Substituted tricyclicheterocyclylsulfonamide derivatives and uses thereof

Abstract

Provided herein are compounds, compositions, and methods for the preparation and use of substituted tricyclicheterocyclylsulfonamide derivative compounds, and compositions comprising the same, for modulating TRPML1. In some embodiments, the compounds and compositions are provided for treatment of neurodegenerative diseases.

Description

Attorney Docket No. 01295-0002-00PCTSUBSTITUTED TRICYCLICHETEROCYCLYLSULFONAMIDE DERIVATIVES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 693,027, filed September 10, 2024, and US Provisional Application No. 63 / 865,887, filed August 18, 2025, each of which is incorporated herein by reference in its entirety for any purpose.FIELD

[0002] The present disclosure relates generally to compounds, compositions, and methods for the preparation and use of substituted tricyclicheterocyclylsulfonamide derivative compounds and compositions for modulating TRPML and / or for treating neurodegenerative diseases.BACKGROUND

[0003] Transient receptor potential (TRP) channels are multifunctional signaling molecules involved in sensory perception and cellular physiology. The 28 members of the mammalian TRP channel superfamily are divided into six subfamilies, one of which is mucolipins (TRPML1-3). Mucolipin TRP channel subfamily 1 (TRPML1) is the main Ca2+-releasing channel localized at the lysosomal membrane (Zeevi et al., Biochim. Biophys. Acta 2007, 1772 851-858). Lysosomal Ca2+released through the TRPML1 channel promotes the dephosphorylation and subsequent nuclear translocation of transcription factor EB (TFEB), which increases the transcription of genes that promote autophagy and lysosomal biogenesis (Tedeschi et al., Cell 2019, 8, 1216). Due to its important regulatory function and ability to clear pathogenic molecules, TRPML 1 has attracted attention as a potential target for lysosomal storage diseases, metabolic diseases, cardiovascular diseases, inflammatory disorders, immunological disorders, cancer, aging, and neurodegenerative diseases (Krogsaeter et al., Cell Calcium 2022, 103, 102553 and Park et al., Front. Cell Dev. Biol. 2022, 10, 811701). For instance, TRPML1 was shown to regulate a-synuclein exocytosis in dopaminergic neurons in a Parkinson’s disease mouse model (Tsunemi et al., J. Neurosci. 2019, 39, 5760-5772). These studies identify novel small molecule agonists that activate TRPML 1 and that are useful for treatment of diseases and disorders related to lysosomal and autophagy-related diseases and disorders.

[0004] Accordingly, in one aspect, provided herein are compounds that modulate TRPML 1.SUMMARY

[0005] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.Attorney Docket No. 01295-0002-00PCT

[0006] Provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, whereinV is chosen from H, halo, Ci-6 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, -S(O)2-Ci-6 alkyl, -S(O)2(heterocyclyl), -S(O)(NRc)N(Ra)(Rb), -S(O)(NH)-CI-6alkyl, -S(O)(NRa)(heterocyclyl), and -S(O)2N(Ra)(Rb), wherein each alkyl, alkoxy, cycloalkyl, and heterocyclyl group is optionally substituted with 1, 2, or 3 groups selected from halo and N(Ra)(Rb); n is 1 to 4; each Raand Rbis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and -C(O)(Ci-4 alkyl);Rcis P, wherein P is a cleavable group;Ring A is C3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl;L is a bond, C1-3 alkylene, NRa, or O; each of X1, X2, X3, and X4is independently C(RX) or N;R1is H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl;W is C(R2)2, NR2, O, or SO2; each R2is independently chosen from H; halo; OH; C1-4 alkyl; C1-4 haloalkyl; C1-10 alkoxy optionally substituted with halo, C3-8 cycloalkyl; N(Rc)(Rd), or heterocyclyl;-(OCH2CH2)I-6OCH3; -(OCH2CH2)i-3N(Rc)(Rd); -O-CH2-(C3-6 cycloalkyl); -O-(Ci-4haloalkyl);-C(O)(Ci -40 alkyl, wherein the alkyl is optionally substituted with C1-6 alkoxy, heterocyclyl, or C3-8 cycloalkyl); -C(O)(C3-6 cycloalkyl); -C(O)(heteroaryl); -C(O)(heterocyclyl); -C(O)(aryl, wherein the aryl is optionally substituted with halo); -C(0)0(Ci-3o alkyl, wherein the alkyl is optionally substituted with C1-4 alkoxy, C3-8 cycloalkyl, heterocyclyl, or heteroaryl);-C(O)O(heterocyclyl); -C(O)O(aryl, wherein the aryl is optionally substituted with 1 or 2 groups chosen from halo, CN, and C1-3 alkyl); -C(O)N(Rc)(Rd); and -S(O)2(Ci-4 alkyl); each Rcand Rdis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkyl-Ci-4Attorney Docket No. 01295-0002-00PCT alkoxy, or Rcand Rdjoin together with the atom to which they are bonded to form a 3 to 6 membered cycloalkyl, heterocyclyl group;R3aand R3bare both H; or R3aand R3btaken together form an oxo group; andR4aand R4bare independently H or OH; or R4aand R4btaken together form an oxo group.

[0007] Also provided are pharmaceutical compositions comprising the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] Also provided are methods of modulating Mucolipin TRP channel subfamily 1 (TRPML1) comprising contacting TRPML1 with an effective amount of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein.

[0009] Also provided are methods of treating a disease associated with TRPML1 comprising administering to the subject an effective amount of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein.DETAILED DESCRIPTIONDefinitions

[0010] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0011] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0012] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0013] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.Attorney Docket No. 01295-0002-00PCT

[0014] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated.

[0015] An “alkyl” group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms (Ci-Cio alkyl), typically from 1 to 8 carbons (Ci-Cs alkyl) or, in some embodiments, from 1 to 6 (Ci-Ce alkyl), 1 to 4 (C1-C4 alkyl), 1 to 3 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group has monovalency. Examples of alkyl groups with monovalency include, but are not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2(CH3), -CH2(CH2)2CH3, -CH2CH(CH3)CH3, -CH2(CH2)3CH3, -CH2(CH2)4CH3, -CH2(CH2)5CH3, -CH2(CH2)6CH3, and the like. In some embodiments, the alkyl group has bivalency. Examples of alkyl groups with bivalency include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CEhCH(CH3)-, -CH2(CH2)2CH2-, -CH2CH(CH3)CH2-, -CH2(CH2)3CH2-, -CH2(CH2)4CH2-, -CH2(CH2)5CH2-, -CH2(CH2)eCH2-, and the like. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3 -methylpentyl, -4-methylpentyl, -2,3 -dimethylbutyl and the like. In some embodiments, an alkyl group is an unsaturated alkyl group, also termed an alkenyl or alkynyl group. An “alkenyl” group is an alkyl group that contains one or more carbon-carbon double bonds. An “alkynyl” group is an alkyl group that contains one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C=CH, -C=C(CH3), -C=C(CH2CH3), -CH2OCH, -CH2C=C(CH3) and -C hO C hCHs), among others. An alkyl group can be substituted or unsubstituted. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy,Attorney Docket No. 01295-0002-00PCT heterocycloalkylalkyloxy; oxo (=0); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino, cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(0H)2. In certain embodiments, when the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; -B(0H)2, or -O(alkyl)aminocarbonyl.

[0016] A “cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms (C3-C10 cycloalkyl) having a single cyclic ring or multiple condensed or bridged rings. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (C3-C8 cycloalkyl), whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5 (C3-C5 cycloalkyl), 3 to 6 (C3-C6 cycloalkyl), or 3 to 7 (C3-C7 cycloalkyl). In some embodiments, the cycloalkyl groups are saturated cycloalkyl groups. Such saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl, 2- methylcyclooctyl, and the like, or multiple or bridged ring structures such as l- bicyclo[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. In other embodiments, the cycloalkyl groups are unsaturated cycloalkyl groups. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.

[0017] A “heterocyclyl” is a non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom. In some embodiments, heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8Attorney Docket No. 01295-0002-00PCT ring members. In some embodiments, heterocyclyl groups include one to three heteroatoms, whereas other such groups have one to two heteroatoms or one heteroatom. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. Heterocyclyl groups encompass saturated and partially saturated ring systems. Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. The phrase also includes bridged polycyclic ring systems containing a heteroatom. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4- dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(lH)-one. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.

[0018] An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms (Ce- Ci4 aryl) having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons (Ce-Cu aryl), and in others from 6 to 12 (Ce-Cn aryl) or even 6 to 10 carbon atoms (Ce-Cio aryl) in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase “aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl as defined herein. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl, as defined herein. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl.

[0019] A “heteroaryl” group is an aromatic ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 10 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. In some embodiments, heterocyclyl groups have one to three heteroatoms, whereas other such groups have one to twoAttorney Docket No. 01295-0002-00PCT heteroatoms or one heteroatom. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl -2-onyl or isoindolin-l-onyl), azaindolyl (pyrrol opyridyl or lH-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., lH-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl), pyrazol opyridyl, tri azol opyridyl, benzotri azolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzoxazolyl(e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadi azolyl, isoxazolopyridyl, thianaphthal enyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin- l(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. A heteroaryl group can be substituted or unsubstituted. If a heteroaryl group is fused with a heterocyclyl, the resulting ring system is heterocyclyl. If a heteroaryl group is fused with a cycloalkyl, the resulting ring system is heterocyclyl.

[0020] A “halogen” or “halo” is fluorine, chlorine, bromine or iodine.

[0021] A “haloalkyl” group is an alkyl group, as defined herein with one or more halogen groups bonded to the alkyl group. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, di chloroethyl, tri chloroethyl, and the like.

[0022] An “oxo” group is a “=O” group bonded to a carbon.

[0023] When the groups described herein, with the exception of alkyl group, are said to be “substituted,” they may be substituted with any appropriate substituent or substituents.Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=0); -B(OH)2, - O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroarylAttorney Docket No. 01295-0002-00PCT(e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

[0024] Embodiments of the disclosure are meant to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein, such as the compounds of Formulas (I) and all sub-formulae, as well as the compounds in Table 1.

[0025] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride, formic, and mesylate salts. Others are well-known in the art, see for example, Remington ’s Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

[0026] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereoisomerically pure” means one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers ofAttorney Docket No. 01295-0002-00PCT the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds disclosed herein can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0027] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007);Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0028] It should also be noted the compounds disclosed herein can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of the E and Z isomers.

[0029] Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:Attorney Docket No. 01295-0002-00PCT

[0030] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present disclosure.

[0031] It should also be noted the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the compounds disclosed herein, for example, the isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or2H), that is, the compound is enriched in deuterium in at least one position.

[0032] It is understood that, independently of stereoisomerical or isotopic composition, each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereoisomerical composition of each compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective compound or salt thereof disclosed herein, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective compound.

[0033] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0034] “Activation” as used herein, means a method of making a biological molecule reactive, active, or effective in carrying out its function. In one embodiment, the biological molecule is a signaling molecule. In one embodiment, the biological molecule is TRPML1.Attorney Docket No. 01295-0002-00PCT

[0035] The term “agonist” as used herein refers to a molecule that can bind to and activate a receptor to produce a biological response.

[0036] “Modulation” as used herein, means a method of altering the activity of another biological molecule, wherein the activity can increase or decrease.

[0037] “Treating” or “treatment” of a disease or a disorder, which are herein used interchangeably, in a subject refers to 1) preventing at least one symptom or preventing the recurrence of at least one symptom; 2) inhibiting the disease or at least one symptom thereof or arresting its development; or 3) ameliorating or causing regression of the disease, or at least one symptom thereof. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For the purposes of this disclosures, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a subject. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.

[0038] The term “effective amount” in connection with a compound disclosed herein means an amount capable of treating a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0039] The term “subject” or “patient” as used herein include an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having an TRPML1 mediated disease, or a symptom thereof.

[0040] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.Attorney Docket No. 01295-0002-00PCTCompounds

[0041] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinV is chosen from H, halo, Ci-6 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, -S(O)2-Ci-6 alkyl, -S(O)2(heterocyclyl), -S(O)(NRc)N(Ra)(Rb), -S(O)(NH)-CI-6alkyl, -S(O)(NRa)(heterocyclyl), and -S(O)2N(Ra)(Rb), wherein each alkyl, alkoxy, cycloalkyl, and heterocyclyl group is optionally substituted with 1, 2, or 3 groups selected from halo and N(Ra)(Rb); n is 1 to 4; each Raand Rbis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and -C(O)(Ci-4 alkyl);Rcis P, wherein P is a cleavable group;Ring A is C3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl;L is a bond, C1-3 alkylene, NRa, or O; each of X1, X2, X3and X4is independently C(RX) or N;R1is H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl;W is C(R2)2, NR2, O, or SO2; each R2is independently chosen from H; halo; OH; C1-4 alkyl; C1-4 haloalkyl; C1-10 alkoxy optionally substituted with halo, C3-8 cycloalkyl; N(Rc)(Rd), or heterocyclyl;-(OCH2CH2)I-6OCH3; -(OCH2CH2)i-3N(Rc)(Rd); -O-CH2-(C3-6 cycloalkyl); -O-(Ci-4haloalkyl);-C(O)(Ci -40 alkyl, wherein the alkyl is optionally substituted with C1-6 alkoxy, heterocyclyl, or C3-8 cycloalkyl); -C(O)(C3-6 cycloalkyl); -C(O)(heteroaryl); -C(O)(heterocyclyl); -C(O)(aryl, wherein the aryl is optionally substituted with halo); -C(0)0(Ci-3o alkyl, wherein the alkyl is optionally substituted with C1-4 alkoxy, C3-8 cycloalkyl, heterocyclyl, or heteroaryl);Attorney Docket No. 01295-0002-00PCT-C(O)O(heterocyclyl); -C(O)O(aryl, wherein the aryl is optionally substituted with 1 or 2 groups chosen from halo, CN, and C1-3 alkyl); -C(O)N(Rc)(Rd); and -S(O)2(Ci-4 alkyl); each Rcand Rdis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkyl-Ci-4 alkoxy, or Rcand Rdjoin together with the atom to which they are bonded to form a 3 to 6 membered cycloalkyl, heterocyclyl group;R3aand R3bare both H; or R3aand R3btaken together form an oxo group; andR4aand R4bare independently H or OH; or R4aand R4btaken together form an oxo group.

[0042] In some embodiments, P is chosen from -C(O)R5, wherein -C(O)R5is derived from one or more natural or unnatural amino acids. In some embodiments, P is chosen from -C(O)R6, wherein R6is optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted piperazinyl, optionally substituted phenyl, or optionally substituted pyridyl. In some embodiments, -C(O)R5is derived from alanine, valine, leucine, glycine, phenylalanine, aspartic acid, glutamic acid, or any combination of thereof. In some embodiments, R6is optionally substituted C1-4 alkyl.

[0043] In some embodiments, V is chosen from H; halo; C1-4 alkyl; C1-4 haloalkyl; Ci alkoxy; cyclopropyl optionally substituted with halo, NH2, or NfCH^h; -C(CH3)2NH2; - C(CH3)2N(CH3)2; -S(O)2N(CH3)2; -S(O)(NH)N(CH3)2; -S(O)(NCH3)N(CH3)2; - S(O)(NH)(CHF2); -S(O)2CH3OCH3; -S(O)2(4-membered heterocyclyl comprising N); -S(O)2(Cn 2 alkyl) optionally substituted with halo; and -S(O)(NRa)N(CH3)2. In some embodiments, V is chosen from H,Attorney Docket No. 01295-0002-00PCT

[0044] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1.Attorney Docket No. 01295-0002-00PCT

[0045] In some embodiments, Ring A is chosen from C5 cycloalkyl; 6-membered heterocyclyl comprising N, O, or S; 6-membered aryl optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl group; and 6-membered heteroaryl group comprising N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl group. In some embodiments, Ring A is chosen from

[0046] In some embodiments, L is NH, O, CH2, or a bond. In some embodiments, L is a bond. In some embodiments, L is a CH2.

[0047] In some embodiments, R1is H, CN, halo, or methyl optionally substituted by 1 to 3 halo groups. In some embodiments, R1is H, -CF3, -CH3, CN, F, or Cl. In some embodiments, R1is H. In some embodiments, R1is Cl. In some embodiments, R1is CN.

[0048] In some embodiments, one or two of X1, X2, X3, and X4is N. In some embodiments, each of X1, X2, X3, and X4is CR1. In some embodiments, each of X1, X2, X3, and X4is CR1and each R1is independently chosen from H, -CF3, -CH3, or Cl.

[0049] In some embodiments, W is C(R2)2, NR2, O, or SO2. In some embodiments, W is CHR2or NR2.

[0050] In some embodiments, R2is chosen from H; OH; C1-3 alkyl optionally substituted with halo; C1-7 alkoxy optionally substituted with F, Cl, C4-8 cycloalkyl, NRcRd, 4- to 8- membered heterocyclyl comprising N, O, or S; -(OCH2CH2)I-4OCH3; -(OCH2CH2)I-2N(CH3)2; - C(O)(C1 -30 alkyl, wherein the alkyl is optionally substituted with C1-3 alkoxy, 4- to 6-membered heterocyclyl comprising N, O, or S, or C4-6 cycloalkyl); -C(O)(C3-6 cycloalkyl); -C(O)(4- to 6- membered heteroaryl comprising N, O, or S); -C(O)(4- to 6-membered heterocyclyl comprising N, O, or S); -C(O)(4- to 6-membered aryl) wherein the aryl is optionally substituted with halo); - C(O)O(C1 -20 alkyl, wherein the alkyl is optionally substituted with C1-3 alkoxy, C3-6 cycloalkyl, 4- to 6-membered heterocyclyl comprising N, O, or S, or 4- to 6-membered heteroaryl comprising N, O, or S); -C(O)O(4- to 6-membered heterocyclyl comprising N, O, or S); - C(O)N(CH3)(CI-3alkyl)(Ci-3alkoxy); -C(O)NH(CI-3alkyl)(Ci-3alkoxy); -C(O)NH(CI-3alkyl); - S(O)2(Ci-3alkyl); -C(O)NH2; and -C(O)N(CH3)2.Attorney Docket No. 01295-0002-00PCT

[0051] In some embodiments, R2is chosen from H; OH; C1-2 alkyl optionally substituted with halo; C1-7 alkoxy optionally substituted with F, C4-6 cycloalkyl, N(CHs)2, 4-membered heterocyclyl comprising O, or -(OCH2CH2)I-3OCH3; -(OCH2CH2) N(CH3)2; -C(O)(Ci-29 alkyl, wherein the alkyl is optionally substituted with Ci alkoxy, 6-membered heterocyclyl comprising O, or Ce cycloalkyl); C(O)(C3-6 cycloalkyl); -C(O)(5-membered heteroaryl comprising N or S); - C(O)(4- to 6-membered heterocyclyl comprising O); -C(O)(phenyl, wherein the phenyl is optionally substituted with F or Cl); -C(O)O(Ci-i8 alkyl, wherein the alkyl is optionally substituted with Ci alkoxy, C4-6 cycloalkyl, 6-membered heterocyclyl comprising O, or 5- membered heteroaryl comprising N or S); -C(O)O(4- to 6-membered heterocyclyl comprising O); -C(O)O(5-membered heterocyclyl comprising N); -C(O)N(CH3)(C2 alkyl)(Ci alkoxy); - C(O)NH(C2alkyl)(Ci alkoxy); -C(O)NH(Ci alkyl); -S(O)2(Ci-2alkyl); -C(O)NH2; and - C(O)N(CH3)2.

[0052] In some embodiments, R3aand R3bare both H. In some embodiments, R3aand R3btaken together form an oxo group.

[0053] In some embodiments, R4aand R4bare both H. In some embodiments, one of R4aand R4bis OH. In some embodiments, R4aand R4btaken together form an oxo group.

[0054] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (la), or a pharmaceutically acceptable salt thereof:

[0055] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (lb), or a pharmaceutically acceptable salt thereof:Attorney Docket No. 01295-0002-00PCT

[0056] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (II), (Ila), and (lib), or a pharmaceutically acceptable salt thereof:lib).

[0057] In some embodiments, wherein the compound is a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, R2is Ci-io alkoxy optionally substituted with halo, C3-8 cycloalkyl, N(Rc)(Rd), or heterocyclyl.

[0058] In some embodiments, wherein the compound is a compound of Formula (lib), or a pharmaceutically acceptable salt thereof, R2is -C(0)0(Ci-3o alkyl, wherein the alkyl is optionally substituted with C1-4 alkoxy, C3-8 cycloalkyl, heterocyclyl, or heteroaryl).

[0059] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (III), (Illa), and (Illb), or a pharmaceutically acceptable salt thereof:Attorney Docket No. 01295-0002-00PCT

[0060] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (IV), (IVa), (IVb), (Vic), (Vid), and (Vie), or a pharmaceutically acceptable salt thereof:(Vic), (Vid), and (Vie)

[0061] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (V), (Va), and (Vb), or aAttorney Docket No. 01295-0002-00PCT pharmaceutically acceptable salt thereof:

[0062] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (VI), (Via), (VIb), (Vic), (Vid), and (Vie), or a pharmaceutically acceptable salt thereof:

[0063] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety may be combined with every description, variation,Attorney Docket No. 01295-0002-00PCT embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to X of Formula (I) may be combined with every description, variation, embodiment, or aspect of R1, R2, R3, and R4the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to any of the formulae as detailed herein, such as Formulae (II), (Ila), (lib), (III), (Illa), (Hlb), (IV), (IVa), (IVb), (Vic), (Vid), (Vie), (V), (Va), (Vb), (VI), (Via), and (VIb), and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. Further a reference to compounds of Formula (I) refers to all subformulae (II), (Ila), (lib), (III), (Illa), (Illb), (IV), (IVa), (IVb), (Vic), (Vid), (Vie), (V), (Va), (Vb), (VI), (Via), and (VIb).

[0064] In some embodiments, provided is a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 1, may be presented as specific stereoisomers and / or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, are herein described.Table 1.Atorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAttomey Docket No. 01295-0002-00PCTor a pharmaceutically acceptable salt thereof. In one embodiment, a tautomer, stereoisomer, and deuterated form of any of the compounds of the present disclosure is encompassed.

[0065] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is chosen from:N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(cyclohexylmethoxy)-2,3,4,9,10,10a-hexahydro-lH-Attorney Docket No. 01295-0002-00PCT4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(2,2-difluoroethoxy)-2,3,4,9,10,10a-hexahydro-lH- 4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(2-methoxyethoxy)-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(cyclobutylmethoxy)-2,3,4,9,10,10a-hexahydro-lH- 4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl(p-{(2S,10aR)-5-chloro-2-[2-(2-methoxyethoxy)ethoxy]-2,3,4,9,10,10a- hexahydro-lH-4a,9-diazaphenanthr-9-yl sulfonyl } phenyl sulfonyljamine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-propoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-ethoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S, 10aR)-2-ethoxy-2,3,4,9, 10, 10a-hexahydro-lH-4a,9-diazaphenanthr-9- ylsulfonyl]phenylsulfonyl}amine; dodecyl (10aR)-9-[p-(dimethylaminosulfonyl)phenylsulfonyl]-2,3,4,9, 10, lOa-hexahydro-lH- 2,4a,9-triazaphenanthrene-2-carboxylate; and N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-methoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine.

[0066] It is understood that in the present description, combinations of substituents and / or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

[0067] Furthermore, all compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the present disclosure can be converted to their free base or acid form by standard techniques.Methods of Use

[0068] Embodiments of the present disclosure provide a method for modulating TRPML1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure. Modulation (e.g., inhibition or activation) of TRPML1 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays can be utilized for determining whether and to what degree TRPML1 has been modulated.Attorney Docket No. 01295-0002-00PCT

[0069] In one aspect, provided herein is a method of modulating TRPML1 comprising contacting TRPML1 with an effective amount of a compound of the present disclosure. In some embodiments, a compound of the present disclosure activates TRPML1. In some embodiments, a compound of the present disclosure is an agonist of TRPML1.

