Therapeutic alkaloid compounds

Abstract

Disclosed are compounds useful for inhibiting SERT, and related methods of preparing and using these compounds.

Description

[0001] THERAPEUTIC ALKALOID COMPOUNDS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 600,928, filed November 20, 2023, the contents of which are hereby incorporated by reference in their entirety.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to the field of medicine, including the discovery of alkaloid compounds useful for eliciting antidepressant and / or anxiolytic effects by inhibiting, in part, the serotonin transporter protein (5-HT).

[0006] BACKGROUND

[0007] Serotonin (5-HT) is an essential neurotransmitter for the normal function of the central nervous system. This neurotransmission system in the brain controls various important behaviors, including sleep awake cycle, mood, temperature, appetite, etc. In addition, several commonly used anti-anxiety drugs.

[0008] Certain SERT Inhibitors, including the selective serotonin transporter inhibitors, also called selective serotonin reuptake inhibitors (SSRI's), are used as therapeutic antidepressant drugs. They are believed to exert their effect by increasing extracellular 5-HT levels in the serotoninergic terminal fields such as the hippocampus and prefrontal cortex.

[0009] A fundamental evaluation in drug development is the assessment of absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME / PK). The first ADME screen that a novel chemical entity is subjected to is an in vitro metabolic stability screen. Drug stability upon exposure to human liver microsomes and liver S9 cellular fractions is a common in vitro assay to approximate in vivo, liver-based drug metabolism. First-pass metabolism is also often approximated in vitro using intestinal microsome and cellular S9 fractions. Further, it is well known that human serum, and particularly circulating serum esterases can contribute to systemic drug metabolism.

[0010] There remains a need for therapeutic compounds that inhibit SERT with desired ADME and PK properties, such as extended half-life and metabolic stability. SUMMARY

[0011] In certain embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof; wherein X and Y are each independently N, CH, or CR1; R1is hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; R2is - OR2and R3is -OR3, wherein each of R2and R3is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or -ORa; or R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, Ci-4 alkyl, Ci-4 haloalkyl, or halo; each of R8and R9is independently hydrogen, deuterium, halo, Ci-4 alkyl, Ci-4 haloalkyl, cyano, Ci-4 alkoxy, C(O)Reor C(O)ORewherein each hydrogen atom in Ci- 4 alkyl is optionally substituted by deuterium; R10is Ci-4 alkyl; each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and Reis hydrogen or alkyl.

[0012] In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, -ORa, -NRaRb, -CHO, -C(O)Ra, -C02Ra, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, - NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; R2is -OR2’ and R3is -OR3, wherein each of R2and R3is independently H, Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce aryl or 5-6 membered heteroaryl; wherein each hydrogen atom in alkyl is optionally substituted by halo, deuterium, C3-6 cycloalkyl, aryl, or -ORa; wherein each hydrogen atom in cycloalkyl, alkenyl, alkynyl, heteroaryl and aryl is optionally substituted by halo, deuterium, C3-6 cycloalkyl, or -ORa; or R2and R3together with the atoms to which they are attached combine to form a 5-6 membered heterocyclyl comprising one or more O, N or S heteroatoms, or 5-6 membered heteroaryl comprising one or more O, N or S heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, methyl, or fluoro; each of R8and R9is independently hydrogen, deuterium, halo, C1-4 alkyl, Ci-4 haloalkyl, cyano, Ci-4 alkoxy, C(O)Reor C(O)ORe; wherein each hydrogen atom in Ci-4 alkyl is optionally substituted by deuterium; R10is Ci-4 alkyl; each of Raand Rbis independently H, Ci-4 alkyl, Ci-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, Ci-4 alkyl, Ci-4 alkanol, Ce aryl, 5-6 membered heteroaryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, Ci-4 alkyl, Ci-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl; and R° is hydrogen or Ci-4 alkyl. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Ra, Rb, Rc, and Rdis independently H, or Ci-4 alkyl; each of R2and R3is independently H, Ci-4 alkyl, or Ci-4 haloalkyl; and R10is methyl. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently N or CH. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of R6and R7is independently hydrogen. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of R8and R9is independently hydrogen, fluoro, or cyano. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R10is methyl. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R2and R3are independently hydrogen, deuterium, halogen, Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5-6 membered heteroaryl or Ce aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, heteroaryl, aryl, or -ORa. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R2and R3are independently hydrogen, Ci-4 alkyl or Ci-4 haloalkyl. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen, halo, cyclopropyl, Ci-4 alkyl, C1-4 alkoxyl, or Ci-4 haloalkyl. In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen or fluoro.

[0013] In some embodiments, the compound is a compound of Formula (La) or a pharmaceutically acceptable salt thereof,

[0014]

[0015] (I-a); or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently N or CH; R1is hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl; R2and R3is independently hydrogen, Ci-4 alkyl, or Ci-4 haloalkyl; R6and R7is independently hydrogen or methyl; R8and R9is independently hydrogen, halo, Ci-4 alkyl, Ci-4 haloalkyl, CN or C(O)Me; and R10is methyl or ethyl.

[0016] In some embodiments, the compound is a compound of Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein X and Y are each CH; R1is hydrogen or fluoro; R2and R3is independently hydrogen, methyl optionally substituted with one or more fluoro; R6and R7is independently hydrogen; R8and R9is independently hydrogen, fluoro, methyl, CN or C(O)Me; and R10is methyl. In some embodiments, the compound is a compound of Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the atoms to which they are attached combine to form a 5-6 membered heterocyclyl comprising one or more O, N or S heteroatoms, or 5-6 membered heteroaryl comprising one or more O, N or S heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa.

[0017] In some embodiments, the compound is a compound of Formula (III) or a pharmaceutically acceptable salt thereof

[0018] wherein X and Y are each O, S or NRXand Rxis hydrogen or Ci-4 alkyl; Ri is hydrogen, halo, C1-4 alkyl or Ci-4 haloalkyl; Rs and R9 are each independently CN, hydrogen, halo, Ci-4 alkyl or Ci-4 haloalkyl; Rio is Ci-4 alkyl; and R11 and R12 are each independently hydrogen, halo, C1-4 alkyl or Ci-4 haloalkyl.

[0019] In some embodiments, the compound is a compound of Formula (III-A) or a pharmaceutically acceptable salt thereof:

[0020] (III-A), or a pharmaceutically acceptable salt thereof, wherein X and Y are each O, or NRXand Rxis hydrogen or methyl; Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro; Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro; Rio is methyl; and R11 and R12 are each independently hydrogen, fluoro, methyl or methyl optionally substituted with one or more fluoro. In some embodiments, the compound is a compound selected from: or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound i pharmaceutically acceptable salt thereof. In some embodiments, the compound i pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is 105 , or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound i pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound i pharmaceutically acceptable salt thereof. In some embodiments, the compound i pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0026] In some embodiments, the present disclosure provides a method of treating a mental health disorder, comprising administering to a mammal in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the present disclosure provides a method of treating anxiety, stress, or depression. In some embodiments, the present disclosure provides a method of treating anxiety. In some embodiments, the present disclosure provides a method of treating stress. In some embodiments, the present disclosure provides a method of treating depression. In some embodiments, the present disclosure provides a method of treating a human.

[0027] In certain embodiments, the present disclosure provides a method of treating a central nervous condition, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.

[0028] In certain embodiments, the present disclosure provides a method of treating a central nervous condition, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.

[0029] In certain embodiments, the present disclosure provides a method of treating a condition by administering a SERT inhibitor, comprising administering to a subject in need thereof an effective amount a compound of the present disclosure.

[0030] Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein. DETAILED DESCRIPTION

[0031] The present invention is based, at least in part, on analogs of mesembrine and mesembrenone. Although (-) mesembrine is bioactive with certain desirable pharmacologic effects, certain other properties are less than ideal for use as a therapeutic. For example, the pharmacokinetics described for (-) mesembrine show rapid metabolism and excretion, which an undesirably low half-life in plasma of less than 2 hours. To take advantage of the desirable properties of mesembrine and mesembrenone, compounds have been developed and described here.

