S)-7-benzyl-2-(l-(4-fluorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine F18 (170.0 mg, 0.45 mmol, 1 eq.) were reacted in toluene (3.5 mL) and methanol (3.5 mL) according to General Procedure E. The HC1 salt was converted to the free base by dissolving in water and extracting with EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, and evaporated to give (S)-2-(l-(4-fluorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine (Example 16) (38.2 mg, 19% yield) light brown oil. 'H NMR (400 MHz, DMSO-d6) 87.92 (s, 1H), 7.54 - 7.44 (m, 2H), 7.22 - 7.11 (m, 2H), 6.10 (q, J= 6.5 Hz, 1H), 3.06 (s, 1H), 2.97 - 2.84 (m, 4H), 2.84 - 2.71 (m, 4H), 1.57 (d, J= 6.5 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -114.90 (tt, J= 9.1, 5.6 Hz). HRMS (ESI) m / z calcd. for C16H18N3O [M + H]+: 304.1216; found, 304.1223. HPLC purity = 95%.

[0213] Synthesis of 2-((2-chloro-4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino [2, 3-d] azepine hydrochloride (Example 17).

[0214] 1-chloroethyl chloroformate (0.18 mL, 1.63 mmol, 5 eq.) and 7-benzyl-2-((2-chloro-4-fluorobenzyl)oxy)-6.7.8.9-tetrahydro-57 / -pyrazino|2.3-t / |azepine F20 (130.0 mg, 0.33 mmol, 1 eq.) were reacted in toluene (3 mL) and methanol (3 mL) according to General Procedure E to give 2-((2-chloro-4-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine hydrochloride (Example 17) (62.1 mg, 55% yield) as an off white solid. 'H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 2H), 8.15 (s, 1H), 7.69 (dd, J= 8.6, 6.3 Hz, 1H), 7.53 (dd, J = 8.9, 2.6 Hz, 1H), 7.28 (td, J= 8.5, 2.6 Hz, 1H), 5.40 (s, 2H), 3.32 - 3.22 (m, 8H).19F NMR (377 MHz, DMSO-d6) δ -111.29 (td, J = 8.6, 6.1 Hz). HRMS (ESI) m / z calcd. for C15H15ClFN3O [M + H]+: 308.0966; found, 308.0974. HPLC purity = 95.2%. Elemental Anal.calcd for C15H15ClFN3O HCI: C, 52.34; H, 4.69; N, 12.21; Cl, 20.60; F, 5.52. Found: C, 52.08; H, 4.60; N, 11.96; Cl, 20.55; F, 5.51 - Best Result: C15H15ClFN3O • 1 HC1 • 0.15 H2O.

[0215] Synthesis of 2-fluoro-5-(((6,7,8,9-tetrahydro-5 / 7-pyrazino[2,3-rf]azepin-2-yl)oxy)methyl)benzonitrile hydrochloride (Example 18).

[0216] 1-chloroethyl chloroformate (0.10 mL, 0.90 mmol, 5 eq.) and 5-(((7-benzyl- 6.7.8.9-tetrahydro-57 / -pyrazino[2,3-< / ]azepin-2-yl)oxy)methyl)-2-fluorobenzonitrileF21 (70.0 mg, 0.18 mmol, 1 eq.) were reacted in toluene (2 mL) and methanol (2 mL) according to General Procedure E to give 2-fluoro-5-(((6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepin-2-yl)oxy)methyl)benzonitrile hydrochloride (Example 18) (56.0 mg, 89% yield) as a tan solid. 'H NMR (400 MHz, DMSO- L) 89.49 (s, 2H), 8.15 (s, 1H), 8.07 (dd, J= 6.3, 2.3 Hz, 1H), 7.91 (ddd, J= 8.7, 5.3, 2.3 Hz, 1H), 7.57 (t, J= 9.1 Hz, 1H), 5.38 (s, 2H), 3.34 - 3.21 (m, 8H).19F NMR (377 MHz, DMSO- L) 8 -109.51 (dt, J= 9.2, 5.7 Hz). HRMS (ESI) m / z calcd. for C16H15FN4O [M + H]+: 299.1308; found, 299.1313. HPLC purity > 99%. Elemental Anal. calcd for C16H15FN4O·HCl: C, 57.40; H, 4.82; N, 16.74; Cl, 10.59; F, 5.67. Found: C, 55.11; H, 4.86; N, 15.78; Cl, 10.47; F, 5.30 - Best Result: C16H15FN4O · 1.05 HCl · 0.75 H2O.

[0217] Synthesis of 4-(((6.7.8.9-tetrahydro-5 / / -pyrazino|2.3-f / |azepin-2-yl)oxy)methyl)benzonitrile hydrochloride (Example 19).