[0070] In some embodiments, a compound of the present disclosure modulates the activity of TRPML1 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of the present disclosure modulates the activity of TRPML1 by about 1-100%, 5-100%, 10-100%, 15- 100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60- 100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0071] Also provided in certain embodiments of the present disclosure is a method for activating TRPML1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure. Activation of TRPML1 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays, including cell-based assays, can be utilized for determining whether and to what degree TRPML1 has been activated.

[0072] In one aspect, provided herein is a method of activating TRPML1 comprising contacting TRPML1 with an effective amount of a compound of the present disclosure. In some embodiments, the compound of the present disclosure partially activates TRPML1. In some embodiments, the compound of the present disclosure fully activates TRPML1.

[0073] In some embodiments, a compound of the present disclosure activates TRPML1 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound of the present disclosure activates TRPML1 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30- 100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75- 100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0074] In another aspect, provided herein is a method for treating a disease associated with TRPML1 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, provided herein is a method for treating a disease associated with TRPML1 in a subject in need thereof, comprisingAttorney Docket No. 01295-0002-00PCT administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0075] In some embodiments, administering a compound of the present disclosure to a subject that is predisposed to a disease associated with TRPML1 prevents the subject from developing any symptoms of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject that does not yet display symptoms of a disease associated with TRPML1 prevents the subject from developing any symptoms of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof diminishes the extent of the disease associated with TRPML1 in the subject. In some embodiments, administering a compound of the present disclosure to a subject in need thereof stabilizes the disease associated with TRPML1 (prevents or delays the worsening of the disease associated with TRPML1). In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays the occurrence or recurrence of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof slows the progression of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof provides a partial remission of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof provides a total remission of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof decreases the dose of one or more other medications required to treat the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof enhances the effect of another medication used to treat the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof delays the progression of the disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof increases the quality of life of the subject having a disease associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof prolongs survival of a subject having a disease associated with TRPML1. In some embodiments, the disease associated withAttorney Docket No. 01295-0002-00PCTTRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0076] In one aspect, provided herein is method of preventing a subject that is predisposed to a disease associated with TRPML1 from developing any symptoms of the disease associated with TRPML1, the method comprising administering a compound of compounds of the present disclosure to the subject. In some embodiments, provided herein is a method of treating a subject that does not yet display symptoms of a disease associated with TRPML1 from developing any symptoms of the disease associated with TRPML1, the method comprising administering a compound of compounds of the present disclosure to the subject. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0077] In some aspects, provided herein is a method of diminishing the extent of a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, provided herein is a method of stabilizing a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, the method prevents the worsening of the disease associated with TRPML1. In some embodiments, the method delays the worsening of the disease associated with TRPML1. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0078] In another aspect, provided herein is a method of delaying the occurrence or recurrence of a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatoryAttorney Docket No. 01295-0002-00PCT disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0079] In some embodiments, provided herein is a method of slowing the progression of a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, the method provides a partial remission of the disease associated with TRPML1. In some embodiments, the method provides a total remission of the disease associated with TRPML1. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0080] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0081] Also provided here is a method of delaying the progression of a disease associated with TRPML1 in a subject, the method comprising administering a compound of the present disclosure to the subject. In some embodiments, the method increases the quality of life of the subject having a disease associated with TRPML1. In some embodiments, the method prolongs survival of the subject having a disease associated with TRPML1. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).Attorney Docket No. 01295-0002-00PCT

[0082] In another aspect, provided herein is a method for treating symptoms associated with TRPML1 caused by a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, provided herein is a method for treating symptoms associated with TRPML1 caused by a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, administering a compound of the present disclosure to a subject that is predisposed to a disease which causes symptoms associated with TRPML1 prevents the subject from developing any symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject that is does not yet display symptoms associated with TRPML1 of a disease which causes symptoms associated with TRPML1 prevents the subject from developing any symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof diminishes the extent of the symptoms associated with TRPML1 caused by the disease in the subject. In some embodiments, administering a compound of the present disclosure to a subject in need thereof stabilizes the symptoms associated with TRPML1 of the disease (prevents or delays the worsening of the symptoms associated with TRPML1). In some embodiments, administering a compound of the present disclosure to a subject in need thereof delays the occurrence or recurrence of the symptoms associated with TRPML1 caused by the disease. In some embodiments, administering a compound of the present disclosure to a subject in need thereof slows the progression of the symptoms associated with TRPML1 caused by the disease. In some embodiments, administering a compound of the present disclosure to a subject in need thereof provides a partial remission of the disease which causes symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof provides a total remission of the disease which causes symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof decreases the dose of one or more other medications required to treat the disease which causes symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof enhances the effect of another medication used to treat the symptoms associated with TRPML1 of the disease. In some embodiments, administering a compound of the present disclosure to a subject in need thereof delays the progression of the disease which causes symptoms associated with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof increases the quality of life of the subject having a disease which causes symptoms associatedAttorney Docket No. 01295-0002-00PCT with TRPML1. In some embodiments, administering a compound of the present disclosure to a subject in need thereof prolongs survival of a subject having a disease which causes symptoms associated with TRPML1. In some embodiments, the disease is associated with TRPML1. In some embodiments, the disease associated with TRPML1 is a neurodegenerative disease, lysosomal storage disease, mitochondrial disease, renal disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging. In some embodiments, the neurodegenerative disease is Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).

[0083] In some embodiments, compounds of the present disclosure are useful for treating a disease selected from Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV-associated dementia, Huntington’s disease, or Alzheimer’s disease (AD).Pharmaceutical Compositions and Routes of Administration

[0084] The compounds the present disclosure can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.

[0085] The compounds the present disclosure can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrrolidone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compounds of Formula (I) in the pharmaceutical composition may be at a level that will exerciseAttorney Docket No. 01295-0002-00PCT the desired effect; for example, about 0.005 mg / kg of a subject’s body weight to about 10 mg / kg of a subject’s body weight in unit dosage for both oral and parenteral administration.

[0086] The dose of a compound of the present disclosure to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.

[0087] A compound of the present disclosure can be administered orally for reasons of convenience. In one embodiment, when administered orally, a compound of the present disclosure is administered with a meal and water. In another embodiment, the compound of the present disclosure is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or a suspension.

[0088] The compounds the present disclosure can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.

[0089] In one embodiment, provided herein are capsules containing a compound of the present disclosure without an additional carrier, excipient or vehicle.

[0090] In another embodiment, provided herein are compositions comprising an effective amount of a compound of the present disclosure and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0091] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like. Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound of the present disclosure with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.Attorney Docket No. 01295-0002-00PCT

[0092] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0093] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, com and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0094] When it is desired to administer a compound of the present disclosure as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.

[0095] The effect of the compound of the present disclosure can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the compound of the present disclosure can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound of the present disclosure in oily or emulsified vehicles that allow it to disperse slowly in the serum.Attorney Docket No. 01295-0002-00PCTEXAMPLES

[0096] The following preparations of compounds of Formula (I) and intermediates are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. The following Examples are presented by way of illustration, not limitation.Compounds are named using the automatic name generating tool provided in ChemDraw professional Version: 22.2.0.3348 (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0097] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0098] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, or from about 0 °C to about 125 °C or at about room (or ambient) temperature, e.g., about 20 °C.

[0099] Compounds of Formula (I) and subformulae and species described herein, including those where the substituent groups as defined herein, can be prepared as illustrated and described below.

[0100] Unless otherwise noted, all reagents were used without further purification.JH NMR spectra were obtained in CDCh, DMSO-tC, or CD3OD at room temperature on a Bruker 300 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of1H NMR spectra were recorded in parts perAttorney Docket No. 01295-0002-00PCT million (ppm) on the d scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. LC-MS conditions are described below

[0101] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HC1) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HC1).

[0102] For certain compounds disclosed herein the absolute stereochemistry has not been independently confirmed. At least one or more of the stereocenters’ absolute stereochemistry are believed to be accurately represented in the name and structure of the disclosed compounds. For some compounds, the stereochemistry is assigned based on the stereochemistry of the starting materials, which was purchased in a pure chiral form and assumed to be correctly assigned, and an expectation that the chirality of the stereocenter(s) does not change during the synthesis of the final compound. Stereochemistry assigned in this manner is designated as “absolute” stereochemistry in the tables that follow.

[0103] In some instances, the stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., the stereochemistry of one chiral center is known and the remaining chiral centers are arbitrarily assigned, or the stereochemistry all the chiral centers could be unknown). Stereochemistry assigned in this manner is designated as “assigned” stereochemistry in the tables that follow. Accordingly, the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a prep chiral HPLC, chiral SFC, NMR shift, optical rotation, or its biological activities (e.g., as described further in the Examples). Thus, if the stereochemistry assigned to any is ultimately shown to be incorrectly represented herein, then the analytical data (e.g., prep chiral HPLC, chiral SFC, NMR shift, optical rotation, or biological activity) associated with each compound is determinative of the actual identity of the compound. In addition, in light of such corrected stereochemical designation, appropriate adjustments to the stereochemistry identification contained in the description, examples, tables, and claims should be adjusted as needed.

[0104] The following abbreviations may be relevant for the application. AbbreviationsAttorney Docket No. 01295-0002-00PCTSynthetic ExamplesAnalytical Methods

[0105] Unless otherwise noted, all reagents were used without further purification.1H NMR spectra were obtained in DMSO-tA, CD3OD or CDCI3 at room temperature on a Bruker 300 MHz or an Agilent 400 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one is reported. Chemical shifts of1H NMR spectra wereAttorney Docket No. 01295-0002-00PCT recorded in parts per million (ppm) on the 5 scale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

[0106] LC-MS and HPLC conditions were described below:

[0107] General LC method A

[0108] Column: Agilent Zorbax XDB C18 (4.6 mm x 50 mm), 3.5pm

[0109] Mobile phase A: 0.1% formic acid in water

[0110] Mobile phase B: MeOH

[0111] Flow rate: 1.0 mL / min

[0112] Run time: 2 min gradient (20%-90% B), then 3 min @90% B

[0113] Column temperature: 30 °C.

[0114] General LC method B

[0115] Column: X Select CSH C18 2.5 um; 3.0x50 mm

[0116] Mobile Phase A: 0.05% FA in Water + 5% ACN

[0117] Mobile Phase B: 0.05% FA in ACN

[0118] Flow Rate: 1.2 mL / min

[0119] Column temperature: 50 °C

[0120] Run time (Time / B%): 0 / 2%, 0.2 / 2%, 2.2 / 98%, 3 / 98%, 3.2% / 2, 4 / 2%

[0121] General LC method C

[0122] Column: X-Bridge BEH C18, (50 mm*3.0 mm), 2.5pm

[0123] Mobile Phase A: 2.5mM Ammonium bicarbonate in Water + 5% ACN

[0124] Mobile Phase B: 100% ACN

[0125] Flow rate: 1.2 mL / min

[0126] Column temperature: 50°C

[0127] Run time (Time / B%): 0.0 / 0%, 1.4 / 100%, 2.4 / 100%, 2.6 / 0%, 3.0 / 0%

[0128] General HPLC Method A

[0129] Column: Agilent SB-C18 (4.6 mm x 150 mm), 3.5pm

[0130] Mobile phase A: 0.02% TFA in water

[0131] Mobile phase B: MeOH

[0132] Flow rate: 1.0 mL / min

[0133] Run time: 0.5 min @10% B, 9.5 min gradient (10%-90% B), then 10 min @90% B

[0134] Temperature: 30 °C.

[0135] General HPLC Method BAttorney Docket No. 01295-0002-00PCT

[0136] Column: X-Select CSH C18 (4.6 mm x 150 mm), 5pm

[0137] Mobile phase A: 0.02% TFA in water

[0138] Mobile phase B: MeOH

[0139] Flow rate: 1.0 mL / min,

[0140] Run time: 0.5 min @10% B, 9.5 min gradient (10%-90% B), then 10 min @90%B

[0141] Temperature: 30 °C.Preparation of common intermediatesExample 1-1. Synthesis of common intermediate 1

[0142] Common intermediate 1 was made according to procedures described in WO 2017 / 141049 and WO 2018 / 005713.Example 1-2. Synthesis of common intermediate 2

[0144] A solution of (2A, -AS')- l -( / c / 7-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid (1.8 g, 7.3 mmol) in HCl / dioxane (30 mL, 4.0 mol / L) was stirred at rt for 4 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 1.5 g of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / r. 146 [M+H]+.

[0145] Step 2Attorney Docket No. 01295-0002-00PCT

[0146] To a solution of the crude (2R, -LS)-4-hydroxypiperidine-2-carboxylic acid HC1 salt (1.5 g, 8.3 mmol) in DMF (30 mL) at rt was added K2CO3 (3.0 g, 22.0 mmol) and l-fluoro-2 -nitrobenzene (1.2 g, 8.8 mmol). The reaction was then heated to 120 °C and stirred overnight. After the completion of the reaction as indicated by TLC analysis, the reaction was cooled to rt and acidified with a diluted HC1 solution (3 M) to pH ~ 3. Water (300 mL) was added to dilute the solution. The aqueous solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 2.9 g of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 267 [M+H]+.

[0147] Step 3

[0148] To a solution of the crude (2A, 45)-4-hydroxy-l-(2-nitrophenyl)piperidine -2- carboxylic acid (2.9 g, 10.7 mmol) in DMF (40 mL) at rt was added K2CO3 (3.0 g, 21.4 mmol) and CH3I (2.3 g, 16.1 mmol). The reaction was stirred at rt overnight. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 2: 1 to 1 : 1) to give 1.8 g of the title compound as a brown oil. LC-MS (ESI+) m / z: 281 [M+H]+.

[0149] Step 4H a N O H \^*OH

[0150] To a solution of methyl (2A, 45)-4-hydroxy-l-(2-nitrophenyl)piperidine-2- carboxylate (1.8 g, 6.4 mmol) in EtOH (20 mL) at rt was added saturated NH4CI aqueous solution (20 mL) and Fe powder (1.1 g, 19.3 mmol). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase wasAttorney Docket No. 01295-0002-00PCT dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 20: 1) to give 1.1 g of the title compound as an off-white solid. Yield: 78.6%. LC-MS (ESI+) m / z'. 219 [M+H]+.

[0152] To a solution of (6aR, S5)-8-hydroxy-7,8,9,10-tetrahydro-5H-pyrido [7,2- a]quinoxalin-6(6a77)-one (1.1 g, 4.8 mmol) in anhydrous THF (15 mL) under N2 at rt was added borane tetrahydrofuran complex (14 mL, 1 mol / L in THF). The reaction was then stirred at 80 °C overnight. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 20: 1) to give 975 mg of common intermediate 2 as a white solid. Yield: 94.7%. LC-MS (ESI+) m / z 205 [M+H]+.Example 1-3. Synthesis of common intermediate 3

[0154] To a solution of (27?, -AS')- l -( / c / 7-butoxycarbonyl)-4-hydroxypiperidine-2- carboxylic acid (1.0 g, 4.1 mmol) in dichloromethane (20 mL) at rt was added TFA (5 mL). The reaction was stirred at rt for 3 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 1.1 g of the crudeAttorney Docket No. 01295-0002-00PCT title compound, which was directly used for the next step without purification. LC-MS (ESI+) m / z 146 [M+H]+.

[0155] Step 2

[0156] To a solution of the crude (2 A, 45)-4-hydroxypiperidine-2-carboxylic acid TFA salt (1.1 g) in DMF (20 mL) at rt was added K2CO3 (1.7 g, 12.2 mmol) and 1 -chi oro-3 -fluoro-2- nitrobenzene (934 mg, 5.3 mmol). The reaction was stirred at 120 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was cooled to rt and acidified with a diluted HC1 solution (3 N) to pH ~ 3. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1.9 g of the crude title compound, which was directly used for the next step without further purification. LC-MS m / z 301 [M+H]+.

[0157] Step 3

[0158] To a solution of the crude (2 A, 45)-l-(3-chloro-2-nitrophenyl)-4 - hydroxypiperidine-2-carboxylic acid (1.9 g) in methanol (20 mL) at 0 °C was added SOCI2 (4 mL). The reaction was stirred at rt for 3 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 3: 1) to give 488 mg of the title compound. LC-MS (ESI+) m / z 315 [M+H]+.

[0159] Step 4

[0160] To a solution of methyl (2A,45)-l-(3-chloro-2-nitrophenyl)-4-hydroxypiperidine -2-carboxylate (488 mg, 1.6 mmol) in EtOH (8 mL) at rt was added saturated NH4CI aqueousAttorney Docket No. 01295-0002-00PCT solution (8 mL) and Fe powder (261 mg, 4.7 mmol). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (8 mL), and the aqueous solution was extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 20: 1) to give 314 mg of the title compound. Yield: 80.2%. LC- MS (ESI+) m / z 253 [M+H]+.

[0161] Step 5

[0162] To a solution of (6aR, S5)-l-chloro-8-hydroxy-7,8,9,10-tetrahydro-5H - pyrido[l,2-a]quinoxalin-6(6aH)-one (395 mg, 1.6 mmol) in anhydrous THF (5 mL) under N2 at rt was added borane tetrahydrofuran complex (6 mL, 1 mol / L in THF). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (4 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 20: 1) to give 360 mg of common intermediate 3. Yield: 96.5%. LC-MS (ESI+) m / z-. 239 [M+H]+.Example 1-4. Synthesis of common intermediate 4Attorney Docket No. 01295-0002-00PCT

[0164] To a solution of (RJ-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (9.5 g, 41.3 mmol) in EtOH (100 mL) at rt was added l-fluoro-2-nitrobenzene (7.0 g, 49.5 mmol) and NaHCCh (10.4 g, 123.8 mmol). The reaction mixture was stirred at 80 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction was cooled to rt and acidified with diluted HC1 aqueous solution (3 M) to pH ~ 4. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The aqueous solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 12.2 g of the crude title compound as orange oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z'. 352 [M+H]+.

[0165] Step 2

[0166] To a solution of crude (RJ-4-(tert-butoxycarbonyl)-l-(2-nitrophenyl)piperazine-2- carboxylic acid (10.9 g) in methanol (100 mL) at rt was added 5% Pd / C (1 g). The reaction was stirred under H2 atmosphere at rt for 7 h. After the reaction was completed as indicated by LC- MS analysis, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 3.5 g of the title compound as a gray solid. LC-MS (ESI+) m z 304 [M+H]+.

[0167] Step 3

[0168] To a solution of tert-butyl (7? -5-oxo-l,2,4,4a,5,6- hexahydro-3H-pyrazino[l,2- a]quinoxaline-3 -carboxylate (1.5 g, 5.0 mmol) in anhydrous THF (10 mL) at rt was added borane tetrahydrofuran complex (20 mL, 1 M in THF). The reaction was stirred at 70 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 1.3 g of common intermediate 4 as a white solid. Yield: 93%. LC- MS (ESI+) m z 290 [M+H]+.Attorney Docket No. 01295-0002-00PCTExample 1-5. Synthesis of common intermediate 5:

[0170] To a solution of 1 -chi oro-2-fluoro-3 -nitrobenzene (2.0 g, 11.4 mmol) in n-BuOH (80 mL) at rt was added 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (6.5 g, 28.5 mmol) and NaHCCh (2.8 g, 34.2 mmol). The reaction mixture was stirred at 80 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was acidified with a diluted HC1 solution (2 M) to pH ~ 3 and diluted with water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 3.9 g of the title compound as a yellow oil. Yield: 87%. LC-MS (ESI+) m / z 386 [M+H]+.

[0171] Step 2

[0172] To a solution of 4-(tert-butoxy carbonyl)- l-(2-chl oro-6-nitrophenyl)piperazine-2- carboxylic acid (5.0 g, 13.0 mmol) in DMF (50 mL) at rt was added CH3I (2.8 g, 19.5 mmol) and K2CO3 (3.5 g, 26.0 mmol). After the reaction was stirred at rt for 1.5 h, the reaction wasAttorney Docket No. 01295-0002-00PCT quenched with water (300 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 4.9 g of the title compound as a yellow oil. Yield: 94%. LC-MS (ESI+) m / z 400 [M+H]+.

[0173] Step 3

[0174] To a solution of saturated NH4CI aqueous solution (40 mL) in EtOH (40 mL) at 75 °C was added Fe power (3.0 g, 53.1 mmol). The mixture was stirred at this temperature for 30 min. A solution of 1 -(tert-butyl) 3-methyl 4-(2-chloro-6-nitrophenyl)piperazine-l,3- dicarboxylate (5.3 g, 13.3 mmol) in THF (30 mL) was slowly added to the above mixture. The reaction was stirred at 75 °C for another 6 h. After the reaction was completed as indicated by LC-MS analysis, the reaction was filtered, and the filtrate was diluted with water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine twice, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 4: 1 to 2: 1) to give 1.6 g of the title compound as a pale yellow solid. Yield: 64%. LC- MS (ESI+) m / z 338 [M+H]+.

[0175] Step 4

[0176] To a solution of tert-butyl 10-chloro-5-oxo-l,2,4,4a,5,6- hexahydro-3H- pyrazino[l,2-a]quinoxaline-3 -carboxylate (1.5 g, 4.5 mmol) in anhydrous THF (20 mL) at rt under N2 was added borane tetrahydrofuran complex (30 mL, 1 mol / L in THF). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to give 1.0 g of the title compound as a white solid. Yield: 70%. LC-MS (ESI+) m / z 324 [M+H]+.Attorney Docket No. 01295-0002-00PCT

[0177] Step 5

[0178] To a solution of tert-butyl 10-chloro-l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a] quinoxaline-3 -carboxylate (990 mg, 3.1 mmol) in pyridine (25 mL) at rt was added 4-(N,N- dimethyl sulfamoyl) benzenesulfonyl chloride (common intermediate 1; 1.7 g, 6.1 mmol). The reaction was stirred at 60 °C for 6 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 1.6 g of the title compound as a yellow solid. Yield: 92%. LC-MS (ESI+) m / z 571 [M+H]+.

[0179] Step 6

[0180] To a solution of tert-butyl 10-chloro-6-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl) -l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a]quinoxaline-3- carboxylate (1.5 g, 2.6 mmol) in dichloromethane (20 mL) was added TFA (3 mL). The reaction was stirred at rt for 7 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated under reduced pressure to give 1.2 g of the crude common intermediate 5 as a brown solid, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 471 [M+H]+.Attorney Docket No. 01295-0002-00PCTExample 1-6. Synthesis of common intermediate 6:

[0182] To a solution of 2-fluoro-l-methyl-3-nitrobenzene (1.8 g, 11.4 mmol) in n-BuOH(80 mL) at rt was added 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (6.5 g, 28.5 mmol) and NaHCCh (2.8 g, 34.2 mmol). The reaction mixture was stirred at 80 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was acidified with a diluted HC1 solution (2 M) to pH ~ 3 and diluted with water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 3.6 g of the title compound as a yellow oil. Yield: 87%. LC-MS (ESI+) m / z 365 [M+H]+.

[0183] Step 2

[0184] To a solution of 4-( / c / 7-butoxy carbonyl)- l-(2-methyl-6-nitrophenyl)piperazine-2- carboxylic acid (4.7 g, 13.0 mmol) in DMF (50 mL) at rt was added CH3I (2.8 g, 19.5 mmol) and K2CO3 (3.5 g, 26.0 mmol). After the reaction was stirred at rt for 1.5 h, the reaction was quenched with water (300 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 4.6 g of the title compound as a yellow oil. Yield: 94%. LC-MS (ESI+) m / z 379 [M+H]+.

[0185] Step 3Attorney Docket No. 01295-0002-00PCT

[0186] To a solution of saturated NH4CI aqueous solution (40 mL) in EtOH (40 mL) at75 °C was added Fe power (3.0 g, 53.1 mmol). The mixture was stirred at this temperature for30 min. A solution of 1 -(tert-butyl) 3-methyl 4-(2-methyl-6-nitrophenyl)piperazine-l,3- di carboxylate (5.0 g, 13.3 mmol) in THF (30 mL) was slowly added to the above mixture. The reaction was stirred at 75 °C for another 6 h. After the reaction was completed as indicated by LC-MS analysis, the reaction was filtered, and the filtrate was diluted with water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine twice, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 4: 1 to 2: 1) to give 2.7 g of the title compound as a pale yellow solid. Yield: 64%. LC- MS (ESI+) m / z 317 [M+H]+.