[0032] Compounds of the Invention

[0033] Described herein are compounds Formula (I):

[0034] CI) or a pharmaceutically acceptable salt thereof; wherein

[0035] X and Y are each independently N, CH, or CR1; each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2R1, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; each of R2and R3is independently -OR2or -OR3, wherein each of R2and R3is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0036] - IO - wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0037] R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, of fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0038] R10is Ci-4 alkyl. each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; and each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0039] In some embodiments, a compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein

[0040] X and Y are each independently CH; each R1is independently deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -C02Ra, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; each of R2and R3is independently -OR2or -OR3, wherein each of R2and R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; each of R6and R7is independently hydrogen, deuterium, methyl, or fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0041] R10is H, methyl or ethyl, wherein each hydrogen atom in methyl or ethyl is optionally substituted by halo or deuterium; each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; and each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0042] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:

[0043] (II).

[0044] In certain aspects, the invention relates to compounds of Formula (I):

[0045] or a pharmaceutically acceptable salt thereof; wherein

[0046] X and Y are each independently N, CH, or CR1; each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2R1, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; each of R2and R3is independently -OR2or -OR3, wherein each of R2and R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0047] R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, or halo; each of R8and R9is independently hydrogen, deuterium, halo, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0048] R10is C1-4 alkyl. each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; and each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0049] In some embodiments, a compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein

[0050] X and Y are each independently CH; each R1is independently deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -C02Ra, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; each of R2and R3is independently -OR2or -OR3, wherein each of R2and R3is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl, cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; each of R6and R7is independently hydrogen, deuterium, or halo; each of R8and R9is independently hydrogen, deuterium, halogen, Ci-4 alkyl, CN, or C(O)Ci-4 alkyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0051] R10is H, or C1-4 alkyl optionally substituted by halo or deuterium; each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; and each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, Rio in Formula (I) is H, methyl or ethyl, wherein each hydrogen atom in methyl or ethyl is optionally substituted by halo or deuterium.

[0052] X and Y

[0053] In some embodiments, X and Y are each independently N, CH, or CR1. In some embodiments, X is N, and Y is N, CH, or CR1. In some embodiments, X is N, and Y is N. In some embodiments, X is CR1, and Y is CR1. In some embodiments, X is CH, and Y is CH. In some embodiments, X is N, and Y is CH. In some embodiments, X is CH, and Y is N. In some embodiments, X is N, and Y is N.

[0054] Ri

[0055] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein each R1is independently hydrogen, halo, Ci-4 alkyl, or C3-6 cycloalkyl; wherein each hydrogen atom in Ci-4 alkyl, or C3-6 cycloalkyl is optionally substituted by halo or Ci-4 alkyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein: each R1is independently hydrogen, halo, methyl, ethyl, or cyclopropyl; wherein each hydrogen atom in methyl, ethyl, or cyclopropyl is optionally substituted by halo, methyl or halomethyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein each R1is independently hydrogen, fluoro, methyl optionally substituted with one or more fluoro, or cyclopropyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein each R1is independently hydrogen,

[0056] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Ri is halo. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Ri is fluoro. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Ri is cyclopropyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Ri is hydrogen.

[0057] In certain embodiments, R1is hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, - CO2R1, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb. In certain embodiments, R1is halo, haloalkyl, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, -ORa(e.g., alkoxy), -NRaRb(e.g., -NH2), -CHO, -C(O)Ra(e.g., -C(O)alkyl, such as -C(O)CH3), -CN, or nitro. In some embodiments, R1is hydrogen, halo, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, -ORa, - NRaRb, -CHO, C(O)Ra, -CN, or nitro. In some further embodiments, R1is alkyl. In some further embodiments, R1is haloalkyl.

[0058] In certain embodiments, R1is halo, cycloalkyl, -ORa(e.g., alkoxy), -NRaRb(e.g., -NH2), C(O)Ra(e.g., -C(O)alkyl, such as -C(O)CH3), -CN, or nitro. For example, R1can be halo, cycloalkyl, alkoxy, -NH2, C(O)alkyl, -CN, or nitro. In some embodiments, R1is -C(O)alkyl, such as -C(O)CH3. In some embodiments, R1is alkoxy, such as methoxy. In some embodiments, R1is cycloalkyl, such as cyclopropyl.

[0059] In certain embodiments, R1is halo, cyclopropyl, -OCH3, -NH2, -C(O)CH3, -CN, or nitro. In some embodiments, R1is halo. In some embodiments, R1is -CN. In some embodiments, R1is nitro. In some embodiments, R1is -NH2. In certain embodiments, R1is halo, haloalkyl, alkyl, cyclopropyl, -NH2, -NO2, -C(O)Ra, or -CN. In certain embodiments, R1is halo. In certain embodiments, R1is haloalkyl. In certain embodiments, R1is alkyl. In certain embodiments, R1is cyclopropyl. In certain embodiments, R1is methyl. In certain embodiments, R1is ethyl. In certain embodiments, R1is -NH2. In certain embodiments, R1is -NO2. In certain embodiments, R1is -C(O)Ra, wherein Rais hydrogen or alkyl. In certain embodiments, R1is -C(O)Ra, wherein Rais hydrogen or methyl. In certain embodiments, R1is -CN.

[0060] In certain embodiments, each Raand Rbis independently H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocycloalkyl or heteroaryl. For example, if R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to

[0061] L hich they are attached to formN'S w_. In certain embodiments, each Raand Rbis independently H. In certain embodiments, each Raand Rbis independently H or methyl.

[0062] R2 and Rs

[0063] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2 is -OR2, wherein R2is halomethyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2 is -CHF2 or -CF3. In certain embodiments, R2is -OR2, wherein R2is Ci-4 alkyl or Ci-4 haloalkyl. In certain embodiments, R2is -OR2wherein R2is methyl optionally substituted with one or more fluoro. In further embodiments, R2is -OR2, wherein R2is halomethyl such as a methyl substituted with at least one fluoro (e.g., CHF2 or CF3). In certain embodiments, R2is -OR2, wherein R2is benzyl and R3is hydrogen or methyl optionally substituted with one or more fluoro.

[0064] In certain embodiments, R3is -OR3, wherein R3is methyl. In further embodiments, R3is -OR3, wherein R3is halomethyl such as a methyl substituted with at least one fluoro (e.g., CHF2 or CF3). In some embodiments, R3is -OR3, wherein R3is benzyl. In some embodiments, R3is -OR3’ wherein R3is benzyl and R2is -OR2, wherein R2is hydrogen or methyl optionally substituted with one or more fluoro.

[0065] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa. In certain embodiments, each Rais H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Rais H, Ci-4 alkyl, or Ci-4 haloalkyl. In certain embodiments, Rais H. In certain embodiments, each Rais H or methyl optionally substituted with one or more fluoro. In certain embodiments, Rais CF3.

[0066] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5- or 6- membered heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5-membered heterocyclyl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, C1-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5-membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of O, N and S, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5-membered heterocyclyl comprising one or more oxygen heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5-membered heterocyclyl comprising one or more oxygen heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by fluoro, methyl optionally substituted with one or more fluoro, Ci-4 haloalkyl, or ORa, wherein Rais H or methyl optionally substituted with one or more fluoro.

[0067] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 6- membered heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 6-membered heterocyclyl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 5-membered heterocyclyl comprising one or more heteroatoms selected from the group consisting of O, N and S, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 6-membered heterocyclyl comprising one or more oxygen heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2and R3together with the atoms to which they are attached combine to form a 6-membered heterocyclyl comprising one or more oxygen heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by fluoro, methyl optionally substituted with one or more fluoro, Ci-4 haloalkyl or ORa, wherein Rais H or methyl optionally substituted with one or more fluoro.

[0068] Re and R7 In certain embodiments, each of R6and R7is independently hydrogen, deuterium, or fluoro. In certain embodiments, each of R6and R7is independently hydrogen, or fluoro. In certain embodiments, each of R6and R7is independently hydrogen.

[0069] Rs and R9

[0070] In certain embodiments, each of R8and R9is independently hydrogen, deuterium, halogen, Ci-4 alkyl, CN or C(O)Ci-4 alkyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In certain embodiments, each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by halo.