[0218] 1-chloroethyl chloroformate (0.0.09 mL, 0.88 mmol, 5 eq.) and 4-(((7-benzyl- 6.7.8.9-tetrahydro-57 / -pyrazino[2,3-< / ]azepin-2-yl)oxy)methyl)benzonitrile F22 (65.0 mg, O.18 mmol, 1 eq.) were reacted in toluene (2 mL) and methanol (2 mL) according to General Procedure E to give 4-(((6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepin-2-yl)oxy)methyl)benzonitrile hydrochloride (Example 19) (54.4 mg, 82% yield) as a tan solid. 'H NMR (400 MHz, DMSO- L) 89.23 (s, 1H), 8.19 (s, 1H), 7.90 - 7.84 (m, 2H), 7.70 - 7.63 (m, 2H), 5.47 (s, 2H), 3.45 - 3.12 (m, 8H). HPLC purity = 96.2%. Elemental Anal, calcd for C16H16N4O·HCl: C, 60.66; H, 5.41; N, 17.69; Cl, 11.19. Found: C, 60.06; H, 5.33; N, 16.62; Cl, 10.35 - Best Result: C16H16N4O · 1.15 HCl.

[0219] Synthesis of 2-((3-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d] azepine hydrochloride (Example 20).

[0220] 1-chloroethyl chloroformate (0.39 mL, 3.58 mmol, 5 eq.) and 7-benzyl-2-((3-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine F23 (260.0 mg, 0.72 mmol,1 eq.) were reacted in toluene (4 mL) and methanol (4 mL) according to General Procedure E to give 2-((3-fluorobenzyl)oxy)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine hydrochloride (Example 20) (186.4 mg, 81% yield) as an off-white solid. 'H NMR (400 MHz, DMSO- L) 5 9.52 (s, 2H), 8.15 (s, 1H), 7.44 (td, J= 8.0, 6.1 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.22 - 7.11 (m, 1H), 5.38 (s, 2H), 3.34 - 3.22 (m, 8H).19F NMR (377 MHz, DMSO- L) 8 -113.17 (td, J= 9.7, 6.5 Hz). HRMS (ESI) m / z calcd. for C15H16FN3O [M + H]+: 274.1356; found, 274.1361. HPLC purity > 99%. Elemental Anal, calcd for C15H16FN3O HCI: C, 58.16; H, 5.53; N, 13.56; Cl, 11.44; F, 6.13. Found: C, 55.73; H, 5.60; N, 13.07; Cl, 13.84; F, 6.16 - Best Result: C15H16FN3O • 1.25 HC1 • 0.2 H2O.

[0221] Synthesis of (A)-2-(l-(2-chloiophenyl)ethoxy)-7-methyl-6,7,8,9-tet rally dro-5 / / -pyrazino [2, 3-d] azepine (Example 21).

[0222] (S)-2-(l-(2-chlorophenyl)ethoxy)-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-d]azepine hydrochloride (70.0 mg, 0.21 mmol, 1 eq.) was reacted with formaldehyde (37 wt% in water, 20.0 pL, 0.27 mmol, 1.3 eq.), acetic acid (15.3 pL, 0.27 mmol, 1.3 eq.), and sodium triacetoxyborohydride (65.3 mg, 0.31 mmol, 1.5 eq.) in DCM (2.0 mL) and reacted according to General Procedure C to give (S)-2-(l-(2-chlorophenyl)ethoxy)-7-methyl-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-d]azepine (Example 21) (29.4 mg, 45% yield) as a light yellow oil. 'H NMR (400 MHz, DMSO- L) 8 8.01 (s, 1H), 7.53 (dd, J= 7.4, 2.0 Hz, 1H), 7.44 (dd, J = 7.6, 1.6 Hz, 1H), 7.37 - 7.24 (m, 2H), 6.36 (q, J= 6.5 Hz, 1H), 2.97 (tq, J= 8.0, 5.1, 4.0 Hz, 2H), 2.92 - 2.80 (m, 2H), 2.59 - 2.51 (m, 2H), 2.49 - 2.40 (m, 2H), 2.27 (s, 3H), 1.58 (d, J= 6.5 Hz, 3H). HRMS (ESI) m / z calcd. for C17H20ClN3O [M + H]+: 318.1373; found, 318.1377. LCMS (ESI), [M+H]+= 318.1 m / z. HPLC purity > 99%.

[0223] Synthesis of 3-[(LS')-l-(2-chlorophenyl)ethoxy|-7-ethyl-5,6,8,9-tetrahydropyrazino [2, 3-r / | azepine (Example 22).