[0187] Step 4

[0188] To a solution of tert-butyl tert-butyl 10-methyl-5-oxo-l,2,4,4a,5,6-hexahydro- 3J / -pyrazino[l,2-a]quinoxaline-3-carboxylate (1.4 g, 4.5 mmol) in anhydrous THF (20 mL) at rt under N2 was added borane tetrahydrofuran complex (30 mL, 1 mol / L in THF). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to give 1.0 g of the common intermediate 6 as a white solid. Yield: 77%. LC-MS (ESI+) m / z 303 [M+H]+.Example 1-7. Synthesis of common intermediate 7 and 7’Attorney Docket No. 01295-0002-00PCT

[0190] To a solution of 4-methylpicolinic acid (40.0 g, 0.279 mol) in water (500 mL) was added PtCh (4.0 g, 0.018 mmol). The reaction was stirred at 80 °C under H2 atmosphere (2.0 MPa) for 48 h. After the reaction was completed as indicated by1H-NMR analysis, the reaction was filtered, and concentrated under reduced pressure to give 45.0 g of the title compound, which was directly used for the next step without purification.

[0191] Step 2:

[0192] To a solution of mixture of re / -(2R,4S)-4-methylpiperidine-2-carboxylic acid (45.0 g, 0.315 mol) in n-BuOH (900 mL) and water (45 mL) was added NaHCCL (105.7 g, 1.26 mol) and 1 -chi oro-2-fluoro-3 -nitrobenzene (82.6 g, 0.472 mol). The reaction was stirred at 115 °C for 48 h. After the reaction was completed as indicated by LC-MS and TLC, the reaction was acidified pH to 3 with a diluted HC1 solution (6 M), followed by addition of water (500 mL). The mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 100:0 to 20: 1) to give 22.2 g of the title compound. LC-MS (ESI+) m / z 299 [M+H]+.Attorney Docket No. 01295-0002-00PCT

[0193] Step 3:

[0194] To a solution of re / -(2S,4R)-l-(2-chloro-6-nitrophenyl)-4-methylpiperidine-2- carboxylic acid (22.2 g, 74.5 mmol) in DMF (400 mL) at rt was added K2CO3 (30.8 g, 223.5 mmol) and CH3I (31.7g, 223.5 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was quenched with water (2000 mL) and extracted with EtOAc (500 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 26.5 g of the crude title compound, which was directly used for the next step without purification. LC-MS (ESI+) m / z: 313 [M+H]+.

[0195] Step 4:

[0196] To a solution of crude re / -(2S,4R)-methyl -l-(2-chloro-6-nitrophenyl)-4- methylpiperidine-2-carboxylate (26.5 g, 84.9 mmol) in EtOH (250 mL) at rt was added saturated NH4CI aqueous solution (250 mL) and iron powder (14.3 g, 254.7 mmol). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered, and concentrated in vacuo. The residue was diluted with water(400 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1 :2) to give 17.4 g of the title compound. LC-MS (ESI+) m / z: 251 [M+H]+.

[0197] Step 5:

[0198] To a solution of re / -(6aS,8R)-l-chloro-8-methyl-7,8,9,10-tetrahydro-5H- pyrido[l,2-a]quinoxalin-6(6aH)- one (17.4 g, 69.6 mmol) in anhydrous THF (300 mL) under N2 at rt was added BH3-THF (1 mol / L in THF, 104 mL). The reaction was stirred at 80 °CAttorney Docket No. 01295-0002-00PCT overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to give 14.5 g of the title compound. LC-MS (ESI+) m / z: 237 [M+H]+.

[0199] Step 6:

[0200] Chiral column separation of re / -(6aS,8R)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro- 5H-pyrido[l,2-a]quinoxaline

[0201] The re / -(6aS,8R)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a] quinoxaline was separated by SFC chiral separation using the method below. After removal of the solvents, the first eluting isomer (Common intermediate 7, peak 1, 6.5 g, retention time = 6.54 min) and the second eluting isomer (Common intermediate 7’, peak 2, 7.0 g, retention time = 7.12 min) were obtained.

[0202] SFC chiral separation method:Instrument: SFC- 150 (Thar, Waters)Column: AD 25*250 mm, 10 um (Daicel)Column temperature: 35 °CMobile phase: CCh / EtOH (0.01%Methylamine in Methanol) = 80 / 20Flow rate: lOO g / min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 minSample solution: 14.5 g dissolved in 40 ml Methanol Injection volume: 1.2 mL

[0203] Analytical chiral HPLC condition:Instrument: Waters 2695Column: Regis REFLECT C-Amylose A 4.6*250mm, 5pmColumn temperature: 30 °CMobile phase: n-hexane / EtOH (0.1% DEA) = 70 / 30 Flow rate: 0.8 mL / minDetection wavelength: 250 nm (Detector: W2996 PDA)Attorney Docket No. 01295-0002-00PCTExample 1-8. Synthesis of common intermediate 8

[0205] To a solution of 2-fluoro-l-nitro-4-(trifluoromethyl)benzene (700 mg, 3.35 mmol) in EtOH (30 mL) at rt was added (R -morpholine-3-carboxylic acid (729 mg, 4.35 mmol) and NaHCCf (744 mg, 10.04 mmol). The reaction mixture was stirred at 90 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was acidified with a diluted HC1 solution (3 M) to pH ~ 2 and water (200 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 780 mg of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 321 [M+H]+.

[0206] Step 2

[0207] To a solution of (RJ-4-(2-nitro-5-(trifluoromethyl)phenyl)morpholine-3- carboxylic acid (640 mg, 2.00 mmol) in MeOH (20 mL) at rt was added SOCh (3 mL).The reaction was stirred at rt for 4 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to give 650 mg of the title compound. Yield: 97%. LC-MS (ESI+) m / z 335 [M+H]+.

[0208] Step 3Attomey Docket No. 01295-0002-00PCT

[0209] To a solution of K -methyl 4-(2-nitro-5-(trifluoromethyl)phenyl)morpholine-3- carboxylate (600 mg, 1.80 mmol) in EtOH (18 mL) and saturated NH4CI aqueous solution (18 mL) at rt was added Fe powder (300 mg, 5.39 mmol). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was filtered, and the filtrate was concentrated. To the residue was added water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 380 mg of the title compound. Yield: 78%. LC-MS (ESI+) m / z 273[M+H]+.

[0210] Step 4

[0211] To a solution of (RJ-9-(trifluoromethyl)-l,2,4,4a-tetrahydro -[l,4]oxazino[4,3- a]quinoxalin-5(6H)-one (300 mg, 1.10 mmol) in anhydrous THF (10 mL) at rt was added borane tetrahydrofuran complex (4 mL, 1 mol / L in THF). After the reaction was stirred at 60 °C overnight, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 8: 1) to give 240 mg of common intermediate 8. Yield: 84%. LC-MS (ESI+) m / z 259 [M+H]+.Example 1-9. Synthesis of common intermediate 9

[0212] To a solution of (6aR, &S)-6,6a,7,8,9,10-hexahydro-5H-pyrido[7,2-a]quinoxalin- 8-0I (common intermediate 2; 965 mg, 3.2 mmol) in THF (20 mL) at rt was added 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride (common intermediate 1; 1.2 g, 4.1 mmol) andAttorney Docket No. 01295-0002-00PCT pyridine (1.1 g, 14.2 mmol). The reaction was then stirred at 60 °C for 6 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (di chloromethane: methanol = 150:1 to 50: 1) to give 1.6 g of common intermediate 9 as a yellow solid. Yield: 75%. LC-MS (ESI+) m / r. 452 [M+H]+.Example 1-10. Synthesis of common intermediate 7’Intermediate 7'

[0213] Step 1

[0214] To a solution of (2A, -LS)-l-((benzyloxy)carbonyl)-4-methylpiperidine-2- carboxylic acid (5 g, 18 mmol) in i-PrOH (10 mL) was added 10% Pd / C (500 mg). The reaction was stirred at rt with a PE balloon overnight. After the reaction was completed, the reaction was filtered, and concentrated in vacuo to provide 2.57 g (18 mmol) of the product, which was directly used for the next step without purification.

[0215] Step 2

[0216] To a solution of (2A, 45)-l-(2-chloro-6-nitrophenyl)-4-methylpiperidine-2- carboxylic acid (2.59 g, 18.1 mmol) in n-BuOH (20 mL) was added NaHCCh (4.57 g, 54.3 mmol) and 1 -chi oro-2-fluoro-3 -nitrobenzene (5.5 g, 32.5 mmol). The reaction was stirred at 110 °C for 5 days. After the reaction was almost completed as indicated by LC-MS and TLC, the reaction was directly concentrated in vacuo. The residue was purified by silica gel columnAttorney Docket No. 01295-0002-00PCT chromatography (EtOAc:PE = 1 : 10 to DCM / MeOH = 10: 1) to give 5.2 g of impure compound.LC-MS (ESI+) m / z: 299 [M+H]+.

[0217] Step 3

[0218] To a solution of (2A, 45)-l-(2-chloro-6-nitrophenyl)-4-methylpiperidine-2- carboxylic acid (5.2 g impure from above) in DMF (35 mL) was added K2CO3 (7.2 g, 52.35 mmol) and CH3I (7.4 g, 52.35 mmol) at rt for 2 h. After the reaction was completed as indicated by TLC and LC-MS analysis, water (100 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5.4 g of the crude product, which was directly used for the next step without purification. LC-MS (ESI+) m / z: 313 [M+H]+.

[0219] Step 4

[0220] To a solution of the crude (2R,4S)-methyl -l-(2-chloro-6-nitrophenyl)-4- methylpiperidine-2-carboxylate (5.4 g crude from above) in EtOH (25 mL) was added saturated NH4CI aqueous solution (25 mL) and iron powder (2.9 g, 51.7 mmol) at rt. The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered. The filter cake was washed with EtOH. The filtrate was concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1: 10 to 1 :4) to give 2.69 g (10.7 mmol) of the product. LC-MS (ESI+) m / z: 251 [M+H]+.

[0221] Step 5

[0222] To a solution of (6aR, S5)-l-chloro-8-methyl-7,8,9,10-tetrahydro-5H-pyrido[l,2- a]quinoxalin-6(6aH)- one (2.69 g, 10.7 mmol) in anhydrous THF (25 mL) was added BH3-THF (1 mol / L in THF, 300 mL) under N2 at rt. The reaction was then stirred at 60 °C overnight. AfterAttorney Docket No. 01295-0002-00PCT the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1 : 10 to 1 :9) to give 2.2 g (9.3 mmol) of the product. LC- MS (ESI+) m / z: 237 [M+H]+. *H NMR (400 MHz, CDC13) 6.71 (dd, J= 8.0, 1.6 Hz, 1H), 6.53 (t, .7= 8.0 Hz, 1H), 6.41 (dd, J= 8.0, 1.6 Hz, 1H), 4.23 (dd, J= 8.8, 3.6 Hz, 1H), 3.63 (brs, 1H), 3.28-3.20 (m, 1H), 3.18-3.06 (m, 2H), 2.70 (td, J= 8.8, 2.4 Hz, 1H), 1.76-1.67 (m, 3H), 1.48- 1.37 (m, 1H), 1.15-1.11 (m, 1H), 0.99 (d, J= 6.0 Hz, 3H).Preparation of TRPML1 modulators

[0223] Example SI. Synthesis of Compound 78

[0224] To a solution of 4-(((6aR,&S)-8-hydroxy-6,6a,7,8,9,10-hexahydro -5H- pyrido[7,2-a]quinoxalin-5-yl)sulfonyl)-A,7V-dimethylbenzenesulfonamide (common intermediate 9, 86 mg, 0.2 mmol) in anhydrous DMF (1.5 mL) under N2 at 0 °C was added NaH (15 mg, 0.4 mmol, 60% in mineral oil). The reaction was stirred at 0 °C for 15 min. 1- bromobutane (39 mg, 0.3 mmol) was added to the above reaction mixture. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to give 13.6 mg of the title compound as a pale yellow solid. Yield: 14.1%. LC-MS (ESI+) m / z 508 [M+H]+; *HNMR (300 MHz, CD3OD) 3 7.86 (d, J= 8.5 Hz, 2H), 7.71 (d, J= 8.5 Hz, 2H), 7.52 (dd, J= 8.0, 1.6 Hz, 1H), 7.11 (t, J= 7.4 Hz, 1H), 6.84 (d, J= 8.2 Hz, 1H), 6.74 (t, J= 7.6 Hz, 1H), 4.25 (dd, J= 14.4, 4.5 Hz, 1H), 3.76 (d, J= 13.3 Hz, 1H), 3.46 (t, J= 6.4 Hz, 2H), 3.19-3.11 (m, 1H), 2.69 (s, 6H), 2.47-2.38 (m, 1H), 2.14-2.03 (m, 1H), 2.03-1.90 (m, 2H), 1.55-1.44 (m, 2H), 1.43-1.19 (m, 5H), 0.92 (t, J= 7.3 Hz, 3H).

[0225] The compounds in Table 2 were prepared according to the procedure of the synthesis of Compound 78 using appropriate starting materials.Atorney Docket No. 01295-0002-00PCTTable 2.Attorney Docket No. 01295-0002-00PCT

[0226] Example S2. Synthesis of Compound 131

[0227] To a solution of (6aR,&S)-l-chloro-6,6a,7 ,8,9 ,10-hexahydro-577-pyrido[7 ,2- a]quinoxalin-8-ol (300 mg, 1.3 mmol) in THF (6 mL) at rt was added 4-(N,N- dimethylsulfamoyl)benzenesulfonyl chloride (472 mg, 1.6 mmol) and pyridine (297 mg, 3.8 mmol). The reaction was then stirred at 60 °C for 6 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (dichloromethane: methanol = 150: 1 to 50: 1) to give 400 mg of the title compound. Yield: 65.5%. LC-MS (ESI+) m / z 486 [M+H]+; 'HNMR (300 MHz, CD3OD) 3 7.95 (d, J= 8.1 Hz, 2H), 7.82 (d, J= 8.1 Hz, 2H), 7.54 (d, J= 8.1 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 6.81 (t, J= 8.1 Hz, 1H), 4.26 (dd, J= 13.8, 4.4 Hz, 1H), 3.85-3.80 (m, 1H), 3.53-3.47 (m, 1H), 3.28-3.24 (m, 1H), 2.75-2.70 (m, 1H), 2.70 (s, 6H), 1.94-1.89 (m, 1H), 1.80-1.72 (m, 2H), 1.58-1.54 (m, 1H), 1.21-1.14 (m, 1H).

[0228] Example S3. Synthesis of Compound 130

[0229] To a solution of 4-(((6aR,S5)-l-chloro-8-hydroxy-6,6a,7,8,9,10 -hexahydro-577- pyrido[7,2-a]quinoxalin-5-yl)sulfonyl)-7V,7V-dimethylbenzenesulfonamide (380 mg, 0.8 mmol) in anhydrous DMF (5 mL) at 0 °C was added NaH (93 mg, 2.3 mmol, 60% in mineral oil). The reaction was stirred at 0 °C for 15 min. CH3I (226 mg, 1.6 mmol) was added to the above reaction mixture. The reaction was stirred at rt for 4 h. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (30 mL) and extracted withAttorney Docket No. 01295-0002-00PCT ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 3: 1) to give 200 mg of the title compound. Yield: 51.2%. LC-MS (ESI+) m / z-. 500 [M+H]+; 'HNMR (300 MHz, CDC13) 3 7.85 (d, J= 8.3 Hz, 2H), 7.75 (d, J= 8.3 Hz, 2H), 7.57 (d, J= 7.9 Hz, 1H), 7.19 (d, J= 8.9 Hz, 1H), 6.81 (t, J= 8.1 Hz, 1H), 4.17 (dd, J= 13.8, 4.4 Hz, 1H), 3.62-3.51 (m, 1H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.24-3.12 (m, 1H), 2.75-2.72 (m, 1H), 2.71 (s, 6H), 1.99-1.87 (m, 3H), 1.66-1.59 (m, 1H), 1.37-1.22 (m, 1H).

[0230] The compounds in Table 3 were prepared according to the procedures for the synthesis of Compound 131 and Compound 130 using appropriate starting materials.Table 3.Attorney Docket No. 01295-0002-00PCT

[0231] Example S4. Synthesis of Compound 46

[0232] To a solution of tert-butyl (RJ-l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2- a]quinoxaline -3 -carboxylate (common intermediate 4, 597 mg, 1.3 mmol) in THF (10 mL) at rt was added 4-(N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1;1.2 g, 4.1 mmol) and pyridine (490 mg, 6.2 mmol). The reaction was stirred at 60 °C for 3 h. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (20 mL). The aqueous solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to give 1.0 g of the title compound as a yellow solid. Yield: 537 [M+H]+.300 MHz, CDC13) 3 7.80 (d, J= 8.1 Hz, 2H), 7.67-7.60 (m, 3H), 7.21- 7.13 (m, 1H), 6.84 (t, J= 7.8 Hz, 1H), 6.71 (t, J= 8.4 Hz, 1H), 4.30-4.25 (m, 1H), 4.05-3.98 (m, 2H), 3.51 (s, 3H), 3.37-3.29 (m, 1H), 2.90-2.80 (m, 6H), 2.60-2.29 (m, 2H); 1.33 (s, 9H).

[0234] Example S5. Synthesis of Compound 79Attomey Docket No. 01295-0002-00PCT

[0235] Step 1

[0236] To a solution of tert-butyl (7?J-6-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)- l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a]quinoxaline-3-carboxylate (1.0 g, 1.9 mmol) in dichloromethane (15 mL) was added TFA (5 mL). The reaction was stirred at rt overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 1.5 g of the crude title compound as black oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 437 [M+H]+.

[0237] Step 2

[0238] To a solution of KJ-4-((l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a]quinoxalin-6- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (100 mg, 0.2 mmol) in dichloromethane (2 mL) at rt was added palmitoyl chloride (70 mg, 0.3 mmol) and DIEA (89 mg, 0.7 mmol). After the reaction was stirred at rt for 20 min, the reaction mixture was quenched with water (5 mL). The mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 33.9 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z 675 [M+H]+;JH NMR (300 MHz, CD3OD) 3 7.85 (d, J= 7.8 Hz, 2H), 7.71 (d, J= 6.9 Hz, 2H), 7.60-7.57 (m, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.86-6.80 (m, 2H), 4.37-4.27 (m, 2H), 3.91-3.88 (m, 1H), 3.70-3.66 (m, 1H), 3.37-2.79 (m, 2H), 2.67 (s, 6H), 2.35-2.31 (m, 4H), 2.22-2.18 (m, 1H), 1.59-1.55 (m, 2H), 1.45-Attorney Docket No. 01295-0002-00PCT1.29 (m, 24H), 0.90-0.87 (m, 3H).

[0239] The compounds in Table 4 were prepared according to the procedure of the synthesis of Compound 79 using appropriate starting materials.Table 4.Atorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAtorney Docket No. 01295-0002-00PCTAttorney Docket No. 01295-0002-00PCT

[0240] Example S6. Synthesis of Compound 165 and its stereoisomers Compound104 and Compound 105

[0241] Step 1

[0242] To a solution of 4-((10-chloro-l,2,3,4,4a,5-hexahydro -6H-pyrazino[l,2- a]quinoxalin-6-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (common intermediate 5, 200 mg, 0.4 mmol) in DMF (5 mL) at rt was added 2,2-difluoroethyl trifluoromethanesulfonate (184 mg, 0.9 mmol) and K2CO3 (178 mg, 1.3 mmol). The reaction was stirred at 100 °C for 20 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (5 mL x 3). TheAttorney Docket No. 01295-0002-00PCT combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 37.4 mg of Compound 165 as a pale yellow solid. Yield: 16.4%. LC-MS (ESI+) m / z 535 [M+H]+; ^NMR (300 MHz, DMSO ) 3 7.96 (d, J= 8.1 Hz, 2H), 7.87 (d, J == 8.1 Hz, 2H), 7.61 ( d, . / 8.1 Hz, 1H), 7.25 (d, . / 7.5 Hz, 1H), 7.00 (d, . / 8.1 Hz, 1H), 6.12 (t, J= 55.5 Hz, 1H), 4.15-4.02 (m, 1H), 3.78-3.65 (m, 1H), 2.90-2.85 (m, 1H), 2.83-2.65 (m, 5H), 2.61 (s, 6H), 2.56-2.52 (m, 3H).

[0243] Step 2: Chiral separation of Compound 165

[0244] 4-((10-Chloro-3-(2,2-difluoroethyl)-l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a] quinoxalin-6-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (Compound 165) was separated by chiral column separation using:Instrument: SFC-150 (Thar, Waters)Column: AD 25*250mm, 10 um (Daicel)Column temperature: 35 °CMobile phase: CO2 / IPA = 76 / 24Flow rate: lOO g / minBack pressure: 100 barDetection wavelength: 220 nmCycle time: 1.5 minSample solution: 32 mg dissolved in 5 ml MethanolInjection volume: 1.0 mL

[0245] The first eluting isomer rel- ( ?J-4-((10-chloro-3-(2,2-difluoroethyl)-l,2,3,4,4a,5- hexahydro-6H-pyrazino[l,2-a]quinoxalin-6-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (peak 1, 8.6 mg, retention time = 11.81 min) and the second eluting isomer rel- (lS)-4-((10- chloro-3-(2,2-difluoroethyl)-l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a]quinoxalin-6- yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (peak 2, 10.6 mg, retention time = 14.73 min) were obtained.

[0246] Peak 1 (Compound 105): LC-MS (ESI+) m / z: 535 [M+H]+;1H NMR (300 MHz,Attorney Docket No. 01295-0002-00PCTCDC13) 3 7.85 (d, J= 8.4 Hz, 2H), 7.83-7.73 (m, 3H), 7.17 (d, J= 7.5 Hz, 1H), 6.92 (t, J= 8.1 Hz, 1H), 5.85 (t, J= 51.9 Hz, 1H), 4.09 (dd, J= 12.9, 3.6 Hz, 1H), 3.74 (t, J= 12.0 Hz, 1H), 3.01-2.75 (m, 4H), 2.77 (s, 6H), 2.76-2.48 (m, 5H).

[0247] Peak 2 (Compound 104): LC-MS (ESI+) m / z 535 [M+H]+;1H NMR (300 MHz, CDC13) 3 7.85 (d, J= 8.4 Hz, 2H), 7.83-7.73 (m, 3H), 7.17 (d, J= 7.5 Hz, 1H), 6.92 (t, J= 8.1 Hz, 1H), 5.85 (t, J= 51.9 Hz, 1H), 4.09 (dd, J= 12.9, 3.6 Hz, 1H), 3.74 (t, J= 12.0 Hz, 1H), 3.01-2.75 (m, 4H), 2.77 (s, 6H), 2.76-2.48 (m, 5H).

