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 patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 606,781 filed December 6, 2023, which is incorporated by reference herein in its 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 (SSRIs), 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] Described herein arc compounds of Formula (I): or a pharmaceutically acceptable salt thereof; wherein compound of formula (I); and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently hydrogen, 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is -OR2and R3is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or R2and R3together with the atoms to which they are attached combine to form hctcrocyclyl or hctcroaryl, wherein each hydrogen atom in hctcrocyclyl and hctcroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, 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;

[0012] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided the compound of formula (I) is not:

[0013] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, provided that when ring A is: and R6, R7and R9are each H, then R8is not H, CM alkyl or CM haloalkyl.

[0014] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring the attachment points of ring A to the compound of formula (I); ring

[0015] X, Y and Z arc each independently N or CR1; each R1is independently hydrogen, halo, CM alkyl, or C3-6 cycloalkyl; each of R2 and R3 is independently CM alkyl, CM haloalkyl, C3-6 cycloalkyl; or each of R2 is -OR2and Ra is -OR3wherein R2and R3are each independently Ci- 4 alkyl, or CM haloalkyl; or R2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, CM alkyl, CM haloalkyl, or -ORa; each of R6and R7is independently hydrogen, or fluoro; each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Mc, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium; R10is methyl; Rais H, CM alkyl, wherein each hydrogen atom in alkyl is optionally substituted by halo, -ORC, -NRcRd, -CHO, -C(O)RC, - CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, or

[0016] Ci-4 alkyl; and provided the compound is not

[0017] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are each independently N or CR1, provided that no more than one of X, Y and Z is N. In some embodiments, each R1is independently hydrogen, fluoro, methyl, or cyclopropyl; each of R2 and R3 is independently C1-4 alkyl, C1-4 haloalkyl, cyclopropyl; or each of R2is -OR2and Ra is -OR3wherein R2and R3are each independently methyl optionally substituted with one or more fluoro; or R2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by fluoro, or methyl optionally substituted with one or more fluoro; each of R6and R7is independently hydrogen, or fluoro; each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by fluoro; and R10is methyl. In some embodiments, R2and R3 are each independently -OH, -OCH3, -OCF3, -OCHF2, -OCH2F or cyclopropyl. In some embodiments, R2and R3 are each independently -OCH3. In some embodiments, R2is -OH or -CHF2and R3 is -OCH3; or R2is - OR2’ or cyclopropyl and R3 is -OR3S or R3 is -OR3’ or cyclopropyl, and R2’ and R3 are each independently -H, -CH3, -CF3, -CHF2, or -CH2F.

[0018] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rs and R9 are each independently hydrogen, fluoro or methyl. In some embodiments, Ri is hydrogen. In some embodiments, Rs and R9 are both hydrogen. In some embodiments, R6and R7are both hydrogen.

[0019] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, CM alkyl, Ci-4 haloalkyl, or -ORA In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein is a compound of Formula (IV), or Formula (IV-A) or Formula (VI-A), or a pharmaceutically acceptable salt thereof: , wherein Ring C is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and hctcroaryl is optionally substituted by halo, CM alkyl, CM haloalkyl, or -ORa; V and W are each O or NRXand Rxis hydrogen or CM alkyl; Ri is hydrogen, halo, CM alkyl or CM haloalkyl; Rx and R9 are each independently CN, hydrogen, halo, CM alkyl or CM haloalkyl; Rio is CM alkyl; Rn, R12, R13, and R14 are each independently hydrogen, halo, CM alkyl or CM haloalkyl; and n is 0 or 1.

[0020] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein is a compound of Formula (IV), or Formula (IV-A) or Formula (VI-A), or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen; Rs and R9 are each independently hydrogen, fluoro or methyl; and Rio is methyl. In some embodiments, Rs and R9 are each independently hydrogen.

[0021] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

[0022] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are each independently N or CR1, provided that no more than one of X, Y and Z is N; R1is hydrogen; R2and R3together with the atoms to which they are attached combine to form a 5-6 membered heteroaryl comprising one or more nitrogen or oxygen hctcroatoms, wherein each hydrogen atom in hctcroaryl is optionally substituted by methyl; each of R6and R7is independently hydrogen, or fluoro; and each of R8and R9is independently hydrogen, fluoro, or methyl. In some embodiments, each of R6and R7is independently hydrogen; and each of R8and R9is independently hydrogen.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein.

[0027] DETAILED DESCRIPTION

[0028] 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.

[0029] Compounds of the Invention

[0030] Described herein are compounds Formula (I):

[0031] or a pharmaceutically acceptable salt thereof; wherein wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or - OR2and R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and hctcroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0032] 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 fluoro; each of R8and R9is independently hydrogen, deuterium, halo, CN, C1-4 alkyl, -O-C1-4 alkyl, -C(O)-Ci-4 alkyl, wherein each hydrogen atom in the C1-4 alkyl is optionally substituted by halo or deuterium;

[0033] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0034] In certain embodiments, the compound is a compound of Formula (I), wherein ring A is

[0035] In certain embodiments, the compound is a compound of Formula (I), provided that when are each H, then R8is not H, Ci-4 alkyl or

[0036] Ci-6 haloalkyl.

[0037] In certain embodiments, the compound is a compound of Formula (I), wherein ring B is a phenyl, a 9-10 membered fused carbocycle, a 5-6 membered heteroaryl ring, or a fused bicyclic heteroaryl, wherein Ring B is optionally substituted with R2and R3wherein: each of R2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or - OR2and R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or -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

[0038] 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; and

[0039] Rais hydrogen or alkyl.

[0040] In certain embodiments, the compound is a compound of Formula (I), wherein ring B is a phenyl substituted with R2and R3, as defined above with respect to Formula (I).

[0041] In certain embodiments, the compound is a compound of Formula (I), wherein ring B is a 6-membered heteroaryl comprising X, Y and Z wherein X, Y and Z are each independently N or CR1provided that at least one of X, Y and Z is N, and R1is as defined above with respect to Formula (1), and ring B is optionally substituted with one or more of R1, R2and R3.

[0042] In certain embodiments, the compound is a compound of Formula (I), wherein ring B is , wherein X, Y and Z are each independently N or CR1and R1is as defined above with respect to Formula (I). In some embodiments, the compound is a compound of Formula (I), wherein ring B is a 9-10 membered fused carbocyclc comprising a phenyl fused to a saturated, or unsaturated 5- membered heterocyclyl or carbocyclyl ring each optionally substituted with one or more of R1, R2and R3as defined above with respect to Formula (I), or a phenyl fused to a 6-membered aromatic ring substituted with one or more of R1, R2and R3as defined above with respect to Formula (I). In some embodiments, the compound is a compound of Formula (I), wherein ring B is an imidazole optionally substituted with R2and R3. In some embodiments, the compound is a compound of Formula (I), wherein ring B is an imidazole optionally substituted with one or more methyl.

[0043] 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: wherein X, Y and Z are each independently N, CH, or CR1; and R1, R2, R3, R6, R7, R8, R9and R10are as defined with respect to Formula (I) herein.

[0044] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

[0045] wherein R1, R2, R3, R8, R9and R10are as defined with respect to Formula (I) herein.

[0046] In certain aspects, the invention relates to compounds of Formula (I): or a pharmaceutically acceptable salt thereof; wherein wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with R1, R2and R3and the heterocyclyl or hctcroaryl ring structure optionally includes one or more heteroatom (e.g., S, O, N); each R1is independently 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or - OR2and R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or -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

[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, CN, C1-4 alkyl, -O-C1-4 alkyl, -C(O)-Ci-4 alkyl, wherein each hydrogen atom in the C1-4 alkyl 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments, the compound is a compound of Formula (I), provided that when r , is 0, 1, 2, or 3, and R6, R7and R9are each H, then Rsis not H, Ci-4 alkyl or Ci-6 haloalkyl.

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

[0050] Ring B is optionally substituted with one or more of Rl, R2 and R3 each independently selected from the group consisting of: a carbocycle selected from the group consisting of: a 5-7 membered monocyclic or a 8-12 membered bicyclic ring, wherein the bicyclic carbocycle is selected from saturated, unsaturated and aromatic rings; a heterocyclyl having substituted or unsubstituted non-aromatic ring structures with 3- to 10-membered rings; an aryl group having a 5- to 7- membered ring; or a polycyclic ring system having two or more cyclic rings in which two or more carbons arc common to two adjoining rings wherein at least one of the rings is aromatic or heteroaryl ring structure, wherein each ring of the polycycle contains from 3 to 10 atoms in the ring; each R1is independently hydrogen, deuterium, halo, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C4-6 cycloalkenyl, 3-10 membered heterocyclyl, Ce aryl, 5-7 membered 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, CM alkyl, CM alkanol (-alkyl-OH), Ce 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, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-10 membered heterocycloalkyl, Ce aryl or 5-7 membered heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, C3-6 cycloalkyl, Ce aryl, or ORa; or

[0051] R2and R3together with the atoms to which they are attached combine to form 3-10 membered heterocyclyl or 5-7 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, CM alkyl, C M haloalkyl, or ORil; each of R6and R7is independently hydrogen, deuterium, or halo; each of R8and R9is independently hydrogen, deuterium, halo, CM alkyl, CN, or C(O)(Ci- 4 alkyl), wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0052] R10is H, CM alkyl, wherein each hydrogen atom in alkyl is optionally substituted by halo or deuterium; each of Raand Rbis independently H, CM alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-10 membered heterocyclyl, Ce aryl, or 5-7 membered 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, CM alkyl, CM alkanol, C6aryl, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, CM alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-10 membered heterocyclyl, Ce aryl, or 5-7 membered heteroaryl; provided the compound of formula (I) is not: ch H, then R8is not H, Ci-4 alkyl or Ci-6 haloalkyl.

[0053] In some embodiments, a compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein the compound is not In some embodiments, a compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein the compound is not .

[0054] In some embodiments, a compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof; wherein each R1is independently 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; each of R2is alkyl, cycloalkyl, or -OR2and R3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or -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; each of R6and R7is independently hydrogen, deuterium, or halo; each of R8and R9is independently hydrogen, deuterium, halo, CN, C1-4 alkyl, -O-C1-4 alkyl, -C(O)-Ci-4 alkyl, wherein each hydrogen atom in the C1-4 alkyl is optionally substituted by halo or deuterium;

[0055] R10is H, or CM 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, Rio in Formula (1) is H, methyl or ethyl, wherein each hydrogen atom in methyl or ethyl is optionally substituted by halo or deuterium.

[0056] In some embodiments, each of R8and R9in Formula (I) is independently hydrogen, deuterium, fluoro, or methyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In some embodiments, each of R8is hydrogen and R9in Formula (I) is independently hydrogen, deuterium, fluoro, hydroxyl or methyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium. In some embodiments, each of R8is hydrogen and R9in Formula (I) is independently hydrogen, fluoro, hydroxyl or methyl. In some embodiments, each of R8and R9in Formula (I) is independently hydrogen. In some embodiments, each of R8and R9in Formula (I) is independently fluoro.

[0057] In certain aspects, the invention relates to compounds of Formula (II): or a pharmaceutically acceptable salt thereof; wherein

[0058] X, Y and Z 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, -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; each of R2is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or - OR2and R3 is alkyl, alkenyl, alkynyl, cycloalkyl, hctcrocycloalkyl, aryl or hctcroaryl or -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

[0059] 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 fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro or methyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0060] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0061] In some embodiments, the compound of formula (II) is not:

[0062] In certain embodiments, the compound of Formula (I) is a compound of Formula (Il-a) :

[0063] or a pharmaceutically acceptable salt thereof, wherein each of X, Y and Z is independently N, CH or CR1, and R1, R2, R3, R6, R7, R8, R9and R10are each as defined herein with respect to Formula (I).

[0064] In certain embodiments, the compounds of Formula (Il-a) have the absolute stereochemistry shown, provided the compound of formula (Il-a) is not:

[0065] In certain embodiments, ring wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein Rs and R9 are as described herein for Formula (I). In certain embodiments, ring A is attachment points of ring A to the compound of formula (I), and wherein Rs and R9 are as described herein for Formula (I). In certain embodiments, ring A is , wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein Rg and R9 arc as described herein for Formula (I). In certain embodiments, ring B is wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein Rg and R9 are as described herein for Formula (I). In certain embodiments, ring A is ein * denotes the attachment points of ring A to the compound of formula nd R9 are as described herein for Formula (I). In certain embodiments, ring wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein Rg and R9 are as described herein for Formula (I).

[0066] In some embodiments, when a compound is any compound of Formula (I) and when ring 1-4 alkyl or

[0067] C1-6 haloalkyl. In some embodiments, when a compound is any compound of Formula (I) and when ring

[0068] A is: are each H, then

[0069] R8is not methyl.

[0070] Ring B

[0071] In certain embodiments, Ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3, as defined with respect to Formula (I).

[0072] In certain embodiments, Ring wherein X, Y and Z are each independently N, CH, or CR1and R1, R2and R3are each as defined with respect to Formula (I).

[0073] In certain embodiments, Ring B is 9-14 membered fused bicyclic heteroaryl optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0074] In certain embodiments, Ring B is phenyl fused to a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or a C4-6 carbocyclyl ring, or Ring B is a 5-6 membered heteroaryl fused to a phenyl, a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or a C4-6 carbocyclyl ring, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl fused to a 5-6 membered heteroaryl, a 4-6 membered heterocyclyl, or a C4-6 carbocyclyl ring, or Ring B is a 5-6 membered heteroaryl fused to a phenyl, a 4-6 membered heterocyclyl, or a C4-6 carbocyclyl ring, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl fused to a 4-6 membered heterocyclyl or a C4-6 carbocyclyl ring, or Ring B is a 5-6 membered heteroaryl fused to a 4-6 membered heterocyclyl or a C4-6 carbocyclic ring, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl fused to a 5-6 membered heteroaryl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl fused to a 4-6 membered heterocyclyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl fused to a C4-6 carbocyclic ring, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is a 5-6 membered heteroaryl fused to a phenyl, wherein Ring B is optionally substituted with substituents R2and R3.

[0075] In certain embodiments, Ring B is a 5-6 membered heteroaryl fused to a 4-6 membered heterocyclyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is a 5-6 membered heteroaryl fused to a C4-6 carbocyclic ring, wherein Ring B is optionally substituted with substituents R2and R3.

[0076] In certain embodiments, Ring B is benzoxazolyl, indazolyl, isoquinolinyl, tetrahydroisoquinolinyl, tctrahydroisoxazolo|4,5-c|pyridinyl, tetrahydroisoxazolo [5, 4- c]pyridinyl, quinazolinyl, triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2- a]pyridinyl, pyrazolo[l,5-a]pyrimidinyl, [l,2,4]triazolo[4,3-a]pyridinyl, quinolinyl, benzoisoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, indolyl, or quinoxalinyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is benzoxazolyl, indazolyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2-a]pyridinyl, quinolinyl, benzoisoxazolyl, benzoimidazolyl, or quinoxalinyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is quinazolinyl, imidazo[l,2-a]pyrazinyl, benzoisoxazolyl, or benzopyrazolyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is phenyl, quinazolinyl, imidazo[l,2-a]pyrazinyl, benzoisoxazolyl, or benzopyrazolyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is quinazolinyl, imidazo[l,2-a]pyrazinyl, benzoisoxazolyl, or benzopyrazolyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is quinazolinyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is imidazo[l,2- a]pyrazinyl, wherein Ring B is optionally substituted with substituents R2and R3. In certain embodiments, Ring B is benzoisoxazolyl, wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl). In certain embodiments, Ring B is bcnzopyrazolyl, wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0077] In certain embodiments, Ring B is C9-14 fused bicyclic aryl, wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0078] In certain embodiments, Ring , wherein Ring B is optionally substituted with substituents one or more methyl).

[0079] In certain embodiments, Ring B wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0080] In certain embodiments, Ring , wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0081] In certain embodiments, Ring

[0082] , wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0083] In certain embodiments, Ring optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0084] In certain embodiments, Ring , wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl). more methyl).

[0085] In certain embodiments, Ring substituents R2and R3(e.g., one or more methyl).

[0086] In certain embodiments, Ring , . , wherein Ring B is optionally substituted with substituents R and R (e.g., one or more methyl).

[0087] In certain embodiments, Ring wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl). In certain embodiments, Ring wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0088] In certain embodiments, Ring wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0089] In certain embodiments. Ring wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0090] wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0091] In certain embodiments, Ring , wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0092] wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl).

[0093] In certain embodiments, Ring , wherein Ring B is optionally substituted with substituents R2and R3(e.g., one or more methyl). substituted with substituents R2and R3(e.g., one or more methyl).

[0094] In certain embodiments, Ring certain embodiments, Ring B is

[0095] certain embodiments, Ring certain embodiments, Ring B

[0096] In certain embodiments, Ring In certain embodiments, Ring

[0097] In certain embodiments, Ring

[0098] In certain embodiments, Ring

[0099] In certain embodiments, Ring , X , Y and Z

[0100] In some embodiments, X, Y and Z arc each independently N, CH, or CR1. In some embodiments, X is CH and Y is CH and Z is N. In some embodiments, X is N and Y is CH and Z is CH. In some embodiments, X is CH and Y is N and Z is CH. In some embodiments, X is N, Y is CR1and Z is CH. In some embodiments, X is N, Y is CH and Z is CR1. In some embodiments, X is CR1, Y is CH and Z is CH. In some embodiments, X is N, Y is CH and Z is CR1.

[0101] R1

[0102] 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, CM alkyl, or C3-6 cycloalkyl; wherein each hydrogen atom in CM alkyl, or C3-6 cycloalkyl is optionally substituted by halo or CM 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,

[0103] 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.

[0104] In certain embodiments, R1is hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, - CChRa, -C(O)NRaRb, -CN, nitro, or -P(O)ORilORb. 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.

[0105] 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)CHa), -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.

[0106] 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.

[0107] 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 which they are attached to form . In certain embodiments, each Raand R is independently H. In certain embodiments, each Raand Rbis independently H or methyl.

[0108] In some embodiments, Rais H, or CM alkyl, wherein each hydrogen atom in alkyl is optionally substituted by -ORC, and Rcis H, or CM alkyl.

[0109] R2and R3

[0110] In certain embodiments, the compound is a compound of Formula (I), or Formula (II) wherein R2 is -OR2and R3 is -OR3. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2is halomethyl. In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R2is -CHF2 or -CF3. In certain embodiments, R2is CM alkyl or CM haloalkyl. In certain embodiments, R2is methyl optionally substituted with one or more fluoro. In further embodiments, R2is halomcthyl such as a methyl substituted with at least one fluoro (e.g., CHF2 or CF3). In certain embodiments, R2is benzyl and R3is hydrogen or methyl optionally substituted with one or more fluoro.

[0111] In certain embodiments, R3is methyl. In further embodiments, R3is halomethyl such as a methyl substituted with at least one fluoro (e.g., CHF2 or CF3). In some embodiments, R3is benzyl. In some embodiments, R3is benzyl and R2is hydrogen or methyl optionally substituted with one or more fluoro.

[0112] 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 or CM alkyl or CM 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. In some embodiments, one or both of R2and R3is CM alkyl, wherein one or more hydrogen atom(s) in the alkyl is optionally substituted by -ORC, and Rcis H, or CM alkyl.

[0113] 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, CM alkyl, CM 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, CM alkyl, CM 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, CM alkyl, CM 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 hctcroatoms, wherein each hydrogen atom in heterocyclyl and hctcroaryl is optionally substituted by halo, CM alkyl, CM 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, CM haloalkyl or ORa, wherein Rais H or methyl optionally substituted with one or more fluoro.

[0114] 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, CM alkyl, CM 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, CM alkyl, CM 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, CM alkyl, CM 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, CM alkyl, CM 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, CM haloalkyl or ORa, wherein Rais H or methyl optionally substituted with one or more fluoro.

[0115] R6and 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.

[0116] R8and R9

[0117] In certain embodiments, each of R8and R9is independently hydrogen, deuterium, halogen, CM 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.

[0118] In certain embodiments, each of R8is independently hydrogen, deuterium, halogen, CM alkyl, CN or C(O)CM 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.

[0119] In certain embodiments, each of R9is independently hydrogen, deuterium, halogen, CM alkyl, CN or C(O)CM 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.

[0120] In certain embodiments, R9is hydrogen and R8is independently hydrogen, deuterium, halogen, CM alkyl, CN or C(O)CM 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.

[0121] 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. In certain embodiments, R8is independently 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, 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 certain embodiments, R9is hydrogen and R8is independently hydrogen, deuterium, fluoro, methyl, CN or C(O)Me wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium.

[0122] 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, 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, 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. In certain embodiments, R8is 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, 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.

[0123] 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.

[0124] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, provided that when ring A is: and R6, R7and R9are each H, then R8is not H, CM alkyl or C1-6 haloalkyl.

[0125] R10

[0126] In certain embodiments, the compound is a compound of Formula (I), or Formula (II), wherein R10is 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.

[0127] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

[0128] (III), wherein

[0129] Ri, R2, R3, Rs, R9 and Rw are as defined above with respect to Formula (1).

[0130] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and wherein

[0131] Ri is hydrogen, halo, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkyl or C1-4 haloalkyl; R2is -OR2and R3is -OR3wherein R2and R3are independently hydrogen, halo, C1-4 alkyl, or C1-4 haloalkyl; wherein the C1-4 alkyl, or C1-4 haloalkyl is optionally substituted with aryl or heteroaryl;

[0132] R8and R9are each independently hydrogen, halo, CN, C1-4 alkyl, C1-4 haloalkyl, or C(O)- C1-4 alkyl optionally substituted with one or more halo;

[0133] R10is C1-4 alkyl or C1-4 haloalkyl.

[0134] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and wherein

[0135] R1is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro, cyclopropyl, or benzyl;

[0136] R2is -OR2and R3is -OR3wherein R2and R3are independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl;

[0137] R8and R9are each independently hydrogen, fluoro, CN, methyl optionally substituted with one or more fluoro, or C(O)-Ci-4 alkyl;

[0138] R10is methyl.

[0139] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and wherein

[0140] R1is hydrogen or fluoro;

[0141] R2is -OR2and R3is -OR3wherein R2and R3are independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl, provided that at least one of R2 and R3 is hydrogen;

[0142] R8and R9are each independently hydrogen, fluoro, CN, methyl optionally substituted with one or more fluoro, or C(O)-Me, provided that at least one of R8and R9is hydrogen;

[0143] R10is methyl.

[0144] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and wherein

[0145] R1is hydrogen;

[0146] R2is -OR2and R2is hydrogen or methyl optionally substituted with one or more fluoro; R3is -OR3and R3is each independently hydrogen, methyl optionally substituted with one or more fluoro, or benzyl, provided that at least one of R2and R3is hydrogen;

[0147] R8and R9are each independently hydrogen, fluoro, or CN; and

[0148] R10is methyl or ethyl.

[0149] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and wherein

[0150] R1is hydrogen, fluoro, or methyl optionally substituted or C1-4 haloalkyl;

[0151] R2is -OR2and R3is -OR3wherein R2and R3are independently hydrogen, halo, Ci-4 alkyl, or C1-4 haloalkyl; wherein the C1-4 alkyl, or C1-4 haloalkyl is optionally substituted with aryl or heteroaryl;

[0152] R8and R9are each independently hydrogen, halo, CN, C1-4 alkyl, C1-4 haloalkyl or -C(O)- Ci-4alkyl, provided that at least one of Rs and R9 is hydrogen; and

[0153] R10is methyl or ethyl.