[0224] A mixture of 3-[(l< S)-l-(2-chlorophenyl)ethoxy]-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-d]azepine hydrochloride (70.0 mg, 0.21 mmol) and potassium carbonate (85.2 mg, 0.62 mmol) were stirred in acetonitrile (1 mL) before iodoethane (0.03 mL, 0.41 mmol) was added and reacted according to General Procedure D to give 3-[(lS)-l-(2-chlorophenyl)ethoxy]-7-ethyl-5,6,8,9-tetrahydropyrazino[2,3-<7]azepine (Example 22) (38.9 mg, 56% yield) as a brown viscous oil. 'H NMR (400 MHz, DMSO- L) 8 8.02 (s, 1H), 7.54 (dd, J= 7.5, 2.0 Hz, 1H), 7.44 (dd, J= 7.6, 1.6 Hz, 1H), 7.38 - 7.25 (m, 2H), 6.36 (q, J= 6.5Hz, 1H), 2.93 (d, J= 34.6 Hz, 4H), 2.57 (s, 6H), 1.58 (d, J= 6.5 Hz, 3H), 1.02 (t, J= 7.2 Hz, 3H). HRMS (ESI) m / z calcd. for C18H22ClN3O [M + H]+: 332.1530; found, 332.1532. HPLC purity 98.6%.

[0225] Synthesis of 3-[(lS)-l-(4-fluoiophenyl)ethoxy|-7-methyl-5,6,8,9-tet rally d ropy razino 12.3-< / |azepine (Example 23).

[0226] Formaldehyde (0.03 mL, 0.40 mmol) and acetic acid (0.02 mL, 0.40 mmol) were added to a solution of 3-[( IS)- 1 -(4-fluorophenyl)ethoxy |-6.7.8.9-tetrahydro-5 / / -pyrazino[2,3-d]azepine hydrochloride (100.0 mg, 0.31 mmol) in DCM (5 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (98.2 mg, 0.46 mmol) was added and then reacted according to general procedure C. The crude product smelled like acetic acid and was triturated with heptane and dried. The product still contained acetic acid and was dissolved in 2 mL of DCM before MP-Carbonate (308.8 mg, 0.46 mmol) was added. The mixture was stirred for 2 hours then the solids were removed by filtration and the filtrate was dried to give 3-|(lS)-l-(4-lluorophenyl)ethoxy |-7-methyl-5.6.8.9-tetrahydropyrazino|2.3-e / |azepine (Example 23) (26.6 mg, 28% yield) as a brown oil. 'H NMR (400 MHz, DMSO- L) 57.96 (s, 1H), 7.54 - 7.44 (m, 2H), 7.22 - 7.11 (m, 2H), 6.11 (q, J= 6.5 Hz, 1H), 2.99 -2.93 (m, 2H), 2.91 (dd, J= 7.5, 3.1 Hz, 2H), 2.49 - 2.39 (m, 4H), 2.27 (s, 3H), 1.57 (d, J= 6.5 Hz, 3H).19F NMR (377 MHz, DMSO- e) 8 -114.67. HRMS (ESI) m / z calcd. for C17H20FN3O [M + H]+: 302.1668; found, 302.1679. HPLC purity 99.0%.

[0227] Synthesis of 7-ethyl-3-[(lS)-l-(4-fluorophenyl)ethoxy]-5,6,8,9-tetrahydropyrazino [2, 3-ti| azepine (Example 24).

[0228] Acetaldehyde (0.02 mL, 0.40 mmol) and acetic acid (0.04 mL, 0.77 mmol) were added to a solution of 3-[( IS)- 1 -(4-lluorophenyl)ethox |-6.7.8.9-tetrahydro-57 / -pyrazino[2,3-<7]azepine hydrochloride (100.0 mg, 0.31 mmol) in DCM (5 mL). The reaction was stirred for 30 minutes before sodium triacetoxyborohydride (98.2 mg, 0.46 mmol) was added and reacted according to general procedure C to give 7-ethyl-3-[(lS)-l-(4-lluorophenyl)ethoxy |-5.6.8.9-tetrahydropyrazino|2.3-e / |azepine (Example 24) (47.1 mg, 48% yield) as a brown viscous solid. 'H NMR (400 MHz, DMSO- L) 87.96 (s, 1H), 7.54 - 7.44 (m, 2H), 7.22 - 7.11 (m, 2H), 6.11 (q, J= 6.5 Hz, 1H), 2.94 (dt, J= 17.9, 5.4 Hz, 4H), 2.57 (d, J= 29.1 Hz, 6H), 1.57 (d, J= 6.5 Hz, 3H), 1.01 (t, J= 7.1 Hz, 3H).19F NMR (377 MHz,DMSO- L) 8 -114.88. HRMS (ESI) m / z calcd. for C18H22FN3O [M + H]+: 316.1825; found, 316.1827. HPLC purity > 99%.

[0229] Synthesis of 3-[(L )-l-(2-chloio-4-fhioio-phenyl)ethoxy|-6,7,8,9-tet rally dro-5 / / -pyrazino [2, -r / | azepine hydrochloride (Example 25).