[0248] Example S7. Synthesis of Compound 166 and its stereoisomers Compound 107 and Compound 106

[0249] Step 1

[0250] To a solution of 4-((10-chloro-l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a] quinoxalin-6-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (200 mg, 0.4 mmol) in dichloromethane (5 mL) at rt was added methyl chloroformate (81 mg, 0.9 mmol) and DIEA (166 mg, 1.3 mmol). The reaction was stirred at rt for 2 h. After the reaction was completed as indicated by LC-MS analysis, water (10 mL) was added. The mixture was extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1 :1) to give 48.0 mg of the title compound as a pale yellow solid. LC-MS (ESI+) m / z 529 [M+H]+; ^NMR (300 MHz, I)MS()-<. ) S 7.95 (d, . / 8. 1 Hz, 2H), 7.87 (d, . / 8. 1 Hz, 2H), 7.61 (d, . / 8.4 Hz, 1 H), 7.28 (d, J= 8.1 Hz, 1H), 7.03 (t, J= 8.1 Hz, IH), 4.21-4.10 (m, 1H), 3.64 (s, 3H), 3.57-3.42 (m, 2H), 3.41-3.37 (m, 2H), 2.83-2.70 (m, 2H), 2.61 (s, 6H), 2.41-2.28 (m, 2H).Attorney Docket No. 01295-0002-00PCT

[0251] Step 2

[0252] Methyl 10-chloro-6-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-l,2,4,4a,5,6 - hexahydro-3H-pyrazino[l,2-a]quinoxaline-3 -carboxylate (Compound 166) was separated by chiral column separation using:Instrument: SFC-150 (Thar, Waters)Column: AD 25*250mm, 10 um (Daicel)Column temperature: 35 °CMobile phase: CO2 / EtOH = 75 / 25Flow rate: lOO g / minBack pressure: 100 barDetection wavelength: 220 nmCycle time: 2.5 minSample solution: 40 mg dissolved in 6 ml MethanolInjection volume: 1.0 mL

[0253] The first eluting isomer rel-(7? -methyl 10-chloro-6-((4-(N,N- dimethylsulfamoyl)phenyl)sulfonyl)-l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a]quinoxaline-3- carboxylate (peak 1, 16.6 mg, retention time = 22.02 min) and the second eluting isomer rel-(S)- methyl 10-chloro-6-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-l,2,4,4a,5,6-hexahydro-3H- pyrazino[l,2-a]quinoxaline-3 -carboxylate (peak 2, 16.2 mg, retention time = 26.50 min) were obtained.

[0254] Peak 1 (Compound 107): LC-MS (ESI+) m / z 529 [M+H]+; ' H NMR (300 MHz, CDCh) 3 7.85 (d, J= 8.1 Hz, 2H), 7.77 (d, .7 = 8.4 Hz, 2H), 7.71 (d, .7 = 7.8 Hz, 1 H), 7.20 (d, .7 = 8.1 Hz, 1H), 6.93 (t, J= 8.1 Hz, 1H), 4.22-4.15 (m, 1H), 3.74 (s, 3H), 3.71-3.58 (m, 1H), 3.56- 3.38 (m, 3H), 3.37-3.02 (m, 2H), 2.95-2.86 (m, 1H), 2.72 (s, 6H), 2.50-2.23 (m, 1 H).

[0255] Peak 2 (Compound 106): LC-MS (ESI+) m / z 529 [M+H]+; ' H NMR (300 MHz, CDC13) 3 7.85 (d, J == 8.1 Hz, 2H), 7.76 (d, . / 8.4 Hz, 2H), 7.71 (d . / 7.8 Hz, 1 H), 7.20 (d, . / 8.4 Hz, 1H), 6.93 (t, J= 7.8 Hz, 1H), 4.22-4.15 (m, 1H), 3.74 (s, 3H), 3.71-3.58 (m, 1H), 3.55- 3.38 (m, 3H), 3.37-3.02 (m, 2H), 2.95-2.86 (m, 1H), 2.72 (s, 6H), 2.52-2.23 (m, 1H).

[0256] The compounds in Table 5 were prepared according to the procedures for theAttorney Docket No. 01295-0002-00PCT synthesis of Compound 166, Compound 107, and Compound 106, using appropriate starting materials.Table 5.

[0257] Example S8. Synthesis of Compound 135 and Compound 134(stereoisomers)

[0258] Step 1

[0259] To a solution of tert-butyl 10-methyl-l,2,4,4a,5,6-hexahydro-3J / -pyrazino[l,2- a]quinoxaline-3-carboxylate (common intermediate 6; 940 mg, 3.1 mmol) in pyridine (25 mL) at rt was added 4-(N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1;1.6 g, 6.1 mmol). The reaction was stirred at 60 °C for 6 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (200 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was driedAttorney Docket No. 01295-0002-00PCT over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 1.6 g of tert-butyl 6-((4-(A,A-dimethylsulfamoyl)phenyl)sulfonyl)-10-methyl-l,2,4,4a,5,6- hexahydro-3rt-pyrazino[ l ,2-a]quinoxaline-3-carboxylate as a yellow solid. Yield: 93%. LC-MS (ESI+) m / z 550 [M+H]+.

[0260] Step 2

[0261] SFC separation of tert-butyl 6-((4-(A,A-dimethylsulfamoyl)phenyl)sulfonyl)-10- methyl- l ,2,4,4a,5,6-hexahydro-3rt-pyrazino[ l ,2-a]quinoxaline-3-carboxylate 8 (the first eluting isomer, peak 1) and 8’ (the second eluting isomer, peak 2) were prepared according to the synthesis described in Example S6 step 1.

[0262] To a solution of tert-butyl (RJ-6-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)- 10- methyl-l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a]quinoxaline-3-carboxylate (50 mg, 0.1 mmol) at rt in dichloromethane (0.9 mL) was added TFA (0.3 mL). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with ISfeCCh aqueous solution (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 33.6 mg of the title compound as a yellow solid. Yield: 82%. Compound 135: LC-MS (ESI+) m z 451 [M+H]+; ’HNMR (300 MHz, CDC13) 3 7.83-7.74 (m, 5H), 6.96-6.91 (m, 2H), 3.97-3.88 (m, 2H), 3.06-3.02 (m, 1H), 2.92-2.89 (m, 1H), 2.81-2.75 (m, 3H), 2.70 (s, 6H), 2.40-2.28 (m, 1H), 2.25-2.15 (m, 4H)

[0263] To a solution of tert-butyl (NJ-6-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-Attorney Docket No. 01295-0002-00PCT10- methyl-l,2,4,4a,5,6-hexahydro-3H-pyrazino[l,2-a]quinoxaline-3-carboxylate (50 mg, 0.1 mmol) at rt in dichloromethane (0.9 mL) was added TFA (0.3 mL). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with Na2COs aqueous solution (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 29.1 mg of the title compound as a yellow solid. Yield: 71%. Compound 134: LC-MS (ESI+) m z 451 [M+H]+; H l N R (300 MHz, CDC13) (5 7.83-7.76 (m, 5H), 6.96-6.91 (m, 2H), 4.00-3.89 (m, 2H), 3.07-3.03 (m, 1H), 2.92-2.88 (m, 1H), 2.87-2.75 (m, 3H), 2.70 (s, 6H), 2.38-2.28 (m, 1H), 2.27-2.14 (m, 4H)

[0264] Example S9. Synthesis of Compound 177 and its stereoisomers Compound 155 and Compound 154

[0265] Step 1

[0266] To a solution of N,N-dimethyl-4-((10-methyl-l,2,3,4,4a,5-hexahydro-6H- pyrazino[l,2-a]quinoxalin-6-yl)sulfonyl)benzenesulfonamide (50 mg, 0.11 mmol) in dichloromethane (1 mL) at rt was added pivaloyl chloride (27 mg, 0.22 mmol) and DIEA (43 mg, 0.33 mmol). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by LC-MS analysis, water (15 mL) was added to the reaction mixture. The mixture was extracted with di chloromethane (15 mL x 1). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 3: 1) to give 40 mg of the title compound. LC-MS (ESI+) m / z 535 [M+H]+; ‘H NMR (300 MHz, CD3OD) 3 l. (d, . / 8.1 Hz, 2H), 7.76 (d, . / 8.1 Hz, 3H), 7.09-6.95 (m, 2H), 4.20-4.09 (m, 1H), 4.08-3.91 (m, 2H), 3.64-3.51 (m, 1H), 3.46-3.37 (m, 2H), 3.06-2.94 (m, 1H), 2.67 (s,Attorney Docket No. 01295-0002-00PCT6H), 2.54-2.43 (m, 1H), 2.22 (s, 3H), 2.14-2.03 (m, 1H), 1.27 (s, 9H).

[0267] Step 2

[0268] N,N-Dimethyl-4-((10-methyl-l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a] quinoxalin-6-yl)sulfonyl)benzenesulfonamide was separated by chiral column separation using: Instrument: SFC-150 (Thar, Waters) Column: AD 25*250mm, 10 um (Daicel) Column temperature: 35 °C Mobile phase: CO2 / IPA = 77 / 23 Flow rate: lOO g / min Back pressure: 100 bar Detection wavelength: 220 nm Cycle time: 2.0 minSample solution: 30 mg dissolved in 5 ml MethanolInjection volume: 1.0 mL

[0269] The first eluting isomer rel-(7? - N,N-dimethyl-4-((10-methyl-l,2,3,4,4a,5- hexahydro-6H-pyrazino[l,2-a] quinoxalin-6-yl)sulfonyl)benzenesulfonamide (peak 1, 3.1 mg, retention time = 31.22 min) and the second eluting isomer rel-(S)- N,N-dimethyl-4-((10-methyl- l,2,3,4,4a,5-hexahydro-6H-pyrazino[l,2-a] quinoxalin-6-yl)sulfonyl)benzenesulfonamide (peak 2, 3.8 mg, retention time = 26.20 min) were obtained.

[0270] Peak 1 (Compound 155): LC-MS (ESI+) m z 535 [M+H]+;JH NMR (300 MHz, CDCI3) 3 7.78-7.70 (m, 5H), 7.00 (d, J= 5.1 Hz, 2H), 4.25-4.12 (m, 1H), 4.02-3.95 (m, 1H), 3.94-3.83 (ra, 1H), 3.67-3.50 (m, 1H), 3.40-3.22 (m, 2H), 3.08-2.95 (m, 1H), 2.70 (s, 6H), 2.50- 2.38 (m, 1H), 2.21 (s, 3H), 2.15-2.02 (m, 1H), 1.26 (s, 9H).

[0271] Peak 2 (Compound 154): LC-MS (ESI+) m / z: 535 [M+H]+;XH NMR (300 MHz, CDCI3) S 7.80-7.70 (m, 5H), 7.00 (d, . / = 5.1 Hz, 2H), 4.25-4.12 (m, 1H), 4.02-3.95 (m, 1H), 3.94-3.83 (m, 1H), 3.67-3.50 (m, 1H), 3.40-3.22 (m, 2H), 3.08-2.95 (m, 1H), 2.70 (s, 6H), 2.50- 2.38 (m, 1H), 2.21 (s, 3H), 2.15-2.02 (m, 1H), 1.26 (s, 9H).Attorney Docket No. 01295-0002-00PCT

[0272] The compounds in Table 6 were prepared according to the procedures for the synthesis of Compound 134, Compound 135, Compound 177, Compound 155, and Compound 154, using appropriate starting materials.Table 6.Attorney Docket No. 01295-0002-00PCT* Stereochemical configurations were assigned arbitrarily after separation by SFC.

[0273] Example S10. Synthesis of Compound 174 its stereoisomers Compound 139 and Compound 138

[0274] Step 1

[0275] To a solution of 2-fluoro-5-methyl-3-nitropyridine (500 mg, 3.2 mmol) in DMAC(10 mL) was added methyl piperidine-2-carboxylate (687 mg, 4.8 mmol) and K2CO3 (1.4 g, 9.6 mmol). The reaction was stirred at 100 °C for 5 h. After the reaction was completed as indicated by LC-MS analysis, water (50 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 30: 1 to 10: 1) to give 430 mg of the title compound. Yield: 48%. LC-MS (ESI+) m / z 280 [M+H]+.

[0276] Step 2

[0277] To a solution of methyl l-(5-methyl-3-nitropyridin-2-yl)piperidine-2-carboxylate (400 mg, 1.4 mmol) in EtOH (10 mL) and saturated NH4CI aqueous solution (5 mL) was added Fe power (722 mg, 12.9 mmol). The reaction was stirred under reflux for 2 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) andAttorney Docket No. 01295-0002-00PCT extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (15 mL), dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 290 mg of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 218 [M+H]+.

[0278] Step 3

[0279] To a suspension of LiAlH4 (262 mg, 6.9 mmol) in anhydrous THF (10 mL) at 0 °C was added a solution of 3-methyl-7,8,9,10- tetrahydro-5H-dipyrido[l,2-a:3',2'-e]pyrazin- 6(6aH)-one (250 mg, 1.2 mmol) in anhydrous THF (10 mL). The reaction was stirred at 0 °C for7 h. After the reaction was completed as indicated by LC-MS analysis, the reaction was quenched with ice water and NaOH aqueous solution (2 mL, 15 wt. %). After filtration, the filtrate was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 223 mg of the crude title compound, which was directly used for the next step without further purification. LC- MS (ESI+) m / z 204 [M+H]+.

[0280] Step 4

[0281] To a solution of 3-methyl-6,6a,7,8,9,10-hexahydro-5H-dipyrido[l,2-a:3',2'- e]pyrazine (200 mg, 1.0 mmol) in THF (4 mL) was added 4-(N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1, 333 mg, 1.2 mmol) and pyridine (387 mg, 4.9 mmol). The reaction was stirred at 70 °C for 4 h. After the reaction was completed as indicated by TLC analysis, water (8 mL) was added. The mixture was extracted with ethyl acetate (4 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 3: 1) to give 46.5 mg of the title compound (Compound 174). LC-MS (ESI+) m / r. 451 [M+H]+; *H NMR (300 MHz, CDC13) 3 7.91-7.75 (m, 3H), 7.74-7.61 (m, 3H), 4.65 (d, J= 13.5 Hz, 1H), 4.15 (dd, J= 14.4, 3.9 Hz, 1H), 3.19 (t, J= 13.8 Hz, 1H), 2.72 (s, 6H), 2.39-2.30 (m, 1H), 2.24 (s, 3H), 2.07-1.95 (m, 1H), 1.82-Attorney Docket No. 01295-0002-00PCT1.72 (m, 1H), 1.68-1.55 (m, 2H), 1.45-1.32 (m, 1H), 1.20-1.01 (m, 2H).

[0282] After separation by SFC, 12.5 mg of peak 1 and 13.6 mg of peak 2 were obtained.

[0283] Peak 1 (Compound 139): LC-MS (ESI+) m / z 451 [M+H]+;1H NMR (300 MHz, CDC13) 3 7.91-7.75 (m, 3H), 7.74-7.61 (m, 3H), 4.65 (d, J= 13.5 Hz, 1H), 4.15 (dd, J= 14.4, 3.9 Hz, 1H), 3.19 (t, J= 13.8 Hz, 1H), 2.72 (s, 6H), 2.39-2.30 (m, 1H), 2.24 (s, 3H), 2.07-1.95 (m, 1H), 1.82-1.72 (m, 1H), 1.68-1.55 (m, 2H), 1.45-1.32 (m, 1H), 1.20-1.01 (m, 2H).

[0284] Peak 2 (Compound 138): LC-MS (ESI+) m / z: 451 [M+H]+;1H NMR (300 MHz, CDCI3) 3 7.91-7.75 (m, 3H), 7.74-7.61 (m, 3H), 4.65 (d, J= 13.5 Hz, 1H), 4.15 (dd, J= 14.4, 3.9 Hz, 1H), 3.19 (t, J= 13.8 Hz, 1H), 2.72 (s, 6H), 2.39-2.30 (m, 1H), 2.24 (s, 3H), 2.07-1.95 (m, 1H), 1.82-1.72 (m, 1H), 1.68-1.55 (m, 2H), 1.45-1.32 (m, 1H), 1.20-1.01 (m, 2H).

[0285] The compounds in Table 7 were prepared according to the procedures for the synthesis of Compound 174, Compound 139, and Compound 138, using appropriate starting materials.Table 7.Attomey Docket No. 01295-0002-00PCT

[0286] Example Sil. Synthesis of Compound 176 its stereoisomers Compound 143 and Compound 142

[0287] Step 1

[0288] To a solution of l-fluoro-2-nitrobenzene (500 mg, 3.5 mmol) in EtOH (5 mL) and water (5 mL) at rt was added NaHCCh (744 mg, 8.9 mmol) and piperidine-2-carboxylic acid (458 mg, 3.5 mmol). The reaction was stirred under reflux overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated and acidified with a diluted HC1 solution (1 M) to pH ~ 3. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (di chloromethane: methanol = 20: 1) to give 710 mg of the title compound as a brown solid. Yield: 80%. LC-MS (ESI+) m / z 251 [M+H]+.

[0289] Step 2

[0290] To a solution of l-(2-nitrophenyl)piperidine-2-carboxylic acid (710 mg, 2.8 mmol) in methanol (5 mL) at rt was added SOCL (0.5 mL). The reaction was stirred at rt overnight. After the reaction was completed as indicated by LC-MS analysis, saturated NaHCCL aqueous solution (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give 660 mg of the title compound as yellow oil. Yield: 88%. LC-Attorney Docket No. 01295-0002-00PCTMS (ESI+) m / z 265 [M+H]+.

[0291] Step 3

[0292] To a solution of methyl l-(2-nitrophenyl)piperidine-2-carboxylate (660 mg, 2.5 mmol) in EtOH (10 mL) and saturated NH4CI aqueous solution (10 mL) was added Fe power (558 mg, 10.0 mmol). The reaction was stirred at 40 °C for 2 h. After the reaction was completed as indicated by TLC analysis, the reaction was filtered, and the filtrate was concentrated. The resulting solution was diluted with brine (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 420 mg of the title compound as a white solid. Yield: 88%. LC-MS (ESI+) m / z 203 [M+H]+.

[0293] Step 4

[0294] To a solution of 7,8,9, 10-tetrahydro-5H-pyrido[l,2-a]quinoxalin-6(6aH)-one (100 mg, 0.5 mmol) in anhydrous THF (5 mL) at rt was added NaH (40 mg, 1.0 mmol). The reaction was stirred for 30 min. Then, 4-(N,N-dimethyl sulfamoyl) benzenesulfonyl chloride (common intermediate 1, 281 mg, 1.0 mmol) was added. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give 45.4 mg of the title compound (Compound 176) as a white solid. Yield: 20%. LC-MS (ESI+) m / z 450 [M+H]+; *H NMR (300 MHz, CDCI3) 3 8.23 (d, J= 8.4 Hz, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 7.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.03 (t, J= 7.8 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.61-3.50 (m, 1H), 3.28-3.12 (m, 1H), 2.75 (s, 6H), 2.67-2.56 (m, 1H), 2.20-2.08 (m, 1H), 1.91-Attorney Docket No. 01295-0002-00PCT1.72 (m, 2H), 1.42-1.25 (m, 3H). After SFC separation, 16.1 mg of peak 1 and 15.2 mg of peak 2 were obtained.

[0295] Peak 1 (Compound 143): LC-MS (ESI+) m / z 450 [M+H]+;1H NMR (300 MHz, CDC13) 3 8.23 (d, J= 8.4 Hz, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 7.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.03 (t, J= 7.8 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.61-3.50 (m, 1H), 3.28-3.12 (m, 1H), 2.75 (s, 6H), 2.67-2.56 (m, 1H), 2.20-2.08 (m, 1H), 1.91-1.72 (m, 2H), 1.41-1.25 (m, 3H).

[0296] Peak 2 (Compound 142): LC-MS (ESI+) m / z 450 [M+H]+;1H NMR (300 MHz, CDCI3) d 8.23 (d, J= 8.4 Hz, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 7.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.03 (t, J= 7.8 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.61-3.50 (m, 1H), 3.28-3.12 (m, 1H), 2.75 (s, 6H), 2.67-2.56 (m, 1H), 2.20-2.08 (m, 1H), 1.91-1.72 (m, 2H), 1.41-1.25 (m, 3H).

[0297] Example S12. Synthesis of Compound 164 and Compound 163 (stereoisomers)

[0298] Step 1

[0299] To a solution of methyltriphenylphosphonium bromide (12.5g, 35.0 mmol) in anhydrous THF (100 mL) at 0 °C was added t-BuOK (35 mL, 1.0 mol / L in THF). After stirring at 0 °C for 1 h, a solution of 1 -(tert-butyl) 2-methyl 4-oxopiperidine-l,2-dicarboxylate (3.0 g, 11.7 mmol) in anhydrous THF (10 mL) was added to the above mixture. The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC, the reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to give 2.0 g of the title compound as colorless oil. Yield: 67%. LC- MS (ESI+) m / z 256 [M+H]+.Attorney Docket No. 01295-0002-00PCT

[0300] Step 2

[0301] To a solution of 1 -(tert-butyl) 2-methyl 4-methylenepiperidine- 1,2-di carboxylate (2.0 g, 7.8 mmol) in methanol (10 mL) was added 5% Pd / C (200 mg). The reaction was stirred at rt under H2 atmosphere for 2 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2.0 g of the crude title compound as colorless oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z'. 258[M+H]+.

[0302] Step 3

[0303] To a solution of 1 -(tert-butyl) 2-methyl 4-methylpiperidine-l,2-dicarboxylate (1.9 g, 7.4 mmol) in THF (20 mL) and water (5 mL) was added LiOHTLO (929 mg, 22.2 mmol).The reaction was stirred at rt overnight. After the reaction was completed as indicated by LC- MS analysis, the reaction mixture was acidified with a diluted HC1 solution (1 M) to pH ~ 4. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 1.8 g of the crude title compound as pale-yellow oil, which was directly used for the next step without further purification. LC-MS (ESI+) m z 244 [M+H]+.

[0304] Step 4

[0305] To a solution of l-(tert-butoxycarbonyl)-4-methylpiperidine-2-carboxylic acid (1.8 g, 7.4 mmol) in 1,4-dioxane (5 mL) was added HC1 solution (5 mL, 4.0 mol / L in 1, 4- dioxane). The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 1.3 g of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m z 144 [M+H]+.

[0306] Step 5Attorney Docket No. 01295-0002-00PCT

[0307] To a solution of 5-methylpiperidine-2-carboxylic acid (600 mg, 3.3 mmol) in EtOH (20 mL) and water (20 mL) was added NaHCCL (982 mg, 11.7 mmol) and l-fluoro-2- nitrobenzene (471 mg, 3.3 mmol). The reaction was stirred under reflux overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure and acidified with a diluted HC1 aqueous solution (1 M) to pH ~ 3. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (di chloromethane: methanol = 20: 1) to give 470 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z 265 [M+H]+.

[0308] Step 6

[0309] To a solution of 5-methyl-l-(2-nitrophenyl)piperidine-2-carboxylic acid (470 mg, 1.8 mmol) in methanol (25 mL) at rt was added SOCL (2.5 mL). The reaction was stirred at 50 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction was concentrated and quenched with saturated NaHCCL aqueous solution (15 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give 300 mg of the title compound (trans isomer) and 80 mg of the title compound (cis isomer).

[0310] Trans isomer, LC-MS (ESI+) m / z: 279 [M+H]+;1H NMR (300 MHz, CDCI3) 3 7.77 (d, J= 8.1 Hz, 1H), 7.46 (t, J= 7.8 Hz, 1H), 7.30-7.26 (m, 1H), 7.00 (t, J= 7.8 Hz, 1H), 4.09-4.05 (m, 1H), 3.64 (s, 3H), 3.62-3.59 (m, 1H), 3.17-3.13 (m, 1H), 2.15-2.04 (m, 1H), 1.74- 1.63 (m, 2H), 1.52-1.34 (m, 2H), 0.98 (d, J= 6.0 Hz, 3H).

[0311] Cis isomer, LC-MS (ESI+) m / z: 279 [M+H]+;1H NMR (300 MHz, CDCI3) d 7.67 (d, J= 7.8 Hz, 1H), 7.47 (t, J= 7.8 Hz, 1H), 7.31-7.26 (m, 1H), 7.20 (t, J= 7.5 Hz, 1H), 3.83 (d, J= 10.2 Hz, 1H), 3.64 (s, 3H), 3.62-3.59 (m, 1H), 2.64 (t, J= 11.1 Hz, 1H), 2.05-2.01 (m, 1H), 1.72-1.62 (m, 2H), 1.52-1.40 (m, 2H), 1.00 (d, J= 5.7 Hz, 3H).Attorney Docket No. 01295-0002-00PCT

[0312] Step 7

[0313] To a solution of rec-methyl (25, 4S)-4- methyl- 1 -(2 -nitrophenyl)piperidine-2- carboxylate (300 mg) in methanol (5 mL) at rt was added 5% Pd / C (30 mg). The mixture was stirred under H2 atmosphere at 35 °C for 1.5 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 170 mg of the title compound. LC-MS (ESI+) m / z: 217 [M+H]+.