[0154] In some embodiments, the compound of formula (III) is not:

[0155] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (IV), or Formula (IV-A), or a pharmaceutically acceptable salt thereof:

[0156]

[0157] (IV-A), wherein:

[0158] V and W, R1, R8, R9and R10are as defined above with respect to Formula (I), and R11and R12are each independently hydrogen, halo, haloalkyl or alkyl.

[0159] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (IV) or Formula (IV-A), or a pharmaceutically acceptable salt thereof, and wherein X and Y, R1, R8, R9and R10are as defined above with respect to Formula (I), and R11and R12are each independently hydrogen, halo, C1-4 alkyl or C1-4 haloalkyl.

[0160] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (IV) or Formula (IV-A), or a pharmaceutically acceptable salt thereof, and wherein

[0161] V and W are each O or NRXand Rxis hydrogen or CM alkyl;

[0162] R1is hydrogen, halo, CM alkyl or C1-4 haloalkyl;

[0163] R8and R9are each independently CN, hydrogen, halo, C1-4 alkyl or C1-4 haloalkyl;

[0164] R10is C1-4 alkyl; and

[0165] Rn, R12, R13and R14are each independently hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl and ORa;

[0166] Rais H, C1-4 alkyl (e.g., methyl), C1-4 haloalkyl or C1-4 alkenyl; and n is 0 or 1.

[0167] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (IV) or Formula (IV-A), or a pharmaceutically acceptable salt thereof, and wherein

[0168] V and W are each O or NRXand Rxis hydrogen or methyl; R1is hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl;

[0169] R8and R9arc each independently CN, hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl; and

[0170] R10is C1-2 alkyl; and

[0171] R11and R12are each independently hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl.

[0172] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (IV) or Formula (IV-A), or a pharmaceutically acceptable salt thereof, and wherein

[0173] V and W are each O;

[0174] R1is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0175] R8and R9are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0176] R10is methyl; and

[0177] R11and R12are each independently hydrogen, fluoro, or methyl optionally substituted with one or more fluoro.

[0178] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (V), Formula (VI- A), or a pharmaceutically acceptable salt thereof:

[0179] (V),

[0180] (VI-A), wherein:

[0181] Ring C is a fused 5- or 6-mcmbcrcd hctcroaryl, a fused 5-6 membered heterocyclyl, or a fused C5-6 cycloalkyl, and Ring A is optionally substituted with halo, alkyl, haloalkyl, or ORa; and Rais H, alkyl (e.g., methyl), haloalkyl or alkenyl;

[0182] R1is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0183] R8and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0184] R10is C1-4 alkyl.

[0185] In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (VII) or Formula (VII- A) or a pharmaceutically acceptable salt thereof:

[0186] (VII-A), wherein X, Y, Z are each independently N or CH, provided that at least one of X, Y and Z is CH, R2and R3and R8and R9arc as defined above with respect to Formula (I). In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (VII) or Formula (VII-A) or a pharmaceutically acceptable salt thereof, wherein X, Y, Z are each independently N or CH, provided that up to one of X, Y and Z is N; and R2is cyclopropyl, or hydroxyl, methoxy optionally substituted with one or more fluoro, and R3is methoxy; and R8and R9are each independently fluoro, methyl or hydrogen. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (VII) or Formula (VII-A) or a pharmaceutically acceptable salt thereof, wherein X, Y, Z are each independently N or CH, provided that up to one of X, Y and Z is N; and R2is methoxy, and R3is methoxy; and R8and R9are both fluoro or hydrogen, or R8is hydrogen and R9is methyl. In certain embodiments, the compound is a compound of Formula (I), wherein the compound is a compound of Formula (VII) or Formula (VII-A) or a pharmaceutically acceptable salt thereof, wherein X, Y, Z are each independently N or CH, provided that up to one of X, Y and Z is N; and R2is cyclopropyl, or hydroxyl, and R3is methoxy; and R8and R9are both fluoro or hydrogen, or R8is hydrogen and R9is methyl.

[0187] In certain embodiments, the compound is selected from:

[0188]

[0189] In certain embodiments, the compound

[0190] In certain embodiments, the compound is selected from:

[0191]

[0192] In certain embodiments, the compound is selected any one or more of the following

[0193] 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.

[0194] 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).

[0195] In some embodiments, pharmaceutical compositions comprising compounds of a compound of Formula (I) or Formula (II), 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 a compound of Forumula (I) or Formula (II). The drug product can be prepared by first manufacturing the compound of a compound of Formula (I) or Formula (II) 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 a compound of Formula (I) or Formula (II) 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 a compound of Formula (I) or Formula (II) 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.

[0196] 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.

[0197] 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.

[0198] 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: (I) 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, he 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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 base- addition 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.

[0203] In some embodiments, a compound of a compound of Formula (I) or Formula (II) can provide additional beneficial properties. For example, the compounds described herein may provide beneficial therapeutic properties while minimizing emesis. For example, compounds of a compound of Formula (I) or Formula (II) may have improved metabolic stability and activity for inhibiting SERT. In some embodiments, the compounds of a compound of Formula (I) or Formula (II) 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 braimplasma ratios (expressed as Kp) > 0.3 and ideally > 0.7 are most desirable. In some embodiments, a compound of a compound of Formula (I) or Formula (II) can inhibit SERT with an IC50 of less than about 1 micromolar in the assay of Example Al.

[0204] DEFINITIONS

[0205] 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 ail.

[0206] 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 cd.”, 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).

[0207] 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.

[0208] 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.

[0209] 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).

[0210] “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.

[0211] 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.

[0212] “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. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0213] 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.

[0214] 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. 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.

[0215] 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.

[0216] 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 in chemically stable compounds which can be readily synthesized by techniques known in the ail, 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.

[0217] 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-CFF-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.

[0218] 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 hranched-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.

[0219] 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.

[0220] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0221] 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.

[0222] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0223] 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-.

[0224] The term “amide”, as used herein, refers to a group

[0225] Az Rfwherein 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.

[0226] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0227] 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-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0228] 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.

[0229] 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 zR6 © Re

[0230] <N or VN."Rf

[0231] R’ 'RSwherein 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.

[0232] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0233] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0234] 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.

[0235] The term “carbamate” is art-recognized and refers to a group

[0236] 0 0

[0237] S 11 ReS 0RfS'O N or ‘’'N O'

[0238] RfRewherein Reand Rfindependently represent hydrogen or a hydrocarbyl group.

[0239] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclc 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.

[0240] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0241] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0242] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0243] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0244] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0245] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0246] 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, pyrazolc, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl groups also include, for example, azaindole and azaindazole, and the like.

[0247] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0248] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0249] 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.

[0250] 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.

[0251] The term “hydroxy alkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0252] 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 appeal- 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).

[0253] 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 polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0254] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0255] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein Reand Rfindependently represents hydrogen or hydrocarbyl.

[0256] The term “sulfoxide” is art-recognized and refers to the group -S(O)-.

[0257] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0258] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0259] 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 alkoxycarbonyl, 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.

[0260] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0261] The term “thioester”, as used herein, refers to a group -C(O)SReor -SC(O)Rewherein Rerepresents a hydrocarbyl.

[0262] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0263] The term “urea” is art-recognized and may be represented by the general formula wherein Reand Rfindependently represent hydrogen or a hydrocarbyl.

[0264] 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.

[0265] “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.

[0266] The term “pharmaceutically acceptable acid addition salt” as used herein means any nontoxic organic or inorganic salt of any base compounds represented by Formula (I) and Formula (II). 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, phenyl acetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-tolucnc 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 (II) 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) for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0267] 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 (II) 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.

[0268] 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.

[0269] 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.

[0270] 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 intrastcrnal 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.

[0271] 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 a 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.

[0272] 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.

[0273] 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.

[0274] “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 (II)). 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 depho sphorylated 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 (IA) and Formula (IB). 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.

[0275] 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.

[0276] 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.

[0277] 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) or Formula (II), can be provided in an oral dosage form such as a capsule or tablet. The oral dosage form optionally comprises one or more fillers, disintigrants, 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) or Formula (II) 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. 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, premenstrual dysphoric disorder. Exemplary inflammatory conditions include chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.

[0278] 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) or Formula (II), 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) or Formula (II), 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) or Formula (II), 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) or Formula (II), 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) or Formula (II), for the treatment of anxiety and hysteria or anxiety and depression.

[0279] 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 with ' or bonds, such a depiction may be denoting relative stereochemistry based on elution peaks from a chiral separation.

[0280] Additional Embodiments

[0281] In certain embodiments, the compound is a compound of one or more of the following embodiments, or a pharmaceutically acceptable salt thereof:

[0282] 1. A compound of Formula (I) : or a pharmaceutically acceptable salt thereof; wherein wherein * denotes the attachment points of ring A to the compound of formula (1); and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CChR3, - 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is -OR2and R3is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0283] 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 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;

[0284] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided the compound of formula (I) is not: The compound of embodiment 1, wherein the compound is of Formula (Il-a): or a pharmaceutically acceptable salt thereof, provided the compound of formula (Il-a) is not: The compound of embodiment 2, wherein X, Y and Z are each CH. The compound of embodiment 2, wherein a. X is N, Y is CR1and Z is CH; b. X is N, Y is CH and Z is CR1; c. X is CH, Y is N and Z is CR1; d. X is CR1, Y is N and Z is CH; e. X is CR1, Y is CH and Z is N; f. X is CH, Y is CR1and Z is N; g. X is CR1, Y is CH, and Z is CH; h. X is CH, Y is CR1, and Z is CH; or i. X is CH, Y is CH, and Z is CR1. The compound of embodiment 4, wherein each R1is independently hydrogen, halo, CM alkyl, CM alkenyl, CM alkynyl, C3-6 cycloalkyl, C3-6 cycloalkcnyl, 3-6 membered heterocyclyl, Cr> aryl, 5-6 membered heteroaryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CChR3, -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, CM alkyl or CM haloalkyl, and wherein Raand Rbare each independently CM alkyl. 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 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. The compound of any one of embodiments 1-6, wherein each of R2is -OR2and R3 is - OR3wherein R2and R3are independently H, CM alkyl, CM alkenyl, CM alkynyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, 6-membered aryl or 5-6 membered heteroaryl; wherein each hydrogen atom in CM alkyl, CM alkenyl, CM alkynyl, C3-8 cycloalkyl, 3-6 membered heterocyclyl, 6-membered aryl and 5-6 membered heteroaryl is optionally substituted by halo, or CM alkyl; and each hydrogen atom in CM alkyl, CM alkenyl, and CM alkynyl is optionally substituted with 6-membered aryl or 5-6 membered heteroaryl optionally substituted with halo, CM alkyl or CM haloalkyl. The compound of embodiment 8, wherein each of R2is -OR2and R3 is -OR3wherein R2and R3are independently H, or methyl optionally substituted with one or more fluoro. The compound of embodiment 8, wherein each of R2is -OR2and R3 is -OR3wherein R2and R3arc independently H, methyl or benzyl. The compound of any one of embodiments 1-6, wherein each of R2is -OR2and R3is - OR3wherein R2and R3are independently H, or CM alkyl optionally substituted with one or more fluoro. The compound of any one of embodiments embodiment 9-11, wherein at least one of R2is -OR2and R3is -OR3wherein R2and R3arc independently H or methyl. 13. The compound of any one of embodiments 1-12, wherein each of R6and R7is independently hydrogen or fluoro.

[0285] 14. The compound of any one of embodiments 1-12, wherein each of R6and R7is independently methyl.

[0286] 15. The compound of any one of embodiments 13-14, wherein at least one of R6and R7is hydrogen.

[0287] 16. 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 fluoro.

[0288] 17. The compound of embodiment 16, wherein at least one of R8and R9is hydrogen.

[0289] 18. The compound of embodiment 17, wherein at least one of R8and R9is fluoro, methyl or C(O)Me.

[0290] 19. The compound of embodiment 16, wherein R8and R9are each hydrogen.

[0291] 20. The compound of embodiment 16, wherein R8is hydrogen.

[0292] 21. The compound of embodiment 16, wherein R9is hydrogen.

[0293] 22. The compound of any one of embodiments 1-21, wherein R10is methyl.

[0294] 23. The compound of any one of embodiments 1-21, wherein R10is ethyl.

[0295] 24. The compound of any one of embodiments 1-23, wherein each of Raand Rbis independently H or methyl.

[0296] 25. The compound of any one of embodiments 1-24, wherein each of Rcand Rdis independently H, or methyl.

[0297] 26. A compound of Formula (III):

[0298] (HD; or a pharmaceutically acceptable salt thereof; wherein each R1is independently hydrogen, deuterium, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkcnyl, hctcrocyclyl, aryl, hctcroaryl, -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; each of 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

[0299] 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, -O-C1-4 alkyl or C(O)Re, and Reis C1-4 alkyl, wherein each hydrogen atom in the methyl or the C1-4 alkyl in R8and R9is optionally substituted by halo or deuterium;

[0300] 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, -ORC, -NRcRd, -CHO, -C(O)Re, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0301] Reis hydrogen or alkyl; provided the compound of formula (III) is not: The compound of embodiment 26, wherein a. each of Raand Rbis independently H, or CM alkyl; b. each of Rcand Rdis independently H, C1-4 alkyl or C1-4 haloalkyl; and c. each Reis hydrogen or C 1-4 alkyl. The compound of any one of embodiments 26-27, wherein each R1is independently hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl or 3-6 membered heterocyclyl. The compound of embodiment 28, wherein R1is hydrogen, fluoro, cyclopropyl or methyl optionally substituted with one or more fluoro. The compound of embodiment 28, wherein R1is hydrogen, or fluoro. The compound of any one of embodiments 26-30, wherein each of R2 is -OR2and R3 is - OR3wherein R2and R3are independently H, or C1-4 alkyl optionally substituted with phenyl or 5-6 membered heteroaryl, provided that one of R2and R3is H. The compound of any one of embodiments 26-30, wherein each of R2 is -OR2and R3 is - OR3wherein R2and R3are independently H, or benzyl optionally substituted with one or more halo, C1-4 alkyl or C1-4 haloalkyl, provided that one of R2and R3is H. The compound of any one of embodiments 26-30, wherein each of R2 is -OR2and R3 is - OR3wherein R2and R3are independently H, halo, C1-4 alkyl or C1-4 haloalkyl. The compound of any one of embodiments 26-30, wherein each of R2and R3R2 is -OR2and R3 is -OR3wherein 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 (IV) or a pharmaceutically acceptable salt thereof:

[0302] (IV), wherein

[0303] V and W are each O or NRXand Rxis hydrogen or Ci-4 alkyl;

[0304] Ri is hydrogen, halo, CM alkyl or CM haloalkyl;

[0305] Rs and R9 are each independently CN, hydrogen, halo, C1-4 alkyl or C1-4 haloalkyl;

[0306] Rio is C1-4 alkyl;

[0307] Rn, R12, R13, and R14 are each independently hydrogen, halo, C1-4 alkyl or C1-4 haloalkyl; and n is 0 or 1. The compound of embodiment 40, wherein the compound is a compound of Formula (IV-A): or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 40-41, wherein:

[0308] V and W are each O or NRXand Rxis hydrogen or methyl;

[0309] Ri is hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl;

[0310] Rs and R9 are each independently CN, hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl; and

[0311] Rio is C1-2 alkyl; and

[0312] R11 and R12 are each independently hydrogen, halo, C1-2 alkyl or C1-2 haloalkyl. The compound of any one of embodiments 40-41, wherein:

[0313] V and W are each O;

[0314] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0315] Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0316] Rio is methyl; and

[0317] R11 and R12 are each independently hydrogen, fluoro, or methyl optionally substituted with one or more fluoro. The compound of any one of embodiments 40-41, wherein:

[0318] V and W are each O;

[0319] Ri is hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0320] Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0321] Rio is methyl; and

[0322] R11 and R12 are each independently hydrogen, fluoro, or methyl. A compound of Formula (V) or a pharmaceutically acceptable salt thereof:

[0323]

[0324] (V), wherein:

[0325] Ring C is a fused 5- or 6-membered heteroaryl, a fused 5-6 membered heterocyclyl, or a fused C5-6 cycloalkyl, and Ring A is optionally substituted with halo, alkyl, haloalkyl, or ORa; and Rais H, alkyl, haloalkyl or alkenyl;

[0326] Ri is hydrogen, fluoro, cyclopropyl, or methyl optionally substituted with one or more fluoro;

[0327] Rx and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0328] Rio is C1-4 alkyl. The compound of embodiment 45, wherein the compound is a compound of Formula (VI-A):

[0329] (VI-A) The compound of any one of embodiments 45-46, wherein Ring C is a fused 5- or 6-membered heteroaryl, a fused 5-6 membered hctcrocyclyl, or a fused C5-6 cycloalkyl, and Ring A is optionally substituted with halo, alkyl, haloalkyl, or ORa;

[0330] Rais H, CM alkyl, CM haloalkyl or CM alkenyl;

[0331] Ri is hydrogen, fluoro, cyclopropyl, or methyl optionally substituted with one or more fluoro;

[0332] Rs and R9 are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0333] Rio is CM alkyl. pound of any one of embodiments 45-46, wherein

[0334] Ring C is a fused 5- or 6-membered heteroaryl, a fused 5-6 membered heterocyclyl, or a fused C5-6 cycloalkyl, and Ring A is optionally substituted with halo, CM alkyl, CM haloalkyl and ORa;

[0335] Rais H, CM alkyl, or CM haloalkyl;

[0336] Ri is hydrogen, fluoro, cyclopropyl or methyl optionally substituted with one or more fluoro;

[0337] Rs and Ry are each independently CN, hydrogen, fluoro, or methyl optionally substituted with one or more fluoro;

[0338] Rio is methyl.

[0339]

[0340] 50. The compound of embodiment 1, selected from:

[0341]

[0342] 51. The compound of embodiment 1 , selected from:

[0343]

[0344] 52. The compound of embodiment 1, selected from: 53. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein ring wherein * denotes the attachment points of ring A to the compound of formula (I); and wherein ring B is a carbocycle, heterocyclyl, aryl or hctcroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently 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; each of R2is -OR2and R3 is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or

[0345] 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 fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro or methyl, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;

[0346] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided the compound of formula (I) is not:

[0347] 54. The compound of embodiment 53, wherein R6and R7are each hydrogen.

[0348] 55. The compound of any one of embodiments 53-54, wherein R8and R9are each hydrogen.

[0349] 56. The compound of any one of embodiments 53-55, wherein R10is methyl.

[0350] 57. The compound of embodiment 56, wherein Ring B is phenyl substituted with R2and R3.

[0351] 58. The compound of embodiment 57, wherein R2is -OR2and R3is -OR3.

[0352] 59. The compound of embodiment 58, wherein R2is hydrogen, cyclopropyl or methyl optionally substituted with one or more fluoro.

[0353] 60. The compound of embodiment 59, wherein R3is methyl.

[0354] 61. The compound of embodiment 56, wherein Ring B is an indazole optionally substituted with one or more Ci-4 alkyl, Ci-4 haloalkyl, halo, CN or amino.

[0355] 62. The compound of embodiment 56, wherein Ring B is an indazole optionally substituted with one or more Ci-4 alkyl. The compound of embodiment 56, wherein Ring B is a phthalazine optionally substituted with one or more methyl. The compound of embodiment 56, wherein Ring B is a phthalazine optionally substituted with one or more Ci-4 alkyl, Ci-4 haloalkyl, halo, CN or amino. The compound of embodiment 56, wherein Ring B is a phthalazine optionally substituted with one or more CM alkyl. The compound of embodiment 56, wherein Ring B is a phthalazine optionally substituted with one or more methyl. The compound of embodiment 56, wherein Ring B is a benzoisoxazole optionally substituted with one or more Ci-4 alkyl, Ci-4 haloalkyl, halo, CN or amino. The compound of embodiment 56, wherein Ring B is a benzoisoxazole optionally substituted with one or more Ci-4 alkyl. The compound of embodiment 56, wherein Ring B is a benzoisoxazole optionally substituted with one or more methyl. The compound of embodiment 56, wherein Ring B is a benzodioxine optionally substituted with one or more Ci-4 alkyl. The compound of embodiment 56, wherein Ring B is a benzodioxine optionally substituted with one or more methyl. The compound of embodiment 56, wherein Ring B is an imidazopyridine or a triazopyridine optionally substituted with one or more C1-4 alkyl. The compound of embodiment 56, wherein Ring B is an imidazopyridine or a triazopyridine optionally substituted with one or more methyl. The compound of embodiment 56, wherein Ring B is phenyl or pyridinyl optionally substituted with one or more hydroxyl, Ci-4 alkoxy optionally substituted with one or more halo or cyclopropyl. The compound of embodiment 56, wherein Ring B is phenyl or pyridinyl optionally substituted with one or more hydroxyl, methoxy optionally substituted with one or more fluoro, or cyclopropyl. The compound of embodiment 56, wherein Ring B is an imidazopyridine or a quinoxaline optionally substituted with one or more CM alkyl. The compound of embodiment 56, wherein Ring B is an imidazopyridine or a quinoxaline optionally substituted with one or more methyl. The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring ents 53-60, wherein Ring ents 53-60, wherein Ring ents 53-60, wherein Ring ents 53-60, wherein Ring ents 53-60, wherein Ring ents 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring The compound of any one of embodiments 53-60, wherein Ring wherein a. X, Y and Z are each independently N or CH; b. R2is cyclopropyl or -OR2; c. R2is hydrogen or methyl optionally substituted with one or more fluoro; d. R3is -OR3or benzyl; and e. R3is methyl optionally substituted with fluoro. The compound of embodiment 95, wherein a. X, Y and Z are each CH; or b. X is N, Y is CH and Z is CH; or c. X is CH, Y is N and Z is CH; or d. X is CH, Y is CH and Z is N. The compound of any one of embodiments 95-96, wherein R2is cyclopropyl and R3is methyl. The compound of any one of embodiments 95-96, wherein R2is -OR2. The compound of embodiment 98, wherein R2is H. . The compound of embodiment 98, wherein R2is methyl. . The compound of embodiment 98, wherein R2is -CHF2. . The compound of any one of embodiments 53-101, wherein ring A is wherein * denotes the attachment points of ring A to the compound of formula (I). . The compound of any one of embodiments 53-101, wherein ring A is , wherein * denotes the attachment points of ring A to the compound of formula (I). . The compound of any one of embodiments 53-101, wherein ring A is wherein * denotes the attachment points of ring A to the compound of formula (I).

[0356] A compound of the formula 201 or a pharmaceutically acceptable salt thereof. . A compound of the formula or a pharmaceutically acceptable salt thereof. . A compound of the formula or a pharmaceutically acceptable salt thereof. . A compound of the formula 205 or a pharmaceutically acceptable salt thereof.

[0357] pharmaceutically acceptable salt09. thereof.

[0358] HO. A compound of the formula 301 or a pharmaceutically acceptable salt thereof.

[0359] Hl. A compound of the formula 221 or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt

[0360] 112. thereof.

[0361] A compound of the formula 206 or a pharmaceutically acceptable salt thereof. . A compound of the formula 207 or a pharmaceutically acceptable salt thereof.

[0362] A compound of the formula 233 or a pharmaceutically acceptable salt thereof. . A compound of the formula pharmaceutically acceptable salt thereof. . A compound of the formula 236 or a pharmaceutically acceptable salt thereof. . A compound of the formula 238or apharmaceutically acceptable salt thereof. . pharmaceutically acceptable salt thereof. . A compound of the formula 217or apharmaceutically acceptable salt thereof.