[0071] In certain embodiments, each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium.

[0072] In certain embodiments, each of R8and R9is independently hydrogen, deuterium, halo, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In certain embodiments, each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by fluoro. In certain embodiments, each of R8is H and R9is hydrogen, deuterium, fluoro, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In certain embodiments, each of R9is H and R8is hydrogen, deuterium, fluoro, methyl, CN, or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In certain embodiments, each of R8and R9is independently hydrogen.

[0073] In certain embodiments, each of R8is CN and R9is hydrogen. In certain embodiments, each of R9is CN and R8is hydrogen. In certain embodiments, each of R8is C(O)Me and R9is hydrogen. In certain embodiments, each of R9is CN and R8is C(O)Me.

[0074] Rio

[0075] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Rio is Ci-4 alkyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Rio is methyl optionally substituted with one or more fluoro. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein Rio is ethyl optionally substituted with one or more fluoro.

[0076] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:

[0077] (II), wherein

[0078] Ri, R2’, R3’, RS, R9 and Rio are as defined above with respect to Formula (I).

[0079] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein

[0080] Ri is hydrogen, halo, C3-6 cycloalkyl, 3-6 membered heterocyclyl, Ci-4 alkyl, or Ci-4 haloalkyl;

[0081] R2’ is -OR2and R3’ is -OR3, wherein R2and R3is each independently hydrogen, halo, C1-4 alkyl, or Ci-4 haloalkyl; wherein the Ci-4 alkyl, or Ci-4 haloalkyl is optionally substituted with aryl or heteroaryl;

[0082] Rs and R9 are each independently hydrogen, halo, CN, Ci-4 alkyl, Ci-4 haloalkyl, or C(O)- C1-4 alkyl optionally substituted with one or more halo;

[0083] Rio is C1-4 alkyl or Ci-4 haloalkyl.

[0084] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein

[0085] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro, cyclopropyl, or benzyl; R2and R3are each independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl;

[0086] Rs and R9 are each independently hydrogen, fluoro, CN, methyl optionally substituted with one or more fluoro, or C(O)-Ci-4 alkyl;

[0087] Rio is methyl.

[0088] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein

[0089] Ri is hydrogen or fluoro;

[0090] R2and R3are each independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl, provided that at least one of R2 and R3 is hydrogen;

[0091] Rs and R9 are each independently hydrogen, fluoro, CN, methyl optionally substituted with one or more fluoro, or C(O)-Me, provided that at least one of Rs and R9 is hydrogen;

[0092] Rio is methyl.

[0093] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein

[0094] Ri is hydrogen;

[0095] R2is hydrogen or methyl optionally substituted with one or more fluoro;

[0096] R3is independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl, provided that at least one of R2 and R3 is hydrogen;

[0097] Rs and R9 are each independently hydrogen, fluoro, or CN; and

[0098] Rio is methyl or ethyl.

[0099] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein

[0100] Ri is hydrogen, fluoro, or methyl optionally substituted or Ci-4 haloalkyl;

[0101] R2and R3are each independently hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl; wherein the C1-4 alkyl, or Ci-4 haloalkyl is optionally substituted with aryl or heteroaryl;

[0102] Rs and R9 are each independently hydrogen, halo, CN, Ci-4 alkyl, Ci-4 haloalkyl or -C(O)- Ci-4alkyl, provided that at least one of Rs and R9 is hydrogen; and Rio is methyl or ethyl.

[0103] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III) or Formula (III- A), or a pharmaceutically acceptable salt thereof:

[0104] (III-A), wherein:

[0105] X and Y, Ri, Rs, R9 and Rio are as defined above with respect to Formula (I), and Rn and R12 are each independently hydrogen, halo, haloalkyl, or alkyl.

[0106] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III) or Formula (III-A), or a pharmaceutically acceptable salt thereof, and wherein X and Y, Ri, Rs, R9 and Rio are as defined above with respect to Formula (I), and Rn and R12 are each independently hydrogen, halo, C1-4 alkyl, or C1-4 haloalkyl. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III) or Formula (III- A), or a pharmaceutically acceptable salt thereof, and wherein

[0107] X and Y are each O or NRXand Rxis hydrogen, or Ci-4 alkyl;

[0108] Ri is hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;

[0109] Rs and R9 are each independently CN, hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;

[0110] Rio is C1-4 alkyl; and

[0111] R11 and R12 are each independently hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl.

[0112] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III) or Formula (III- A), or a pharmaceutically acceptable salt thereof, and wherein

[0113] X and Y are each O or NRXand Rxis hydrogen or methyl;

[0114] Ri is hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl;

[0115] Rs and R9 are each independently CN, hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl; and

[0116] Rio is C1-2 alkyl; and

[0117] R11 and R12 are each independently hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl.

[0118] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III) or Formula (III- A), or a pharmaceutically acceptable salt thereof, and wherein

[0119] X and Y are each O;

[0120] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0121] Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0122] Rio is methyl; and

[0123] R11 and R12 are each independently hydrogen, fluoro, or methyl optionally substituted with one or more fluoro.

[0124] In certain embodiments, the compound is selected from:

[0125]

[0126] In certain embodiments, the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier. The pharmaceutical composition can be a medicament.

[0127] Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, parenteral administration (e.g., intravenously, subcutaneously, or intramuscularly), oral administration (for example, tablets, and capsules); absorption through the oral mucosa (e.g., sublingually), or transdermally (for example as a patch applied to the skin), or topically (for example, as a cream, ointment or spray applied to the skin).

[0128] In some embodiments, pharmaceutical compositions comprising a compound of Formula (I), (I-a), (II), (III), or (Ill-a), or pharmaceutically acceptable salts thereof can be formulated for oral administration. For example, a compound provided herein can be combined with suitable compendial excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of a compound of Formula (I), (I-a), (II), (III), or (IILa). The drug product can be prepared by first manufacturing the compound of Formula (I), (I-a), (II), (III), or (IILa) as an active pharmaceutical ingredient (API), followed by roller compaction / milling with intragranular excipients and blending with extra granular excipients. A Drug Product can contain the selected compound of Formula (I), (I-a), (II), (III), or (IILa) as the API and excipient components in a tablet in a desired dosage strength of Compound 1. The blended material can be compressed to form tablets and then film coated. The excipients can be selected from materials appropriate for inclusion in a pharmaceutical composition for an intended purpose and route of delivery including providing a desired manufacturing and stability properties and / or desired in vivo characteristics or other properties to the pharmaceutical composition. In some embodiments, the pharmaceutical composition can include a compound of Formula (I), (I-a), (II), (III), or (IILa) as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a glidant (e.g., colloidal silicon dioxide) and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition can comprise a material such as an extended release or disintegrant involved in carrying or transporting the API pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject, including materials to desirable control the absorption of the API in the intestine.

[0129] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0130] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0131] To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using suitable excipients. The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and / or auxiliary agents. In some embodiments, the pharmaceutical compositions according to the present invention may contain conventional carrier agents including a binder, a lubricant and / or a glidant selected from those products and materials generally used in pharmaceutical industry for preparation of pharmaceutical compositions for an intended route of administration.

[0132] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0133] Liquid dosage forms useful for oral administration include pharmaceutically acceptable carriers and the active ingredient provided as a solid form for reconstitution prior to administration, or as a liquid (e.g., solutions, suspensions, or emulsions). In addition to the active ingredient, a liquid dosage forms may contain inert diluents commonly used in the art. For example, formulations of pharmaceutically acceptable compositions for injection can include aqueous solutions such as water, or physiologically buffered saline, or other solvents or vehicles suitable for the intended route of administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0134] The therapeutically effective amount of a pharmaceutical composition can be determined by human clinical trials to determine the safe and effective dose for a patient with a relevant diagnosis. It is generally understood that the effective amount of the compound may vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the pharmaceutical composition at a dose and dose interval determined to be safe and effective for the patient.