[0230] 1-Chloroethyl chloroformate (0.40 mL, 3.74 mmol) was added to a solution of 7-benzyl-3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-5,6,8,9-tetrahydropyrazino[2,3-t / |azepine (308.5 mg, 0.75 mmol) in toluene (4 mL) and was reacted according to general procedure F. The residue was suspended in acetonitrile with sonication. The mixture was stirred vigorously for 1 hour before the solid was collected by filtration, washed with acetonitrile, and dried to give 3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-6, 7,8,9-tetrahydro-57 / -pyrazino|2.3-t / |azepine hydrochloride (Example 25) (114.6 mg, 43% yield) as a tan solid. 'H NMR (400 MHz, DMSO- L) 89.44 (s, 2H), 8.12 (s, 1H), 7.60 (dd, J = 8.8, 6.2 Hz, 1H), 7.46 (dd, J= 8.9, 2.6 Hz, 1H), 7.23 (td, J= 8.5, 2.6 Hz, 1H), 6.34 (q, J = 6.5 Hz, 1H), 3.29 - 3.04 (m, 8H), 1.59 (d, J= 6.5 Hz, 3H).19F NMR (377 MHz, DMSO- L) 8 -112.34. HRMS (ESI) m / z calcd. for C16H18Cl2FN3O [M + H]+: 322.1122; found, 322.1125. HPLC purity >99%. Elemental Anal. Calcd for C16H17ClFN3O·HCl: C, 53.64; H, 5.06; N, 11.72; Cl, 19.79; F, 5.30. Found: C, 50.60; H, 5.24; N, 11.47; Cl, 18.64; F, 4.80 - Best Result: C16H18Cl2FN3O · 1 HCl · 1.05 H2O.

[0231] Synthesis of 3-[(LS')-l-(2-chloro-4-fhioro-phenyl)ethoxy|-7-methyl-5,6,8,9-tetrahydropyrazino [2, 3-r / | azepine (Example 26).

[0232] Formaldehyde (29.7 uL, 0.40 mmol) and acetic acid (22.8 uL, 0.40 mmol) were added to a mixture of 3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-6, 7,8,9-tetrahydro-57 / -pyrazino[2,3-<7]azepine hydrochloride (110.0 mg, 0.31 mmol) in DCM (5 mL). After stirring at room temperature for 30 min, sodium triacetoxyborohydride (97.6 mg, 0.46 mmol) was added and reacted according to general procedure C to give 3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-7-methyl-5,6,8,9-tetrahydropyrazino[2,3-<7]azepine (65.2 mg, 62% yield) as a brown oil (Example 26). 'H NMR (400 MHz, DMSO- L) 88.01 (s, 1H), 7.57 (dd,.7= 8.7, 6.2 Hz, 1H), 7.44 (dd, J= 8.9, 2.7 Hz, 1H), 7.21 (td, J= 8.5, 2.6 Hz, 1H), 6.32 (q, J = 6.5 Hz, 1H), 3.03 - 2.90 (m, 2H), 2.90 - 2.79 (m, 2H), 2.49 - 2.36 (m, 4H), 2.25 (s, 3H), 1.57 (d, J= 6.5 Hz, 3H).19F NMR (377 MHz, DMSO- L) 8 -112.59. HRMS (ESI) m / z calcd. for C17H19ClFN3O [M + H]+: 336.1279; found, 336.1278. HPLC purity 98.8%.

[0233] Synthesis of 3-[(L )-l-(2-chloro-4-fluoro-phenyl)ethoxy|-7-ethyl-5,6,8,9-tet rally d ropy razino 12.3-< / |azepine (Example 27).

[0234] Acetaldehyde (20.3 uL, 0.40 mmol) and acetic acid (43.9 uL, 0.77 mmol) were added to a solution of 3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-6,7,8,9-tetrahydro-57 / -pyrazino[2,3-< / ]azepine hydrochloride (110.0 mg, 0.31 mmol) in DCM (5 mL). After 30 minutes of stirring, sodium triacetoxyborohydride (97.6 mg, 0.46 mmol) was added and the reaction was allowed to react according to general procedure C over the weekend to give 3-[(lS)-l-(2-chloro-4-fluoro-phenyl)ethoxy]-7-ethyl-5,6,8,9-tetrahydropyrazino[2,3-< / ]azepine (32.2 mg, 30% yield) (Example 27) as a yellow oil.1H NMR (400 MHz, DMSO- e) 88.00 (s, 1H), 7.57 (dd, J= 8.7, 6.2 Hz, 1H), 7.44 (dd, J= 8.8, 2.6 Hz, 1H), 7.21 (td, J= 8.5, 2.7 Hz, 1H), 6.32 (q, J= 6.5 Hz, 1H), 2.95 (dt, J = 6.3, 2.8 Hz, 2H), 2.92 -2.83 (m, 2H), 2.54 (s, 4H), 2.47 (d, J = 7.7 Hz, 2H), 1.57 (d, J = 6.5 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO- e) 8 -112.71. HRMS (ESI) m / z calcd. for C18H21ClFN3O [M + H]+: 350.1435; found, 350.1437. HPLC purity >99%.