[0363] . The compound of any one of embodiments 53-60, wherein Ring B is . The compound of any one of embodiments 53-60, wherein Ring B is . The compound of any one of embodiments 53-60, wherein Ring B is . A pharmaceutical composition comprising a compound of any one of embodiments 1-128, and a pharmaceutically acceptable excipient or carrier. . 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 1-128 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 129. . The method of embodiment 130, wherein the mental health disorder is anxiety, stress, or depression. . The method of embodiment 130, wherein the mental health disorder is anxiety.. The method of embodiment 130, wherein the mental health disorder is stress.. The method of embodiment 130, wherein the mental health disorder is depression. 135. The method of any one of embodiments 131-134, wherein the mammal is a human.

[0364] 136. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein wherein * denotes the attachment points of ring A to the compound of formula (I); and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is -OR2and R3 is -OR3wherein R2and R3are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; or R2and R3together with the atoms to which they are attached combine to form hctcrocyclyl or hctcroaryl, wherein each hydrogen atom in hctcrocyclyl and hctcroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, 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;

[0365] 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided the compound of formula (I) is not:

[0366] 137. A compound of Formula (VII) or Formula (VII- A) or a pharmaceutically acceptable salt thereof:

[0367] wherein

[0368] X, Y, Z are each independently N or CH, provided that at least one of X, Y and Z is CH, R2and R3are each independently -OCH3, -OCHF2, -OH or cyclopropyl;

[0369] R8and R9are each independently hydrogen, fluoro or methyl.

[0370] 138. The compound of embodiment 137, wherein R2and R3are each independently - OCH3.

[0371] 139. The compound of claim 137 or 138, wherein R8and R9are each independently hydrogen.

[0372] 140. The compound of claim 137 or 138, wherein R8is methyl and R9is hydrogen.

[0373] 141. A compound of Formula (IX) or Formula (IX- A) or a pharmaceutically acceptable salt thereof:

[0374]

[0375] (IX-A), wherein

[0376] Ai, A2 and A3 are each independently O, N, NRg, or CRg;

[0377] W, X, Y, Z are each independently N, CH or C;

[0378] R8and R9are each independently hydrogen, fluoro or methyl; and

[0379] Rgis H or C1-4 alkyl.

[0380] 142. The compound of embodiment 141, or a pharmaceutically acceptable salt thereof, wherein only one of W, X, Y, and Z are N and each Rgis independently H or methyl.

[0381] 143. The compound of embodiment 141 or 142, or a pharmaceutically acceptable salt thereof, wherein Ai is N, A 2 is CH and A3 is NRg, and Rgis methyl.

[0382] 144. The compound of embodiment 143, or a pharmaceutically acceptable salt thereof, wherein Z is C. 145. The compound of embodiment 141 or 142, or a pharmaceutically acceptable salt thereof, wherein Ai is NRg, A2 is N and A3 is CRg.

[0383] 146. The compound of embodiment 145, or a pharmaceutically acceptable salt thereof, wherein Rgis methyl.

[0384] 147. The compound of embodiment 141 or 142, or a pharmaceutically acceptable salt thereof, wherein Ai is CRg, A2 is N and A3 is O.

[0385] 148. The compound of embodiment 141 or 142, or a pharmaceutically acceptable salt thereof, wherein Ai is NRg, A2 is CRgand A3 is CRg.

[0386] 149. The compound of embodiment 141 or 142, or a pharmaceutically acceptable salt thereof, wherein Ai is N(CH3), A2 is CH and A3 is CH or C(CH3).

[0387] 150. The compound of any one of embodiments 141-149, wherein W is N, X and Y are CH and Z is C.

[0388] 151. The compound of any one of embodiments 141-149, wherein W, X and Y are CH and Z is C.

[0389] EXAMPLES

[0390] 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 “om” 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).

[0391] 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):

[0392] 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 C18 30*2.1mm, 5 «m.

[0393] 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 z / m.

[0394] Table of Abbreviations

[0395] General Synthetic Method A for synthesis of methylenecyclohexane and methylcyclohexene compounds from corresponding cyclohexanone compounds:

[0396] Step 1: To a solution of methyl(triphenyl)phosphonium bromide (740 mg, 2.07 mmol) in THF (6.0 mL) was added Z-BuOK (IM in THF, 2.07 mL) at 0 °C over 0.5 hours. The corresponding cyclohexanone compound (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 reverse-phase HPLC (0.1% FA condition).

[0397] Step 2: To a solution of methylenecyclohexane compound (696 pmol) in dioxane (10 mL) was added TfOH (1.39 mmol). The mixture was allowed to stir at 80 °C for 2 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep- HPLC to give a residue. The residue was separated by SFC to the corresponding methylcyclohexene compound.

[0398] General Synthetic Method B for methylenecyclohexane and methylcyclohexene compounds:

[0399] Treatment of a ketone compound such as A with a phosphonium salt, such as that formed by the treatment of methyl(triphenyl)phosphonium bromide with an alkoxide, such as t-BuOK, in a solvent, such as THF, at a low temperature, such as 0 °C, is a method that can be used to prepare methylenecyclohexane compounds such as B.

[0400] Treatment of methylenecyclohexane compounds such as B with an acid, such as trifluoromethanesulfonic acid (TfOH), in a solvent, such as dioxane, at an elevated temperature, such as 80 °C, is a method that could be used to prepare methylcyclohexene compounds such as C and D.

[0401] General Synthetic Method C:

[0402] 016

[0403] Step 1:

[0404] To a solution of methyl(triphenyl)phosphonium bromide 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. 016 (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).

[0405] Step 2:

[0406] To a solution of 3a-(3,4-dimethoxyphenyl)-l-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-lH- indole (696 umol) in dioxane (10 mL) was added TfOH (1.39 mmol). The mixture was allowed to stir at 80 °C for 2 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC.

[0407] Example 1: Synthesis of (+ / -)-Mesembrenone (016) (+ / -)-Mesembrine (022)

[0408]

[0409] Step 1: Synthesis of l-(3,4-dimethoxyphenyl)cyclopropane-l-carbonitrile

[0410] 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. l-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 (l 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 (SiCh, 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, 7 = 2.4 Hz, 2H).

[0411] Step 2: Synthesis of l-(3,4-dimethoxyphenyl)cyclopropane-l-carbaldehyde

[0412] 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 Na2SCL to give l-(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, 7 = 2.8 Hz, 6H), 1.61 - 1.52 (m, 2H), 1.42 - 1.37 (m, 2H). Step 3: Synthesis of (Z)-l-(1 -(3,4-dimethoxyphenyl)cyclopropyl)-A-methylmethanimine To a solution of l-(3, 4-dimcthoxyphcnyl)-cyclopropanccarbaldchydc (5.0 g, 24.2 mmol) in DCM (50 mL) was added MeNfh (2 M, 121 mL) and Na2SC>4 (15.5 g, 109 mmol, 11.0 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)- / V- methylmethanimine (5.1 g, 99%) as white solid. LC-MS (ESI+) m / z 219.9 (M+H)+; NMR (400 MHz, CDC13) 87.55 (q, J= 1.2 Hz, 1H), 6.93 - 6.77 (m, 3H), 3.88 (d, 7 = 7.2 Hz, 6H), 3.24 (d, J= 1.6 Hz, 3H), 1.29 - 1.23 (m, 2H), 1.18 - 1.12 (m, 2H).

[0413] Step 4: Synthesis of 4-(3,4-dimethoxyphenyl)-l-methyl-2,3-dihydro-177-pyrrole

[0414] 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 NaiSCb, and filtered. The filtrate was concentrated under reduced pressure to give 4-(3,4-dimethoxyphenyl)-l-methyl-2,3-dihydro-lH-pyrrole (6.25 g, 80%) as yellow oil. LC-MS (ESI+) m / z 220.0 (M+H)+.!H NMR (400 MHz, CDCh) 6 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).

[0415] Step 5: Synthesis of rac-3a-(3,4-dimethoxyphenyl)-l-methyl-l,2,3,3a,7,7a-hexahydro-6H-indol- 6-one 1016) 4-(3,4-Dimethoxyphenyl)-l-methyl-2,3-dihydro-17 / -pyrrole (6.25 g, 28.5 mmol) was dissolved in DCM (100 mL). To this solution was added HO (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 C18 (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, CDCh) 8 6.90 - 6.88 (m, 1H), 6.87 - 6.83 (m, 2H), 6.74 (dd, 7 = 2.0, 10.1 Hz, 1 H), 6.1 1 (d, J= 10.0 Hz, 1H), 3.89 (d, J = 4.0 Hz, 6H), 3.33 (dt, 7= 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)

[0416] Step 6: Synthesis of rac-3a-(3,4-dimethoxyphenyl)- l-methyloctahydro-677-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, CDCI3) 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).

[0417] Procedures similar to those described above in Example 1 were used to prepare ketones in the following table from the appropriate starting materials:

[0418] Example 2: SFC Separation of rac-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6Z / -indol-

[0419] 6-one (022) to give (-)-Mesembrine (001) and (+)-Mesembrine (002)

[0420] 022 001 002

[0421] 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.

[0422] 001: LC-MS (ESI+) m / z 290.4 ( 5 6.99 - 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J = 1.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, 7 = 3.6 Hz, 1H), 2.69 - 2.56

[0423] (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0424] 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, 7= 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, 7 = 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). Procedures similar to those described above in Example 2 were used to prepare ketones in the following tabic from the appropriate starting materials:

[0425] Example 3: Synthesis of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-6,6-difluoro-l-methyl- octahydro- 1H- indole (101)

[0426] 001 101

[0427] To a mixture of 001 (150 mg, 518 pmol), XtalFluor-E (178 mg, 778 pmol), N,N - diethylethanamine trihydrofluoride (83.6 mg, 518 pmol) in DCE (3 mL) was degassed and purged with N2 3 times, and then the mixture was allowed to stir at 80 °C under an atmosphere of N2. When reaction was judged to be complete, 2 ml 5% aqueous sodium bicarbonate solution was added to the reaction mixture at 25 °C. The mixture was further diluted with water (10 mL) and extracted with DCM (5 mL*3). The organic solutions were combined, dried, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Daisogel SP ODS RPS 150*25mm*5um; mobile phase: [water( NFLHCChj-ACN]; gradient:35%-65% B over 10 min) to give 101 (37.8 mg) as a yellow gum. LC-MS (ESI+) m / z 311.9 (M+H)+.1H NMR (400 MHz, CDCI3) 86.84 - 6.73 (m, 3H), 3.82 (d, J = 5.6 Hz, 6H), 3.17 (d, J = 4.0 Hz, 1H), 2.73 (s, 1H), 2.34 - 2.17 (m, 6H), 1.97 (d, J= 5.2 Hz, 1H), 1.94 - 1.91 (m, 1H), 1.89 - 1.85 (m, 1H), 1.84 - 1.76 (m, 1H), 1.67 - 1.55 (m, 1H), 1.26 - 1.17 (m, 1H).

[0428] Example 4: Synthesis of ( 3a.S’, 7aS)-3a-(3, 4-dimethoxyphenyl )-l -methyloctahydro- 1H- indole (201)

[0429] 001 201

[0430] Step 1: Synthesis of Af'-((3a.S'.7a.S'.E)-3a-(3.4-dimcthoxyphenyl )- l -mcthyloctahydro-6 / / -indol-6- ylidene)-4-methylbenzenesulfonohydrazide

[0431] To a solution of 001(500 mg, 1.73 mmol) and 4-methylbenzenesulfonohydrazide (643 mg, 3.46 mmol) in EtOH (5.0 mL) was added AcOH (10.3 mg, 172 pmol, 9.89 pL). The mixture was allowed to stir at 60 °C for 3 hr and then concentrated. The residue was purified by reversed- phase HPLC (0.1% NH4HCO3 condition) to give A'-((3a5,7aS)-3a-(3,4-dimethoxyphenyl)-l- methyloctahydro-lH-indol-6-yl)-4-methylbenzenesulfonohydrazide (600 mg) as a white solid. LC-MS (ESI+) m / z 458.0 (M+H)+.

[0432] Step 2: Synthesis of A^-((3a5, 7a5)-3a-(3, 4-dimethoxyphenyl)- l-methyloctahydro-lH-indol-6- yl)-4-methylbenzenesulfonohydrazide

[0433] To a solution of A7-((3a5,7aS)-3a-(3, 4-dimethoxyphenyl)- 1 -methyloctahydro- lH-indol-6-yl)-4- methylbenzenesulfonohydrazide (600 mg, 1.31 mmol) in MeOH (5.0 mL) and THF (5.0 mL) was added dropwise NaBH3CN (90.6 mg, 1.44 mmol) in MeOH (0.5 mL) at 0 °C. After the addition was complete, the mixture was allowed to stir at 0 °C for 10 min, and then HC1 (1 M) in EtOH (5 x 1 mL portions at 10 min intervals) was added dropwise via syringe. The reaction mixture was allowed to stir at 0 °C for 2 hr and then concentrated to give the product. On completion, the reaction mixture was concentrated in vacuo to give A7-((3a5,7a5)-3a-(3,4- dimethoxyphenyl)- 1 -methyloctahydro- 1 H-i ndol-6-yl )-4-methylbenzenesul fonohydrazide (600 mg) as a white solid. LC-MS (ESI+) m / z 460.0 (M+H)+.

[0434] Step 3: Synthesis of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-l / / -indole (201) A mixture of Af-((3a5,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-l / / -indol-6-yl)-4- methylbenzenesulfonohydrazide (600 mg, 1.31 mmol) and KO Ac (640 mg, 6.53 mmol) in EtOH (10 mL) was degassed and purged with N2 3 times. The mixture was allowed to stir at 70 °C for 2 hr under an atmosphere of N2 and then concentrated. The resulting residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um; mobile phase: [water(NH3H2O)-ACN]; gradient: 43%-73% B over 12 min) to give 201 (352 mg) as a yellow gum. LC-MS (ESI+) m / z 275.9 (M+H)+; ’ H NMR (400 MHz, CDCI3) 87.00 - 6.89 (m, 2H), 6.84 (d, J= 8.4 Hz, 1H), 3.90 (d, J = 7.2 Hz, 6H), 3.26 (dt, J= 4.4, 9.2 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.34 (s, 3H), 2.34 - 2.23 (m, 1H), 1.97 (d, J= 3.6 Hz, 2H), 1.89 (d, J= 2.0 Hz, 1H), 1.87 - 1.77 (m, 2H), 1.64 - 1.55 (m, 2H), 1.55 - 1.46 (m, 1H), 1.43 - 1.32 (m, 1H), 1.28 - 1.12 (m, 1H).

[0435] Compounds in the table below were prepared from the appropriate starting material according to a procedure similar to that described above in Example 4:

[0436] Procedures similar to those described above in Example 4 could also be used to prepare compounds in the following table from the appropriate starting materials: Example 5: Synthesis of (3aS,6 / ?,7aS)-3a-(3,4-dimethoxyphenyl)-l,6-dimethyloctahydro-

[0437] 1H- indole (203)

[0438] Step 1: Synthesis of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-6-methyleneoctahydro- indole

[0439] To a solution of mcthyl(triphcnyl)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 (3aS,7aS)-3a-(3,4- di methoxy phenyl)- 1 -met hyl-6-methy leneoctahydro- 1 / / -indole (137.7 mg) as a yellow gum. LC- MS (ESI+) m / z 288.2 (M+H)+. ‘H NMR (400 MHz, CDCb) 5 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).

[0440] Step 2: Synthesis of (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-l,6-dimethyloctahydro-lH-indole (203)

[0441] To a solution of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-6-methyleneoctahydro-lH-indole (150 mg, 522 pmol) in EtOAc (5 mL) was added Pd / C (55.5 mg, 52.1 pmol, 10%) under an atmosphere of N2. The suspension was degassed and purged with Hi 3 times. The reaction mixture was allowed to stir under an atmosphere of H2 (15 psi) at 25 °C for 12 hr. The reaction mixture was filtered and concentrated. The crude product was purified by reversed-phase HPLC (column: Waters Xbridgc 150*25mm* 5um; mobile phase: [watcr(NH3H2O)- ACN] ; gradient: 52%-82% B over 12 min ) to give 203 (75.4 mg) as a yellow gum. LC-MS (ESI+) m / z 290.3 NMR (400 MHz, CDCh) 5 6.87 - 6.80 (m, 2H), 6.78 - 6.70 (m, 1H), 3.81 (d, J= 6.2 Hz, 5H), 3.18 (dt, 7= 4.4, 9.2 Hz, 1H), 2.52 (s, 1H), 2.38 - 2.15 (m, 4H), 1.91 (dd, 7= 3.2, 8.8 Hz, 2H), 1.86 - 1.65 (m, 4H), 1.42 - 1.32 (m, 1H), 1.22 - 1.09 (m, 1H), 0.84 - 0.78 (m, 1H), 0.77

[0442] - 0.73 (m, 3H).

[0443] Example 6: Prep-HPLC Separation of 150 to give 232 and 233

[0444] The enantiomers of rac-(3a5,7aS')-3a-(2,2-difluorobenzo[7][l,3]dioxol-5-yl)-l-methyloctahydro- 6 / 7-indol-6-onc were separated by prep-HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [Neu-MeOH]; B%: 25%-25%, C6.0; 54min) to give Peak 1 (34 mg, 42%) as yellow oil and Peak 2 (35 mg, 53%) as white oil.

[0445] Peak 1: LC-MS (ESP) m / z 310.1 (M+H)+. ‘H NMR (400 MHz, CDCh) 87.18 - 7.08 (m, 2H), 7.07 - 7.02 (m, 1H), 3.23 - 3.11 (m, 1H), 2.93 (s, 1H), 2.67 - 2.54 (m, 2H), 2.53 - 2.42 (m, 1H), 2.40 - 2.29 (m, 4H), 2.26 - 2.22 (m, 1H), 2.21 - 2.16 (m, 1H), 2.16 - 2.07 (m, 3H).

[0446] Peak 2: LC-MS (ESP) m / z 310.1 87.15 - 7.08 (m, 2H), 7.06 - 7.02 (m, 1H), 3.21 - 3.11 (m, 1H), 2.93 (t, 7 = 3.2 Hz, 1H), 2.60 (dd, 7= 3.6, 6.1 Hz, 2H), 2.52 - 2.43 (m, 1H), 2.39 - 2.29 (m, 4H), 2.28 - 2.22 (m, 1H), 2.21 - 2.16 (m, 1H), 2.16 - 2.06 (m, 3H).

[0447] Example 7: Synthesis of 206 and 207

[0448]

[0449] 206 207

[0450] Procedures similar to those described above in Example 7 could also be used to prepare compounds in the following table from the appropriate starting materials:

[0451]

[0452] Example 8: Synthesis of 301 and 302

[0453] 301 302

[0454] Example 9: Synthesis of 221 and 222 reaction scheme

[0455]

[0456] Example 10: Synthesis of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-3, 4,5,6,7,7a- hexahydro-2H-indole

[0457] Step 1 - N-[(E)-[(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-2,3,4,5,7,7a-hexahydroindol-6- ylidenelaminol-4-methyl-benzenesulfonamide

[0458] SNTX-001 2 To a solution of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-2,3,4,5,7,7a-hexahydroindol-6- one (500 mg, 1.73 mmol), 4-mcthylbcnzcncsulfonohydrazidc (643 mg, 3.46 mmol) in EtOH (5.0 mL) was added AcOH (10.3 mg, 172 pmol, 9.89 pL). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give N-[(E)- [(3aS,7aS)-3a-(3,4- dimethoxyphenyl)- l-methyl-2, 3, 4, 5,7, 7a-hexahydroindol-6-ylidene] amino] - 4-methyl-benzenesulfonamide (600 mg, 66% yield) as a white solid

[0459] LC-MS (ESI+) m / z 458.0 (M+H)+

[0460] Step 2 - N'-[(3aS,7aS}-3a-(3,4-dimethoxyphenyl}-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-6- yl ]-4- methyl-benzenesulfonohydrazide

[0461] 2 3

[0462] To a solution of N-[(E)-[(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-2,3,4,5,7,7a- hexahydroindol -6-ylidene] amino] -4-methyl-benzenesulfonamide (600 mg, 1.31 mmol) in MeOH (5.0 mL) and THF (5.0 mL) was added dropwise NaBHaCN (90.6 mg, 1.44 mmol) in MeOH (0.5 mL) at 0 °C. After addition, the mixture was stirred at this temperature for 10 minutes, and then HC1 (1 M) in EtOH (5 x 1 mL portions at 10 minutes intervals) was added drop wise by syringe. The resulting mixture was slimed at 0 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the residue to give N'-[(3aS,7aS)-3a-(3,4- dimethoxypheny 1)- 1 -methyl-3 ,4,5 ,6,7 ,7 a-hexahydro-2H-indol- 6-yl] -4-methyL benzenesulfonohydrazide (600 mg, 79 % yield) as a white solid.

[0463] LC-MS (ESI+) m / z 460.0 (M+H)+

[0464]

[0465] A mixture of N'-[(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-6-yl] -4-methyl-benzenesulfonohydrazide (600 mg, 1.31 mmol), KO Ac (640 mg, 6.53 mmol) in EtOH (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by prcp-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(NH3H2O)- ACN];gradient:43%-73% B over 12 min) to give (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-l-methyl- 3,4,5,6,7,7a-hexahydro-2H-indole (352 mg, 92% yield) as a yellow gum.

[0466] LC-MS (ESI+) m / z 275.9 (M+H)+;

[0467] ’H NMR (400 MHz, CDCI3) 57.00 - 6.89 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 3.90 (d, J= 7.2 Hz, 6H), 3.26 (dt, J= 4.4, 9.2 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.34 (s, 3H), 2.34 - 2.23 (m, 1H), 1.97 (d, 7 = 3.6 Hz, 2H), 1.89 (d, J = 2.0 Hz, 1H), 1.87 - 1.77 (m, 2H), 1.64 - 1.55 (m, 2H), 1.55 - 1.46 (m, 1H), 1.43 - 1.32 (m, 1H), 1.28 - 1.12 (m, 1H)

[0468] Example 11: Synthesis of (3aR,7aR)-3a-(3,4-dimethoxyphenyl)-l-methyl-3,4,5,6,7,7a- hexahydro-2H-indole Step 1 - N-f (E)-[( 3aR, 7aR )-3a-( 3,4-dimethoxyphenyl)-l -methyl-2,3,4,5, 7, 7 a-hexahydroindol -6-ylidene]amino]-4-methyl-benzenesulfonamide (Int 2)

[0469] SNTX-002 2

[0470] To a solution of (3aR,7aR)-3a-(3,4-dimethoxyphenyl)-l-methyl-2,3,4,5,7,7a-hexahydroindol-6- one (1 g, 3.46 mmol) in EtOH (10 mL) was added AcOH (20.8 mg, 346 pmol, 19.8 pL) and 4- methylbenzenesulfonohydrazide (1.29 g, 6.91 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered, concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give the N-[(E)- [(3aR,7aR)- 3a-(3,4-dimethoxyphenyl)-l-methyl-2,3,4,5,7,7a-hexahydroindol-6-ylidene]amino]- 4-methyl-benzenesulfonamide (1.3 g, 74% yield) as a yellow solid.