[0135] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. Pharmaceutically acceptable salts include, for example, acid-addition salts and baseaddition salts. The acid that is added to a compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to a compound to form a baseaddition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically acceptable salt is a metal salt, in some embodiments, a pharmaceutically acceptable salt is an ammonium salt. For example, a pharmaceutically acceptable acid addition salt can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0136] In some embodiments, a compound of Formula (I), (I-a), (II), (III), or (IILa) can provide additional beneficial properties. For example, the compounds described herein may provide beneficial therapeutic properties while minimizing emesis. For example, a compound of Formula (I), (I-a), (II), (III), or (IILa) may have improved metabolic stability and activity for inhibiting SERT. In some embodiments, a compound of Formula (I), (I-a), (II), (III), or (Ill-a) described herein inhibit SERT and have a desired metabolic stability and / or other desired ADME properties. Furthermore, compounds that have a high brain exposure with brain: plasma ratios (expressed as Kp) > 0.3 and ideally > 0.7 are most desirable. In some embodiments, a compound of Formula (I), (I-a), (II), (III), or (Ill-a) can inhibit SERT with an ICso of less than about 1 micromolar in the assay of Example Al.

[0137] DEFINITIONS

[0138] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0139] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0140] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0141] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0142] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0143] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0144] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0145] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.

[0146] Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0147] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0148] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0149] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0150] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0151] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0152] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CHz-O-alkyl, - OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0153] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups, C1-C10 branched- chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Preferably, the “alkyl” group refers to C1-C7 straight- chain alkyl groups or C1-C7 branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C3 straight-chain alkyl groups or C1-C3 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4- octyl and the like. The “alkyl” group may be optionally substituted.

[0154] The term “haloalkyl” refers to an alkyl group substituted with at least one hydrogen atom on a carbon replaced by a halogen. Illustrative halogens include fluoro, chloro, bromo, and iodo. Illustrative haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0155] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6 alkyl group, for example, contains from one to six carbon atoms in the chain.

[0156] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0157] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0158] The term “amide”, as used herein, refers to a group wherein Reand Rfeach independently represent a hydrogen or hydrocarbyl group, or Reand Rftaken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0159] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0160] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0161] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0162] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Preferably, the “alkoxy” group refers to C1-C7 straight-chain alkoxy groups or C1-C7 branched- chain alkoxy groups. Representative alkoxy groups include methoxy, ethoxy, propoxy, tertbutoxy and the like.

[0163] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein Re, Rf, and Rg, each independently represent a hydrogen or a hydrocarbyl group, or Reand Rftaken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0164] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0165] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0166] The term “aryl” as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring, for example a phenyl. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0167] The term “carbamate” is art-recognized and refers to a group wherein Reand Rfindependently represent hydrogen or a hydrocarbyl group.

[0168] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0169] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5- cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1 ,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0170] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0171] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0172] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0173] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0174] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0175] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0176] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0177] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0178] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0179] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0180] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0181] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0182] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains six or fewer carbon atoms, preferably four or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0183] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0184] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein Reand Rfindependently represents hydrogen or hydrocarbyl.

[0185] The term “sulfoxide” is art-recognized and refers to the group -S(O)-.

[0186] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0187] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0188] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxy carbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0189] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SReor -SC(O)Rewherein Rerepresents a hydrocarbyl.

[0190] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0191] The term “urea” is art-recognized and may be represented by the general formula O 11 ReS'N N

[0192] ReRfwherein Reand Rfindependently represent hydrogen or a hydrocarbyl.

[0193] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0194] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0195] The term “pharmaceutically acceptable acid addition salt” as used herein means any nontoxic organic or inorganic salt of any base compounds, e.g., represented by Formula (I), (I-a), (II), (III), or (Ill-a). Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula (I) and Formula (I-a) are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula (I) and Formula (I-a) for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0196] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula (I) and Formula (I-a) or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0197] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0198] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0199] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraocular (such as intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0200] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in an R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0201] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0202] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0203] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of Formula (I) and Formula (I-a)). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs include using ester or phosphoramidate as biologically labile or cleavable (protecting) groups. The prodrugs of this disclosure are metabolized to produce a compound of Formula (I) and Formula (I-a). The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0204] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0205] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter. Methods of using compounds disclosed herein are also provided. The disclosure also includes pharmaceutical compositions comprising one or more SERT inhibiting compounds, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet or the like). Pharmaceutical compositions comprising a compound of Formula (I), (I-a), (II), (III), or (Ill-a), can be provided in an oral dosage form such as a capsule or tablet. The oral dosage form optionally comprises one or more fillers, disintegrants, lubricants, glidants, anti-adherents and / or anti-statics. In some embodiments, an oral dosage form is prepared via dry blending. In some embodiments, an oral dosage form is a tablet and is prepared via dry granulation. For example, a SERT inhibitor compound of Formula (I), (I-a), (II), (III), or (Ill-a) of the present disclosure can be formulated as a test article for evaluation in animal models and (if appropriate) subsequent human clinical trials to determine the dosed at a therapeutically effective dose and dose frequency for humans. The pharmaceutical compositions may be orally administered in any orally acceptable dosage form. Accordingly, a patient and / or subject can be selected for treatment using a compound described herein by first evaluating the patient and / or subject to determine whether the subject is in need of inhibition of SERT, and if the subject is determined to be in need of inhibition of SERT, then administering to the subject a pharmaceutical composition comprising one or more compounds described herein, or pharmaceutically acceptable salts thereof.

[0206] The compounds described herein may be administered to treat CNS disorders and / or inflammatory conditions. Exemplary CNS disorders include generalized anxiety, acute anxiety and panic attacks, social anxiety, panic disorders, major depressive disorder, cognitive disorders, including Alzheimer's disease and other neurodegenerative disorders, neurodevelopmental disorders, schizophrenia, bipolar disorder, obsessive-compulsive disorder, multiple sclerosis, attention deficit-hyperactivity disorder, Bulimia nervosa, Huntington's disease, stroke, autism, and premenstrual dysphoric disorder. Exemplary inflammatory conditions include chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.

[0207] In some embodiments, methods of treating a patient suffering from a disease comprise administering to a patient a composition comprising a compound disclosed herein for the treatment or prevention of a mental health disorder. In some embodiments, methods of treating a patient suffering from a disease comprise administering to a patient a composition comprising a compound disclosed herein for the treatment or prevention of a diagnosed condition selected from anxiety and depression. In some embodiments, the compound disclosed herein is administered to the patient in a unit dose. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I), (I-a), (II), (III), or (Ill-a), for the treatment of a disease selected from the group consisting of mild to moderate depression and major depressive episodes. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I), (I-a), (II), (III), or (ni-a), for the treatment of anxiety. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I), (I-a), (II), (III), or (Ill-a), for the treatment of depression. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I), (I-a), (II), (III), or (Ill-a), for the treatment of a condition selected from the group consisting of: anxiety associated with depression, anxiety with depression, mixed anxiety and depressive disorder. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I), (I-a), (II), (III), or (Ill-a), for the treatment of anxiety and hysteria or anxiety and depression.

[0208] Unless otherwise indicated in the tables of compounds herein, the abbreviation RAC or rac indicates a racemic mixture, and DIAST indicates a specific diastereomer. In illustrative embodiments, although a compound may be depicted withor bonds, such a depiction may be denoting relative stereochemistry based on elution peaks from a chiral separation.

[0209] In some embodiments, this disclosure provides one or more of the following embodiments of the invention, or variations thereof:

[0210] 1. A compound of F ormula (I) :

[0211] or a pharmaceutically acceptable salt thereof; wherein

[0212] X and Y are each independently N, CH, or CR1; each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2R1, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb;

[0213] R2is -OR2and R3is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0214] R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, methyl, or fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN, or C(O)Rewherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0215] R10is Ci -4 alkyl; each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0216] Reis hydrogen or alkyl.

[0217] 2. The compound of embodiment 1, wherein the compound is of Formula (I-a): or a pharmaceutically acceptable salt thereof.

[0218] 3. The compound of embodiment 1, wherein X is CH.

[0219] 4. The compound of any one of embodiments 1-3, wherein Y is CH.

[0220] 5. The compound of embodiment 4, wherein each R1is independently hydrogen, halo, Ci-4 alkyl, C1-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocyclyl, Ce aryl, 5-6 membered heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -C02Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb, wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, Ci-4 alkyl or Ci-4 haloalkyl, and wherein Raand Rbare each independently Ci-4 alkyl.