[0235] II. Biological Evaluation

[0236] (a) 5-HT2 Receptor Assays-IP one assay

[0237] Serotonin 5-HT receptors belong to the superfamily of G protein-coupled seven transmembrane proteins with the exception of the 5-HT3 subtype, which belongs to the ligand gated cation superfamily of receptors. G-protein-coupled receptors constitute one of the major signal transduction systems in eukaryotic cells. Coding sequences for these receptors, in those regions believed to contribute to the agonist-antagonist binding site, are strongly conserved across mammalian species. Serotonin 5-HT2 receptors are widely distributed in the central nervous system and peripheral tissues. The 5-HT2 receptor class couples preferentially to Gq / Gll to increase hydrolysis of inositol phosphates and elevate cytosolic [Ca2+],

[0238] Compounds of the present application bind to the 5HT2 receptor subtypes in the following assays:

[0239] Human recombinant serotonin 5-HT2A, 5-HT2B and 5-HT2C receptor stably expressed in HEK-293 or CHO-K1 cells were used. Test compound and / or vehicle were incubated with the cells (5 x 105 / ml) in stimulation buffer of IP1 Tb kit for 30 minutes at 37°C. Test compound-induced increase of fluorescence by 50 percent or more (>50%)relative to the 1 or 10 pM serotonin response indicated serotonin 5-HT2 receptor agonist activity. Test compound-induced inhibition of 0.3 pM serotonin-induced fluorescence response by 50 percent or more (>50%) indicated receptor antagonist activity. (Eurofins Laboratory, France). Dose-response curves for the test compounds were generated over the concentration range of 10 to 30,000 nM to determine effective concentration (EC50), (“relative response”). Preferably the compounds of the present application bind to the 5- HT2A and / or 5HT2C receptor. Preferably the compounds of the present application do not bind, or minimally bind, to the 5-HT2B receptor.Table 25-HT2A 5-HT2B 5-HT2C ExampleStructure (ECso; max (EC50; max (EC50, max Numberactivity) activity) activity z. N ^,z.23 nM; 240 nM;< 10 nM; Example 1 / -x f NHJ O N' z z 0x _ / 100 %95% 55%O10 nM; 72 nM;< 10 nM; Example 2 b 113 %98% 51%u.5100 nM; 2500 nM; 190 nM; Example 3 xx 1 L £ NH[| y o100% 28% 101 %100 nM; 880 nM; < 10 nM; Example 4 Jr! 1^ - 93% 51% 99 %120 nM; 23000 nM; 16 nM; Example 590% 47% 106 %5-HT2A 5-HT2B 5-HT2C ExampleStructure (ECso; max (EC50; max (EC50, max Numberactivity) activity) activity88 nM; 660 nM;< 10 nM; Example 6104 % 86 % 38%620 nM; 990 nM; 280 nM; Example 7z z91 % 44% 105 % 01m 1500 nM; 13,000 nM; 130 nM; Example 8101 % 58% 97 % 0 QQ 0 z z z zz z Q z z z z Q 5300 nM; 30,000 nM; 450 nM; z zExample 9o O Oo O100% 23% 91 % ^ zb bu. u. 85 nM; 30,000 nM; < 10 nM;LL jf T N-MeExample 10 -751 % 4% 99 %11 nM; 510 nM;< 10 nM; Example 11100 % 104 % 35 %29 nM; >30,000 nM; < 10 nM; Example 1291 % 18 % 95 %30 nM; >30,000 nM; 85 nM; Example 1393 % 26 % 95 %5-HT2A 5-HT2B 5-HT2C ExampleStructure (ECso; max (EC50; max (EC50, max Numberactivity) activity) activity 180 nM; >30,000 nM; 1620 nM; Example 1497 % 30 % 120 %11 nM; 51 nM; <10 nM; Example 15 AA JL Rnh95 % 35 % 100 %. HCl43 nM; 7280 nM; 19 nM; Example 1694 % 100 % 107 %Example 17 304 nM; 7,810 nM; 34nM;§x J z zNN QI^NH^ X---7o 84 % 100 % 108 %. HClLL LLExample 18 305 nM; 438 nM; 87 nM;NC^^JLX / NH94 % 34 % 93 %. HClExample 19 370 nM; >30,000 nM; 950 nM;]T jTNHN^ X---792 % 43 % 102 % NCT '^. HCl5-HT2A 5-HT2B 5-HT2C ExampleStructure (ECso; max (EC50; max (EC50, max Numberactivity) activity) activity Example 20 33 nM; 365 nM; <10 nM;J J NH80 % 47 % 97 %. HC10o 0Q z z z zz zExample 21 62 nM; >30,000 nM; 12 nM;o59 % 1 % 96 % O■n T1 nExample 22 35 nM; >30,000 nM; 28 nM;86 % 3 % 114 % oExample 23 z z 310 nM; >30,000 nM; 310 nM;51 % 1 % 100 % 01Example 24 380 nM; >30,000 nM; 400 nM;100 % 9 % 105 %Example 25 40 nM; 3100 nM; 14 nM;HO;N1 JL A 101 % 52 % 110 % ’HCIExample 26 270 nM; >30,000 nM; 79 nM;47 % 6 % 86 %5-HT2A 5-HT2B 5-HT2C ExampleStructure (ECso; max (EC50; max (EC50, max Numberactivity) activity) activity Example 27 140 nM; >30,000 nM; 190 nM;74 % 12 % 93%Serotonin 12 nM; 2nM; 4nM;0I X > 100 % 100 % 100 % H" Fl