[0314] To a solution of methyl rec-(2R, 4S)-4- methyl-l-(2-nitrophenyl)piperidine-2- carboxylate (82 mg) in methanol (2 mL) at rt was added 5% Pd / C (10 mg). The mixture was stirred under H2 atmosphere at 35 °C for 1.5 h. After the reaction was completed as indicated by LC-MS analysis, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 30 mg of the title compound. LC-MS (ESI+) m / z 217 [M+H]+.

[0315] Step 8

[0316] To a solution of rec-8-methyl-7,8,9,10-tetrahydro-5H-pyrido[l,2-a] quinoxalin- 6(6aH)-one (1.0 eq) in anhydrous THF (5 mL) was added NaH (2.0 eq). The reaction was stirred at rt for 30 min. Then 4-(N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1, 2.0 eq) was added. The reaction was stirred at rt for 2 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (10 mL) and extracted ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 14: 1) to give the title compound as an off white solid.Attorney Docket No. 01295-0002-00PCT

[0317] 46.9 mg of rec-N,N-dimethyl-4-(((6aS',AS')-8-methyl-6-oxo-6,6a,7,8,9, I O- hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)benzenesulfonamide (trans isomer) was obtained from 70 mg of rec-(6a ,&S)-8-methyl-7,8,9,10-tetrahydro-5H-pyrido[l,2-a] quinoxalin- 6(6aH)-one according the procedure above. Yield: 31%. Compound 163: LC-MS (ESI+) m / z 464 [M+H]+; *H NMR (300 MHz, CDC13) 3 8.22 (d, J= 8.1 Hz, 2H), 7.92 (d, J= 8.1 Hz, 2H), 7.61 (d, J= 8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.10-7.00 (m, 2H), 3.46-3.42 (m, 1H), 3.13-3.11 (m, 1H), 2.98-2.92 (m, 1H), 2.75 (s, 6H), 2.00-1.92 (m, 1H), 1.78-1.67 (m, 3H), 1.55 (s, 1H), 0.97 (d, J = 6.9 Hz, 3H).

[0318] 16.9 mg of rec-N,N-dimethyl-4-(((6a / ?,&S')-8-methyl-6-oxo-6,6a,7,8,9,10- hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)benzenesulfonamide (cis isomer) was obtained from 30 mg of rec-(6a / ?,S5)-8-methyl-7,8,9,10-tetrahydro-5H-pyrido[l,2-a] quinoxalin-6(6aH)-one according the procedure above. Yield: 26%. Compound 164: LC-MS (ESI+) m / z 464 [M+H]+; *H NMR (300 MHz, CDCI3) d 8.23 (d, J= 8.1 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.57 (d, J= 8.1 Hz, 1H), 7.25-7.20 (m, 1H), 7.03 (t, J= 7.8 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.61-3.57 (m, 1H), 3.25-3.23 (m, 1H), 2.75 (s, 6H), 2.71-2.61 (m, 1H), 2.13-2.07 (m, 1H), 1.80-1.70 (m, 1H), 1.50-1.40 (m, 1H), 1.38-1.30 (m, 1H), 1.11-1.02 (m, 1H), 0.97 (d, J= 6.6 Hz, 3H).

[0319] Example S13. Synthesis of Compound 156

[0320] Step 1

[0321] To a solution of (methoxymethyl)triphenylphosphonium chloride (4.4 g, 12.8 mmol) in anhydrous THF (70 mL) at 0 °C was added t-BuOK (13 mL, 1.0 mol / L in THF, 12.8 mmol). After stirring at 0 °C for 20 min, a solution of quinoxaline-2-carbaldehyde (1.0 g, 6.4 mmol) in anhydrous THF (20 mL) was added. The reaction was stirred at 0 °C for 3 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (300 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 580 mg of the title compound as yellow oil. Yield: 49%. LC- MS (ESI+) m / z 187 [M+H]+.Attorney Docket No. 01295-0002-00PCT

[0322] Step 2

[0323] To a solution of (E)-2-(2-methoxyvinyl)quinoxaline (580 mg, 3.1 mmol) in 1,4- dioxane (15 mL) at 0 °C was added a diluted HC1 solution (15 mL, 3 M). The reaction was stirred at 0 °C for 30 min. After the reaction was completed as indicated by TLC analysis, the reaction mixture was neutralized with saturated NaHCCh aqueous solution to pH ~ 8. The mixture was extracted with ethyl acetate (15 mL x 4). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 896 mg of the crude title compound as brown oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 173 [M+H]+.

[0324] Step 3

[0325] To a solution of 2-(quinoxalin-2-yl)acetaldehyde (896 mg, 3.1 mmol) in dichloromethane (40 mL) at rt was added ethyl (triphenylphosphanylidene)acetate (2.2 g, 6.2 mmol). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, water (50 mL) was added. The mixture was extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give 680 mg of the title compound as brown oil. LC-MS (ESI+) m / z 243 [M+H]+.

[0326] Step 4

[0327] To a solution of ethyl (E)-4-(quinoxalin-2-yl)but-2-enoate (680 mg, 2.8 mmol) in ethyl acetate (25 mL) at rt was added 10% Pd(OH)2 / C (80 mg). The reaction was stirred at rt under H2 atmosphere for 7 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 285 mg of the title compound as a yellow solid. Yield: 41%. LC-MS (ESI+) m / z 249 [M+H]+.

[0328] Step 5Attorney Docket No. 01295-0002-00PCT

[0329] To a solution of ethyl 4-(l,2,3,4-tetrahydroquinoxalin-2-yl)butanoate (285 mg, 1.15 mmol) in EtOH (10 mL) was added EtONa (1.5 mL, 20wt% in EtOH, 4.6 mmol). The reaction was stirred under reflux for 2 h. The hydrolyzed acid product was detected by LC-MS analysis. The reaction mixture was quenched with H2O (8 mL) and adjusted with saturated NaHCOs aqueous solution to pH ~ 8. The mixture was extracted with ethyl acetate (10 mL x 2). The aqueous solution was concentrated. The residue was washed with EtOH (10 mL) and ethyl acetate (10 mL). The combined organic phase was concentrated under reduced pressure to give 180 mg of the crude title compound as brown oil. LC-MS (ESI+) m / z l\ [M+H]+.

[0330] Step 6

[0331] To a solution of 4-(l,2,3,4-tetrahydroquinoxalin-2-yl)butanoic acid (162 mg, 0.7 mmol) in dichloromethane (15 mL) was added HATU (364 mg, 1.0 mmol) and DIEA (380 mg, 2.9 mmol). The reaction was stirred at rt for 2 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1 to 1 : 1) to give 125 mg of the title compound as a brown solid. Yield: 84%. LC-MS (ESI+) m / z'. 203 [M+H]+.

[0332] Step 7

[0333] To a solution of 5,6,6a,7,8,9-hexahydro-10H-pyrido[l,2-a]quinoxalin-10-one(125 mg, 0.6 mmol) in CH3CN (20 mL) was added 4-(N,N-dimethyl sulfamoyl) benzenesulfonyl chloride (common intermediate 1, 228 mg, 0.8 mmol) and KOH (70 mg, 1.2 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, water (80 mL) was added. The mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleumAttorney Docket No. 01295-0002-00PCT ether: ethyl acetate = 3 : 1 to 1 : 1) to give 45.1 mg of the title compound (Compound 156) as a white solid. Yield: 16%. LC-MS (ESI+) m / z 450 [M+H]+; *H NMR (300 MHz, CDC13) 8 7.82- 7.78 (m, 3H), 7.66-7.60 (m, 3H), 7.26-7.20 (m, 2H), 4.09 (d, J= 9.2 Hz, 1H), 3.74-3.63 (m, 2H), 2.75 (s, 6H), 2.38-2.27 (m, 1H), 2.14-1.99 (m, 2H), 1.83-1.73 (m, 1H), 1.70-1.58 (m, 2H).

[0334] Example S14. Synthesis of Compound 87

[0335] To a solution of (RJ-9-(trifluoromethyl)-l,2,4,4a,5,6-hexahydro-[l,4]oxazino[4,3- a] quinoxaline (common intermediate 8, 100 mg, 0.39 mmol) in THF (4 mL) at rt was added 4- (N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1, 165 mg, 0.58 mmol) and pyridine (92 mg, 1.16 mmol). After the reaction was stirred at 60 °C overnight, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 2: 1) to give 39.1 mg of the title compound (Compound 87). LC-MS (ESI+) m / z 506 [M+H]+; *H NMR (300 MHz, CDCI3) 8 7.86 (d, J= 8.1 Hz, 2H), 7.78 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.4 Hz, 2H), 7.07 (d, J= 8.1 Hz, 1H), 6.92 (s, 1H), 4.21-4.15 (m, 1H), 4.01-3.91 (m, 1H), 3.80-3.75 (m, 1H), 3.59-3.41 (m, 2H), 3.28-3.19 (m, 1H), 3.08 (t, J= 10.8 Hz, 1H), 2.72 (s, 6H), 2.68-2.60 (m, 2H).

[0336] The following compounds in Table 8 were prepared according to the synthesis of Compound 87, using appropriate starting materials.Table 8.Attorney Docket No. 01295-0002-00PCT

[0337] Example S15. Synthesis of Compound 88Attorney Docket No. 01295-0002-00PCT

[0338] Step 1

[0339] To a solution of (7?J-4-(tert-butoxycarbonyl)thiomorpholine-3 -carboxylic acid(1.0 g, 4.05 mmol) in dichloromethane (10 mL) at rt was added TFA (3 mL). The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 2.1 g of the crude title compound as black oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 148 [M+H]+.

[0340] Step 2

[0341] To a solution of (RJ-thiomorpholine-3-carboxylic acid (2.1 g, 4.00 mmol) inDMAC (10 mL) at rt was added l-fluoro-2-nitrobenzene (500 mg, 3.54 mmol) and CS2CO3 (5.7 g, 17.70 mmol). The reaction was stirred at 100 °C for 6 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (50 mL). The aqueous phase was acidified with a diluted HC1 aqueous solution (3 M) to pH = 2 ~ 3. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 700 mg of the crude title compound as yellow oil, which was used for the next step without further purification. LC-MS (ESI+) m / z 269 [M+H]+.

[0342] Step 3Attorney Docket No. 01295-0002-00PCT

[0343] To a solution of (RJ-4-(2-nitrophenyl)thiomorpholine-3-carboxylic acid (600 mg, 2.23 mmol) in MeOH (10 mL) at rt was added SOCI2 (800 mg, 6.71 mmol). The reaction mixture was stirred at rt for 4 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 400 mg of the title compound as brown oil. Yield: 63%. LC-MS (ESI+) m / z 283 [M+H]+.

[0344] Step 4

[0345] To a solution of K -methyl 4-(2-nitrophenyl)thiomorpholine-3-carboxylate (200 mg, 0.71 mmol) in EtOH (5 mL) and H2O (2.5 mL) at 0 °C was added oxone (1.3 g, 2.13 mmol). The reaction was stirred at 0 °C for 2 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated and diluted with water (20 mL). The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 170 mg of the title compound as yellow oil. Yield: 76%. LC-MS (ESI+) m / z 315 [M+H]+.

[0346] Step 5

[0347] To a solution of K -methyl 4-(2-nitrophenyl)thiomorpholine-3-carboxylate 1,1- di oxide (170 mg, 0.54 mmol) in EtOH (2 mL) and saturated ammonium chloride aqueous solution (2 mL) at rt was added Fe power (273 mg, 4.38 mmol). The reaction mixture was stirred at 80 °C for 3 h. After the reaction was completed as indicated by LC-MS analysis, theAttorney Docket No. 01295-0002-00PCT reaction mixture was filtered, and concentrated. The resulting solution was diluted with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 100 mg of the title compound as a pink solid. Yield: 73%. LC- MS (ESI+) m / z 253 [M+H]+.

[0348] Step 6

[0349] To a solution of (RJ-l,2,4,4a-tetrahydro-[l,4]thiazino[4,3-a] quinoxalin-5(6H)- one 3,3-dioxide (100 mg, 0.40 mmol) in anhydrous THF (3 mL) at rt under N2 was added borane tetrahydrofuran complex (2 mL, 1 mol / L in THF). The reaction was stirred at 60 °C for 3 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 90 mg of the title compound as a yellow solid. Yield: 94%. LC-MS (ESI+) m / z 239 [M+H]+.

[0350] Step 7

[0351] To a solution of A)-l,2,4,4a,5,6-hexahydro-[l,4]thiazino[4,3-a]quinoxaline 3,3- dioxide (90 mg, 0.32 mmol) in THF (4 mL) at rt was added 4-(N,N-dimethylsulfamoyl) benzenesulfonyl chloride (common intermediate 1, 160 mg, 0.57 mmol) and pyridine (90 mg, 1.15 mmol). The reaction was stirred at 60 °C for 4 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 3: 1 to 1 : 1) toAttorney Docket No. 01295-0002-00PCT give 47.7 mg of the title compound (Compound 88) as a yellow solid. Yield: 26%. LC-MS (ESI+) m / z 486 [M+H]+; *H NMR (300 MHz, CDC13) 7.89 (d, J= 8.1 Hz, 2H), 7.80 (d, J= 8.7 Hz, 2H), 7.45 (d, J= 8.4 Hz, 1H), 7.17 (t, J= 7.7 Hz, 1H), 6.87 (t, J= 7.8 Hz, 1H), 6.78 (t, J =7.5 Hz, 1H), 4.24-4.18 (m, 1H), 4.07-4.03 (m, 1H), 3.69-3.55 (m, 2H), 3.06-2.82 (m, 5H), 2.76 (s, 6H).

[0352] Example S16. Synthesis of Compound 121 and Compound 120 (stereoisomers)

[0353] Step 1

[0354] To a solution of (7? -l-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid(2.0 g, 8.22 mmol) in dichloromethane (15 mL) at rt was added TFA (5 mL). The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 3.7 g of the crude title compound as black oil, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 144 [M+H]+.

[0355] Step 2

[0356] To a solution of K)-4-oxopiperidine-2-carboxylic acid (3.7 g, 8.22 mmol) in acetonitrile (30 mL) at rt was added 1 -chi oro-2-fluoro-3 -nitrobenzene (1.74 g, 9.87 mmol) and CS2CO3 (8.4 g, 24.67 mmol). The reaction mixture was stirred at 60 °C for 2 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (50 mL). The aqueous phase was acidified with a diluted HC1 solution (3 M) to pH ~ 4 and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 1.1 g of the crude title compound as a brown solid, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 299 [M+H]+.

[0357] Step 3Attomey Docket No. 01295-0002-00PCT

[0358] To a solution of (RJ-l-(2-chloro-6-nitrophenyl)-4-oxopiperidine-2-carboxylic acid (1.08 g,3.62 mmol) in DMF (20 mL) at 0 °C was added methyl iodide (670 mg, 4.71 mmol) and potassium carbonate (1.0 g 7.25 mmol). The reaction mixture was stirred at rt for 2 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduces pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 670 mg of the title compound as brown oil. Yield: 59%. LC-MS (ESI+) m / z 313 [M+H]+.

[0359] Step 4

[0360] To a solution of K -methyl l-(2-chloro-6-nitrophenyl)-4-oxopiperidine-2- carboxylate (670 mg, 2.15 mmol) in EtOH (5 mL) and saturated ammonium chloride aqueous solution (5 mL) at rt was added Fe power (360 mg, 6.44 mmol). The reaction mixture was stirred at 80 °C for 4 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was filtered, and the filtrate was concentrated. The resulting solution was diluted with water (30 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 360 mg of the title compound as a yellow solid. Yield: 67%. LC-MS (ESI+) m / z 251 [M+H]+.

[0361] Step 5

[0362] To a solution of (R -l-chloro-6a,7,9,10-tetrahydro-5H- pyrido[l,2-a]quinoxaline-Attomey Docket No. 01295-0002-00PCT6,8-dione (440 mg, 1.76 mmol) in anhydrous THF (10 mL) at 0 °C under N2 was added methylmagnesium bromide (3.5 mL, 1 mol / L in THF). The reaction was stirred at 0 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1 : 1) to give 230 mg of the mixture of the title compounds as yellow oil. Yield: 49%. LC-MS (ESI+) m / z 267 [M+H]+.

[0363] Step 6

[0364] To a solution of (6aR,S5)-l-chloro-8-hydroxy-8- methyl-7,8,9,10-tetrahydro-5H- pyridof 1 ,2-a]quinoxalin-6(6aH)-one and ( 6aR, 8R)~ 1 -chloro-8-hydroxy-8-methyl-7,8,9, 10- tetrahydro-5H-pyrido[l,2-a]quinoxalin-6(6aH)-one (210 mg, 0.79 mmol) in anhydrous THF (5 mL) at rt under N2 was added borane tetrahydrofuran complex (3.2 mL, 1 mol / L in THF). The reaction was stirred at 80 °C for 7 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1 to 3: 1) to give 100 mg of the mixture of the title compounds as yellow oil. Yield: 50%. LC-MS (ESI+) m / z: 253 [M+H]+.

[0365] Step 7

[0366] To a solution of (6aA,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido [l,2-a]quinoxalin-8-ol and (6aA,SA)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro- 5H- pyrido[l,2-a]quinoxalin-8-ol (80 mg, 0.32 mmol) in THF (3 mL) at rt was added 4-(N,N-Attorney Docket No. 01295-0002-00PCT dimethylsulfamoyl)benzenesulfonylchloride (134 mg, 0.48 mmol) and pyridine (76 mg, 0.95 mmol). The reaction was stirred at 60 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 27.7 mg of Compound 121 and 6.4 mg of Compound 120. The stereo configuration of these two compounds was arbitrarily assigned.

[0367] Compound 121: LC-MS (ESI+) m / z 500 [M+H]+; 'H NMR (300 MHz, CDC13) 3 7.84 (d, J= 8.2 Hz, 2H), 7.80-7.67 (m, 3H), 7.18 (d, J= 8.0 Hz, 1H), 6.90 (t, J= 8.1 Hz, 1H), 4.06 (dd, J= 13.1, 3.7 Hz, 1H), 3.81 (t, J= 12.5 Hz, 1H), 2.95-2.80 (m, 2H), 2.71 (s, 6H), 2.48- 2.37 (m, 1H), 1.84-1.68 (m, 2H), 1.53-1.48 (m, 1H), 1.20 (s, 3H), 1.19-1.16 (m, 1H).

[0368] Compound 120: LC-MS (ESI+) m / z 500 [M+H]+;1H NMR (300 MHz, CDCI3) 3 7.86 (d, J= 8.1 Hz, 2H), 7.75 (d, J= 8.1 Hz, 2H), 7.54 (d, J =8.1 Hz, 1H), 7.20 (d, J= 7.8 Hz, 1H), 6.76 (t, J= 8.1 Hz, 1H), 4.22 (d, J= 7.3 Hz, 1H), 3.83 (d, J= 11.7 Hz, 1H), 3.15-3.03 (m, 2H), 2.72 (s, 6H), 2.11-1.71 (m, 2H), 1.56-1.41 (m, 2H), 1.28-1.25 (m, 1H), 1.21 (s, 3H).

[0369] The following compounds in Table 9 were prepared according to the synthesis of Compound 121 and Compound 120, using appropriate starting materials.Table 9.

[0370] Example S17. Synthesis of Compound 128

[0371] Step 1

[0372] To a solution of 5-bromopicolinonitrile (3.0 g, 16.4 mmol) and titanium tetraisopropanolate (5.1 g, 18.0 mmol) in anhydrous THF (160 mL) at -10 °C was slowly addedAttorney Docket No. 01295-0002-00PCTEtMgBr (57 mL, 1.0 mol / L in THF, 57.4 mmol). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (150 mL). After filtration, the solution was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 200: 1 to 100: 1) to give 1.5 g of the title compound as a brown solid. Yield: 43%. LC-MS (ESI+) m / z 213 [M+H]+.

[0373] Step 2

[0374] To a solution of l-(5-bromopyridin-2-yl)cyclopropan-l -amine (1.4 g, 6.6 mmol) in dichloromethane (65 mL) was added TEA (2.0 g, 19.7 mmol) and (Boc)2O (2.2 g, 9.9 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (80 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to give 1.3 g of the title compound as a yellow solid. Yield: 63%. LC-MS (ESI+) m / z 313 [M+H]+.

[0375] Step 3

[0376] A solution of tert-butyl (l-(5-bromopyridin-2-yl) cyclopropyl)carbamate (1.3 g, 4.2 mmol), benzyl mercaptan (775 mg, 6.2 mmol), DIEA (1.6 g, 12.5 mmol), Xantphos (243 mg, 0.4 mmol), and Pd2(dba)s (307 mg, 0.4 mmol) in toluene (40 mL) under N2 was stirred at 100 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 7: 1) to give 840 mg of the title compound as yellow oil. Yield: 57%. LC-MS (ESI+) m / z 357 [M+H]+.

[0377] Step 4Attorney Docket No. 01295-0002-00PCT

[0378] To a solution of tert-butyl (l-(5-(benzylthio)pyridin-2-yl)cyclopropyl)carbamate (810 mg, 2.3 mmol) in di chloromethane (18 mL) and water (3 mL) at 0 °C was added cone. HC1 (810 mg). After stirring for 20 min, TCCA (1.1 g, 4.5 mmol) was added to the above mixture. The reaction was stirred at 0 °C for 2 h. After the reaction was completed as indicated by LC- MS analysis, the reaction mixture was quenched with water (30 mL). The mixture was extracted with dichloromethane (15 mL x 2). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 780 mg of the title compound as black oil, which was directly used for the next step without further purification.

[0379] Step 5

[0380] To a solution of da ,&R -l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido [l,2-a]quinoxaline (50 mg, 0.2 mmol) in THF (2 mL) at rt was added tert-butyl (l-(5- (chlorosulfonyl)pyridin-2-yl)cyclopropyl)carbamate (150 mg, 0.4 mmol) and pyridine (50 mg, 0.6 mmol). The reaction was stirred at 65 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction was quenched with water (10 mL) and extracted ethyl acetate (15 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to give 90 mg of the title compound as a yellow solid. LC-MS (ESI+) m / r. 533 [M+H]+.

[0381] Step 6

[0382] To a solution of tert-butyl (l-(5-(((6a5,SA)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)pyridin-2-yl)cyclopropyl)carbamate (90Attorney Docket No. 01295-0002-00PCT mg, 0.2 mmol) in dichloromethane (1.2 mL) at 0 °C was added TFA (0.4 mL). The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 190 mg of the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 433 [M+H]+.

[0383] Step 7

[0384] To a solution of crude l-(5-(((6a5,SA)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro -5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)pyridin-2-yl)cyclopropan-l-amine (170 mg, 0.4 mmol) in methanol (4 mL) was added formaldehyde solution (2 mL, 37 wt.% in H2O). After the reaction was stirred at rt for 30 min, NaBH(OAc)3 (255 mg, 1.2 mmol) was added. The reaction was stirred at rt for 4 h. After the reaction was completed as indicated by LC-MS analysis, the reaction mixture was quenched with water (15 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 33.2 mg of the title compound (Compound 128) as a white solid. LC-MS (ESI+) m / z 461 [M+H]+;JH NMR (300 MHz, CDCI3) 3 8.74 (s, 1H), 7.70 (dd, J= 6.0, 2.1 Hz, 1H), 7.55-7.45 (m, 2 H), 7.17 (d, J= 6.9 Hz, 1H), 6.71 (t, J= 7.5 Hz, 1H), 4.23 (dd, J= 14.1, 4.2 Hz, 1H), 4.05 (d, J=13.2 Hz, 1 H), 3.12-3.03 (m, 1H), 2.81-2.78 (m, 1H), 2.37 (s, 6H), 1.72-1.61 (m, 2H), 1.52-1.48 (m, 1H), 1.47-1.38 (m, 2H), 1.26-1.11 (m, 4H), 0.91 (d, J= 5.7 Hz, 3H), 0.88-0.81 (m, 1H).