[0471] LC-MS (ESI+) m / z 458.0 (M+H)+

[0472] *H NMR (400 MHz, CDCI3) 57.91 - 7.78 (m, 2H), 7.32 (d, 7 = 8.0 Hz, 2H), 6.96 - 6.78 (m, 1H), 6.77 - 6.70 (m, 2H), 3.89 - 3.81 (m, 6H), 2.99 - 2.75 (m, 2H), 2.74 - 2.63 (m, 1H), 2.48 - 2.39 (m, 4H), 2.35 - 2.28 (m, 1H), 2.27 - 2.15 (m, 5H), 2.07 - 1.95 (m, 3H), 1.95 - 1.83 (m, 2H)

[0473] Step 2 - N'-f(3aR,7aR)-3a-(3,4-dimethoxyphenyl)-l-methyl-3,4,5,6,7,7a-hexahvdro-2H-indol-6- yll -4-methyl-benzenesulfonohydrazide (Int 3) To a solution of N-[(E)-[(3aR,7aR)-3a-(3,4-dimethoxyphenyl)-l-methyL2,3,4,5,7,7a- hexahydroindol -6-ylidene]amino]-4-methyl-benzenesulfonamide (1.3 g, 2.84 mmol) in MeOH (5 mL) and THF (5 mL) was added NaBH?CN (268 mg, 4.26 mmol) and HC1 (1 M, 5.68 mL). The mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered, concentrated in vacuo to give the N'-[(3aR,7aR)-3a -(3,4-dimethoxyphenyl)-l-methyl-3,4,5,6,7,7a-hexahydro- 2H-indol-6-yl]-4-methyl-benzenesulfonohydrazide (1.3 g, 61% yield) as a yellow solid. LC-MS (ESI+) m / z 460.0 (M+H)+

[0474] Step 3 - (3aR,7aR}-3a-(3,4-dim.ethoxyphenyl)-l-methyl-3,4.5,6,7,7a-hexahydro-2H-indole

[0475] To a solution of N'-[(3aR,7aR)-3a-(3,4-dimethoxyphenyl)- l-methyl-3,4,5,6,7,7a-hexahy dro-2H- indol-6-yl]-4-methyl-benzenesulfonohydrazide (1.3 g, 2.83 mmol) in EtOH (10 mL) was added KOAc (1.39 g, 14.1 mmol). The mixture was stirred at 75 °C for 1 hour. The mixture was poured to the water (100 mL) and extracted with ethyl acetate (100 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give the (3aR,7aR)-3a-(3,4 - dimethoxyphenyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (227 mg, 22% yield) as a yellow gum.

[0476] LC-MS (ESI+) m / z 275.9 (M+H)+

[0477] !H NMR (400 MHz, CDC13) 57.00 - 6.88 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 3.89 (d, J= 7.0 Hz, 6H), 3.33 - 3.17 (m, 1H), 2.59 (br s, 1H), 2.43 - 2.24 (m, 4H), 2.00 - 1.92 (m, 2H), 1.91 - 1.75 (m, 3H), 1.63 - 1.55 (m, 2H), 1.54 - 1.44 (m, 1H), 1.44 - 1.31 (m, 1H), 1.27 - 1.08 (m, 1H) Example 12: Synthesis of l,3-dimethyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-

[0478] 2H-indol-3a-yl]indazole and l,3-dimethyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a- hexahydro-2H-indol-3a-yl]indazole

[0479] Step 1 - 2-( 1 ,3-dimethylindazol-6-yl}cyclohexanorie

[0480] A mixture of 6-bromo-l,3-dimethyl-indazole (15 g, 66.6 mmol), cyclohexanone (7.85 g, 80.0 mmol, 8.29 mL), Pd(OAc)2 (748 mg, 3.33 mmol), t-BuONa (9.61 g, 100 mmol) and t-Bu ;P (13.5 g, 6.66 mmol, 15.6 mL, 10% purity) in THF (150 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured to the water (500 mL) and extracted with ethyl acetate (300 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to give the 2-(l,3-dimethylindazol-6 -yl)cyclohexanone (12 g, 72% yield) as a yellow solid.

[0481] LC-MS (ESI+) m / z 243.0 (M+H)+;

[0482] 1H NMR (400 MHz, CDCh) 57.60 (d, 7= 8.4 Hz, 1H), 7.11 (s, 1H), 6.99 - 6.82 (m, 1H), 3.98 (s, 3H), 3.83 - 3.72 (m, 1H), 2.61 - 2.54 (m, 4H), 2.54 - 2.45 (m, 1H), 2.40 - 2.32 (m, 1H), 2.26 - 2.06 (m, 3H), 1.94 - 1.82 (m, 2H)

[0483] Step 2 - 2-[ l-( l,3-dimethylindazol-6-yl}-2-oxo-cyclohexyl]acetonitrile

[0484] To a solution of 2-(l,3-dimethylindazol-6-yl)cyclohexanone (8 g, 33.01 mmol) in DMF (80 mL) was added dropwise NaH (1.58 g, 39.6 mmol, 60% purity) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-chloroacetonitrile (3.74 g, 49.5 mmol, 3.13 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (200 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1) to give the 2-[l-(l,3-dimethylindazol-6-yl)-2-oxo-cyclohexyl]acetonitrile (5.2 g, 42% yield) as a yellow solid.

[0485] LC-MS (ESI+) m / z 282.1 (M+H)+;

[0486] *H NMR (400 MHz, CDC13) 57.69 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 6.98 - 6.86 (m, 1H), 4.05 - 3.98 (m, 3H), 3.14 - 3.05 (m, 1H), 2.86 - 2.71 (m, 2H), 2.56 (s, 3H), 2.47 - 2.36 (m, 2H), 2.01 - 1.70 (m, 5H)

[0487] Step 3 - 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,3-dimethyl-indazole

[0488] To a solution of 2-[l-(l,3-dimethylindazol-6-yl)-2-oxo-cyclohexyl]acetonitrile (5 g, 17.8 mmol) in MeOH (50 mL) was added Raney-Ni (1.83 g, 21.3 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi.) at 25 °C for 12 hours. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1) to give the 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,3-dimethyl-indazole (1.7 g, 22% yield) as a yellow solid.

[0489] LC-MS (ESI+) m / z 268.2 (M+H)+;

[0490] To a solution of 6-(2,3,4,5,6,7-hexahydroindoL3a-yl)-l,3-dimethyl-indazole (1.5 g, 5.61 mmol) in DCM (15 mL) was added NaBHaCN (1.06 g, 16.8 mmol) and AcOH (337 mg, 5.61 mmol, 321 pL). The mixture was stirred at 25 °C for I hour. On completion, the mixture was poured to the water (20 mL) and extracted with ethyl acetate (30 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the 6-(l,2,3,4,5,6,7,7a-octahydroindol- 3a-yl)-l,3-dimethyl-indazole (1.5 g crude) as a yellow solid.

[0491] LC-MS (ESI+) m / z Z1Q2 (M+H)+;

[0492] Step 5 - l,3-dimelhyl-6-( l-melhyl-3,4, 5,6,7, 7a-hexahydro-2H-indol-3a-yl)indazole

[0493] To a solution of 6-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l,3-dimethyl-indazole (1.5 g, 5.57 mmol) in DCM (15 mL) was added dropwise HCHO (1.11 g, 11.1 mmol, 1.02 mL, 30% purity), AcOH (669 mg, 11.1 mmol, 638 pL) at 25 °C. After addition, the mixture was stirred at this temperature for 30 min, and then NaBHaCN (1.05 g, 16.7 mmol) was added dropwisc at 25 °C. The resulting mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the l,3-dimethyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl)indazole (350 mg, 22% yield) as a yellow solid.

[0494] LC-MS (ESI+) m / z 284.2 (M+H)+;

[0495] !H NMR (400 MHz, CDC13) 57.67 (d, J= 8.4 Hz, 1H), 7.22 (s, 1H), 7.11 - 7.00 (m, 1H), 4.29 - 4.10 (m, 1H), 4.03 (s, 3H), 3.77 (br s, 1H), 3.18 - 3.03 (m, 1H), 2.97 (s, 3H), 2.63 - 2.52 (m, 3H), 2.42 - 2.21 (m, 3H), 2.19 - 2.10 (m, 1H), 2.09 - 2.00 (m, 2H), 1.97 - 1.86 (m, 1H), 1.74 - 1.55 (m, 2H), 1.33 - 1.20 (m, 1H)

[0496] Step 6- l,3-dimethyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-mdol-3a-yl]indazole

[0497] & 1 ,3-dimethyl-6-[rac-( 3aR, 7aR )-7 -methyl-3,4,5, 6, 7, 7a-hexahydro-2H-indol-3a-yl lindazole

[0498] The l,3-dimethyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)indazole was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2- EtOH(0.1%NH3H2O)];B%:30%, isocratic elution mode) to give the l,3-dimethyl-6-[rac- (3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-ylJindazole (56.95 mg, 18% yield) as a off-white solid, and l,3-dimethyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol- 3 a-yl] indazole (52.02 mg, 16% yield) as an off-white solid. 1.3-dimethyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]indazole (retention time: 2.167 min): LC-MS (ESI+) m / z 284.2 (M+H)+.

[0499] H NMR (400 MHz, CDC13) 57.59 (d, J= 8.4 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.14 (d, J= 8.6 Hz, 1H), 4.01 (s, 3H), 3.61 - 3.29 (m, 1H), 3.01 - 2.75 (m, 1H), 2.55 (s, 3H), 2.45 (br s, 4H), 2.17 - 2.00 (m, 3H), 1.95 (br d, J = 7.2 Hz, 2H), 1.73 (br d, 7= 7.2 Hz, 2H), 1.55 (br d, 7 = 12.6 Hz, 1H), 1.48 - 1.41 (m, 1H), 1.25 - 1.10 (m, 1H)

[0500] 1.3-dimethyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]indazole

[0501] (retention time: 2.302 min): LC-MS (ESI+) m / z 284.3 (M+H)+.

[0502] *H NMR (400 MHz, CDCI3) 57.59 (d, 7= 8.6 Hz, 1H), 7.28 (s, 1H), 7.15 (d, 7= 8.4 Hz, 1H), 4.01 (s, 3H), 3.43 - 3.28 (m, 1H), 2.78 (br s, 1H), 2.55 (s, 3H), 2.46 - 2.31 (m, 4H), 2.15 - 2.03 (m, 2H), 2.02 - 1.96 (m, 1H), 1.95 - 1.85 (m, 2H), 1.76 - 1.61 (m, 2H), 1.58 - 1.48 (m, 1H), 1.45 - 1.37 (m, 1H), 1.25 - 1.11 (m, 1H)

[0503] Example 13: Synthesis of l,4-Dimethyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-

[0504] 2H-indol-3a-yl]phthalazine and l,4-dimethyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a- hexahydro-2H-indol-3a-yl]phthalazine

[0505] Stepl-N-[(E}-l-(4-bromo-2-hydroxy-phenyl)ethylideneamino]acetamide

[0506] To a solution of l-(4-bromo-2-hydroxy-phenyl) ethanone (100 g, 465 mmol) in i-PrOH (400 mL) was addedacetohydrazide (34.4 g, 465.02mmol). The mixture was stirred at 100 °C for 12 hours. The precipitated soild were collected by filtration and washed with PrOH (100ml). The crude product was used into the next step without further purification. The compound N-[(E)-l-(4- bromo-2-hydroxy -phenyl) ethylideneamino] acetamide (120 g, 80% yield,) was obtained as a yellow solid.

[0507] !H NMR (400 MHz, DMSO-76) 8 13.75 - 13.66 (m, 1H), 11.17 - 10.96 (m, 1H), 7.58 (d, 7= 8.4 Hz, 1H), 7.13 (s, 2H), 2.56 (s, 3H), 2.14 (s, 3H). Step2-l-(2-Acetyl-4-bromo-phenyl)ethanone

[0508] To a solution of N- [(E)- l-(4-bromo-2-hydroxy-phenyl)ethylideneamino] acetamide (60 g , 188 mmol) in DCM (200 mL) was added PhI(OAc)2 (185 g, 574 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was partitioned between DCM (300 mL*3) and water (200 mL). The organic phase was separated, washed with brine 600mL (200mL * 3), dried over, concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g ScpaFlash® Silica Flash Column, Eluent of 0~20%Ethylacetate / Petroleum ethergradient @ 100 mL / min).The crude product was purified by reversed-phase HPLC( 0.1 %FA condition). The compound 1 -(2-acetyl-4-bromo-phenyl) ethanone (28 g, 32 % yield) was obtained as a Brown oil.

[0509] NMR (400 MHz, CDC13) 57.60 (dd, J= 1.6, 8.4 Hz, 1H), 7.55 (d, J= 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 2.46 (d, J = 8.4 Hz, 6H).

[0510] Step3-6-Bromo-l,4-dimethyl-phthalazine

[0511] To a solution of l-(2-acetyl-4-bromo-phenyl) ethanone (15 g, 62.2 mmol) in MeOH (300 mL) was added N2H4.H2O (55 g, 933 mmol, 53.26 mL, 85% purity) at 25 °C. The mixture was stirred at 60 °C for 5 hours. The reaction mixture was quenched by addition the solution of NH4CI 200 mL at 25°C, and then diluted with water 500 mL and extracted with EA 600 mL (200 mL * 3). The combined organic layers were washed with brine 300 mL (100 mL * 3), dried over [Drying agent], the resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0-100% Ethylacetate / Petroleum ethergradient @ 60 mL / min). The compound 6-bromo- 1 ,4- dimcthyl-phthalazinc (10 g, 61% yield) was obtained as a Brown oil.

[0512] 1H NMR (400 MHz, CDCI3) 8 8.14 (s, 1H), 7.93 - 7.84 (m, 2H), 2.88 (d, J = 5.2 Hz, 6H).

[0513] A mixture of 6-bromo- 1 ,4-dimethyl-phthalazine (10 g, 42 mmol), cyclohexanone (12.4 g, 127 mmol), x-antphos (2.44 g, 4.22 mmol), Pd2(dba)a (1.93 g, 2.11 mmol) and t-BuONa (6.08 g, 63.3 mmol) in THF (150 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 5 hours under N2 atmosphere. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethylacetate / Petroleum ethergradient @ 50 mL / min). The crude product was purified by reversed-phase HPLC (0.1% FA condition). The compound 2-(l,4- dimethylphthalazin -6-yl) cyclohexanone (5 g, 63% yield) was obtained as a Brown oil.

[0514] LC-MS (ESI+) m / z 255.2 (M+H)+.

[0515] To a solution of 2-(l,4-dimethylphthalazin-6-yl)cyclohexanone (2.5 g, 9.83 mmol) in THF (30 mL) was added dropwise t-BuOK (2 M in THF, 14.8 mL) at 0 °C . After addition, the mixture was stirred at this temperature for 30 minutes, and then 2-iodoacetonitrile (2.46 g, 14.7 mmol) was added dropwise at 25 °C. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=l / l to Dichloromethane / Methanol = 20 / 1). Compound 2-[l-(l , 4- dimethylphthalazin-6-yl)-2-oxo-cyclohexyl] acetonitrile (3 g, 94% yield) was obtained as a Brown oil.

[0516] NMR (400 MHz, CDC13) 5 8.09 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 1.6 Hz, 1H), 7.68 (dd, J = 1.6, 8.8 Hz, 1H), 3.42 (s, 1H), 3.08 (d, J= 2.4 Hz, 1H), 2.92 (s, 6H), 2.77 (d, J = 3.8 Hz, 2H), 2.41 (s, 1H), 2.30 - 2.21 (m, 1H), 1.97 (s, 2H), 1.87 (s, 1H), 1.78 - 1.74 (m, 1H).

[0517] Step 6-6-( 2, 3, 4, 5, 6, 7-Hexahydroindol-3a-yl )-l,4-dimethyl-phthalazine

[0518] 9 10

[0519] To a solution of 2-[l-(l,4-dimethylphthalazin-6-yl)-2-oxo-cyclohexyl]acetonitrile (2.5 g, 8.52 mmol) in MeOH (30 mL) was added Raney-Ni (146 mg, 1.70 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 60 °C for 12 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give a residue. The crude product was used into the next step without further purification. The comound 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,4- dimethyl-phthalazine (2.5 g, 4.47 mmol, 53% yield) was obtained as a Brown oil. LC-MS (ESI+) m / z 280.1 (M+H)+ .

[0520] Step 7-6-( 1,2, 3, 4, 5,6, 7, 7A-octahydroindol-3a-yl)-l,4-dimethyl-phthalazine

[0521]

[0522] To a solution of 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,4-dimethyl-phthalazine (1.5 g, 2.15 mmol) in DCM (15 mL) was added dropwise NaBH3CN (405 mg, 6.44 mmol) and CH3COOH (129 mg, 2.15 mmol) at 25 °C. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The crude product was used into the next step without further purification. Compound 6- (1,2,3,4,5,6,7,7a -octahydroindol -3a-yl) - 1,4 - dimethyl-phthalazine (1 g, 83 % yield) was obtained as a red oil.

[0523] LC-MS (ESI+) m / z 282.1 (M+H)+ .

[0524] Step 8-1 ,4-Dimethyl-6-( 1 -methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)phthalazine

[0525] To a solution of 6-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l,4-dimethyl-phthalazine (1 g, 1.78 mmol) in DCM (20 mL) was added dropwise HCHO (56.9 mg, 1.78 mmol) at 0 °C . After addition, the mixture was stirred at this temperature for 30 minutes, and then NaBHiCN (334.99 mg, 5.33 mmol) was added at 25 °C. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by reversed - phase HPLC ( 0.1% TFA condition).JH NMR (400 MHz, MeOD) 5 8.67 (s, 1H), 8.49 (s, 2H), 4.34 (s, 1H), 4.10 - 4.01 (m, 1H), 3.47 (d, J= 3.6 Hz, 1H), 3.23 - 3.19 (m, 3H), 3.15 (d, J = 12.0 Hz, 6H), 2.52 (d, J = 12 Hz, 2H), 2.36 (s, 2H), 2.15 - 2.03 (m, 1H), 1.94 - 1.83 (m, 1H),

[0526] 1.77 - 1.62 (m, 4H).

[0527] 1.4-dimethyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)phthalazine (150 mg, 508 pmol) was separated by SFC (column: Chiralpak AS-3 50x4.6mm I.D., 3um Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05%DEA); Gradient elution: B in A from 5% to 40% Flow rate: 3mL / min;Detector: PDA; Column Temp: 35C;Back Pressure: lOOBar" ) to give

[0528] 1.4-dimcthyl -6-[rac-(3aS,7aS) -l-mcthyl-3,4,5,6,7,7a-hcxahydro-2H-indol-3a-yl] phthalazine as a yellow gum (40 mg, 90% purity, Peak 1) and 1,4-dimethyl- 6-[rac-(3aR,7aR)- 1-methyl- 3,4,5,6,7,7a-hexahydro

[0529] -2H-indol-3a-yl]phthalazine (45 mg, 30% yield, Peak2) as a yellow gum. Then the Peak 1 was purified by prep- HPLC (column: CD20-Waters Xbidge BEH C18 250*25*10um; mobile phase: [water ( NH4HCO3) - ACN] gradient: 11%-41% B over 15 min ). To give the target (17.3 mg, 12% yield).

[0530] 1.4-Dimethyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a- yl]phthalazine (retention time: 1.153 min): LC-MS (ESI+) m / z 296.2 (M+H)+.

[0531] H NMR (400 MHz, MeOD) 5 8.26 (d, J= 8.8 Hz, 1H), 8.18 - 8.13 (m, 2H), 2.98 (s, 3H), 2.95 (s, 3H), 2.95 - 2.93 (m, 1 H), 2.46 (d, J = 10.4 Hz, 1 H), 2.43 (s, 3H), 2.25 - 2. 17 (m, 1 H), 2.10 (d, J= 13.6 Hz, 2H), 2.07 - 1.91 (m, 3H), 1.81 - 1.65 (m, 2H), 1.58 (d, J = 13.6 Hz, 1H), 1.50 - 1.43 (m, 1H), 1.15 (d, 7= 12.8 Hz, 1H). l,4-dimethyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]phthalazine (retention time: 1.445 min): LC-MS (ESI+) m / z 296.2 (M+H)+.

[0532] *H NMR (400 MHz, MeOD) 5 8.26 (d, 7= 8.8 Hz, 1H), 8.19 - 8.12 (m, 2H), 2.98 (s, 3H), 2.95 (s, 3H), 2.94 (s, 1H), 2.47 (d, 7 = 6.6 Hz, 1H), 2.42 (s, 3H), 2.19 (s, 1H), 2.10 (dd, 7 = 3.2, 13.4 Hz, 2H), 2.06 - 1.92 (m, 3H), 1.81 - 1.63 (m, 2H), 1.62 - 1.55 (m, 1H), 1.48 (s, 1H), 1.22 - 1.08 (m, 1H).

[0533] Example 14: Synthesis of 6-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l- methyl-indazole and 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l- methyl-indazole

[0534] Step 1 -2-( 1 -methylindazol-6-yl)cyclohexanone

[0535] 1 3

[0536] A mixture of 6-bromo-l-methyl-indazole (18 g, 85.2 mmol), cyclohexanone (25.2 g, 254 mmol,

[0537] 26.4 mL), Pd(OAc)2 (956 mg, 4.26 mmol), t-BuaP (862 mg, 4.26 mmol, 1 mL) and NaOtBu (10.7 g, 111 mmol) in THF (600 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured to the water (400 mL) and extracted with ethyl acetate (1.2 L). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 5 / 1) to give 2- (l-methylindazol-6-yl)cyclohexanone (3.2 g, 13% yield) as a white solid.

[0538] *H NMR (400 MHz, CDCI3) 57.93 (s, 1H), 7.70 - 7.64 (m, 1H), 7.18 (s, 1H), 6.93 (dd, J = 1.0,

[0539] 8.4 Hz, 1H), 4.05 (s, 3H), 3.82 - 3.73 (m, 1H), 2.61 - 2.49 (m, 2H), 2.39 - 2.32 (m, 2H), 2.24 - 2.16 (m, 2H), 1.89 (dd, J - 3.2, 9.2 Hz, 2H). Step 2 - 2-fl-( l-methylindazol-6-yl}-2-oxo-cyclohexyl] acetonitrile

[0540] 3 5

[0541] To a solution of 2-(l-methylindazol-6-yl)cyclohexanone (3.2 g, 14.0 mmol) in DMF (40 mL) was added NaH (840 mg, 60%purity, 21.0 mmol) at 0°C for 0.5 hour. Then 2-chloroacetonitrile (1.27 g, 16.8 mmol, 1.06 mL) was added the mixture. The mixture was stirred at 0 °C for 2 hours. On completion, the mixture was poured to the water (50 mL) at 0°C and extracted with ethyl acetate (100 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (0.1% FA). 2-[l-(l- methylindazol-6-yl)-2 -oxo-cyclohexyl] acetonitrile (1.6 g, 36% yield) as a yellow solid.

[0542] NMR (400 MHz, CDC13) 57.98 (s, 1H), 7.80 - 7.74 (m, 1H), 7.28 (s, 1H), 6.96 (dd, J = 1.4, 8.4 Hz, 1H), 4.10 (s, 3H), 3.09 (dd, J = 2.6, 13.6 Hz, 1H), 2.80 (d, J = 5.6 Hz, 2H), 2.45 - 2.40 (m, 2H), 2.07 - 1.99 (m, 2H), 1.87 (td, J = 3.0, 9.6 Hz, 3H).

[0543] Step 3 - 6-(2,3,4,5,6,7-hexahydroindol-3a-yl}-l-methyl-indazole

[0544] 5 6

[0545] To a solution of 2-[l-(l-methylindazol-6-yl)-2-oxo-cyclohexyl]acetonitrile (500 mg, 1.87 mmol) in THF (10 mL) was added Raney-Ni (32.1 mg, 374 pmol) .The mixture was stirred at 25 °C for 16 hours under H2(15Psi) atmosphere. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (0.1% FA) to give 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l -methyl-indazole (0.5 g, 56% yield) as a colourless gum.

[0546] LC-MS (ESI+) m / z 254.3 (M+H)+

[0547] Step 4 -6-( l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l-methyl-indazole

[0548] To a solution of 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l-methyl-indazole (0.5 g, 1.97 mmol) in DCM (5 mL) was added NaBHaCN (186 mg, 2.96 mmol) at 0°C for 5 minutes. Then AcOH (118 mg, 1.97 mmol, 113 pL) was added the mixture at 0°C. The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (300 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue, the filtrate concentrated in vacuo to give 6-(l,2,3,4,5,6,7,7a- octahydroindol-3a-yl)-l-methyl-indazole (0.45 g, 41% yield) as a brown solid.