[0221] 6. The compound of embodiment 5, wherein each R1is independently hydrogen, fluoro, cyclopropyl, or methyl optionally substituted with one or more fluoro. The compound of any one of embodiments 1-6, wherein each of R2is -OR2and R3is - OR3, wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa. The compound of any one of embodiments 1-6, wherein each of R2is -OR2and R3is - OR3wherein R2and R3are independently H, Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, 6-membered aryl or 5-6 membered heteroaryl; wherein each hydrogen atom in Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-8 cycloalkyl, 3-6 member heterocyclyl, 6-membered aryl and 5-6 membered heteroaryl is optionally substituted by halo, or Ci-4 alkyl; and each hydrogen atom in Ci-4 alkyl, Ci-4 alkenyl, and C1-4 alkynyl is optionally substituted with 6-membered aryl or 5-6 membered heteroaryl optionally substituted with halo, C1-4 alkyl, or C1-4 haloalkyl. The compound of embodiment 8, wherein each of R2is -OR2and R3is -OR3wherein R2and R3are independently H, or methyl optionally substituted with one or more fluoro. The compound of embodiment 8, wherein each of R2is -OR2and R3is -OR3wherein R2and R3are independently H, methyl, or benzyl. The compound of any one of embodiments 1-6, wherein each of R2 is -OR2and R3 is - OR3, wherein R2and R3are independently H, or Ci-4 alkyl optionally substituted with one or more fluoro. The compound of any one of embodiments 9-11, wherein at least one of R2is -OR2and R3is -OR3, wherein R2and R3are independently H or methyl. The compound of any one of embodiments 1-12, wherein each of R6and R7is independently hydrogen or fluoro. The compound of any one of embodiments 1-12, wherein each of R6and R7is independently methyl. The compound of embodiment 13 or 14, wherein at least one of R6and R7is hydrogen. The compound of any one of embodiments 1-15, wherein each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo. The compound of embodiment 16, wherein at least one of R8and R9is hydrogen. 18. The compound of embodiment 16, wherein at least one of R8and R9is CN, fluoro, methyl, or C(O)Me.

[0222] 19. The compound of embodiment 16, wherein R8and R9are each hydrogen.

[0223] 20. The compound of embodiment 16, wherein R8is hydrogen.

[0224] 21. The compound of embodiment 16, wherein R9is hydrogen.

[0225] 22. The compound of any one of embodiments 1-21, wherein R10is methyl.

[0226] 23. The compound of any one of embodiments 1-21, wherein R10is ethyl.

[0227] 24. The compound of any one of embodiments 1-23, wherein each of Raand Rbis independently H or methyl.

[0228] 25. The compound of any one of embodiments 1-24, wherein each of Rcand Rdis independently H, or methyl.

[0229] 26. A compound of Formula (II): or a pharmaceutically acceptable salt thereof; wherein each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2R1, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; each of R2 is -OR2and R3 is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or R2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN or C(O)Rewherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0230] R10is Ci-4 alkyl. each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0231] Reis hydrogen or alkyl.

[0232] 27. The compound of embodiment 26, wherein a. each of Raand Rbis independently H, or Ci-4 alkyl; b. each of R° and Rdis independently H, Ci-4 alkyl, or Ci-4 haloalkyl; and c. each Reis hydrogen or Ci-4 alkyl.

[0233] 28. The compound of embodiment 26 and 27, wherein each R1is independently hydrogen, halo, C1-4 alkyl, Ci-4 haloalkyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0234] 29. The compound of embodiment 28, wherein R1is hydrogen, fluoro, cyclopropyl, or methyl optionally substituted with one or more fluoro.

[0235] 30. The compound of embodiment 28, wherein R1is hydrogen or fluoro.

[0236] 31. The compound of any one of embodiments 26-30, wherein each of R2is -OR2and R3is - OR3wherein R2and R3are independently H, or Ci-4 alkyl optionally substituted with phenyl or 5-6 membered heteroaryl, provided that one of R2and R3is H.

[0237] 32. The compound of any one of embodiments 26-30, wherein each of R2is -OR2and R3is - OR3wherein R2and R3are independently H, or benzyl optionally substituted with one or more halo, Ci-4 alkyl, or Ci-4 haloalkyl, provided that one of R2and R3is H. The compound of any one of embodiments 26-30, wherein each of R2is -OR2and R3is - OR3, wherein R2and R3are independently H, halo, Ci-4 alkyl, or Ci-4 haloalkyl. The compound of any one of embodiments 26-30, wherein each of R2is -OR2and R3is - OR3, wherein R2and R3are H or methyl. The compound of any one of embodiments 26-30, wherein each of R2and R3is methyl. The compound of any one of embodiments 26-30, wherein each of R2and R3is independently H or methyl substituted with one or more fluoro. The compound of any one of embodiments 26-30, wherein each of R2and R3is independently H or -CHF2 or -CF3. The compound of any one of embodiments 33-37, wherein one of R2and R3is H. The compound of embodiment 32, wherein R2is methyl, and R3is H or R2is H, and R3is methyl. A compound of Formula (III) or a pharmaceutically acceptable salt thereof: wherein

[0238] X and Y are each O or NRXand Rxis hydrogen or Ci-4 alkyl;

[0239] Ri is hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;

[0240] Rs and R9 are each independently CN, hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;

[0241] Rio is C1-4 alkyl; and

[0242] R11 and R12 are each independently hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl. The compound of embodiment 40, wherein the compound is a compound of Formula (III-

[0243] A):

[0244] (III-A), or a pharmaceutically acceptable salt thereof. The compound of embodiment 40 or 41, wherein:

[0245] X and Y are each O or NRXand Rxis hydrogen or methyl;

[0246] Ri is hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl;

[0247] Rs and R9 are each independently CN, hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl; and

[0248] Rio is C1-2 alkyl; and

[0249] R11 and R12 are each independently hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl. The compound of embodiment 40 and 41, wherein:

[0250] X and Y are each O;

[0251] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0252] Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0253] Rio is methyl; and

[0254] R11 and R12 are each independently hydrogen, fluoro, or methyl optionally substituted with one or more fluoro. The compound of embodiments 40 and 41, wherein:

[0255] X and Y are each O;

[0256] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro; Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0257] Rio is methyl; and

[0258] Rn and R12 are each independently hydrogen, fluoro, or methyl. The compound of any one of embodiments 26-45, wherein each compound has the absolute stereochemistry shown. A pharmaceutical composition comprising a compound of any one of embodiments 1 -46, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of treating a mental health disorder, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of embodiments 1- 46 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 47.

[0259] 49. The method of embodiment 48, wherein the mental health disorder is anxiety, stress, or depression.

[0260] 50. The method of embodiment 48, wherein the mental health disorder is anxiety.

[0261] 51. The method of embodiment 48, wherein the mental health disorder is stress.

[0262] 52. The method of embodiment 48, wherein the mental health disorder is depression.

[0263] 53. The method of any one of embodiments 48-52, wherein the mammal is a human.

[0264] EXAMPLES

[0265] Certain compounds in the following examples are labeled using the MDL enhanced stereorepresentation. For example, the label “ABS” denotes the absolute stereochemistry at a particular stereocenter. The label “or n” or “orn” where n is an integer (e.g., “orl”), denotes a stereoisomer that has either the stereochemistry as drawn or is the epimer at that particular stereocenter. The label “and n” or “&n,” where n is an integer (e.g., “and 1” or “&1”) represents a mixture of two epimers at the stereocenter, i.e., the structure as drawn and the epimer in which the stereogenic center has the opposite configuration (e.g., a racemic mixture).

[0266] LC / MS spectra were obtained using Agilent 1200\G1956A or SHIMADZU LCMS-2020. Standard LC / MS conditions were as follows (running time 1.55 min):

[0267] Acidic condition: Mobile Phase A: 0.0375% TFA in water (v / v). Mobile Phase B: 0.01875% TFA in acetonitrile (v / v); Column: Kinetex EVO Cl 8 30*2.1mm, 5 / / m.