[0385] Example S18. Synthesis of Compound 157Step 1 & 2

[0386] To a solution of benzene- 1 ,4-dithiol (1.0 g, 7.0 mmol) in DMF (10 mL) at 0 °C was added terLbutyl 3 -iodoazetidine- 1 -carboxylate (1.4 g, 4.9 mmol) and K2CO3 (1.9 g, 14.1Attorney Docket No. 01295-0002-00PCT mmol). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by LC-MS analysis, BnBr (2.4 g, 14.1 mmol) was added. After the reaction was stirred at rt for 1 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to give 1.3 g of the title compound. Yield: 48% for two steps. LC-MS (ESI+) m / z 388 [M+H]+.

[0387] Step 3

[0388] To a solution of tert-butyl 3 -((4-(benzylthio)phenyl)thio)azetidine-l -carboxylate (1.3 g, 3.4 mmol) in CH3CN (52 mL) at 0 °C was added a diluted HC1 aqueous solution (5.2 mL, 2 M) and NCS (2.2 g, 16.8 mmol). After the reaction was stirred at 0 °C for 30 min, oxone (2.5 g, 4.0 mmol) was added. The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by TLC analysis, water (100 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give 1.5 g of the crude title compound.

[0389] Step 4

[0390] To a solution of (6a ,SA)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxaline (30 mg, 0.1 mmol) in THF (3 mL) at rt was added tert-butyl 3-((4- (chlorosulfonyl)phenyl)sulfonyl)azetidine-l -carboxylate (150 mg, 0.4 mmol) and pyridine (30 mg, 0.4 mmol). The reaction was stirred at 90 °C overnight. After the reaction was completed as indicated by TLC analysis, water (10 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 23 mg of the titleAttorney Docket No. 01295-0002-00PCT compound. LC-MS (ESI+) m / z 596 [M+H]+.

[0391] Step 5

[0392] To a solution of tert-butyl 3-((4-(((6a ,SA)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro-5H-pyrido[ 1 ,2-a]quinoxalin-5-yl)sulfonyl)phenyl)sulfonyl)azetidine- 1 -carboxylate (23 mg) in dichloromethane (3 mL) at rt was added TFA (1 mL). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction was adjusted with saturated NaHCCL aqueous solution to pH ~ 9. The mixture was extracted with dichloromethane (2 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was washed with Et2O and filtered to give 11 mg of the title compound (Compound 157). Yield: 58%. LC- MS (ESI+) m / z 496 [M+H]+; *H NMR (300 MHz, CD3OD) 3 8.09 (d, J= 8.1 Hz, 2H), 7.83 (d, J= 8.1 Hz, 2H), 7.47 (d, J= 7.8 Hz, 1H), 7.21 (d, J= 7.8 Hz, 1H), 6.77 (t, J= 7.51 Hz, 1H), 4.51-4.44 (m, 1H), 4.30-4.27 (m, 1H), 4.04-3.94 (m, 3H), 3.74-3.67 (m, 2H), 3.53-3.50 (m, 1H), 3.12-3.03 (m, 1H), 2.65-2.61 (m, 1H), 1.63-1.60 (m, 1H), 1.54-1.50 (m, 1H), 1.33-1.29 (m, 2H), 0.91 (d, J= 6.0 Hz, 3H), 0.80-0.76 (m, 1H).

[0393] Example S19. Synthesis of Compound 168

[0394] Step 1

[0395] To a solution of 6-chloropyridine-3 -sulfonyl chloride (1.0 g, 4.2 mmol) in dichloromethane (10 mL) at 0 °C was added dimethylamine hydrochloride (344 mg, 4.2 mmol) and DIEA (1.6 g, 12.7 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, water (10 mL) was added to the above reaction mixture. The mixture was extracted with dichloromethane (10 mL x 2). The combined organicAttorney Docket No. 01295-0002-00PCT phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give 845 mg of the title compound. Yield: 81%. LC-MS (ESI+) m / z l\ [M+H]+.

[0396] Step 2

[0397] To a solution of 6-chloro-N,N-dimethylpyridine-3-sulfonamide (200 mg, 0.9 mmol) in DMAC (5 mL) was added MeSNa (255 mg, 3.6 mmol). The reaction was stirred at 120 °C overnight. After the reaction was completed as indicated by LC-MS analysis, the reaction was acidified with a diluted HC1 aqueous solution (1 M) to pH ~ 3. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrousNa2SO4, filtered, and concentrated under reduced pressure to give the crude title compound, which was directly used for the next step without further purification. LC-MS (ESI+) m / z 219 [M+H]+.

[0398] Step 3

[0399] To a solution of 6-mercapto-N,N-dimethylpyridine-3-sulfonamide (50 mg, 0.2 mmol) in dichloromethane (1 mL) and water (0.2 mL) at 0 °C was added cone. HC1 (50 mg). After the reaction was stirred at 20 min, TCCA (70 mg, 0.3 mmol) was added to the above mixture. The reaction was stirred at 0 °C for 2 h. After the reaction was completed as indicated by TLC analysis, water (5 mL) was added. The mixture was extracted with dichloromethane (2 mL x 2). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 60 mg of the crude title compound.

[0400] Step 4Attorney Docket No. 01295-0002-00PCT

[0401] To a solution of (6a5',S7?)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido [l,2-a]quinoxaline (50 mg, 0.2 mmol) in THF (5 mL) was added 5-(N,N- dimethylsulfamoyl)pyridine-2-sulfonyl chloride (59 mg, 0.2 mmol) and pyridine (50 mg, 0.6 mmol). The reaction was stirred under reflux overnight. After the reaction was completed as indicated by LC-MS analysis, water (5 mL) was added. The mixture was extracted with ethyl acetate (5 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica- gel column chromatography (petroleum ether: ethyl acetate = 24: 1 to 5: 1) to give 36.6 mg of the title compound (Compound 168). LC-MS (ESI+) m / z 485 [M+H]+; 'H NMR. (300 MHz, CD3OD) 3 9.07 (s, 1H), 8.38 (d, J= 7.8 Hz, 1H), 8.08 (d, J= 8.1 Hz, 1H), 7.41 (d, J= 7.8 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 6.66 (t, J= 8.1 Hz, 1H), 4.33-4.31 (m, 1H), 4.21-4.16 (m, 1H), 3.15-3.11 (m, 2H), 2.75 (s, 6H), 2.16-2.11 (m, 1H), 1.72-1.62 (m, 2H), 1.62-1.53 (m, 1H), 1.39- 1.35 (m, 1H), 0.96 (d, J= 6.0 Hz, 3H), 0.89-0.87 (m, 1H).

[0402] The compounds in Table 10 were prepared according to the synthesis of Compound 128 and Compound 168 using common intermediate 7, and appropriate starting materials.Table 10.Atorney Docket No. 01295-0002-00PCTAttorney Docket No. 01295-0002-00PCT

[0403] Example S20. Synthesis of Compound 233 and Compound 252

[0405] To a solution of 4-bromobenzenethiol (90 g, 0.476 mmol) in anhydrous DCM(800 mL) was added AcOH (30 mL) under N2 at rt. Then sulfuryl dichloride (160 mL, 1.97 mmol) was added slowly at -40 °C. The reaction was stirred at rt overnight. After the reactionAttorney Docket No. 01295-0002-00PCT was completed as indicated by TLC analysis, the reaction mixture was concentrated in vacuo (below 30 °C) to provide 110 g of the crude product.

[0406] Step 2

[0407] To a solution of dimethylamine / THF (300 mL, 2M, 0.6 mol) and EtsN (200 mL) in anhydrous THF (100 mL) was added 4-bromobenzenesulfmic chloride in 250 mL anhydrous THF slowly under N2 at -60 °C. The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, H2O (1.5 L) was added. The mixture was extracted with EtOAc (500 mL x 2). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1 :5 to 1 :3) to provide 116 g (0.467 mol) of the product. LC-MS (ESI+) m / z: 248 / 250 [M+H]+

[0408] Step 3O=i=NH i

[0409] To a solution of 4-bromo-N,N-dimethylbenzenesulfinamide (116 g, 0.467 mol) in MeOH (2 L) was added PIDA (450 g, 1.40 mol) and NH2COONH4(180 g, 2.31 mol) at 0 °C. The reaction was stirred at rt for 36 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated to ~ 400 mL. H2O (2 L) was added. The mixture was extracted with DCM (1 L x 2). The combined organics were washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1 :5 to 1 :3) to provide 76 g (0.289 mol) of the product. LC-MS (ESI+) m / z: 263 / 265 [M+H]+. *H NMR (400 MHz, CDCI3) 7.77 (d, J= 8.4 Hz, 2H), 7.67 (d, J = 8.14 Hz, 2H), 2.70 (s, 6H), 2.52 (brs, 1H).Attorney Docket No. 01295-0002-00PCT

[0411] To a solution of 4-bromo-N,N-dimethylbenzenesulfonimidamide (28 g, 0.106 mol) and Pyridine (30 mL, 3 eq) in DCM (300 mL) was added AcCl (16 mL, 2 eq) at 0 °C. The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc:PE = 1 :5 to 1 :3) to provide 21.4 g (0.070 mol) of the product. LC-MS (ESI+) m / z: 305 / 307 [M+H]+. *H NMR (400 MHz, CDC13) J7.76 (d, J= 8.4 Hz, 2H), 7.69 (d, J = 8.14 Hz, 2H), 2.79 (s, 6H), 2.17 (s, 3H).

[0412] Step 5: SFC separation

[0413] The N-((4-bromophenyl)(dimethylamino)(oxo)-16-sulfanylidene)acetamide was separated by SFC separation using the method listed below:Instrument: SFC-150 (Thar, Waters)Column: AD 25*250 mm, 10 mm (Daicel)Column temperature: 35 °CMobile phase: CCh / MeOH (0.01%Methylamine in Methanol) (80 / 20)Flow rate: 100 g / minBack pressure: 100 barDetection wavelength: 220 nmCycle time: 1.2 minSample solution: 21.4 g dissolved in 260 ml MethanolInjection volume: 1.4 mLChiral analytical HPLC method:Instrument: Waters 2695Column: CHIRAL PAK IG 4.6*250 mm, 5 pmColumn temperature: 30°CMobile phase: n-hexane / Isopropanol (0.1% DEA) = 70 / 30Flow rate: 0.8 mL / minDetection wavelength: 254 nmDetector: W2996 PDAAttorney Docket No. 01295-0002-00PCTAfter removal of the solvents, the first eluting isomer (6, peak 1, 7.1 g, retention time = 18.33 min) and the second eluting isomer (6’, peak 2, 7.6 g, retention time = 22.37 min) were obtained.

[0414] Step 6

[0415] To a solution of (5)-N-((4-bromophenyl)(dimethylamino)(oxo)-16- sulfanylidene)acetamide (5.8 g, 19 mmol) in toluene (70 mL) was added BnSH (5.0 g, 38 mmol), Pd2(dba)s (1.12 g, 1.5 mmol), Xantphos (1.1 g, 1.9 mmol) and DIEA (7.4 g, 57 mmol). The reaction mixture was charged with N2 three times and stirred at 90 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc:PE = 1 :4 to 100:0) to provide 6.5 g (18.6 mmol) of the product. LC-MS (ESI+) m / z: 349 [M+H]+. 'HNMR(400 MHz, CDC13) <57.74 (d, J= 8.4 Hz, 2H), 7.43-7.27 (m, 7H), 4.22 (s, 6H), 2.76 (s, 6H), 2.16 (s, 3H).

[0416] Step 7

[0417] To a solution of (5)-N-((4-(benzylthio)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)acetamide (6.5 g, 18.6 mmol) in DCM (80 mL) and H2O (20 mL) was added TCCA (8.6 g, 37.2 mmol). The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered. H2O (50 mL) was added to the filtrate. The mixture was extracted with DCM (50 mL x 3). The combined organics were dried over Na2SO4, concentrated in vacuo to provide 6.18 g of the crude product.

[0418] Step 8Attorney Docket No. 01295-0002-00PCT

[0419] To a solution of (6aA,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxaline (3.75 g, 15.9 mmol) in DCM (60 mL) was added Pyridine (3.76 g, 48 mmol) and (5)-4-(N'-acetyl-N,N-dimethylsulfamidimidoyl)benzenesulfonyl chloride (6.18 g, 19.1 mmol). The reaction mixture was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc:PE = 1 :4 to 100:0) to provide 6.6 g (12.6 mmol) of the product. LC-MS (ESI+) m / z: 525 [M+H]+. *HNMR (400 MHz, CDC13) 8 7.97 (d, J= 8.8 Hz, 2H), 7.74 (dd, J= 8.8 Hz, 2H), 7.47 (dd, J= 8.0, 1.6 Hz, 1H), 7.19 (dd, J= 8.0, 1.6 Hz, 1H), 6.72 (t, J= 8.0 Hz, 1H), 4.22 (dd, J= 14.4, 4.8 Hz, 1H), 4.07 (d, J= 12.8 Hz, 1H), 3.08 (dd, J= 14.4, 12.0 Hz, 1H), 2.79 (s, 6H), 2.64-2.60 (m, 1H), 2.15 (s, 3H), 1.68-1.58 (m, 1H), 1.57-1.54 (m, 1H), 1.54-1.50 (m, 1H), 1.41-1.25 (m, 2H), 0.91 (d, J= 6.0 Hz, 3H), 0.87-0.81 (m, 1H).

[0420] Step 9

[0421] To a solution of N-((5 -(4-(((6aR,S5)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)acetamide (6.6 g, 12.6 mmol) in MeOH (30 mL) and THF (10 mL) was added 15% NaOH aq (10 mL). The reaction mixture was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, most of the solvent was concentrated in vacuo. H2O (50 mL) was added. The mixture was filtered. The filter cake was slurried in DCM / Hex to provide 5.5 g (11.4 mmol) of the product. LC-MS (ESI+) m / z: 483 [M+H]+; 'H NMR (400 MHz, CDCI3) 81.99 (dd, J= 6.8, 1.6 Hz, 2H), 7.73 (dd, J= 6.8, 1.6 Hz, 2H), 7.48 (dd, J= 8.0, 1.6 Hz, 1H), 7.19 (dd, J= 8.0, 1.6 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 4.24 (dd, J= 14.4, 4.8 Hz,Attorney Docket No. 01295-0002-00PCT1H), 4.07 (d, J= 12.8 Hz, 1H), 3.09 (dd, J= 14.4, 12.0 Hz, 1H), 2.70 (s, 6H), 2.69-2.66 (m, 1H), 2.59 (s, 1H), 1.69-1.58 (m, 2H), 1.54-1.46 (m, 1H), 1.40-1.30 (m, 2H), 0.91 (d, J= 6.0 Hz, 3H), 0.89-0.81 (m, 1H).

[0422] Example S21. Synthesis of Compound 245

[0424] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (160 g, 0.55 mol) in anhydrous DCM (I L) was added SOCL (160 mL) slowly at 0 °C. The reaction was stirred at 40 °C under N2 atmosphere for 5 h. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was concentrated in vacuo to provide 170 g of the crude product, which was used directly for the next step without purification.

[0425] Step 2

[0426] To a solution of (5)-4-(((6aR,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (77.6 g, 0.16 mol), pyridine (39 mL, 0.48 mol) in DCM (600 mL) was added (9H-fluoren-9-yl)methyl (5)-(l- chloro-l-oxopropan-2-yl)carbamate (170 g crude from above) in DCM (400 mL) slowly. The reaction was stirred at rt for 16 h. After the reaction was completed as indicated by LC-MS and TLC, Na2COs aq (300 mL) was added. After separation of the layers, the aqueous solution was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1 :3 to 1 : 1) to provide the desired compound (190 g,Attorney Docket No. 01295-0002-00PCT impure). LC-MS (ESI+) m / z: 776 [M+H]+.

[0427] Step 3

[0428] To a solution of (9H-fluoren-9-yl)methyl ((5)-l-(((5)-(4-(((6aA,S5)-l-chloro-8- methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)amino)-l-oxopropan-2-yl)carbamate (190 g, impure from above) in CH3CN (400 mL) was added piperidine (72 mL, 0.73 mol) slowly. The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was concentrated in vacuo and purified by silica gel column chromatography (EA:PE = 1 : 1 to DCM: MeOH = 10: 1) to provide the desired product (70 g, 0.126 mol). LC-MS (ESI+) m / z: 554 [M+H]+; 'HNMR (400 MHz, CD3OD) 8.04 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.48 (dd, J= 8.0, 1.6 Hz, 1H), 7.21 (dd, J= 8.0, 1.6 Hz, 1H), 6.76 (t, J= 8.0 Hz, 1H), 4.27 (dd, J= 14.4, 4.8 Hz, 1H), 4.04-3.99 (m, 1H), 3.49 (q, J= 7.2 Hz, 1H), 3.11-3.04 (m, 1H), 2.80 (s, 6H), 2.62-2.57 (m, 1H), 1.69-1.52 (m, 3H), 1.40-1.34 (m, 1H), 1.33 (d, J= 7.2 Hz, 3H), 1.31-1.27 (m, 1H), 0.90 (d, J= 6.4 Hz, 3H), 0.82-0.75 (m, 1H).

[0429] Step 4

[0430] To a solution of (5)-2-amino-N-((N)-(4-(((6aA,S5)-l-chloro-8-methyl- 6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)propanamide (70 g, 0.126 mol) in DCM (400 mL) was added 4 M HCl / dioxane (60 mL). The reaction was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo. The residue was suspended in Et2O (200 mL). The product was collected by filtration and then washed with Et2O (2 x 200 mL) to provide the desired compound (73 g, 0.123 mol). LC-MS (ESI+) m / z: 554 [M+H]+; 1H-NMR (400 MHz,Attorney Docket No. 01295-0002-00PCTCD3OD) 5 8.09 (dd, J= 6.8, 1.6 Hz, 2H), 7.84 (dd, J= 6.8, 1.6 Hz, 2H), 7.47 (dd, J= 8.0, 1.6 Hz, 1H), 7.22 (dd, J= 8.0, 1.6 Hz, 1H), 6.77 (t, J= 8.0 Hz, 1H), 4.29 (dd, J= 14.4, 4.8 Hz, 1H), 4.06-3.98 (m, 2H), 3.12-3.06 (m, 1H), 2.83 (s, 6H), 2.65-2.63 (m, 1H), 1.63-1.51 (m, 3H), 1.57 (d, J= 7.2 Hz, 3H), 1.34-1.28 (m, 1H), 0.91 (d, J= 6.0 Hz, 3H), 0.82-0.78 (m, 1H).

[0431] Example S22. Synthesis of Compound 243

[0432] To a solution of (5)- N-((5)-(4-(((6aA,SN)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)-2-(methylamino)propanamide (prepared according to the procedure of Compound 245, 980 mg, 1.818 mmol) in MeOH / THF (5 mL / 5 mL) was added 37% HCHO (1 mL). The reaction was stirred at rt for 1 h. Then NaBH3CN (229 mg, 3.636 mmol) was added. The reaction was stirred at rt for 16 h. After being concentrated in vacuo, the residue was directly purified by silica gel column chromatography (DCM to DCM: MeOH = 10: 1) to provide the desired product (800 mg, 1.37 mmol). LC-MS (ESI+) m / z: 582 [M+H]+.

[0433] To above freebase in DCM (6 mL) was added 4 M HCl / dioxane (2 mL). The reaction was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo. The residue was washed with Et2O (2 x 10 mL) to provide the desired compound (820 mg, 1.33 mmol).

[0434] LC-MS (ESI+) m / z: 582 [M+H]+; 'HNMR (400 MHz, CD3OD) § 8.10 (d, J= 8.4 Hz, 2H), 7.84 (d, J= 8.4 Hz, 2H), 7.48 (dd, J= 8.0, 1.6 Hz, 1H), 7.22 (dd, J= 8.0, 1.2 Hz, 1H), 6.77 (t, J= 8.0 Hz, 1H), 4.30 (dd, J= 14.4, 4.8 Hz, 1H), 4.10-4.06 (m, 1H), 4.01-3.99 (m, 1H), 3.10 (dd, .7 = 14.4, 12.0 Hz, 1H), 2.87-2.83 (m, 12H), 2.68-2.61 (m, 1H), 1.67-1.62 (m, 5H), 1.55-1.52 (m, 1H), 1.36-1.31 (m, 2H), 0.92 (d, = 6.0 Hz, 3H), 0.81-0.78 (m, 1H).

[0435] The following 20 compounds were prepared according to the procedure of the synthesis of Compound 252, Compound 233, Compound 245, and Compound 243. The structures represent absolute stereochemistry.Atorney Docket No. 01295-0002-00PCTAttorney Docket No. 01295-0002-00PCT

[0436] Example S23. Synthesis of Compound 251

[0437] Step 1Attorney Docket No. 01295-0002-00PCT

[0438] To a solution of (5)-2-amino-N-((N)-(4-(((6a / ?,S5)-l-chloro-8-methyl- 6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)-3-methylbutanamide (prepared according to the procedure of Compound 245, 500 mg, 0.861 mmol) in DCM (6 mL) was added (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (585 mg, 1.721 mmol), HATU (982 mg, 2.583 mmol), TEA (435 mg, 4.305 mmol) and DMAP (10.5 mg, 0.086 mmol). The reaction was stirred at rt for 16 h. After the reaction was completed as indicated by LC-MS and TLC, H2O (10 mL) was added. After separation of the layers, the aqueous solution was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM to DCM:MeOH = 50: 1) to provide the desired compound (500 mg, 0.553 mmol). LC-MS (ESI+) m / z: 903 [M+H]+.

[0439] Step 2

[0440] To a solution of (9H-fluoren-9-yl)methyl ((5)- 1 -(((5)- 1 -(((S)-(4-(((6aR, 8S)-1- chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)amino)-3 -methyl- 1 -oxobutan-2- yl)amino)-3 -methyl- 1 -ox obutan-2-yl)carbamate (500 mg, 0.553 mmol) in CH3CN (5 mL) was added piperidine (141 mg, 1.659 mmol). The reaction was stirred at rt for 2 h. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was concentrated in vacuo and purified by silica gel column chromatography (DCM to DCM:MeOH = 20: 1) to provide the desired product (300 mg, 0.440 mol). LC-MS (ESI+) m / z: 681 [M+H]+.

[0441] To above freebase in DCM (3 mL) was added 4 M HCl / dioxane (1 mL). TheAttorney Docket No. 01295-0002-00PCT reaction was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo. The residue was washed with Et2O (2 x 10 mL) to provide the desired compound (310 mg, 0.432 mmol). LC-MS (ESI+) m / z: 681 [M+H]+; *H NMR (400 MHz, CD3OD) 8.03 (d, J= 7.6 Hz, 2H), 7.79 (d, J= 7.2 Hz, 2H), 7.47 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 6.76 (t, J= 8.4 Hz, 1H), 4.30-4.25 (m, 2H), 4.06-4.03 (m, 1H), 3.74 (d, J= 5.2 Hz, 1H), 3.12-3.05 (m, 1H), 2.81 (s, 6H), 2.65-2.60 (m, 1H), 2.26-2.11 (m, 2H), 1.64-1.60 (m, 2H), 1.53-1.51 (m, 1H), 1.31-1.26 (m, 2H), 1.03-1.01 (m, 9H), 0.99-0.91 (m, 6H), 0.81-0.78 (m, 1H).

[0442] Example S24. Synthesis of Compound 253

[0444] To a solution of P(OBn)s (3.56 g, 10.1 mmol) in anhydrous DCM (10 mL) was added E (2.36 g, 9.27 mmol). The reaction was stirred until the mixture turned colorless. To the solution of ethyl 4-hydroxybutanoate (1 g, 8.43 mmol) in DCM (10 mL) was added above mixture solution and pyridine (2.66 g, 33.7 mmol) at -10 °C under N2. The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was quenched with citric acid aq (20 mL). After separation of the layers, the aqueous solution was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1 to 2: 1) to provide the desired compound (2.66 g, 6.78 mmol).