[0549] LC-MS (ESI+) m / z 256.3 (M+H)+

[0550] Step 5 - l-methyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)indazole

[0551] To a solution of 6-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l-methyl-indazole (0.4 g, 1.57 mmol) in DCM (5 mL) was added HCHO (282 mg, 9.40 mmol, 258 pL) and AcOH (94.1 mg, 1.57 mmol, 89.7 pL) at 0°C for 5 minutes. Then NaBITjCN (148 mg, 2.35 mmol) was added the mixture at 0°C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (200 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the l-methyl-6-(l-methyl- 3,4,5,6,7,7a-hexahydro -2H-indol-3a-yl)indazole (100 mg, 7.82% yield, 33% purity) as a yellow soli.

[0552] NMR (400 MHz, CDCh) 57.96 (s, 1H), 7.77 - 7.70 (m, 1H), 7.29 (s, 1H), 7.15 - 7.09 (m, 1H), 4.13 - 4.08 (m, 4H), 3.54 (br s, 1H), 2.86 - 2.79 (m, 4H), 2.37 - 2.26 (m, 1H), 2.25 - 2.05 (m, 5H), 2.05 - 1.88 (m, 3H), 1.70 - 1.49 (m, 3H)+

[0553] Step 6 - 6-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l-methyl-indazole & 6-

[0554] [ ( 3aR, 7aR )-l-methyl-3,4, 5, 6, 7, 7a-hexahydro-2H-indol-3a-yl ]-l-methyl-indazole

[0555] The residue was separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give 6-[(3aS,7aS)-l-methyl- 3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l-methyl-indazole (15.57 mg, 15% yield) as a yellow solid, and 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro - 2H-indol-3a-yl]-l-methyl-indazole (19.67 mg, 18% yield) as a yellow solid.

[0556] 6-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l-methyl-indazole (retention time: 0.877 min): LC-MS (ESI+) m / z 270.0 (M+H)+;

[0557] H NMR (400 MHz, CDC13) 57.93 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.20 - 7.14 (m, 1H), 4.09 (s, 3H), 3.58 - 3.44 (m, 1H), 3.01 - 2.88 (m, 1H), 2.49 (s, 4H), 2.19 - 1.91 (m, 6H), 1.76 (d, J = 7.6 Hz, 2H), 1.57 (d, J = 12.4 Hz, 1H), 1.27 - 1.15 (m, 1H). 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l-methyl-indazole (retention time: 1.191 min): LC-MS (ESI+) m / z 27Q.Q (M+H)+;

[0558] H NMR (400 MHz, CDCI3) 57.98 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.11 (s, 3H), 3.78 - 3.71 (m, 1H), 3.01 - 2.95 (m, 4H), 2.42 - 2.30 (m, 3H), 2.29 - 2.16 (m, 3H), 2.11 - 2.02 (m, 1H), 1.80 - 1.71 (m, 1H), 1.28 - 1.23 (m, 2H).

[0559] Example 15: Synthesis of (3aS,7aS)-3a-f4-(difluoromethoxy)-3-methoxy-phenyl]-l-methyl- 3,4,5,6,7,7a-hexahydro- 2H-indole

[0560] Step 1 - N-[(E)-[(3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-l-methyl-2,3,4,5,7,7a- hexahydroindol-6-ylidene]amino]-4-methyl-benzenesulfonamide

[0561] SNTX-341 2

[0562] To a solution of (3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-l-methyl-2,3,4,5,7,7a- hexahydroindol-6-one (400 mg, 1 .23 mmol), 4-methylbenzenesulfonohydrazide (457 mg, 2.46 mmol) in EtOH (3.0 mL) was added AcOH (7.38 mg, 122 pmol). The mixture was stirred at 60 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give N-[(E)-[(3aS,7aS)-3a-[4-(difhioromethoxy)-3-methoxy-phenyl]-l-methyl-2,3,4,5,7,7a- hexahydroindol-6-ylidene]amino]-4-methyl-benzenesulfonamide (500 mg, 78% yield) as a white solid.

[0563] LC-MS (ESI+) m / z 493.9 (M+H)+; Step 2 - N'-[(3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-l -methyl-3,4,5,6,7,7a- hexahydro-2H-indol-6-yl]-4-methyl-benzenesidfonohydrazide

[0564] 2 3

[0565] To a solution of N-[(E)-[(3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-l-methyl-2,3,4, 5,7,7a-hexahydroindol-6-ylidene]amino]-4-methyl-benzenesulfonamide (500 mg, 1.01 mmol) in MeOH (2.0 mL) and THF (2.0 mL) was added dropwise NaBHsCN (70.0 mg, 1.11 mmol) in MeOH (0.5 mL) at 0°C. After addition, the mixture was stirred at this temperature for 10 minutes, and then HC1 (I M, 2.08 mL) in EtOH (5 x 0.4 mL portions at 10 minutes intervals) was added dropwise by syringe. The resulting mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give N'-[(3aS,7aS)-3a-[4- (difluoromethoxy)-3-methoxy-phenyl] -l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-6-yl]-4- methyl-benzenesulfonohydrazide (500 mg, 79% yield) as a white solid.

[0566] LC-MS (ESI+) m / z 495.9 (M+H)+;

[0567] Step 3 - (3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-l -methyl-3,4,5,6,7,7a- hexahydro- 2H-indole A mixture of N'-[(3aS,7aS)-3a-[4-(difluoromcthoxy)-3-mcthoxy-phcnyl]-l-mcthyl-3,4,5,6,7,7a- hexahydro-2H-indol-6-yl]-4-methyl-benzenesulfonohydrazide (500 mg, 1.01 mmol), KO Ac (495 mg, 5.04 mmol) in EtOH (5.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH4HCO3 condition) to give (3aS,7aS)-3a-[4-(difluoromethoxy)-3- methoxy-phenyl]-l -methyl- 3,4,5,6,7,7a-hexahydro-2H-indole (124 mg, 37% yield) as a yellow gum.

[0568] LC-MS (ESI+) m / z 312.1 (M+H)+;

[0569] NMR (400 MHz, CDCI3) 57.02 (d, J = 8.4 Hz, 1H), 6.95 - 6.75 (m, 2H), 6.47 (t, J = 75.2 Hz, 1H), 3.82 (s, 3H), 3.22 (dt, J= 5.2, 9.2 Hz, 1H), 2.55 (s, 1H), 2.37 - 2.15 (m, 4H), 1.92 - 1.71 (m, 5H), 1.42 (s, 1H), 1.36 - 1.29 (m, 1H), 1.19 (s, 1H), 1.11 - 1.00 (m, 1H), 0.81 (s, 1H).

[0570] Example 16: Synthesis of rac-(3aR,7aS)-3a-(5,6-dimethoxy-2-pyridyl)-l-methyl- 3.4.5.6.7,7a-hexahydro-2H-indole and rac-(3aS,7aR)-3a-(5,6-dimethoxy-2-pyridyl)-l- methyl-3,4,5,6,7,7a-hexahydro-2H-indole

[0571] Step 1 - 6-bromo-2,3-dimethoxx-pyridme

[0572] 1 2

[0573] To a solution of 6-bromo-2-fluoro-3-methoxy-pyridine (15.0 g, 72.8 mmol) in DMF (100 mL) was added NaOMe (19.7 g, 364mmol). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (300 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue purified by prep-TLC (petroleum ether: ethyl acetate = 0:1) to give the 6-bromo-2,3-dimethoxy-pyridine (14.5 g, 82% yield) as a white solid.!H NMR (400 MHz, CDC13) 5 = 6.98 - 6.61 (m, 2H), 4.00 - 3.91 (m, 3H), 3.84 - 3.71 (m, 3H)

[0574] Step 2 - 2-(5,6-dimethoxy-2-pyridyl)cyclohexanone

[0575] A mixture of 6-bromo-2,3-dimethoxy-pyridine (13.8 g, 63.3 mmol) , cyclohexanone (18.6 g, 190 mmol), t-BuONa (9.12 g, 94.9 mmol), Xantphos (3.66 g, 6.33 mmol) and Pd2(dba)3 (2.90 g, 3.16 mmol) in THF (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (300 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 0 / 1 to 3 / 1) to give the 2-(5,6- dimcthoxy-2-pyridyl)cyclohcxanonc (8.50 g, 51% yield) as a yellow solid.

[0576] H NMR (400 MHz, CDCI3) 5 = 7.01 (d, J= 8.0 Hz, 1H), 6.73 - 6.63 (m, 1H), 4.06 - 3.94 (m, 3H), 3.89 - 3.81 (m, 3H), 3.71 - 3.61 (m, 1H), 2.65 - 2.52 (m, 1H), 2.49 - 2.39 (m, 1H), 2.37 - 2.28 (m, 1H), 2.25 - 2.18 (m, 1H), 2.11 - 2.02 (m, 1H), 1.90 - 1.82 (m, 1H), 1.80 - 1.68 (m, 2H)

[0577] Step 3 - 2- [ 1 -( 5, 6-dimethoxy-2-pyridyl}-2-oxo-cyclohexyl] acetonitrile

[0578] To a solution of 2-(5,6-dimethoxy-2-pyridyl)cyclohexanone (8.50 g, 36.1 mmol) in DMF (50 mL) was added NaH (1.73 g, 43.4 mmol) at 0 °C , then the mixture was stirred at 0 °C for 30 minutes. After that, the mixture was added 2-chloroacetonitrile (5.46 g, 72.3 mmol). The mixture was stirred at 25 °C for 1 .5 hours. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (300 mL). The organic layers was dried hy sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 5:1) to give the 2-[l-(5,6-dimethoxy-2- pyridyl)-2-oxo-cyclohexyl] acetonitrile (2.85 g , 26% yield) as a yellow oil.

[0579] *H NMR (400 MHz, CDC13) 5 = 7.08 ( d, 7 = 8.0 Hz, 1H), 6.88 (d, 7= 8.0 Hz, 1H), 3.91 (d, 7 = 18.0 Hz, 6H), 2.99 (d, 7= 10.8 Hz, 1H), 2.84 - 2.69 (m, 2H), 2.45 - 2.33 (m, 2H), 2.02 (d, 7= 3.6 Hz, 1H), 1.84 - 1.68 (m, 4H)

[0580] Step 4 - 3a-(5,6-dimethoxy-2-pyridyl)-2,3,4,5,6,7-hexahydroindole

[0581] To a solution of 2-[l-(5,6-dimethoxy-2-pyridyl)-2-oxo-cyclohexyl]acetonitrile (2.80 g, 9.35 mmol) in MeOH (15 mL) was added Raney-Ni (93.7 mg, 1 .09 mmol). The mixture was stirred at 50 °C for 16 hours under H2 (50PSI) atmosphere. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. to give the 3a-(5,6-dimethoxy-2-pyridyl)- 2,3,4,5,6,7-hexahydroindole (2.80 g, 63% yield) as a yellow oil.

[0582] LC-MS (ESI+) m / z 263.2 (M+H)+.

[0583] Step 5 - 3a-(5,6-dimethoxy-2-pyridyl)-l,2,3,4,5,6,7,7a-octahydroindole To a solution of 3a-(5,6-dimethoxy-2-pyridyl)-2,3,4,5,6,7-hexahydroindole (2.80 g, 10.76 mmol) in DCM (28 mL) was added NaBHaCN (1.35 g, 21.5 mmol) and AcOH (64.6 mg, 1.08 mmol). T he mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture was filtered, c oncentrated in vacuo to give 3a-(5,6-dimethoxy-2-pyridyl)-l,2,3,4,5,6,7,7a-octahydroindole (2.8 0 g, 60% yield) as a yellow oil.

[0584] LC-MS (ESI+) m / z 261.2 (M+H)+.

[0585] Step 6 - 3a-(5,6-dimethoxy-2-pyridyl}-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole

[0586] 8 9

[0587] To a solution of 3a-(5,6-dimethoxy-2-pyridyl)-l,2,3,4,5,6,7,7a-octahydroindole (2.80 g, 10.67 m mol) in DCM (38 mL) was added HCHO (641 mg, 21.4 mmo) for 0.2 hours. The mixture was ad ded NaBHaCN (1.34 g, 21.4 mmol). The mixture was stirred at 25 °C for 0.3 hours. On completi on, the mixture was poured to the water (10 mL) and extracted with ethyl acetate (30 mL). The o rganic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cis (250*70mm,10 um);mo bile phase: [water(FA)-ACN];gradient:8%-38% B over 20 min) and (basic condition) to give the 3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole

[0588] (600 mg, 19 % yield) as a yellow oil.

[0589] LC-MS (ESI+) m / z 277.3 (M+H)+;

[0590] Step 7- rac-(3aR,7aS)-3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole

[0591] & rac-( 3aS, 7aR )-3a-( 5, 6-dimethoxy-2-pyridyl}-l -methyl -3, 4.5, 6, 7, 7a-hexahydro-2H-indole

[0592]

[0593] The 3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indoleseparated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%N H3H2O)];B%:45%, isocratic elution mode), to give the rac-(3aR,7aS)-3a-(5,6-dimethoxy-2-pyrid yl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (102 mg, 17% yield) as a colourless oil. And rac- (3aS,7aR)-3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (100 mg, 1 6% yield) as a yellow gum. rac-(3aR,7aS)-3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (retention time: 2.211 min): LC-MS (ESI+) m / z 277.2 (M+H)+.

[0594] NMR (400 MHz, CDCh) 5 = 7.01 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 8.0 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.27 (d, J = 1.4 Hz, 1H), 2.82 (d, J = 2.0 Hz, 1H), 2.34 (s, 3H), 2.09 (d, J = 13.5 Hz, 1H), 1.98 - 1.76 (m, 4H), 1.75 - 1.48 (m, 4H), 1.41 - 1.33 (m, 1H), 1.31 - 1.07 (m, 1H) rac-(3aS,7aR)-3a-(5,6-dimethoxy-2-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (retention time: 2.423 min): LC-MS (ESI+) m / z 277.2 (M+H)+.

[0595] !H NMR (400 MHz, CDCh) 5 = 6.99 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H), 3.36 - 3.13 (m, 1H), 2.79 (s, 1H), 2.38 - 2.25 (m, 4H), 2.08 (d, J= 13.2 Hz, 1H), 1.96 - 1.75 (m, 4H), 1.74 - 1.63 (m, 1H), 1.62 - 1.45 (m, 2H), 1.41 - 1.31 (m, 1H), 1.28 - 1.12 (m, 1H)

[0596] Example 17: Synthesis of Rac-(3aS,7aS)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl- 3.4.5.6.7,7a-hexahydro-2H-indole and Rac-(3aR,7aR)-3a-(2,3-dihydro-l,4-benzodioxin-6- yl)- l-methyl-3,4,5,6,7,7a -hexahydro-2H-indole

[0597] Step 1 -2-(2,3-Dihydro-l A-benzodioxin-6-yl)cyclohexancme

[0598] 1 3

[0599] A mixture of 2,3-dihydro-l,4-benzodioxin-6-ylboronic acid (10.1 g, 56.1 mmol), 2- chlorocyclohexanone (6.20 g, 46.8 mmol, 5.34 mL), NaiCCh (7.43 g, 70.1 mmol) and in HFIP (130 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 16 hours under N2 atmosphere. The filter liquor were collected by filtration. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ethergradient @ 60 mL / min) to give the compound 2- (2,3-dihydro-l,4-benzodioxin-6-yl)cyclohexanone (9 g, 75% yield) as a white solid.

[0600] 1H NMR (400 MHz, CDC13) 8 6.74 (d, 7= 8.4 Hz, 1H), 6.58 (d, 7= 2.0 Hz, 1H), 6.53 (dd, 7 = 2.0, 8.4 Hz, 1H), 4.16 (s, 4H), 3.47 - 3.39 (m, 1H), 2.42 (t, 7 = 3.2 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.21 - 2.12 (m, 1H), 2.09 - 2.01 (m, 1H), 1.94 - 1.86 (m, 2H), 1.76 - 1.68 (m, 2H).

[0601] To a solution of 2-(2,3-dihydro-l,4-benzodioxin-6-yl)cyclohexanone (7 g, 30.1 mmol) in DMF (80 mL) was added NaH (1.81 g, 45.2 mmol, 60% purity) at 0 °C. After addition, the mixture was stirred at this temperature for 30 minutes, and then 2-chloroacetonitrile (2.73 g, 36.2 mmol, 2.29 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was addition water 10 mL and then extracted with ethyl acetate 300ml (lOOmL *3). The combined organic layers were washed with brine (lOOmL *2), dried over, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, Eluent of 0-15% Ethyl acctatc / Pctrolcum cthcrgradicnt @ 60 mL / min) to give the compound 2-[l-(2,3- dihydro-l,4-benzodioxin-6-yl)-2-oxo-cyclohexyl]acetonitrile (3.9 g, 40% yield) as a yellow oil.

[0602] NMR (400 MHz, CDC13) 86.81 (d, J= 8.4 Hz, 1H), 6.67 (d, 7= 2.4 Hz, 1H), 6.61 - 6.57 (m, 1H), 4.23 - 4.16 (m, 4H), 2.83 - 2.76 (m, 1H), 2.68 - 2.53 (m, 2H), 2.37 - 2.31 (m, 1H), 2.30 - 2.24 (m, 1H), 1.97 (s, 2H), 1.79 - 1.71 (m, 2H), 1.67 - 1.60 (m, 1H).

[0603] To a solution of 2-[l-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-oxo-cyclohexyl]acetonitrile (3.5 g, 12.90 mmol) in MeOH (5 mL) was added Raney-Ni (221 mg, 2.58 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi) at 25 °C for 16 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give the compound 3a-(2,3-dihydro-l,4-benzodioxin -6-yl)- 2, 3, 4, 5, 6, 7 - hcxahydroindolc (2.8 g, 71% yield) as a yellow oil.

[0604] LC-MS (ESI+) m / z 258.2 (M+H)+.

[0605] Step3-3A-(2,3-dihydro-l,4-benzodioxin-6-yl)-l,2,3,4,5,6,7,7a-octahydroindole To a solution of 3a-(2,3-dihydro- l ,4-benzodioxin-6-yl)-2,3,4,5,6,7-hexahydroindole (2.8 g, 10.9 mmol) in DCM (40 mL) was added NaBHaCN (2.05 g, 32.6 mmol) and AcOH (653 mg, 10.9 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was added water 10 mL at 25 °C, and extracted with ethyl acetate 120 mL (40 mL * 3). The combined organic layers were washed with brine 40 mL (20 mL * 2), dried over, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed - phase HPLC (0.1% FA condition) to give the compound rac-(3aS,7aS) -3a-(2,3-dihydro-l,4- benzodioxin-6- yl)- l,2,3,4,5,6,7,7a-octahydroindole (1.5 g, 87% yield) as a yellow oil.

[0606] !H NMR (400 MHz, DMSO-ri6) 6 6.89 (d, J = 1.6 Hz, 1H), 6.83 (s, 2H), 4.22 (s, 4H), 3.86 (s, 1H), 3.35 - 3.12 (m, 3H), 2.14 (s, 1H), 1.95 (s, 1H), 1.90 - 1.81 (m, 1H), 1.77 (d, J = 4.0 Hz, 2H), 1.69 - 1.54 (m, 2H), 1.48 - 1.37 (m, 2H), 1.09 (d, J= 10.4 Hz, 1H).

[0607] To a solution of rac-(3aS,7aS)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l,2,3,4,5,6,7,7a- octahydroindole (1.50 g, 5.78 mmol) in DCM (10 mL) was added dropwise AcOH (694 mg, 11.6 mmol) and HCHO (174 mg, 5.78 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 30 minutes, and then NaBFTCN (1.09 g, 17.4 mmol) was added at 25 °C. The resulting mixture was stir red at 25 °C for 1 hour. The reaction mixture was added water 2 mL at 25°C, dried over and concentrated under reduced pressure to give a residue. The crude product was purified by reversed -phase HPLC (0.1% FA condition). Compound 3a-(2,3-dihydro -1,4- benzodioxin -6-yl)- 1 -methyl- 3, 4, 5, 6, 7,7a-hexahydro-2H-indole (1 g, 57% yield) was obtained as a yellow oil.

[0608] NMR (400 MHz, CDC13) 5 11.49 - 10.38 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 - 6.68 (m, 2H), 4.23 (s, 4H), 4.18 - 4.12 (m, 1H), 3.50 (s, 1H), 2.96 (s, 1H), 2.88 (s, 3H), 2.13 (s, 4H), 2.01 (s, 2H), 1.97 - 1.88 (m, 1H), 1.78 (d, J = 14.4 Hz, 2H), 1.66 - 1.50 (m, 2H), 1.25 - 1.13 (m, 1H). Step3-Rac-(3aS,7aS)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a-hexahydro-

[0609] 2H-indole & Rac-(3aR,7aR)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a - hexahydro-2H-indole

[0610] 3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (200 mg, 731 .61 pmol) was separated by SFC(column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:35%, isocratic elution mode) to give the compound rac-(3aS,7aS)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl- 3,4,5,6,7,7a-hexahydro-2H-indole (29.36 mg, 14% yield) as a yellow gum and compound rac- (3aR,7aR) -3a- (2,3-dihydro -1,4- benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (59.08 mg, 28% yield, FA salt) as a yellow gum.

[0611] Rac-(3aS,7aS)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indole (retention time: 1.560 min): LC-MS (ESI+) m / z 274.2 (M+H)+.

[0612] *H NMR (400 MHz, CDC13) 86.93 - 6.78 (m, 3H), 4.28 (s, 4H), 3.39 (d, J = 5.2 Hz, 1H), 2.73 (s, 1H), 2.43 (s, 3H), 2.28 - 2.14 (m, 1H), 1.95 (d, J= 10.4 Hz, 1H), 1.85 (s, 3H), 1.66 (d, J= 10.4 Hz, 2H), 1.52 (d, J= 12.8 Hz, 1H), 1.43 (d, J = 2.4 Hz, 1H), 1.31 - 1.17 (m, 2H)

[0613] Rac-(3aR,7aR)-3a-(2,3-dihydro-l,4-benzodioxin-6-yl)-l-methyl-3,4,5,6,7,7a -hexahydro- 2H-indole (retention time: 1.71 min): LC-MS (ESI+) m / z 274.2 (M+H)+

[0614] NMR (400 MHz, CDC13) 8 10.93 - 10.46 (m, 1H), 6.94 - 6.86 (m, 1H), 6.82 - 6.75 (m, 2H),

[0615] 4.34 - 4.27 (m, 1H), 4.30 (s, 2H), 4.25 - 4.16 (m, 1H), 3.63 - 3.54 (m, 1H), 3.10 - 2.99 (m, 1H),

[0616] 2.98 - 2.93 (m, 3H), 2.27 (s, 4H), 2.21 - 2.20 (m, 1H), 2.26 - 2.18 (m, 2H), 2.17 - 2.12 (m, 1H), 2.16 - 2.1 1 (m, 1H), 2.10 - 2.06 (m, 1H), 2.05 - 1.96 (m, 1H), 1.90 - 1.77 (m, 2H), 1.72 - 1.55 (m,

[0617] 2H), 1.31 - 1.24 (m, 1H), 1.32 (s, 1H)

[0618] Example 18: Synthesis of 5-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3 -dimethyl-pyrazolo[3,4-b]pyridine &5- [(3aR,7aR)- 1 -met hyl-3,4,5,6,7,7a-hexahyd ro-2 H-ind ol-3a-yl]-l,3-dhnethyl-pyrazolo[3,4-b]pyridine

[0619] Step 1 - l-( 5 -bromo-2-fluoro-3 -pyridyl) ethanol

[0620] To a solution of 5-bromo-2-fluoro-pyridine-3-carbaldehyde (45.0 g, 221 mmol) in THF (450 mL) was added MeMgBr (3 M, 110 mL) at -78 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was poured to the water (500 mL) and extracted with ethyl acetate (1.5 L). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the l-(5-bromo-2-fluoro-3-pyridyl) ethanol (27.0 g, 53% yield) as a yellow oil. *H NMR (400 MHz, CDC13) 5 - 8.14 - 8.04 (m, 2H), 5.07 (d, 7 - 6.0 Hz, 1H), 3.29 (s, 1H), 1.47 (d, 7= 6.4 Hz, 3H)

[0621] Step 2 - l-(5-bromo-2-fluoro-3-pyridyl)ethanone

[0622] To a solution of l-(5-bromo-2-fluoro-3-pyridyl) ethanol (26.0 g, 118 mmol) in DCM (260 mL) was added DMP (75.2 g, 177 mmol). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was poured to the water (500 mL) and extracted with ethyl acetate (1500 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:1) to give the l-(5-bromo-2-fluoro-3-pyridyl)ethanone (18.5 g, 57% yield) as a white solid.