[0240] (b) Microsomal stability Assays

[0241] Liver microsomal metabolic stability

[0242] In Phase I analysis test compounds were incubated at a final concentration of 1 pM (this concentration is assumed to be well below the Km values to ensure linear reaction conditions i.e. to avoid saturation). Working stocks were initially diluted to a concentration of 40.0 pM in 0.1 M potassium phosphate buffer (pH 7.4) before addition to the reaction vials. CD-I mouse (male) or pooled human liver microsomes (Coming Gentest) were utilized at a final concentration of 0.5 mg / mL (protein). Duplicate wells were used for each time point (0 and 60 minutes). Reactions were carried out at 37°C in an orbital shaker at 175 rpm, and the final DMSO concentration was kept constant at 0.1%. The final volume for each reaction was 100 pL, which included the addition of an NADPH-Regeneration Solution (NRS) mix. This NRS mix was comprised of glucose 6-phosphate dehydrogenase, NADP+, MgCl2, and glucose 6-phosphate. Upon completion of the 60 minute time point, reactions were terminated by the addition of 2-volumes (200 pL) of ice-cold, acetonitrile containing 0.5% formic acid and internal standard. Samples were then centrifuged at 4,000 rpm for 10 minutes to remove debris and precipitated protein. Approximately 150 pL of supernatant is subsequently transferred to a new 96 well microplate for LC / MS analysis:

[0243] Narrow-window mass extraction LC-MS analysis was performed for all samples in this study using a Waters Xevo™ quadrupole time-of-flight (QTof) massspectrometer to determine relative peak areas of test compounds. The percent remaining values were calculated using the following equation:% remaining = (A ) / A0×100where:A is area response after incubationAo is area response at initial time point.

[0244] For the intrinsic clearance assay, incubation mixtures contained probe substrate, liver microsomes and an NADPH regenerating system (1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 U ml-1 glucose 6-phosphate dehydrogenase, 3.3 mM magnesium chloride) in 0.1 M potassium phosphate buffer (pH 7.4). CD-I mouse (male) or pooled human liver microsomes (Coming Gentest) were utilized at a final concentration of 0.5 mg / mL (protein). 12.5 pL of each drug solution were placed into a well of 96 well plate. Reactions were initiated by the addition of activated microsome solutions (500 pL) to drug solutions. Reactions were carried out at 37°C in an orbital shaker at 175 rpm, and the final DMSO concentration was kept constant at 0.1%. Test compounds were incubated at a final concentration of 1 pM. 50 pL of aliquots of reaction mixtures were quenched by mixing with two parts of stop solution (internal standard containing 0.5% formic acid in acetonitrile) at appropriate time-points and mixed well. Then, solutions were centrifuged at 4000 rpm for 10 min. Supernatants were transferred to a new 96-well plate and analyzed by a Waters Q-TOF mass spectrometer coupled with an UPLC System. Recovery analysis was performed using relative peak areas and narrow window mass extraction. The ln(%remaining) was plotted against time and the gradient of the line determined.Elmination Constant (k) = -slopeHalf-life (t½) (min) = ln2 / k =0.693 / kV(μL / mg) =volume of incubation (μL) / protein in the incubation (mg)Intrinsic Clearance (CLint)(μL / min / mg protein)=V· 0.693 / t½ =V· kTable 3Human liver Mouse liver Example microsome or microsome or StructureNumber HLM MLM (t / 1 / 2, minutes) (t / 1 / 2, minute)Example 1 205 5Example 2 >300 17Jb JL 0 jl NH XExample 3 n j o X >300 10zCl Mb QI O z z z z z zz zExample 4 MZb -1" 107 4o o o bOZ^ b> J> z U. HhExample 5 LL u. u. 155 16Example 6 192 5Example 7 >300 25Example 8 176 68Human liver Mouse liver Example microsome or microsome or StructureNumber HLM MLM (t / 1 / 2, minutes) (t / 1 / 2, minute)Example 9 >300 31Example 10 44 1z z z z001Example 11 13 m 11 <1 < D XExample 12Q 0 Q Qz z z z z z5 z z ■ 43 <1 ooExample 13 b \1"b bI I u. 59 5 LLExample 14130 29ci - Example 15Jx X f NH76 9. HC1Example 16148 10Human liver Mouse liver Example microsome or microsome or StructureNumber HLM MLM (t / 1 / 2, minutes) (t / 1 / 2, minute) Example 17 A J(NX^ANH81 3. HC100 z z N^z - \Example 18 z z0 ZoN80 7. HC1 oTlo—Example 19if jT- o1 nh61 7 z z. HC1Example 20 0 Jf J NH186 3. HC1Example 2118 9Example 2212 2Example 2358 2Human liver Mouse liver Example microsome or microsome or StructureNumber HLM MLM (t / 1 / 2, minutes) (t / 1 / 2, minute) Example 2450 6Example 25 6HONI 1 A 165 11■HCIExample 26u. U.Tl 22 1 55Example 27 O 014 2z z z z0IP: In progress 0