[0268] Basic condition: Mobile Phase A: 0.025% NH3 H2O in water (v / v). Mobile Phase B: Acetonitrile; Column: Kinetex EVO Cl 8 2.1X30mm, 5 / / m.

[0269]

[0270] Table of Abbreviations

[0271] Example 1: Synthesis of (+ / -)-Mesembrenone (016) (+ / -)-Mesembrine (022)

[0272] Step 1 : Synthesis of 1 -(3, 4-dimethoxyphenyl)cycl opr opane-1 -carbonitrile

[0273] To a solution of 2-(3,4-dimethoxyphenyl)acetonitrile (20 g, 112 mmol) in DMF (93 mL) was added NaH (18.0 g, 451 mmol, 60% purity) in portions. The mixture was allowed to stir at 25°C for 20 min. 1 -Bromo-2-chloro-ethane (16.1 g, 112 mmol) was added, and the mixture was allowed to stir at 25°C for 16 hr. The reaction was quenched by the addition of a MeOH / water mixture (1: 1, 1000 mL) and the resulting solution was extracted with EtOAc (3 x 500 mL). The organic solutions were combined, washed with water (4 x 500 mL) and brine (1 x 200 mL) and dried over (Na2SO4). The solution was filtered and the solvent was evaporated under reduced pressure. The resulting solid was purified by column chromatography (SiO2, Petroleum ether / EtOAc =10 / 1 to 3 / 1) to give l-(3,4-dimethoxyphenyl)cyclopropane-l-carbonitrile (15 g, 65%) as yellow oil. ' H NMR (400 MHz, CDCh) 8 6.88 (s, 1H), 6.82 (d, J= 1.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 1.68 - 1.65 (m, 2H), 1.35 (d, J = 2.4 Hz, 2H).

[0274] Step 2: Synthesis of l-(3.4-dimethoxyphenyl)cvclopropane-l-carbaldehvde

[0275] To a solution of l-(3,4-dimethoxyphenyl)cyclopropane-l-carbonitrile (11 g, 54.1 mmol) in THF (160 mL) was added DIBAL-H (IM in toluene, 81.2 mb). The mixture was allowed to stir at 25°C for 3 hr and then the reaction was cautiously quenched by addition of aqueous 2M HC1. The solution was extracted with DCM (3 x 200 mL). The organic solutions were combined, washed with water (2 x 200 mL) and brine (2 x 200 mL), and then dried over Na2SO4 to give 1- (3,4-dimethoxyphenyl)cyclopropane-l-carbaldehyde (9.6 g, 85%) as yellow oil. LC-MS (ESI+) m / z 207.0 (M+H)+. 'H NMR (400 MHz, CDCh) 8 9.26 (s, 1H), 6.94 - 6.61 (m, 3H), 3.89 (d, J = 2.8 Hz, 6H), 1.61 - 1.52 (m, 2H), 1.42 - 1.37 (m, 2H)

[0276] Step 3: Synthesis of (Z)-l-(l-(3.4-dimethoxyphenyl)cvclopropyl)-A-methylmethanimine To a solution of l-(3, 4-dimethoxyphenyl)-cyclopropanecarbaldehyde (5.0 g, 24.2 mmol) in DCM (50 mL) was added MeNH2(2 M, 121 mL) and Na2SO4(15.5 g, 109 mmol, l l.O mL). The mixture was allowed to stir at 25°C for 16 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (Z)-l-(l-(3,4-dimethoxyphenyl)cyclopropyl)-A- methylmethanimine (5.1 g, 99%) as white solid. LC-MS (ESI+) m / z 219.9 (M+H)+; 'H NMR (400 MHz, CDCh) 8 7.55 (q, J= 1.2 Hz, 1H), 6.93 - 6.77 (m, 3H), 3.88 (d, J= 7.2 Hz, 6H), 3.24 (d, J= 1.6 Hz, 3H), 1.29 - 1.23 (m, 2H), 1.18 - 1.12 (m, 2H).

[0277] Step 4: Synthesis of 4-(3.4-dimethoxyphenyl)-l-methyl-2.3-dihydro-l / 7-pyrrole

[0278] To a solution of (Z)-l-(l-(3,4-dimethoxyphenyl)cyclopropyl)-A-methylmethanimine (5.4 g, 24.6 mmol) in DMF (19 mL) was added Nal (366 mg, 2.44 mmol) and TMSC1 (267 mg, 2.46 mmol). The mixture was allowed to stir at 90°C for 3 hr. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic solutions were combined, washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 4-(3,4-dimethoxyphenyl)- l -methyl-2,3-dihydro- l / 7-pyrrole (6.25 g, 80%) as yellow oil. LC-MS (ESI+) m / z 220.0 (M+H)+. ' H NMR (400 MHz, CDCh) 8 6.90 - 6.66 (m, 3H), 6.31 (t, J= 1.6 Hz, 1H), 3.95 - 3.80 (m, 6H), 3.18 - 3.11 (m, 2H), 2.79 (dt, J= 1.2, 9.0 Hz, 2H), 2.65 (s, 3H).

[0279] Step 5: Synthesis of rac-3a-(3.4-dimethoxyphenyl)-l-methyl-1.2.3.3a.7.7a-hexahvdro-67 -indol- 6-one 016)

[0280] 4-(3,4-Dimethoxyphenyl)-l-methyl-2, 3 -dihydro- 1H- pyrrole (6.25 g, 28.5 mmol) was dissolved in DCM (100 mL). To this solution was added HC1 (IM in dioxane, 25 mL, 100 mmol). The mixture was evaporated to dryness and then dissolved in ACN (90 mL). To this solution was added (E)-4- methoxybut-3-en-2-one (4.28 g, 42.7 mmol). The reaction mixture was allowed to stir at 90°C for 16 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex luna Cl 8 (250*70mm, 10 um); mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-52%, 20min). The eluant was acidified with aq. HC1 to give 016 (3.0 g, 30%) as a white solid. LC-MS (ESI+) m / z 288.3 (M+H)+. ' H NMR (400 MHz, CDChJ 8 6.90 - 6.88 (m, 1H), 6.87 - 6.83 (m, 2H), 6.74 (dd, .7= 2.0, 10.1 Hz, 1H), 6.11 (d, J= 10.0 Hz, 1H), 3.89 (d, J= 4.0 Hz, 6H), 3.33 (dt, J= 2.4, 8.8 Hz, 1H), 2.69 - 2.66 (m, 1H), 2.58 - 2.51 (m, 2H), 2.50 - 2.41 (m, 2H), 2.33 (s, 3H), 2.27 - 2.18 (m, 1H)

[0281] Step 6: Synthesis of rac-3a-(3.4-dimethoxyphenyl)-l-methyloctahydro-67 / -indol-6-one (022) A mixture of 016 (12.0 g, 43.9 mmol) and 10% Pd / C (300 mg) in EtOAc (120 mL) was degassed and then purged with H2 for 3 times. The mixture was allowed to stir at 25°C for 2 hr under 15 psi H2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 022 (10 g, 80%) as brown oil. LC-MS (ESI+) m / z 290.4 (M+H)+. 'H NMR (400 MHz, CDCh) 8 6.99- 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J= 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J= 3.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0282] Procedures similar to those described above in Example 1 were used to prepare ketones in the following table from the appropriate starting materials:

[0283] Example 2: SFC Separation of rac-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6Zf-indol-

[0284] 6-one (022) to give (-)-Mesembrine (001) and (+)-Mesembrine (002)

[0285] 022 001 002

[0286] Compound 022 (15g, 90% purity) was subjected to separation by SFC (column: DAICEL CHIRALCEL OD (250mm* 50mm, lOum); mobile phase: [Neu-MeOH]; B%: 25%-25%, 2; 1230 min) to give 001 (peak 1, 5.4 g, free base, 36%) as yellow oil and 002 (peak 2, 5.6 g, free base, 37%) as yellow oil. 001: LC-MS (ESI+) m / z 290.4 (M+H)+'H NMR (400 MHz, CDCh) 8 6.99 - 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J= 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0287] 002: LC-MS (ESI+) m / z 290.4 (M+H)+'H NMR (400 MHz, CDCh) 8 6.99 - 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J= 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0288]

[0289] Procedures similar to those described above in Example 2 were used to prepare ketones in the following table from the appropriate starting materials:

[0290] Example 3: Synthesis of 2-((3aN,7aN,£)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6Zf- indol-6-ylidene)acetonitrile (101) and 2-((3aN,7aNyZ)-3a-(3,4-dimethoxyphenyl)-l- inetliyl()ctaliydro-6 / / -iiid()l-6-ylidene)acetonitrile (102)

[0291] To a solution of 2-diethoxyphosphorylacetonitrile (122 mg, 691 pmol, 111 pL) in THF (2.0 mL) was added NaH (27.6 mg, 691 pmol, 60% purity). The mixture was allowed to stir at 0°C for 20 min and then 001 (100 mg, 345 pmol) was added. The reaction mixture was allowed to stir at 20°C for 2 hr and was then poured into saturated ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (15 mL). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiCh, DCM: MeOH = 15:1) to give 102 (27 mg) as a white solid and 101 (29 mg) as a white solid.