[0623] H NMR (400 MHz, CDCI3) 5 = 10.23 (s, 1H), 8.58 - 8.28 (m, 3H), 2.66 (d, 7= 4.8 Hz, 3H)

[0624] Step 3 - 5-bromo-l ,3-dimethyl-pyrazolo{ 3,4-b]pyridine

[0625] To a solution of l-(5-bromo-2-fluoro-3-pyridyl)ethanone (18.5 g, 84.9 mmol) in butan-l-ol (250 mL) was added methylhydrazine (19.5 g, 170 mmol). The mixture was stirred at 150 °C for 4 hours. On completion, the mixture was poured to aq NH4CI (200 mL) to adjust pH=6, then 200 ml aq NaHCO-. was added to mixture to adjust pH =7 and extracted with ethyl acetate (1200 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiOi, petroleum ether: ethyl acetate = 0:1) to give the 5-bromo-l,3-dimethyl-pyrazolo[3,4-b]pyridine (22.0 g, 80% yield) as a white solid.

[0626] ’H NMR (400 MHz, CDCI3) 5 = 8.47 (d, 7= 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 4.02 (s, 3H), 2.49 (s, 3H)

[0627] Step 4 - 2-( 1 ,3-dimethylpyrazolo[ 3,4-b]pyridin-5-yl)cyclohexanone

[0628] A mixture of 5-bromo-l,3-dimcthyl-pyrazolo[3,4-b]pyridinc (22.0 g, 97.3 mmol), cyclohexanone (11.5 g, 117 mmol), Pd(OAc)i (1.09 g, 4.86 mmol), t-BuONa (14.0 g, 146 mmol) and t-BusP (1.97 g, 9.74 mmol) in THF (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured to the water (200 mL) and extracted with ethyl acetate (600 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate=O / l to 3 / 1) to give the 2-(l,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)cyclohexanone (1.70 g, 7.0% yield) as a yellow solid.

[0629] LC-MS (ESI+) m / z 243.9 (M+H)+;

[0630] *H NMR (400 MHz, CDCI3) 5 - 8.20 (d, 7 - 1.2 Hz, 1H), 7.70 (d, 7= 1.6 Hz, 1H), 4.00 (s, 3H), 3.76 - 3.50 (m, 1H), 2.65 - 2.38 (m, 5H), 2.35 - 2.24 (m, 1H), 2.20 - 2.10 (m, 1H), 2.01 - 1.94 (m, 2H), 1.86 - 1.73 (m, 2H)

[0631] Step 5 - 2-[ l-( l,3-dimethylpyrazolo[3,4-blpyridin-5-yl)-2-oxo-cyclohexyl]acetonitrile

[0632] 7 9

[0633] To a solution of 2-(l,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)cyclohexanone (1.70 g, 6.99 mmol) in DMF (17 mL) was added NaH (419 mg, 10.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The mixture was added 2-iodoacetonitrile (2.33 g, 14.0 mmol). The mixture was stirred at 25 °C for 1.5 hours. On completion, the mixture was poured to the water (30 mL) and extracted with ethyl acetate (150 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (TFA condition) to give the 2-[l-(l,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)-2-oxo- cyclohexyl] acetonitrile (850 mg, 41% yield) as a yellow oil.

[0634] H NMR (400 MHz, CDCI3) 5 = 8.42 (d, 7= 2.0 Hz, 1H), 7.92 (d, 7 = 2.2 Hz, 1H), 4.11 (s, 3H), 3.20 - 3.06 (m, 1H), 2.91 - 2.76 (m, 2H), 2.60 (s, 3H), 2.51 - 2.33 (m, 2H), 2.19 - 1.67 (m, 5H)

[0635] Step 6 - 5-(2,3,4,5,6,7-hexahydroindol-3a-yl}-l ,3-dimethy-pyrazolo[ 3,4-blpyridine

[0636]

[0637] To a solution of 2-[l-(l ,3-dimethylpyrazolo[3,4-b]pyridin-5-yl)-2-oxo-cyclohexyl]acetonitrile (850 mg, 2.86 mmol) in MeOH (10 mL) was added Raney-Ni (27.3 mg, 319 pmol). The mixture was stirred at 50 °C for 16 hours under H2(50PSI) atmosphere. On completion, The reaction mixture was filtered, concentrated in vacuo to give the 5-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,3- dimethy -pyrazolo[3,4-b]pyridine (800 mg, 75% yield) as a yellow oil.

[0638] LC-MS (ESI+) m / z 269.3 (M+H)+;

[0639] To a solution of 5-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l,3-dimethyl-pyrazolo[3,4-b]pyridine (800 mg, 2.98 mmol) in DCM (4 mL) was added NaBHaCN (281 mg, 4.47 mmol). The mixture was stirred at 25 °C for 15 minutes. On completion, the reaction mixture was filtered, concentrated in vacuo to give 5-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l,3-dimethyl-pyrazolo[3,4-b]pyridine (800 mg, 50% yield,) as a yellow oil.

[0640] LC-MS (ESI+) m / z. T1\A (M+H)+;

[0641] Step 8 1 ,3-dimethyl-5-( 1 -methyl-3 ,4,5,6,7 ,7a-hexahydro-2H-indol-3a-yl)pyrazolol 3 ,4-b]pyridine

[0642]

[0643] 11 12

[0644] To a solution of 5-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l,3-dimethyl-pyrazolo[3,4-b]pyridine (800 mg, 2.96 mmol) in DCM (8 mL) was added HCHO (107 mg, 3.55 mmol) for 0.2 hours.

[0645] The mixture was added NaBJTCN (372 mg, 5.92 mmol) and AcOH (178 mg, 2.96 mmol). The mixture was stirred at 25 °C for 0.3 hours. On completion, the mixture was poured to water (8 mL) and extracted with DCM (40 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prcp-HPLC (c olumn: CD04-Welch Utimate Cis 150*25*7um;mobile phase: [water(FA)-ACN] gradient: l%-30 % B over 8 min) to give l,3-dimethyl-5-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyraz olo[3,4-b]pyridine (140 mg, 16% yield) as a white solid.

[0646] LC-MS (ESI+) m / z 285.2 (M+H)+;

[0647] Step 9- 5-[(3aS,7aS)-]-methyl-3,4,5,6,7,7a4iexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolof3, 4-b Ipyridine &5-[ ( 3aR, 7aR)-l -methyl-3,4.5,6, 7, 7 a-hexahydro-2H-indol-3a-yl ]-l,3-dimethyl-pyr azolo! 3 ,4-bi pyridine The 1 ,3-dimethyl-5-(l -methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrazolo[3,4-b]pyridine w as separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobilc phase: [CO2-MeOH(0.1%NH3H2O)];B%:20%, isocratic elution mode) to give the 5-[(3aS,7aS)-l-meth yl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-b]pyridine (48 mg, 33% yi eld,) as a yellow gum and 5-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-di methyl-pyrazolo[3,4-b]pyridine (43 mg, 29% yield) as a yellow gum.

[0648] 5-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4- b]pyridine (retention time: 0.898 min): LC-MS (ESI+) m / z 285.2 (M+H)+.

[0649] *H NMR (400 MHz, CDCh) 5 = 8.59 (d, 7= 2.0 Hz, 1H), 7.91 (d, 7 = 2.0 Hz, 1H), 4.08 (s, 3H), 3.43 - 3.22 (m, 1H), 2.73 (d, 7= 8.0 Hz, 1H), 2.58 (s, 3H), 2.48 - 2.29 (m, 4H), 2.15 - 1.98 (m, 3H), 1.97 - 1.82 (m, 2H), 1.71 - 1.65 (m, 1H), 1.55 (d, 7= 15.2 Hz, 2H), 1.41 (d, 7= 3.2 Hz, 1H), 1.25 - 1.05 (m, 1H)

[0650] 5-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-b ]pyridine (retention time: 1.108 min): LC-MS (ESI+) m / z 285.2 (M+H)+.

[0651] 'H NMR (400 MHz, CDCh) 5 = 8.59 (d, 7= 2.0 Hz, 1H), 7.91 (d, 7= 2.0 Hz, 1H), 4.08 (s, 3H), 3.32 (s, 1H), 2.82 - 2.65 (m, 1H), 2.58 (s, 3H), 2.37 (s, 4H), 2.10 - 1.96 (m, 3H), 1.95 - 1.77 (m, 2H), 1.66 - 1.60 (m, 2H), 1.56 (s, 1H), 1.41 (d, 7 = 3.6 Hz, 1H), 1.23 - 1.06 (m, 1H)

[0652] Example 19: Synthesis of l-methyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl]benzimidazole and l-methyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro- 2H-indol-3a-yl]benzimidazole

[0653] Step 1 - 2-(3-methylbenzimidazol-5-yl)cyclohexanone A mixture of 6-bromo-l-methyl-benzimidazole (10 g, 47.4 mmol), cyclohexanone (13.9 g, 142 mmol, 14.7 mL), t-BuONa (6.83 g, 71.1 mmol), Pd2(dba)3(2.17 g, 2.37 mmol) and x-antphos (2.74 g, 4.74 mmol) in THF (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 hours under N2 atmosphere. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0:1) to give the 2-(3- methylbenzimidazol-5-yl)cyclohexanone (8 g, 62% yield) as a yellow solid.

[0654] LC-MS (ESI+) m / z 229.1 (M+H)+;

[0655] ^ NMR (400 MHz, CDC13) 57.94 (s, 1H), 7.76 (d, 7= 8.4 Hz, 1H), 7.21 (s, 1H), 7.11 - 7.04 (m, 1H), 3.86 - 3.82 (m, 3H), 3.82 - 3.76 (m, 1H), 2.61 - 2.47 (m, 2H), 2.39 - 2.34 (m, 1H), 2.27 - 2.05 (m, 3H), 1.94 - 1.80 (m, 2H)

[0656] Step 2 - 2-[ l-(3-methylbenzimidazol-5-yl}-2-oxo-cyclohexyl]acetonitrile

[0657] To a solution of 2-(3-methylbenzimidazol-5-yl)cyclohexanone (8 g, 35.0 mmol) in THF (80 mL) was added dropwise t-BuOK (I M, 52.6 mL) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-iodoacetonitrile (7.61 g, 45.6 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 0:1) to give the 2-[l-(3-methylbenzimidazol-5-yl)-2-oxo-cyclohexyl]acetonitrile (7 g, 65% yield) as a yellow oil. LC-MS (ESI+) m / z 268.0 (M+H)+;

[0658] H NMR (400 MHz, CDCI3) 5 8.29 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.31 (s, 1H), 7.21 - 7.14 (m, 1H), 3.93 (s, 3H), 3.17 - 3.03 (m, 1H), 2.80 (d, J = 1.2 Hz, 2H), 2.43 (br d, 7 = 4.6 Hz, 1H), 2.40 (br d, 7= 5.4 Hz, 1H), 2.04 - 1.93 (m, 2H), 1.92 - 1.88 (m, 1H), 1.87 - 1.70 (m, 2H) Step 3 - 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l-methyl-benzimidazole

[0659] 5 6

[0660] To a solution of 2-[l-(3-methylbenzimidazol-5-yl)-2-oxo-cyclohexyl]acetonitrile (1 g, 3.74 mmol) in MeOH (10 mL) was added Raney-Ni (160 mg, 1.87 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi ) at 60 °C for 12 hours. On completion, the reaction mixture was filtered, concentrated in vacuo to give the 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l-methyl-benzimidazole (800 mg, 42% yield) as a yellow oil.

[0661] LC-MS (ESI+) m / z 254.1 (M+H)+;

[0662] Step 4 - 6-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l-methyl-benzimidazole

[0663] To a solution of 6-(2,3,4,5,6,7-hexahydroindol-3a-yl)-l-methyl-benzimidazole (800 mg, 3.16 mmol) in DCM (8 mL) was added NaBTLCN (595 mg, 9.47 mmol) and AcOH (190 mg, 3.16 mmol, 181 p.L). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured to the water (20 mL) and extracted with DCM (20 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the 6-(l,2,3,4,5,6,7,7a- octahydroindol-3a-yl)-l-methyl-benzimidazole (800 mg, 23% yield) as a yellow solid.

[0664] LC-MS (ESI+) m / z 256.2 (M+H)+; Step 5 - l-methyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)benzimidazole

[0665] 7 8

[0666] To a solution of 6-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-l-methyl-benzimidazole (800 mg, 3.13 mmol) in DCM (8 mL) was added dropwise HCHO (627 mg, 6.27 mmol, 575 pL, 30% purity) and AcOH (376 mg, 6.27 mmol, 359 pL) at 25 °C. After addition, the mixture was stirred at this temperature for 30min, and then NaBfTCN (591 mg, 9.40 mmol) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) and reversed-phase HPLC (0.1% NH4HCO3 condition), to give the l-methyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a- yl)benzimidazole (100 mg, 12% yield) as a yellow solid.

[0667] LC-MS (ESI+) m / z 270.4 (M+H)+;

[0668] ^ NMR (400 MHz, DMSO-de) 8 8.10 (s, 1H), 7.57 (d, 7= 8.4 Hz, 1H), 7.48 (d, 7= 1.4 Hz, 1H), 7.29 - 7.16 (m, 1H), 3.83 (s, 3H), 3.22 - 3.08 (m, 1H), 2.72 (br s, 1H), 2.33 - 2.18 (m, 4H), 2.08 - 1.98 (m, 1H), 1.97 - 1.68 (m, 4H), 1.65 - 1.46 (m, 2H), 1.42 (br d, J= 13.6 Hz, 1H), 1.34 - 1.21 (m, 1H), 1.14 - 0.98 (m, 1H)

[0669] Step 6- l-methyl-6-frac-(3aS,7aS}-l-methyl-3,4.5,6,7,7a-hexahydro-2H-indol-3a- yl Ibenzimidazole & 1 -melhyl-6-[ rac-( 3aR, 7aR)-l -methyl- 3, 4, 5, 6, 7, 7a-hexahydro-2H-indol-3a- yllbenzimidazole

[0670]

[0671] The l-methyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)benzimidazole was separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:25%, isocratic elution mode) and purified by prep-HPLC (column: CD07-DaisogclSP-100-8-ODS-PK150*25*10um;mobilcphasc:[watcr(NH4HC03)-

[0672] ACN];gradient:8%-38% B over 10 min) to give the l-methyl-6-[rac-(3aS,7aS)-l-methyl- 3,4,5,6,7,7a-hexahydro- 2H-indol-3a-yl]benzimidazole (15.1 mg, 13% yield) as a yellow gum and 1-methyl- 6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]benzimidazole (35.35 mg, 35% yield) as a yellow gum. l-methyl-6-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]benzimidazole (retention time: 1.476 min): LC-MS (ESI+) m / z 270.2 (M+H)+.

[0673] NMR (400 MHz, CDC13) 57.91 (s, 1H), 7.79 (d, J= 8.6 Hz, 1H), 7.33 (s, 1H), 7.26 (br d, J = 1.6 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.88 (s, 3H), 3.45 (br s, 1H), 2.88 - 2.66 (m, 4H), 2.31 - 2.22 (m, 1H), 2.21 - 2.02 (m, 4H), 2.00 - 1.82 (m, 2H), 1.68 - 1.56 (m, 1H), 1.56 - 1.46 (m, 1H), 1.32 - 1.13 (m, 1H) l-methyl-6-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]benzimidazole (retention time: 1.740 min): LC-MS (ES1+) m / z 270.2 (M+H)+.

[0674] *H NMR (400 MHz, CDCI3) 57.84 (s, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.40 - 7.30 (m, 2H), 3.86 (s, 3H), 3.32 (br d, J= 3.6 Hz, 1H), 2.77 (br s, 1H), 2.46 - 2.31 (m, 4H), 2.14 - 2.02 (m, 2H), 2.02 - 1.96 (m, 1H), 1.93 - 1.85 (m, 2H), 1.74 - 1.68 (m, 1H), 1.66 - 1.57 (m, 1H), 1.57 - 1.48 (m, 1H), 1.47 - 1.36 (m, 1H), 1.25 - 1.12 (m, 1H) Example 20: Synthesis of 6-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a- yl] quinoxaline & 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]quinoxaline

[0675] Step 1 - 2-quinoxalin-6-ylcyclohexanone

[0676] A mixture of 6-bromoquinoxaline (10 g, 47.8 mmol), cyclohexanone (5.63 g, 57.4 mmol, 5.95 mL), Pd(OAc)2 (537 mg, 2.39 mmol), t-BuONa (6.90 g, 71.8 mmol) and t-BuaP (9.68 g, 4.78 mmol, 11.2 mL, 10% purity) in THF (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1) to give the 2-quinoxalin- 6-ylcyclohexanone (2.8 g, 23.8% yield) as a yellow oil.

[0677] LC-MS (ESI+) m / z 227.0 (M+H)+;

[0678] NMR (400 MHz, CDCh) 5 8.83 (s, 2H), 8.09 (d, J= 8.6 Hz, 1H), 7.89 (d, J= 1.6 Hz, 1H), 7.63 - 7.55 (m, 1H), 3.97 - 3.79 (m, 1H), 2.66 - 2.49 (m, 2H), 2.47 - 2.37 (m, 1H), 2.29 - 2.21 (m, 1H), 2.20 - 2.13 (m, 1H), 2.13 - 2.07 (m, 1H), 1.98 - 1.86 (m, 2H)

[0679] Step 2 - 2-allyl-2-quinoxalin-6-yl-cyclohexannne

[0680] 3 5

[0681] To a solution of 2-quinoxalin-6-ylcyclohexanone (2.2 g, 9.72 mmol) in THF (20 mL) was added dropwise t-BuOK (1 M in THF, 9.72 mL) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then 3-bromoprop-l-ene (1.41 g, 11.7 mmol) was added drop wise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (50 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the 2-allyl-2-quinoxalin- 6-yLcyclohexanone (2.4 g, 83% yield) as a yellow oil.

[0682] LC-MS (ESI+) m / z 267.1 (M+H)+;

[0683] *H NMR (400 MHz, CDCI3) 5 8.86 (d, J = 1.0 Hz, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.60 - 7.51 (m, 1H), 5.54 - 5.39 (m, 1H), 4.97 - 4.83 (m, 2H), 2.91 - 2.78 (m, 1H), 2.70

[0684] - 2.61 (m, 1H), 2.61 - 2.50 (m, 1H), 2.45 - 2.36 (m, 1H), 2.35 - 2.25 (m, 1H), 2.03 - 1.95 (m, 1H), 1.91 - 1.82 (m, 3H), 1.76 (br s, 1H)

[0685] Step 3 - 2-(2-oxo-l-quinoxalin-6-yl-cyclohexyl}acetaldehyde

[0686] To a solution of 2-allyl-2-quinoxalin-6-yl-cyclohexanone (1 g, 3.75 mmol) in 1,4-dioxane (9 mL) was added dropwise 2,6-LUTIDINE (805 mg, 7.51 mmol, 875 pL) and H2O (3 mL). Then, the mixture reaction was added K2OSO4.2H2O (55.3 mg, 150 pmol) and NalCL (402 mg, 1.88 mmol, 104 pL) at 25 °C. After addition, the mixture was stirred at this temperature for 30 min, and then NalCE (2.81 g, 13.1 mmol, 728 pL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. On completion, the mixture was poured to the aq.Na2SO3 (100 mL) and extracted with ethyl acetate (100 mL*3). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:2) to give the 2-(2-oxo-l- quinoxalin-6-yl-cyclohcxyl)acctaldchydc (270 mg, 24% yield) as a yellow solid.

[0687] LC-MS (ESI+) m / z 269.2 (M+H)+;

[0688] *H NMR (400 MHz, CDCI3) 5 8.86 (d, J= 1.0 Hz, 2H), 8.10 (d, J= 8.8 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.60 - 7.51 (m, 1H), 5.54 - 5.39 (m, 1H), 4.97 - 4.83 (m, 2H), 2.91 - 2.78 (m, 1H), 2.70 - 2.61 (m, 1H), 2.61 - 2.50 (m, 1H), 2.45 - 2.36 (m, 1H), 2.35 - 2.25 (m, 1H), 2.03 - 1.95 (m, 1H), 1.91 - 1.82 (m, 3H), 1.76 (br s, 1H) Step 4 - 6-( l-methyl-3,4,5,6,7,7a4wxahydro-2H-indol-3a-yl}quinoxaline

[0689] To a solution of 2-(2-oxo-l -quinoxalin-6-yl-cyclohexyl)acetaldehyde (270 mg, 1.01 mmol) in MeOH (5 mL) was added MeNH2(2 M in THF, 1.01 mL), NaBH3CN (189 mg, 3.02 mmol) and AcOH (121mg, 2.01 mmol, 115 pL). The mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition), to give the 6-(l-methyl-3,4,5,6,7,7a- hexahydro-2H-indol-3a-yl)quinoxaline (200 mg, 67% yield) as a yellow solid.

[0690] LC-MS (ESI+) m / z 268.1 (M+H)+;

[0691] H NMR (400 MHz, CDC13) 5 8.88 (s, 2H), 8.16 (d, J= 8.8 Hz, 1H), 8.01 (s, 1H), 7.79 (br d, J = 9.0 Hz, 1H), 4.12 - 3.94 (m, 1H), 3.67 (br s, 1H), 3.42 (s, 1H), 3.11 - 2.97 (m, 1H), 2.89 (s, 3H), 2.40 - 2.25 (m, 2H), 2.14 (br d, J= 14.8 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.91 - 1.76 (m, 1H), 1.72 - 1.57 (m, 2H), 1.29 - 1.14 (m, 1H)

[0692] Step 5- 6-[(3aS, 7aS}-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yllquinoxaline & 6-[(3aR,7aR)-l- methxl-3,4, 5, 6, 7, 7a-hexahydro-2H-indol-3a-yl ] quinoxaline

[0693] The 6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)quinoxaline was separated by SFC (column:

[0694] DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-

[0695] MeOH(0.1%NH3H2O)];B%:40%, isocratic elution mode ) and purified by prep-HPLC (column: CD04-

[0696] Welch Utimate C18 150*25*7um;mobile phase: [water(FA)-ACN];gradient:l%-25% B over 8 min) to give the 6-[(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]quinoxaline (24.0 mg, 11% yield) as a brown gum and 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]quinoxaline (14.7 mg, 7.2% yield) as a yellow gum.