[0245] III. Preparation of Pharmaceutical Dosage Forms

[0246] Example 1: Oral capsule

[0247] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0248] Example 2: Solution for injection

[0249] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof, and can be formulated as a solution in sesame oil at a concentration of 50 mg-eq / mL.

[0250] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

1. CLAIMSWe claim:

1. A compound that has the structure of Formula (I):or is or pharmaceutically acceptable salt or solvate thereof,wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, with the proviso that when Z is phenyl, at least one of R1, R2and R3is not H.

2. The compound of claim 1, wherein R1and R2are different.

3. The compound of claim 1 or 2, wherein R1and R2are independently H or C1-6alkyl.

4. The compound of claim 3, wherein R1and R2are independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

5. The compound of any one of claims 1 to 4, wherein R3is H or C1-6 alkyl.

6. The compound of claim 5, wherein R3is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

7. The compound of any one of claims 1 to 6, wherein Z is phenyl, pyridyl, substituted phenyl or substituted pyridyl.

8. The compound of claim 5, wherein Z is phenyl or phenyl mono- or di-substituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group.

9. The compound of claim 6, wherein Z is pyridyl or pyridyl mono- or di-substituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group, wherein the di- substituted pyridyl is substituted with the same or different halo subsitituents.

10. The compound of claim 6, wherein Z is phenyl mono- or di-substituted with a halo (e.g., chloro or fluoro), wherein the di-substituted phenyl is substituted with the same or different halo subsitituents.

11. A compound having a structure as provided in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

12. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 ot 11 and a pharmaceutically acceptable excipient.

13. Use of a 5-HT2Aand / or 5-HT2creceptor agonist for treatment of a disease or disorder mediated by the 5-HT2 receptor in a subject in need thereof, wherein the 5-HT2Aand / or 5-HT2creceptor agonist is a compound that has the structure of Formula (I):or that is pharmaceutically acceptable salt or solvate thereof,wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl (such as fluoroalkyl), optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; or R1and R2, together with the atom to which they are bound, are joined to form a spyrocylic ring system, such as C1-6 cycloalky or C1-6 heterocycloalkyl;R3is H, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl or optionally substituted C3-6 heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

14. The use according to claim 13, wherein when Z is phenyl, at least one of R1, R2and R3is not H.

15. The use according to claim 13 or 14, wherein R1and R2are different.

16. The use according to any one of claims 13 to 15, wherein R1and R2are independently H or C1-6alkyl.

17. The use according to claim 16, wherein R1and R2are independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

18. The use according to any one of claims 13 to 17, wherein R3is H or C1-6 alkyl.

19. The use according to claim 18, wherein R3is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

20. The use according to any one of claims 13 to 19, wherein Z is phenyl, pyridyl, substituted phenyl or substituted pyridyl.

21. The use according to claim 20, wherein Z is phenyl, phenyl mono- or di-substituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group, pyridyl or pyridyl mono- or di-substituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group, wherein the di-substituted phenyl or di-substituted pyridyl is substituted with the same or different subsitituents.