[0292] 101: LC-MS (ESI+) m / z 313.3 (M+H)+. ' H NMR (400 MHz, CDCh) 8 6.95 - 6.77 (m, 3H), 5.15 (s, 1H), 3.90 (d, J= 6.4 Hz, 6H), 3.26 (d, J= 7.2 Hz, 1H), 2.98 - 2.83 (m, 1H), 2.74 (dd, J= 3.2, 10.8 Hz, 1H), 2.58 (s, 2H), 2.38 (s, 4H), 2.25 - 2.09 (m, 3H), 2.06 - 1.87 (m, 2H).

[0293] 102: LC-MS (ESI+) m / z 313.3 (M+H)+. ' H NMR (400 MHz, CDCh) 8 6.97 - 6.78 (m, 3H), 5.17 (s, 1H), 3.90 (d, J= 6.4 Hz, 6H), 3.38 - 3.20 (m, 1H), 3.14 (d, J= 14.8 Hz, 1H), 3.04 - 2.87 (m, 1H), 2.47 (s, 4H), 2.41 - 2.22 (m, 2H), 2.21 - 2.06 (m, 3H), 1.95 (d, J= 3.6 Hz, 2H).

[0294] Example 4: Synthesis of (3aN,7aN)-3a-(3,4-dimethoxyphenyl)-l-methyl-6- methyleneoctahydro- TH- indole (103)

[0295] 001 103

[0296] To a solution of methyl(triphenyl)phosphonium bromide (740 mg, 2.07 mmol) in THF (6.0 mL) was added t-BuOK (IM in THF, 2.07 mL) at 0°C over 0.5 hours. 001 (300 mg, 1.04 mmol) in THF (1 mL) was added to the mixture. The reaction mixture was allowed to stir at 25°C for 16 hr and then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solutions were dried over sodium sulfate, filtered and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 103 (137.7 mg) as a yellow gum. LC-MS (ESI+) m / z 288.2 (M+H)+. 'H NMR (400 MHz, CDCh) 8 6.88 - 6.79 (m, 2H), 6.78 - 6.72 (m, 1H), 4.70 (s, 2H), 3.81 (d, J= 6.0 Hz, 6H), 3.37 (ddd, J= 5.2, 8.4, 9.8 Hz, 1H), 2.90 (t, J= 4.0 Hz, 1H), 2.45 (s, 2H), 2.42 - 2.35 (m, 4H), 2.16 - 2.08 (m, 1H), 1.98 (d, J = 3.6 Hz, 2H), 1.96 - 1.86 (m, 3H). Compounds in the table below were prepared from the appropriate ketone starting material according to a procedure similar to that described above in Example 4:

[0297] Example 5: Synthesis of ( aN.7aN)-6-(difluoromethylene)-3a-(3,4-dimeth oxyphenyl)- 1- methyloctahydro- 1H- indole (201)

[0298]

[0299] A mixture of 001 (400 mg, 1.38 mmol), 2-(difluoromethylsulfonyl)pyridine (320 mg, 1.66 mmol) and Z-BuOK (IM in THF, 2.49 mL) in DMF (5 mL) was degassed and purged with N2 3 times. The reaction mixture was allowed to stir at -50°C for 0.5 hours under an atmosphere of N2 and then poured into water (20 ml) and extracted with ethyl acetate (10*3 mL). The organic solutions were combined, washed with brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by reversed-phase HPLC (0.1% NHsHLO) and then by column chromatography (column: Welch Ultimate XB-NH2 150*25* lOum; mobile phase: [Hexane-EtOH]; gradient: 0%-l 5% B over 20 min) to give 201 (60.6 mg) as a colorless gum. LC-MS (ESI+) m / z 324.2 (M+H)+. 'H NMR (400 MHz, CDCh) 8 6.95 - 6.88 (m, 2H), 6.87 - 6.82 (m, 1H), 3.90 (d, J= 6.0 Hz, 6H), 3.23 (d, J= 5.2 Hz, 1H), 2.74 (s, 1H), 2.57 (d, J= 15.6Hz, 1H), 2.39 (s, 3H), 2.35 (d, J= 7.6 Hz, 1H), 2.31 (d, J= 8.4 Hz, 1H), 2.25 (s, 1H), 2.03 - 1.98 (m, 2H), 1.97 - 1.90 (m, 2H), 1.84 - 1.73 (m, 1H).

[0300] Example 6: Synthesis of 107, 108 and 109 Example Al: SERT Inhibition Assay

[0301] SERT inhibition was measured using a Neurotransmitter Transportation Fluorescence assay. Briefly, stable 5HHH cells were prepared in a 384 micro well plate. Compounds were prepared in assay buffer (20 mM HEPES, 0.1% BSA). The compounds were added to the plated cells and incubated for 30 minutes at 37°C. 25 pL of dye solution (Molecular Devices Neurotransmitter Transporter Uptake Assay Kit) was added per well and incubated for 30 minutes at 37°C. The plates were then read on a plate reader.

[0302] The results are shown in Table 1 as follows: A: ICso < / = 50 nM or lower; B: 50 nM < ICso < / = 100 nM; C: 100 nM < IC50 < / = 500 nM; D: 500 nM < IC50 < / = 1 micromolar; E: IC50 > 1 micromolar.

[0303] Table 1

[0304] Example A2: PDE4 Inhibition Assay

[0305] Recombinant PDE assay

[0306] Recombinant PDE assay inhibition can be measured according to the BPSBioscience

[0307] PDE4 assay kit, as described below.

[0308] Step 1 :

[0309] 1) Dilute 20 pM FAM-Cyclic-3', 5 -AMP stock 100-fold with PDE buffer to make a 200 nM solution. Make only sufficient quantity needed for the assay; store remaining 20 pM stock solution in aliquots at -20°C.

[0310] 2) Add 25 pL of FAM-Cyclic-3', 5 '-AMP (200 nM) to each well designated “Positive Control”, “Test Inhibitor”, and “Substrate Control”. 3) Add 20 pL of PDE assay buffer to each well designated “Substrate Control" and 45 pL of PDE assay buffer to each well designated “Blank”.

[0311] 4) Add 5 pL of inhibitor solution to each well designated “Test Inhibitor”. For the wells labeled “Positive Control", “Substrate Control” and “Blank”, add 5 pL of the same solution without inhibitor (inhibitor buffer).

[0312] 5) Thaw PDE on ice. Upon first thaw, briefly spin tube containing enzyme to recover the full contents of the tube.

[0313] 6) Dilute PDE4 in PDE buffer to 7.5 pg / pL (0.15 ng / reaction)*. Initiate reaction by adding 20 pL of PDE4 (7.5 pg / pL) to the wells designated “Positive Control” and “Test Inhibitor.”

[0314] 7) Incubate at room temperature for 1 hour.

[0315] Step 2:

[0316] 1) Mix binding agent thoroughly and dilute binding agent 1 : 100 with binding agent diluent.

[0317] 2) Add 100 pL diluted binding agent to each microwell. Incubate at room temperature for 1 hour with slow shaking.