[0697] 6-l(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]quinoxaline (retention time: 1.339 min): LC-MS (ESI+) m / z 268.2 (M+H)+.

[0698] *H NMR (400 MHz, CDCI3) 5 8.87 (s, 2H), 8.14 (d, 7 = 8.8 Hz, 1H), 8.03 (d, J= 1.4 Hz, 1H), 7.88 - 7.70 (m, 1H), 4.09 - 3.91 (m, 1H), 3.40 (br s, 1H), 2.83 - 2.67 (m, 4H), 2.36 - 2.25 (m, 1H), 2.24 - 2.08 (m, 4H), 2.02 - 1.81 (m, 2H), 1.71 - 1.59 (m, 1H), 1.59 - 1.47 (m, 1H), 1.25 - 1.10 (m, 1H)

[0699] 6-[(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]quinoxaline (retention time: 1.578 min): LC-MS (ESI+) m / z 268.2 (M+H)+.

[0700] H NMR (400 MHz, CDCI3) 5 8.83 (d, J= 5.2 Hz, 2H), 8.16 - 7.98 (m, 2H), 7.92 - 7.75 (m, 1H), 3.38 (br d, J = 1.8 Hz, 1H), 2.98 - 2.72 (m, 1H), 2.41 (br s, 4H), 2.18 - 2.00 (m, 3H), 1.94 (br d, J = 11.2 Hz, 2H), 1.73 (br d, J = 13.6 Hz, 2H), 1.57 (br d, J = 13.4 Hz, 1H), 1.49 - 1.38 (m, 1H), 1.27 - 1.11 (m, 1H)

[0701] Example 21: Synthesis of 2-methoxy-4-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl]phenol and 2-methoxy-4-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl] phenol

[0702] Step 1 - 2-(4-benzyloxy-3-methoxy-phenyl)cyclohexanone

[0703] 1 3

[0704] A mixture of (4-benzyloxy-3-methoxy-phenyl)boronic acid (4.0 g, 15.5 mmol), 2-chlorocyclohexanone (1.64 g, 12.4 mmol, 1.42 mL), NaiCCh (2.46 g, 23.2 mmol) in HFIP (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 65 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was filtered, the filtrate concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiCF, petroleum ether: ethyl acetate = 3:1) to give 2-(4- benzyloxy-3-methoxy-phenyl)cyclohexanone (3.0 g, 59% yield) as a off-white solid.

[0705] LC-MS (ESI+) m / z 311.0 (M+H)+;

[0706] 3 5

[0707] To a solution of 2-(4-benzyloxy-3-methoxy-phenyl)cyclohexanone (2.6 g, 8.38 mmol) in THF (30 mL) was added t-BuOK (1 M in THF, 12.5 mL) under N2 atmosphere. The mixture was stirred at 0 °C for 15 minutes. Then 2-iodoacetonitrile (2.10 g, 12.5 mmol) was added above mixture. The reaction mixture was stirred at 25 °C for 16 hours. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (250 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:1) to give 2-[ l-(4- bcnzyloxy-3-mcthoxy-phcnyl)-2-oxo-cyclohcxyl] acetonitrile (2.0 g, 66% yield) as a yellow oil LC-MS (ESI+) m / z. 3222 (M+ Na)+;

[0708] JH NMR (400 MHz, CDCI3) 57.42 - 7.34 (m, 2H), 7.31 (t, 7 = 7.2 Hz, 2H), 7.27 - 7.21 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 2.4, 8.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 3.80 (s, 3H), 2.89 - 2.76 (m, 1H), 2.62 (d, J = 52 Hz, 2H), 2.41 - 2.23 (m, 2H), 1.94 (ddd, J = 2.8, 6.0, 9.2 Hz, 1H), 1.85 - 1.70 (m, 3H), 1.70 - 1.58 (m, 1H).

[0709] Step 3 - 2-[ l-(4-hydroxy-3-methoxy-phenyl)-2-oxo-cyclohexyl]acetonitrile To a solution of 2-2-[l-(4-benzyloxy-3-methoxy-phenyl)-2-oxo-cyclohexyl]acetonitrile (2.5 g, 7.15 mmol) in MeOH (20 mL) was added Raney-Ni (100 mg, 192 nmol ) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 hours. On completion, the reaction liquid was filtered through the diatom soil layer in a mild N2 atmosphere, and it should be noted that the diatom soil layer should not be drained too dry. The filtrate concentrated in vacuo to give 4-(2,3,4,5,6,7-hexahydroindol-3a-yl)-2-methoxy-phenol (0.5 g, 3% yield). LC-MS (ESI+) m / z 246.0 (M+H)+;

[0710] Step 5 - l,3-dimethyl-6-(l-methyl-3,4,5,6,7, 7a-hexahydro-2H-indol-3a-yl}indaz.ole

[0711] To a solution of 4-(2,3,4,5,6,7-hexahydroindol-3a-yl)-2-methoxy-phenol (0.5 g, 2.04 mmol) in DCM (20 mL) was added NaBHaCN (449 mg, 7.15 mmol). The mixture was stirred at 0 °C for 30 minutes. Then AcOH (14.3 mg, 238 pmol) was added above mixture, the reaction mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was poured to the water (50 mL) and extracted with ethyl acetate (100 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give 4-(l,2,3,4,5,6,7,7a-octahydroindol-3a-yl)-2-methoxy- phenol (0.5 g, 25% yield) as a yellow oil

[0712] LC-MS (ESI+) m / z 248.2 (M+H)+;

[0713] Step 6 - -methoxy-4-( l-methyl-3,4,5,6,7, 7a-hexahydro-2H-indol-3a-yl)phenol

[0714]

[0715] 8 9

[0716] To a solution of 4-(l,2,3,4,5,6,7,7a-octahydroindoL3a-yl)-2-methoxy-phenol (0.5 g, 2.02 mmol), AcOH (242 mg, 4.04 mmol, 231 pL) in DCM (10 mL) was added HCHO (404 mg, 4.04 mmol, 371 pL, 30% purity). The mixture was stirred at 0 °C for 30 minutes. Then NaBHsCN (381 mg, 6.06 mmol) was added above mixture. The reaction mixture was stirred at 0 °C for 0.5 hours. On completion, the mixture was poured to the water (50 mL) and extracted with ethyl acetate (60 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 2-methoxy-4-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol -3a-yl)phenol (150 mg, 25 % yield) as a pink oil.

[0717] LC-MS (ESI+) m / z 262.0(M+H)+;

[0718] !H NMR (400 MHz, CDCh) 5 6.82 (d, J= 9.2 Hz, 1H), 6.76 - 6.66 (m, 2H), 4.05 - 3.92 (m, 1H), 3.84 (s, 3H), 3.27 (s, 1H), 2.80 - 2.59 (m, 4H), 2.16 - 2.07 (m, 1H), 2.06 - 1.95 (m, 2H), 1.95 - 1.87 (m, 2H), 1.87 - 1.73 (m, 2H), 1.58 - 1.47 (m, 1H), 1.47 - 1.38 (m, 1H), 1.34 - 0.98 (m, 2H).

[0719] Step 7- 2-methoxy-4-frac-(3aS,7aS}-l-methNl-3,4,5,6,7, 7a-hexahydro-2H-mdol-3a-yl]phenol and 2- methoxy-4-f rac-( 3aR, 7aR)-l -methyl-3,4,5,6, 7, 7a-hexahydro-2H-indol-3a-yl ] phenol The residue was separated by SFC (column: DAICEL CHIRALPAK IK(250mm*30mm,10um);mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:30%, isocratic elution mode) to give 2-methoxy-4-[rac- (3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]phenol (47.4 mg, 45 % yield) as a white solid and t2-methoxy-4-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro -2H-indol-3a-yl]phenol (33.2 mg, 31 % yield) as a white solid

[0720] 2-methoxy-4-[rac-(3aS,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]phenol (retention time: 1.780 min): LC-MS (ESI+) m / z 262.2 (M+H)+.

[0721] H NMR (400 MHz, CDCI3) 5 6.79 (s, 3H), 3.83 (s, 3H), 3.23 (s, 1H), 2.56 (s, 1H), 2.36 - 2.17 (m, 4H), 1.87 (d, J= 5.6 Hz, 2H), 1.84 - 1.68 (m, 3H), 1.55 (d, J= 8.4 Hz, 2H), 1.42 (d, J= 12.0 Hz, 1H), 1.31 (d, 7= 3.6 Hz, 1H), 1.15 - 0.99 (m, 1H).

[0722] 2-methoxy-4-[rac-(3aR,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl] phenol (retention time: 1.904 min): LC-MS (ESI+) m / z 262.2 (M+H)+.

[0723] H NMR (400 MHz, CDCI3) 5 6.88 (s, 3H), 5.52 (s, 1H), 3.92 (s, 3H), 3.47 - 3.09 (m, 1H), 2.62 (d, 7= 4.0 Hz, 1H), 2.37 (d, J= 1.2 Hz, 4H), 1.96 (d, 7= 5.6 Hz, 2H), 1.87 (d, 7= 8.4 Hz, 3H), 1.59 - 1.46 (m, 3H), 1.41 (s, 1H), 1.26 - 1.11 (m, 1H).

[0724] Example 22: Synthesis of (3aS,7aS)-3a-(5,6-dimethoxy-3-pyridyl)-l-methyl-3,4,5,6,7,7a- hexahydro-2H-indole

[0725] Stepl - 2-(5,6-dimethoxy-3-pyridyl)cyclohexanone

[0726] 1 3

[0727] A mixture of 5-bromo-2,3-dimethoxy-pyridine (200 g, 917 mmol), cyclohexen-l-yloxy (trimethyl )silane (281 g, 1.65 mol), XPhos Pd G3 (7.76 g, 9.17 mmol,), t-BuONa (176 g, 1.83 mol) in THF (2 L) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was filtered, co nccntratcd in vacuo to give the residue. The residue was purified by column chromatography (Si O2, petroleum ether: ethyl acetate = 3:1) to give 2-(5,6-dimethoxy-3-pyridyl)cyclohexanone (155 g, 65% yield) as a yellow solid.

[0728] !H NMR (400 MHz, CDCh) 5 = 7.45 (s, 1H), 6.83 (s, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 3.61 - 3.48 (m, 1H), 2.55 - 2.37 (m, 2H), 2.29 - 2.08 (m, 2H), 2.02 - 1.88 (m, 2H), 1.85 - 1.71 (m, 2H)

[0729] Step2 - 2-allyi-2-( 5, 6-dimethoxy-3-pyridyl)cyclohexanone

[0730] 3 5

[0731] To a solution of 2-(5,6-dimethoxy-3-pyridyl)cyclohexanone (155 g, 659 mmol) in THF (1.6 L) w as added t-BuOK (1 M, 658.79 mL) at 0°C. The mixture was stirred at for 0.5 hours. Then the 3- bromoprop-l-ene (95.6 g, 791 mmol) was added the mixture at 0 °C. The mixture was stirred at 25 for 1.5 hours. On completion, the mixture was poured to the water (I L) and extracted with et hyl acetate (3 L). The organic layers was dried by sodium sulfate, filtered and concentrated in va cuo to give the residue. The residue was purified by column chromatography (SiOz, petroleum et her: ethyl acetate = 4:1) to give 2-allyl-2-(5,6-dimethoxy-3-pyridyl)cyclohexanone (153 g, 80% yield) as a yellow oil.

[0732] NMR (400 MHz, CDC13) 5 = 7.59 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.60 - 5.34 (m, 1H), 5.11 - 4.83 (m, 2H), 4.00 (s, 3H), 3.83 (s, 3H), 2.64 - 2.49 (m, 2H), 2.47 - 2.37 (m, 1H), 2.36 - 2.27 (m, 2H), 2.01 - 1.92 (m, 1H), 1.85 - 1.58 (m, 4H)

[0733] Step3 - 2-[l -( 5, 6-diniethoxy-3-pyridyl}-2-oxo-cyclohexyl lacetaldehyde

[0734] 5 6

[0735] To the solution of 2-allyl-2-(5,6-dimethoxy-3-pyridyl)cyclohexanone (153 g, 556 mmol) in DC M (1.5 L) was added ozone (26.7 g, 3 mmol) stirred at -78 °C, after addition, the mixture was stir red at this temperature for 0.5 h. then the mixture was added PPhs (291 g, 1.11 mol) at 0 °C for 0.5 hours. The mixture was stirred at 25 °C for 14.5 hours. On completion, the reaction mixture was filtered, concentrated in vacuo to give the residue. The residue was purified by column chro matography (SiOi, petroleum ether: ethyl acetate = 1:1) to give 2-[l-(5,6-dimethoxy-3-pyridyl)-2 -oxo-cyclohexyl] acetaldehyde (50 g, 31% yield) as a yellow oil.

[0736] H NMR (400 MHz, CDC13) 5 = 9.61 (t, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.79 (d, J= 2.0 Hz, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 2.81 - 2.63 (m, 3H), 2.48 - 2.38 (m, 2H), 2.13 - 2.03 (m, 1H), 2.02 - 1.96 (m, 1H), 1.87 - 1.69 (m, 3H)

[0737] 6 7

[0738] To a solution of 2-[l-(5,6-dimethoxy-3-pyridyl)-2-oxo-cyclohexyl]acetaldehyde (50 g, 180. mm ol)in MeOH (500 mL) was added MeNH2 (30% purity, 37.3 g, 361 mmol) and AcOH (21.7 g, 3 61 mmol) at 25 °C for 30 minutes. The mixture was added NaBHaCN (22.7 g, 361 mmol). The mixture was stirred at 25 °C for 15.5 hours. On completion, the mixture was poured to the NaH CO3 (500 mL) and extracted with ethyl acetate (2000 mL). The organic layers was dired by sodi um sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified hy c olumn chromatography (SiCh, DCM: McOH = 10:1) to give the residue. The residue was purifi ed by prep_HPLC (fa condition) to give 3a-(5,6-dimethoxy-3-pyridyl)-l-methyl-3,4,5,6,7,7a-he xahydro-2H-indole (30 g, 57% yield) as a yellow oil.

[0739] !H NMR (400 MHz, CDCh) 5 = 7.74 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H),

[0740] 4.01 (s, 3H), 3.89 (s, 3H), 3.39 - 3.19 (m, 1H), 2.62 (s, 1H), 2.43 - 2.26 (m, 4H), 1.98 - 1.75 (m, 5H), 1.67 - 1.47 (m, 3H), 1.45 - 1.35 (m, 1H), 1.25 - 1.07 (m, 1H)

[0741] Step5 - ( 3aS,7aS)-3a-( 5,6-dimethoxy-3-pyridyl)-l -methyl-3 ,4,5 ,6,7 ,7a-hexahydro-2H-indole

[0742] 3a-(5,6-dimethoxy-3-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (30 g, 1 09 mmol) was separated by SFC (column: DAICEL CHIRALPAK AS(250mm*50 mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:20%, isocratic elution mode) to give (3aS,7aS)-3a-(5,6-dimethoxy-3-pyridyl)-l-methyl-3,4,5,6,7,7a-hexa hydro-2H-indole (10 g, 33% yield) as a yellow oil.

[0743] (3aS,7aS)-3a-(5,6-dimethoxy-3-pyridyl)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indole (retention time: 1.043 min, Peak2): LC-MS (ESI+) m / z 277.2 (M+H)+

[0744] !H NMR (400 MHz, CDCh) 5 = 7.75 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.36 - 3.16 (m, 1H), 2.56 (s, 1H), 2.37 - 2.26 (m, 4H), 2.05 - 1.84 (m, 4H), 1.81 - 1.73 (m, 1H), 1.66 - 1.45 (m, 3H), 1.45 - 1.31 (m, 1H), 1.26 - 1.07 (m, 1H)

[0745] Example 23: Synthesis of 6-[(3aR,7aS)-l-Methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl]-l,3-dimethyl-pyrazolo[4,3-c]pyridine and 6-[(3aS,7aR)-l-Methyl-

[0746] 3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo

[0747] 13

[0748] To a solution of 4,6-dichloropyridine-3-carboxylic acid (50 g, 260 mmol) ,N- methoxymethanamine (31.8 g, 521 mmol) in DMF (250 mL) was added EDCI (99.8 g, 521 mmol), DIEA (101 g, 781 mmol, 136 mL) and HOBt (70.4 g, 521 mmol). The mixture was stirred at 20 °C for 16 hours. On completion, the reaction mixture was partitioned between water 500 mL and EA 300 mL*3. The organic phase was separated, washed with water 600 mL (300 mL * 2), dried over [Drying agent], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give 4,6-dichloro-N- methoxy-N-methyl-pyridine-3-carboxamide (45 g, 66% yield) as a white solid.

[0749] LC-MS (ESI+) m / z 235.1 (M+H)+.

[0750] XH NMR (400 MHZ,CDC13) 88.29 (s, 1H), 7.38 (s, 1H), 3.43 (s, 3H), 3.35 - 3.35 (m, 1H), 3.32 (s, 2H)

[0751] Step 2 l-(4,6-Dichloro-3-pyridxl}ethanone

[0752] To a solution of 4,6-dichloro-N-methoxy-N-methyl-pyridine-3-carboxamide (45 g, 191 mmol) in THF (250 mL) was added dropwise MeMgBr (3 M, 159.53 mL) at 0 °C . After addition, the resulting mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was quenched by addition NH4CI 100 mL at 0 °C, and then diluted with water 200 mL and extracted with Ethylacetate (200 mL * 3). The combined organic layers were washed with Brine 200 mL (100 mL * 2), dried over [Drying agent], filtered and concentrated under reduced pressure to give l-(4,6-dichloro-3-pyridyl)ethanone (25 g, 62 % yield) as a yellow oil LC-MS (ESI+) m / z 190.0 (M+H)+.

[0753] !H NMR (400 MHz, CDCh) 5 8.54 (s, 1H), 7.38 (s, 1H), 2.61 (s, 3H)

[0754] Stev3-6-Chloro-l,3-dimethyl-pyrazolo[4,3-c]pyridine

[0755] 4 6

[0756] To a solution of l-(4,6-dichloro-3-pyridyl)ethanone (25 g, 132 mmol) in EtOH (300 mL) was added methylhydrazine (30.3 g, 263 mmol, 34.64 mL) at 25 °C. The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was quenched by addition NH4CI 100 mL at 0 °C, and then diluted with water 300 mL and extracted with Ethylacetate 600 mL (200 mL * 3). The combined organic layers were washed with Brine 200 mL (100 mL * 2), dried over [Drying agent], filtered and concentrated under reduced pressure to give 6-chloro -1,3- dimethyl - pyrazolo [4,3-c]pyridine (22 g, 83% yield) as a white solid LC-MS (ESI+) m / z 270.1 (M+H)+.

[0757] NMR (400 MHz, CDCh)68.67 (s, 1H), 7.18 (s, 1H), 3.88 (s, 3H), 2.53 (s, 3H) Step 4 2-( l,3-Dimethylpyrazolo[4,3-c]pyridin-6-yl)cyclohexanone

[0758] 6 8

[0759] A mixture of 6-chloro-l,3-dimethyl-pyrazolo[4,3-c]pyridine (5.8 g, 31.9 mmol) , cyclohexanone (31.3g, 319 mmol) , XPhos Pd G3 (2.7 g, 3.19 mmol) , t-BuONa (6.14g, 63.9mmol) in THF (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hours under N2 atmosphere. On completion, the filter liquor were collected by filtration. And then diluted with water 200 mL and extracted with Ethylacetate 300 mL (100 mL * 3). The combined organic layers were washed with Brine 120 mL (40 mL * 3), dried over [Drying agent], filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition). Compound 2-(l,3-dimethylpyrazolo[4,3- c]pyridin-6-yl)cyclohexanone (3 g, 9.86 mmol, 39% yield) was obtained as a yellow solid. LC-MS (ESI+) m / z 244.1 (M+H)+.

[0760] *H NMR (400 MHz, CDCI3) 57.37 (s, 1H), 7.20 (s, 1H), 4.07 - 4.05 (m, 1H), 4.04 (s, 3H), 2.61 (s, 3H), 2.59 - 2.49 (m, 2H), 2.44 (d, J= 10.4 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.07 - 1.99 (m, 2H), 1.94 (s, 1H), 1.79 (d, J = 13.2 Hz, 1H)

[0761] Step 5-2-Allyl-2-(J,3-dimethylpyrazolof4,3-c]pyridin-6-yl)cyclohexanone

[0762] 8 10

[0763] To a solution of 2-(l,3-dimethylpyrazolo[4,3-c]pyridin-6-yl)cyclohexanone (3 g, 9.86 mmol) in

[0764] THF (28 mL) was added dropwise t-BuOK (1 M, 10.69 mL) at 0°C . After addition, the mixture was stirred at this temperature for 30 min, and then 3-bromoprop- 1 -ene (2.39g, 19.73mmol) was added drop wise at 0 °C. The resulting mixture was stirred at 20 °C for 2 hours. On completion, the crude product was purified by reversed-phase HPLC ( 0.1% FA condition) to give 2-allyl-2- (1,3-dimethylpyrazolo [4,3-c]pyridin-6-yl)cyclohexanone (1.1g, 3.48 mmol, 39% yield) as a yellow solid

[0765] LC-MS (ESI+) m / z 284.1 (M+H)+.

[0766] *H NMR (400 MHz, CDCE) 5 8.88 (s, 1H), 6.96 (s, 1H), 5.48 (d, 7 = 8.4 Hz, 1H), 4.91 - 4.74 (m, 2H), 3.91 (s, 3H), 2.80 (d, 7= 7.6 Hz, 1H), 2.54 (s, 5H), 2.36 - 2.23 (m, 2H), 1.87 (s, 1H), 1.68 (d, 7 = 6.0 Hz, 4H)

[0767] Step 62-[ 1 -( 1 ,3-Dimethylpyrazolo[4,3-c]pyridin-6-yl)-2-oxo-

[0768] NalO4, K2OSO4H2O, 2,6-lutidine, dioxane / H2O

[0769] 10 11

[0770] A mixture of 2-allyl-2-(l,3-dimethylpyrazolo[4,3-c]pyridin-6-yl)cyclohexanone (550 mg, 1.94 mol) ,NaIO4 (208 mg, 970 pmol), 2,6-dimethylpyridine (416 mg, 3.88 mmol) and K2OSO4.2H2O (22.1 mg, 123 pmol) in dioxane (21 mL) and H2O ( 9mL) at 25 °C, After addition, the mixture was stirred at this temperature for 30 minutes, and then NaIO4 (1.25 g, 5.83 mmol) was added at 25 °C. Then the mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched by addition Na2SOa 10 mL at 25°C, The reaction mixture diluted with water 80 mL and extracted with Ethylacetate 120 mL (40 mL *3). The combined organic layers were washed with Brine 60 mL (30 mL *2), dried over [Drying agent], filtered and concentrated under reduced pressure to give 2-[l-(l,3-dimethylpyrazolo[4,3-c]pyridin-6-yl)-2-oxo- cyclohexyl] acetaldehyde (400 mg, 53% yield,) as a yellow oil LC-MS (ESI+) m / z 286.0 (M+H)+.

[0771] To a solution of 2-[l-(l,3-dimcthylpyrazolo[4,3-c]pyridin-6-yl)-2-oxo-cyclohcxyl]acctaldchydc (400 mg, 1139 pmol) in MeOH (15 mL) was added MeNEh (305 mg, 2.94 pmol)and AcOH (124 mg, 2.28 mmol). After addition, the mixture was stirred at this temperature for 30 minutes, and then NaBI ECN (215mg, 3.42 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 1 hours. On completion, the reaction mixture was quenched by adding it to a cold saturated aqueous sodium hydroxide solutiontill pH = 8. The aqueous layer was extracted with Ethylacetate (50 mL*3) and water (50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the residue. The crude product was purified by reversed-phase HPLC (0.1% NH3*H2O ). Compound 1,3- dimethyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrazolo[4,3-c]pyridine (100 mg, 28% yield) was obtained as a yellow oil.