22. The use according to claim 13, wherein the 5-HT2Aand / or 5-HT2creceptor agonist is a compound having a structure as provided in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

23. The use according to any one of claims 13 to 22, wherein the disease or disorder is a CNS disorder or condition, a neurological disorder or condition, a neurocognitivedisorder or condition, neurodegenerative disorder or condition, or a neurodevelopmental disorder or condition, a schizophrenia spectrum or other psychotic disorder, a bipolar and related disorder, a depressive disorder, an anxiety disorder, an obsessive-compulsive or related disorder, trauma, a stressor-related disorder, a dissociative disorder, a somatic syndrome or a related condition, a feeding or eating disorder, an elimination disorder, a sleep-wake disorder, a disruptive, impulse-control, or conduct disorder, a substance-related disorder, an addiction disorder, a neurocognitive disorder, a personality disorder, a gender dysphoria, a sexual dysfunction, a paraphilic disorder, pain (such as chronic pain), depression, post-traumatic stress disorder (PTSD), panic disorder, phobia, psychopathy, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, autism, or a compulsive disorder (such as to obsessive compulsive disorder (OCD), gambling, or aberrant sexual behavior).

24. The use according to any one of claims 13 to 23, wherein the disease or disorder is selected from epilepsy, pain, tubular sclerosis, attention disorders, diseases with monogenic alterations, psychological, cognitive, behavioral, and / or mood disorders.

25. The use according to any one of claims 13 to 24, wherein the treatment provides improved motivation, attention, accuracy, speed of response, perseveration, weight loss, executive function and / or cognitive engagement in the subject.

26. A method for treating a disease or disorder mediated by the 5-HT2 receptor in a subject in need thereof, said method comprising administering a 5-HT2A and / or 5- HT2C receptor agonist, wherein the 5-HT2Aand / or 5-HT2creceptor agonist is a compound that has the structure of Formula (I):or that is pharmaceutically acceptable salt or solvate thereof,wherein,R1and R2are independently H, optionally substituted Ci-6 alkyl (such as methyl, ethyl, propyl, isopropyl), optionally substituted Ci-6 alkylene, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6haloalkyl (such as fluoroalkyl), optionally substituted C3-6cycloalkyl or optionally substituted C3-6heterocycloalkyl;R3is H, optionally substituted C1-6alkyl, optionally substituted C1-6alkylene, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl or optionally substituted C3-6heterocycloalkyl; andZ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

27. The method according to claim 26, wherein when Z is phenyl, at least one of R1, R2and R3is not H.

28. The method according to claim 26 or 27, wherein R1and R2are different.

29. The method according to any one of claims 26 to 27, wherein R1and R2are independently H or C1-6alkyl.

30. The method according to claim 29, wherein R1and R2are independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

31. The method according to any one of claims 26 to 30, wherein R3is H or C1-6 alkyl.

32. The method according to claim 31, wherein R3is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

33. The method according to any one of claims 26 to 32, wherein Z is phenyl, pyridyl, substituted phenyl or substituted pyridyl.

34. The method according to claim 33, wherein Z is phenyl, phenyl mono- or disubstituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group, pyridyl or pyridyl mono- or di-substituted with a halo (e.g., chloro or fluoro), cyano and / or isocyano group, wherein the di-substituted phenyl or the di-substituted pyridyl is substituted with the same or different halo subsitituents.

35. The method according to claim 26, wherein the 5-HT2Aand / or 5-HT2creceptor agonist is a compound having a structure as provided in Table 1 or a pharmaceutically acceptable salt or solvate thereof.

36. The use according to any one of claims 26 to 35, wherein the disease or disorder is a CNS disorder or condition, a neurological disorder or condition, a neurocognitive disorder or condition, neurodegenerative disorder or condition, or a neurodevelopmental disorder or condition, a schizophrenia spectrum or other psychotic disorder, a bipolar and related disorder, a depressive disorder, an anxiety disorder, an obsessive-compulsive or related disorder, trauma, a stressor-related disorder, a dissociative disorder, a somatic syndrome or a related condition, a feeding or eating disorder, an elimination disorder, a sleep-wake disorder, a disruptive, impulse-control, or conduct disorder, a substance-related disorder, an addiction disorder, a neurocognitive disorder, a personality disorder, a gender dysphoria, a sexual dysfunction, a paraphilic disorder, pain (such as chronic pain), depression, post-traumatic stress disorder (PTSD), panic disorder, phobia, psychopathy, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, autism, or a compulsive disorder (such as to obsessive compulsive disorder (OCD), gambling, or aberrant sexual behavior).

37. The method according to any one of claims 26 to 36, wherein the disease or disorder is selected from epilepsy, pain, tubular sclerosis, attention disorders, diseases with monogenic alterations, psychological, cognitive, behavioral, and / or mood disorders.

38. The method according to any one of claims 26 to 37, wherein the treatment provides improved motivation, attention, accuracy, speed of response, perseveration, weight loss, executive function and / or cognitive engagement in the subject.

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