[0318] 3) Read the fluorescent polarization of the sample in a microtiter-plate reader equipped for the measurement of fluorescence polarization, capable of excitation at wavelengths ranging from 485 ± 5 nm and detection of emitted light ranging from 528 ± 10 nm. Blank value is subtracted from all other values.

[0319] Cell-based assay

[0320] Cells can be dispensed at a density of 1000 cells / well in black, clear bottom, tissue culture treated, 1536 well plates (Kalypsys, San Diego, CA) in 3 pL assay medium containing DMEM, 2 % FBS, 50 units / mL penicillin and 50 pg / mL streptomycin and can be incubated 24 hr at 37°C with 5 % CO2 prior to compound screening. 3 pL / well of 1 x membrane potential dye was added and incubated for 1 hr at the room temperature. The library compounds in DMSO solution or the positive control, RO 20-1724, can be added at 23 nL / well with a Pintool Station (Kalypsys, San Diego, CA). After a 30-minute incubation with compounds at the room temperature, the assay plate can be measured in an Envision fluorescence plate reader (PerkinElmer, Woburn, MA) in bottom reading mode with an excitation of 535 (±20) nm and emission of 590 (±20) nm. A flying reagent dispensing (FRD) workstation (Aurora Discovery, San Diego, CA) can be used to dispense cells and reagents to 1536-well plates. The Kalypsys Pintool Station can be used to transfer 23 nL compounds in DMSO solution to the 1536-well assay plate. The final DMSO concentration in the assay plates can be under 0.5%.

Claims

CLAIMSWe claim:

1. A compound of F ormula (I) :or a pharmaceutically acceptable salt thereof; whereinX and Y are each independently N, CH, or CR1;R1is hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb;R2is -OR2and R3is -OR3, wherein each of R2and R3is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or -ORa; orR2and R3together with the atoms to which they are attached combine to form heterocyclyl or heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, Ci-4 alkyl, Ci-4 haloalkyl, or halo;each of R8and R9is independently hydrogen, deuterium, halo, Ci-4 alkyl, Ci-4 haloalkyl, cyano, Ci-4 alkoxy, C(O)Re, or C(O)ORewherein each hydrogen atom in Ci-4 alkyl is optionally substituted by deuterium;R10is Ci -4 alkyl; each of Raand Rbis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or if an instance of R1is -NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, alkyl, alkanol, aryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; andReis hydrogen or alkyl.

2. The compound of claim 1 , whereinR1is hydrogen, halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, -ORa, -NRaRb, -CHO, -C(O)Ra, -C02Ra, - C(O)NRaRb, -CN, nitro, or -P(O)ORaORb; wherein each hydrogen atom in alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by halo, alkyl, alkanol, aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, -CN, nitro, or -P(O)ORaORb;R2is -OR2and R3is -OR3, wherein each of R2and R3is independently H, Ci-4 alkyl, C1-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce aryl or 5-6 membered heteroaryl; wherein each hydrogen atom in alkyl is optionally substituted by halo, deuterium, C3-6 cycloalkyl, aryl, or -ORa; wherein each hydrogen atom in cycloalkyl, alkenyl, alkynyl, heteroaryl and aryl is optionally substituted by halo, deuterium, C3-6 cycloalkyl, or -ORa; orR2and R3together with the atoms to which they are attached combine to form a 5-6 membered heterocyclyl comprising one or more O, N or S heteroatoms, or 5-6 membered heteroaryl comprising one or more O, N or S heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, Ci-4 alkyl, Ci-4 haloalkyl, or ORa;each of R6and R7is independently hydrogen, deuterium, methyl, or fluoro; each of R8and R9is independently hydrogen, deuterium, halo, Ci-4 alkyl, Ci-4 haloalkyl, cyano, Ci-4 alkoxy, C(O)Re, or C(O)ORewherein each hydrogen atom in Ci-4 alkyl is optionally substituted by deuterium;R10is Ci-4 alkyl. each of Raand Rbis independently H, Ci-4 alkyl, Ci-4 alkenyl, C3-6 cycloalkyl, 3-6 membeedr heterocyclyl, Ce aryl, or 5-6 membered heteroaryl; or if an instance of R1is - NRaRb, then Raand Rbmay combine with the nitrogen atom to which they are attached to form 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by halo hydroxy, Ci-4 alkyl, Ci-4 alkanol, Ce aryl, 5-6 membered heteroaryl, -OR0, -NR°Rd, -CHO, -C(O)R°, -CO2R0, -C(O)NR°Rd, -CN, nitro, or -P(O)OR°ORd; each of R° and Rdis independently H, Ci-4 alkyl, Ci-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, Ce aryl, or 5-6 membered heteroaryl; andReis hydrogen or Ci-4 alkyl.

3. The compound of claim 2, wherein each of Ra, Rb, R°, and Rdis independently H or Ci-4 alkyl; each of R2and R3is independently H, Ci-4 alkyl, or Ci-4 haloalkyl;R10is methyl.

4. The compound of claim 3, wherein X and Y are each independently N or CH.

5. The compound of claim 4, wherein each of R6and R7is independently hydrogen.

6. The compound of claim 5, wherein each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium.

7. The compound of claim 6, wherein each of R8and R9is independently hydrogen, fluoro, or cyano.

8. The compound of claim 7, wherein R10is methyl.

9. The compound of claim 8, wherein R2and R3are independently hydrogen, deuterium, halogen, Ci-4 alkyl, Ci-4 alkenyl, Ci-4 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 5-6 membered heteroaryl or Ce aryl; wherein each hydrogen atom inalkyl cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted by halo, deuterium, cycloalkyl, heteroaryl, aryl, or -ORa.

10. The compound of claim 9, wherein R2and R3are independently hydrogen, Ci-4 alkyl, or Ci-4 haloalkyl.

11. The compound of claim 10, wherein R1is hydrogen, halo, cyclopropyl, Ci-4 alkyl, Ci-4 alkoxyl, or Ci-4 haloalkyl.

12. The compound or claim 10, wherein R1is hydrogen or fluoro.

13. The compound of claim 1, wherein the compound is of Formula (I-a):(I-a); or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently N or CH;R1is hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;R2and R3is independently hydrogen, Ci-4 alkyl, or Ci-4 haloalkyl;R6and R7is independently hydrogen or methyl;R8and R9is independently hydrogen, halo, Ci-4 alkyl, Ci-4 haloalkyl, CN, or C(O)Me; andR10is methyl or ethyl.

14. The compound of claim 13, whereinX and Y are each CH;R1is hydrogen or fluoro;R2and R3is independently hydrogen, or methyl optionally substituted with one or more fluoro;R6and R7is independently hydrogen;R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me; and R10is methyl.

15. The compound of any one of claims 2-8, wherein R2and R3together with the atoms to which they are attached combine to form a 5-6 membered heterocyclyl comprising one or more O, N or S heteroatoms, or 5-6 membered heteroaryl comprising one or more O, N or S heteroatoms, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa.

16. The compound of claim 15, wherein the compound is a compound of Formula (III) or a pharmaceutically acceptable salt thereof:whereinX and Y are each O, S, or NRXand Rxis hydrogen or Ci-4 alkyl;Ri is hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;Rs and R9 are each independently CN, hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl;Rio is C1-4 alkyl; andR11 and R12 are each independently hydrogen, halo, Ci-4 alkyl, or Ci-4 haloalkyl.

17. The compound of claim 16, wherein the compound is a compound of Formula (III- A):(III-A), or a pharmaceutically acceptable salt thereof, whereinX and Y are each O or NRX, and Rxis hydrogen or methyl;Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;Rio is methyl; andR11 and R12 are each independently hydrogen, fluoro, methyl or methyl optionally substituted with one or more fluoro.

18. The compound of claim 1, selected from:or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound ipharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein the compound ipharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is 105 , or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound ipharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound ipharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compoundpharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. A method of treating a mental health disorder, comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1-24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25.

26. The method of claim 26, wherein the mental health disorder is anxiety, stress, or depression.

27. The method of claim 27, wherein the mental health disorder is anxiety.

28. The method of claim 27, wherein the mental health disorder is stress.

29. The method of claim 27, wherein the mental health disorder is depression.

30. The method of any one of claims 26-30, wherein the mammal is a human.

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