[0445] Step 2Attorney Docket No. 01295-0002-00PCT

[0446] To a solution of ethyl 4-((bis(benzyloxy)phosphoryl)oxy)butanoate (2.66 g, 6.78 mmol) in MeOH / THF (10 mL / 10 mL) was added 15% NaOH aq (5 mL). The reaction was stirred at rt for 1 h. The reaction mixture was adjusted pH to 4~5 with 2N HC1 and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide the desired product (1.81 g, 4.97 mmol).

[0447] Step 3

[0448] To a solution of (5)-4-(((6a7?,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (700 mg, 1.45 mmol) in CH3CN (20 mL) was added 4-((bis(benzyloxy)phosphoryl)oxy)butanoic acid (1.05 g, 2.90 mmol) and TCFH (1.21 g, 4.35 mmol), NMI (476 mg, 5.8 mmol). Some of the starting material was remained. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EtOAc = 5: 1 to 1 : 1) to provide the desired compound (600 mg, 0.723 mmol). LC-MS (ESI+) m / z: 829 [M+H]+.

[0449] Step 4

[0450] To a solution of dibenzyl (4-(((5)-(4-(((6a7?,S5)-l-chloro-8-methyl-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)amino)-4-oxobutyl) phosphate (600 mg, 0.723 mmol) in CH3OH / DCM (5 mL / 0.5Attorney Docket No. 01295-0002-00PCT mL) was added 10% Pd / C (60 mg). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC and LC-MS analysis, the reaction was concentrated in vacuo. The residue was dissolved in THF (10 mL). And then NaHCCL aq (5 mL) was added. The reaction was stirred for 5 min. After being concentrated, the residue was purified by preparative HPLC to provide the desired compound (160 mg, 0.23 mmol).

[0451] LC-MS (ESI+) m / z: 649 [M+H]+; 'H NMR (400 MHz, CD3OD) § 8.03 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 8.4 Hz, 2H), 7.47 (d, J= 7.2 Hz, 1H), 7.20 (d, J= 7.2 Hz, 1H), 6.75 (t, J= 8.0 Hz, 1H), 4.25 (dd, J= 14.4, 3.2 Hz, 1H), 4.01 (d, J= 12.8 Hz, 1H), 3.91-3.81 (m, 2H), 3.06 (t, J= 12.0 Hz, 1H), 2.78 (s, 6H), 2.61-2.49 (m, 3H), 1.98-1.84 (m, 2H), 1.69-1.50 (m, 3H), 1.42-1.36 (m, 1H), 1.33-1.23 (m, 1H), 0.90 (d, J= 6.0 Hz, 3H), 0.82-0.69 (m, 1H)

[0452] Example S25. Synthesis of Compound 254

[0454] To a solution of BTC (694 mg, 2.34 mmol) in toluene (5 mL) was added pyridine(370 mg, 4.68 mmol). The reaction was stirred at rt for 30 min under N2. Then 2,2,3,3,9,9,10,10- octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol in toluene (5 mL) was added. The reaction was stirred at rt for 4 h. After filtration, the mixture was concentrated in vacuo to provide the crude desired product (600 mg) as a white solid.Attorney Docket No. 01295-0002-00PCT

[0455] Step 2

[0456] To a solution of (5)-4-(((6aA,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (100 mg, 0.21 mmol), pyridine (66 mg, 0.84 mol) in DCM (3 mL) was added 2,2,3,3,9,9,10,10-octamethyl-4,8- dioxa-3,9-disilaundecan-6-yl carb onochlori date (160 mg, 0.42 mmol). The reaction was stirred at rt for 16 h. After the reaction was completed as indicated by LC-MS and TLC, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:PE = 1 :5) to provide the desired compound (150 mg, 0.18 mmol). LC- MS (ESI+) m / z: 829 [M+H]+.

[0457] Step 3

[0458] To a solution of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl ((S)-(4-(((6aR,8S)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)carbamate (120 mg, 0.15 mmol) in THF (10 mL) was added TBAF (0.075 mL, IM, 0.075 mmol). The reaction was stirred at rt for 20 min. After the reaction was completed as indicated by LC-MS and TLC, EEO (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH = 20: 1) to provide the desired compound (50 mg, 0.083 mmol). LC-MS (ESI+) m / z: 601 [M+H]+.

[0459] Step 4Attorney Docket No. 01295-0002-00PCT

[0460] To a solution of l,3-dihydroxypropan-2-yl ((S)-(4-(((6aR,8S)-l-chloro-8-methyl- 6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)carbamate (50 mg, 0.083 mmol) in DCM (3 mL) was added EtsN (24 mg, 0.24 mmol) and palmitoyl chloride (55 mg, 0.2 mmol). The reaction was stirred at rt for 16 h. After the reaction was completed as indicated by LC-MS and TLC, H2O (5 mL) was added. The mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE:EtOAc = 3: 1) to provide the desired compound (50 mg, 0.046 mmol). LC-MS (ESI+) m / z: 1078 [M+H]+;JH NMR (400 MHz, CDCI3) 7.99 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.47 (d, J= 8.8 Hz, 1H), 7.20 (d, J= 8.8 Hz, 1H), 6.72 (t, J= 8.0 Hz, 1H), 5.07-5.05 (m, 1H), 4.36-4.28 (m, 2H), 4.27-4.14 (m, 2H), 4.13-4.04 (m, 2H), 3.12-3.06 (m, 1H), 2.80 (s, 6H), 2.67-2.58 (m, 1H), 2.35-2.29 (m, 4H), 1.64-1.58 (m, 5H), 1.27-1.23 (m, 52H), 0.91-0.86 (m, 9H), 0.85-0.80 (m, 1H).

[0461] Example S26. Synthesis of Compound 270

[0462] This Compound 270 was prepared according to the procedure of the synthesis of Compound 233 and Compound 252. LC-MS (ESI+) m / z: 483 [M+H]+; *HNMR (400 MHz, CDCI3) d 7.99 (d, J= 8.4 Hz, 2H), 7.73 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.72 (t, J= 8.0 Hz, 1H), 4.25 (dt, J= 14.0, 4.4 Hz, 1H), 4.07 (d, J= 13.0 Hz, 1H), 3.09 (dd, J= 14.1, 11.8 Hz, 1H), 2.78-2.62 (m, 7H), 2.58 (s, 1H), 1.70-1.58 (m, 2H), 1.55-1.47Attorney Docket No. 01295-0002-00PCT(m, 1H), 1.40-1.25 (m, 2H), 0.95-0.89 (m, 3H), 0.85-0.81 (m, 1H).

[0463] Example S27. Synthesis of Compound 287

[0465] To a solution of 4-(((6a5,SA)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (90 mg, 0.187 mmol) in THF (2 mL) was added pyridine (30 mg, 0.374 mmol) and chloromethyl carb onochlori date (48 mg, 0.374 mmol) at rt. The reaction was stirred at rt for 3 h. After the reaction was completed as indicated by TLC analysis and LC-MS, the reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the desired product (80 mg, 0.139 mmol). LC-MS (ESI+) m / z: 575 [M+H]+.

[0466] Step 2

[0467] To a solution of chloromethyl ((4-(((6a5, 8R)- 1 -chi oro-8-methyl-6, 6a, 7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)carbamate (65 mg, 0.113 mmol) in CH3CN (2 mL) was added((bis(benzyloxy)phosphoryl)oxy)silver (56 mg, 0.147 mmol) at rt. The reaction was stirred inAttorney Docket No. 01295-0002-00PCT dark at rt under N2 for 24 h. After the reaction was completed as indicated by TLC analysis and LC-MS, the reaction was filtered. After being concentrated, the residue was purified by preparative HPLC to give the desired product (60 mg, 0.073 mmol). LC-MS (ESI+) m / z: 817 [M+H]+.

[0468] Step 3

[0469] To a solution of ((bis(benzyloxy)phosphoryl)oxy)methyl ((4-(((6aS,8R)-l-chloro- 8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)carbamate (50 mg, 0.061 mmol) in CH3OH / DCM (1 mL / 1 mL) was added 10% Pd / C (5 mg) at rt. The reaction was stirred at rt under H2 (1 atm) for 1 h. After the reaction was completed as indicated by TLC analysis and LC-MS, the reaction was filtered. The filtrate was concentrated to provide the desired product (30 mg, 0.047 mmol). LC-MS (ESI+) m / z: 637 [M+H]+; 'H NMR (400MHz, CD3OD) 8.07 (dd, J= 8.8, 5.2 Hz, 2H), 7.82 (dd, J= 8.8, 3.2 Hz, 2H), 7.48 (dd, J= 9.6, 1.6 Hz, 1H), 7.21 (dd, J= 8.4, 1.6 Hz, 1H), 6.76 (t, J= 8.0 Hz, 1H), 5.52 (dd, J= 12.8, 4.4 Hz, 2H), 4.27 (dd, J= 14.4, 4.8 Hz, 1H), 4.09-3.99 (m, 1H), 3.31-3.30 (m, 1H), 2.81 (s, 6H), 2.65-2.51 (m, 1H), 1.71-1.51 (m, 3H), 1.45-1.35 (m, 1H), 1.30-1.20 (m, 1H), 0.90 (t, J= 6.4 Hz, 3H), 0.80-0.71 (m, 1H).

[0470] Example S28. Synthesis of Compound 289

[0472] To a solution of (6aA,S5)-l-chloro-8-methyl-6,6a,7,8,9,10-hexahydro-5H- pyrido[l,2-a]quinoxaline (490 mg, 2.07 mmol) in DMF (10 mL) was added Zn(CN)2 (725 mg,Attomey Docket No. 01295-0002-00PCT6.17 mmol) and X-Phos (416 mg, 1.0 mmol), t-Buxphos-Pd-Gs (397 mg, 0.5 mmol) at rt. The reaction mixture was charged with N2 three times and stirred at 120 °C for 4 h. After the reaction was completed as indicated by TLC analysis and LC-MS, the reaction was quenched with NaHCCh aq (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give the desired product (286 mg, 1.26 mmol). LC-MS (ESI+) m / z: 228 [M+H]+.

[0473] Step 2

[0474] To a solution of (6aA,S5)-8-methyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2- a]quinoxaline-l -carbonitrile (150 mg, 0.66 mmol) in pyridine (5 mL) was added 4-(N'-acetyl- N,N-dimethylsulfamidimidoyl)benzenesulfonyl chloride (320 mg, 0.98 mmol). The reaction mixture was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated in vacuo and the residue was directly used for the next step. LC-MS (ESI+) m / z: 516 [M+H]+.

[0475] Step 3

[0476] To a solution of N-((4-(((6aA,S5)-l-cyano-8-methyl-6, 6a, 7,8,9, 10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16- sulfanylidene)acetamide (crude residue from above) in MeOH (5 mL) was added 15% NaOH aq (0.5 mL). The reaction mixture was stirred at rt for 2 h. After the reaction was completed as indicated by TLC analysis, NH4CI aq (20 mL) was added. The mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine, dried over anhydrousAttorney Docket No. 01295-0002-00PCTNa2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 3: 1) to give the desired product (170 mg, 0.36 mmol). LC-MS (ESI+) m / z: 474 [M+H]+; 'HNMR (300MHz, CD3OD) 8.03 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 7.8 Hz, 2H), 7.71 (dd, J= 7.8, 1.2 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 6.81 (t, J= 8.1 Hz, 1H), 4.35 (dd, J= 14.7, 5.4 Hz, 1H), 4.15-4.08 (m, 1H), 3.18-3.08 (m, 1H), 2.76-2.71 (m, 1H), 2.68 (s, 6H), 2.11-2.00 (m, 1H), 1.71-1.60 (m, 2H), 1.58-1.42 (m, 1H), 1.36-1.26 (m, 1H), 0.93 (d, J = 6.3 Hz, 3H), 0.79-0.74 (m, 1H).

[0477] The following 21 compounds were prepared according to the procedure of the synthesis of Compound 270, Compound 245 and Compound 253, Compound 289. The structures represent absolute stereochemistry.Atorney Docket No. 01295-0002-00PCTAttorney Docket No. 01295-0002-00PCT

[0478] Example S29. Synthesis of Compound 269, Compound 267, Compound 268, and Compound 266

[0480] To a solution of (2R, 45)-l-(tert-butoxycarbonyl)-4-hydroxypiperidine-2- carboxylic acid (1.0 g, 4.1 mmol) in dichloromethane (20 mL) at rt was added TFA (5 mL). TheAttorney Docket No. 01295-0002-00PCT reaction was stirred at rt for 3 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure to give 1.1 g of the crude title compound, which was directly used for the next step without purification. LC-MS (ESI+) m / z 146 [M+H]+.

[0481] Step 2

[0482] To a solution of the crude (2A, 45)-4-hydroxypiperidine-2-carboxylic acid TFA salt (1.1 g) in DMF (20 mL) at rt was added K2CO3 (1.7 g, 12.2 mmol) and 1 -chi oro-3 -fluoro-2- nitrobenzene (934 mg, 5.3 mmol). The reaction was stirred at 120 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was cooled to rt and acidified with a diluted HC1 solution (3 N) to pH ~ 3. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give 1.9 g of the crude title compound, which was directly used for the next step without further purification. LC-MS m / z 301 [M+H]+.

[0483] Step 3

[0484] To a solution of the crude (2A, 45)-l-(3-chloro-2-nitrophenyl)-4 - hydroxypiperidine-2-carboxylic acid (1.9 g) in methanol (20 mL) at 0 °C was added SOCh (4 mL). The reaction was stirred at rt for 3 h. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (PE:EtOAc= 5: 1 to 3: 1) to give 488 mg of the title compound. LC-MS (ESI+) m / z 315 [M+H]+.

[0485] Step 4

[0486] To a solution of methyl (2A,45)-l-(3-chloro-2-nitrophenyl)-4-hydroxypiperidine - 2-carboxylate (488 mg, 1.6 mmol) in EtOH (8 mL) at rt was added saturated NH4CI aqueous solution (8 mL) and Fe powder (261 mg, 4.7 mmol). The reaction was stirred at 80 °C overnight.Attorney Docket No. 01295-0002-00PCTAfter the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (8 mL), and the aqueous solution was extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (dichloromethane: methanol = 20: 1) to give 314 mg of the title compound. Yield: 80.2%. LC- MS (ESI+) m / z 253 [M+H]+.

[0487] Step 5

[0488] To a solution of (6aR, S5)-l-chloro-8-hydroxy-7,8,9,10-tetrahydro-5H - pyrido[l,2-a]quinoxalin-6(6aH)-one (395 mg, 1.6 mmol) in anhydrous THF (5 mL) under N2 at rt was added borane tetrahydrofuran complex (6 mL, 1 mol / L in THF). The reaction was stirred at 80 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (4 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (DCM:MeOH= 20: 1) to give 360 mg of the title compound. Yield: 96.5%. LC-MS (ESI+) m / z 239 [M+H]+.

[0489] Step 6Boc

[0490] To a solution of (6aR,&S)-l-chloro-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a] quinoxalin-8-ol (2.7 g, 11.3 mmol) in dioxane (60 mL) at rt was added (Boc)2O (12.4 g, 56.7 mmol). The reaction was then stirred at 100 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (PE:EtOAc = 1 :0 to 3: 1) to give 3.3 g of the title compound as yellow oil. Yield: 86.1%. LC-MS (ESI+) m / z 339 [M+H]+.

[0491] Step 7Attorney Docket No. 01295-0002-00PCTBoc

[0492] To a solution of tert-butyl (6aA,S5)-l-chloro-8-hydroxy-6,6a,7,8,9,10-hexahydro -5H-pyrido[l,2-a]quinoxaline-5-carboxylate (500 mg, 1.5 mmol) in anhydrous DMF (10 mL) was added NaH (237 mg, 5.9 mmol) at rt under N2. The reaction was stirred at rt for 30 min. And then 1-Iodopropane (1.3 g, 7.4 mmol) was added to the mixture. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 600 mg of the title compound as yellow oil. LC-MS (ESI+) m / z 381 [M+H]+.

[0493] Step 8

[0494] To a solution of tert-butyl (6aR,&S)-l-chloro-8-propoxy-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxaline-5-carboxylate (600 mg, 1.6 mmol) in DCM (10 mL) at rt was added TFA (2 mL). The reaction was stirred at rt for 4 hrs. After the reaction was completed as indicated by TLC analysis, the reaction was concentrated in vacuo. The residue was adjusted to pH ~ 9 with NaHCCh aqueous solution. The aqueous solution was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 10: 1) to provide 320 mg of the title compound as a yellow oil. LC-MS (ESI+) m / z 281 [M+H]+.

[0495] Step 9

[0496] To a solution of oxetan-3-yl 4-m ethylbenzenesulfonate (10 g, 43.8 mmol) in DMF (100 mL) was added 4-bromobenzenethiol (9.9 g, 52.6 mmol), K2CO3 (6.7 g, 48.2 mmol) and Nal (6.6 g, 43.8 mmol) at rt. The reaction was stirred at 130 °C overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was driedAttorney Docket No. 01295-0002-00PCT over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 20: 1) to give 10 g of the title compound as a yellow oil. LC-MS (ESI+) m / z 245 / 247 [M+H]+.

[0497] Step 10

[0498] To a solution of 3-((4-bromophenyl)thio)oxetane (10 g, 40.8 mmol) in DCM (100 mL) was added mCPBA (10.0 g, 58.1 mmol) at 0 °C. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NaHCCf aqueous solution (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3 : 1 to EtOAc) to give 9.6 g of the title compound as a white solid. LC-MS (ESI+) m / z 261 / 263 [M+H]+.

[0499] Step 11

[0500] To a solution of 3-((4-bromophenyl)sulfinyl)oxetane (9.6 g, 36.9 mmol) in MeOH (100 mL) at rt was added PIDA (35.7 g, 110.8 mmol) and ammonium carbaminate (11.5 g, 147.7 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NaHCCf aqueous solution (30 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE:EtOAc = 3: 1 to EtOAc) to give 9.3 g of the title compound as a yellow oil. LC-MS (ESI+) m / z 276 / 278 [M+H]+.

[0501] Step 12

[0502] To a solution of (4-bromophenyl)(imino)(oxetan-3-yl)-16-sulfanone (9.3 g, 33.7 mmol) in DCM (100 mL) at 0 °C was added AcCl (5.3 g, 67.4 mmol). The reaction was stirred at rt for 2 hrs. After the reaction was completed as indicated by TLC analysis, the reactionAttorney Docket No. 01295-0002-00PCT mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (EtOAc) to give 9.3 g of the title compound as a yellow solid. LC-MS (ESI+) m / z 276 [M+H]+.

[0503] Step 13

[0504] To a solution of N-((4-(benzylthio)phenyl)(oxetan-3-yl)(oxo)-16-sulfanylidene) acetamide (9.3 g, 29.3 mmol) in toluene (100 mL) was added BnSH (4.7 g, 38.1 mmol), Pd2(dba)s (1.1 g, 1.5 mmol), XantPhos (1.7 g, 2.9 mmol), and DIEA (11.4 g, 88.0 mmol) at rt. The reaction was stirred at 100 °C overnight under N2. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give 6.3 g of the title compound as a yellow solid. LC-MS (ESI+) m / z 362 [M+H]+.

[0505] Step 14

[0506] To a solution of N-((4-(benzylthio)phenyl)(oxetan-3-yl)(oxo)-16-sulfanylidene) acetamide (600 mg, 1.7 mmol) in DCM / water (10 mL / 2 mL) at 0 °C was added TCCA (579 g, 2.5 mmol). The reaction was stirred at 0 °C for 2 hrs. After the reaction was completed as indicated by TLC analysis, the reaction mixture was filtered and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 520 mg of the title compound as yellow oil. LC-MS (ESI+) m / z-. 338 [M+H]+.

[0507] Step 15Attorney Docket No. 01295-0002-00PCT

[0508] To a solution of (do / ?,&S)-l-chloro-8-propoxy-6,6a,7,8,9,10-hexahydro-5El- pyrido [l,2-a]quinoxaline (160 mg, 0.6 mmol) in Py (6 mL) at rt was added 4-(N-acetyloxetane- 3-sulfonimidoyl)benzenesulfonyl chloride (385 mg, 1.1 mmol). The reaction was stirred at rt overnight. After the completion of the reaction as indicated by LC-MS analysis, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=3 : 1 to 1 : 1) to give 260 mg of the title compound as a yellow solid.LC-MS (ESI+) m / z-. 582 [M+H]+.

[0509] Step 16

[0510] After SFC separation ofN-((4-(((da / ?,&S)-l-chloro-8-propoxy-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(oxetan-3-yl)(oxo)-16- sulfanylidene)acetamide (260 mg), Compound 269 (Peak 1, 120 mg) and Compound 267 (Peak 2, 120 mg) were obtained.

[0511] Compound 269: ee% 99.3%; LC-MS (ESI+) m / z: 582 [M+H]+;1H NMR (400 MHz, CDC13) J7.98 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.57 (d, J= 92 Hz, 1H), 7.20 (d, .7= 9.6 Hz, 1H), 6.81 (t, .7= 8.0 Hz, 1H), 5.15-5.13 (m, 1H), 4.93 (t, J= 8.0 Hz, 1H), 4.84- 4.71 (m, 1H), 4.70-4.62 (m, 1H), 4.60-4.55 (m, 1H), 4.14 (dd, J= 14.0, 4.4 Hz, 1H), 3.49-3.23 (m, 5H), 2.68-2.66 (m, 1H), 2.10 (s, 3H), 1.96-1.82 (m, 3H), 1.64-1.58 (m, 2H), 1.55-1.54 (m, 1H), 1.32-1.29 (m, 1H), 0.92 (t, J= 7.6 Hz, 3H);

[0512] Compound 267: ee% 99.1%; LC-MS (ESI+) m / z: 582 [M+H]+;1H NMR (400 MHz, CDCI3) J7.98 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 9.6 Hz, 1H), 7.20 (d, .7= 9.6 Hz, 1H), 6.81 (t, .7= 8.0 Hz, 1H), 5.15 (dd, J= 7.2, 6.0 Hz, 1H), 4.94 (t, J= 7.6 Hz,Attorney Docket No. 01295-0002-00PCT1H), 4.72-4.60 (m, 2H), 4.59-4.56 (m, 1H), 4.14 (dd, J= 14.0, 4.4 Hz, 1H), 3.68-3.64 (m, 1H), 3.39-3.23 (m, 4H), 2.63-2.62 (m, 1H), 2.12 (s, 3H), 1.98-1.91 (m, 3H), 1.62-1.59 (m, 2H), 1.55- 1.54 (m, 1H), 1.31-1.27 (m, 1H), 0.92 (t, J= 7.6 Hz, 3H).

[0513] Step 17

[0514] To a solution of N-((N)-(4-(((6a7?,S5)-l-chloro-8-propoxy-6,6a,7,8,9,10- hexahydro- 5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(oxetan-3-yl)(oxo)-16- sulfanylidene)acetamide (100 mg, 0.2 mmol) in MeOH (3 mL) at rt was added 15% NaOH aqueous solution (1 mL). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give 54 mg of the title compound (Compound 268) as a yellow solid. LC-MS (ESI+) m / z: 540 [M+H]+; 'HNMR (400 MHz, CDCI3) 88.05 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.4 Hz,2H), 7.60 (d, J= 9.6 Hz, 1H), 7.19 (d, J= 9.6 Hz, 1H), 6.83 (t, J= 8.0 Hz, 1H), 4.97-4.93 (m, 1H), 4.86-4.80 (m, 2H), 4.72 (t, J= 7.6 Hz, 1H), 4.48-4.45 (m, 1H), 4.17 (dd, J= 13.6, 4.0 Hz, 1H), 3.52-3.45 (m, 2H), 3.37 (t, J= 6.4 Hz, 2H), 3.31-3.29 (m, 1H), 2.78-2.77 (m, 1H), 2.06- 1.96 (m, 2H), 1.90-1.88 (m, 1H), 1.60-1.57 (m, 3H), 1.38-1.34 (m, 1H), 0.93 (t, J= 7.6 Hz, 3H).