[0772] LC-MS (ESI+) m / z 285.1 (M+H)+.

[0773] H NMR (400 MHz, CDC13) 58.88 (s, 1H), 7.13 (s, 1H), 3.91 (s, 3H), 3.24 (dt, J= 4.4, 8.8 Hz, 1H), 2.94 (s, 1H), 2.53 (s, 3H), 2.38 - 2.33 (m, 1H), 2.31 (s, 3H), 2.18 (d, J= 13.6 Hz, 1H), 1.94 (s, 2H), 1.89 - 1.83 (m, 1H), 1.81 (s, 1H), 1.56 (d, J= 10.0 Hz, 2H), 1.49 (d, J= 13.6 Hz, 1H), 1.32 (d, 7 = 2.8 Hz, 1H), 1.11 (d, J= 12.4 Hz, 1H)

[0774] Step-76-[(3aR,7aS)-l-Methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl- pyrazolo[4,3-c]pyridine and 6-f(3aS.7aR)-l -Methyl-3,4.5,6, 7,7a-hexahvdro-2H-indol-3a-yl]- 1 ,3-dimethyl-pyrazolo

[0775] I,3-dimethyl-6-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrazolo[4,3-c]pyridine (100 mg, 352 pmol) was separated by SFC( column: DAICEL CHIRALPAK IK(250mm*30mm,10um);mobile phase: [CO2-i-PrOH(0.1%NH3H2O)];B%:45%, isocratic elution mode ) to give 6-[(3aR,7aS) -l-methyl-3,4,5,6,7,7a -hexahydro-2H-indol-3a-yl] -1,3- dimethyl - pyrazolo [4,3-c]pyridine (17.56 mg, 17 % yield) as a yellow gum and 6-[(3aS,7aR) -

[0776] 1- methyl- 3,4,5,6,7,7a -hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[4,3-c]pyridine (19.54 mg, 19% yield) as a yellow gum.

[0777] 6-[(3aR,7aS)-l-Methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[4,3- c]pyridine_(retention time: 2.047min): LC-MS (ESI+) m / z 285.2 (M+H) +.

[0778] !H NMR (400 MHz, CDCh) 5 8.84 (s, 1H), 7.19 (s, 1H), 4.29 - 4.15 (m, 2H), 3.94 (s, 3H), 3.01 - 2.91 (m, 1H), 2.86 (s, 3H), 2.55 (s, 3H), 2.26 - 2.13 (m, 3H), 2.12 - 2.02 (m, 1H), 1.96 (d, J =

[0779] I I.6 Hz, 2H), 1.81 - 1.64 (m, 2H), 1.48 - 1.38 (m, 1H), 1.30 - 1.17 (m, 1H).

[0780] 6-[(3aS,7aR)-l-Methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo (retention time: 2.157min): LC-MS (ESI+) m / z 285.2 (M+H) +

[0781] !H NMR (400 MHz, CDCh) ‘H NMR (400 MHz, CHLOROFORM-d) 8.84 (s, 1H), 7.19 (s, 1H), 4.29 - 4.15 (m, 2H), 3.94 (s, 3H), 3.01 - 2.91 (m, 1H), 2.86 (s, 3H), 2.55 (s, 3H), 2.26 - 2.13 (m, 3H), 2.12 - 2.02 (m, 1H), 1.96 (d, J = 11.6 Hz, 2H), 1.81 - 1.64 (m, 2H), 1.48 - 1.38 (m, 1H), 1.30 - 1.17 (m, 1H). Example 24: Synthesis of 5-[(3aR,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H- indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-c]pyridine and 5-[(3aS,7aR)-l-methyl-

[0782] 3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-c]pyridine

[0783] Stepl-(2-bromo-5-fluoro-4-pyridyl)ethanone

[0784] The residue was purified by column chromatography (SiCh, petroleum ether: ethyl acetate = 3:1) to give-(2-bromo-5-fluoro-4-pyridyl)ethanone (60 g, 220 mmol, 53% yield, 80% purity) as a red oil.

[0785] LC-MS (ESI+) m / z 218.2 (M+H)+.

[0786] 1H NMR (400 MHz, CDCh) 8 = 8.33 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 5.3 Hz, 1H), 2.59 (d, J = 4.1 Hz, 3H).

[0787] Step 2- 5-bromo-l,3-dimethyl-pyrazolo[3,4-c]pyridine

[0788] 3 5

[0789] A mixture of l-(2-bromo-5-fluoro-4-pyridyl)ethanone (30 g, 137 mmol,), methylhydrazine (31.7 g, 275 mmol, 36.2 mL) in EtOH (300 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16hr under N2 atmosphere. On completion, the reaction mixture was quenched by addition NH4CI (100 mL) at 0 °C, and then diluted with water 300 mL and extracted with EA 600 mL (200 mL * 3). The combined organic layers were washed with Brine 200 mL (100 mL * 2), dried over, filtered and concentrated under reduced pressure to give 5-bromo- l,3-dimethyl-pyrazolo[3,4-c]pyridine (8 g, 32.5 mmol, 36% yield,) as a brown oil. LC-MS (ESI+) m / z 226 (M+H) +.

[0790] 1H NMR (400 MHz, CDCh) 8 = 8.68 - 8.64 (m, 1H), 7.76 - 7.72 (m, 1H), 4.11 - 4.08 (m, 3H), 2.55 (s, 3H)

[0791] Step 3- 2-(l,3-dimethylpyrazolof3,4-cli}yridin-5-yl)cyclohexanone

[0792] A mixture of 5-bromo- 1 ,3-dimethyl-pyrazolo[3,4-c]pyridine (4 g, 17.7 mmol) , cyclohexanone (17.4 g, 177 mmol, 18.3 mL), Pdi(dba)3 (810 mg, 884 pmol) , Xantphos (1.13 g, 1.95 mmol) and K3PO4 (8.64 g, 40.7 mmol) in Tol. (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hours under N2 atmosphere. On completion, the mixture was poured to the water (300 mL) and extracted with ethyl acetate (900 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prcp-HPLC (0.1 %FA condition) to give the compound 2- (l,3-dimethylpyrazolof3,4-c]pyridin-5-yl)cyclohexanone (600 mg, 54% yield) as a colourless gum.

[0793] *H NMR (400 MHz, CDCI3) 5 8.91 - 8.84 (m, 1H), 7.44 - 7.39 (m, 1H), 4.10 (s, 3H), 4.01 (J = 5.6, 12.2 Hz, 1H), 2.56 (s, 3H), 2.48 - 2.33 (m, 2H), 2.31 - 2.15 (m, 2H), 2.12 - 1.99 (m, 1H), 1.94 - 1.75 (m, 3H)

[0794] Step 4- 2-allyi-2-( 1 ,3-dimethyipyrazolo[ 3,4-clr>yridin-5-yl)cyclohexanone

[0795] To a solution of 2-(l,3-dimethylpyrazolo[3,4-c]pyridin-5-yl)cyclohexanone (600 mg, 2.46 mmol ) in THF (20 mL) was added t-BuOK (1 M, 2.46 mL), the mixture was stirred at 0°C for 0.5 hour . Then 3-bromoprop-l-ene (358 mg, 2.96 mmol ) was added the mixture . The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (300 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (0.1 %FA condition) to give the compound 2-allyl-2-(l,3-dimethylpyrazolo[3,4-c]pyridin-5- yl)cyclohexanone (300 mg, 38% yield) as a yellow solid.

[0796] H NMR (400 MHz, CDCL) 5 8.91 - 8.81 (m, 1H), 7.40 - 7.33 (m, 1H), 5.61 - 5.47 (m, 1H), 4.93 - 4.87 (m, 1H), 4.10 (s, 3H), 2.93 - 2.80 (m, 1H), 2.67 - 2.51 (m, 5H), 2.42 - 2.28 (m, 2H), 2.02 - 1.87 (m, 1H), 1.82 - 1.68 (m, 4H), 1.65 - 1.57 (m, 1H) -cyclohexyl]acetaldehyde

[0797] 10

[0798] To a solution of 2-allyl-2-(l,3-dimethylpyrazolo[3,4-c]pyridin-5-yl)cyclohexanone (300 mg, 1.06 mmol) in dioxane (3 mL) and H2O (1 mL) was added 2,6-LUTIDINE (227 mg, 2.12 mmol, 246 pL) , K2OSO4.2H2O (7.80 mg, 21.2 pmol) and NalCL (113 mg, 529 pmol, 29.3 pL) at 25°C, the mixture was stirred at 25°C for 0.5 hours .Then NalCU (679 mg, 3.18 mmol, 176 pL) was added the mixture at 25 °C, the mixture was stirred at 25 °C for 2 hours . On completion, the mixture was poured to the water (100 mL) and extracted with ethyl acetate (200 mL). The organic layers was dried by sodium sulfate, filtered and concentrated in vacuo to give 2-[l-(l,3- dimethylpyrazolo [3 ,4-c]pyridin-5-yl)-2

[0799] -oxo-cyclohexyl] acetaldehyde (300 mg, crude, 61% yield) as a yellow gum.

[0800] LC-MS (ESI+) m / z 286.3 (M+H)+.

[0801] Step 6- l,3-dimethyl-5-( l-methyl-3,4.5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrclzolo[3,4- c ] pyridine racemate

[0802] To a solution of 2-[l-(l,3-dimethylpyrazolo[3,4-c]pyridin-5-yl)-2-oxo-cyclohexyl]acetaldehyde (200 mg, 700 pmol) in MeOH (3 mL) was added McNH? (145 mg, 1.40 mmol, 30% purity) and AcOH (4.21 mg, 70.1 pmol, 4.01 pL) at 25 °C , the mixture was stirred at 25 °C for 0.5 hours. Then NaBHaCN (132 mg, 2.10 mmol) was added the mixture was stirred at 40 °C for 16 hours. On completion, the reaction mixture was quenched added sodium hydroxide solution till pH = 8. The aqueous layer was extracted with EA (100 mL*3) and water (100ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (0.1 %FA condition) to give 1,3- dimethyl-5-( 1 -methyl- 3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrazolo|3,4-cJpyridine (80 mg, 37% yield) as a colorless gum.

[0803] LC-MS (ESI+) m / z 285.4 (M+H)+. Step7-5-[(3aR,7aS)-l -methyl-3,4,5, 6,7, 7a-hexahydro-211-indol-3a-yl]-l ,3 -dimethyl- pyrazolo! 3,4-c]pyridine and 5-[ ( 3aS, 7aR)-l -methyl-3,4,5, 6, 7, 7a-hexahydro-2H-indol-3a-yl 1-1,3- dimethyl-pyrazolol 3,4-clpyridine l,3-dimethyl-5-(l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl)pyrazolo[3,4-c]pyridine (80 mg, 281 |imol) was separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give 5-[(3aR,7aS)

[0804] -1 -methyl-3,4,5, 6, 7, 7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-c]pyridine (20 mg, 87% purity, Peakl) and 5-[(3aS,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3- dimethyl- pyrazolo[3,4-c]pyridine (20 mg, 88% purity, Peak 2). The Peakl was purified by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150*25* 10um;mobile phase: [water( NH4HCO3)- ACN] gradient:

[0805] 16%-46% B over 10 min)5-[(3aR,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl] -l,3-dimethyl-pyrazolo[3,4-c]pyridine (4.4 mg, 5 % yield) as a yellow gum. The Peak2 was purified by prep-HPLC (column: CD07-Daisogel SP-100-8-ODS-PK 150*25* 10um;mobile phase: [water( NH4HCO3)-ACN];gradient:16%-46% B over 10 min) to5-[(3aS,7aR)-l -methyl- 3,4,5

[0806] ,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4-c]pyridine (3.4 mg, 4% yield) as a yellow gum. 5-[(3aR,7aS)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4- c]pyridine (retention time: 1.324 min): LC-MS (ESI+) m / z 285.4 (M+H)+.

[0807] H NMR (400 MHz, CDC13) 5 8.89 - 8.85 (m, 1H), 7.54 - 7.48 (m, 1H), 4.09 (s, 3H), 3.37 - 3.28 (m, 1H), 3.05 - 2.97 (m, 1H), 2.58 (s, 3H), 2.48 - 2.35 (m, 4H), 2.25 (d, 7= 14.0 Hz, 1H), 2.07 - 1.81 (m, 5H), 1.64 ( d, J = 9.6 Hz, 2H), 1.56 ( d, 7= 15.2 Hz, 2H)

[0808] 5-[(3aS,7aR)-l-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-3a-yl]-l,3-dimethyl-pyrazolo[3,4- c]pyridine

[0809] (retention time: 1.524 min): LC-MS (ESI+) m / z 285.4 (M+H)+

[0810] *H NMR (400 MHz, CDCI3) 5 8.90 - 8.85 (m, 1H), 7.53 - 7.50 (m, 1H), 4.09 (s, 3H), 3.39 - 3.29 (m, 1H), 3.06 - 2.96 (m, 1H), 2.59 (s, 3H), 2.46 - 2.35 (m, 4H), 2.28 - 2.22 (m, 1H), 2.07 - 1.83 (m, 5H), 1.67 - 1.61 (m, 2H), 1.59 - 1.53 (m, 1H), 1.45 - 1.37 (m, 1H).

[0811] Example Al: SERT Inhibition Assay

[0812] SERT inhibition was measured using a Neurotransmitter Transportation Fluorescence assay. Briefly, stable 5HHH cells were prepared in a 384 microwell 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.

[0813] The results are shown in Table Al as follows: A: IC50 < / = 50 nM or lower; B: 50 nM < IC50 < / = 100 nM; C: 100 nM < IC50 < / = 500 nM; D: 500 nM < IC50 < / = 1 micromolar; E: IC50 > 1 micromolar.

[0814] Table Al.

[0815]

[0816]

[0817]

[0818] Example A2: PDE4 Inhibition Assay

[0819] Recombinant PDE assay

[0820] Recombinant PDE assay inhibition can be measured according to the BPSBioscience PDE4 assay kit, as described below.

[0821] Step 1:

[0822] 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.

[0823] 2) Add 25 pl of FAM-Cyclic-3'.5'-AMP (200 nM) to each well designated “Positive Control”, “Test Inhibitor”, and “Substrate Control”.

[0824] 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”. 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).

[0825] 5) Thaw PDE on ice. Upon first thaw, briefly spin tube containing enzyme to recover the full contents of the tube.

[0826] 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.”

[0827] 7) Incubate at room temperature for 1 hour.

[0828] Step 2:

[0829] 1) Mix binding agent thoroughly and dilute binding agent 1:100 with binding agent diluent.

[0830] 2) Add 100 pl diluted binding agent to each microwell. Incubate at room temperature for 1 hour with slow shaking.

[0831] 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.

[0832] Cell-based assay

[0833] 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%. Example A3: In vitro human hepatocyte Stability

[0834] Hepatocyte Stability:

[0835] 10 mM stock solutions of test compounds and positive control were prepared in DMSO. Thawing medium and supplement incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes prior to use. Stock solutions were diluted to 100 pM by combining 198 pL acetonitrile and 2 pL of 10 mM stock solution. Verapamil was used as positive control in the assay. Vials of cryopreserved pooled human mixed gender hepatocytes were removed from storage, ensured that vials remain at cryogenic temperatures. The pressure was removed by loosening and re-tightening the cap. The vials were thawed in a 37°C water bath with gently shaking. Vials remained in water bath until all ice crystals had dissolved and were no longer visible. Vials were sprayed with 70% ethanol before being transferred to a biosafety cabinet. And then the contents were poured into the 50 mL thawing medium conical tube. Vials were centrifuged at 100 g for 10 minutes at room temperature. Thawing medium was aspirated and hepatocytes were re-suspended with serum-free incubation medium to yield ~1.5 x 106cells / mL. Cell viability and density were counted using Cellometer® Vision, and then cells were diluted with serum-free incubation medium to a working cell density of 0.5xl06viable cells / mL.

[0836] Aliquots of 198 pL hepatocytes were dispensed into each well of a 96- well non-coated plate. The plate was placed in the incubator on an orbital shaker at 500 rpm for approximately 10 minutes. Aliquots of 2 pL of the 100 pM test compounds or verapamil were added into respective wells of the non-coated 96-well plate to start the reaction. This assay was performed in duplicate. The plate was incubated in the incubator on an orbital shaker at 500 rpm for the designed time points. 25 pL of contents were transferred and mixed with 5 volumes (125 pL) of cold acetonitrile with IS (100 nM alprazolam, 100 nM labetalol and 100 nM tolbutamide) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples were centrifuges for 30 minutes at 3,220 g. Then transfer 100 pL of the supernatant to new 96-well plates for analysis. Add 100 pL of distilled water to each sample and mix for analysis by LC-MS / MS. Peak areas were determined from extracted ion chromatograms. Determine the in vitro half-life (ti / 2) of parent compound by regression analysis of the percent parent disappearance vs. time curve. The in vitro half-life (in vitro ti / 2) was determined from the slope value: in vitro ti / 2 = 0.693 / k. b. Conversion of the in vitro ti / 2 (in min) into the in vitro intrinsic clearance (in vitro CLint, in p L / min / 106cells) is done using the following equation: in vitro CLint = kV / N

[0837] V = incubation volume (0.2 mL);

[0838] N = number of hepatocytes per well (0.1 x 106cells).

[0839] Hepatocyte Stability Data in table Bl expressed as CLint Times (X) improvement relative to compound 001.

[0840] Table A3

[0841] Comparativc Hepatocyte Stability Data

[0842] Example A4: Mouse pharmacokinetic (PK) profile

[0843] Mouse PK studies were carried out by intraperitoneal administration of each compound to CD-I male mice at 3mg / kg dose (n=3). Plasma and brain samples were collected from each animal at various time points. Samples were further processed and subjected to bioanalysis by LC- MS / MS. Data was analyzed to generate PK parameters such as tl / 2, Cmax and AUC of each compound.

[0844] Comparative Mouse Pharmacokinetic Data

[0845]

Claims

CLAIMSWc claim:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof; whereinwherein * denotes the attachment points of ring A to the compound of formula (I); and wherein ring B is a carbocycle, heterocyclyl, aryl or heteroaryl ring structure, wherein Ring B is optionally substituted with one or more of R1, R2and R3; each R1is independently 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 (-alkyl-OH), aryl, -ORa, -NRaRb, -CHO, -C(O)Ra, -CO2Ra, -C(O)NRaRb, - CN, nitro, or -P(O)ORaORb; each of R2is -OR2and R3 is -OR3wherein R2and R3are independently alkyl, H, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each hydrogen atom in alkyl cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl is optionally substituted by halo, deuterium, cycloalkyl, aryl, or ORa; orR2and R3together with the atoms to which they are attached combine to form hctcrocyclyl or hctcroaryl, wherein each hydrogen atom in hctcrocyclyl and hctcroaryl is optionally substituted by halo, alkyl, haloalkyl, or ORa; each of R6and R7is independently hydrogen, deuterium, or fluoro; each of R8and R9is independently hydrogen, deuterium, fluoro, methyl, CN, or C(0)Me, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium;R10is methyl, H 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, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and each of Rcand Rdis independently H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; provided that when (a) ring A is:are each H, then R8is not H, C1-4 alkyl or Ci-6 haloalkyl; and provided the compound of formula (I) is not:A to the compound of formula (I); and whereinwherein X, Y and Z arc each independently N or CR1; c. each R1is independently hydrogen, halo, C1-4 alkyl, or C3-6 cycloalkyl; d. each of R2 and R3 is independently C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl; or each of R2 is -OR2and R3 is -OR3wherein R2and R3are each independently C1-4 alkyl, or C1-4 haloalkyl; orR2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and hctcroaryl is optionally substituted by halo, Ci- 4 alkyl, C1-4 haloalkyl, or -ORa; e. each of R6and R7is independently hydrogen, or fluoro;f. each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by halo or deuterium; g. R10is methyl; h. Rais H, C1-4 alkyl, wherein each hydrogen atom in alkyl is optionally substituted by halo, -ORC, -NRcRd, -CHO, -C(O)RC, -CO2RC, -C(O)NRcRd, -CN, nitro, or -P(O)ORcORd; and i. each of Rcand Rdis independently H, or C1-4 alkyl; and provided the compound is not3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are each independently N or CR1, provided that no more than one of X, Y and Z is4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: a. each R1is independently hydrogen, fluoro, methyl, or cyclopropyl; b. each of R2 and R3 is independently C1-4 alkyl, C1-4 haloalkyl, cyclopropyl; or each of R2 is -OR2and R3 is -OR3wherein R2and R3are each independently methyl optionally substituted with one or more fluoro; orR2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and hctcroaryl is optionally substituted by fluoro, or methyl optionally substituted with one or more fluoro; c. each of R6and R7is independently hydrogen, or fluoro; d. each of R8and R9is independently hydrogen, fluoro, methyl, CN, or C(O)Me, wherein each hydrogen atom in methyl is optionally substituted by fluoro; and e. R10is methyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 arc each independently -OH, -OCH3, -OCF3, -OCHF2, -OCH2F or cyclopropyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently -OCH3.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein a. R2 is -OH or -CHF2 and R3 is -OCH3; or b. R2 is -OR2 or cyclopropyl and R3 is -OR3S or R3 is -OR3’ or cyclopropyl, and R2’ and R3’ are each independently -H, -CH3, -CF3, -CHF2, or -CH2F.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Rs and R9 are each independently hydrogen, fluoro or methyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein Rs and R9 are both hydrogen.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R6and R7both hydrogen.

12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the atoms to which they are attached combine to form 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, C1-4 alkyl, C1-4 haloalkyl, or -ORa.

13. The compound of claim 12, wherein the compound is a compound of Formula (IV), or Formula (IV-A) or Formula (VI-A), or a pharmaceutically acceptable salt thereof:(IV),wherein Ring C is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, wherein each hydrogen atom in heterocyclyl and heteroaryl is optionally substituted by halo, CM alkyl, CM haloalkyl, or -ORa;V and W are each O or NRXand Rxis hydrogen or CM alkyl;Ri is hydrogen, halo, CM alkyl or CM haloalkyl;Rs and R9 are each independently CN, hydrogen, halo, CM alkyl or CM haloalkyl;Rio is CM alkyl;Rn, R12, R13, and R14 are each independently hydrogen, halo, CM alkyl or CM haloalkyl; and n is 0 or 1.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Ri is hydrogen; Rs and R9 arc each independently hydrogen, fluoro or methyl; and Rio is methyl.

15. The compound of claim 14, wherein Rs and R9 are each independently hydrogen.

16. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring B17. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: a. X, Y and Z are each independently N or CR1, provided that no more than one of X, Y and Z is N; b. R1is hydrogen;c. R2and R3together with the atoms to which they are attached combine to form a 5-6 member hctcroaryl comprising one or more nitrogen or oxygen hctcroatoms, wherein each hydrogen atom in heteroaryl is optionally substituted by methyl; d. each of R6and R7is independently hydrogen, or fluoro; and e. each of R8and R9is independently hydrogen, fluoro, or methyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein each of R6and R7is independently hydrogen; and each of R8and R9is independently hydrogen.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a. the compound is selected from:b. or the compound is selected from:c. or the compound is selected from:d. or the compound is selected from:

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

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

22. The compound of claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

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

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

35. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

36. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound of any one of claims 1-36, and a pharmaceutically acceptable excipient or carrier.

38. 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 1-36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37.

39. The method of claim 38, wherein the mental health disorder is anxiety, stress, or depression.

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