[0515] To a solution of N-((7?)-(4-(((6a7?,SN)-l-chloro-8-propoxy-6,6a,7,8,9,10- hexahydro- 5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)phenyl)(oxetan-3-yl)(oxo)-16- sulfanylidene)acetamide (100 mg, 0.2 mmol) in MeOH (3 mL) at rt was added 15% NaOHAttorney Docket No. 01295-0002-00PCT solution (1 mL). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica-gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 3: 1) to give 70 mg of the title compound (Compound 266) as a yellow solid. LC-MS (ESI+) m / z: 540 [M+H]+; HNMR (400 MHz, CDCI3) J8.05 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.60 (d, J= 9.6 Hz, 1H), 7.19 (d, J= 9.2 Hz, 1H), 6.83 (t, J= 8.4 Hz, 1H), 4.98-4.94 (m, 1H), 4.86-4.79 (m, 2H), 4.71 (t, J= 7.6 Hz, 1H), 4.47-4.46 (m, 1H), 4.16 (dd, J= 14.0, 4.4 Hz, 1H), 3.51-3.44 (m, 2H), 3.37 (t, J= 6.4 Hz, 2H), 3.34-3.28 (m, 1H), 2.79-2.78 (m, 1H), 2.05-1.96 (m, 2H), 1.88- 1.84 (m, 1H), 1.61-1.57 (m, 3H), 1.38-1.32 (m, 1H), 0.93 (t, J= 7.2 Hz, 3H).

[0516] Example S30. Synthesis of Compound 264

[0518] To a solution of cyclobutylmethanol (2.8 g, 32.5 mmol) in DCM (30 mL) and TEA (9.9 g, 97.5 mmol) was slowly added TsCl (9.3 g, 48.8 mmol) at 0 °C. The reaction was stirred at rt for 3 hrs. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with water (150 mL) and extracted with DCM (50 mL x 2). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 80: 1 to 50: 1) toAttorney Docket No. 01295-0002-00PCT give 9.1 g of the title compound as a colorless oil.

[0519] Step 2Boc

[0520] To a solution of tert-butyl (6aR,S5)-l-chloro-8-hydroxy-6,6a,7,8,9,10-hexahydro- 5H-pyrido[l,2-a]quinoxaline-5-carboxylate (500 mg, 1.5 mmol) in anhydrous DMF (10 mL) was added NaH (177 mg, 4.4 mmol) under N2 at rt. The reaction was stirred at rt for 30 min. And then cyclobutylmethyl 4-methylbenzenesulfonate (711 mg, 3.0 mmol) was added to the mixture. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 30: 1) to give 750 mg of the title compound as yellow oil. LC-MS (ESI+) m / z 407 [M+H]+.

[0521] Step 3

[0522] To a solution of tert-butyl ( 6a / , NS')- I -chloro-8-(cycl obutyl methoxy )-6, 6a, 7, 8, 9, 10- hexahydro-5H-pyrido[l,2-a]quinoxaline-5-carboxylate (1.5 g, 1.6 mmol) in DCM (10 mL) at rt was added TFA (4 mL). The reaction was stirred at rt for 3 hrs. After the reaction was completed as indicated by TLC analysis, the reaction was filtered and concentrated under reduced pressure. The residue was adjusted pH to 9 using saturated NaHCCL aqueous solution. The aqueous solution was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 20: 1) to give 660 mg of the title compound as yellow oil. LC-MS (ESI+) m / z 307 [M+H]+.

[0523] Step 4Attorney Docket No. 01295-0002-00PCT

[0524] To a solution of (6aR,&S)-l-chloro-8-(cyclobutylmethoxy)-6,6a,7,8,9,10- hexahydro- 5H-pyrido[l,2-a]quinoxaline (660 mg, 2.2 mmol) in pyridine (10 mL) at rt was added (5)-4-(N'-acetyl-N,N-dimethylsulfamidimidoyl)benzenesulfonyl chloride (838 mg, 2.6 mmol). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc =3: 1) to give 1.2 g of the title compound as yellow oil. LC-MS (ESI+) m / z 595 [M+H]+.

[0525] Step 5

[0526] To a solution of N-((N)-(4-(((6aA,S5)-l-chloro-8-(cyclobutylmethoxy)-6, 6a, 7, 8, 9, 10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)acetamide (1.2 g, 2.0 mmol) in MeOH (20 mL) at rt was added 15% NaOH solution (5 mL). The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction mixture was quenched with saturated NH4CI aqueous solution (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1057 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z: 553 [M+H]+; 'HNMR (400 MHz, CDCI3): J7.98 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.8 Hz, 2H), 7.60 (d, J= 9.6 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 6.81 (t, = 8.0 Hz, 1H), 4.19-4.14 (m, 1H), 3.52-3.38 (m, 4H), 3.29-3.26 (m, 1H), 2.81-2.73 (m, 1H), 2.68 (s, 6H), 2.53-2.48 (m, 1H), 2.08-2.04 (m, 3H), 2.03-1.84 (m, 4H), 1.73-1.62 (m, 3H), 1.36-1.31 (m, 1H).Attorney Docket No. 01295-0002-00PCT

[0527] Example S31. Synthesis of Compound 265

[0529] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (1.0 g) in anhydrous DCM (10 mL) at rt was added SOCh (1 mL). The reaction was stirred at 50 °C for 4 hrs. After the reaction was completed as indicated by TLC analysis, the reaction mixture was concentrated under reduced pressure to give the crude title compound as a yellow solid.

[0530] Step 2

[0531] To a solution of (5)-4-(((6aA,S5)-l-chloro-8-(cyclobutylmethoxy)-6,6a,7,8,9,10- hexahydro-5H-pyrido[l,2-a]quinoxalin-5-yl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (500 mg, 0.9 mmol) in anhydrous DCM (5 mL) was added pyridine (213 mg, 2.7 mmol) and the above crude (9H-fluoren-9-yl)methyl (S)-(l -chi oro-3- methyl- l-oxobutan-2-yl)carbamate underAttorney Docket No. 01295-0002-00PCTN2 at 0 °C. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, ISfeCCh aqueous solution (40 mL) was added. The mixture was extracted with DCM (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc = 3: 1) to give 800 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z 874 [M+H]+.

[0532] Step 3

[0533] To a solution of (9H-fluoren-9-yl)m ethyl ((5)-l-(((5)-(4-(((6aA,S5)-l-chloro-8- (cyclobutylmethoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)amino)-3 -methyl- 1 -oxobutan-2- yl)carbamate (750 mg, 0.86 mmol) in CEECN (10 mL) was added piperidine (220 mg, 2.58 mmol) at rt. The reaction was stirred at rt for 1 h. After the reaction was completed as indicated by TLC analysis, the reaction was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (PE:EtOAc = 1 : 1 to DCM: MeOH= 20: 1) to give 500 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z 652 [M+H]+.

[0534] Step 4

[0535] To a solution of (5)-2-amino-N-((N)-(4-(((6aA,S5)-l-chloro-8- (cyclobutylmethoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[l,2-a]quinoxalin-5- yl)sulfonyl)phenyl)(dimethylamino)(oxo)-16-sulfanylidene)-3-methylbutanamide (500 mg, 0.77 mmol) in MeOH (5 mL) at rt was added HCHO (0.5 mL). The reaction was stirred at rt for 30 min. Then NaBEECN was added to the mixture. The reaction was stirred at rt overnight. After the reaction was completed as indicated by TLC analysis, the reaction was concentrated underAttorney Docket No. 01295-0002-00PCT reduced pressure, and the residue was purified by silica-gel column chromatography (PE:EtOAc = 1 : 1) to give 400 mg of the title compound as a yellow solid. LC-MS (ESI+) m / r. 874 [M+H]+.

[0536] To a solution of the above freebase (400 mg, 0.59 mmol) in DCM (4 mL) was added HC1 (4M in dioxane, 2 mL) at rt. After stirring at rt for 30 min, the reaction was concentrated in vacuo. The solid was triturated and washed with Et2O (5 mL x 2) to give 400 mg yellow solid. Further purification by preparative HPLC gave 251 mg of the title compound as a yellow solid. LC-MS (ESI+) m / z: 680 [M+H]+; 'HNMR (400 MHz, CD3OD) 8.06 (d, J= 8.4 Hz, 2H), 7.84 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 6.87 (t, J= 8.0 Hz, 1H), 4.21 (dd, J= 14.0, 4.4 Hz, 1H), 3.84-3.82 (m, 1H), 3.52-3.41 (m, 4H), 3.40-3.38 (m, 1H), 2.88 (s, 3H), 2.84 (s, 6H), 2.83 (s, 3H), 2.82-2.78 (m, 1H), 2.59-2.42 (m, 2H), 2.07- 1.84 (m, 7H), 1.82-1.76 (m, 2H), 1.61-1.58 (m, 1H), 1.32-1.30 (m, 1H), 1.23 (d, J= 7.2 Hz, 3H), 1.04 (d, = 6.8 Hz, 3H).

[0537] The following compounds were prepared according to the synthesis of Compound 264, Compound 269, Compound 267, Compound 268, Compound 266, andCompound 265. The structures represent absolute stereochemistry.Attorney Docket No. 01295-0002-00PCTBiological ExamplesExample Bl. Calcium Flux in HEK293 overexpressing TRPML1 plasma membrane variant - Calcium 6 dyeExample Bl.l Materials

[0538] Cells: HEK293 / TRPML1-PM clone A5, clonal cell line containing mutant TRPML1Attorney Docket No. 01295-0002-00PCT(both N- and C-terminal dileucine targeting motifs deleted) that localizes to the plasma membrane.

[0539] Culture media: DMEM (Gibco cat. #11965-092), 10% FBS (Excell bio cat.#FND500), 1% pen / strep (Gibco cat. #15140-122), 200 mg / ml G418 (Gibco cat. #10131- 035)0.05%; Trypsin (Gibco cat. #25300-054).

[0540] Plates: Greiner 384 well plate (cat. #781090), calcium dye: Fluo-4 Direct, (Invitrogen cat. #F 10471).

[0541] Tips: Molecular Devices 384-well FLIPR Tetra black tips, (cat. #9000-0764).Example B1.2 Method

[0542] HEK293 / TRPML1-PM clone A5 cells were trypsinized from flasks, counted, then diluted in media to 15,000 cells per 20 pL, and seeded into a poly-lysine coated 384-well Greiner plate and cultured overnight.

[0543] One vial of Fluo-4 Direct dye was diluted with 10 mL of assay buffer (DMEM + 0.1% FBS) and 0.2ml probenecid was added. 20 pL of the solution was added per well to the cells.

[0544] After incubating for 2 hours at 37 °C, the plate was moved to the FLIPR in the read position.

[0545] The compounds were diluted in assay buffer to 5x concentration and loaded in a 384- well plate according to the desired plate map for the assay, including DMSO alone control, then the plate was moved to the FLIPR in the source 2 position.

[0546] A box of tips was placed in the source 1 position within the FLIPR to complete the assay set up.

[0547] Once the run was started, an initial baseline fluorescent measurement was performed for 10 seconds (470-495 nm excitation and 515-575 nm emission) prior to adding the compounds.

[0548] lOpL mL of 5x test compound or DMSO alone were added via the FLIPR and realtime fluorescence measurements were performed for an additional 170 seconds with 1 read per second.

[0549] The data was normalized to baseline by calculating maximum fluorescence minus minimum fluorescence and plotted as response (fold) over the baseline versus log (inhibitor concentration). The ECso was determined using a 4-parameter logistic curve fit in Graphpad Prism 9.

[0550] The data from the assay described in Example Bl is summarized in Table 11. Compounds with ECso values at or below 10 mM are considered TRPML1 activators.Atorney Docket No.01295-0002-00PCTTable 11.Attorney Docket No. 01295-0002-00PCT

[0551] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examplesAttorney Docket No. 01295-0002-00PCT should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein in their entirety by reference.

Claims

Attorney Docket No. 01295-0002-00PCTWhat is Claimed:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinV is chosen from H, halo, Ci-6 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, -S(O)2-Ci-6 alkyl, -S(O)2(heterocyclyl), -S(O)(NRc)N(Ra)(Rb), -S(O)(NH)-CI-6alkyl, -S(O)(NRa)(heterocyclyl), and -S(0)2N(Ra)(Rb), wherein each alkyl, alkoxy, cycloalkyl, and heterocyclyl group is optionally substituted with 1, 2, or 3 groups selected from halo and N(Ra)(Rb); n is 1 to 4; each Raand Rbis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and -C(O)(Ci-4alkyl);Rcis P, wherein P is a cleavable group;Ring A is C3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl;L is a bond, C1-3 alkylene, NRa, or O; each of X1, X2, X3, and X4is independently C(RX) or N;R1is H, halo, CN, C1-4 alkyl, and C1-4 haloalkyl;W is C(R2)2, NR2, O, or SO2; each R2is independently chosen from H; halo; OH; C1-4 alkyl; C1-4 haloalkyl; C1-10 alkoxy optionally substituted with halo, C3-8 cycloalkyl; N(Rc)(Rd), or heterocyclyl; -(OCH2CH2)I-6OCH3; -(OCH2CH2)i-3N(Rc)(Rd); -O-CH2-(C3-6 cycloalkyl); -O-(Ci-4Attorney Docket No. 01295-0002-00PCT haloalkyl); -C(O)(C 1-40 alkyl, wherein the alkyl is optionally substituted with Ci-6 alkoxy, heterocyclyl, or C3-8 cycloalkyl); -C(O)(C3-6 cycloalkyl); -C(O)(heteroaryl); -C(O)(heterocyclyl); -C(O)(aryl, wherein the aryl is optionally substituted with halo); -C(O)O(C 1-30 alkyl, wherein the alkyl is optionally substituted with C1-4 alkoxy, C3-8 cycloalkyl, heterocyclyl, or heteroaryl);-C(O)O(heterocyclyl); -C(O)O(aryl, wherein the aryl is optionally substituted with 1 or 2 groups chosen from halo, CN, and C1-3 alkyl); -C(O)N(Rc)(Rd); and -S(O)2(Ci-4 alkyl); each Rcand Rdis independently selected from H, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkyl-Ci-4 alkoxy, or Rcand Rdjoin together with the atom to which they are bonded to form a 3 to 6 membered cycloalkyl, heterocyclyl group;R3aand R3bare both H; or R3aand R3btaken together form an oxo group; andR4aand R4bare independently H or OH; or R4aand R4btaken together form an oxo group.

2. The compound of claim 1, wherein P is chosen from:-C(O)R5, wherein -C(O)R5is derived from one or more natural or unnatural amino acids; or-C(O)R6, wherein R6is optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, optionally substituted piperazinyl, optionally substituted phenyl, or optionally substituted pyridyl.

3. The compound of claim 1 or 2, wherein -C(O)R5is derived from alanine, valine, leucine, glycine, phenylalanine, aspartic acid, glutamic acid, or any combination of thereof; or wherein R6is optionally substituted C1-4 alkyl.

4. The compound of any one of claims 1-3, wherein V is chosen from H; halo; C1-4 alkyl; C1-4 haloalkyl; Ci alkoxy; cyclopropyl optionally substituted with halo, NH2, or N(CH3)2; -C(CH3)2NH2; -C(CH3)2N(CH3)2; -S(O)2N(CH3)2; -S(O)(NH)N(CH3)2;-S(O)(NCH3)N(CH3)2; -S(O)(NH)(CHF2); -S(O)2CH3OCH3; -S(O)2(4-membered heterocyclyl comprising N); -S(O)2(Ci-2 alkyl) optionally substituted with halo; and - S(O)(NRa)N(CH3)2.

5. The compound of any one of claims 1-4, wherein V is chosen from H,Atorney Docket No. 01295-0002-00PCTAttorney Docket No. 01295-0002-00PCT6. The compound of any one of claims 1-5, wherein n is 1, 2, or 3.

7. The compound of any one of claims 1-6, wherein n is 1.

8. The compound of any one of claims 1-7, wherein Ring A is chosen from Cs cycloalkyl;6-membered heterocyclyl comprising N, O, or S; 6-membered aryl optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl group; and 6-membered heteroaryl group comprising N, O, or S, optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl group.

9. The compound of any one of claims 1-8, wherein Ring A is chosen from10. The compound of any one of claims 1-9, wherein L is NH, O, CH2, or a bond.

11. The compound of any one of claims 1-10, wherein L is a bond.

12. The compound of any one of claims 1-10, wherein L is a CH2.

13. The compound of any one of claims 1-12, wherein R1is H, CN, halo, or methylAttorney Docket No. 01295-0002-00PCT optionally substituted by 1 to 3 halo groups.

14. The compound of any one of claims 1-13, wherein R1is H, -CF3, -CH3, CN, F, or Cl.

15. The compound of any one of claims 1-14, wherein R1is H.

16. The compound of any one of claims 1-14, wherein R1is Cl.

17. The compound of any one of claims 1-16, wherein one or two of X1, X2, X3, and X4is N.

18. The compound of any one of claims 1-17, wherein each of X1, X2, X3, and X4is CR1and each R1is independently chosen from H, -CF3, -CH3, or Cl.

19. The compound of any one of claims 1-18, wherein W is C(R2)?, NR2, O, or SO2.

20. The compound of any one of claims 1-18, wherein W is CHR2or NR2.

21. The compound of any one of claims 1-20, wherein R2is chosen from H; OH; C1-3 alkyl optionally substituted with halo; C1-7 alkoxy optionally substituted with F, Cl, C4-8 cycloalkyl, NRcRd, 4- to 8-membered heterocyclyl comprising N, O, or S; -(OCH2CH2)I- 4OCH3; -(OCH2CH2)i-2N(CH3)2; -C(0)(Ci-3o alkyl, wherein the alkyl is optionally substituted with C1-3 alkoxy, 4- to 6-membered heterocyclyl comprising N, O, or S, or C4-6 cycloalkyl); -C(O)(C3-6 cycloalkyl); -C(O)(4- to 6-membered heteroaryl comprising N, O, or S); -C(O)(4- to 6-membered heterocyclyl comprising N, O, or S); -C(O)(4- to 6- membered aryl) wherein the aryl is optionally substituted with halo); -C(0)0(Ci-2o alkyl, wherein the alkyl is optionally substituted with C1-3 alkoxy, C3-6 cycloalkyl, 4- to 6- membered heterocyclyl comprising N, O, or S, or 4- to 6-membered heteroaryl comprising N, O, or S); -C(O)O(4- to 6-membered heterocyclyl comprising N, O, or S); - C(O)N(CH3)(CI-3alkyl)(Ci-3alkoxy); -C(O)NH(CI-3alkyl)(Ci-3alkoxy); -C(O)NH(CI-3alkyl); -S(O)2(Ci-3alkyl); -C(O)NH2; and -C(O)N(CH3)2.

22. The compound of any one of claims 1-21, wherein R2is chosen from H; OH; C1-2 alkyl optionally substituted with halo; C1-7 alkoxy optionally substituted with F, C4-6 cycloalkyl, N(CHs)2, 4-membered heterocyclyl comprising O, or -(OCH2CH2)i-3OCH3; - (OCH2CH2) N(CH3)2; -C(O)(CI -29 alkyl, wherein the alkyl is optionally substituted with Ci alkoxy, 6-membered heterocyclyl comprising O, or Ce cycloalkyl); C(O)(Cs-6 cycloalkyl); -C(O)(5-membered heteroaryl comprising N or S); -C(O)(4- to 6-membered heterocyclyl comprising O); -C(O)(phenyl, wherein the phenyl is optionally substituted with F or Cl); -C(O)O(Ci -is alkyl, wherein the alkyl is optionally substituted with Ci alkoxy, C4-6 cycloalkyl, 6-membered heterocyclyl comprising O, or 5-membered heteroaryl comprising N or S); -C(O)O(4- to 6-membered heterocyclyl comprising O); - C(O)O(5-membered heterocyclyl comprising N); -C(O)N(CH3)(C2 alkyl)(Ci alkoxy); - C(O)NH(C2alkyl)(Ci alkoxy); -C(O)NH(Ci alkyl); -S(O)2(Ci-2alkyl); -C(O)NH2; and -Attorney Docket No. 01295-0002-00PCTC(O)N(CH3)2.

23. The compound of any one of claims 1-22, wherein R3aand R3bare both H.

24. The compound of any one of claims 1-22, wherein R3aand R3btaken together form an oxo group.

25. The compound of any one of claims 1-24, wherein R4aand R4bare both H.

26. The compound of any one of claims 1-24, wherein R4aand R4btaken together form an oxo group.

27. The compound of claim 1, having the structure of a compound of Formula (la), or a pharmaceutically acceptable salt thereof:

28. The compound of claim 1, having the structure of a compound of Formula (lb), or a pharmaceutically acceptable salt thereof:

29. The compound of claim 1, having the structure of a compound of Formula (II), (Ila), or (lib), or a pharmaceutically acceptable salt thereof:Attorney Docket No. 01295-0002-00PCT(II), (Ila), or (lib).

30. The compound of claim 29, wherein the compound is a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, and wherein R2is Ci-io alkoxy optionally substituted with halo, C3-8 cycloalkyl, N(Rc)(Rd), or heterocyclyl.

31. The compound of claim 29, wherein the compound is a compound of Formula (lib), or a pharmaceutically acceptable salt thereof, wherein R2is -C(0)0(Ci-3o alkyl, wherein the alkyl is optionally substituted with C1-4 alkoxy, C3-8 cycloalkyl, heterocyclyl, or heteroaryl).

32. The compound of claim 1, having the structure of a compound of Formula (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof:

33. The compound claim 1, having the structure of a compound of Formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof:Attorney Docket No. 01295-0002-00PCT(IV), (IVa), and (IVb).

34. The compound of claim 1, having the structure of a compound of Formula (V), (Va), or(Vb), or a pharmaceutically acceptable salt thereof:Vb).

35. The compound of claim 1, having the structure of a compound of Formula (VI), (Via),(VIb), (Vic), (Vid), or (Vie), or a pharmaceutically acceptable salt thereof:Attorney Docket No. 01295-0002-00PCT36. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, chosen from:N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(cyclohexylmethoxy)-2,3,4,9,10,10a-hexahydro- lH-4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(2,2-difhroroethoxy)-2,3,4,9,10,10a-hexahydro- lH-4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(2-methoxyethoxy)-2,3,4,9,10,10a-hexahydro- lH-4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-(cyclobutylmethoxy)-2,3,4,9,10,10a-hexahydro- lH-4a,9-diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl(p-{(2S,10aR)-5-chloro-2-[2-(2-methoxyethoxy)ethoxy]-2,3,4,9,10,10a- hexahydro-lH-4a,9-diazaphenanthr-9-yl sulfonyl } phenyl sulfonyl)amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-propoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-5-chloro-2-ethoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine;N,N-dimethyl{p-[(2S,10aR)-2-ethoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine; dodecyl (10aR)-9-[p-(dimethylaminosulfonyl)phenylsulfonyl]-2,3,4,9, 10, lOa-hexahydro- lH-2,4a,9-triazaphenanthrene-2-carboxylate; andN,N-dimethyl{p-[(2S,10aR)-5-chloro-2-methoxy-2,3,4,9,10,10a-hexahydro-lH-4a,9- diazaphenanthr-9-ylsulfonyl]phenylsulfonyl}amine.

38. A pharmaceutical composition comprising the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.Attorney Docket No. 01295-0002-00PCT39. A method of modulating Mucolipin TRP channel subfamily 1 (TRPML1) comprising contacting TRPML1 with an effective amount of the compound of any one of claims 1- 37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 38.

40. A method of treating a disease associated with TRPML1 comprising administering to the subject an effective amount of the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 38.

41. The method of claim 40, wherein the disease is a neurodegenerative disease, lysosomal storage disease, metabolic disease, cardiovascular disease, inflammatory disorder, immunological disorder, cancer, or aging.

42. The method of claim 40, wherein the disease is a neurodegenerative disease.

43. The method of claim 42, wherein the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), HIV- associated dementia, and Huntington’s disease.

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